ASPEN Nutricion Pediatrica

The A.S.P.E.N.
Pediatric Nutrition Support Core Curriculum

EDITOR-IN-CHIEF
Mark R. Corkins, MD, CNSP, SPR, FAAP Associate Professor Indiana University School of Medicine, Riley Hospital for Children Indianapolis, IN
SECTION EDITORS
Jane Balint, MD Director, Intestinal Support Service Pediatric Gastroenterology, Hepatology and Nutrition Nationwide Childrens Hospital Columbus, OH Elizabeth Bobo, MS, RD, LDN, CNSD Clinical Dietitian, Gastroenterology and Nutrition Nemours Childrens Clinic Jacksonville, FL Steve Plogsted, PharmD, BCNSP Clinical Pharmacy Specialist Nutrition Support Pharmacist Nationwide Childrens Hospital Columbus, OH Jane Anne Yaworski, MSN, RN Clinical Nurse Specialist/Nutrition Support Service/Intestinal Care Center Childrens Hospital of Pittsburgh Pittsburgh, PA
MANAGING EDITOR
Nina D. Seebeck
AMERICAN SOCIETY FOR PARENTERAL AND ENTERAL NUTRITION
The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) is a scientific society whose members are health care professionalsphysicians, dietitians, nurses, pharmacists, other allied health professionals, and researchersdedicated to assuring that every patient receives optimal nutrition care. A.S.P.E.N.s mission is to serve as a preeminent, interdisciplinary, nutrition society dedicated to patient-centered clinical practice worldwide through advocacy, education, and research in specialized nutrition support. NOTE: This publication is designed to provide accurate authoritative information in regard to the subject matter covered. It is sold with the understanding that the publisher is not engaged in rendering medical or other professional advice. Trademarked commercial product names are used only for education purposes and do not constitute endorsement by A.S.P.E.N. This publication does not constitute medical or professional advice, and should not be taken as such. To the extent the information published herein may be used to assist in the care of patients, this is the result of the sole professional judgment of the attending health professional whose judgment is the primary component of quality medical care. The information presented herein is not a substitute for the exercise of such judgment by the health professional. All rights reserved. No part of this may be used or reproduced in any manner whatsoever without written permission from A.S.P.E.N. For information write: American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), 8630 Fenton Street, Suite 412, Silver Spring, MD 20910-3805; (301) 587-6315, www.nutritioncare.org, email: aspen@nutr.org.
Copyright 2010. American Society for Parenteral and Enteral Nutrition. ISBN: 978-1-889622-14-9 Printed in the United States of America.
Contents
Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Reviewers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii Acknowledgments & Dedication . . . . . . . . . . . . . . . . . . . . . . . xix
7. Water-Soluble Essential Micronutrients. . . . . . . . . . . . . . 56

Winston Koo, MBBS, FACN, CNS Judith Christie, RN, MSN May Saba, PharmD, BCNSP Mirjana Lulic-Botica, BSc, BCPS Letitia Warren, RD, CSP Winston Koo, MBBS, FACN, CNS May Saba, PharmD, BCNSP Mirjana Lulic-Botica, BSc, BCPS Judith Christie, RN, MSN
8. Fat-Soluble Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
PART I INTRODUCTORY AND BASIC PHYSIOLOGY

1. Mechanics of Nutrient Intake. . . . . . . . . . . . . . . . . . . . . . . 3
Mark R. Corkins, MD, CNSP , SPR, FAAP Carol G. McKown, DDS, MS Anna M. Dusick, MD
9. Fluids and Electrolytes. . . . . . . . . . . . . . . . . . . . . . . . . . . 87

Gerald L. Schmidt, PharmD, BCNSP
2. Gross Digestion Principles: Gastric Grinding and Gastrointestinal Motility. . . . . . . . . . . . . . . . . . . . . . 11

Jane P. Balint, MD
PART II AGE-SPECIFIC NUTRITION FOR GROWTH ANDDEVELOPMENT

10. Nutrition and Early Development . . . . . . . . . . . . . . . . . 105
Russell J. Merritt, MD, PhD, FAAP Barbara Marriage, PhD, RD Ricardo Rueda, MD, PhD Jacqueline J. Wessel, RD, CNSD
3. Carbohydrates: Changes with Development. . . . . . . . . . . 17

Seema Mehta, MD Robert J. Shulman, MD Peggy R. Borum, PhD
4. Fats. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 5. Protein Digestion, Absorption, and Metabolism. . . . . . . . 31

Richard A. Helms, PharmD Emma M. Tillman, PharmD Anup J. Patel, MD John A. Kerner, MD
11. Human Milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 12. Infant Formulas and Complementary Feeding. . . . . . . 129
Kelly Green-Corkins, MS, RD, CNSD Timothy Sentongo, MD Timothy Sentongo, MD
13. Growth Assessment and Monitoring . . . . . . . . . . . . . . 143 14. Obesity and Metabolic Disorders. . . . . . . . . . . . . . . . . 149
Michelle Battista, BS, PhD Candidate Robert Murray, MD Shirley Huang, MD Melanie Katrinak, RD, CSP, LDN
6. Minerals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Winston Koo, MBBS, FACN, CNS Mirjana Lulic-Botica, BSc, BCPS May Saba, PharmD, BCNSP Letitia Warren, RD, CSP
15. Lipid Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
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CONTENTS
16. Use of Fad and Popular Diets. . . . . . . . . . . . . . . . . . . . 169

Catherine Christie, PhD, RD Julia A. Watkins, PhD, MPH Judith C. Rodriguez, PhD, RD
30. Oncology, Hematopoietic Transplant, and Survivorship. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349

Nancy Sacks, MS, RD, LDN Elizabeth Wallace, RD, CNSC, LDN Seema Desai, MS, RD, LDN, CNSD Vinod K Prasad, MD, MRCP (London) David Henry, MS, BCOP Virginia Guzikowski, MSN, CRNP Liesje Nieman Carney, RD, CNSD, LDN Beth Bogucki Wright, MS, RD, CSP, LDN Susan Rheingold, MD Arlet G. Kurkchubasche, MD Arlet G. Kurkchubasche, MD
17. Sports Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

Jackie Buell, PhD, RD, LD, ATC, LAT Diane L. Habash, PhD, RD, LD
PART III DISEASE STATES AND NUTRITION

18. Developmental Delay . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Kathleen J. Motil, MD, PhD
31. Trauma and Burns . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378 32. Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
19. Eating Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

Christina Fitzgerald, MS, RD, LDN Betsy Hjelmgren, MS, RD, LDN, CSP
20. Food Allergies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

Mary Beth Feuling, MS, RD, CD, CNSD Michael B. Levy, MD Praveen S. Goday, MBBS, CNSP Diane Olson, RD, CNSD, CSP , LD W. Frederick Schwenk II, MD
PART IV NUTRITION CARE OF THE PEDIATRIC PATIENT

33. Assessment of Nutrition Status by Age and Determining Nutrient Needs . . . . . . . . . . . . . . . . . 409
Liesje Nieman Carney, RD, CNSD, LDN Jennifer Blair, MA, RD, CSP, LDN
21. Diabetes Mellitus and Other Endocrine Disorders. . . . 226
22. Inborn Errors of Metabolism . . . . . . . . . . . . . . . . . . . . 232

Bridget Reineking, MS, RD, CD Sandra van Calcar, PhD, RD, CD
34. Parenteral and Enteral Nutrition Support: Determining the Best Way to Feed. . . . . . . . . . . . . . . . 433
Liesje Nieman Carney, RD, CNSD, LDN Andrea Nepa, MS, RD, CSP, LDN Sherri Shubin Cohen, MD, MPH Amy Dean, MPH, RD, LDN Colleen Yanni, MS, RD, LDN Goldie Markowitz, MSN, CRNP Beth Lyman, RN, MSN Jennifer M. Colombo, MD Jodi L. Gamis, OTR
23. Cardiac Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

Anupama Chawla, MD, CNSP , DCH (UK) Janice Antino, RD, MS, CNSD, CSP Mindy Freudenberg, RD, MS, CNSD
24. Renal Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256

Christina L. Nelms, MS, RD, CSP , CNSC, LD Marisa Juarez, MPH, RD, LD Bradley A. Warady, MD Donald George, MD Elizabeth Bobo, MS, RD, LDN, CNSD
35. Implementation of the Plan. . . . . . . . . . . . . . . . . . . . . 448
25. Gastrointestinal Disease . . . . . . . . . . . . . . . . . . . . . . . 283
36. Evaluation and Monitoring of Pediatric Patients Receiving Specialized Nutrition Support . . . . . . . . . . . 460
Elaina Szeszycki, PharmD, BCNSP Wendy Cruse, MMSc, RD, CNSD Michelle Strup, PharmD Patrick M. Jones, MD, MA Brian Carter, MD
26. Hepatic Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

Samuel A. Kocoshis, MD Renee A. Wieman, RD, CSP , LD, CNSD Robert H. Squires, Jr., MD
37. Ethical Issues in the Provision of Nutrition . . . . . . . . . 477
27. Intestinal Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 28. Pulmonary Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 323

Allison Mallowe, RD, LDN Suzanne Michel, MPH, RD, LDN Maria Mascarenhas, MBBS Anita Nucci, PhD, RD, LD Sharon Strohm, MBA, RD, LDN Neelam Katyal, MS, RD, LDN Beth Lytle, RD, LDN
Test Your Knowledge Answers . . . . . . . . . . . . . . . . . . . . . . . . 487 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
29. Organ Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . 337
Contributors
Janice Antino, RD, MS, CNSD, CSP Certified Specialist in Pediatric Nutrition, Registered Dietitian Stony Brook University Hospital Stony Brook, NY Jane P. Balint, MD Director, Intestinal Support Service Pediatric Gastroenterology, Hepatology and Nutrition Nationwide Childrens Hospital Columbus, OH Michelle Battista, BS, PhD Candidate The Ohio State University OSUN Interdisciplinary PhD Program Columbus, OH Jennifer Blair, MA, RD, CSP, LDN Clinical Dietitian III The Childrens Hospital of Philadelphia Philadelphia, PA Elizabeth Bobo, MS, RD, LDN, CNSD Clinical Dietitian, Gastroenterology and Nutrition Nemours Childrens Clinic Jacksonville, FL Peggy R. Borum, PhD Professor of Human Nutrition University of Florida Gainesville, FL Jackie Buell, PhD, RD, LD, ATC, LAT Director of Sports Nutrition, Department of Human Nutrition College of Education and Human Ecology Ohio State University Columbus, OH
Brian S. Carter, MD Professor of Pediatrics Vanderbilt University Medical Center Nashville, TN Anupama Chawla, MD, CNSP, DCH (UK) Director of Pediatric Gastroenterology and Nutrition Stony Brook University Hospital Stony Brook, NY Catherine Christie, PhD, RD Chair, Department of Nutrition and Dietetics University of North Florida Jacksonville, FL Judith Christie, RN, MSN Childrens Hospital of Michigan Detroit, MI Sherri Shubin Cohen, MD, MPH Medical Director, Pediatric Feeding and Swallowing Center The Childrens Hospital of Philadelphia Philadelphia, PA Jennifer M. Colombo, MD Pediatric Gastroenterology Fellow Childrens Mercy Hospital Kansas City, MO Mark R. Corkins, MD, CNSP, SPR, FAAP Associate Professor Indiana University School of Medicine, Riley Hospital for Children Indianapolis, IN
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CONTRIBUTORS
Wendy Cruse, MMSc, RD, CNSD Pediatric Dietitian Indianapolis, IN Amy Dean, MPH, RD, LDN Clinical Dietitian The Childrens Hospital of Philadelphia Philadelphia, PA Seema Desai, MS, RD, LDN, CNSD Clinical Dietitian Duke University Medical Center Durham, NC Anna M. Dusick, MD Associate Professor of Clinical Pediatrics Indianapolis University School of Medicine Riley Hospital for Children Indianapolis, IN Mary Beth Feuling, MS, RD, CD, CNSD Clinical Dietitian Specialist Childrens Hospital of Wisconsin Milwaukee, WI Christina Fitzgerald, MS, RD, LDN Owner/President Nourished, Nutrition and Wellness Services Chicago, IL Mindy Freudenberg, RD, MS, CNSD Certified Nutrition Support Dietitian, Registered Dietitian Stony Brook University Hospital Stony Brook, NY Jodi L. Gamis, OTR Occupational Therapist Childrens Mercy Hospital Kansas City, Missouri Donald E. George, MD Division Chief Gastroenterology Nemours Childrens Clinic Jacksonville, FL Praveen S. Goday, MBBS, CNSP Associate Professor Pediatric Gastroenterology, Hepatology and Nutrition Medical College of Wisconsin Milwaukee, WI
Kelly Green-Corkins, MS, RD, CNSD Clinical Dietitian Specialist Clarian Home Care Indianapolis, IN Virginia Guzikowski, MSN, CRNP Nurse Practitioner Division of Oncology The Childrens Hospital of Philadelphia Philadelphia, PA Diane L. Habash, PhD, RD, LD Bionutrition Clinical Research Manager General Clinical Research Center Ohio State University Columbus, OH Richard A. Helms, PharmD Department of Clinical Pharmacy The University of Tennessee Health Science Center Memphis, TN David W. Henry, MS, BCOP Associate Professor, Pharmacy Practice University of Kansas Medical Center Kansas City, KS Betsy Hjelmgren, MS, RD, LD, CSP Founder, Feed to Succeed Chicago, IL Shirley Huang, MD Medical Director, Healthy Weight Program Attending Physician, Division of GI, Hepatology and Nutrition The Childrens Hospital of Philadelphia Philadelphia, PA Patrick M. Jones, MD, MA Clinical Fellow (Neonatology) Vanderbilt Childrens Hospital Nashville, TN Marisa Juarez, MPH, RD, LD Pediatric Renal Dietitian Texas Childrens Hospital Houston, TX Melanie Katrinak, RD, CSP, LDN Clinical Nutritionist The Childrens Hospital of Philadelphia Philadelphia, PA
CONTRIBUTORS
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Neelam Katyal, MS, RD, LDN Clinical Dietitian Childrens Hospital of Pittsburgh Pittsburgh, PA 15213 John A. Kerner, MD Pediatric Gastroenterology, Hepatology and Nutrition Stanford University Palo Alto, CA Samuel A. Kocoshis, MD Professor of Pediatrics University of Cincinnati College of Medicine Director, Nutrition and Small Bowel Transplantation Cincinnati Childrens Hospital Medical Center Cincinnati, OH Winston Koo, MBBS, FACN, CNS Clinical Director, NICU Hutzel Womens Hospital Professor of Pediatrics Childrens Hospital of Michigan Carman and Ann Adams Department of Pediatrics Wayne State University Detroit, MI Arlet G. Kurkchubasche, MD Associate Professor of Surgery and Pediatrics Alpert Medical School Brown University Providence, RI Michael B. Levy, MD Associate Professor Allergy-Immunology Medical College of Wisconsin Milwaukee, WI Mirjana Lulic-Botica, BSc, BCPS Hutzel Womens Hospital Detroit, MI Beth Lyman, RN, MSN Senior Program Coordinator for the Nutrition Support Team Childrens Mercy Hospital Kansas City, MO Beth Lytle, RD, LDN Clinical Dietitian Childrens Hospital of Pittsburgh Pittsburgh, PA
Allison Mallowe, RD, LDN Clinical DietitianPediatric The Childrens Hospital of Philadelphia Philadelphia, PA Goldie Markowitz, MSN, CRNP Pediatric Nurse Practitioner The Childrens Hospital of Philadelphia Philadelphia, PA Barbara Marriage, PhD, RD Senior Research Scientist Abbott Nutrition Columbus, OH Maria Mascarenhas, MBBS Section Chief, Nutrition, Division of Gastroenterology andNutrition The Childrens Hospital of Philadelphia Associate Professor of Pediatrics University of Pennsylvania School of Medicine Philadelphia, PA Carol G. McKown, DDS, MS Owner/President Carol G. McKown, M.S., D.D.S., P.C Volunteer Faculty, Riley Hospital Pediatric Dentistry Dept. Carmel, IN Seema Mehta, MD Department of Pediatric Gastroenterology, Hepatology, and Nutrition Baylor College of Medicine Texas Childrens Hospital Houston, TX Russell J. Merritt, MD, PhD, FAAP Director of Medical Affairs Abbott Nutrition Columbus, OH Medical Director, Nutrition Support & Intestinal Rehabilitation Childrens Hospital of Los Angeles Keck School of Medicine University of Southern California Los Angeles, CA Suzanne Michel, MPH, RD, LDN Clinical Dietitian, Pediatric Cystic Fibrosis Center The Childrens Hospital of Philadelphia Philadelphia, PA
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CONTRIBUTORS
Kathleen J. Motil, MD, PhD Associate Professor of Pediatrics USDA/ARS Childrens Nutrition Research Center Baylor College of Medicine Houston, TX Robert Murray, MD Nationwide Childrens Hospital Center for Healthy Weight and Nutrition Columbus, OH Christina L. Nelms, MS, RD, CSP, CNSC, LD Clinical Nutrition Specialist, Pediatric Renal Dietitian Childrens Mercy Hospitals and Clinics Kansas City, KS Andrea Nepa, MS, RD, CSP, LDN The Childrens Hospital of Philadelphia Philadelphia, PA Liesje Nieman Carney, RD, CNSD, LDN Clinical Dietitian IV, Publication Specialist The Childrens Hospital of Philadelphia Philadelphia, PA Anita Nucci, PhD, RD, LD Assistant Professor Georgia State University Division of Nutrition Atlanta, GA Diane L. Olson, RD, CNSD, CSP, LD Assistant Professor of Pediatrics Mayo Clinic College of Medicine Rochester, MN Anup J. Patel, MD Pediatric Gastroenterology, Hepatology and Nutrition Stanford University Palo Alto, CA Vinod K. Prasad, MD, MRCP (London) Attending Physician Pediatric Bone Marrow and Stem Cell Transplant Service Duke University Medical Center Durham, NC Bridget Reineking, MS, RD, CD Clinical Dietitian Specialist Childrens Hospital of WisconsinMilwaukee Milwaukee, WI
Susan R. Rheingold, MD Assistant Professor of Pediatrics Division of Oncology The Childrens Hospital of Philadelphia Philadelphia, PA Judith C. Rodriguez, PhD, RD Professor University of North Florida Jacksonville, FL Ricardo Rueda, MD, PhD Associate Director Discovery Technology Abbott Nutrition Granada, Spain May Saba, PharmD, BCNSP Childrens Hospital of Michigan Department of Pharmacy Practice Detroit, MI Nancy Sacks, MS, RD, LDN Clinical Dietitian/Research Coordinator Division of Oncology The Childrens Hospital of Philadelphia Philadelphia, PA Gerald L. Schmidt, PharmD, BCNSP Nutrition Specialist Shands Jacksonville Jacksonville, FL Clinical Associate Professor University of Florida College of Pharmacy Gainesville, FL W. Frederick Schwenk II, MD Professor of Pediatrics Mayo Clinic College of Medicine Rochester, MN Timothy Sentongo, MD Assistant Professor University of Chicago Chicago, IL Robert J. Shulman, MD Professor of Pediatrics Baylor College of Medicine Texas Childrens Hospital Foundation Chair in Pediatric Gastroenterology Texas Childrens Hospital Childrens Nutrition Research Center Houston, TX
CONTRIBUTORS
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Robert H. Squires, Jr., MD Clinical Director, Pediatric Gastroenterology Childrens Hospital of Pittsburgh Pittsburgh, PA Sharon Strohm, MBA, RD, LDN Dietitian Coordinator Childrens Hospital of Pittsburgh Pittsburgh, PA Michelle Strup, PharmD Home Infusion Pharmacist Clarian Home Care Indianapolis, IN Elaina Szeszycki, PharmD, BCNSP Clinical Pharmacist Nutrition Support and Pediatric Gastroenterology Riley Hospital for Children Indianapolis, IN Emma M. Tillman, PharmD Fellow, Department of Clinical Pharmacy The University of Tennessee Health Science Center Memphis, TN Sandy van Calcar, PhD, RD, CD Metabolic Dietitian Biochemical Genetics Program University of WisconsinMadison Madison, WI Elizabeth Wallace, RD, CNSC, LDN Clinical Dietitian The Childrens Hospital of Philadelphia Philadelphia, PA Bradley A. Warady, MD Professor of Pediatrics University of Missouri-Kansas City School of Medicine Associate Chairman, Department of Pediatrics Chief, Section of Pediatric Nephrology Director, Dialysis and Transplantation The Childrens Mercy Hospital Kansas City, MO
Letitia Warren, RD, CSP Childrens Hospital of Michigan Detroit, MI Julia A. Watkins, PhD, MPH Associate Professor Department of Nutrition and Dietetics University of North Florida Jacksonville, FL Jacqueline J. Wessel, RD, CNSD Neonatal Nutritionist Cincinnati Childrens Hospital Cincinnati, OH Renee A. Wieman, RD, CSP, LD, CNSD Registered Dietician II Liver and Intestinal Transplantation Services and Comprehensive Nutrition Center Cincinnati Childrens Hospital Medical Center Cincinnati, OH Beth Bogucki Wright, MS, RD, CSP, LDN Clinical Dietician IV, Technology Specialist Clinical Nutrition Development The Childrens Hospital of Philadelphia Philadelphia, PA Colleen Yanni, MS, RD, LDN Clinical Dietitian & Education Coordinator (Outpatient) The Childrens Hospital of Philadelphia Philadelphia, PA
Reviewers
Judith M. Bailer, BS, RD, LDN Clinical Dietitian II Childrens Hospital of Philadelphia Philadelphia, PA Jane P. Balint, MD Director, Intestinal Support Service Pediatric Gastroenterology, Hepatology and Nutrition Nationwide Childrens Hospital Columbus, OH Laura E. Beerman, RD, CNSD Regional Home Nutrition Support Dietitian Walgreens-Optioncare Home IV Infusion Company Omaha, NE Jatinder Bhatia, MD Professor and Chief, Section of Neonatology Medical College of Georgia Augusta, GA Susan Carlson, MMSc, RD, CSP, LD Neonatal Dietitian University of Iowa Childrens Hospital at The University of Iowa Hospitals and Clinics Iowa City, IA Pamela Charney, PhD, RD Lecturer, Nutrition Sciences and Affiliate Associate Professor, Pharmacy University of Washington Seattle, WA
Katherine H. Chessman, PharmD, FCCP, BCPS, BCNSP Professor, Clinical Pharmacy and Outcome Sciences; Clinical Pharmacy Specialist, Pediatrics/Pediatric Surgery South Carolina College of Pharmacy Medical University of South Carolina Campus Medical University of South Carolina Childrens Hospital Charleston, SC Michael L. Christensen, PharmD Stevens Professor, Pharmacy Director Department of Clinical Pharmacy University of Tennessee Health Science Center and Le Bonheur Childrens Medical Center Memphis, TN Conrad R. Cole, MD, MPH, MSc Assistant Professor Division of Gastroenterology, Hepatology and Nutrition Department of Pediatrics Emory University School of Medicine Atlanta, GA Mark R. Corkins, MD, CNSP, SPR, FAAP Associate Professor Indiana University School of Medicine Riley Hospital for Children Indianapolis, IN Kimberly Cover, MS, RD, CSSD, LDN Sports Nutrition Therapist/Clinical Specialist The Sports Medicine and Performance Center of the Childrens Hospital of Philadelphia King of Prussia, PA
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REVIEWERS
Wendy Cruse, MMSc, RD, CNSD Pediatric Dietitian Indianapolis, IN Douglas Drenckpohl, MS, RD, CNSC, LDN Advanced Practice Dietitian-Neonatal Childrens Hospital of Illinois at OSF Saint Francis Medical Center Peoria, IL Jeanne Ann Farrell, MS, RD, CNSC, LD/N Clinical Dietitian All Childrens Hospital St. Petersburg, FL Dianne Frazier, PhD, MPH, RD Professor of Pediatrics University of North Carolina Department of Pediatrics, Division of Genetics and Metabolism Chapel Hill, NC Praveen S. Goday, MBBS, CNSP Associate Professor Pediatric Gastroenterology, Hepatology and Nutrition Medical College of Wisconsin Milwaukee, WI David E. Goldstein, MD Professor Emeritus University of Missouri Health Sciences Center Columbia, MO Susan Goode, MS, RD, MD Assistant Professor of Pediatrics Tufts University School of Medicine Attending Physician Pediatric Gastroenterology & Nutrition Baystate Childrens Hospital Springfield, MA Barbara Goodin, MS, RD Pediatric Nutrition Specialist in Cystic Fibrosis, Inborn Errors of Metabolism and Diabetes University of Virginia Health System Department of Pediatrics/Div of Genetics Metabolic Diseases Program Charlottesville, VA Lori Grant, MEd, RD, CSP, LD Pediatric Dietitian The University of Texas Health Science Center at San Antonio San Antonio, TX
Kelly Green-Corkins, MS, RD, CNSD Clinical Dietitian Specialist Clarian Home Care Indianapolis, IN Kathleen M. Gura, BS, PharmD, BCNSP Clinical Pharmacy Specialist GI/Nutrition Associate Professor Pharmacy Practice Childrens Hospital Boston Massachusetts College of Pharmacy and Health Sciences Boston, MA Geraldine Hennies, RN III Nutrition Support Nurse, Case Manager Cincinnati Childrens Hospital Medical Center Cincinnati, OH Simon Horslen, MB ChB FRCPCH Professor of Pediatrics, Medical Director, Liver & Intestine Transplantation University of Washington and Seattle Childrens Hospital Seattle, WA Shirley Huang, MD Medical Director, Healthy Weight Program Attending Physician, Division of GI, Hepatology and Nutrition The Childrens Hospital of Philadelphia Philadelphia, PA Susanna Y. Huh, MD, MPH Instructor in Pediatrics Harvard Medical School, Childrens Hospital Boston Boston, MA Khursheed Jeejeebhoy, MBBS, PhD, FRCPC Emeritus Professor of Medicine University of Toronto and St. Michaels Hospital Toronto Ontario Canada Doron D. Kahana, MD, FAAP Assistant Clinical Professor Pediatric Gastroenterology & Nutrition Harbor-UCLA Medical Center Torrance, CA Ajay Kaul, MBBS, MD Director, Impedance/Motility Disorders Program Cincinnati Childrens Hospital Medical Center Cincinnati, OH
REVIEWERS
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Craig Lawrence Kien, MD, PhD The Mary Kay Davignon Green and Gold Professor, Depts. of Pediatrics and Medicine The University of Vermont College of Medicine Burlington, VT Angela Kirkwood, RN, BSN, IBCLC, RLC Nurse Feeding Specialist and Board Certified Lactation Consultant Childrens Hospital of Pittsburgh of UPMC Clinical Nutrition Department Pittsburgh, PA Ronald E. Kleinman, MD Physician in Chief, Massachusetts General Hospital for Children Chair, Department of Pediatrics Chief, Pediatric Gastrointestinal and Nutrition Unit Massachusetts General Hospital Charles Wilder Professor of Pediatrics Harvard Medical School Boston, MA Susan Konek, MA, RD, CSP, CNSD, LDN Director of Clinical Nutrition The Childrens Hospital of Philadelphia Philadelphia, PA Carolyn Kusenda, MS, RD, CNSD, LD Neonatal Nutrition Support Specialist/Clinical Nutrition Manager Childrens National Medical Center Washington, DC Joel Lim, MD Assistant Professor of Clinical Pediatrics Riley Hospital for Children Indiana University Indianapolis, IN Allison M. Mallowe, RD, LDN Clinical Pediatric Dietitian The Childrens Hospital of Philadelphia Philadelphia, PA Maria R Mascarenhas, MBBS Section Chief, Nutrition, Division of Gastroenterology and Nutrition The Childrens Hospital of Philadelphia Associate Professor of Pediatrics University of Pennsylvania School of Medicine Philadelphia, PA
Carrie McFarland, RD, CNSD Pediatric and Neonatal Clinical Dietitian UCSF Medical Center San Francisco, CA Clare McLaughlin, RD, CNSD, CSP Pediatric Dietitian Clarian Health Inc. Indianapolis, IN Catherine M. McDonald, PhD, RD, CNSD Clinical Dietitian Primary Childrens Medical Center Salt Lake City, UT Kate Micucci, MS, RD, LD Dietitian Specialist The University of Pittsburgh Medical Center Boardman, OH Shideh Mofidi, MS, RD, CSP Metabolic Dietitian and Clinical Coordinator in the Inherited Metabolic Disease Center Maria Fareri Childrens Hospital West Chester, NY Linda V. Muir, MD Dietitian, Pediatric Gastroenterologist Swedish Medical Center Seattle, WA Anita Nucci, PhD, RD, LD Assistant Professor Georgia State University Atlanta, GA Patricia OBrien, RD Senior Supervising Dietitian, Pediatric University of California at Davis Health System Sacramento, CA Surekha Pendyal, MSc, MEd, RD Assistant Professor of Pediatrics Metabolic Nutritionist University of North Carolina Chapel Hill, NC Barbara Robinson, MPH, RD, CNSD Pediatric Nutrition Specialist Hasbro Childrens Hospital Clinical Teaching Associate Alpert Medical School of Brown University Providence, RI
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REVIEWERS
Jill Rockwell, RD, LD, CNSD Childrens Medical Center Dallas Dallas, TX Carol J. Rollins, MS, RD, CNSD, PharmD, BCNSP Coordinator, Nutrition Support Team University Medical Center Tucson, AZ William O. San Pablo, Jr., MD Director, Nutrition Support and Inflammatory Bowel Disease Program Assistant Professor of Pediatrics Childrens Mercy Hospital and Clinics, UMKC School of Medicine Kansas City, MO Sue Schiller, RD Pediatric Clinical Dietitian III Inova Fairfax Hospital for Children Falls Church, VA Timothy Sentongo, MD Assistant Professor of Pediatrics, Director Pediatric Nutrition Support Service The University of Chicago Medical Center Chicago, IL Robert J. Shulman, MD Professor of Pediatrics Baylor College of Medicine Texas Childrens Hospital Foundation Chair in Pediatric Gastroenterology Texas Childrens Hospital Childrens Nutrition Research Center Houston, TX
Eric Sibley, MD, PhD Associate Professor of Pediatrics Stanford University School of Medicine Palo Alto, CA Edwin Simpser, MD Chief Medical Officer St. Marys Hospital for Children Assistant Professor of Pediatrics, NYU School of Medicine Bayside, NY Jonathan M. Spergel, MD, PhD Chief, Allergy Section Associate Professor of Pediatrics Director, Center for Pediatric Eosinophilic Disorders Division of Allergy and Immunology The Childrens Hospital of Philadelphia University of Pennsylvania School of Medicine Philadelphia, PA Nancy Spinozzi, RD, LDN Renal Dietitian Childrens Hospital Boston, MA Christina J. Valentine, MD, MS, RD Medical Director, Neonatal Nutrition and Lactation Section of Neonatology, The Ohio State University and Nationwide Childrens Hospital Columbus, OH Wendy Wittenbrook, MA, RD, CSP, LD Clinical Dietitian Texas Scottish Rite Hospital for Children Dallas, TX
Foreword
I am very pleased to be asked to write the foreward to The A.S.P.E.N. Pediatric Nutrition Support Core Curriculum an outgrowth of the pediatric section concept which Russ Merritt, MD, PhD, Bill Byrne, MD, Walter Faubion, RN, and I started in the early 1980s. We recognized early on the importance of programmatic recognition within A.S.P.E.N. of the special needs of infants and children, and the advantages of continuing the multidisciplinary approach to pediatric nutrition which has been the hallmark of the success of the A.S.P.E.N. model. The evolution of the art and science of pediatric nutrition support is well demonstrated in the postgraduate courses, seminars, workshops, round tables, and paper/poster presentations that have punctuated our annual clinical congresses. The Pediatric Nutrition Support Core Curriculum is a well-earned and anticipated culmination of the multidisciplinary approach developed and refined over the years. It has been shaped by A.S.P.E.N.s Standards of Practice, Clinical Guidelines, and Interdisciplinary Nutritional Support Competencies. In addition, it is designed to serve as: (1) a companion resource to the A.S.P.E.N. Nutrition Support Practice Manual, and the A.S.P.E.N. Nutrition Support Core Curriculum: A Case-Based Approachthe Adult Patient; (2) an educational resource for those preparing for the specialization certification examination in nutrition support; (3) a valuable clinical resource for the generalist: and (4) an interdisciplinary document that recognizes both the common body of knowledge and the unique skills that each member of the multidisciplinary team possesses. Currently, there are general guidelines that allude to the importance of nutrition for infants and children and the need for training in pediatric nutrition. However, there is no defined curriculum that states explicitly what a pediatric caregiver is required
to know. Dr. Corkins, his co-authors, and all of us who have lived and contributed to the evolution of pediatric nutrition science believe that a well-organized and disciplined core curriculum for pediatric caregivers is greatly needed. A wide range of specialty fields require a working knowledge of pediatric nutrition and form our target audience: dietetics, nursing, pharmacy, medicine, gastroenterology, surgery, and pediatrics. In addition to the expected comprehensive treatment of the basics of developmental physiology of the digestive process and the nutrition requirements of various organ systems, chapters include Obesity and Metabolic Disorders, Use of Fad and Popular Diets, Sports Nutrition, Implementation of the Plan, and Ethical Issues in the Provision of Nutrition. Each chapter contains evidencebased background information emphasizing core science, intended for the professional who already possesses a basic understanding of the principles of food biochemistry, and nutrition in wellness and disease. The layout of each chapter includes a table of contents, learning objectives, and a concluding set of self-assessment questions to test the readers understanding of the subject matter. It is my hope that this book will provide an effective learning experience and referenced resource for all health professionals caring for infants and children, leading to improved patient care. John R. Wesley, MD, FACS, FAAP Adjunct Professor of Surgery Pediatric Surgery Childrens Memorial Medical Center Feinberg School of Medicine Northwestern University
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Preface
The A.S.P.E.N. Pediatric Nutrition Support Core Curriculum is the result of a question. One of the pediatric residency directors asked me several years ago if A.S.P.E.N. had a curriculum for teaching the residents about nutrition. They had been looking for a way to teach the residents nutrition and found nothing. I sadly told her no. It turned out that in the pediatric section I was not the only person who saw the need for a pediatric core curriculum. This curriculum is designed to start with the basic nutrition physiology then progress through the principles for nutrition in disease states. It ends with the nuts and bolts for daily care. Each chapter begins with an outline of the important contents of that chapter and then ends with test your knowledge questions. These are designed to help you find out if you learned the important concepts of the chapter. What this curriculum doesnt have is in-depth coverage of neonatal nutrition, although some of this is covered in the context of the physiology of development. It is also not exhaustive in its coverage of nutrition in the various disease states. This is designed to be the pediatric core curriculum; to be a disease-specific specialist will require study beyond this starting point. The desire here is to create a firm foundation of pediatric nutrition that anyone can build on any way they wish. Mark R. Corkins Editor-in-Chief
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Acknowledgments & Dedication
I have to thank Michelle Spangenburg and Nina Seebeck for keeping everything on track to pull this book together. Ialso must thank my Associate EditorsJane Balint, Elizabeth Bobo, Steve Plogsted, and Jane Anne Yaworskifor their input and help with the legwork that goes into pulling lots of authors and reviewers together and helping with ideas to improve the curriculum. Finally, I wish to thank Amy Cevario and Pattie Covert at Clayton Design Group. I have to dedicate this book to the best pediatric learning experience ever, my children and my personal dietitian, best friend, and wife, Kelly. Mark R. Corkins Editor-in-Chief
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PART I
INTRODUCTORY AND BASIC PHYSIOLOGY
1. Mechanics of Nutrient Intake. . . . . . . . . . . . . . . . . . . . 3 Mark R. Corkins, MD, CNSP, SPR, FAAP Carol G. McKown, DDS, MS Anna M. Dusick, MD 2. Gross Digestion Principles: Gastric Grinding and Gastrointestinal Motility. . . . . . . . . . . . . . . . . . . 11 Jane P. Balint, MD 3. Carbohydrates: Changes with Development. . . . . . . . 17 Seema Mehta, MD Robert J. Shulman, MD 4. Fats. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Peggy R. Borum, PhD 5. Protein Digestion, Absorption, and Metabolism. . . . . 31 Richard A. Helms, PharmD Emma M. Tillman, PharmD Anup J. Patel, MD John A. Kerner, MD 6. Minerals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Winston Koo, MBBS, FACN, CNS Mirjana Lulic-Botica, BSc, BCPS May Saba, PharmD, BCNSP Letitia Warren, RD, CSP 7. Water-Soluble Essential Micronutrients. . . . . . . . . . . 56 Winston Koo, MBBS, FACN, CNS Judith Christie, RN, MSN May Saba, PharmD, BCNSP Mirjana Lulic-Botica, BSc, BCPS Letitia Warren, RD, CSP 8. Fat-Soluble Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . 74 Winston Koo, MBBS, FACN, CNS May Saba, PharmD, BCNSP Mirjana Lulic-Botica, BSc, BCPS Judith Christie, RN, MSN 9. Fluids and Electrolytes. . . . . . . . . . . . . . . . . . . . . . . . 87 Gerald L. Schmidt, PharmD, BCNSP
Mechanics of Nutrient Intake

Mark R. Corkins, MD, CNSP, SPR, FAAP, Carol G. McKown, DDS, MS, and Anna M. Dusick, MD
CONTENTS
Background. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appetite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mastication/Dentition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Feeding Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Swallowing Feeding Skills in the First Year Feeding Skills in the Second Year 3 3 4 5
Learning Objectives
1. Understand how societal and behavioral influences guide food consumption. 2. Identify the psychological, mechanical, biochemical, and hormonal inputs that determine appetite and intake. 3. Describe the developmental stages in deglutition and corresponding changes in appropriate feedings inchildren.
Dysphagia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Feeding Teams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Background
This is a curriculum for nutrition in the pediatric age group. Thus, by necessity, it focuses on the biological and physiological needs of pediatric patients. Unlike other areas of medicine directed by genetic programming, a great deal of emotions and memories are associated with nutrition right from the start. The original source of nutrition is food, yet food is so much more than nutrition. It is symbolic, from the stalk of wheat in the A.S.P.E.N. logo to the traditional birthday cake. Marion Winkler, in her 2007 A.S.P.E.N. presidential address, related the story of the foods her mother requested when dying from cancer. Winkler realized that it was about more than just food, stating It was always about the nostalgic stories that surrounded the food, the memories, the social aspects, and the companionship of the sharing ofmeals.1 When we begin to explore the desire to eat, we realize that appetite has a cultural aspect.2 Part of this derives from the environment; certain foods are more available in different geographic regions, and one cultures delicacy may be unacceptable in another. Childrens memories and associations will thus influence their intake. 3 Also, human beings will
3
Appetite
THE A.S.P.E.N. PEDIATRIC NUTRITION SUPPORT CORE CURRICULUM
eat some foods just because they taste good. The reward of taste stimulates feeding even in the absence of a true energy deficit.4 There are critical periods of infant development that hinge upon exposures to new tastes and textures. Genetic input affects the sense of taste itself, including the strength of response to sweet, salty, bitter, and sour. 5 Studies show that breastfed infants have greater willingness to try new tastes2,6; this is believed to be from their exposure to various flavors in breast milk. Early exposure to tastes determines taste and food preferences before the child develops neophobia. 2 Neophobia is the developmental stage between 18 months to 2 years of age when children resist trying new foods. 2,5 The more a child is exposed to a taste, the more likely it is to be accepted as a preferred taste. 5,6 Studies indicate that it may take 5 to 10 exposures before a food becomes an accepted taste. 6 Also, there appears to be a critical period for beginning solid foods, due to their texture, which is before 10 months of age. Northstone et al reported on long-term feeding problems related to acceptance of the taste and texture of foods.7 Feeding difficulties in children identified by 9,360 parents were found to occur more often in those children whose parents delayed initiating solid foods until after 10 months of age.7 Biological preferences are also altered by modeling that children see when observing their parents and peers.2,5 Eating with others influences the feeding behaviors and the food preferences that children ultimately develop.6 Appetite control is centered in the hypothalamus of the brain and integrates information from multiple sources.4,8 The general level of appetite is influenced by the amount of the hormone, leptin, produced by the bodys adipose tissue.4,9 The liver also sends appetite-influencing signals to the brain, primarily through the energy products fat and glucose and the level of adenosine triphosphate (ATP) in the liver cells.8 The insulin level produced by the pancreas in response to serum glucose levels influences the general appetite level as well.4,8 Leptin and insulin suppress inhibition, or drive the appetite, via the hypothalamus.10 The first stage in appetite is the cephalic phase, which is a biological response to feeding cues. This concept was first presented by Ivan Pavlov. Pavlov demonstrated that he could condition dogs to salivate at the ringing of a bell by developing an association with feedings.11 A variety of studies have shown that visual, olfactory, gustatory, tactile, and auditory inputs stimulate processes in the salivary glands, gastrointestinal (GI) tract, pancreas, and cardiovascular and renal systems.12 These responses are quick and prepare the body for the digestion and absorption of
2010 A.S.P.E.N. www.nutritioncare.org
the anticipated meal.12 The rest of the responses from the stomach and small intestine tend to decrease appetite.9 Once beyond the cephalic phase, appetite level is modified by inputs from the enteric nervous system (ie, from chemical and stretch receptors in the GI tract) and hormonal and metabolic signals.9 During the gastric phase the brain receives signals concerning the volume of food ingested and data about its nutrient content.9 Endocrine cells in the stomach produce ghrelin that stimulates appetite4; ghrelin levels are high when the stomach is empty and fall after eating.4,10 Emptying of the stomach also influences the neural control of appetite with gastric distention signaling via the vagus nerve to decrease appetite.10 The intestinal phase is communicated by a variety of signaling peptides that are released into the circulation. These peptides act to decrease appetite and are released in proportion to the amount of various nutrients ingested.4 These include peptide YY, glucagon-like peptide 1, oxyntomodulin, cholecystokinin, and pancreatic polypeptide.4 A variety of other peptides may influence appetite but these await confirmatory studies. The hypothalamus integrates all of these signals to regulate appetite. The heightened appetite drive that occurs in pediatric patients that increases the caloric intake for growth is not well understood. This drive may derive from programming within the hypothalamus itself or from signals indicating increased nutrient needs due to growth.
Mastication/Dentition
An important part of digestion is the initial homogenization of food that takes place in the mouth. Mastication, or the act of chewing, depends on the teeth to make foods a uniform consistency. Human beings are born toothless, which necessitates a reliance on liquid feedings. The muscles used in mastication are the temporalis, the masseter, and the medial and lateral pterygoids. The trigeminal nerve is the primary nerve involved in mastication. The act of chewing involves two sets of teeth, the anterior teeth (incisors and canines) and the posterior teeth (premolars and molars). The anatomy of the incisors and canines with their single cusps and their anterior position in the mouth allow themto tear food. The anatomy of the premolars and molars with multiple cusps and their posterior position in the mouth allow them to grind and chew food, preparing it for swallowing.13 The primary dentition, or development and eruption of teeth, consists of 20 teeth, all of which begin development between 13 to 20 weeks in utero. Teething, the act of tooth eruption, may cause infants malaise, with increased drooling plus stomach or bowel changes, but it is not associated with
MECHANICS OF NUTRIENT INTAKE
fevers. The mandibular central incisors are the first teeth to erupt between ages 6 to 10 months. The next teeth to erupt are the maxillary central incisors between ages 8 to 12 months. Over the next 2 years the other primary teeth come in as shown in Table 1-1.
Table 1-1 Primary Teeth by Age of Eruption
Primary Teeth Age of Eruption
Feeding Development
Swallowing
The process of swallowing is divided into 3 distinct physiological phases. These phases are the oral phase, the pharyngeal phase, and the esophageal phase. Each phase depends on the correct anatomy and neurophysiology of the muscles for feeding and appropriate ventilation. The oral phase consists of the preparatory stage and the movement of food being propelled to the back of the mouth. Infants take most liquids into the mouth already on the back third of the tongue; this changes as they develop more skill in the front of the mouth (tongue, jaw, and lips), and develop teeth. Purees and solids are propelled to the back of the mouth by the tongue. (Later in infant development the lips are used for assisting with eating during the oral phase. Skills such as taking purees off a spoon or drinking through a straw will occur in the last half of the first year.) The pharyngeal phase consists of the liquid or food coming to the back of the mouth, the pharynx, and reflexively being swallowed. The soft palate and uvula lift so that liquid or food will not pass into the nasopharynx. The larynx closes by muscle contractions and the downward movement of the epiglottis. Respiration ceases briefly (deglutition apnea) and, after the food has started its descent, expiration then inspiration will occur. In the infant, the swallow can occur at any part of the respiratory cycle and it is variable.15 The upper esophageal sphincter relaxes so that the food can enter the esophagus in the beginning of the esophageal phase. The cricopharyngeus muscle relaxes at the upper end of the esophagus and food travels to the stomach by peristalsis. Successful swallowing depends on all of these structures, muscles, and neurological and respiratory systems working in coordinated millisecond timing.16,17 Anatomical or physiological abnormalities with these systems will affect feeding effectiveness and efficiency.
Mandibular central incisors Maxillary central incisors Maxillary lateral incisors Mandibular lateral incisors Maxillary first molars Mandibular first molars Maxillary canines Mandibular canines Second molars
610 mo 812 mo 913 mo 1016 mo 1319 mo 1418 mo 1622 mo 1723 mo 23 y
The primary dentition stays intact until ages 5 to 7 years when the permanent dentition begins to erupt. As the root end of the permanent tooth develops in the bone, it causes the crown of the tooth to emerge, which resorbs the root of the primary tooth leaving only the crown. The crown of the primary tooth is then shed, allowing the permanent tooth to erupt. The mandibular central incisors and mandibular and maxillary first molars are the first permanent teeth to erupt between ages 6 and 7 years. Their hard tissue formation begins shortly after birth. The subsequent progression of permanent tooth acquisition is shown in Table 1-2.
Table 1-2 Permanent Teeth by Age of Eruption
Permanent Teeth Age of Eruption
Mandibular central incisors Mandibular first molars Maxillary first molars Maxillary central incisors Mandibular lateral incisors Maxillary lateral incisors Mandibular canines Maxillary premolars Mandibular premolars Maxillary second premolars Mandibular second premolars Maxillary canines
67 y 67 y 67 y 78 y 78 y 89 y 910 y 1011 y 1012 y 1012 y 1112 y 1112 y
Feeding Skills in the First Year

The typical newborn is ready to feed shortly after birth. The reflexive root allows the infant to open the mouth, turn toward the food source, latch, and begin to suck. The newborn will suck, swallow, and breathe in a rhythmic sequence. This pattern is established with the help of the early reflexes and behaviors that are developed in utero and improves by the third day of life.18 The rooting reflex is among the most important and is activated by a light touch on or near the infants mouth. Once latched onto the nipple, the infants tongue and jaw work together to stroke the nipple and express milk.19 The infant will feed in a burst 2010 A.S.P.E.N. www.nutritioncare.org
The permanent third molars, or wisdom teeth, are the most common missing teeth and normally erupt between ages 17 and 21 years.14
pause pattern that is usually quite regular, with the bursts being suck-swallow-and-breathe cycles and the pauses being brief and regular rest periods. Bursts of 8 sucks or more are seen in the typical newborn. 20 Sensing changes in the nipple, the infant can vary the suck pressure quite easily to control the flow of milk. During early infancy, the infant will increase the rate of expression per minute with age. Studies have varied on the changes in the volume of expression; however, it ranges from 0.26 to 0.4 mL per suck. 21,22 In a typical newborn, one suck-swallow-breathe cycle including all 3 phases lasts approximately 1 second. 21 As the infants oromotor skills develop, the increase in control and efficiency of intake allows the older infant to take more milk in less time. Pacifier sucking differs from feeding. In pacifier sucking (non-nutritive sucking), the suck rate is twice as fast as nutritive sucking.20 Only the oral phase is seen in non-nutritive sucking. The swallow-and-breathe phases of feeding are not coordinated. This is why many non-feeding infants can nonnutritively suck but have difficulty when liquid is introduced by a nipple. Readiness for transitioning to spoon feeding has been debated, and recommendations have changed over the years. Brain growth and neural pathway maturation support development of a larger variety of oromotor movements. The tongue no longer moves in a forward-backward patterned response. The infants tongue is able to stay in the mouth, not thrust out, and move side to side in response to stimulation, such as mouthing his or her fingers or hand. The infant no longer has a single oral response of suck-swallow-breathe, or bursts of sucking without swallowing as in pacifier sucking. At 5 to 6 months of age an infant typically has some sitting balance and wants to feed in an upright position. The infant can anticipate the food and will open his or her mouth for the spoon. The lips will close on the spoon to pull the food off.23 The food is moved all around in the mouth, not strictly kept over the center of the tongue for propulsion back for swallowing. The tongue and the jaw no longer work only as a single unit. The gag is diminished to allow for non-liquids and will continue to be modulated as the experience with textures continues.24 When infants begin to pick up objects, at age 6 to 7 months, they naturally put them into their mouths. As the tongue can move in multiple directions and mouth objects, the parent introduces meltable solids and foods with greater texture (lumps) for the infant to handle. In late infancy, the infant begins to munch or use an up-down motion of the jaw to begin mastication of foods. This chewing increases in efficiency with age.25 Soft solid foods are then provided
with small single bite-size pieces for the infant to move around in the mouth and eventually swallow. There is less rhythm to this feeding as compared to nutritive sucking. The movements are volitional and no longer directed by reflex. Early reflexes are fading between 4 to 8 months and volitional patterns of oromotor skills are the norm. 26 By 9 months of age, with the development of the fine motor skills of reach, grasp, and release, self-feeding is established. Now the infant is skillful at watching others, communicating interests in foods and eating. Cup and straw drinking begin as the infant is guided by a parent. The infant will not gum the cup, but opens his or her mouth to accept liquids from the cup that is guided by the parent. At this age, both breastfeeding and bottle feeding begin to diminish as the infant takes in a greater proportion of liquids by cup and solids by spoon or hand.24 Problems in Infant Feeding Skills Infant feeding difficulties can be broadly related to problems with anatomy, neurodevelopment, or respiration. Anatomical abnormalities of the head and neck are typically congenital and may affect the muscles of feeding as well as the physiological timing and efficiency of feeding, and lead to poor efficiency of intake. In the extreme, dysphagia (or swallowing dysfunction) can be seen. Classically, cranial nerve abnormalities cause dysphagia, and it is being recognized earlier along with the subtle effects of muscle tone and posture on feeding. Neurodevelopmental problems, such as an infant with muscle tone abnormalities, persistence of early reflexes, or abnormal oral reflexes, can also lead to dysphagia.27 Infants with hypotonia (as may be seen in infants with Down syndrome) may have significant oromotor dysfunction, dysphagia, and aspiration.28 Even infants with normal development can have difficulty feeding if they have abnormal respirations or gastroesophageal reflux. They may tire easily and self-limit their intake, or they may have difficulty with the suck-swallow-breathe sequence and self-limit due to aspiration, which is passage of liquid or solids into the airway during swallowing.29 Premature infants frequently have feeding difficulties because of either, or both, respiratory problems and neurodevelopmental problems. Early birth does not allow for the typical developmental sequence of oral skills. Poor growth, of especially the youngest gestational age infants, may not allow for maturation of neural pathways. Many premature infants have difficulty with newborn skills when they are at a term-adjusted age and may have significant feeding problems. Premature infants with bronchopulmonary dysplasia have been seen to have abnormal development of
suck patterns. 30 Some infants, who had significant limitations in oral feeding attempts due to a high level of illness or respiratory disorders, can display aversion to attempts at oral feeding. In others, a persistent rapid breathing rate can interfere with establishing an efficient feeding rhythm. Evaluation of the infant who is not feeding appropriately can be performed by a physician, nurse, occupational therapist, or speech therapist trained in, and experienced with, infant feeding. The evaluation will include a medical history, developmental history, and a neurological examination as well as an oromotor assessment including feeding or feeding attempt. A multidisciplinary approach is required. Pediatric specialists in gastroenterology, neurology, rehabilitation, development, and others may be needed. The evaluation, under the direction of a physician, may include radiological testing such as a feeding study, esophagram, or studies for reflux or gastric emptying. Neurological studies of the central nervous system may be needed for the diagnosis of neurodevelopmental abnormalities. Studies of respiratory function and sufficiency of ventilation may be needed to provide optimal respiratory support for feeding. It is important to determine the safety of feeding and ensure that the infant is not aspirating as a result of the underlyingproblems. 31 Sometimes, despite extensive evaluations, the etiology of the feeding difficulties is never discovered. There is also a belief that in some situations the initiating organic cause has resolved but the resulting behavior has become established. Once the cause and extent of poor feeding is understood, a treatment plan can be undertaken to work on oral feedings, and/or to provide supplemental feedings for the safety and growth of the infant. Supplemental feedings can consist of nasogastric feedings or feedings into the jejunum. Such treatment plans should be drafted with the parents and a team of medical and therapy providers.
period, chewing improves and changes from the up-down munching motion to the rotary chewing that allows the toddler to grind meat fibers by age 3 years. The toddler will increase chewing efficiency to 5 years of age. 33 Through trial and error, carefully, the parents will supply the toddler with small bites of their own foods and expand the toddlers diet. Meltable solids will be exchanged for non-meltable solids that require biting off and chewing as the parent sees the child is ready for the single bite. Gradually, the diet will reach that of the preschooler. The toddler may initially allow the parent to assist with providing bites, but this will diminish and, by 18 months, the child will insist on exclusive self-feeding. The use of utensils can start as early as 15 months, but is generally not perfected until much later. Initially, sticky foods will be given to help with self-spoon feeding; later the child will learn to spear with a fork as well, particularly soft foods. Eating with his or her fingers to assist the utensil feeding will continue until the preschool age. Also, the child can now drink independently from an open cup.24 Behavior during mealtimes can be challenging as the toddler will seek to exert control over this environment as well. How the parents model and reinforce appropriate behavior to diminish unwanted behavior can affect not only eating but also sleeping habits and play interactions. Routine meals and snacks that are eaten with the child are the best times to teach a child appropriate mealtime behavior. As the toddlers ability to understand language increases, the parents need to demonstrate and explain appropriate behavior at mealtimes. Praise for sitting and eating with the family is necessary, as well as repetitive teaching of appropriate behaviors. Watching the toddlers cues is important, as throwing or playing with food may signal that the child is full. As with all behaviors, routine and consistency will teach both the easy as well as the difficultfeeder. Problems with the Toddler Feeder Problems that affected an infants feeding may still be present when that child reaches toddlerhood. Medical problems of anatomical anomalies, neurodevelopmental problems, or cardio-respiratory concerns require ongoing medical and therapeutic intervention. However, those toddlers who had normal feeding skills in their first year may have new behaviors affecting feedings, or have aversion to advancing on to a variety of flavors and textures. In one population study, parents described 20% of toddlers as having feeding problems. 34 At times a sentinel event can be recalled (he had his tonsils out and couldnt eat); other times, subtle problems with advancing textures in infancy
Feeding Skills in the Second Year

Toddlers typically need to expand their acceptance of foods and master self-feeding, including biting and chewing. This is a tall order as they are also developing independence and have the ability to make choices and affect their environment. The majority of toddlers (from 1 to 3 years of age) enter this stage eating table foods. They have successfully transitioned to some of the foods their families eat by their first birthday. 32 Due to their immature oromotor skills, toddlers need their foods diced, chopped, or cut into small bite-sized pieces. This continues until their ability to bite a single mouthful of food becomes skillful. Only then can a parent rely on the toddler not to choke. During this
were present and not well recognized. Still other problems include the toddler with behavioral problems that are now more evident at this age, such as short attention span, oppositionality, or slow learning. Sometimes the organic process that caused a feeding problem will resolve but the inappropriate feeding behavior persists. Evaluating new feeding problems in the toddler begins with a thorough feeding history of who, what, when, where, how, and how much the child is fed. Often through this history, the initial therapeutic interventions can be determined. Review of the anthropometric measures since birth will identify growth failure, and a physical examination will determine the need for additional cardiac, respiratory, or GI evaluation. The neurological and developmental examination can determine the need forfeeding studies, or further psychological or developmental evaluation. Most therapeutic plans include a mealtime routine and appropriate modeling of eating behavior by parents and caregivers. Choosing a nutritious variety of foods to serve at meals and as snacks will expand the feeding experience of the toddler and decrease pickiness. 3537 It is important to ascertain the toddlers baseline abilities with oromotor function, fine motor development, and cognitive function to determine the level at which to begin. Identification of the problem(s) as well as the parents goals for feeding will direct the therapists plans, dietary plans, and home intervention. In toddlers with weight loss, worsening feeding problems, or significant family stress, referral to a feeding team can be helpful. The toddler with feeding problems may need such a team approach, including a psychologist, occupational and speech therapists, and dietitian, to provide behavioral plans, therapy, and dietary advice.
Dysphagia
Neuromotor impairment in swallowing can also be termed dysphagia. In the infant and young child, feeding proceeds in the developmental sequence mentioned, and abnormalities in feeding abilities need to be evaluated for a neurological cause. This diagnosis is made by history, a neurological examination by a physician, and a feeding observation. Feeding studies, in which the infant or child is fed using the observation of video fluoroscopy, can identify neuromotor problems of pharyngeal pooling, nasopharyngeal reflux, or laryngeal aspiration. During a swallow/feeding study, the infant or child is fed liquids, purees, or solids laced with barium so that the ingested substance is visible under video fluoroscopy. At some institutions, feeding studies can be done with pulse oximetry to see the effect of respiratory effort or deglutition apnea on the total saturation of oxygen.
The real-time images are observed by the therapist or other personnel performing the study, and are further reviewed by a radiologist. When a child aspirates, the feeding plan is modified to avoid liquids or textures that the child is not able to eat safely. Further neurological diagnosis as to the cause of dysphagia should be investigated by the physician. Therapeutic interventions can include: physical, occupational, and speech therapy to advance skills; modifications of liquids or foods offered; adaptation of cups and utensils for feeding; positioning assistance to provide a flexed and upright position for feeding; dietitian adaptation of the diet to meet caloric, nutrition, and volume goals; nutrition support through gastrostomy feedings; diagnosis and treatment of gastroesophageal reflux; medications to normalize tone and posture; and repeated feeding studies. The goals of therapy will be to normalize tone and posture, particularly around head control and seating for feeding. Other goals will be to foster feeding development in the typical sequence as determined by the childs level of function and the safety of the feeding. For example, an infant who has had brain damage from meningitis may be seen to have dysphagia. Methods that lead to relaxation may need to be used on the infant to decrease hypertonicity and foster normal positioning. This infant may require a feeder seat for good positioning, and may need to be offered purees only, because liquids are aspirated. This infant may need dietary assistance with increased caloric density to decrease the volume of intake needed by tube feeding; or he may need to have small and frequent feedings if intolerant of large gastrostomy feeding volumes. Once again, a team approach is needed in the feeding care of the infant or child who has dysphagia. 38
Feeding Teams
Pediatric institutions that form feeding teams draw from the professional expertise at their organizations. With that in mind, each team will determine the problems they feel are appropriate in their setting and for their population. The usual team members include: child and parents; a physician, who may be a developmental pediatrician, gastroenterologist, general pediatrician, or a pediatric physiatrist; a coordinator, who may be in social work, psychology, or nursing;
a child psychologist; a speech and/or occupational therapist; a dietitian; and a social worker. For the feeding team to be successful, the parents must clearly identify their goals and be willing to make changes, and to work with the team members. Each professional must also be willing to work with team members and to support the parents and patient during the process. Setting clear goals with the team and reviewing those goals is an important part of a feeding team program. For example, Abby is a young toddler who has aversiveness to eating because of severe respiratory problems caused by prematurity. Her respiratory status has significantly improved and she needs only occasional bronchodilators. She is gastrostomy fed and is very sensitive to the rate of feedings. Her mother has cut back on her feedings so Abby is also failing to thrive. There are many goals for the team members, and progress may vary in these goals. The family hopes to shorten feeding times and increase Abbys oral feedings so she can eventually stop gastrostomy feedings. These are appropriate goals for the child and the team members; however, these are long-term goals and the progress is incremental and variable. The parents, with the teams help, determine the daily schedule for feeding, and continue in the routine of feedings. The physician and dietitian may work on a short-term goal of improving Abbys weight gain while trying to shorten her feeding times. The therapists may start by improving her ability to stay at the table at mealtime and touch food for short time periods. The dietitian and therapists may use a chaining technique to select foods that are similar to foods Abby likes so as to slowly broaden her food choices. At each follow-up visit with the team, the goals are reassessed and the plan of care is revised based on the childs progress. 39 Referral to a feeding team is generally made by the childs primary care provider and reviewed by the coordinator for appropriateness to the team.
Test Your Knowledge Questions
1. Appetite is suppressed by: A. Sensory stimulus before eating B. Ghrelin release by the stomach C. Intestinal release of glucagon-like peptide 1 D. Low leptin levels 2. An abnormal swallow contains: A. Lift of the soft palate and uvula B. Continued respirations C. Closure of the epiglottis D. Opening of the upper esophageal sphincter 3. Chewing that allows the intake of higher texture foods requires: A. Rotary chewing B. Forward-backward patterning C. Suck-swallow-and breathe cycles D. Up-down motion of the jaw See p. 487 for answers.
References
1. Winkler MF. American Society for Parenteral and Enteral Nutrition presidential address: food for thought: its more than nutrition. J Parenter Enteral Nutr. 2007;31(4):334340. 2. Harris G. Development of taste and food preferences in children. Curr Opin Clin Nutr Metab Care. 2008;11(3): 315319. 3. Lupton D. Food, The Body and the Self. Thousand Oaks, CA: Sage Publications; 1996. 4. Druce M, Bloom SR. The regulation of appetite. Arch Dis Child. 2006;91:183187. 5. Scaglioni S, Salvioni M, Galimberti C. Influence of parental attitudes in the development of children eating behaviour. Br J Nutr. 2008;99(Suppl 1):S22S25. 6. Birch LL, Fisher JO. Development of eating behaviors among children and adolescents. Pediatrics. 1998;101(3) (Suppl):539549. 7. Northstone K, Emmett P, Nethersole F. The effect of age of introduction to lumpy solids on foods eaten and reported difficulties at 6 and 15 months. J Hum Nutr Dietet. 2001;14(1):4354. 8. Erlanson-Albertsson C. Appetite regulation and energy balance. Acta Paediatr. 2005;94(6)(Suppl):4041. 9. Blundell JE. The control of appetite: Basic concepts and practical implications. Schweiz Med Wochenschr. 1999;129(5):182188. 10. Inui A, Asakawa A, Bowers CY, Mantovani G, Laviano A, Meguid MM, et al. Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J. 2004;18:439456. 11. Pavlov IP. The centrifugal (efferent) nerves to the gastric glands and the pancreas. In: Thompson WH, ed. The Work of the Digestive Glands. Philadelphia, PA: Charles Griffin and Co; 1910:4859.
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12. Mattes RD. Physiologic responses to sensory stimulation by food: nutritional implications. J Am Diet Assoc. 1997;97(4):406413. 13. McDonald RE, Avery DR, Dean JA. Dentistry for the Child and Adolescent. 8th ed. St. Louis, MO: Mosby; 2004:176178. 14. Kronfeld R, Schour I. Chronology of the human dentition. J Am Dent Assoc. 1939;26:1832. 15. Kelly BN, Huckabee ML, Jones RD, Frampton CMA. The first year of human life: Coordinating respiration and nutritive swallowing. Dysphagia. 2007; 22(1):3743. 16. Bosma JF. Development of feeding. Clin Nutr. 1986;5(5): 210218. 17. Derkay SD, Schechter GL. Anatomy and physiology of pediatric swallowing disorders. Otolaryngol Clin North Am. 1998;31(3):397404. 18. Weber F, Wollridge MW, Baum JD. An ultrasonographic study of the organisation of sucking and swallowing by newborn infants. Dev Med Child Neurol. 1986;28(1)1924. 19. Tamura Y, Horikawa Y, Yoshida S. Co-ordination of tongue movements and peri-oral muscle activities during nutritive sucking. Dev Med Child Neurol. 1996;38(6):503510. 20. Wolff PH. The serial organization of sucking in the young infant. Pediatrics. 1968;42(6):943956. 21. Qureshi MA, Vice FL, Taciak VL, Bosma JF, Gewolb IH. Changes in rhythmic suckle feeding patterns in term infants in the first month of life. Dev Med Child Neurol. 2002;44(1): 3439. 22. McGowan JS, Marsh RR, Fowler SM, Levy SE, Stallings VA. Developmental patterns of normal nutritive sucking in infants. Dev Med Child Neurol. 1991;33(10):891897. 23. Ayano R, Tamura F, Ohtsuka Y, Mukai Y. The development of normal feeding and swallowing: Showa University study of the feeding function. Int J Orofacial Myology. 2000;26:2432. 24. Gesell A, Ilg FL. Feeding Behavior in Infants. A Pediatric Approach to the Mental Hygiene of Early Life. Philadelphia, PA: J.B. Lippincott Co; 1937. 25. Gisel EG. Effect of food texture on the development of chewing of children between six months and two years of age. Dev Med Child Neurol. 1991;33(1):6979. 26. Sheppard JJ, Mysak ED. Ontogeny of infantile oral refluxes and emerging chewing. Child Dev. 1984;55(3):831843.
27. Arvedson JC. Dysphagia in pediatric patients with neurologic damage. Semin Neurol. 1996;16(4):371385. 28. Frazier JB, Friedman B. Swallow function in children with Down syndrome: A retrospective study. Dev Med Child Neurol. 1996;38(8):695703. 29. Mercado-Deane MG, Burton EM, Harlow SA, et al. Swallowing dysfunction in infants less than 1 year of age. Pediatr Radiol. 2001;31(6):423428. 30. Gewolb IH, Bosma JF, Taciak VL, Vice FL. Abnormal developmental patterns of suck and swallow rhythms during feeding in preterm infants with bronchopulmonary dysplasia. Dev Med Child Neurol. 2001;43(7):454459. 31. Arvedson J, Rogers B, Buck G, Smart P, Msall M. Silent aspiration prominent in children with dysphagia. Inter J Pediatr Otorhinolaryngol. 1994;28(23):173181. 32. Briefel RR, Reidy K, Karwe V, Jankowski L, Hendricks K. Toddlers transition to table foods: Impact on nutrient intakes and food patterns. J Am Diet Assoc. 2004;104(1)(Suppl 1):S3844. 33. Gisel EG. Chewing cycles in 2- to 8-year-old normal children: A developmental profile. Am J Occup Ther. 1988;41(1):4046. 34. Wright CM, Parkinson KN, Shipton D, Drewett RF. How do toddler eating problems relate to their eating behavior, food preferences, and growth? Pediatrics . 2007;120(4):e1069e1075. 35. Gidding SS, Dennison BA, Birch LL, Daniels SR. Dietary recommendations for children and adolescents: A guide for practitioners. Pediatrics. 2006;17(2)544559. 36. Satter E. How to Get Your Kid to Eat: But Not Too Much. Boulder, CO: Bull Publishing Co; 1987. 37. Jana L, Shu J. Food Fights: Winning the Nutritional Challenges of Parenthood Armed with Insight, Humor, and a Bottle of Ketchup. Washington, DC: American Academy of Pediatrics; 2008. 38. Dusick AM. Investigation and management of dysphagia. Semin Pediatr Neurol. 2003;10(4):255264. 39. Fraker C, Fishbein M, Cox S, Walbert L. Food Chaining: The Proven 6-Step Plan to Stop Picky Eating, Solve Feeding Problems, and Expand Your Childs Diet. New York, NY: Marlowe & Co; 2007.
Gross Digestion Principles: Gastric Grinding and Gastrointestinal Motility

Jane P. Balint, MD
CONTENTS
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Gastric Motility. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12 Small Bowel Motility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Effect of Intake on Motor Activity. . . . . . . . . . . . . . . . . . . . 13
Consistency Nutrient Content Caloric Density Osmolarity
Learning Objectives
1. Describe the normal response of the stomach to nutrientintake. 2. Explain the different motor patterns of the smallintestine in the fasting and fed states. 3. Predict the response of the intestinal tract to different types of nutrients. 4. Develop management strategies for altered gastrointestinal motility.
Altered Patterns of Motility and Potential Interventions . 13

Delayed Gastric Emptying Dumping Slow Intestinal Transit Rapid Intestinal Transit
Background
Gastrointestinal (GI) motility is necessary for the movement of nutrients from the stomach through the intestinal tract as well as for the breakdown and mixing of these nutrients with digestive enzymes, which in turn allows for digestion and absorption. An elementary understanding of these processes is helpful in planning and managing nutrition support. The motor activity of the GI tract is regulated by the enteric nervous system (ENS), which consists of two nerve plexuses. The myenteric plexus (Auerbachs plexus) lies between the outer longitudinal muscle layer and the inner circular muscle layer. This plexus is key to the motility of the GI tract, including regulation of the normal motor patterns seen in the GI tract described below. The submucosal plexus (Meissners plexus), found between the muscularis mucosa and the circular muscle layer, affects absorption, secretion, and blood flow. While the ENS can act independently, it receives input from the parasympathetic nervous system (primarily the vagus nerve), the sympathetic nervous system, and sensory nerves in the intestine, as well as from mast cells, paracrine signals, and endocrine signals. In addition, the ENS has multiple neurotransmitters for signaling, including acetylcholine, norepinephrine, serotonin,
11
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vasoactive intestinal peptide, nitric oxide, somatostatin, and tachykinins.14 Integral to the functioning of the GI tract are the interstitial cells of Cajal (ICC). There are two types: those around the myenteric plexus that generate and propagate electrical slow waves (pacemakers), and those between neural fibers and smooth muscle cells providing communication between the two. The ICC help to coordinate peristaltic movement of the GI tract. 5,6 Slow waves have variable frequency in different parts of the GI tract. In the stomach, the slow-wave rhythm is 3 cycles per minute. In the proximal small bowel the rhythm is 11 to 12 cycles per minute, decreasing to 7 to 9 cycles per minute in the distal ileum. Slow waves do not generate contractions but dictate the frequency at which they can occur.4,7
The preterm infant has an immature pattern of GI motility affecting both gastric emptying and small bowel motility, which impacts feeding. The normal electrical activity of the stomach, with a slow wave frequency of 3 cycles per minute, does not develop until 32 weeks gestation and does not become the dominant pattern until 35 weeks gestation. This results in slower gastric emptying in these more premature infants in comparison to the term infant.4,12,13
Small Bowel Motility
Gastric Motility
The gastric fundus, which is the uppermost portion of the stomach, acts as a reservoir for ingested food. It is in the antrum and body of the stomach where food is ground into small particles prior to passage into the small intestine. With swallowing at the onset of a feeding or meal, vagally mediated relaxation of the fundus occurs. As food enters the stomach, there is further relaxation of the proximal stomach to provide a reservoir for nutrients. This receptive relaxation/gastric accommodation allows for an initial increase in the volume of the stomach without an increase in pressure. However, ultimately the pressure will increase, leading to a tonic contraction that then pushes the gastric contents toward the antrum. With this there is the start of regular phasic contractions at 3 cycles per minute that both mix and grind (triturate) the gastric contents. During the churning process, the food bolus is first pushed toward the antrum where some grinding takes place. Distention of the antrum results in fundic relaxation and in turn retropulsion of contents back to the body of the stomach. Grinding is important for creating small particles, less than 1 to 2 mm in size, that will pass into the duodenum through the pylorus. Mixing with gastric acid and pepsin begins the chemical digestion of food. This initial phase of mixing and grinding is the lag phase in gastric emptying that occurs after ingestion of nutrients.1,4,811 Once the ingested nutrients are appropriately mixed and solid material is ground into small particles, antral contractions accompanied by pyloric relaxation allow small aliquots of this chyme to empty into the duodenum. This begins the second or linear gastric emptying phase. The time for gastric emptying is variable, and depends upon a variety of factors as discussed below, but is generally complete by 4 hours.1,4,7,8,10,11
Motor activity of the small intestine serves a number of important functions, including mixing chyme with intestinal secretions for further digestion, enhancing contact between enteric contents and the mucosa for absorption, moving ingested contents distally, and clearing the intestinal tract by powerful contractions that propagate in an aboral direction.14 In the fasting state, or interdigestive period, there are 3 phases of the migrating motor complex (MMC). Phase I is a quiescent phase. In phase II there are intermittent, irregular contractions. Phase III is characterized by strong, propagating contractions that begin almost simultaneously in the stomach and duodenum and travel through the small bowel. This phase III of the MMC provides the housekeeping function of intestinal motility, sweeping material through the small bowel. It occurs at irregular intervals, ranging from 18 to 145 minutes with an average occurrence of every 80 minutes, and lasts from 2 to 14 minutes.1,4,1416 In the fed state, there is a combination of mixing and propulsion of intestinal contents. In general, there are random bursts of activity, primarily resulting in mixing. When a contraction occurs, intestinal contents move. If the contraction in one region of the small intestine occurs in a coordinated manner with proximal and distal bowel, then the intestinal contents will be propelled downstream. If the contraction is not coordinated with activity of adjacent areas, then the intestinal contents moves both retrograde and antegrade in the intestine, resulting in mixing. 3,15 As noted above, the premature infant has not developed a normal pattern of intestinal motility. The fasting pattern of premature infants is characterized by short bursts of activity called clusters that do not progress aborally as a mature phase III MMC does. The nature of these clusters is different depending upon the gestational age. The length of a cluster increases with gestational age from less than 90 seconds in the 27- to 28-week gestation infant to 5 to 6 minutes at 36 weeks gestation. At the same time the frequency with which the clusters occur decreases. The fed pattern also differs in the premature infant with most demonstrating
GROSS DIGESTION PRINCIPLES: GASTRIC GRINDING AND GASTROINTESTINAL MOTILITY
13
an abrupt cessation of intestinal contractions after a bolus feeding. Not surprisingly, intestinal transit is slower in the preterm infant. There is some evidence that feeding premature infants, even small amounts, can promote maturation of intestinal motility.12,1719
Caloric Density
Increased calorie content of the ingested food or liquid will result in slower emptying from the stomach.21,30 It has also been demonstrated that a higher calorie content meal will result in a longer fed pattern in the small bowel leading to a longer transit time through the small intestine. 31
Effect of Intake on Motor Activity
Gastric emptying can be affected by a variety of characteristics of the ingested material as well as the rapidity of transit through the GI tract. With this, the time for gastric emptying can vary from 1 to 4 hours. The effect of nutrient composition on motor activity has been more clearly delineated for the stomach than the small bowel.
Osmolarity
Finally, solutions that have a higher osmolarity will empty more slowly from the stomach than those that are lower in osmolarity.27 While each of these factors individually can influence gastric emptying in the older infant, child, and adult, the same has not been found to be true in premature infants. In one study of 25 to 30 weeks gestation infants, it was demonstrated that altering osmolality, caloric density, or the volume of the feeding separately did not change gastric emptying. However, when the volume of the feeding was increased in combination with decreasing the osmolality, gastric emptying was more rapid. 32 Additionally, across age groups in clinical practice, these factors can clearly overlap as nutrient content is closely tied to caloric density. For example, a meal or formula higher in fat will likely be higher in calories.
Consistency
Liquids will empty from the stomach more quickly than solids. In turn, clear liquids will empty more rapidly than full liquids, with non-nutritive liquids emptying the fastest, leaving the stomach in about 20 minutes.11,20 The viscosity of the feeds will also affect the speed of gastric emptying, with lower viscosity material emptying more rapidly. Thus both soluble and insoluble fibers mixed with the feedings will slow emptying.21,22 In addition to delaying gastric emptying, soluble fibers can prolong transit through the GI tract by prolonging the duration of the fed pattern of small bowel motor activity.22
Nutrient Content
The response to the type of nutrient ingested is complex. There are both hormonal and neural responses to food that regulate motor activity of the stomach and small intestine. These are interrelated in that neural activity can affect the release of some GI hormones. Once chyme starts to pass through the pylorus, there is feedback via vagal afferents from receptors in the duodenum that regulate gastric emptying. These receptors include those that detect fat, amino acids, glucose, pH, and osmolarity.23 A component of the response is mediated by release of gastrin, cholecystokinin, pancreatic polypeptide, glucagon-like peptide 1, and peptide YY.4,24,25 It has been demonstrated that carbohydrates will empty from the stomach before proteins, with fats emptying the most slowly.4,26,27 Fats reaching the distal ileum inhibit both gastric emptying and small intestinal motility, a mechanism known as the ileal brake.28 Complex carbohydrates that reach the distal small intestine can also stimulate the ileal brake.1 In addition to the actual nutrient content, the pH will affect gastric emptying as well with more acidic material emptying more slowly from the stomach.29
Altered Patterns of Motility and Potential Interventions
Disordered motility in any part of the GI tract can impact feeding tolerance.
Delayed Gastric Emptying

As noted above, slower gastric emptying occurs in the premature infant and may impair feeding advancement. Premature infants who require tube feedings due to immature suck and swallow may benefit from a slower intermittent infusion over as long as 2 hours, rather than a 15-minute bolus, as this slower infusion has been demonstrated to result both in improved gastric emptying and a more mature duodenal motor pattern. 33,34 In the older infant or child, delayed emptying may occur during or following a viral illness, associated with a significant systemic illness, as well as after surgery, resulting in fullness, bloating, decreased appetite, and emesis. 35 Management strategies depend on the degree of the problem and how the child was being fed prior to the onset of the problem. If the child was eating a regular diet, smaller more frequent meals that are lower in fat, in fiber, and in caloric density may empty better from the stomach. 36 As liquids empty more readily than solids, increasing the liquid content of the meal may help. If the child is unable to
14
tolerate any solids, a trial of liquid nutritional supplements is warranted. If the child was tube fed prior to the onset of the delayed gastric emptying, then adjusting the formula or the manner of delivery may be necessary. The osmolarity, caloric content, fat content, and fiber content of the formula should be evaluated and a determination made as to whether a change is possible, as the higher each of these are, the slower emptying will be even under normal circumstances. Drip feedings, rather than bolus feedings, may need to be considered. There are few pharmacologic options available currently. Erythromycin, which acts as a motilin receptor agonist, can accelerate gastric emptying. 37 If the problem is severe enough, continuous transpyloric or jejunal feedings may be necessary, at least temporarily.
bowel. There are some data to indicate that amoxicillinclavulonic acid may promote small bowel motility.42 In more severe cases, octreotide may be beneficial. This somatostatin analogue has a wide range of effects on the GI tract, including induction of phase III MMC when given in small doses subcutaneously.43
Rapid Intestinal Transit

Rapid intestinal transit may occur following a systemic illness or due to surgery on the GI tract. This can result in malabsorption of nutrients and diarrhea. Feeding strategies will be discussed in detail in later chapters, including those on GI disease and intestinal failure. However, one approach that may be beneficial, regardless of the feeding selected or route of delivery, is the addition of soluble fiber such as pectin or guar gum to the feeding as these will prolong intestinal transit time.22,44 Various drugs can be used in an effort to slow transit through the small bowel. Loperamide, a peripherally acting opioid analogue, inhibits both small bowel and colonic motility. Anticholinergic agents, such as hyoscyamine, can also help to slow intestinal transit. While it is important to consider the impact of gastric and intestinal motility on feeding, this is only one of many factors that must be taken into account as will be discussed in subsequent chapters.
Dumping
Very rapid gastric emptying, or dumping, is relatively uncommon in pediatrics. 35 It can occur as a result of surgery, particularly involving the pylorus, or with damage to the vagal nerve such as during a fundoplication or cardiac surgery. Symptoms include nausea, abdominal distention, cramping, diarrhea, and vasomotor changes associated with swings in glucose. Some management strategies are the opposite of those suggested for use in delayed emptying. One can try to take advantage of normal physiology by increasing the fat and protein content of the diet and increasing the fiber content of the diet, including the addition of pectin and guar gum.36 Rather than mixing liquids with the meal, liquids should be taken separately from solids. On the other hand, some of the same strategies recommended for treatment of delayed gastric emptying may also be helpful in too rapid emptying, specifically smaller more frequent meals as well as continuous drip or post-pyloric feedings. Pharmacologic therapeutic options are limited. Acarbose, an alpha-glucosidase inhibitor, has been used to treat dumping syndrome as it delays the hydrolysis of carbohydrates with resultant delayed absorption of glucose38,39 Octreotide, an analogue of somatostatin, can be beneficial as one of its specific actions is to delay gastric emptying.40,41
Slow Intestinal Transit

Slow intestinal transit may occur following surgery (postoperative ileus), following a viral illness or other systemic illness, as a side effect of many drugs, or as part of a significant motility disorder, the most extreme being chronic intestinal pseudoobstruction. There is no clear evidence or consensus opinion upon which to make recommendations in terms of nutrition interventions that may be beneficial in these circumstances. Currently, there are also a paucity of drugs available to help promote motility of the small
1. Gastric emptying can be slowed by all of the following except: A. Soluble fibers B. Fats C. Liquids D. Protein 2. In the fed state, small bowel motor activity is characterized by: A. A quiescent phase B. Random bursts of activity C. Intermittent, irregular contractions D. Strong, propagating contractions 3. Which of the following is true for the premature infant? A. Bolus feeds will promote normal small bowel motor activity. B. Transit through the small bowel is shorter than in the older infant. C. Gastric emptying is more rapid than in the older infant. D. Feeding can promote the development of intestinal motility. See p. 487 for answers.
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References
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34. De Ville K, Knapp E, Al-Tawil Y, Berseth CL. Slow infusion feedings enhance duodenal motor responses and gastric emptying in preterm infants. Am J Clin Nutr. 1998;68:103108. 35. Di Lorenzo C, Ciamarra P. Pediatric gastrointestinal motility. In: Schuster MM, Crowell MD, Koch KL, eds. Schuster Atlas of Gastrointestinal Motility in Health and Disease. 2nd ed. Hamilton, Ontario: BC Decker, Inc; 2002:411428. 36. Karamanolis G, Tack J. Nutrition and motility disorders. Best Pract Res Clin Gastroenterol. 2006;20:485505. 37. Karamanolis G, Tack J. Promotility medications now and in the future. Dig Dis. 2006;24:297307. 38. Ng DD, Ferry RJ, Kelly A, et al. Acarbose treatment of postprandial hypoglycemia in children after Nissen fundoplication. J Pediatr. 2001;139:877879. 39. Zung A, Zadik Z. Acarbose treatment of infant dumping syndrome: extensive study of glucose dynamics and long-term follow-up. J Pediatr Endocrinol Metab. 2003;16:905915.
40. Lamers CB, Bijlstra AM, Harris AG. Octreotide, a long-acting somatostatin analog, in the management of post-operative dumping syndrome. An update. Dig Dis Sci. 1993;38:359364. 41. Scarpignato C. The place of octreotide in the medical management of the dumping syndrome. Digestion. 1996;57(Suppl 1):114118. 42. Caron F, Ducrotte P, Lerebours E, et al. Effects of amoxicillin-clavulanate combination on the motility of the small intestine in human beings. Antimicrob Agents Chemother. 1991;35:10851088. 43. Di Lorenzo C, Lucanto C, Flores AF, Idries S, Hyman PE. Effect of octreotide on gastrointestinal motility in children with functional gastrointestinal symptoms. J Pediatr Gastroenterol Nutr. 1998;27:508512. 44. Finkel Y, Brown G, Smith HL, et al. The effects of a pectinsupplemented elemental diet in a boy with short bowel syndrome. Acta Paediatr Scand. 1990;79:983986.
Carbohydrates: Changes with Development

Seema Mehta, MD and Robert J. Shulman, MD
Contents
Digestion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Lactose Starch
Learning Objectives
Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Malabsorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
1. Describe the structure and classification of carbo hydrates. 2. Describe the process of carbohydrate digestion and absorption. 3. Identify diseases related to carbohydrate malab sorption.
Digestion
Carbohydrates supply 50% of the bodys total energy requirement. Dietary carbohydrates consist of sugars and starches. Sugars include both monosaccharides (ie, glucose, galactose, and fructose) and disaccharides (ie, lactose, sucrose, maltose, and trehalose). Starches, also known as storage carbohydrates, consist of large chains of sugars linked together.1 Complex carbohydrate is another term used for starch. It commonly refers to starch used in formulas (ie, corn syrup solids, glucose polymers) and is a smaller carbohydrate molecule than those found in other food starches (ie, potato, corn). Small-chain starches, generally 3 to 10 glucose units in length, are referred to as oligosaccharides whereas long-chain starches are referred to as polysaccharides.
Lactose
Lactose is the primary carbohydrate present in human milk and most infant formulas.2 Lactose is hydrolyzed by the enzyme lactase into the monosaccharides glucose and galactose (Figure 3-1).
17
18
Figure 3-1 Digestion of Carbohydrates Overall schema of complex carbohydrate digestion.5
Figure 3-2 Age at Full Feedings versus Lactase Activity There is a negative relationship between the time full enteral feedings are achieved and lactase activity.2
Reprinted from Shulman RJ. Intraluminal digestion and absorption in the small intestine. In: Gluckman PD, Heymann MA. Pediatrics and Perinatology: The Scientific Basis. 2nd ed. New York, NY: Oxford University Press; 1996. Reproduced by permission of Edward Arnold (Publishers) Ltd.
Reprinted from Shulman RJ, Schanler RJ, Lau C, Heitkemper M, Ou CN, Smith EO. Early feeding, feeding tolerance, and lactase activity in preterm infants. J Pediatr. 1998;133(5):645-649 with permission from Elsevier.
Lactase, the sole enzyme responsible for the hydrolysis of lactose, is located along the brush border of the enterocytes lining the villi of the small intestine. The optimum pH for lactase activity is 6.0. Activity peaks in the jejunum and progressively decreases toward the ileum. This gradient is established by 11 weeks gestation. Antenatally, lactase activity increases until term with the greatest increase occurring during the third trimester. At the beginning of the third trimester, lactase activity is approximately 25% of that at term. 3,4 Early in fetal life, some lactase activity is demonstrable in the colon, but by 28 weeks gestation it is undetectable. 5 In preterm infants, it has been suggested that incomplete digestion of lactose may be linked to the pathogenesis of necrotizing enterocolitis (NEC), thereby resulting in a reluctance to feed preterm infants lactose.6 The time to reach full enteral feedings was found to be inversely related to lactase activity (Figure 3-2).2 Offsetting the apprehension for complications related to early feedings are the potential benefits. It has been demonstrated that early enteral feedings in preterm infants promote the development of lactase activity (Figure 3-3). Infants fed human milk were found to have greater lactase activity than those fed formula.
Figure 3-3 Lactase Development with Age and Type of Feeding Lactase activity increases with age but the increase is greater in the early fed group when compared with the standard group (p < 0.01).2 Lactase activity in the early fed group is greater than that in the standard group at 10 and 28 days of age (p = 0.004) but not at 50 days of age (p > 0.5).2
Reprinted from Shulman RJ, Schanler RJ, Lau C, Heitkemper M, Ou CN, Smith EO. Early feeding, feeding tolerance, and lactase activity in preterm infants. J Pediatr. 1998;133(5):645-649 with permission from Elsevier.
In many individuals, lactase activity begins to decline with advancing age. This genetically predetermined process, also known as primary lactase deficiency or
CARBOHYDRATES: CHANGES WITH DEVELOPMENT
19
primary hypolactasia, starts between 3 to 5 years of age and continues into adulthood.4 The prevalence of hypolactasia varies amongst individuals of different ethnic backgrounds ranging from 90% amongst Asians, 80% for AfricanAmericans, followed by 53% for Hispanics, and 15% to 25% for non-Hispanic whites.7 In contrast to the adult-type hypolactasia, congenital lactase deficiency, also a primary lactase deficiency, is an extremely rare autosomal recessive disorder associated with a complete absence of lactase expression.8 Symptoms in these patients manifest at birth with the introduction of a lactose-containing diet. Secondary lactase deficiency results as a consequence of mucosal injury to the small intestine. It occurs most commonly in infants with an infectious gastroenteritis and generally resolves with the resolution of the illness.8 Many otherwise healthy infants may demonstrate no signs or symptoms of lactose intolerance during the course of their illness.9 Other infants with either a poor nutrition status or more prolonged illness may show clinical signs of lactose intolerance and benefit from a lactose-free formula until their symptoms resolve.10
Figure 3-4: Development Profile of Pancreatic and Salivary Amylase There is little pancreatic amylase activity prior to birth but salivary amylase demonstrates some activity prior to 40 weeks gestation.20
Reprinted from McClean P , Weaver LT. Ontogeny of human pancreatic exocrine function. Arch Dis Child. 1993;68:62-65, with permission from BMJ Publishing Group Ltd.
Starch
Formula-fed infants are exposed to a variety of other carbohydrates in infancy including starches. The simplest form of starch is amylose, a linear polymer of glucose molecules linked by -1,4 glycosidic bonds. Amylopectin, a plant starch, is the major form of carbohydrate in the diet. Structurally it is similar to amylose, but for every 20 to 30 glucose units there are -1,6 branch points.11 Digestion of starch begins with intraluminal digestion by salivary and then pancreatic amylases. Amylase hydrolyzes starch at the internal -1,4 bonds (Figure 3-1). It is not active against those bonds located next to the -1,6 bonds or those at the reducing end of the starch molecule. Amylase cleaves amylose and amylopectin into maltotriose, maltose, and -limit dextrans (Figure 3-1).12 Salivary amylase, secreted by the salivary glands, is present in preterm infants. Amylase activity increases with gestational age, rising rapidly after birth and approaching adult values by 6 months to 1 year of age. Salivary amylase is inactivated at pH < 4.5 In newborns, however, salivary amylase tends to remain active because they have poorly acidified stomachs.13 Pancreatic amylase, secreted by the pancreas, is present at low levels in preterm and full-term infants. Activity begins to increase at 4 to 6 months of age and reaches adult values by 1 to 2 years of age (Figure 3-4).2
Further digestion of the disaccharides and oligosaccharides occurs at the level of enterocytes. Glucoamylase, like lactase, is located in the brush border of the small intestine. It cleaves -1,4 bonds of primarily non-branching glucose polymers (ie, amylose) and non-reducing ends of polysaccharides (Figure 3-1). Short chains (ie, < 10 glucose units) are more easily digested by glucoamylase than longer-chain units.14 Glucoamylase activity is detectable by 20 weeks gestation. At the beginning of the third trimester, the activity level is about half that at 36 to 38 weeks gestation. 5 In addition, it is also present in low levels in the colon only early in fetal life. 5 Therefore, in newborn infants, glucoamylase is the primary enzyme for complex carbohydrate digestion since pancreatic amylase activity is low. Young infants and older children have similar glucoamylase activity levels which are approximately half those in adults.15 Sucrase-isomaltase is a disaccharidase also found in the brush border of the small intestine. At 20 weeks gestation, sucrase-isomaltase activity is almost half to three-quarters that of term newborns and adults. 5 Similar to lactase, sucrase-isomaltase activity is highest in the proximal small intestine. Activity remains high over the course of an individuals life. Sucrase-isomaltase is cleaved into sucrase and isomaltase by pancreatic proteases. 5 Sucrase hydrolyzes sucrose into the monosaccharides glucose and fructose (Figure 3-1). Isomaltase cleaves the -1,6 glycosidic bonds of amylopectin (Figure 3-1). 5 A genetic deficiency of sucrase-isomaltase known as congenital sucrase-isomaltase deficiency is an autosomal recessive disorder. All patients with this deficiency lack sucrase and have varying degrees of isomaltase activity.16
20
Dietary carbohydrates are absorbed in the form of the monosaccharides glucose, galactose, and fructose. Active transport of glucose and galactose is present by 10 weeks gestation. 5 The absorption rate of glucose increases through gestation and continues to increase postnatally into adulthood. Galactose absorption rate reaches adult values between 4 to 8 years of age.8 Access into enterocytes occurs via carrier molecules. Glucose and galactose are actively transported via the sodium-glucose linked transporter (SGLT1) located at the brush border. Glucose and galactose entry is coupled to the entry of sodium along its electrochemical gradient. This electrochemical gradient is maintained via the sodium-potassium-adenosine triphosphatase (Na+-K+ ATPase) located at the basolateral surface. SGLT1 has binding sites for both glucose and sodium. Two sodium molecules are absorbed for every glucose molecule. Once both sites are occupied, the transporter translocates across the brush border membrane and releases the glucose and sodium into the enterocyte.11 The sodium-linked transport of glucose provides the basis for adding glucose or starches to oral rehydration solutions. Passive absorption of glucose also can occur across the brush border.8 Fructose transport across the brush border membrane occurs passively down its concentration gradient. The fructose transporter, GLUT5, is not sodium dependent. Transport of glucose, galactose, and fructose across the basolateral membrane also occurs by facilitated transport via the sodium-independent transporter, GLUT2.11 Recently GLUT2 has been recognized in the brush border membrane, and glucose transported by SGLT1 promotes the activation of GLUT2 already in the apical membrane and rapid insertion of GLUT2 from vesicles.17 This observation explains the enhancement of fructose absorption in the proximal intestine in the presence of equimolar amounts ofglucose.17 Incomplete digestion and absorption of carbohydrates can occur in the small intestine. The remaining mono- , di- , and oligosaccharides create an osmotic gradient that drives water into the lumen. Upon reaching the colon, these carbohydrates are fermented by colonic bacteria to short-chain fatty acids which then are absorbed by the colon.18 If the rate of malabsorption of carbohydrates exceeds their ability to be fermented and absorbed as short-chain fatty acids, osmotic diarrhea can result. Carbohydrate malabsorption can be detected by testing stool pH, stool-reducing substances, and/or a hydrogen
Absorption
breath test. Stool pH of < 5.5 is indicative of short-chain fatty acids in the stool, whereas stool-reducing substances present in the stool denote the presence (ie, malabsorption) of sugars, usually glucose. A positive breath hydrogen test reflects the passage of carbohydrate into the colon and its fermentation but interpretation depends on the carbohydrate. A significant rise in breath hydrogen would be expected after ingestion of a starch such as corn but not after sucrose. Disorders of carbohydrate absorption can be congenital or acquired (Table 3-1).12,19 Treatment varies because it is dependent on the clinical entity causing carbohydrate malabsorption. Treatment options include special diets and formulas (eg, gluten-free diet for patients with celiac disease) and enzyme supplements (eg, pancreatic enzymes for patients with cystic fibrosis).12,19
Table 3-1 Disorders Associated with Carbohydrate Malabsorption Sucrase-isomaltase deficiency Glucose-galactose malabsorption Congenital lactase deficiency Congenital trehalase deficiency Fructose malabsorption Adult-type hypolactasia Cystic fibrosis Shwachman-Diamond syndrome Congenital microvillus atrophy Tufting enteropathy Autoimmune enteropathy Celiac disease Postviral enteritis Postradiation enteritis
Metabolism
Malabsorption
Glucose is the most abundant carbohydrate in humans. Dietary carbohydrates are converted into glucose and then metabolized for energy. Starting soon after birth, gluconeogenesis contributes 30% to 70% of the bodys glucose. Glucose that is not immediately utilized is stored in the form of glycogen (ie, a storage carbohydrate).1 Insulin is the hormone responsible for glycogenesis (glycogen synthesis), while glucagon is the hormone responsible for glycogenolysis (glycogen degradation).
1. Which one of the following is a polysaccharide? A. Lactose B. Sucrose C. Maltose D. Amylose
CARBOHYDRATES: CHANGES WITH DEVELOPMENT
21
2. Lactose is hydrolyzed by the enzyme lactase into the monosaccharides and . A. Glucose; glucose B. Galactose; glucose C. Glucose; fructose D. Galactose; fructose 3. Which enzyme is present in the lowest amount in preterm infants compared with term infants? A. Glucoamylase B. Lactase C. Sucrase D. Salivary amylase 4. Which ethnic group has the lowest prevalence of primary hypolactasia? A. Asians B. African-Americans C. Hispanics D. Non-Hispanic whites See p. 487 for answers.
References
1. American Academy of Pediatrics, Committee on Nutrition. Carbohydrate and dietary fiber. In: Kleinman RE, ed. Pediatric Nutrition Handbook. 5th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2004:247253. 2. Shulman RJ, Schanler RJ, Lau C, Heitkemper M, Ou CN, Smith EO. Early feeding, feeding tolerance, and lactase activity in preterm infants. J Pediatr. 1998;133(5):645649. 3. Antonowicz I, Chang SK, Grand RJ. Development and distribution of lysosomal enzymes and disaccharidases in human fetal intestine. Gastroenterology. 1974;67:5158. 4. Raul F, Lacroix B, Aprahamian M. Longitudinal distribution of brush border hydrolases and morphological maturation in the intestine of the preterm infant. Early Hum Dev. 1986;13:225234. 5. Shulman RJ. Intraluminal digestion and absorption in the small intestine. In: Gluckman PD, Heymann MA. Pediatrics and Perinatology: The Scientific Basis. 2nd ed. New York, NY: Oxford University Press; 1996:630637.
6. Kliegman RM. Neonatal necrotizing enterocolitis: Bridging the basic science with the clinical disease. J Pediatr. 1990;117:833835. 7. Sahi T. Genetics and epidemiology of adult-type hypolactasia. Scand J Gastroenterol. 1994;202(suppl):720. 8. American Academy of Pediatrics, Committee on Nutrition. Infant nutrition and the development of gastrointestinal function. In: Kleinman RE, ed. Pediatric Nutrition Handbook. 5th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2004:47. 9. Brown KH, Peerson JM, Fontaine O. Use of nonhuman milks in the dietary management of young children with acute diarrhea: a meta-analysis of clinical trials. Pediatrics. 1994;93:1727. 10. Caballero B, Solomons NW. Lactose-reduced formulas for the treatment of persistent diarrhea. Pediatrics. 1990;86:645646. 11. Johnson LR. Digestion and absorption. In: Johnson LR, ed. Gastrointestinal Physiology. 6th ed. St. Louis, MO: Mosby; 2001:122127. 12. Schmitz J. Maldigestion and malabsorption. In: Walker AW, et al., eds. Pediatric Gastrointestinal Diseases. 4th ed. Hamilton, Ontario: BC Decker Inc; 2004:820. 13. Hodge C, Lebenthal E, Lee PC, Topper W. Amylase in the saliva and in the gastric aspirates of premature infants: Its potential role in glucose polymer hydrolysis. Pediatr Res. 1983;12:9981001. 14. Shulman RJ, Kerzner B, Sloan HR, et al. Absorption and oxidation of glucose polymers of different lengths in young infants. Pediatr Res. 1986;20(8):740743. 15. Lebenthal E, Lee PC. Glucoamylase and disaccharidase activities in normal subjects and in patients with mucosal injury of the small intestine. J Pediatr. 1980;97:389393. 16. Savilahti E, Launiala K, Kuitunen P. Congenital lactase deficiency: A clinical study on 16 patients. Arch Dis Child. 1983;58:246252. 17. Kellett GL, Brot-Laroche E. Apical GLUT2: A major pathway of intestinal sugar absorption. Diabetes. 2005;54:30563062. 18. Cummings JH, Macfarlane GT. Colonic microflora: Nutrition and health. Nutrition. 1997;13:476478. 19. Montalto M, Santoro L, DOnofrio F, et al. Classification of malabsorption syndromes. Dig Dis. 2008;26(2):104111. 20. McClean P, Weaver LT. Ontogeny of human pancreatic exocrine function. Arch Dis Child. 1993;68:6265.
Fats
Peggy R. Borum, PhD
4
Learning Objectives
1. List the different types of fatty acids. 2. Contrast the different fatty acid oxidation pathways. 3. Relate different pathological conditions to altered fat metabolism.
CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Different Types of Fat Essential Fatty Acids Different Functions of Adipose Tissue Importance of Dietary Fat in Infants
Digestion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Metabolism During Normal Physiology. . . . . . . . . . . . . . . . 26

Synthesis of Fatty Acids Beta-Oxidation of Long-Chain Fatty Acids inMitochondria Beta-Oxidation of Medium-Chain Fatty Acids inMitochondria Steps of Beta-Oxidation Beta-Oxidation of Very Long-Chain Fatty Acids inPeroxisomes Omega-Oxidation of Fatty Acids
Introduction
Metabolism During Pathophysiologies. . . . . . . . . . . . . . . . 27

Fat As Fuel for Preterm Infants Lipid Emulsions Containing Fish Oils As Fuel forParenteral Nutrition In Pediatrics To Esterify or To Oxidize: That Is the Cells Question
Lipids are one of three macronutrients in the diet, the other two being carbohydrates and protein. Triglycerides (lipids containing 3 fatty acids) are one of the main storage forms of metabolic energy in the body. Since fatty acids are highly reduced hydrocarbons, they are calorically dense, providing more metabolic energy per gram than the other dietary macronutrients. This characteristic is advantageous when a patient has a limited stomach capacity or is fluid-restricted and yet needs additional calories for rapid growth or due to critical illness. Fat is often viewed negatively by the public as a nutrient that should be reduced in the diet. However the problem may not be excess fat, but rather excess calories. Once the diet provides appropriate calories, careful attention should be given to the types of fatty acids included in the diet.
Different Types of Fat

Fats are extraordinarily diverse in structure but they have in common poor solubility in water. Triglycerides are the major dietary form of lipid and, as noted above, consist of 3 fatty acids joined by a glycerol backbone. Typical fatty acids are carboxylic acids with hydrocarbon chains ranging from 4 to 24 carbons (Figure 4-1). The chains are often unbranched, but can contain a variety of substituents including rings, hydroxyl groups, and methyl groups. The chain can be saturated (no double bonds), monounsaturated (1 double
22
FATS
23
bond), or polyunsaturated (2 or more double bonds).1 As diagrammed in Figure 4-2, fatty acids can be classified according to degree of chain saturation as well as chain length. Although there is no consensus definition for the general terms of short chain (26 carbons), medium chain (812 carbons), and long chain (14 carbons or more), the chain lengths of the fatty acids will contribute to both the physical characteristics of the food and the metabolism of the fat once it enters the body via ingestion, tube feeding, or parenteral nutrition. The shorter the chain and the more unsaturated the chain, the lower the melting point of fat with the result that the fat is more likely to be liquid at room temperature. Thus, an animal product with a significant amount of stearic acid (18 carbons, no double bonds) (Figure 4-1) is solid at room temperature, whereas a medium-chain triglyceride oil (812 carbons) with a significant amount of saturated fatty acids is liquid at room temperature. Olive oil, with a higher percentage of monounsaturated oleic acid (18 carbons, 1 double bond), is a liquid at room temperature.1
Figure 4-1 Structural Representation of a Saturated Fatty Acid
concentration of polyunsaturated fatty acids (PUFAs) in the membrane increases membrane susceptibility to oxidation and peroxidation. Because vitamin E is a major antioxidant in the membrane, an increase in dietary PUFAs should always be accompanied by a careful evaluation of adequate vitamin E intake. Since the fatty acid composition of the membrane reflects the fatty acid composition of the diet, careful attention to the type of fatty acid in the diet is warranted.2 Optimizing the dietary fatty acid profile can alter membrane structure which in turn can possibly alter cell signaling associated with clinical symptomatology.
Figure 4-2 Classification of Fatty Acids
Membrane fluidity is important in the function of many cell types and is greatly influenced by the degree of saturation of the fatty acids in the membrane phospholipids.1 A three-dimensional view of saturated fatty acids reveals that the hydrocarbon chains are straight and thus can be packed very tightly in membrane phospholipids. Most physiological unsaturated fatty acids have cis double bonds (ie, the chains on the same side of the double bond). Every cis double bond puts a kink into the hydrocarbon chain. The result is that the trans-fatty acid (where chains are on the opposite side of the double bond) is a straight hydrocarbon and can be packed very tightly in membranes, reducing membrane fluidity. Phospholipids containing unsaturated fatty acids cannot be packed as tightly, resulting in a membrane with increased fluidity. In the food industry, trans-fatty acids are made from unsaturated fatty acids to both change the consistency of the fat product to a less liquid-like product at room temperature and to increase shelf life by reducing the double bonds that make the fat product susceptible to rancidity. An increased
Essential Fatty Acids

There are two different methods to number the carbons of a fatty acid. The chemist usually begins the numbering with the carboxylic acid carbon. In the field of nutrition, the numbering usually begins with the methyl carbon or omega carbon () which is at the opposite end of the molecule from the carboxylic acid (Figure 4-1). Using the system of numbering, an omega-3 (-3) fatty acid has its first double bond between C3 and C4 from the carbon, an omega-6 (-6) fatty acid has its first double bond between C6 and C7 from the carbon, and an omega-9 (-9) fatty acid has its first double bond between C9 and C10 from the carbon. Humans cannot synthesize -3 or -6 fatty acids, but many physiological processes are dependent on these fatty acids and their myriad products. Therefore -3
24 2
and -6 fatty acids are required in the human diet and are termed essential fatty acids (EFAs).1 The simplest -6 fatty acid is linoleic acid (LA). Humans can convert LA to arachidonic acid (ARA). The simplest -3 fatty acid is -linolenic acid (-LA). Humans can convert -LA to eicosapentaeonic acid (EPA), and EPA very slowly to docosahexaenoic acid (DHA). The same enzyme pool is used to metabolize LA and -LA to their respective longer-chain metabolites. The more prevalent fatty acid is metabolized preferentially. Thus a diet high in the -6 fatty acid LA will preferentially metabolize it over the -3 fatty acid -LA. ARA (20-carbon polyunsaturated -6) and EPA (20-carbon polyunsaturated -3) are released from membranes and further metabolized to a cascade of eicosanoids. Although it is not quite that simple, eicosanoids from -6 fatty acids generally are considered pro-inflammatory and those from -3 fatty acids are considered weakly anti-inflammatory. The docosanoid products of DHA also have anti-inflammatory actions. 3 Fatty acids and eicosanoids can change the abundance of transcription factors which in turn regulate gene expression. Thus, the fatty acid composition of the diet influences the composition of the cell membranes which influences the availability of appropriate substrate to make either pro- or anti-inflammatory fatty acid products. Traditionally low intake of -3 and -6 fatty acids associated with an increase in an -9 fatty acid known as Mead acid in plasma has been used to diagnose EFA deficiency. A more recent method uses red blood cells and measures two additional parameters.4 The emerging field of investigation known as lipidomics measures all small molecular weight lipids in a sample and will likely provide the nutrition community with improved methods for specific EFA evaluation. With the industrialization of Western society, dietary intake of EFAs has changed, reflecting the trend away from grains to more processed foods high in fat. Intake of LA relative to -LA has increased significantly. Currently the ratio of LA to -LA in the diet is 14:1 in contrast to the 2:1 or 1:1 ratio that is usually recommended.2 Interestingly, the change in dietary fat intake follows a similar temporal pattern to the increase in inflammatory bowel disease incidence in the pediatric population. 5
excreted. Diets with excess calories are frequently high in fat because dietary fat is highly palatable and calorically dense. Excess dietary energy from any of the macronutrients is converted to fatty acids and stored as triglycerides in adipocytes. Therefore, surplus dietary calories will increase adipose depots.
Figure 4-3 The Different Functions of Fat
Different Functions of Adipose Tissue

Storage of a metabolic fuel source and structural elements of membranes are the most generally recognized functions of fats. However, a long list of other functions for fat is now recognized (Figure 4-3). Adipose tissue maintains a balance between clearance of plasma triglycerides and release of fatty acids. Excess dietary energy cannot be
Adipose tissue is not simply a place for the body to store fat. Adipose tissue is a complex organ with many different cell types containing receptors sensitive to inflammatory signals. Thus, changing the size of adipose tissue has farreaching effects. When stimulated, adipose tissue releases more than 20 diverse molecules known as adipokines that have a wide range of metabolic effects both during health and disease. Fat deposits can be found in subcutaneous, intramuscular, and intrathoracic depots that differ in fatty acid composition, adipokine secretion, and storage capacity. Macrophage content of adipose tissue can increase from the usual 5% to 10% to as much as 60% during obesity and secrete an increasing amount of inflammatory cytokines. Taken together, obesity can have a striking effect not only on the size but also on the metabolism of the body.2
Importance of Dietary Fat in Infants

The percent of total body weight that is adipose tissue dramatically increases during human gestation. Fetal white adipose tissue increases at a rate of about 67 mg/d during
FATS
25
the last trimester, and most of that is DHA. The brain also grows rapidly during the last trimester and requires a large amount of DHA for the synthesis of myelin. At birth, the brain of the human is at about 50% of its adult size and continues to grow rapidly until it reaches near adult size at about 2 years of age. Thus, the extremely preterm infant born at 24 or 25 weeks gestation requires a large amount of EFAs, and -3 fatty acids in particular, to achieve the type of growth usually experienced by a fetus in utero during the same period postconception.6,7 Regulation of gene expression by nutrients is critically important in preterm neonates. Regulation of gene expression by -3 fatty acids involves multiple complex processes including regulation of the transcription factors sterol regulatory element-binding proteins (SREBPs) and peroxisome proliferator-activated receptors (PPARs) that modulate many critical steps in metabolism.8,9 The two most abundant long-chain PUFAs in the brain are DHA and ARA. DHA is concentrated in the prefrontal cortex and in some retinal cells.10 Inadequate intake of -3 fatty acids not only results in decreased brain DHA but also increased brain -6 fatty acid concentration.11,12 Worldwide there are a variety of enteral products that vary in their supply of -3 fatty acids and in DHA in particular. However none of them provide the amount of EFAs that would accumulate in the fetal brain during the last trimester of gestation without additional supplementation. Thus, the current diet provided to these infants appears to be deficient in DHA. Although it is not known how these infants would develop if fed to sufficiency, preterm infants fed increased amounts of DHA have been reported to have improved visual acuity and mental development.13,14 A recent multicenter prospective, randomized, double-blind placebo-controlled trial in Italy compared 580 healthy term neonates receiving 20mg of liquid DHA to 580 healthy term infants receiving placebo with a focus on developmental milestones. The infants receiving DHA were able to sit without support 1week earlier, but there was no difference between groups for hands-and-knees crawling, standing alone, and walking alone.15 It is unclear how these data from healthy term neonates relate to preterm neonates. In infants being fed parenterally, the challenge to provide adequate DHA and ARA is even greater with currently available lipid emulsions approved for use in this population.
Digestion
Because dietary lipids are hydrophobic, they must be hydrolyzed and emulsified to very small micelles before they can be absorbed by the intestine. Lingual and gastric lipases
hydrolyze triglycerides to diglycerides and free fatty acids. After activation by colipase, pancreatic lipase hydrolyzes dietary fat to 2-monoglycerides which are poor substrates for continued hydrolysis.16 Gastric lipolysis is incomplete in adults, being responsible for 30% or less of dietary fat lipolysis.17 Since neonates have limited expression of pancreatic enzymes needed for fat digestion in the intestine, it has been assumed that gastric lipolysis has a more important role in neonates.18 Supplementation of infant formula with medium-chain triglycerides (MCTs) has been reported to have conflicting effects on intragastric lipolysis in infants (no effect versus decreased lipolysis).19 This may be related to differences in the MCT concentration of the formula studied.20 The pH increases as the acidic stomach contents move to the intestine. The free fatty acid products of gastric lipase are ionized and become oriented to the outside of the oil droplets, surrounding the oil droplet with charge and stabilizing the emulsion. Some of the free fatty acids dissociate from thedroplet and interact with the intestinal epithelium. These fatty acids are potent stimuli of cholecystokinin (CCK) release. CCK stimulates an increase in pancreatic enzymes, relaxes the sphincter of Oddi which allows the pancreatic juice to flow into the intestinal lumen, and contracts the gallbladder to provide a bolus of concentrated bile needed to form micelles.17 Secreted bile contains bile salts made in the liver that emulsify the products of lipid digestion. The resulting micelles transport the digested fat products through the aqueous intestinal lumen making close contact with the brush border of the mucosal cells. Bile salts continue to the ileum where they are absorbed into the enterohepatic circulation.16 Phospholipase A 2 from the pancreas cleaves the fatty acid in the 2 position of dietary phospholipids. Pancreatic juice also contains cholesterol esterase that hydrolyzes cholesterol esters, esters of vitamins A, D, and E, and all 3 fatty acids in triglycerides.17 Cystic fibrosis (CF) affects many aspects of metabolism, including adequate secretion of pancreatic enzymes for dietary fat absorption. Administration of pancreatic enzyme supplements can assist with the problem. Careful monitoring is required to assure that children with CF do not develop EFA deficiency or deficiency in fat-soluble vitamins. Breast milk lipase produced by the mammary gland of lactating females is similar to cholesterol esterase. Breast milk lipase also has broad specificity and may predigest the lipid components of breast milk and thus increase the efficiency of theiruptake.17,19
26
Absorption
Bile acids play an important role in solubilizing the products of lumenal lipolysis and facilitating their transfer to the absorptive epithelium. Fatty acids and monoglycerides have enough solubility in the lumenal contents that they can diffuse to the brush border and be absorbed.16 The intestinal epithelium is the site of significant metabolic activities. The absorbed 2-monoglycerides are re-acylated to triglycerides. Some 1-monoglycerides in the emulsion are absorbed and hydrolyzed to fatty acids and glycerol. The glycerol released within the intestinal epithelium is reutilized for triglyceride synthesis. Long-chain fatty acids (LCFAs) are esterified to triglycerides, secreted into the lymphatics as chylomicrons, and enter the blood via the thoracic duct. Free short- and medium-chain fatty acids are absorbed into the hepatic portal vein.16
EPA, and DHA.22,23 The optimal ratio of preformed EPA and DHA has not been established, but ratios of 1:2 to 2:1 are expected to be effective.24
Beta-Oxidation of Long-Chain Fatty Acids inMitochondria

Lipoprotein lipase in the capillary endothelium releases free fatty acids delivered to tissues by chylomicrons. Hormonesensitive lipase mobilizes triglycerides from adipose tissue when needed. The fatty acids are carried in the blood bound to albumin and delivered to the tissues to use for fuel. When fatty acids are to be used for fuel, they are activated to the fatty acyl-CoA at the outer mitochondrial membrane. Fatty acyl-CoA is the correct high-energy state for beta-oxidation (-oxidation), but the enzymes for -oxidation are located within the mitochondrial matrix (Figure 4-4) and the fatty acyl-CoA cannot cross the inner membrane of the mitochondria to reach these enzymes. In order to use LCFAs for metabolic energy, fatty acyl-CoA is converted to fatty acylcarnitine via carnitine palmitoyltransferase 1, transported across the inner mitochondrial membrane via carnitineacylcarnitine translocase in exchange for free carnitine, and reconverted to fatty acyl-CoA in the matrix of the mitochondria via carnitine palmitoyltransferase 2. The end result is that the high-energy fatty acyl-CoA is now in the same location as the metabolic machinery for -oxidation. Fatty acid oxidation and fatty acid synthesis do not occur at the same time because malonyl-CoA (an early intermediate in fatty acid synthesis) inhibits carnitine palmitoyltransferase1 and thus prevents the fatty acyl-CoA from reaching the site of -oxidation.1,25
Figure 4-4 Sites of Fatty Acid Oxidation
Metabolism During Normal Physiology
Dietary fat can enter a diverse set of metabolic pathways intricately controlled and coordinated to meet the needs of the body. The cell can either oxidize fatty acids for immediate metabolic energy or synthesize fatty acids from other dietary components and store them for later use.
Synthesis of Fatty Acids

Excess calories in the form of protein, carbohydrate, or fat cannot be eliminated from the body once ingested or administered and must be stored in the form of fatty acids. Six cytosolic enzymes plus an acyl carrier protein (ACP) are needed for fatty acid synthesis from acetyl-coenzyme A (acetyl-CoA). In the first step, malonyl-CoA is formed from acetyl-CoA which has been shuttled out of the mitochondria. This reaction-forming malonyl-CoA is the regulatory step for fatty acid synthesis. The sequence of reactions that follows is a condensation, a reduction, a dehydration, and a second reduction. Both reduction reactions use nicotinamide adenine dinucleotide phosphate (NADPH) as the electron donor. The sequence of reactions adds 2 carbons at a time and is repeated until a chain length of about 16 carbons is made and released from the ACP.1 As discussed in the Essential Fatty Acids section, humans cannot synthesize LA or LA. Although humans have the necessary enzymes to make EPA from -LA and DHA from EPA, the capacity to do so is very low.21 Only about 5% of -LA can be converted to EPA and less than 0.5% of -LA can be converted to DHA. There is also a low capacity to convert LA to ARA. Thus, although only LA and -LA are termed EFAs, the administration of only LA or -LA often has only a negligible effect on plasma ARA,
FATS
27
Patients with high plasma levels of triglycerides are sometimes given heparin (assuming that it will stimulate lipolysis of triglycerides) and carnitine (assuming it will stimulate -oxidation of the released fatty acids). Definitive data to confirm these assumptions in patients on special nutrition support are yet to be obtained. In addition, it should be remembered that supplemented heparin and carnitine each have a variety of effects on the bodys metabolism.
shortened fatty acyl-CoA and acetyl-CoA. When the fatty acyl-CoA is a medium-chain fatty acyl-CoA, the oxidation sequence stops. Acetyl-CoA and the medium-chain fatty acyl-CoA must be transported out of the peroxisome via a carnitine shuttle. The medium-chain fatty acyl carnitine is transported into mitochondria to complete the oxidation to acetyl-CoA.1
Beta-Oxidation of Medium-Chain Fatty Acids inMitochondria

In liver cells, medium-chain fatty acids (MCFAs) are transported into mitochondria (Figure 4-4) as free fatty acids and then activated to medium-chain fatty acyl-CoA. Therefore, oxidation of MCFAs is carnitine independent in the liver. However, other tissues activate MCFAs to mediumchain fatty acyl-CoA on the cytoplasmic side of the inner mitochondrial membrane and require the carnitine shuttle for -oxidation.26,27 Thus, if dietary MCFAs are provided in quantities where they are expected to be a fuel substrate for skeletal muscle, carnitine will be required for their oxidation.
Omega-Oxidation of Fatty Acids

Omega-oxidation of fatty acids occurs in the endoplasmic reticulum in the cytoplasm (Figure 4-4). The omega carbon is first converted to an alcohol by a cytochrome P450 mixed function oxidase which requires both oxygen and NADPH. Alcohol dehydrogenase and aldehyde dehydrogenase convert the alcohol to a carboxylic acid on the omega carbon. Thus, the fatty acid is converted to a dicarboxylic acid which can be esterified to carnitine and transported to the mitochondrial matrix. There it can enter the -oxidation pathway to be shortened at both ends of the molecule at the same time. Omega-oxidation of fatty acids is normally a minor pathway. Dysfunctional -oxidation in the mitochondria will increase omega-oxidation.28
Steps of Beta-Oxidation
In mitochondria, 4 repeating reactions (dehydrogenation requiring flavin adenine dinucleotide (FAD), hydration, dehydrogenation requiring nicotinamide adenine dinucleo tide (NAD), and cleavage requiring CoA) produce a fatty acyl-CoA shortened by 2 carbons and acetyl-CoA. The shortened fatty acyl-CoA reenters the sequence and the acetyl-CoA is oxidized to carbon dioxide in the citric acid cycle. The citric acid cycle coupled to the oxidative phosphorylation pathway yields metabolic energy as adenosine triphosphate (ATP). Oxidation of unsaturated fatty acids requires 2 additional enzymes in the mitochondria to oxidize the double bonds.1
Metabolism During Pathophysiologies
Many chronic pathological conditions, including type 2 diabetes, hypertension, atherosclerosis, and obesity, are associated with altered fat metabolism. In some situations, inappropriate dietary fat quantity and/or composition contribute to the observed pathology.
Fat As Fuel for Preterm Infants

Early introduction of lipid emulsions to preterm neonates has not been shown to increase complications, 29 but also has not been shown to improve short-term growth or prevent morbidity and mortality. 30 An emulsion with a mixture of medium-chain and long-chain fatty acids appears to be superior to an emulsion containing only LCFAs in terms of incorporation of EFAs and long-chain PUFAs into circulating lipids. 31 Adequate energy intake during the first days of life is associated with improved brain function. A recent study of 148 extremely low-birth-weight survivors showed that every 42 kJ (10 kcal)/kg/d provided during the first postnatal week is associated with a 4.6 point increase inthe Mental Development Index. 32
Beta-Oxidation of Very Long-Chain Fatty Acids inPeroxisomes

Peroxisomes are subcellular organelles in the cytoplasm that carry out -oxidation in 4 repeating steps similar to those in the mitochondria. The difference is that the first reaction transfers electrons directly to oxygen-producing hydrogen peroxide. Peroxisomes oxidize very LCFAs (Figure 4-4) and branched fatty acids. Fatty acids enter the peroxisome before they are esterified to fatty acyl-CoA, so the carnitine shuttle is not needed to deliver the fatty acids to the peroxisomes. The very LCFAs are shortened by 2 carbons during each reaction sequence producing the
Lipid Emulsions Containing Fish Oils As Fuel forParenteral Nutrition In Pediatrics

As discussed earlier, -3 fatty acids including EPA and DHA (sometimes called fish oils) have several important functions
28
in the body both during health and disease. Twelve children with pediatric short bowel syndrome who developed parenteral nutrition-associated liver disease received parenteral -3 fatty acids while awaiting liver transplant. They showed restoration of liver function to the point that 9 of the children were no longer considered for liver transplant. The remaining 3 children received a liver transplant with no complications attributable to the -3 emulsion. 33 In another study, 18 infants who developed cholestasis while receiving a parenteral emulsion high in -6 fatty acids were switched to an emulsion high in -3 fatty acids and compared to 21 historical controls who had similar symptoms and had been maintained on the -6 fatty acid emulsion. Patients receiving the -3 fatty acids experienced a reversal of cholestasis 6.8 times faster when the data were adjusted for baseline bilirubin concentration, gestational age, and diagnosis of necrotizing enterocolitis. The -3 fatty acid cohort had had 2 deaths and no liver transplants and the historical control cohort had 7 deaths and 2 liver transplantations. 34 Parenteral lipid emulsions containing fish oil are still not approved for use in children or available in the United States and Canada.
fatty acid catabolism, resulting in a situat ion some have termed glucolipotoxicity.23 Intake of excess carbohydrate increases cellular malonyl-CoA concentrations which in turn inhibits carnitine palmitoyltransferase 1 activity, impairing -oxidation of fatty acids. Insulin resistance is associated not only with the intake of excess calories but also with high intakes of saturated fat. Substituting saturated fat with unsaturated fat seems to improve insulin sensitivity. 35
Figure 4-5 Path to Lipid Overload or Lipotoxicity
To Esterify or To Oxidize: That Is the Cells Question

The ability to synthesize or to oxidize fatty acids allows the cell to store excess calories as fat and to mobilize the stored fatty acids for metabolic fuel which is a life-saving adaptation during times of starvation. When products of digested macronutrients enter the cell during normal physiological situations, the cell responds to metabolic signals indicating the metabolic fuel status of the cell and either uses the fuel substrates to produce needed metabolic energy or stores the fuel substrate as fatty acids in triglycerides. If excess calories are chronically delivered to the cell, however, the ability of adipose tissue to serve as a sink and protect non-adipose tissues from fatty acid spillover appears to become saturated. As diagrammed in Figure 4-5, the result is lipid overload or lipotoxicity that overwhelms the abilities of both the endoplasmic reticulum and mitochondria to maintain cellular homeostasis and results in systemic release of both free fatty acids and inflammatory cytokines. Accumulation of fatty acids in skeletal muscle, heart, liver, and pancreas is likely the underlying factor during the development of insulin resistance, cardiomyopathy, liver steatosis, and type 2 diabetes. During normal physiological conditions, there is intricate coordination of the use of fatty acids for energy and the use of glucose for energy. Likewise during chronic intake of excess calories, excess lipids inhibit the utilization of glucose and hyperglycemia interferes with
Metabolism of dietary fat is altered in overweight patients. For example, overweight patients with a fatty liver have a higher postprandial triglyceride response and an increased production of large very low-density lipoproteins after a fat load compared to control subjects. 36 When providing nutrition support, it is important not only to provide appropriate calories for the specific patient, but to carefully evaluate how the patients current metabolic status may impact the bodys metabolism of the nutritional fat substrate provided.
FATS
29
1. In order to maintain health and prevent a home parenteral nutrition patient from becoming overweight, the optimal nutrition support prescription: A. Restricts fat to an absolute minimum while providing a generous amount of glucose. B. Provides adequate calories including a fatty acid blend with appropriate chain length, chain saturation, and ratios of LA, -LA, ARA, EPA, and DHA. C. Provides 80% of the calories recommended for oral intake. D. Provides all the fat calories as the essential fatty acids LA and -LA. 2. The cellular site(s) for fatty acid oxidation in the body is (are): A. Mitochondria B. Peroxisomes C. Cytoplasm D. Mitochondria, peroxisomes, and cytoplasm 3. The essential fatty acid needs of a critically ill 24-week neonate in the neonatal intensive-care unit requires dietary: A. LA and -LA B. -LA and DHA C. LA and ARA D. LA, -LA, ARA, and DHA See p. 487 for answers.
References
1. Nelson DL, Cox MM. Lehniger Principles of Biochemistry. 5th ed. New York, NY: W.H. Freeman and Co; 2008. 2. Innis SM. Dietary lipids in early development: relevance to obesity, immune and inflammatory disorders. Curr Opin Endocrinol Diabetes Obes. 2007;14(5):359364. 3. Fritsche K. Fatty acids as modulators of the immune response. Annu Rev Nutr. 2006;26:4573. 4. Fokkema MR, Smit EN, Martini IA, Woltil HA, Boersma ER, Muskiet FAJ. Assessment of essential fatty acid and omega 3-fatty acid status by measurement of erythrocyte 20:39 (Mead acid), 22:56/20:46 and 22:56/22:63. Prostaglandins Leukot Essent Fatty Acids. 2002;67(5):345356. 5. Innis SM, Jacobson K. Dietary lipids in early development and intestinal inflammatory disease. Nutr Rev. 2007;65(12) (pt 2):S188S193. 6. Marszalek JR, Lodish HF. Docosahexaenoic acid, fatty acid-interacting proteins, and neuronal function: breastmilk and fish are good for you. Annu Rev Cell Dev Biol. 2005;21:633657. 7. Heird WC, Lapillonne A. The role of essential fatty acids in development. Annu Rev Nutr. 2005;25:549571. 8. Deckelbaum RJ, Worgall TS, Seo T. n-3 fatty acids and gene expression. Am J Clin Nutr. 2006;83(6):1520S1525S.
9. Sampath H, Ntambi JM. Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annu Rev Nutr. 2005;25:317340. 10. Agostoni C. Role of long-chain polyunsaturated fatty acids in the first year of life. J Pediatr Gastroenterol Nutr. 2008;47(suppl 2):S41S44. 11. Innis SM. Dietary omega 3 fatty acids and the developing brain. Brain Res. 2008;1237:3543. 12. Novak EM, Dyer RA, Innis SM. High dietary omega-6 fatty acids contribute to reduced docosahexaenoic acid in the developing brain and inhibit secondary neurite growth. Brain Res. 2008;1237:136145. 13. Hay WW Jr. Strategies for feeding the preterm infant. Neonatology. 2008;94(4):245254. 14. Innis SM. Omega-3 Fatty acids and neural development to 2 years of age: do we know enough for dietary recommendations? J Pediatr Gastroenterol Nutr. 2009;48 (Suppl 1):S16S24. 15. Agostoni C, Zuccotti GV, Radaelli G et al. Docosahexaenoic acid supplementation and time at achievement of gross motor milestones in healthy infants: a randomized, prospective, double-blind, placebo-controlled trial. Am J Clin Nutr. 2009;89(1):6470. 16. Bender DA, Mayes PA. Nutrition, digestion, & absorption. In: Murray RK, Granner DK, Rodwell VW, eds. Harpers Illustrated Biochemistry. 27th ed. New York, NY: McGraw-Hill; 2006. 17. Barrett KE. Lipid assimilation. In: Barrett KE, ed. Gastrointestinal Physiology. New York, NY: McGraw-Hill; 2006. 18. Hamosh M. Digestion in the newborn. Clin Perinatol. 1996;23(2):191209. 19. Hernell O, Blackberg L. Human milk bile salt-stimulated lipase: functional and molecular aspects. J Pediatr. 1994;125(5) (pt 2):S56S61. 20. Hamosh M, Bitman J, Liao TH, et al. Gastric lipolysis and fat absorption in preterm infants: effect of medium-chain triglyceride or long-chain triglyceride-containing formulas. Pediatrics. 1989;83(1):8692. 21. Russo GL. Dietary n-6 and n-3 polyunsaturated fatty acids: from biochemistry to clinical implications in cardiovascular prevention. Biochem Pharmacol. 2009;77(6):937946. 22. Plourde M, Cunnane SC. Extremely limited synthesis of long chain polyunsaturates in adults: implications for their dietary essentiality and use as supplements. Appl Physiol Nutr Metab. 2007;32(4):619634. 23. Brenna JT, Salem N Jr, Sinclair AJ, Cunnane SC. alpha-Linolenic acid supplementation and conversion to n-3 long-chain polyunsaturated fatty acids in humans. Prostaglandins Leukot Essent Fatty Acids 2009;80(2-3):8591. 24. Harris WS, Mozaffarian D, Lefevre M, et al. Towards establishing dietary reference intakes for eicosapentaenoic and docosahexaenoic acids. J Nutr. 2009;139(4):804S819S. 25. Rasmussen BB, Wolfe RR. Regulation of fatty acid oxidation in skeletal muscle. Annu Rev Nutr. 1999;19:463484. 26. Groot PHE, Hulsmann WC. The activation and oxidation of octanoate and palmitate by rat skeletal muscle mitochondria. Biochim Biophys Acta. 1973;316:124135. 27. Rssle C, Carpentier YA, Richelle M, et al. Medium-chain triglycerides induce alterations in carnitine metabolism. Am J Physiol Endocrinol Metab. 1990;258:E944E947.
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28. Croston G. BioCarta omega oxidation pathway. http://www. biocarta.com/pathfiles/omegaoxidationPathway.asp. 2009. Accessed July 1, 2009. 29. Drenckpohl D, McConnell C, Gaffney S, Niehaus M, Macwan KS. Randomized trial of very low birth weight infants receiving higher rates of infusion of intravenous fat emulsions during the first week of life. Pediatrics. 2008;122(4):743751. 30. Simmer K, Rao SC. Early introduction of lipids to parenterally-fed preterm infants. Cochrane Database Syst Rev. 2005;(2);CD005256. 31. Krohn K, Koletzko B. Parenteral lipid emulsions in paediatrics. Curr Opin Clin Nutr Metab Care. 2006;9(3):319323. 32. Stephens BE, Walden RV, Gargus RA, et al. First-week protein and energy intakes are associated with 18-month developmental outcomes in extremely low birth weight infants. Pediatrics. 2009;123(5):13371343.
33. Diamond IR, Sterescu A, Pencharz PB, Kim JH, Wales PW. Changing the paradigm: omegaven for the treatment of liver failure in pediatric short bowel syndrome. J Pediatr Gastroenterol Nutr. 2009;48(2):209215. 34. Gura KM, Lee S, Valim C, et al. Safety and efficacy of a fish-oil-based fat emulsion in the treatment of parenteral nutrition-associated liver disease. Pediatrics. 2008;121(3):e678e686. 35. Riserus U. Fatty acids and insulin sensitivity. Curr Opin Clin Nutr Metab Care. 2008;11(2):100105. 36. Assy N, Nassar F, Nasser G, Grosovski M. Olive oil consumption and non-alcoholic fatty liver disease. World J Gastroenterol. 2009;15(15):18091815.
Protein Digestion, Absorption, andMetabolism

Richard A. Helms, PharmD, Emma M. Tillman, PharmD, Anup J. Patel, MD, and John A. Kerner, MD
CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ontogeny of the Gastrointestinal Tract inRelation to Protein. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Protein Digestion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Protein Absorption. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Digestion and Absorption of Whey and Casein . . . . . . . . . Amino Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conditionally Essential Amino Acids Amino Acids of the Urea Cycle Useful Classification of Amino Acids for the Clinician 31 31 32 33 34 35
Learning Objectives
1. Explain how protein metabolism and physiology is profoundly affected by the ontogeny of the gastrointestinal tract. 2. Describe the roles of the liver and kidney in amino acid metabolism. 3. Understand the functions of amino acids and proteins, protein requirements for age, and protein energy ratios during growth. 4. Discuss protein turnover, assessment of plasma amino acids, and nitrogen balance.
Liver and Kidney: Roles in Amino AcidMetabolism. . . . . . 38 Functions of Amino Acids and Proteins . . . . . . . . . . . . . . . 39 Protein Requirements and Protein-Energy Ratio DuringGrowth. . . . . . . . . . . . . . . . . . 40
Assessment of Protein Status Monitoring Plasma Amino Acids
Introduction
Case Presentation and Discussion. . . . . . . . . . . . . . . . . . . 41
There is an extraordinary range of knowledge related to protein in human nutrition. The basics of protein in adult nutrition have been nicely reviewed in The A.S.P.E.N. Nutrition Support Core Curriculum, and materials covered in that publication will not be extensively revisited here.1 Because this chapter is restricted to protein in pediatrics, it will focus particularly on the rapidly developing neonate and infant. Ontogenic events relating to protein metabolism and physiology render the small child as much different than the older child and adult. This chapter will review aspects of digestion, absorption, and metabolism of protein focusing on these differences.
Ontogeny of the Gastrointestinal Tract inRelation to Protein
The gastrointestinal (GI) tract has been described as the largest endocrine organ. It produces numerous regulatory gut peptides that are involved in GI tract development, growth, absorption, secretion, and gut motility. They function in classic endocrine, autocrine, paracrine, and
31
32
neurocrine pathways.2,3 Selected gastrointestinal regulatory peptides involved with the ontogeny of the GI tract as it relates to proteins are outlined in Table 5-1. All of these peptides are present by the end of the first trimester in the fetus, but adult levels may not be present until term.4 These peptides that function as hormones are released in response to feeding. The release of some of these hormones is limited in the newborn compared to the adult.4,5 There are significant differences in the ontogeny of the two main enzymes secreted by the gastric mucosa. In the human, even though both pepsin and gastric lipase are located at the same site (ie, in the chief cells of the gastric mucosa), the enzymes have different developmental patterns.6 Pepsin activity and output are much lower in infants than adults.7,8 In contrast, gastric lipase activity and output are equal in infants and adults.7,8 The ontogeny of the brush border amino-oligopeptidases as well as the dipeptide and amino acid transport systems parallel that of the carbohydrate enzymes. Aminooligopeptidases are first detected immunohistochemically by 10 to 16 weeks gestation. By 28 to 30 weeks gestation, enzyme levels are approximately one-half of the values found in term infants. Therefore, all aspects of intestinal
proteolysis and transport are relatively intact, even in the preterm infant.9 Initial protein digestion occurs in the stomach, where proteins are exposed to hydrochloric acid (HCl) and pepsin. Gastric acid produces an acidic environment in the stomach, and denatures protein.10,11 Although protein digestive activity within the GI tract has been identified as early as 16 weeks gestation, there are relatively low amounts of gastric acid secretion and consequently less protein denaturation in both preterm and term infants. In fact, there is relatively minimal functional protein digestion in the stomach in the first few weeks of life. It is not until about 2 years of age that adult levels of gastric acid secretion are reached.9 Chief cells secrete proenzymes (pepsinogen 1 and 2) into the stomach, which undergo auto-activation to form pepsins in the acidic milieu.12 This acidic environment is critical for pepsin function as evidenced by its inactivity in the duodenum, where the pH is neutral.13 These pepsins function as endopeptidases; they hydrolyze internal bonds of the polypeptides to primarily form shorter polypeptides, oligopeptides, and some free amino acids.9,11 Gastrin
Protein Digestion
Table 5-1 Gastrointestinal Regulatory Peptides2

Regulatory Peptide Sources Mechanisms Actions
Epidermal Growth Factor
Salivary glands Brunner glands Paneth cells Gastrointestinal tract Liver Ileum Colon Ileum Central nervous system All tissues Pancreas Proximal small intestine Gastrointestinal tract Central nervous system
Hormone Paracrine Hormone Autocrine Paracrine Hormone Hormone Neurocrine Neurocrine Hormone Hormone Hormone Paracrine Neurocrine
Stimulates mucosal proliferation and differentiation Regulates gastrointestinal secretion Has cytoprotective/ulcer-healing effects Stimulates crypt cell proliferation and enterocyte differentiation Promotes intestinal adaptation Stimulates gut mucosal growth Regulates gut motility Inhibits gastric emptying and acid secretion Promotes secretomotor, vasodilatation, and smooth musclerelaxation Inhibits pancreatic enzyme secretion and gallbladder contraction Stimulates gastrointestinal motility Inhibits gastric acid secretion and gut motility
Insulin-like Growth Factor
Enteroglucagon Neurotensin Vasoactive Intestinal Polypeptide Pancreatic Polypeptide Motilin Peptide YY
Reprinted from Gilger MA. Normal gastrointestinal function. Table 342-1. In: McMillan JA, Feigin RD, DeAngelis C, Jones MD, eds. Oskis Pediatrics. 4th ed. Copyright 2006 with permission from Lippincott Williams & Wilkins.
PROTEIN DIGESTION, ABSORPTION, ANDMETABOLISM
33
stimulates both gastric acid and pepsin production and secretion, which initiates protein digestion in the stomach.10 The protein denaturation within the stomach does not appear to be critical because patients with a more neutral gastric pH do not have impaired protein digestion. However, the amino acids that are produced from protein digestion in the stomach do assist in releasing cholecystokinin (CCK) or pancreozymin.12 CCK has a role in protein digestion by helping to release pancreatic digestive enzymes, stimulate gallbladder contraction, and relax the sphincter of Oddi.11,12 In contrast, the hormone secretin promotes pancreatic secretion of bicarbonate-rich fluid to help establish a favorable pH.10 The pancreatic digestive enzymes are secreted in their inactive proenzyme form, similar to the secretion of pepsin as pepsinogen in the stomach. The pancreas secretes both endopeptidases (trypsinogen, chymotrypsinogen, and proelastase) and exopeptidases (procarboxypeptidase A and B) into the proximal small intestine.11 The activated endo- and exopeptidases hydrolyze the proteins at peptide bonds within the polypeptide chains to form oligopeptides and at the carboxyl terminal to form single amino acids, respectively.911 Bile acids and trypsinogen together cause the release of enterokinase, a brush border enzyme, which converts trypsinogen into its active form trypsin. Trypsin then converts the remaining pancreatic peptidases into their respective active forms (chymotrypsin, elastase, and carboxypeptidase A and B), and assists in forming more trypsin from trypsinogen (see Figure 5-1).9,10,13 Overall, the products of lumenal protein digestion are about 70% oligopeptides and 30% free amino acids.9 Enterokinase and trypsin have been detected at 26 and 28 weeks gestation, respectively. Enterokinase levels at time of birth are about 10% of adult levels except in those rare infants with congenital enterokinase deficiency.9,14 Trypsin activity in duodenal juice of the premature infant is slightly less than in the full-term infant but does increase in response to food as it does in full-term infants. Infants have been found to have decreased trypsin activity in duodenal fluid compared to older children.15 This reduced trypsin activity has been demonstrated to increase over the first 4 months of life, possibly resulting from their relative increased enteral protein intake.9 However, the significance of these differences is unclear given that protein digestion and absorption is fairly efficient even in preterm infants. It is estimated that term infants digest and absorb about 80% to 85% of lumenal proteins while estimates for adults range from 95% to 98%.9,11
Figure 5-1 Pancreatic Enzyme Activation10
Reprinted from Wahbeh GT, Christie DL. Basic aspects of digestion and absorption. In: Wyllie R, Hyams JS, eds. Pediatric Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 3rd ed. Copyright 2006 with permission from Elsevier.
Normal protein absorption involves lumenal processing, absorption into the intestinal mucosa, and transport into the circulation.12 At the brush border of enterocytes, there are different types of peptidases, including oligopeptidases, that further hydrolyze the partially digested proteins into amino acids, dipeptides, and tripeptides (see Figure 5-2).9,10,12,16 Oligopeptidases have been detected as early as 10 to 16 weeks gestation, and they increase to nearly half of full-term levels by 28 to 30 weeks gestation.9 Absorption into the enterocyte involves both sodiumdependent and -independent transport systems.9 The sodium-dependent amino acid transporters are driven by a low intracellular sodium concentration and negative intracellular potential resulting from the sodium-potassium-adenosine triphosphatase (Na+-K+ ATPase) pump.12 There are many different transporters including those for neutral, acidic, and basic amino acids with narrow substrate specificity, and for di- and tripeptides with a broad substrate specificity (see Figure 5-3).9,10,12,16 Once the amino acids are transported into the cytoplasm, there is additional processing by cytoplasmic peptidases, mostly dipeptidases and tripeptidases, which convert the di- and tripeptides into free amino acids.10,12,13 Although most of these amino acids are transported into the blood stream, it is estimated that about 10% of amino acids, particularly glutamine and glutamic acid, are used directly by the enterocyte.10,13 This coincides with the observation that animals receiving total parenteral nutrition without enteral feeds have developed mucosal atrophy.10 Some of the sodium-independent amino acid transporters are located on the basolateral surface of the enterocyte, and function to transport amino acids into the
Protein Absorption
34
Figure 5-2 Overview of Protein Digestion and Absorption
Reprinted from Roy CC, Silverman A, Alagille D. Pediatric Clinical Gastroenterology. Malabsorption syndrome. p. 307. (Modified and published with permission from Ahnen DJ. Protein digestion and assimilation. In Yamada T, et al. Textbook of Gastroenterology, Philadelphia. 1991. Lippincott.) Copyright 1995 with permission from Elsevier.
portal vein.9 Although a significant majority of the protein that enters the portal circulation is in the form of free amino acids, there are small amounts of di- and tripeptides that enter the blood stream intact through normal transport systems.10 Studies have shown that an infants intestine may have a higher capacity for absorption of macromolecules than the adult intestine.17 Thus, among susceptible infants, for example infants who sustain severe post-infectious villous injury, the early introduction of specific foods of increased antigenic potential may increase their risk of protein sensitization.18,19 Given the broad substrate specificity for di- and tripeptidases at the brush border, it is not surprising that clinically significant deficiencies resulting from specific amino acid transport abnormalities are uncommon. Two of the more well-known inherited defects of protein absorption include Hartnup syndrome and cystinuria. In Hartnup syndrome, neutral amino acid transport is defective and patients present with pellagra-like skin eruptions. In cystinuria (see Chapter 24), there is a defect in cystine reabsorption resulting in excessive cystine in the urine and subsequent renal stone formation. In contrast, acquired defects of protein absorption, including exocrine pancreatic insufficiency and transient brush border enzyme deficiency from gastroenteritis, are more common.8
Figure 5-3 The Transport of Amino Acids
Reprinted from Roy CC, Silverman A, Alagille D. Pediatric Clinical Gastroenterology. 4th ed. Copyright 1995 with permission from Elsevier.
Digestion and Absorption of Whey and Casein
The major proteins in milk are whey and casein. Unmodified cows milk is approximately 18% whey and 82% casein. When this unheated casein-predominant protein enters the acidic environment of the stomach, it forms a relatively hard curd of casein and minerals that can be difficult to digest. In contrast, human milk protein is approximately 60% to 70% whey and 30% to 40% casein.20,21 Human milk forms a very small, soft curd in acid. Some infant formula companies have developed whey-predominant formulas by combining equal amounts of demineralized whey protein
35
and skim milk protein to yield a formula with 60% whey and 40%casein. There are other important differences between these two types of proteins. Whey results in a faster gastric emptying time, and is overall more easily digested. In contrast, casein is less soluble and has a slower rate of digestion, which results in an extended release of amino acids into the circulation. In human studies, casein-predominant formulas result in lower zinc bioavailability than whey-predominant formulas, presumably because of less complete digestion of casein.22 Other types of human whey proteins include secretory IgA and lactoferrin.21 Secretory IgA attaches to the lining of the GI tract and prevents potential pathogenic microorganisms from adhering.9 Lactoferrin is an iron-binding protein that limits the ability of bacteria to thrive in the intestines. Because this protein is biochemically similar to transferrin, it is suggested that it may have a significant role in iron absorption. However, in vivo studies do not definitively establish this role.23 Also, there is some evidence that suggests that lactoferrin has a role in stimulating intestinal mucosa growth.24 These two proteins found in human milk, secretory IgA and lactoferrin, and the main protease inhibitors, alpha 1-antitrypsin and alpha 1-antichymotrypsin, are not well-digested in early infancy.24,25 In fact, it has been estimated that about 10% of intact milk proteins have been found in infant stools prior to 1 month of age while this decreases to about 3% at 4 months of age.24 In vitro studies suggest that alpha 1-antitrypsin resists proteolysis by pepsin and pancreatic enzymes.24,26 Alpha 1-antitrypsin has been found in considerable quantities in both human milk and in the stool of infants fed human milk; therefore it should not be used to ascertain enteric protein loss in breastfed infants.26 Overall, infant formulas traditionally contain more protein than human milk due to the concern that proteins found in infant formulas are less digestible. This is supported by the observation that formula-fed infants have higher blood urea nitrogen (BUN) levels due to the higher exposure to proteins. These formulas also have a higher proportion of whey, which should increase their digestibility. In addition, it is important to note that heat treatment of milk proteins does affect their digestibility. It has been observed that protein digestibility in powdered formulas is increased in comparison to identical liquid solutions. The heat treatment for powdered formulas is less intense than liquid formulas with a lower maximum temperature and shorter duration. As a result, protein digestibility is increased with less intense heat treatment.24
Amino Acids
There are literally hundreds of amino acids found in nature, but only 20 are considered relevant in human nutrition. Lafayette B. Mendel (1872-1935) demonstrated for the first time that some amino acids cannot be synthesized in rats, and, hence, defined them as essential amino acids required in their diet. In an amazing series of experiments completed in the 1940s and 1950s, William C. Rose (1887-1985, who completed his training under Mendel) and co-investigators determined the amino acid requirements of normal adults.27 These experiments revealed 8 amino acids that resulted in negative nitrogen balance when excluded from the diet. Upon resumption of these amino acids in adequate amounts, there was a complete reversal of the negative nitrogen balance. These 8 amino acids are isoleucine, leucine, valine, lysine, methionine, phenylalanine, threonine, and tryptophan (Table 5-2). Other amino acids could be withheld without appreciable effect on nitrogen balance. Studies have confirmed these findings in infants and schoolage children.
Table 5-2 Essential, Non-Essential, and Conditionally Essential Amino Acids in the Human Nutrition
Essential Conditionally Essential Non-Essential
Histidine* Isoleucine Leucine Lysine Methionine Phenylalanine Threonine Tryptophan Valine
Cyst(e)ine Taurine Tyrosine
Alanine Aspartic Acid Asparagine Glutamic Acid Glutamine Glycine Proline Serine Arginine
Cyst(e)ine = sum of cysteine and cystine. Glycine and Serine carbon skeletons can be readily synthesized by neonates and infants, but the rate of transamination is low. * Not initially identified by Rose as being an essential amino acid. Laidlaw-Kopple classification as acquired indispensible (see Table 5-4).
Amino acids are capable of existing in two isomeric forms. The L-amino acids are utilized in humans and most animals. The stereoselectivity is related to enzymes that only recognize and utilize the L isomer. Amino acids do exist as D isomers, but only D-methionine can be converted to L-methionine by some animals, but not humans. For the rest of this chapter the authors will not identify amino acids as the L isomer; one can assume the L isomer is being discussed.
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Conditionally Essential Amino Acids

Investigations that followed Roses extraordinary work generated questions as to whether other amino acids may be required in the diet under certain conditions of immaturity, metabolic imbalance, organ failure, disease, and highly defined diets such as parenteral nutrition (PN). Histidine is now considered essential in the human diet. While the original exclusion studies by Rose did not demonstrate negative nitrogen balance, Nasset was able to demonstrate that the hemoglobin of Roses subjects fell while on histidine-free diets.28 These investigators calculated that the loss of hemoglobin was sufficient to supply the subjects with 240 mg/d of histidine. Histidine stores are particularly high in hemoglobin and in carnosine (found in large quantities in muscle). Observations by Kopple confirmed these findings.29,30 It is widely accepted that histidine is the ninth essential amino acid in humans (Table 5-2). Snyderman established histidine intake requirements in infants of 24 mg/kg/d, which is generally less than other essential amino acids. 31 In studies by Heird, the histidine requirements in neonates and infants on PN were greater than demonstrated by these earlier studies and than predicted from older child and adult requirements (adjusted by kilogram of weight). 32,33 The Guidelines for the Use of Parenteral and Enteral Nutrition in Adult and Pediatric Patients34 states that histidine is a conditionally essential amino acid for neonates and infants up to 6 months of age. Sulfur amino acid requirements of infants and children have been an area of intense research. The sulfur amino acids include methionine (defined as essential by Rose) and cysteine and taurine (both defined as nonessential in adults by Rose). Cysteine contains a free sulfhydryl group, and is oxidized with another cysteine moiety to form the dimer cystine. After cysteine is incorporated into newly synthesized protein, the formation of cystine dimers aid in proper protein folding and stability. Cysteine is metabolized from methionine, and can replace 50% to 80% of methionine intake. Because it can reduce the intake of an essential amino acid, it has been classified as a conditionally essential amino acid by Jackson. 35 Snyderman36 defined intakes of cysteine in infants at 85 mg/kg/d, similar to many of the essential amino acids. Pohlandt37 discovered that the requirement for cysteine continues in diet into infancy, perhaps to 5 months of age. Most of the metabolic machinery for the metabolism of methionine and cysteine resides in liver parenchymal tissue near the portal vein. The transsulfuration pathway for methionine metabolism is a complex series of enzymatic steps leading to cysteine and taurine production (Figure
5-4). Many investigators have shown that multiple enzymes in this pathway have lower or no activity in the fetal liver, or in the livers of infants of various gestational ages who died from non-liver-related causes. 38,39 -cystathionase and cystathionine -synthase were found to be absent or to have activity of less than half of the older child or adult. Zlotkin40 demonstrated that -cystathionase in liver of premature and term infants did not reach adult activity until 6 to 9 months postnatal age. This may be the reason that human milk is relatively rich in cysteine content. This renders cysteine as conditionally essential in neonates and infants.
Figure 5-4 The Transsulfuration Pathway in the Metabolism of Methionine
Cysteine is gradually oxidized to the dimer cystine in aqueous solution at neutral pH. Therefore, for PN solutions containing cysteine, cysteine is added at the time of preparation. The commonly used intravenous additive is provided as the cysteine hydrochloride salt. The pediatric daily requirement for cysteine has been studied by Helms et al.41,42 These investigators found that a dose of 77.4 mg/kg/d, close to that of Snyderman, appears to be required for ideal nitrogen retention, nitrogen balance, and growth in infants on PN. 36 Problems of acidosis occasionally occur in very low birth-weight (VLBW) infants, and require the substitution of acetate for chloride in PN solutions. For every 160mg of cysteine HCl that is infused as part of PN, 1 mmol of HCl is given to the pediatric patient. For the preterm infant and neonate, the prescriber should consider substitution of 1 mmol of acetate for 1 mmol of additional chloride given as part of cysteine HCl.
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Taurine is one of the most abundant free amino acids in humans. It is not incorporated into protein in that no aminoacyl tRNA synthetase recognizing taurine has been identified. Taurine is actually a sulfonic acid (rare in nature) and does not contain a carboxyl group as do other amino acids. It has a host of important biological functions (Table 5-3). It is essential in the feline diet, and its absence results in retinal degeneration and blindness. In children on home parenteral nutrition (HPN) with no added taurine, degenerative changes in electroretinograms were observed.43 Cysteine sulfinic acid decarboxylase is key to production of taurine from cysteine (Figure 5-4). The enzyme has much lower overall activity in humans than in rats and cats, but its activity is even lower in human fetal liver.44 Taurine is found in high concentrations in human milk when compared to cows milk.45 Formulas made from cows milk protein require taurine supplementation, and taurine deficiency may occur in synthetic formulas not containing taurine. In neonates and premature infants these infants continue to renally waste taurine even in the presence of low serum taurine.46
Table 5-3 Taurine Functions Neurotransmitter Bile acid conjugation Brain and central nervous system development Osmoregulation Immunoregulation Antioxidant Retinal physiology Platelet function Mitochondrial function
kg/d in preterm infants. 36 Classic phenylketonuria (PKU), the absence of the enzyme phenylalanine hydroxylase, results in extreme elevations in phenylalanine concentration, and a requirement for tyrosine in diet. PKU can lead to brain damage and possibly death if untreated. Tyrosine may be conditionally essential in patients with liver disease, and is the precursor for the neurotransmitter, dopamine. Tyrosine content in parenteral amino acid solutions is restricted because of poor solubility. Christensen found that N-acetyl-tyrosine (NAT), an aqueously soluble form of tyrosine with good stability in solution, was a reasonable intravenous source of tyrosine in older infants.48 However, clearance and non-renal clearance was significantly decreased in younger infants of lower postconceptional age, suggesting NAT may not be the ideal tyrosine source in VLBW neonates. This investigative group was unable to normalize plasma tyrosine concentrations in most infants at a dose of approximately 50 mg/kg/d. Van Goudoever was able to normalize plasma tyrosine levels with NAT intake of 162 mg/kg/d.49
Amino Acids of the Urea Cycle

The amino acids of the urea cycle are considered nonessential (Figure 5-5). Snyderman50 found no evidence that arginine is essential in preterm infants. However, early amino acid solutions with relatively lower concentrations of arginine resulted in hyperammonemia in infants receiving these formulas as part of PN. 51 Higher concentrations of arginine reversed the finding of hyperammonemia. 52 Acute renal failure patients given large doses of protein with little supplemental arginine also present with hyperammonemia, and can be reversed with the supplementation of arginine. 53 Treatment of urea cycle disorders generally involves the supplementation of low-dose essential amino acids, andarginine.
Taurine is added to crystalline amino acid formulas designed for infants. Helms et al. described plasma amino acid concentrations in preterm infants, and in long-term home parenteral nutrition (PN) patients receiving a pediatric-designed amino acid formula as part of their PN.42,47 For infants, these investigators demonstrated that concentrations of the sulfur amino acids remain within age-related norms with the use of one of the commercially available formulas with L-cysteine HCl supplementation. Interestingly, even older children on home PN required cysteine supplementation to normalize plasma taurine concentrations.47 Tyrosine is exclusively metabolized from phenyla lanine. Tyrosine, like cysteine for methionine, can spare dietary requirement for phenylalanine. Snyderman demonstrated a dietary need for tyrosine of approximately 50 mg/
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Figure 5-5 Urea Cycle With Enzymes and Substrates
CPS = carbamyl phosphate synthetase, OTC = ornithine transcarbamylase, ASAS = argininosuccinic acid synthetase, AS = argininosuccinase, A = arginase
Useful Classification of Amino Acids for the Clinician

Laidlaw and Kopple offer an alternative approach to the Jacksonian35 classification of essential and nonessential amino acids. 54 These 5 classifications enable the clinician to better understand the requirement of amino acids in diet (Table 5-4).
Table 5-4 Modification of Amino Acid Classification in Humans54 1. Totally indispensable amino acids. No metabolic precursor or product can be substituted. Lysine and threonine. 2. Carbon-skeleton indispensable. Ketoacid analogue or hydroxyacid analogue can be substituted. Histidine, isoleucine, leucine, methionine, phenylalanine, tryptophan, and valine. 3. Conditionally indispensable. Reduce requirement for indispensable, and become indispensable in the absence of precursor in diet. Tyrosine, cysteine, taurine, and possibly orthnithine, and citrulline. 4. Acquired indispensable. Become indispensable in states of metabolic disorders, immaturity, severe stress. Cysteine, taurine, tyrosine, arginine, citrulline, glycine, serine, and proline. 5. Dispensible. Alanine, glutamate, aspartate.
Liver and Kidney: Roles in Amino AcidMetabolism
The liver is important in synthesis of transport and other constituent and functional proteins, metabolism of amino acids, gluconeogenesis, and urea formation. 55,56 Major plasma proteins derived from liver, such as albumin, transthyretin (TTR) (also known as prealbumin for its migration pattern during electrophoresis), and retinolbinding protein (RBP) are present at early stages of development. Most liver-derived plasma proteins are at
lower concentrations in plasma in premature infants. Lipoprotein concentrations rise rapidly after birth in response to high dietary fat intake, while albumin and TTR increase toward adult values in the first months to year of life. Acute phase proteins, such as C-reactive protein (CRP), appear to be induceable even in prematurity, and are used to monitor inflammatory response to infection or metabolic stress. Reduction in visceral protein occurs in preterm infants, and response to protein and energy intake can be assessed through monitoring changes in serum concentrations of albumin, TTR, and RBP. 57 The production of glutathione in the liver is essential; however, other tissues can produce the tripeptide. Glutathione is an important sulfhydryl-reducing agent that protects cells from oxygen free radicals. 58 It is synthesized from glutamate, cysteine, and glycine, and studies have shown cysteine is the rate-limiting substrate in glutathione production. It is dependent in two distinct steps on cysteine production via the transsulfuration pathway (principally in the liver), or from dietary intake. The tripeptide also appears to be important in the transport of amino acids, and in the synthesis of leukotrienes via the enzyme gamma-glutamyl transpeptidase. 59,60 The metabolism of amino acids is an important function of the liver. Several enzymes and enzyme systems, such as the transsulfuration pathway and phenylalanine hydroxylase, both predominantly located in the liver, are responsible for the metabolism of the essential amino acids methionine and phenylalanine, respectively. Enzyme activity is reduced in prematurity and early infancy, rendering the products of these enzyme systems as conditionally essential amino acids. Approximately one-third of amino acids entering the liver from portal blood are used for protein synthesis.61 The remainder may be used in energy production, or gluconeogenesis, with perhaps only a third of dietary amino acids entering to the peripheral blood. This explains why plasma amino acids do not fluctuate substantially in the postprandial period. One group of amino acids that are released at higher relative concentrations from the liver in the postprandial period are the branched-chain amino acids.62 These are leucine, isoleucine, and valine. The branched-chain amino acids are preferentially metabolized in the periphery as these amino acids and arginine stimulate insulin release and muscle protein synthesis.63 All is reversed in the postabsorptive period. As insulin concentrations fall, the muscle then provides the principal gluconeogenic substrate, alanine, to the liver for production of glucose in the fasting period.
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In parenterally fed neonates and infants, Heird found that the branched-chain amino acid needs of infants was increased even with their relatively lower muscle mass. 32,33 This would suggest that the shuttling of amino acids between the periphery and the small infant liver is actually higher than in the adult. Increased requirement of amino acids and energy for synthesis may be the likely explanation. The urea cycle is the principal mechanism for nitrogen disposal (Figure 5-5). The catabolism of proteins, and their component amino acids, results in ammonia production. The liver will hydrolyze arginine to form urea and ornithine under the enzymatic control of arginase. Urea then is delivered to the kidney for excretion. In neonates and infants, the quantity of amino acids that enter into urea production is small, presumably due to substantial need of amino acids for growth; therefore, BUN will be low.64 The kidney plays a minor role in amino acid and protein metabolism. Ninety percent of dietary protein nitrogen is incorporated into new tissue, and therefore never requires formation of urea in the liver, and excretion by the kidney. In premature infants and neonates, excretion of nitrogen is limited for the first months of life. Tubular reabsorption of amino acids is reduced in premature infants and neonates,
and may explain increased amino acid needs in these patients when compared to older children, or adults.65,66
Functions of Amino Acids and Proteins
Protein has multiple functions; it is essential for cell structure, maturation, remodeling, and growth. Besides being utilized for energy, amino acids and proteins serve as precursors that are essential for many biological processes.67 When protein is consumed, it is extensively broken down in the GI tract to amino acids, which can then enter cells or continue to circulate in plasma. Once in the cell, amino acids can be combined by peptide linkages to form small peptides (such as glutathione), they can be substrates for protein synthesis, or they can function as individual amino acids in the urea cycle. Specific amino acids can act as substrates, regulators, transporters, and precursors to neurotransmitters and hormones.67 In the cell, protein can be utilized for energy or it can be stored. There is a continuous flux of proteins being broken down. The carbon chain of the amino acids can be utilized for energy, and free amino acids can be released back into the plasma to maintain plasma amino acid concentrations. 67 After synthesis within the cell, many proteins are
Table 5-5 Functions of Amino Acids and Protein67

Function Example
Amino acids Substrates for protein synthesis Regulators of protein turnover Regulators of enzyme activity (allosteric) Precursor of signal transducer Methylation reactions Neurotransmitters Ion fluxes Precursor of physiologic molecules Nitrogen transport Oxidation and reduction Precursor of conditionally indispensable amino acids Gluconeogenic substrate and fuel Proteins Enzymatic catalysis Transport Messenger / signals Movement Structure Storage / sequestration Immunity Growth; differentiation; gene expression
Amino acids with a codon Leucine, arginine Arginine and NAG synthetase, Phe and PAH activation Arginine and nitric oxide Methionine Tryptophan (serotonin); glutamate, glycine, GABA Taurine; glutamate Arginine (creatinine); glutamine Alanine; glutamine Cystine; glutathione Methionine (cys); phe (thy) Alanine; serine; glutamine BCKADH B-12 binding proteins; ceruloplasmin; apolipoproteins Insulin; growth hormones Kinesin; actin Collagens; elastin Ferritin; metallothionein Antibodies; TNF; interleukins EGF; IGFs; transcription factors
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released into the plasma. The three major types of plasma proteins are albumin, globulin, and fibrinogen. Albumins role is to maintain osmotic pressure in the plasma. Globulins are involved in enzymatic activity in the plasma, as well as playing a vital role in natural and acquired immunity. Fibrinogen is essential for coagulation, both in blood clotting and repair of blood vessels.67 For specific examples of the functions of amino acids and protein refer to Table 5-5.
Assessment of Protein Status

Besides monitoring of visceral proteins (ie, albumin, TTR) and acute phase proteins (ie, CRP), nitrogen balance can be a useful tool in monitoring protein repletion and depletion in pediatric patients receiving specialized nutrition support. Nitrogen balance is an estimate of nitrogen intake minus nitrogen excretion. In adults, urinary urea nitrogen (UUN in g/L 1.2 to yield total urinary nitrogen (TUN)) multiplied by the urine volume (L/d) plus 2 to 4 g nitrogen (to reflect all other unmeasured nitrogen lost) results in nitrogen balance. The method for collection and calculation of nitrogen balance is altered in pediatric patients. Urine collections in neonates and infants are problematic, but not impossible. The use of urine bags with attentive clinician support, or collection of diapers with elution of all urinary and stool nitrogen, has been used successfully in the clinical arena to assess nitrogen output in children.72 While 24-hour urine collections have been considered the standard, there is published experience using 6-hour collection in pediatrics.73 These authors are more comfortable using 24-hour urine collections to predict actual nitrogen balance over the period of observation. Nitrogen balance has been reviewed nicely in the Protein chapter of The A.S.P.E.N. Nutrition Support Core Curriculum,1 but several issues should be considered when completing nitrogen balance studies in pediatrics. Helms characterized nitrogen excretion in stressed pediatric intensive care unit patients and sick neonates.74 Urea as a percentage of total nitrogen output was in the range of 40% to 60%, distinctly different from the 80% excretion as urea assumed in adults. Because the percentage of nitrogen excreted as urea is substantially different than the adult patient and varies with clinical condition, it is recommended that TUN be used to increase accuracy and reliability for both children and adults.
Protein requirements (similar to total caloric requirements) are greater for VLBW neonates and gradually decrease with increased age.28 VLBW neonates have the highest protein requirements, often requiring 3 to 4 g/kg/d, while term neonates require 2 to 2.5 g/kg/d. Protein requirements in term infants are based on studies in freely breastfed infants.68 Protein is essential for growth, and its requirement increases during periods of rapid growth and decreases with slowed growth. In infancy, 55% of daily protein is dedicated for growth while 45% is for maintenance. This ratio gradually decreases and by 4 years of age only about 10% of total protein requirement is utilized for growth and the remaining 90% is used for daily maintenance.69 Refer to Table 5-6 for age-based protein requirements.
Table 5-6: Protein Requirements68
Protein (g/kg/d)
Protein Requirements and Protein-Energy Ratio DuringGrowth
Very Low Birth Weight Preterm Infant / neonate Infant Preschool / School age Adolescent
34 2.53 22.5 1.52 11.5 0.81.5
Many studies have demonstrated that adequate protein may be more critical for nutritional status and growth than total caloric requirements in preterm neonates and sick children.18 Protein requirements can be increased by as much as 20% to 50% in critical illness, thermal injury, and catch-up growth.70 Early initiation of protein has been shown to be beneficial in extremely low birth-weight infants. Poindexter et al. concluded that early amino acid administration was significant for better growth outcomes and neurodevelopment when evaluated at 36 weeks postmenstrual age and again at 18 months follow-up.71
Monitoring Plasma Amino Acids

Plasma amino acids have been widely reported in pediatric patients. Storm75 reviewed the hypothesis regarding normalization of plasma amino acids, and its validation as a predictive tool in understanding outcome in neonates and infants receiving PN. This led to a number of investigations suggesting normalization results in improved growth, nitrogen balance, increased calcium and phosphorus intakes, and improved liver health.7680 It is likely that plasma amino acids will continue to be a benchmark for efficacy of newly developed pediatric amino acid formulations. It is unclear whether plasma amino acid assessment
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will ultimately migrate to the clinical environment as a useful tool for evaluating efficacy in the individual pediatric patient; this will require less expensive and more accessible analytical technologies than those currently used in clinical research.
Case Presentation and Discussion
A 2-month-old female was admitted to the hospital today after having been seen by her primary care physician for a well baby visit. She was born at 38 weeks gestation with a birth weight of 3.4 kg. Her weight in the clinic today was 3.1 kg. The mother reports that she had to return to work 2 weeks ago and transitioned her daughter from breast milk to an infant formula. Since then, the infant has had increased fussiness, crying, spitting up, and small specks of blood in the stool. The infant was admitted with a diagnosis of feeding intolerance and failure to thrive. The nutrition team was consulted to evaluate the infants nutrition needs. Question: Explain how the infants symptoms could be associated with the change from breast milk to an infant formula. Comment: Human milk has an increased whey content that is more easily digestible and promotes gastric emptying. Bovine milk is composed of beta-lactoglobulin, which is associated with protein allergy, feeding intolerance, and colic. Question: What are your recommendations for this infants nutrition? Comment: Since this patient has demonstrated feeding intolerance after switching from human milk to this infant formula, it would be prudent to change her to an infant formula that is easier to digest. A hydrolyzed or amino acidbased formula should be considered for this infant. Question: What is the estimated protein requirement for this infant? Comment: Infants require approximately 2 g/kg/d of protein. Because this infant has lost weight from her birth weight, protein should be dosed based on the birth weight of 3.4 kg. This corresponds to a total protein dose of approximately 7 g/d. Question: What is the best nethod of monitoring nutrition status in this patient? Comment: The best method for evaluation of protein and overall nutrition status in this patient would be daily weights. At this time there is no indication that this infant has higher than normal protein or caloric requirements. If the infant does not gain weight with appropriate protein and calories, further evaluation may be necessary.
1. All of the following are functions of taurine EXCEPT: A. Antioxidant B. CNS development C. Nitrogen transport D. Bile acid conjugation E. Immunoregulation 2. Which of the following is an advantage of human milk over bovine milk? A. Human milk contains IgA which is important in host defense. B. Human milk has a decreased whey content that promotes rapid gastric emptying. C. Human milk has an increased caloric density as compared to bovine milk. D. Human milk prevents children from developing colic. E. All of the above are advantages of human milk. 3. Protein digestion: A. Occurs mostly in the small intestine. B. Is dependent on hydrochloric acid and pepsin to denature protein. C. Has been identified as early as 16 weeks gestation, but gastric acid secretion does not reach adult levels until 38 weeks gestation. D. Products include approximately 30% oligopeptides and 70% amino acids. 4. Which of the following is TRUE regarding nitrogen balance? A. Nitrogen balance is not an accurate way to assess protein needs in a pediatric patient. B. In order to estimate a nitrogen balance, you must do a 24-hour urine collection. C. Total urinary nitrogen (TUN) is a better estimate of urinary losses as compared to urinary urea nitrogen (UUN). D. Nitrogen balance is an estimate of nitrogen intake divided by nitrogen excreted. See p. 487 for answers.
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2. Gilger MA. Normal gastrointestinal function. In: McMillan JA, Feigin RD, DeAngelis C, Jones MD, eds. Oskis Pediatrics. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:19151921. 3. Berseth CL. Overview of the development of the gastrointestinal tract. UpToDate Web site. http://www.uptodate.com/ home/index.html. October 11, 2005. Accessed December 19, 2008. 4. Lucas A, Bloom SR, Aynsley-Green A. Development of gut hormone responses to feeding in neonates. Arch Dis Child. 1980;55(9):678682. 5. Berseth CL, Nordyke CK, Valdes MG, Furlow BL, Go VL. Responses of gastrointestinal peptides and motor activity to milk and water feedings in preterm and term infants. Pediatr Res. 1992;31(6):587590. 6. Moreau H, Bernadac A, Gargouri Y, Benkouka F, Laugier R, Verger R. Immunocytolocalization of human gastric lipase in chief cells of the fundic mucosa. Histochemistry. 1989;91(5):419423. 7. Armand M, Hamosh M, Mehta NR, et al. Effect of human milk or formula on gastric function and fat digestion in the premature infant. Pediatr Res. 1996;40(3):429437. 8. Armand M, Hamosh M, DiPalma JS, et al. Dietary fat modulates gastric lipase activity in healthy humans. Am J Clin Nutr. 1995;62(1):7480. 9. Rudolph CD. Structure and development of the gastrointestinal tract. In: Rudolph CD, Rudolph AM, Hostetter MK, Lister GE, Siegel NJ, eds. Rudolphs Pediatrics. 21st ed. New York, NY: McGraw-Hill; 2003. 10. Wahbeh GT, Christie DL. Basic aspects of digestion and absorption. In: Wyllie R, Hyams JS, eds. Pediatric Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 3rd ed. Netherlands: Saunders Elsevier; 2006:1123. 11. Colaizzo-Anas T. Nutrient intake, digestion, absorption, and excretion. In: Gottschlich MM, DeLegge MH, Mattox T, Mueller C, Worthington P, eds. The A.S.P.E.N. Nutrition Support Core Curriculum: A Case-based Approach The Adult Patient. Silver Spring, MD: American Society for Parenteral and Enteral Nutrition; 2007:318. 12. Mason JB. Mechanisms of nutrient absorption and malabsorption. UpToDate Web site. http://www.uptodate.com/ home/index.html. October 18, 2007. Accessed December 19, 2008. 13. DeLegge MH, Ridley C. Nutrient digestion, absorption, and excretion. In: Gottschlich, MM, Fuhrman MP, Hammond KA, Holcombe BJ, Seidner DL, eds. The Science and Practice of Nutrition Support: A Case-Based Core Curriculum. Dubuque, IA: Kendall/Hunt Publishing Co; 2001:116. 14. Hadorn B, Tarlow MJ, Lloyd JK, Wolff OH. Intestinal enterokinase deficiency. Lancet. 1969;1(7599):812813. 15. Johnson TR, Moore WM, Jeffries JE. Developmental Physiology. 2nd ed. Columbus, OH: Ross Laboratories; 1978:150152. 16. Roy CC, Silverman A, Alagille D. Pediatric Clinical Gastroenterology. 4th ed. St. Louis, MO: Mosby-Year Book, Inc; 1995:307309. 17. Axelsson I, Jakobsson I, Lindberg T, Polberger S, Benediktsson B, Rih NC. Macromolecular absorption in preterm and term infants. Acta Paediatr Scand. 1989;78(4):532537.
18. Motil KJ. Meeting protein needs. In: Tsang RC, Zlotkin SH, Nichols BL, Hansen JW, eds. Nutrition During Infancy: Principles and Practice. 2nd ed. Cincinnati, OH: Digital Education Publishing, Inc; 1997:83103. 19. Philipps AF, Sherman MP. Neonatal nutrition and gastrointestinal function. In: Rudolph CD, Rudolph AM, Hostetter MK, Lister GE, Siegel NJ, eds. Rudolphs Pediatrics. 21st ed. New York, NY: McGraw-Hill; 2003. 20. Hansen JW, Boettcher JA. Human milk substitutes. In: Tsang RC, Zlotkin SH, Nichols BL, Hansen JW, eds. Nutrition During Infancy: Principles and Practice. 2nd ed. Cincinnati, OH: Digital Education Publishing, Inc; 1997:441466. 21. Schanler, RJ. Nutritional composition of human milk and preterm formula for the premature infant. UpToDate Web site. http://www.uptodate.com/home/index.html. September 7, 2007. Accessed December 19, 2008. 22. Lnnerdal B, Cederblad A, Davidsson L, Sandstrm B. The effect of individual components of soy formula and cows milk formula on zinc bioavailability. Am J Clin Nutr. 1984;40(5):10641070. 23. Brock, JH. Lactoferrin in human milk: its role in iron absorption and protection against enteric infection in the newborn infant. Arch Dis Child. 1980 Jun;55(6):417421. 24. Lnnerdal B. Digestibility and absorption of protein in infants. In: Rih NC, ed. Protein Metabolism During Infancy. New York, NY: Raven Press; 1994:5365. 25. Lindberg T, Ohlsson K, Westrm B. Protease inhibitors and their relation to protease activity in human milk. Pediatr Res. 1982 Jun;16(6):479483. 26. Davidson LA, Lonnerdal B. Fecal alpha 1-antitrypsin in breast-fed infants is derived from human milk and is not indicative of enteric protein loss. Acta Paediatr Scand. 1990;79(2):137141. 27. Rose WC. The amino acid requirements of adult man. Nutr Abstr Rev. 1957;27:631647. 28. Nasset ES, Gatewood VH. Nitrogen balance and hemoglobin of adult rats fed amino acid diets low in L- and D-histidine. J Nutr. 1956;53:163176. 29. Kopple JD, Swendseid ME. Evidence that histidine is an essential amino acid in normal and chronically uremic man. J Clin Invest. 1975;55:881891. 30. Kopple JD, Swendseid ME. Effect of histidine intake on plasma and urine histidine levels, nitrogen balance and N-methylhistidine excretion in normal and chronically uremic men. J Nutr. 1981;111:931942. 31. Snyderman SE, Boyer A, Roitman E, Holt LE Jr, Prose PH. The histidine requirement of the infant. Pediatrics. 1963;31:786801. 32. Heird WC, Dell RB, Helms RA, et al. Evaluation of an amino acid mixture designed to maintain normal plasma amino acid patterns in infants and children requiring parenteral nutrition. Pediatrics. 1987;80:401408. 33. Heird WC, Hay W, Helms RA, Storm MC, Kashyap S, Dell, RB. Pediatric parenteral amino acid mixture in low birth weight infants. Pediatrics. 1988;81(1):4150.
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34. Anonymous. Practice guidelines: protein requirements. In: Guidelines for the Use of Parenteral and Enteral Nutrition in Adult and Pediatric Patients. J Parenter Enteral Nutr. 2002;26:27SA28SA. 35. Jackson AA. Amino acids: essential and non-essential? Lancet. 1983;1:10341037. 36. Snyderman SE. The protein and amino acid requirements of the premature infant. In: Ionxix JHP, Visser HKA, Troelstra JD, eds. Metabolic Processes in the Fetus and Newborn Infant. Leiden: HE Stenfert Kroesse NV; 1971:128141. 37. Pohlandt F. Cystine: a semi-essential amino acid in the newborn infant. Acta Pediatr Scand. 1974;63:801804. 38. Gaull G, Sturman JA, Raiha NCR. Development of mammalian sulfur metabolism: absence of cystathionase in human fetal tissues. Pediatr Res. 1972;6:538547. 39. Sturman JA, Gaull G, Raiha NCR. Absence of cystathionase in human fetal liver: is cystine essential? Science. 1970;169:7476. 40. Zlotkin SH, Anderson GH. Sulfur balances in intravenously fed infants: effects of cysteine supplementation. Am J Clin Nutr. 1982;36: 862867. 41. Helms RA, Chesney RW, Storm MC. Sulfur amino acid metabolism in infants on parenteral nutrition. Clin Nutr. 1995;14:381387. 42. Helms RA, Christensen ML, Storm MC, Chesney RW. Adequacy of sulfur amino acid intake in infants receiving parenteral nutrition. Nutr Biochem. 1995;6:462466. 43. Vinton NE, Ament ME, Heckenlively JR, et.al. Visual function in patients in patients undergoing home total parenteral nutrient. Am J Clin Nutr. 1986;43:689. 44. Sturman JA, Hayes KC. The biology of taurine in nutrition and development. In: Draper HH, ed. Advances in Nutrition Research. Vol. 3. New York, NY: Plenum Publishing Co; 1980:231299. 45. Rassin DK, Sturman JA, Gaull GE. Taurine and other free amino acids in milk of man and other mammals. Early Hum Dev. 1978;2:113. 46. Zelikovic I, Chesney RW, Freidman AL, Ahlfors CE. Taurine depletion in very low birth weight infants receiving prolonged total parenteral nutrition: Role of renal immaturity. J Pediatr. 1990;116:301306. 47. Helms RA, Storm MC, Christensen ML, Hak EB, Chesney RW. Cysteine supplementation results in normalization of plasma taurine concentrations in children receiving home parenteral nutrition. J Pediatr. 1999; 134:358361. 48. Christensen ML, Helms RA, Veal DF, Boehm KA, Storm MC. Clearance of N-acetyl-L-tyrosine in infants receiving a pediatric amino acid solution. Clin Pharm. 1993;12:606609. 49. Van Goudoever JB, Sulkers EJ, Timmerman M, et al. Amino acid solutions for premature neonates during the first week of life: the role of N-acety-L-cysteine and N-acetyl-L-tyrosine. J Parenter Enteral Nutr. 1994;18:404408. 50. Snyderman SE, Boyer A, Holt LE Jr. The arginine requirement of the infant. AMA J Dis Child. 1959;97:192195. 51. Heird WC, Nicholson JF, Driscoll JM Jr, Schullinger JN, Winters RW. Hyperammonemia resulting from intravenous alimentation using a mixture of synthetic L-amino acids: a preliminary report. J Pediatr. 1972;81:162167.
52. Thomas DW, Sinatra FR, Hack SL, Smith TM, Platzker ACG, Merritt RJ. Hyperammonemia in neonates receiving intravenous nutrition. J Parenter Enteral Nutr. 1982;6:503506. 53. Motil KJ, Harmon WE, Grupe WE. Complications of essential amino acid hyperalimentation in children with acute renal failure. J Parenter Enteral Nutr. 1980;4:3235. 54. Laidlaw SA, Kopple JD. Newer concepts of the indispensable amino acids. Am J Clin Nutr. 1987;46:593605. 55. Raiha NCR, Suihkonen J. Development of urea-synthesizing enzymes in human liver. Acta Pediatr Scand. 1968;57:121124. 56. Raiha NCR, Lindros KO. Development of some enzymes involved in gluconeogenesis in human liver. Ann Med Exp Biol. 1969;47:146150. 57. Helms RA, Dickerson RN, Ebbert ML, Christensen ML, Herrod HG. Retinol-binding protein and prealbumin: useful measures of protein repletion in critically ill, malnourished infants. J Pediatr Gastroenteral Nutr. 1986;5:586592. 58. Beutler E. Nutritional and metabolic aspects of glutathione. Annu Rev Nutr. 1989;9:287302. 59. Meister A. On the enzymology of amino acid transport. Science. 1973;180:3339. 60. Svartz J, Hallin E, Soderstorm M, Hammarstrom S. Identification of regions of leukotriene C4 synthase which direct the enzyme to its nuclear envelope localization. J Cell Biochem. 2006;98;15171527. 61. Yamamoto H, Aikawa T, Matsutaka H, Okuda O, Ishikawa E. Interorganal relationships of amino acid metabolism in fed rats. Am J Physiol. 1974;226;14281433. 62. Munro HN. Fifth annual Jonathan E. Rhoads lecture. Metabolic integration of organs in health and disease. J Parenter Enteral Nutr. 1982;6:271. 63. Rocha DM, Falona GR, Unger RH. Glucagon-stimulating activity of 20 amino acids in dogs. J Clin Invest. 1972;51:2346. 64. Raiha NCR, Kekomaki MP. Studies on the development of ornithine-keto acid amino transferase activity in the liver. Biochem J. 1968;108:521524. 65. Edelman CM, Wolfish NM. Dietary influence on renal maturation in premature infants. Pediatr Res. 1968;2:421422. 66. Brodehl J, Gellissen K. Endogenous renal transport of free amino acids in infancy and childhood. Pediatrics. 1968;42:395404. 67. Protein metabolism. In: Guyton AC, ed. Textbook of Medical Physiology. Philadelphia, PA: W.B. Saunders Co; 1991:765770. 68. Wu PYK, Edwards N, Storm MC. The plasma amino acid pattern of normal term breast-fed infants. J Pediatr. 1986;109:347349. 69. American Academy of Pediatrics, Committee on Nutrition. Protein. In: Kleinman RE. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:325341. 70. Scrimshaw NS. Effect of infection on nutritional status. Proc Natl Sci Counc Repub China B. 1992;16:4664.
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71. Poindexter BB, Langer JC, Dusick AM, Ehrenkranz RA. Early provision of parenteral amino acids in extremely low birth weight infants: relation to growth and neurodevelopmental outcome. J Pediatr. 2006;148:300305. 72. Boehm KA, et al. Assessing the validity of adjusted urinary urea nitrogen as an estimate of total urinary nitrogen in three pediatric populations. J Parenter Enteral Nutr. 1994;18(2):172176. 73. Lopez et al. Estimation of nitrogen balance based on a sixhour urine collection in infants. J Parenter Enteral Nutr. 1986;10(5):517518. 74. Helms RA, Mowatt-Larssen CA, Boehm KA, et al. Urinary nitrogen constituents in the postsurgical preterm neonate receiving parenteral nutrition. J Parenter Enteral Nutr. 1993;17:6872. 75. Strom MC, Helms RA. Normalizing plasma amino acid levels in pediatric patients requiring parenteral nutrition. Nutr Clin Pract. 2007;22:194203.
76. Helms RA, Christensen ML, Muer EC, Storm MC. Comparison of a pediatric versus standard amino acid formulation in preterm neonates requiring parenteral nutrition. J Pediatr. 1987;110:466470. 77. Beck R. Use of a pediatric parenteral amino acid mixture in a population of extremely low birth weight neonates: frequency and spectrum of direct bilirubinemia. Am J Perinatol. 1990 Jan;7(1):8486. 78. Forchielli ML, Gura KM, Sandler R, Lo C. Aminosyn PF or TrophAmine: which provides more protection from cholestasis associated with total parenteral nutrition? J Pediatr Gastroenterol Nutr. 1995;21:374382. 79. Pratt CA, Garcia MG, Poole RL, Kerner JA. Life-long total parenteral nutrition versus intestinal transplantation in children with microvillus inclusion disease. J Pediatr Pharmacol Ther. 2001;6:498503. 80. Fitzgerald KA, MacKay MW. Calcium and phosphate solubility in neonatal parenteral nutrient solutions containing TrophAmine. Am J Hosp Pharm. 1986 Jan;43(1):8893.
Minerals
Winston Koo, MBBS, FACN, CNS, Mirjana Lulic-Botica, BSc, BCPS, May Saba, PharmD, BCNSP, and Letitia Warren, RD, CSP
6
Learning Objectives
1. Understand the physiological basis for the functions of and requirements for calcium, phosphorus, and magnesium. 2. Understand the common risk factors for the development of deficiency in these nutrients. 3. Understand the common manifestations of deficiency states for these nutrients. 4. Understand the potential risks with excessive intake of these nutrients.
CONTENTS
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Biochemistry and Physiology Sources Dietary Requirements Absorption and Excretion Metabolism Deficiency States Excess Intake and Adverse Effects
Calcium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Biochemistry and Physiology Sources Absorption, Excretion, and Metabolism Deficiency States Excess Intake and Adverse Effects
Overview
Biochemistry and Physiology
Calcium (Ca) is the most abundant mineral in the body and together with phosphorus (P) forms the major inorganic constituent of bone. Magnesium (Mg) is the fourth most abundant cation and is the second most common intracellular electrolyte in the body. The total body content of Ca, P, and Mg in the skeleton is about 99%, 85%, and 60%, respectively. Less than 1% of the total body content of Ca, P, and Mg is in the circulation. However, disturbances in serum concentrations of these minerals are associated with disturbances of physiological function. These are manifested by numerous clinical symptoms and signs. Acute changes in the serum concentrations likely reflect adaptive changes and do not reflect the state of tissue store, although chronic and severely lowered serum concentrations of these minerals usually reflect the presence of a deficiency state. From a clinical perspective, the skeleton has the dual function of providing both structural and mechanical support as well as being a reservoir to maintain mineral
45
Phosphorus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Magnesium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
46
homeostasis. Deficiency of Ca and/or vitamin D and in the case of small preterm infants, deficiency of P, can result in osteopenia and rickets in infants and children.1 In addition, numerous physiological functions of all organs are dependent on the maintenance of normal circulating concentrations of Ca, P, and Mg, and the integrity of the skeleton.
Table 6-1 Dietary Reference Intakes for Calcium, Phosphorus and Magnesium2,5
Life Stage Calcium* mg/d Phosphorus mg/d Magnesium mg/d
Sources
Natural foods and a variety of foods and beverages fortified with Ca are good sources for these minerals. Any food that provides 20% or more of the daily recommended intake per serving for a specific nutrient is considered to be high in that nutrient.2 Dietary sources of minerals, including Ca fortified foods and beverages, are preferred to the use of supplements alone because the range of nutrients and the establishment of good dietary habits are enhanced by the use of dietary sources. Nutrient interactions also may be less and tolerance may be greater for minerals provided by food sources. Mineral supplements are freely available. However, use of supplements does not compensate for poor food choices and inadequate diet. Furthermore, the Food and Drug Administration (FDA) regulates dietary supplements under a different set of regulations than drug products (prescription and over-the-counter). As a result, specific contents of dietary supplements and contaminants are not as rigorously monitored. 3
06 mo* 712 mo* 13 y 48 y Males 913 y 1418 y Females 913 y 1418 y Pregnancy 1418 y Lactation 1418 y UL
210 270 500 (2500) 800 (2500) 1300 (2500) 1300 (2500) 1300 (2500) 1300 (2500) 1300 (2500) 1300 (2500)
100 275 460 (3000) 500 (3000) 1250 (4000) 1250 (4000) 1250 (4000) 1250 (4000) 1250 (3500) 1250 (4000)
30 75 80 (65) 130 (110) 240 (350) 410 (350) 240 (350) 360 (350) 400 (350) 360 (350)
* Adequate intake (AI) = observed or experimentally determined estimates of nutrient intake by a group or groups of healthy people. AI is the only reference level provided for infants < 12 mo. Recommended dietary allowance (RDA) = average daily dietary intake sufficient to meet the requirement of 97% to 98% of healthy individuals in a life stage and gender group. Tolerable upper intake level (UL) = highest level of daily nutrient intake that is likely to pose no risk of adverse health effects to almost all individuals in the general population. Upper limit for each life stage is indicated in parenthesis. For magnesium, applies to non-food sources only.
Dietary Requirements
Mineral requirements depend on the needs for tissue synthesis in growing children and the balance among dietary supply, intestinal absorption, renal excretion, and bone exchange for these minerals. There are a number of unique challenges in maintaining mineral homeostasis during infancy, childhood, and adolescence. All neonates must adapt successfully to extrauterine life when the continuous supply of these minerals from the placenta is interrupted at birth. This adaptation is usually achieved with appropriate nutrition support, even in critically ill and preterm neonates.4 Nutrition requirements for these minerals remain high until completion of skeletal growth. Infants and adolescents have the greatest requirements because of their high growth rates. The average gain in skeletal growth over 1 year is > 25 cm for an infant and is even greater for the preterm infant. The peak height gain is about 7 to 10 cm per year during adolescence. The recommended dietary reference intakes (DRIs) for Ca, P, and Mg are shown in Table 6-1.
Absorption and Excretion

Intestinal absorption of these minerals involves a passive paracellular concentration-dependent process as well as a saturable active transcellular process. Vitamin D has some influence on the active intestinal transport but its role under normal circumstances appears to be much less than the passive diet-dependent process in the growing child. Renal reabsorption of these minerals also has passive and active transport components. It is highly efficient but an excessive intake can overwhelm the renal reabsorption capacity, leading to elevated circulating levels for each of these minerals. Conversely, during deficient states, especially if there is abnormal loss from the gastrointestinal (GI) tract or the kidney, renal conservation alone is unable to prevent the development of abnormally low circulating concentrations. Normally, the growing child has net bone (and soft tissue) accretion of these minerals. Some exchange of these minerals occurs normally with bone modeling. The exchangeable portion may be increased during periods of stress and increased turnover. During extreme
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47
circumstances (eg, severe Ca or P deficiency in infants) it is not possible to protect the skeleton or to maintain mineral homeostasis.
Table 6-2 Dietary Sources of Calcium57

Dietary calcium (mg) Calciumenriched food (mg)
Milk 240 mL (285302) Yogurt 240 g (245415) Cheese single-wrapped oz (120), others (140210/oz) Chocolate pudding made with 120 mL 2% milk (153) Sardines with bones 90 g (270) Salmon 90 g (181) Chinese cabbage 1 cup shredded and boiled (158) Broccoli chopped 1 cup (100) Kale 1 cup (90)
Metabolism
Maintaining mineral homeostasis requires a complex interaction of hormonal and non-hormonal factors; adequate functioning of various body systems, in particular the renal, gastrointestinal, skeletal, and endocrine systems; and adequate dietary intake. When assessing changes in serum concentrations of these minerals, it is vital to understand there is an interrelationship among them. For example, hypomagnesemia may cause hypocalcemia, due to the decreased action of parathyroid hormone (PTH). Serum Ca and P have a reciprocal relationship, and hypoalbuminemia can cause hypocalcemia secondary to decreased Ca binding, while ionized calcium (unbound calcium) concentration remains normal. At the intestine-kidney-bone axis, intake of minerals may interact with other nutrients including protein, sodium, potassium, vitamin D, iron, zinc, and copper. There may be significant effects on intestinal absorption, renal excretion, or metabolism of the minerals or on these other nutrients. Direct regulation on this axis by PTH, 1,25-dihydroxyvitamin D, and fibroblast growth factor-23, and indirect regulation by growth-regulating hormones including sex hormones, also significantly affect growth and mineralization of the skeleton, and maintenance of normal circulating concentrations of these minerals. A negative effect on mineral metabolism is possible, particularly if minerals and other nutrients stated above are ingested in large amounts as dietary supplements. Thus, it is vital to manage the cause of the abnormalities in addition to providing symptomatic treatment to the abnormal circulating concentration of the minerals.
Fortified orange and other fruit juices 180 mL (200260) Instant drink mix with 240 mL water (105250) Ready-to-eat cereals 1 cup (1001,000) Breads/English muffins 30 g (30) Tortilla corn one 6 diameter (1.2 oz) (40) Tortilla flour one 6 diameter (1.75 oz) (58) Tofu 3 oz (60150)
Several servings of certain foods with less bioavailable calcium (eg, vegetables) are needed to achieve the same amount of calcium absorbed from 1 serving (240 mL) of milk.
Deficiency States
Low dietary intake for Ca is common in older children. Less than 40% of boys and < 30% of girls 6 years or older receive the recommended daily adequate intake for Ca. Preoccupation with being thin is common in adolescents, especially among females, as is the misconception that all dairy foods are fattening. Many children and adults are unaware that low-fat milk contains at least as much Ca as does whole milk. A list of foods relatively high in Ca is shown in Table 6-2. Low Ca intake places children at risk for fractures, and both Ca and vitamin D deficiency are factors in the development of rickets in infants and young children. 8,9
Risks for mineral deficiency escalate with increased requirement, decreased absorption or increased losses through the GI tract or the kidney, or disturbed metabolism. All rapidly growing infants, especially extremely low birth weight (< 1 kg) preterm infants, are at risk for mineral deficiency because of increased requirement, intolerance to multiple nutrients during acute illness, and interference with mineral retention or metabolism from therapies. Critically ill neonates or children who require parenteral nutrition (PN) are often intolerant to increased nutrient intake, especially the energy load. Thus, it is unrealistic to expect any critically ill child to achieve normal growth (ie, normal anabolic state). In critically ill preterm neonates, growth rarely reaches the in utero rate, thus the needs for minerals are correspondingly less compared to stable and growing patients. There is no convincing evidence of mineral deficiency in the stable small preterm infant who is receiving adequate volumes (> 150 mL/kg/d) of high-energy preterm infant formula or mothers milk with commercial human milk fortifier containing energy and high mineral contents and is not receiving any medications that might interfere with mineral absorption, excretion, or metabolism. Malabsorption states, chronic therapy with loop diuretics and gastric acid inhibitors, or heritable disorders of mineral metabolism are associated with abnormalities in mineral retention and/or metabolism.1,5 In disease states, deficiency involving multiple minerals and additional nutrients may be unmasked during therapy. This is best represented by the development of hypophosphatemia,
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hypomagnesemia, and hypokalemia simultaneously during refeeding of severely malnourished individuals.
Excess Intake and Adverse Effects

The most common risk factor for excessive intake of minerals is associated with increased parenteral intake of minerals from the unrealistic expectation of normal growth in the critically ill child. Minerals delivered via parenteral routes can exceed the excretory capacity, resulting most commonly in hyperphosphatemia and hypermagnesemia with associated hypocalcemia.1,4 These findings may in part reflect shifts in minerals among various compartments but they also suggest that delivery of minerals can occur in excess of the bodys needs. Adverse effects from excess dietary intake of minerals occur rarely in normal pediatric ages. However, it is possible that some healthy infants may develop hyperphosphatemia and secondary hypocalcemia from feeding of standard infant formula. This is the result of a combination of higher intake of P from infant formulas relative to breast milk, and the inability to eliminate the excess P because of immature kidney and parathyroid gland function.1,4 Most of the adverse effects of excess mineral intake are due to excessive intake of supplements in pharmacologic doses and may result in serious morbidity and even mortality. The derivation of the current recommendation for the upper level of intake of Mg is based on the amount of supplement. 2
the cellular level through the action of ionized Ca, which functions both as extra- and intracellular messenger. Its role as a secondary messenger is critical to numerous bodily functions including muscle contraction, blood vessel contraction and expansion, the secretion of hormones and enzymes, and message relay through the nervous system. 2 In 1993 the FDA authorized placement of a health claim on food labels that states adequate Ca intake throughout life is linked to reduced risk of osteoporosis through the mechanism of optimizing peak bone mass during adolescence and early adulthood and decreasing bone loss later in life, and the addition of vitamin D to this claim is currently being considered.11 Calcium may contribute among other nutrition factors to the prevention of chronic diseases such ashypertension.12
Sources
Calcium is present in many dietary sources with dairy products having the best bioavailability (Table 6-2) and accounting for > 70% of dietary Ca intake in the United States.2,5 Non-fat and reduced fat dairy products contain the same amount of Ca as regular dairy products. Some food sources (eg, fruit juices, fruit drinks, tofu, and cereals) are fortified with various Ca compounds that are well absorbed. Calcium is present in human milk in relatively constant amounts between 200 to 250 mg/L. Various Ca salts are added to cows milk formulas for term infants to provide at least 60 mg/100 kcal. This is about twofold higher than the Ca density in human milk.13 Calcium fortification of formulas for small preterm infants may be four- to sixfold higher than human milk. Oral supplements such as calcium compounds containing carbonate and citrate are the most common although preparations containing other anions are available. Naturally occurring products (eg, oyster shell marketed as calcium supplement) contain high levels of lead, mercury, and other potentially toxic contaminants.14 Common parenteral supplements include calcium gluconate and calcium chloride but other compounds also are available. The proportion of elemental calcium by weight varies with the calcium compound and is 40% for carbonate, 38% for tribasic calcium phosphate, 21% for citrate, 13% for lactate, 9% for gluconate, and 6.4% for glubionate.14,15
Calcium
(1 mmol = 40 mg)

Calcium is the most abundant mineral in the human body and accounts for about 1% to 2% of adult human body weight. More than 99% of total body Ca is stored in the bones and teeth where it functions to support their structure. Thus, calcium is critical for normal growth and development of the skeleton and teeth.10 The remaining 1% is found throughout the body in blood, muscle, and other tissues and is critical to numerous physiological functions. In the circulation, ~50% of Ca is ionized and the rest is bound to albumin or complexed to small anions such as citrate, bicarbonate, and phosphorate. Optimal bodily function depends on maintaining the circulating total and especially ionized Ca concentration within a narrow range. Calcium exerts its effect either through a membrane-bound Ca sensing receptor (a member of the G protein-coupled receptor (GPCR) family, expressed on numerous organs and tissues) or at
Absorption, Excretion, and Metabolism

Gastric acid aids in the digestion of natural or Ca fortified food or drink. Some Ca compounds such as calcium citrate are better absorbed in those individuals who have decreased gastric acid when compared to calcium carbonate. About
MINERALS
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90% of the Ca absorbed is through the small intestine and < 10% is absorbed through the large intestine. Paracellular absorption takes place throughout the small intestine and is dependent on concentration gradient. Transcellular absorption takes place largely in the duodenum and is dependent on 1,25-dihydroxyvitamin D. The efficiency of Ca absorption decreases with increased amounts of Ca consumed and with the presence of non-Ca components of the diet. The latter include the type and content of carbohydrate, phytic acid (whole grain bread, wheat bran, beans, seeds, nuts, grains, and soy isolates), and/or oxalic acid (spinach, collard greens, sweet potatoes, rhubarb, and beans) that may bind to Ca and prevent its optimal absorption. These plant substances do not appear to interfere with Ca absorption from other foods. Calcium is excreted through feces, urine, and sweat. Calcium excretion can be increased by many factors including high intake of dietary sodium, protein, and caffeine. High potassium intake lowers urinary Ca thereby affecting the net Ca absorption. 2,16 The effect of dietary P on Ca and bone metabolism is limited if Ca intake is adequate. 5 The detrimental effects of consuming foods high in phosphate such as carbonated soft drinks is probably due to the replacement of milk with soda rather than the phosphate level itself.17 Chronic use of Mg antacids and potent loop diuretics such as furosemide can increase urinary Ca excretion. Aluminum antacids should not be used, especially for those with limited renal function such as infants, because of potential aluminum toxicity.18 Chronic therapy with a proton pump inhibitor raises risks for fractures.19 Retention of Ca generally reflects the bodys need. It is usually higher in individuals undergoing rapid growth and may be > 60% of dietary intake. Adequate intakes of Ca that meet or exceed the amount needed to maintain a nutritional state of adequacy in nearly all members of a specific age and gender group are shown in Table 6-1. The pregnant and lactating adolescent theoretically could have an increased need for Ca because of the need to support the bone mineralization of the mother and the fetus. Limited data indicate there is a compensatory increase in Ca absorption and any decrease in bone mass is replenished upon return of ovarian function and no additional increase in dietary Ca intake is recommended.2 However, pregnant women with adequate diets except for very low Ca intake can lower the fetal bone mineral content. This is prevented by an adequate Ca intake from diet or from Ca supplementation. 20 At all ages,21 particularly in young children, dietary Ca absorption is primarily regulated by Ca 22 rather than vitamin23 intake. Calcium homeostasis is maintained by a combination of
dietary intake and hormonal control of PTH and the active vitamin D metabolite, 1,25-dihydroxyvitamin D, with additional modulation by other factors.1 Classic target organs critical to Ca homeostasis include the GI tract, kidney, and bone. In pediatrics, the gut and kidney act primarily in the capacity of retaining Ca for the growth needs of the bone, hence there is always a positive Ca balance during growth. Dietary Ca, physical activity, and pubertal stage have independent effects on the rate of bone mineralization. 24,25 Maintenance Ca intake generally should be in the form of foods because of the range of other nutrients present in various foods. Foods fortified with Ca have increased the choices of Ca rich foods in the diet. 5
Deficiency States
Risk factors for a deficient state include increased need, such as the rapidly growing infant, or the presence of disease states that affect Ca digestion, absorption, or metabolism. Physically active females, particularly those with secondary menstrual disorders, may have lower Ca absorption and decreased bone formation, and adequate Ca intake is important to their bone health.26 Lactose-intolerant individuals may be at risk for Ca deficiency, not due to an inability to absorb Ca, but rather from the avoidance of dairy products. 2 Drinking milk with a meal and other dietary options (eg, choosing aged cheeses (such as Cheddar and Swiss) which contain little lactose, yogurt which contains live active cultures that aid in lactose digestion, or lactose-reduced and lactose-free milk) may allow increased Ca intake. Strict vegans27 should include adequate amounts of non-dairy sources of Ca in their daily diets or likely will need a Ca supplement to meet the recommended Ca intake. Dietary Ca deficiency is a risk factor for fractures8 although it is usually not associated with clinical or biochemical manifestations unless the Ca intake is extremely low. Hypocalcemia does not usually occur due to low Ca intake alone but occurs with concomitant deficiency of vitamin D or Mg or associated medical problems. Severe hypocalcemia may result in clinical signs and symptoms that may be subtle and vary with maturity of the individuals. Preterm infants often manifest with non-specific symptomatology that may include irritability, jitteriness or lethargy, feeding poorly with and without feeding intolerance, abdominal distention, apnea, cyanosis, and seizures. These features may be confused with manifestations of hypoglycemia, sepsis, meningitis, anoxia, intracranial bleeding, and narcotic withdrawal. The degree of irritability of the infant does not appear to correlate with serum Ca values. In more mature individuals, other symptoms and signs may include
50
tetany from peripheral hyperexcitability of motor nerves. In chronic deficient states, Ca is mobilized from the skeleton to maintain Ca levels in the blood and predisposes to suboptimal bone accretion. In young children, both Ca and vitamin D deficiency have a key role in the development of rickets.9 Resolution of hypocalcemia may not be possible until the underlying cause has been corrected. For example, hypocalcemia secondary to Mg deficit may not be correctable until Mg replacement therapy is initiated.

Excess Ca intake can result in hypercalcemia (serum or plasma total Ca > 11 mg/dL or ionized Ca > 5.6 mg/dL, respectively) and its complications of polyuria and polydipsia, renal calculi, and metastatic calcification. High dietary Ca intakes and routine Ca supplementation generally do not cause hypercalcemia. However, high Ca intake has the potential to interfere with the absorption of other minerals such as iron, zinc, Mg, and P. Calcium supplements have the potential to interact with several prescription and over-the-counter medications. 28,29 Calcium decreases absorption of digoxin, fluroquinolones, levothyroxine, tetracycline, tiludronate disodium, phenytoin, and mineral oil or stimulant laxatives when taken simultaneously with these drugs. Thiazide diuretics can interact with calcium carbonate and vitamin D supplements to increase the risk for hypercalcemia and hypercalciuria. Calcium supplements from natural products such as oyster shell should be avoided because of possible toxic contaminants. Hypercalcemia may be a manifestation of P deficiency (see Phosphorus section). Metastatic deposits of calcium precipitate in the infusion delivery system, in kidneys, and in other organs with an increased mortality have been reported in neonates who received ceftriaxone simultaneously with parenteral solutions containing calcium. 30
tissues of the skeleton and teeth, in biological membranes as phospholipids, and in cells as nucleotides and nucleic acids. About 85% of P is in the skeleton, primarily in the form of hydroxyapatite. Of the remainder, 14% is intracellular (primarily in the soft tissues) and 1% is extracellular in the circulation and interstitial fluid. Of the extracellular P, 70% is organic and contained within phospholipids, and 30% is inorganic. 31 At pH of 7.4, the mono- and di-hydrogen form is in a ratio of about 4:1. For that reason, P is usually expressed in mmol rather than mEq/L. The serum or plasma P concentration is ~1 to 2 mmol/L (3.16.2 mg/dL) and is higher at younger ages. Plasma P concentrations of preterm infants is about 0.5 mmol higher but may be as high as 2.81 mmol/L (8.7 mg/dL) without affecting plasma Ca concentration.1 This minute compartment of P is the major source of exchange of P associated with dietary uptake and absorption, renal excretion and reabsorption, and bone modeling and remodeling. This compartment is also the primary source of P for structural and high-energy phosphate in the cells of all tissues. When extracellular fluid P concentrations are low, cellular dysfunction follows. A normal level of P in the extracellular fluid is necessary for cellular function and skeletal mineralization. The physiological functions include the maintenance of mineral and acid- base homeostasis, the temporary storage of the transfer of energy derived from metabolic fuels, and the activation of many catalytic proteins through phosphorylation. 32 Most of these processes involve the recycling of P. Thus, the function of dietary P is to support tissue growth and to replace excretory and cellular and dermal losses.2
Sources
Phosphorus is ubiquitous in natural foods and is present in both organic and inorganic forms. Various phosphate salts used in food processing for non-nutritive functions (eg, moisture retention, smoothness, and binding) provide significant contributions to dietary P intake. Cola soft drinks contain phosphoric acid as the acidulant and provide about 50 mg of P per 12 oz serving.2 Phosphorus intake fromsoft drinks can be substantial when multiple beverages are consumed. Dairy and meat products have high P density. Plants, nuts, and seeds also are significant sources of P. Animal or synthetic protein has more bioavailable phosphorus than soy or grain-based protein. Phosphorus in plants (beans, peas, cereals, nuts) is present in the poorly digestible phytic acid. However, some phytate P is absorbed from the combined effect of food phytases, colonic bacteria enzymes,
Phosphorus
(1 mmol = 31 mg)

Phosphorus as phosphate is an essential constituent of all known protoplasm. The terms phosphorus and phosphate are often used interchangeably, but the term phosphate actually means the inorganic freely available form. This measurable component is generally referred to as phosphorus (P). Tissue P increases from ~0.5% of the body weight in the neonate to ~1% in the adult from an increase in bone and soft tissue mass. Structurally, P is incorporated in mineralized
MINERALS
51
and yeast products.2 Human milk has low P content, which decreases further with prolonged lactation, although the P bioavailability is higher than all other milks for infants. Compared to human milk, P content is higher in cows milk by five- to sixfold, standard cow milk-based infant formula by about twofold, and soy-based infant formula by about threefold. The Ca:P ratio varies widely in natural foods. However, both the Ca:P ratio and absolute quantities of these minerals are important to optimize mineral accretion in bone and soft tissue. P supplements are available as mono- and dibasic-phosphates, in both oral and parenteral forms. They are usually used for medical indications such as inherited metabolic defects.
hormone and thyroid hormone. Renal P reabsorption is increased with 1,25-dihydroxyvitamin D. The kidney can increase or decrease its P resorptive capacity to accommodate P needs. 32,33 In infants and children, lower glomerular filtration rate is probably the main determinant of the higher serum P because P resorptive capacity is high even in the small preterm infant.1 Healthy infants have lower serum P when breastfed compared to those fed infant formula.1,34 The least renal excretory work to maintain normal P homeostasis during the first year is achieved with human milk as the major source of minerals. In deficient states, renal retention of filtered phosphate is almost complete even in the preterm infant.1

Net absorption of P ranges from 55% to 70% in adults and 65% to 90% in children and infants. The fractional P absorption is virtually constant across a broad range of intake. The bulk of P absorption is passive (paracellular) and concentration-dependent. A saturable, active transcellular sodium (Na+)-dependent involving the type IIb Na+/phosphate cotransporter and facilitated by 1,25-dihydroxyvitamin D also exists. P is not absorbed in the stomach but is absorbed throughout the small bowel. The fractional absorption of P and other minerals is lower from infant formulas compared to human milk although the absolute amounts of each mineral absorbed from infant formulas are higher because of the much higher mineral content in infant formulas. Medications or foods that bind P (antacids, phosphate binders, and calcium) can decrease the net amount of P absorbed by decreasing the free phosphate for absorption. Unabsorbed Ca complexes with phytic acid can interfere with bacterial hydrolysis of phytate and decreases P absorption.2 The kidney is a major regulator of P homeostasis. Renal P is reabsorbed primarily at proximal tubular cells (70% 80%). The remaining is reabsorbed in the distal tubules. Serum P increases as the total P intake and absorption exceeds the renal tubular maximum transport for P. Renal P reabsorption is modulated by changes in basolateral basement membrane abundance of type IIa Na/phosphate cotransporter (Npt2a) protein and requires the interaction of Npt2a with various scaffolding and regulatory proteins. 33 Renal P reabsorption is decreased (ie, excretion is increased) by a decrease in renal Npt2a, an increase in dietary P intake, PTH, or fibroblast growth factor-23, or a loss of Phex function. Although the effects are more minor, renal P excretion is also increased by volume expansion, metabolic acidosis, glucocorticoids, and calcitonin. It is decreased by growth
Deficiency States
Cellular storage of phosphate and the portion of P that can be mobilized from bone are limited. Thus, dietary P is required to maintain extracellular fluid P, which is the source of P for the tissue metabolic phosphate. Normally, because P is ubiquitous in foods, dietary P deficiency rarely occurs unless the individual is subjected to near total starvation. However, small preterm infants with chronically low P intake from prolonged exclusive feeding of non-supplemented mothers milk; infants and children with poorly managed PN with inadequate P content, inappropriate administration of fluid and electrolyte therapy that causes excessive renal P loss; or rapid refeeding in the setting of diabetic ketoacidosis or severe malnourishment, especially if accompanied by diarrhea, are at risk for hypophosphatemia in addition to other electrolyte abnormalities.1,2,35 Individuals with chronic aluminum antacid therapy and heritable defects of P metabolism also can manifest P deficiency. Chronic diuretic therapy that increases urine P can exacerbate the P deficit. Clinical manifestations of P deficiency include anorexia, general debility, anemia, muscle weakness including respiratory compromise, bone pain, rickets and osteomalacia, increased susceptibility to infection, paresthesia, ataxia, confusion, and even death. 36 These severe manifestations usually occur when the extracellular fluid P is < 0.3 mmol/L (0.9 mg/dL). Plasma Ca may be elevated simultaneously, particularly in infants.1

Essentially all the adverse effects of excess P intake from any source are the result of hyperphosphatemia. These include adjustments in the hormonal control system regulating Ca homeostasis and may be complicated by hypocalcemia and its adverse effects, ectopic (metastatic) calcification,
52
particularly of the kidney, and possibly decreases in the intestinal absorption of Ca, iron, zinc, and copper but without documented clinical adverse effects. Hyperphosphatemia usually occurs in the setting of kidney disease and rarely occurs under normal circumstances. One exception is the development of hyperphosphatemia and secondary hypocalcemia in some healthy infants from the use of standard infant formulas. This is the result of a combination of higher intake of P from infant formulas relative to breast milk, and the inability to eliminate excess P because of immature renal and parathyroid functions. Clinically, this is exacerbated by the early introduction of solids or whole cows milk to the infant.1
Abnormalities in circulating Mg concentrations are associated with widespread cellular effects.
Sources
Magnesium is ubiquitous in foods but the Mg content of foods varies substantially. Green leafy vegetables are rich in Mg because chlorophyll is the Mg chelate of porphyrin. Unpolished grains and nuts also have high Mg content, whereas meats and milk have intermediate levels. Refined foods generally have the lowest Mg content.40,41 Water is a variable source of Mg depending on the source of ground water. Typically, hard water has higher concentrations of Mg salts.2,41 Human milk contains adequate amounts of Mg and infant formulas are mandated to contain at least 6mg/100 kcal.13 Supplements containing various Mg salts are freely available in oral forms. The proportion of elemental magnesium by weight is 60.3% for oxide; 28% for carbonate; 16% for citrate; ~12% for chloride, acetate, and lactate; 9.7% for sulfate; 6.8% for phosphate; 6.4% for ascorbate; and 5.4%for gluconate.15 Magnesium sulfate is available in parenteral form. Mg supplements may contribute a substantial portion of daily intake and are used as a basis for the derivation of tolerable upper intake levels.2
Magnesium
(1 mmol = 24 mg)

Magnesium (Mg) is the fourth most abundant cation in the body and is the second most abundant intracellular cation. Total body Mg content is ~25 g (1000 mmol), of which ~60% resides in bone. About one-third of the skeletal Mg is exchangeable and serves as a reservoir for maintaining extracellular Mg concentration. The rest of the Mg is in soft tissues such as muscle and organs, and ~1% is in extracellular fluid. Cellular Mg content is 6 to 9 mmol/kg net weight, and most of this Mg is localized in membrane structures (eg, microsome, mitochondria, plasma membrane). 37,38 The much smaller pool of free Mg in the cell is maintained at ~1 mmol/L and is in an exchanging equilibrium with membrane-bound Mg. This unbound intracellular Mg has a critical role in cellular physiology. 39 Intracellular Mg usually remains stable despite wide fluctuations in serum Mg. In Mg-deficient states, however, the intracellular content of Mg can be low despite normal serum concentrations. Serum Mg has a protein-bound (~30%) and an ultrafiltrable (~70%) portion. Of the latter, 70% to 80% is in ionic form. The remainder is complexed to anions, particularly phosphate, citrate, and oxalate. Magnesium is a required cofactor for > 300 enzyme systems. It is critical for normal ATP function and glucose metabolism and is necessary for both aerobic and anaerobic metabolism. It is important in cellular cytoskeleton contraction and at the myoneural junction, and therefore can alter skeletal and cardiac muscle function. It catalyzes enzymatic processes concerned with the transfer, storage, and use of energy; regulation of movement of potassium and Ca across the cell membranes; and numerous other cell functions.

The net absorption of Mg is about 40% to 60%. Fractional intestinal absorption is inversely proportional to the amount of Mg ingested. Intestinal absorption is via a passive gradient-dependent paracellular and an active saturable vitamin D-dependent transcellular mechanism. Magnesium is absorbed throughout the entire intestinal tract with maximal absorption at the distal jejunum and ileum.2 Magnesium absorption is not significantly affected by other nutrients at the usual dietary intake. It is lowered with high P intake, particularly if there is an associated high fiber and phytate intake, and at low protein intake.2,42 The kidney plays an important role in the homeostasis of divalent ions. Most of the ionized forms of Ca and Mg are reabsorbed at the proximal tubules and the thick ascending limb of Henles loop via a passive paracellular pathway. It is dependent on salt and water reabsorption and rate of fluid flow. At the level of the distal convolute tubule and the connecting tubule, ionized Ca and ionized Mg are reabsorbed via an active transcellular transport. Renal Mg transport also is affected by both hormonal (parathyroid hormone, calcitonin, glucagon, arginine vasopressin, 17 beta estradiol) and non-hormonal factors. High intake of glucose, sodium, Ca, and Mg, chronic excessive
MINERALS
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alcohol intake, as well as elevated serum Mg or Ca, depletion of potassium and phosphate, and metabolic acidosis inhibit Mg and Ca reabsorption, leading to increased urine excretion of both cations.43
Deficiency States
Magnesium deficiency is usually associated with malabsorption, increased losses from the gut or kidney, or during refeeding of severe and chronically malnourished individuals. Chronic therapy with loop diuretics, cisplatin, and tacrolimus are among the increasing list of medications that result in increased renal Mg excretion and predisposition to Mg deficiency.43 There are also increasing reports of patients with heritable defects of Mg transport that lead to Mg wasting and deficiency states.44 The typical deficit required to produce symptomatic hypomagnesemia is approximately 0.5 to 1 mmol (1224 mg)/kg of body weight.45 Hypomagnesemia is usually associated with a significant Mg deficit. These individuals often are at risk for concurrent hypocalcemia, hypokalemia, hypophosphatemia, and possible disturbance of acid-base status. The loss of other nutrients such as zinc from the gastrointestinal secretion also may be considerable. Symptoms and signs of hypomagnesemia, which often coexists with hypocalcemia, may be indistinguishable. Prolonged dietary Mg deprivation in human adults leads to personality change, tremor, muscle fasciculations, spontaneous carpopedal spasm, and generalized spasticity as well as hypomagnesemia, hypocalcemia, and hypokalemia.45 In infants, acute complications associated with clinical manifestations include seizure, apnea, cyanosis and hypoxia, electrocardiographic changes, bradycardia, and hypotension.
received Mg therapy prior to delivery.1 Acute hypotonia, apnea, hypotension, and refractory bradycardia mimicking septic shock syndrome has been reported in premature infants accidentally overdosed with Mg in PN.46 In adults with hypermagnesemia, hypotension and urinary retention occur at serum Mg concentrations of 1.67 to 2.5 mmol/L (46 mg/dL); central nervous system depression, hyporeflexia, and electrocardiographic abnormalities (ie, increased atrioventricular and ventricular conduction time) at 2.5 to 5 mmol/L (612 mg/dL); and respiratory depression, coma, and cardiac arrest above 5 mmol/L (12 mg/dL).47

Ingestion of Mg from natural foods has not been shown to exert any adverse effects. However, adverse effects of excess Mg intake have been reported from non-food sources such as various Mg salts for pharmacologic purposes, particularly in patients with renal dysfunction. The amount of Mg supplement is the basis from which the current upper limit of Mg intake is derived.2 The primary initial manifestation of excessive Mg intake from non-food sources is diarrhea (probably from its osmotic effect), and may be accompanied by nausea and abdominal cramping. Clinical signs of neuromuscular depression with floppiness and lethargy, and respiratory depression are frequent manifestations of severe neonatal hypermagnesemia in infants born to mothers who
1. Which of the following statements on bioavailability of calcium is incorrect? A. Highest in dairy products in the diet B. Presence of phytate in plants can decrease calcium availability C. Calcium supplement from natural sources such as oyster shells may be contaminated with toxic metals D. Vitamin D status is one of the determinants of calcium bioavailability E. Low-fat dairy products have low calcium content 2. Which of the following statements on calcium absorption is incorrect? A. Inversely related to dietary content of calcium B. Lowest in pediatric ages C. Is diminished with steatorrhea D. Varies with type of food consumed E. Dietary zinc decreases calcium absorption 3. Which of the following statements about phosphorus is incorrect? A. It is ubiquitous in natural foods B. Dietary intake of phosphorus is increased with increased consumption of processed foods C. Calcium phosphorus ratio of natural foods varies widely D. Phosphorus deficiency can result in hypercalcemia E. None of the above 4. Extracellular fluid (and serum) inorganic phosphate is regulated by: A. Renal function B. Parathyroid hormone C. Fibroblast growth factor-23 D. All of the above E. None of the above
54
5. All of the following statements associated with magnesium deficit are correct except for: A. May be associated with chronic gastrointestinal losses B. May result in fecal fat loss C. May be associated with deficiency of other nutrients D. May result in hypocalcemia E. May be asymptomatic 6. Which of the following statements about hypermagnesemia is incorrect? A. Can occur with drinking hard water B. Can result in cardiac arrhythmia C. Can cause respiratory failure D. Usually occurs only with pharmacologic doses of magnesium E. Can decrease muscle tone See p. 487 for answers.
References
1. Koo WWK. Neonatal calcium, magnesium and phosphorus disorders. In: Lifshitz F, ed. Pediatric Endocrinology: A Clinical Guide. 5th ed. New York, NY: Marcel Dekker Inc; 2007:497529. 2. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride. Washington, DC: National Academy Press; 1997. 3. U.S. Food and Drug Administration. Dietary supplements. http://www.fda.gov/Food/DietarySupplements/default. htm. Accessed November 20, 2009. 4. Koo WWK, McLaughlin K, Saba M. Nutrition support for the neonatal intensive care patients. In: Merritt R, ed. The A.S.P.E.N. Nutrition Support Practice Manual. 2nd ed. Silver Spring, MD: American Society for Parenteral and Enteral Nutrition; 2005:301314. 5. National Institutes of Health. Office of Dietary Supplements. Dietary supplement fact sheet: Calcium. http://ods.od.nih. gov/factsheets/calcium.asp. Accessed August 14, 2009. 6. Pennington JAT, ed. Bowes & Churchs Food Values of Portions Commonly Used. 18th ed. Philadelphia, PA: J. B. Lippincott; 2005. 7. Calcium content in foods. CalorieKing for Food Awareness Web site. http://www.calorieking.com. Accessed November 25, 2009. 8. Greer FR, Krebs NF, Committee on Nutrition. Optimizing bone health and calcium intakes of infants, children, and adolescents. Pediatrics. 2006;117:578585. 9. Fischer PR, Thacher TD, Pettifor JM. Pediatric vitamin D and calcium nutrition in developing countries. Rev Endocr Metab Disord. 2008;9:181192.
10. U.S. Department of Health and Human Services. Office of the Surgeon General. Bone Health and Osteoporosis: A Report of the Surgeon General. 2004. http://www.surgeongeneral.gov/ library/bonehealth/content.html. Accessed March 20, 2009. 11. U.S. Food and Drug Administration. Guidance for Industry: Food Labeling: Health Claims; Calcium and Osteoporosis, and Calcium, Vitamin D, and Osteoporosis. http://www.fda.gov/ Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/FoodLabelingNutrition/ucm152626.htm. Accessed August 24, 2009. 12. National Heart Lung and Blood Institute, National Institutes of Health. Your guide to lowering your blood pressure with DASH.http://www.nhlbi.nih.gov/health/public/heart/ hbp/dash/index.htm. Accessed August 16, 2009. 13. U.S. Food and Drug Administration. Code of Federal Regulations Title 21. Infant formula nutrient specifications. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFR Search.cfm?fr=107.100&SearchTerm=infant%20 formula. Accessed August 2, 2009. 14. Levenson D, Bockman R. A review of calcium preparations. Nutr Rev. 1994;52:221232. 15. Drug Facts and Comparisons 2009. St. Louis, MO: Wolters Kluwer Health. 16. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate. Washington, DC: National Academy Press; 2004. 17. Heaney RP, Rafferty K. Carbonated beverages and urinary calcium excretion. Am J Clin Nutr. 2001;74:343347. 18. Koo WWK, Kaplan LA. Aluminum and bone disorders: with specific reference to aluminum contamination of infant nutrients. J Amer Coll Nutr. 1988;7:199214. 19. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006;296:29472953. 20. Koo WWK, Walters JC, Esterlitz J, Levine RJ, Bush AJ, Sibai B. Maternal calcium supplementation and fetal bone mineralization. Obstet Gynecol. 1999;94:577582. 21. Bronner F. Recent developments in intestinal calcium absorption. Nutr Rev. 2009;67:109113. 22. Oramasionwu GE, Thacher TD, Pam SD, Pettifor JM, Abrams SA. Adaptation of calcium absorption during treatment of nutritional rickets in Nigerian children. Br J Nutr. 2008;100:387392. 23. Thacher TD, Obadofin MO, OBrien KO, Abrams SA. The effect of vitamin D2 and vitamin D3 on intestinal calcium absorption in Nigerian children with rickets. J Clin Endocrinol Metab. 2009;94:3314-3321. 24. Slemenda CW, Reister TK, Hui SL, Miller JZ, Christian JC, Johnston CC Jr. Influences on skeletal mineralization in children and adolescents: evidence for varying effects of sexual maturation and physical activity. J Pediatr. 1994;125:201207. 25. Specker BL. Evidence for an interaction between calcium intake and physical activity on changes in bone mineral density. J Bone Miner Res. 1996;11:15391544. 26. Nattiv A. Stress fractures and bone health in track and field athletes. J Sci Med Sport. 2000;3:268279.
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27. Key TJ, Appleby PN, Rosell MS. Health effects of vegetarian and vegan diets. Proc Nutr Soc. 2006;65:3541. 28. Shannon MT, Wilson BA, Stang CL. Health Professionals Drug Guide. Stamford, CT: Appleton & Lange; 2000. 29. Jellin JM, Gregory P, Batz F, Hitchens K. Pharmacists Letter/ Prescribers Letter Natural Medicines Comprehensive Database. 3rd ed. Stockton, CA: Therapeutic Research Facility; 2000. 30. U.S. Food and Drug Administration. Information for Healthcare Professionals: Ceftriaxone (marketed as Rocephin and generics). http://www.fda.gov/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ ucm084263.htm#main. Accessed November 20, 2009. 31. Nordin BEC. Phosphorus. J Food Nutr. 1988;45:6275. 32. Takeda E, Taketani Y, Sawada N, Sato T, Yamamoto H. The regulation and function of phosphate in the human body. Biofactors. 2004;21:345355. 33. Tenenhouse HS. Regulation of phosphorus homeostasis by the type IIa Na/phosphate cotransporter. Annu Rev Nutr. 2005;25:197214. 34. Specker BL, Lichtenstein P, Mimouni F, Gormley C, Tsang RC. Calcium-regulating hormones and minerals from birth to 18 months of age: a cross-sectional study. II. Effects of sex, race, age, season, and diet on serum minerals, parathyroid hormone, and calcitonin. Pediatrics. 1986;77:891896. 35. Freiman I, Pettifor JM, Moodley GM. Serum phosphorus in protein energy malnutrition. J Pediatr Gastroenterol Nutr. 1982;1:547550. 36. Lotz M, Zisman E, Bartter FC. Evidence for a phosphorus-depletion syndrome in man. N Engl J Med. 1968;278:409415. 37. Elin RJ. Assessment of magnesium status. Clin Chem. 1987;33:19651970.
38. Reinhart RA. Magnesium metabolism: a review with special reference to the relationship between intracellular content and serum levels. Arch Intern Med. 1988;148:24152420. 39. Saris NE, Mervaala E, Karppanen H, Khawaja JA, Lewenstam A. Magnesium. An update on physiological, clinical and analytical aspects. Clin Chim Acta. 2000;294:126. 40. Egan SK, Tao SS, Pennington JA, Bolger PM. U.S. Food and Drug Administrations Total Diet Study: intake of nutritional and toxic elements, 1991-96. Food Addit Contam. 2002;19:103125. 41. National Institutes of Health. Office of Dietary Supplements. Magnesium. http://ods.od.nih.gov/factsheets/magnesium. asp. Accessed August 14, 2009. 42. Schwartz R, Walker G, Linz MD, MacKellar I. Metabolic responses of adolescent boys to two levels of dietary magnesium and protein. I. Magnesium and nitrogen retention. Am J Clin Nutr. 1973;26:510518. 43. Quamme GA. Renal magnesium handling: new insights in understanding old problems. Kidney Int. 1997;52:11801195. 44. OMIM - Online Mendelian Inheritance in Man. National Center for Biotechnology Information. http://www.ncbi. nlm.nih.gov/sites/entrez. Accessed August 20, 2009. 45. Shils ME. Experimental human magnesium depletion. Medicine. 1969;48:6185. 46. Ali A, Walentik C, Mantych GJ, Sadiq HF, Keenan WJ, Noguchi A. Iatrogenic acute hypermagnesemia after total parenteral nutrition infusion mimicking septic shock syndrome: two case reports. Pediatrics. 2003;112:e7072. 47. Mordes JP, Wacker WE. Excess magnesium. Pharmacol Rev. 1978;29:273300.
Water-Soluble Essential Micronutrients

Winston Koo, MBBS, FACN, CNS, Judith Christie, RN, MSN, May Saba, PharmD, BCNSP, Mirjana Lulic-Botica, BSc, BCPS, and LetitiaWarren, RD, CSP
CONTENTS
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Digestion, Absorption, and Metabolism. . . . . . . . . . . . . . . 57 Dietary Reference Intake. . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Increased Demands and Predisposition toDeficiency States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Management of Deficiency State andSupplementation . 59 Specific Nutrients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 Thiamin (Vitamin B1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 Riboflavin (Vitamin B2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 Niacin (Vitamin B3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Vitamin B6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Folate (Vitamin B9). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Vitamin B12 (Cobalamin) . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Vitamin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Pantothenic Acid (Vitamin B5) . . . . . . . . . . . . . . . . . . . . . . 69 Biotin (Vitamin B7). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Choline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Learning Objectives
1. Understand the physiological basis for the function and requirement common to the group or to the individual water-soluble essential micronutrients. 2. Understand the common risk factors and special considerations in the predisposition for the development of deficiency state for these nutrients. 3. Understand the common manifestations and diagnosis of deficiency state for these micronutrients. 4. Understand the potential risks with excessive intake of these micronutrients. Water-soluble essential micronutrients include the 8 B-complex vitamins: thiamin (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), vitamin B6 (pyridoxine), vitamin B12 , folate (vitamin B9), pantothenic acid (vitamin B5), biotin (vitamin B7); and vitamin C and choline. These micronutrients affect the function of all cells, and many have interrelated transport mechanisms, metabolism, and functions. In pediatric subjects, these cellular functions additionally affect growth and development. Some of these essential nutrients can be synthesized de novo from other nutrients (eg, niacin from tryptophan, choline from methylation of phosphatidylethanolamine) or from intestinal bacteria (eg, riboflavin, pyridoxine, vitamin B12 , pantothenic acid, and biotin), although in amounts inadequate to meet physiological demands. One or more of these micronutrients are used to fortify many food and drink products, some nutrients such as choline are added to foods as an emulsifying agent, and all water-soluble micronutrients are available as individual supplements or as part of multivitamin +/- multinutrient
Overview
56
WATER-SOLUBLE ESSENTIAL MICRONUTRIENTS
57
supplements.19 All are available as oral and parenteral preparations except for choline, which is available in oral form only. Multivitamin preparations used for parenteral nutrition (PN) are shown in Table 7-1. Vitamin B12 is also available in an intranasal form. 5,6,9 Dietary supplements in the form of multivitamins and multiminerals are taken regularly by more than 30% of children in the United States with the lowest use reported among infants younger than 1 year (11.9%) and teenagers 14 to 18 years old (25.7%) and highest use among 4- to 8-year-old children (48.5%).10 Given such extensive use, nutrient intakes from dietary supplements must be included to obtain accurate estimates of overall nutrient intake in children. For healthy near-term or term infants, milk from well-nourished mothers ingesting a varied diet should be sufficient to provide all water-soluble essential micronutrients for their daily needs. Small preterm infants have greater needs for these and other nutrients because of minimal or absent reserves, and for catch-up growth. Human milk fortifier added to mothers milk raises the concentration of these nutrients to multiple folds higher than what is naturally present in human milk and should be sufficient for preterm infants tolerating adequate volumes of enteral intake. 3 For formula-fed infants, the use of commercial milk-based formula designed for term and preterm infants is expected to be adequate. 3 Beyond infancy, a culturally appropriate
varied diet assures the adequacy of intake at all life stages because these essential nutrients are present in a wide range of food products.13,7 These dietary micronutrients are released with the digestion of foods and then absorbed in free form or as small molecular complexes. Absorption is usually by active transport at low nutrient intake and by passive diffusion at high intake. Absorption occurs mainly at the jejunum except for cobalamin which is absorbed only at the ileum under physiological conditions. Some absorption occurs at the stomach (niacin) and proximal colon (riboflavin, biotin).11 Postabsorptive transport usually occurs as an enzyme complex or bound to proteins. Erythrocytes may serve both as transporter and storage source. Tissue uptake is usually specific to each nutrient. Some of these essential nutrients have interrelated metabolism and function. The bioavailability of water-soluble vitamin supplements is generally similar to or better than that from dietary sources when tested under the same conditions.1,2,5,6,9
Digestion, Absorption, and Metabolism
Dietary Reference Intake
The current dietary reference intake (DRI) values for pediatric populations are provided in Table 7-2. However, current reference values are subject to change with increasing understanding of the relationship among various
Table 7-1 Content Per Unit Dose of Multivitamin Preparations for Use with Parenteral Nutrition*
Ingredient M.V.I. Pediatric M.V.I. Adult (for ages 11 y) M.V.I. 12 (no vitamin K)
Unit dose volume (mL) Fat-soluble vitamins Vitamin A (retinol, mg) Vitamin D (ergocalciferol, mcg) Vitamin E (dl--tocopheryl acetate, mg) Vitamin K (phytonadione, mcg) Water-soluble vitamins Vitamin B1 (thiamin, mg) Vitamin B2 (riboflavin 5-phosphate sodium, mg) Niacinamide (vitamin B3, mg) Vitamin B6 (pyridoxine hydrochloride, mg) Folic Acid (vitamin B9, mcg) Vitamin B12 (cyanocobalamin, mcg) Vitamin C (ascorbic acid, mg) Dexpanthenol (d-pantothenyl alcohol, provitamin B5, mg) Biotin (vitamin B7, mcg)
5 0.7 10 7 200 1.2 1.4 17 1 140 1 80 5 20
10 1 5 10 150 6 3.6 40 6 600 5 200 15 60
10 1 5 10 none 6 3.6 40 6 600 5 200 15 60
* Data from manufacturer product insert (Hospira, Inc., Lake Forest, IL). Lyophilized powder reconstituted immediately prior to use. Dual vial liquid formulation. Vial one or lower chamber of unit vial contains fat-soluble vitamins A, D, E, and K; and water-soluble vitamins B1, B2, B6, C, niacinamide, and dexpanthenol. Vial two or upper chamber of unit vial contains: biotin, folic acid, and vitamin B12.
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Table 7-2 Dietary Reference Intake of Water-Soluble Essential Micronutrients in Pediatric Populations1,2
Life Stage Thiamin (B1) mg Riboflavin (B2) mg Niacin (B3) mg B6 (Pyridoxine) mg Folate (B9) mcg B12 (cobalamin) mcg Vitamin C mg Pantothenic acid (B5) mg* Biotin (B7) mcg* Choline mg*
06 m* 712 m* 13 y 48 y Males 913 y 1418 y Females 913 y 1418 y Pregnancy 1418 y Lactation 1418 y Highest intake UL
0.2 0.3 0.5 0.6 0.9 1.2 0.9 1.0 1.2 1.4 11 mg at > 51 y NA
0.3 0.4 0.5 0.6 0.9 1.3 0.9 1.0 1.4 1.6 11 mg at > 70 y NA
2 4 6 (15) 8 (20) 12 (20) 16 (30) 12 (20) 14 (30) 18 (30) 17 (30) 77 mg at 5170 y
0.1 0.3 0.5 (30) 0.6 (40) 1.0 (60) 1.3 (80) 1.0 (60) 1.2 (80) 1.9 (80) 2.0 (80) 3.9 mg at 1930 y
65 80 150 (300) 200 (400) 300 (600) 400 (800) 300 (600) 400 (800) 600 (800) 500 (800) 625 mcg at 5170 y
0.4 0.4 0.9 1.2 1.8 2.4 1.8 2.4 2.6 2.8 36.8 mcg at 1455 y NA
40 50 15 (400) 25 (650) 45 (1200) 75 (1800) 45 (1200) 65 (1800) 80 (1800) 115 (1800) 656 mg at 5170 y
0.2 0.2 2 3 4 5 4 5 6 7 NA NA
0.7 0.7 8 12 20 25 20 25 30 35 NA NA
125 150 200 (1000) 250 (1000) 375 (2000) 550 (3000) 375 (2000) 400 (3000) 450 (3000) 550 (3000) NA
* AI, Adequate intake = observed or experimentally determined estimates of nutrient intake by a group or groups of healthy people. AI is the only reference level provided for infants < 12 months, and for pantothenic acid, biotin, and choline at all life stages and genders. RDA, Recommended dietary allowance is calculated as + 2 standard deviations of the estimated average requirement or in its absence, a coefficient of variation of 10% to 15% for each standard deviation is assumed for a life stage and gender group. UL, Tolerable upper intake level = highest level of daily nutrient intake that is likely to pose no risk of adverse health effects to almost all individuals in the general population. Upper limit for each life stage is indicated in parenthesis. NA = not available. Highest intake = highest reported daily mean intake from both food and supplements at 95th percentile for any life stage or gender group.
nutrients and increasing data on the type and bioavailability of specific nutrients from naturally occurring dietary sources, fortification of foods and drinks, and supplements. For infants, DRI of each essential micronutrient is based on adequate intake (AI): the average daily intake of a specific nutrient in healthy infants fed principally human milk during the first and second 6 months after birth. For ages beyond 1 year, several sets of reference values are used and include AI, estimated average requirement (EAR), and recommended dietary allowance (RDA). Establishing AI depends on the availability of the content of the specific essential micronutrient in food-composition data, largescale epidemiologic studies to determine the dietary and any supplement intake of the nutrient in group/s of healthy people of both genders, and at the specific life stage. These data in turn allow the determination of EAR which is a daily nutrient intake value estimated to meet the requirement of half the healthy individuals, and RDA which is the
average daily dietary intake level that is sufficient to meet the nutrient requirement of nearly all (97% to 98%) healthy individuals. If sufficient data are available, dose response risk assessment to high intakes and setting of upper tolerable levels of intake (UL) are made. The absence or limited data in children and adolescents often necessitated the derivation of EAR, RDA, and UL in these life stages and gender by extrapolation downwards from adult data, and rounded up. AI is used when RDA cannot be determined.1,2
Increased Demands and Predisposition toDeficiency States
Requirements for many water-soluble vitamins generally increase with growth, pregnancy, lactation, physical exertion, fever, and conditions associated with increased metabolic needs. Tobacco and alcohol also affect the needs for these nutrients. More than 15% of in-school youths in the United States are reported to be current cigarette smokers12
59
and there is an association between cigarette smoking and dieting in adolescents even in non-overweight individuals.13 Smokers may have an increased need for antioxidant vitamins because of the oxidative stress from smoking.1 Also there may be a concomitant decreased intake because of inappropriate dieting.13 Alcohol is used by more young people than tobacco and illicit drugs.14 Alcohol abuse is often associated with poor dietary intake of many essential nutrients. In addition, alcohol can directly or indirectly interfere with the digestion, absorption, and metabolism of multiple essential water-soluble micronutrients.1,2,1517
Table 7-3 Predispositions to Deficiency of Water-Soluble Essential Micronutrients* Limited body store particularly in infants and young children Inadequate endogenous synthesis Decreased intake Parenteral nutrition without water-soluble vitamins Food faddism or severe dietary restrictions Food refusal Anorexia nervosa Decreased bioavailability Cooking and storage of foods at high temperatures and prolonged periods Addition of baking soda to vegetables Decreased absorption and/or increased loss Celiac disease, Crohn disease, cystic fibrosis, gastrointestinal bypass surgery, and any malabsorption states Nutrient-nutrient and nutrient-drug interaction (see Table 7-4) Mixed predispositions including some or all of above Hyperemesis gravidarum Chronic renal dialysis Alcohol abuse Human immunodeficiency virus infection * There is usually more than one predisposition to the development of deficiency state. Occurs during production shortage of parenteral multivitamin preparation.
have micronutrient deficiencies, 20 particularly in developed countries, and it is at least theoretically possible that certain micronutrients might exacerbate HIV infection.18,21 Certain drugs including chronic diuretic therapy through its actions on excretion or metabolism of certain nutrients also predisposes individuals to deficiency states (Table 7-4). Thus, the management of deficiency states must take into account all potential predisposing factors.13,22 Isolated water-soluble vitamin deficiency is rare. However, biochemical deficiency of vitamin B12 as indicated by increased urinary methylmalonic acid has been reported in 2- to 14-month-old infants predominantly fed human milk from vegan mothers.23 Thiamin deficiency with cardiac failure and encephalopathy was reported during a shortage of multivitamin preparation for patients requiring total parenteral nutrition.24 Inborn errors of metabolism associated with various aspects of digestion, absorption, transport, and metabolism of specific essential micronutrients also may result in deficiency of the specific micronutrient. These heritable predispositions to deficiency or dependency states have been reported for niacin, vitamin B6, folate, vitamin B12 , biotin, and vitamin C and the number of disorders is expected to increase with improvements in molecular diagnostic techniques. Clinical manifestations of deficiency states may overlap and biochemical indicators of deficiency may be affected by laboratory technique. Normal ranges of laboratory values may vary with life stages and possibly other physiologic factors such as gender. Thus, interpretation of nutrient status must take into account these variables.
Management of Deficiency State andSupplementation
Most deficient states are associated with deficiencies in more than one water-soluble essential micronutrient. There are many potential predispositions to the development of deficiency states and multiple predisposing factors may be present (Table 7-3). Deficiency of multiple micronutrients is commonly associated with human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS). It is likely a complex interplay of primary dietary deficiency, deficiencies secondary to antiretroviral-induced or concomitant diarrheal diseases, and inflammationsuppressed circulating nutrient biomarkers. Micronutrient supplementation probably provides some overall benefits with respect to growth in children and pregnancy outcomes.18,19 However, not all children with HIV infection
Treatment of deficient state requires an understanding of the primary cause, the possibility of deficiency of other nutrients, and concomitant therapies that may interfere with effective replacement therapy. The initial treatment may require an amount of micronutrient that is 10- to 100-fold or greater than the daily requirement and delivered via a route that will ensure delivery to the tissues, for example, parenteral or intranasal delivery rather than oral if there is a significant malabsorption state. Correction of the underlying cause if possible, continued monitoring for clinical response, and normalization of laboratory parameters are warranted. Thus, management of deficient state should be individualized taking into account the cause, concomitant diet, and non-nutritional therapy. Close monitoring of patients requiring total parenteral nutritionparticularly those patients with abnormal gastrointestinal losses, organ
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Table 7-4 Characteristics of Water-Soluble Essential Micronutrients*

Adult Tissue Store Biological Half-life Major Interactions with Other Nutrients Interactions with Drugs Deficiency Major Clinical Manifestations DeficiencyBiochemical Erythrocyte (RC), Blood (WB), Plasma (P) RC or WB Thiamin Toxicity
Thiamin (B1)
~30 mg
918 d
Not available
Excess alcohol & caffeine, diuretics Anticholinergic, tricyclic antidepressant, phenothiazines, phenytoin, probenecid, thiazide diuretics, doxorubicin Isoniazid
Beriberi: wet, dry. Wernicky Encephalopathy Ariboflavinosis: pharyngitis, cheilosis, angular stomatitis, glossitis, seborrheic dermatitis
Riboflavin (B2)
Very low
Minutes
Folate, pyridoxine, niacin
pyrophosphate (TPP); RC transketolase activity with TPP RC Riboflavin; RC erythrocyte glutathione reductase activity coefficient with FAD stimulation; 24 h urine riboflavin
Rapid injection: anaphylactoidlike reaction Photo-oxidation of some amino acids
Niacin (B3)
Not available
45 min
Riboflavin, pyridoxine
Pellegra: diarrhea, RC nicotinamide adenine dementia, dinucleotide:nicotinamide dermatitis adenine dinucleotide phosphate ratio; 24 h U niacin & its metabolites
B6 (Pyridoxine) Folate
160 mg assume muscle has 80% 1228 mg, liver has ~50%
25 d
Riboflavin, niacin, folate, zinc B12
Isoniazid, L-dopa
Seizures
P pyridoxal phosphate, RC Aspartate & alanine
transferase saturation
Vasodilatory, nausea & vomiting, hepatitis, neurovisual disturbance, glucose intolerance Peripheral sensory neuropathy Exacerbates B12 deficient neuropathy
Erythrocyte ~8 wk
Antifolate medications
B12 (cobalamin)
23 mg, liver has 50%+
6d
Folate
Vitamin C
2g
840 d
Pantothenic acid Biotin
Not available Not available Not available
Not available
Glutathione, tocopherol, flavanoid, iron, copper Not available
Bile acid sequestrants, H2 receptor antagonist, proton pump inhibitors Aspirin, warfarin, proton pump inhibitors Not available Not available Not available
Seizures, neuromotor disorder, developmental delay, megaloblastic anemia Macrocystic megaloblastic anemia, Nervous system involvement Scurvy
RC folate, P Homocysteine
P B12, P & U Methylmalonic acid & P Homocysteine
Cyanocobalamin worsens Lebers optic atrophy, use hydroxy cobalamin Nausea, abdominal cramps, and diarrhea Not available Not available
P ascorbate < 0.2 mg/dL, RC and leukocyte
ascorbate
2h Avidin binds (postingestion biotin elimination) 43 h Folate
Choline
Gastrointestinal and nervous system Seizures, developmental delay, rash, alopecia Non-specific
No consistent changes in RC, WB or P

U biotin, 3-hydroxyisovaleric acid
P , RC, and tissue choline
and phosphatidylcholine
Hypotension, cholinergic, fishy odor
* Insufficient data to provide quantitative data in some cells. Selected list. For updated list.9, 35
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failure, or pre-existing nutrient deficiencyis critical to the clinical management. Fortification of selected nutrients, such as folic acid in the diet, is effective in the improvement of folate status of the population. There is no evidence of adverse effect from the consumption of naturally occurring water-soluble nutrients in foods. This is presumably in part the result of lowered fractional absorption at high intakes. The increasing practice of ingesting multinutrient supplements to provide an intake similar to daily need has no documented long-term benefit but is unlikely to result in any long-term side effects. Their use does not compensate for poor food choices and inadequate diet. Furthermore, at high intakes of supplements or if the individual has an underlying metabolic disorder that enhances or interferes with the action of a specific nutrient or the drug, clinical adverse effects may result from nutrient-nutrient and drug-nutrient interactions (Table 7-4). Detailed descriptions of some of these interactions may be obtained from multiple sources.1,2,5,6,9 There is limited understanding of the biochemical and genetic mechanisms whereby impaired metabolism of these essential micronutrients increases the risk for developmental anomalies and disease. Similarly, understanding of the mechanisms whereby elevated intake of these nutrients protects against these pathologies is also limited. Current initiatives to increase intake of some essential nutrients such as folic acid in human populations to ameliorate developmental anomalies and prevent disease, while effective, lack predictive value with respect to unintended adverse outcomes. Systematic studies of excessive intake of some water-soluble essential micronutrients for prolonged periods are extremely limited.13 The lack of reported adverse effects does not mean that there is no potential for adverse effects from prolonged periods of high intakes. Nevertheless sufficient data are available to set the upper limit of intake for niacin, vitamin B6, folate, vitamin C, and choline (Table7-2).
of metabolic reactions: decarboxylation of -keto acids (eg, pyruvate, -ketoglutarate, and branch-chain keto acids) and transketolation (eg, among hexose and pentose phosphates). Thiamin requirement is a function of carbohydrate intake and is critical to the metabolism of carbohydrates and branched-chain amino acids, synthesis of neurotransmitters glutamate and -amino butyric acid, nicotinamide adenine dinucleotide phosphate (NADPH), and the pentose sugars deoxyribose and ribose.1 TPP is also present in nerve membranes and activates a chloride channel for nerve conduction.
Source
Thiamin in the diet includes free thiamin, phosphorylated thiamin, and protein-phosphate complexes. Dietary sources include enriched, fortified, or whole grain rice; pasta and cereals; pork; eggs; yeast; legumes; and nuts. Thiamin is lost during processing to white flour, from milling of brown rice, and during cooking. Thiamin in fortified foods and pharmaceutical preparations are usually thiamin salts: thiamin hydrochloride and thiamin mononitrate. Thiamin supplement is available in oral and injectable forms as thiamin salts or as part of multivitamin preparations. Lipid-soluble thiamin derivatives called allithiamins are also available and may be better absorbed at higher intakes.9
Absorption, Metabolism, and Excretion

Thiamin uptake by the small intestines and by cells within various organs is mediated by a saturable, high-affinity transport system. At high intake, absorption can occur by passive diffusion. Following absorption mainly at the jejunum, thiamin is transported by blood in both erythrocytes (~90%) and plasma. Non-phosphorylated thiamin is weakly bound to plasma proteins. The liver appears to be the major organ for phosphorylation of thiamin although it can occur in all tissues. After an oral dose of thiamin, peak urine excretion occurs in about 2 hours and is nearly complete after 4 to 6 hours. However, the biological half-life of the vitamin is much longer and estimated to be between 9 to 18 days. Total thiamin content in the adult human is estimated to be ~30 mg.17
Specific Nutrients Thiamin (Vitamin B1)

Chemically, thiamin consists of substituted pyrimidine and thiazole rings linked by a methylene bridge. Thiamin exists mainly in various interconvertible phosphorylated forms: thiamin monophosphate (TMP), thiamin triphosphate (TTP), and ~80% as thiamin pyrophosphate (TPP). TPP, the coenzyme form of thiamin, is involved in 2 main types
Deficiency State
Thiamin deficiency can occur with inadequate intake particularly during PN without added water-soluble vitamins,24 or inadequate absorption, and excessive loss from multiple causes. A state of severe depletion may occur in less than 3 weeks from a strict thiamin-deficient diet but the
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most common cause of thiamin deficiency in affluent countries is alcoholism.16,17 Alcohol abuse is often associated with poor dietary intake of many essential nutrients, and decreases the absorption and phosphorylation of thiamin. Patients with end-stage organ failure especially of the liver are at risk for deficiency of thiamin and multiple nutrients. A number of inborn errors of metabolism have been described in which clinical improvements can be documented following administration of pharmacologic doses of thiamin, such as thiamin-responsive megaloblastic anemia with ringed sideroblasts. The latter is part of a clinical triad including diabetes mellitus and sensorineural deafness, associated with an autosomal recessive defect in thiamin transporter.15 The classic clinical syndromes associated with deficiency of thiamin include Beriberi or Wernickes encephalopathy. Beriberi is traditionally classified as dry or wet form. Dry beriberi is characterized by a symmet rical peripheral neuropathy with progressive weakness, muscle wasting, difficulty walking, and ataxia and is accompanied by paresthesia and loss of deep tendon reflex. Wet beriberi is secondary to cardiomyopathic congestive cardiac failure and edema. Infantile beriberi is characterized by shock at 2 to 3 months in a breastfed child with or without a preceding history of weak cry and poor feeding. It generally occurs in the exclusively breastfed infant whose mother has a subclinical thiamin deficiency.25 Wernickes encephalopathy is characterized by altered consciousness as well as the triad of ophthalmoplegia, nystagmus, and ataxia. It is generally seen in adults with alcohol abuse and malnutrition although it has been reported in infants and children. 25,26 Thiamin deficiency from feeding of unfortified soy infant formula due to manufacturing error has been reported.27, 28 Clinical presentation occurred between 2 and 12 months. Initial manifestations were non-specific and included vomiting, lethargy, irritability, abdominal distention, diarrhea, respiratory symptoms, developmental delay, and failure to thrive. Respiratory and gastrointestinal infections were noted in many of the reported cases. Classic manifestation of ophthalmoplegia or death also occurred in several infants. Laboratory investigations include abnormal magnetic resonance imaging at the frontal lobes, basal ganglia, periaqueductal region, thalami, and the mammillary bodies, while magnetic resonance spectroscopy demonstrates a characteristic lactate peak.28 Biochemical diagnosis of thiamin deficiency is by low TPP in erythrocyte and whole blood29 or by the transketolase activation test. 30 The latter measures the whole blood or erythrocyte transketolase
activity at baseline which is increased after adding TPP if the individual is deficient. Acute symptomatic improvement occurs rapidly within one day of treatment.27 However, neurodevelopmental delay, particularly in receptive and expressive language, 31 and recurrent seizures32 have been noted up to 6 years of follow up.
Supplementation
Prophylactic use of thiamin supplements may be warranted in malabsorption disorders. Occasional reports of anaphylactic reaction with parenteral administration of thiamin has been noted but toxic effects of thiamin excess have not been studied systematically.1
Riboflavin (Vitamin B2)

Riboflavin (7,8-dimethyl-10-ribityl-isoalloxazine) is a water-soluble, yellow, fluorescent compound. The primary form of riboflavin is an integral component of the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), the predominant flavoenzyme in body tissues. These coenzymes are involved in multiple oxidation-reduction reactions integral to carbohydrate, protein, and fat metabolism, and are involved in the metabolism of folate, pyridoxine, and niacin. Riboflavin-binding proteins expressed in fetuses of different species are evidently essential to normal fetal development. 33
Source
More than 90% of dietary riboflavin is consumed as a complex of food protein with FAD and FMN and lesser amounts as free vitamin and traces of glycosides and esters. Animal protein (meat, dairy, and eggs) as well as green vegetables and fortified cereals are abundant sources.4 Riboflavin may be synthesized by colonic bacteria but the extent of its contribution to human needs is not known. 33

FAD and FMN from dietary protein are released by gastric acid digestion. They are then hydrolyzed to riboflavin by non-specific pyrophosphatases and phosphatases in the upper small intestine. Riboflavin absorption is relatively poor compared to other water-soluble vitamins but is increased when ingested along with other foods and in the presence of bile salts. Some divalent cations, such as copper, zinc, iron, and manganese, form chelates with riboflavin and lower riboflavin absorption.
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Most absorption occurs in the small intestine via an active or facilitated transport system at low intakes and via passive diffusion at high intakes. A small amount is absorbed in the large intestine. 34 There is also a small component of enterohepatic circulation. Riboflavin is transported in the circulation bound to albumin and immunoglobulins. It is phosphorylated to FMN and FAD in most tissues, in particular, in the small intestine, liver, kidney, and heart. Intracellular phosphorylation is regulated by thyroid hormone and production of FAD is under negative feedback control. Very little riboflavin is stored in body tissues and the excess riboflavin is excreted in the urine secondary to glomerular filtration and active tubular secretion as riboflavin (~60% to 70%) and as a variety of flavin-related products. Riboflavin is more heat stable than thiamin but is very photosensitive. 34 It also interacts with an extensive list of drugs35 (Table 7-4).
will increase the photosensitized oxidation of amino acids and proteins in infants receiving phototherapy for hyperbilirubinemia.
Niacin (Vitamin B3)

Niacin refers to nicotinamide (nicotinic acid amide), nicotinic acid (pyridine-3-carboxylic acid), and derivatives that exhibit the biological activity of nicotinamide. None of the forms are related to the nicotine found in tobacco although their names are similar. 37 The 2 major forms of niacin are chemically modified in the mitochondria to form coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). About 200 enzymes require the niacin coenzymes, NAD and NADP, mainly to accept or donate electrons in the energy-producing oxidation-reduction (redox) reactions. NAD functions most often in energy-producing reactions during degradation (catabolism) of carbohydrate, fat, protein, and alcohol. NADP functions more often in biosynthetic (anabolic) reactions, such as in the synthesis of macromolecules including fatty acids and cholesterol. Nonredox enzymatic reactions important to DNA repair, and stress responses, cell signaling, transcription, regulation or apoptosis, chromatin structure, and cell differentiation require separation of the niacin moiety from NAD and integration of ADP-ribose in these functions.1,3,37
Deficiency State
Riboflavin deficiency is often accompanied by deficiencies of one or more of the other B vitamins. Chronically limited dietary meat or dairy intake (including infants after weaning) is a specific risk factor for riboflavin deficiency. Riboflavin deficiency is also found in protein energy malnutrition states, such as Kwashiorkor and anorexia nervosa, and in patients with other risk factors that are common to all water-soluble micronutrients. Symptoms and signs of mild deficient state can be non-specific. The more characteristic features of severe deficiency state of ariboflavinosis include pharyngitis, cheilosis, angular stomatitis, glossitis (magenta tongue), and seborrheic dermatitis involving nasolabial folds, flexural area of extremities, and the genital areas. Diagnosis of riboflavin deficiency is by low erythrocyte riboflavin quantified by high-performance liquid chromatography and low 24-hour excretion of riboflavin. Erythrocyte glutathione reductase activity coefficient from in vitro stimulation by FAD increased in the ranges of >40%, 20% to 40%, and < 20% are considered as deficient, low, and acceptable levels of riboflavin status. Biochemical deficiency has been reported in infants receiving short-term phototherapy. 36
Source
Unlike most of the water-soluble vitamins, nicotinamide can be synthesized in the liver and kidney from tryptophan. This process requires adequate amounts of riboflavin, pyridoxine, and iron and is highly variable depending on multiple other factors. For instance, tryptophan is used also for protein synthesis which takes priority over NAD and NADP synthesis. An estimated average of 60 mg of tryptophan produces 1 mg of niacin or niacin equivalent. However, dietary intake of niacin is needed to meet the daily requirements. Good sources of niacin include yeast, meats, poultry, red fish (eg, tuna and salmon), cereals (especially fortified cereals), legumes, and seeds. Lesser amounts are found in milk, green leafy vegetables, coffee, and tea. In corn and wheat, niacin may be bound to sugar molecules as glycosides which significantly decrease niacin bioavailability. 38
Supplementation
Excess riboflavin turns urine yellow although there are no demonstrated functional or structural adverse effects in vivo after excess riboflavin intake. This is in part because of the limited absorption of ingested riboflavin. Nevertheless, it is theoretically possible that riboflavin increases photosensitivity to ultraviolet irradiation and excess riboflavin

Intestinal glycohydrolases catalyze the release of nicotinamide from NAD. Nicotinic acid and nicotinamide are
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rapidly absorbed from the stomach and the intestine. They enter cells by simple diffusion and also by sodium-dependent facilitated transport across gut mucosa and erythrocytes. The coenzymes NAD and NADP are synthesized in all tissues. Extracellular nicotinamide appears to regulate the tissue NAD but is itself under hepatic control. Hepatic NAD is hydrolyzed to provide nicotinamide for tissues that lack the ability to synthesize nicotinamide from tryptophan. Tissue store of niacin is in the form of NAD that is not bound to enzymes or as nicotinamide adenine mononucleotide synthesized from tryptophan and nicotinic acid. Excess niacin is methylated in the liver to N1-methyl-nicotinamide and excreted in the urine either unchanged or as its 2-pyridone derivative.
gastrointestinal effects of nausea and vomiting. Some improvement may occur with gradual increase in dosage, co-ingestion of food, or the slow-release form of supplement. Liver dysfunction is more common with slow-release form. At high intakes of niacin, fulminant hepatitis and encephalopathy, glucose intolerance, and ocular effects of blurred vision, toxic amblyopia, macular edema, and cystic maculopathy also may occur.1
Vitamin B6
Vitamin B6 comprises a group of 6 related compounds: pyridoxal (PL), pyridoxine (PN), pyridoxamine (PM), and their respective 5-phosphates (PLP, PNP, and PMP). The major forms in animal tissues are PLP and PMP; plant-derived foods contain primarily PN and PNP, sometimes in the form of a glucoside. PLP is a coenzyme for a multitude of enzymes involved in amino acid metabolism including aminotransferases, decarboxylases, racemases, and dehydratases. It is required for the conversion of tryptophan to both niacin and the neurotransmitter serotonin; from homocysteine to cysteine, dopa to dopamine as well as the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid. Pyridoxine is a coenzyme for -aminolevulinate synthase, the ratelimiting first step in heme synthesis.
Deficiency State
Several conditions uniquely predispose to niacin deficiency. These include carcinoid syndrome in which tryptophan is preferentially oxidized to 5-hydroxytryptophan and serotonin; prolonged treatment with isoniazid which competes with the pyridoxine-derived coenzyme required in the tryptophan-niacin pathway; and Hartnups disease, an autosomal recessive disorder that interferes with the absorption of tryptophan. The classic manifestation of severe niacin deficiency is pellagra, an Italian term meaning rough skin. It is characterized by the triad of diarrhea, dermatitis, and dementia. 39 Gastrointestinal manifestations include glossitis, angular stomatitis, chelitis, and diarrhea in about 50% of patients. Skin lesions begin as painful erythema in sun-exposed areas. Vesicle or bullae formation may occur upon re-exposure to sun and the skin eventually becomes rough, hard, and scaly. Hair and nails tend to be spared. Neuropsychiatric manifestations include insomnia, fatigue, nervousness, irritability, apathy, and memory impairment. Dementia and death may occur in untreated cases. Niacin status is determined by a decreased concentration of NAD relative to NADP in erythrocytes, and low levels of excretion in 24-hour urine niacin and its metabolite N1-methyl-nicotinamide and its 2-pyridone derivative.
Source
Foods rich in pyridoxine include fruits and nuts (bananas, cantaloupe, walnuts), plants (green leafy vegetables, broccoli, peas, carrots, rice husks, brown rice, maize, wheat germ, yeast), and animal products (eggs, chicken, fish, beef), as well as fortified cereals. Microbial synthesis of B6 is possible but the extent to which its contribution to the physiological need is not known.

Bioavailability of vitamin B6 in a mixed diet is ~75% with nonphosphorylated B6 as the major form absorbed. Phosphatase-mediated hydrolysis of PLP and PMP precedes absorption by a nonsaturable passive diffusion transport of the non-phosphorylated form primarily at the jejunum and ileum. Pyridoxine glucoside is absorbed after deconjugation by a mucosal glucosidase and some is absorbed intact, then hydrolyzed in various tissues. The unphosphorylated forms of B6 are absorbed and then converted to 5-phosphate forms by pyridoxal kinase primarily in the liver. PNP and PMP are oxidized to PLP by PNP oxidase. PMP is also generated
Supplementation
Niacin, as a supplement or pharmacologic agent used primarily in the treatment of hyperlipidemia, can result in clinical side effects. Both forms of niacin may result in similar side effects although nicotinamide results in less vasodilatory effects. Nicotinic acid as low as 30 mg daily is associated with vasodilatory effects including flushing, burning, tingling, and itching sensation, and
65
from PLP via aminotransferase reactions. PLP is bound to various proteins in tissues which protects it from the action of phosphatases. Muscle, plasma, and erythrocyte (hemoglobin) have high capacity for PLP-protein binding. When the capacity for protein binding is exceeded, free PLP is rapidly hydrolyzed and non-phosphorylated forms of B6 are released from the tissues into the circulation where albumin is the major PLP-binding protein. Free PLP in the circulation is dephosphorylated then reabsorbed or carried in the erythrocyte. Vitamin B6 is found in various subcellular compartments but primarily in the mitochondria and cytosol. In humans, the major excretory form is 4-pyridoxic acid which accounts for about half the B6 compounds in the urine. At high doses of pyridoxine, much of the dose is excreted unchanged. The bodys B6 content is estimated to be about 167 mg based on muscle biopsy data and assuming that muscle represents about 80% of the store. The overall half-life of vitamin B6 is about 25 days but the muscle turnover for B6 is much slower.40
Supplementation
High-dose pyridoxine supplement of 2 to 6 g daily for 2 to 40 months46 or chronic intake even at doses < 500 mg/d47 may result in peripheral sensory neuropathy.
Folate (Vitamin B9)

Folate is a generic term for this water-soluble B-complex vitamin. Most naturally occurring food folates are pteroyl glutamates containing 1 to 6 glutamate molecules joined in a peptide linkage to the -carboxyl of glutamate. Folic acid (pteroylmonoglutamic acid) is the most oxidized and stable form of folate. It consists of a p-aminobenzoic acid molecule linked at one end to a pteridine ring and at the other end to a glutamic acid molecule, and occurs rarely in food but is the form used in vitamin supplements and in fortified food products. Folate is critical to the metabolism of nucleic and amino acids and promotes cellular growth in general and is necessary for the maturation of red cells. Folate is a substrate (5-methyl-tetrahydrofolate) and vitamin B12 is a coenzyme in the formation of 5,10-methylenetetrahydrofolate (MTHF) and thymidylate synthesis. In either a folate or vitamin B12 deficiency, the megaloblastic changes in bone marrow and other replicating cells result from lack of MTHF. Onset of anemia is usually gradual, and clinical manifestation of anemia typically appears only at an advanced stage of anemia but may be earlier in the elderly. Folate and vitamin B12 deficiency are independent risk factors for neurotube defects including anencephaly and spina bifida.48
Deficiency State
Isolated deficiency of pyridoxine is rare because its metabolism is intimately involved with multiple other nutrients including riboflavin, niacin, zinc, and folate. Special considerations for predisposition to lower plasma PLP may include therapy with isoniazid and L-dopa (react with carbonyl group of PLP); acetaldehyde but not ethanol decreases net PLP formation and may compete with PLP for protein binding. However, the extent to which these situations increase B6 requirements is not known. Clinical manifestations of the B6 deficient state include seizures in infants fed milk formulas without fortification by pyridoxine from error in the manufacturing41,42 and abnormal electroencephalogram in adults from experimental B6 deficiency.43 Both are reversed with reintroduction of B6. Intractable seizures during infancy and childhood may respond to large doses of pyridoxine and sometimes only to pyridoxal phosphate. The latter form may be a result of mutations in the PNPO gene for pyridox(am) ine 5-phosphate oxidase and present as neonatal epileptic encephalopathy.44 Other clinical manifestations of B6 deficiency are non-specific and may include microcytic anemia, glossitis, seborrheic dermatitis, and depression. Plasma PLP is probably the best indicator of B6 status because it appears to reflect tissue stores.45 Erythrocyte aspartate and alanine aminotransferase saturation by PLP or tryptophan metabolites is also a useful indicator of relative B6 status.
Source
Natural sources include fresh green vegetables, liver, yeast, and some fruits. Folic acid is the only water-soluble vitamin mandated as part of prenatal supplement for the prevention of neurotube defects. The generally lower intake of vegetables and fruits contributes to the potentially inadequate intake of folate. Significantly improved folate status as indicated by population survey of red cell and serum folate has been reported since the Food and Drug Administration (FDA) in 1998 required the addition of folic acid to all enriched breads, cereals, flours, corn meal, pasta products, rice, and other cereal grain products sold in the United States.49

Dietary folate equivalent has ~50% lower bioavailability compared to folic acid. Food folates (polyglutamate
66
derivatives) are hydrolyzed by conjugase enzymes to monoglutamate forms, then enter various cells by membrane carrier or folate-binding protein-mediated system. The folate transporter derives from the SLC19 gene family of solute carriers and shares structural homology with the thiamin transporter.15 Monoglutamates, mainly 5-methyl-tetrahydrofolate, are metabolized in the liver and other tissues to polyglutamate derivatives by the enzyme folylpolyglutamate synthetase. Polyglutamates are the forms retained in various tissues or found in blood or bile and are the forms needed for function as a coenzyme in single-carbon transfer reactions. Folate catabolism involves cleavage of intracellular and circulatory polyglutamates to the monoglutamate form. Approximately two-thirds of the folate in plasma is protein bound and albumin accounts for ~50% of the bound folate. Folates freely filter through the glomeruli, are secreted, and reabsorbed by the renal tubules. The bulk of the urine excretory products are folate cleavage products mainly in the monoglutamate form. There is extensive enterohepatic circulation of folate. 50 The estimated total body folate content is between 12 and 28 mg, of which ~50% is in the liver.
concentrations increase when folate status is inadequate to convert homocysteine to methionine.
Supplementation
Excessive folate intake may precipitate or exacerbate neuropathy in vitamin B12 deficient individuals.
Vitamin B12 (Cobalamin)

The term vitamin B12 is usually restricted to cyanocobalamin but can be used to refer to all potentially biologically active cobalamins, a group of cobalt-containing compounds (corrinoids) that contains the sugar ribose, phosphate, and a base (5,6-dimethyl benzimidazole) attached to the corrin ring. The cobalamin coenzymes active in human metabolism exist as methylcobalamin and 5-deoxyadenosylcobalamin. Methylcobalamin is required for the methyl transfer from MTHF to homocysteine to form methionine and tetrahydrofolate with the enzyme methionine synthase. Adenosylcobalamin is required for isomerization of L-methylmalonyl-CoA to succinyl-CoA with the enzyme L-methylmalonyl-CoA mutase. An adequate supply of B12 is essential for normal blood formation and neurological function.
Deficiency State
Patients receiving folate antagonists such as methotrexate and other drugs that have antifolate activity including pyrimethamine, trimethoprim, triamterene, trimetrexate, and sulfasalazine require monitoring for folate status to ensure adequate dietary intake or folate supplementation. Several inborn errors in folate metabolism (MTHF reductase deficiency associated with mutations of alleles on chromosome 1)51 as well as the presence of autoantibody to folate receptor (cerebral folate deficiency)52 predispose the affected individual to folate deficiency. Serum and red cell folate concentration are low in the former and normal in the latter. In cerebral folate deficiency, the transfer of folate from plasma to cerebrospinal fluid is low and cerebrospinal fluid MTHF concentration is low. Clinical features of folate deficiency may begin during infancy and include retarded psychomotor development, poor social contact, decelerating head growth, hypotonia, ataxia, dyskinesia, irritability, visual and hearing deficiency, and seizures. Some neurological manifestations may be reversible with folinic acid supplement. Symptomatology from anemia may be present. Deficiency states are confirmed with low red cell folate which reflects tissue folate store. Plasma folate reflects concurrent folate balance. Plasma total homocysteine
Source
Cobalamin is found in animal foods including meat, fish, poultry, cheese, milk, and eggs. Cereal and soy milks are fortified with varied amounts of B12 . Vitamin B12 content in breast milk is dependent on maternal diet and mature milk has lower content than colostrum. In the United States and Canada, both cyanocobalamin and hydroxocobalamin are available commercially although cyanocobalamin is most commonly used in supplements and pharmaceuticals. Vitamin B12 can be synthesized by intestinal bacteria but its contribution to body pool is not known but likely to be limited.

Cobalamin absorption and cellular uptake require an intact stomach, adequate transport proteins, pancreatic sufficiency, and a normally functioning terminal ileum.11 Haptocorrin (HC), gastric intrinsic factor (IF) and transcobalamin (TC) are critical to B12 transport from food to cell. IF and HC but not TC are glycosylated proteins. There is increasing specificity for binding to cobalamin in the order HC, TC, and IF. 53 Cobalamin released from food is bound to salivary HC. After proteolysis of HC in the duodenum,
67
cobalamin is then bound to IF. The cobalamin-IF complex is absorbed only in the ileum under physiological conditions via endocytosis mediated by a specific receptor. In the enterocyte, the cobalamin-IF complex is degraded and cobalamin is transported to the cells bound to TC and taken up via endocytosis by a specific receptor on most cell types. Vitamin B12 appears in circulation several hours after ingestion. If the circulating B12 exceeds the B12 binding capacity of the blood, the excess is excreted in the urine. About 80% of circulating B12 is bound to the proteins transcobalamin I (TCI) and the remainder to TCII or III. TCII is the form that delivers B12 to the tissues (~50% taken up by the liver) through specific receptors for TCII. HC in the plasma cannot facilitate cellular uptake of cobalamin except in hepatocytes. There is an active enterohepatic circulation which reabsorbs, in the presence of intrinsic factor, almost all B12 secreted into the bile. Unlike other water-soluble vitamins, there is a large store of B12 primarily in the liver. The average B12 content of liver is ~1 mcg/g in healthy adults. The average total body pool of B12 is estimated to be 2 to 3 mg. Daily loss of B12 is ~0.1 to 0.2% of the B12 pool regardless of the size of the store, with the 0.2% value generally applicable to those with pernicious anemia. 54
biochemical indicators of functional B12 deficiency state. Plasma B12 is considered as a less sensitive indicator of B12 deficiency compared to other biochemical changes.
Supplementation
Short-term studies up to 4 months indicate that oral B12 supplement has similar efficacy to intramuscular treatment for B12 deficiency. 59,60 B12 fortification of foods to improve the populations B12 status55 has been advocated. Intranasal delivery of B12 is possible but the bioavailability is ~10% of intramuscular preparation. Periodic parenteral administration of high-dose B12 (1-5 mg) to patients with pernicious anemia (lack of intrinsic factor) supports the lack of adverse effects at high doses. The use of cyanocobalamin is contraindicated in B12 deficient individuals at risk for Lebers optic atrophy, a genetic disorder caused by chronic cyanide (present in tobacco smoke, alcohol, and some plants) intoxication, because the latter may increase the risk of irreversible optic atrophy. Hydroxocobalamin, a cyanide antagonist, 61 can be used instead of cyanocobalamin.1
Vitamin C
Ascorbic acid is the enolic form of an -ketolactone (2,3-didehydro-L-threo-hexano-1,4-lactone) and the 2 enolic hydrogen atoms give the compound its acidic character and provide electrons for its function as a reductant and antioxidant. Vitamin C refers to both ascorbic acid and dehydroascorbic acid. Ascorbic acid is the functional and primary in vivo form of the vitamin. Ascorbate is the free reduced form of ascorbic acid. Ascorbyl radical and dehydroascorbic acid are the 1- or 2-electron oxidation products which readily reduce back to ascorbic acid in vivo, thus a relatively small amount of the vitamin is lost through catabolism. Vitamin C is known to be an electron donor for 8 human enzymes. Three enzymes participate in collagen hydroxylation (also requires iron) and contribute to the biosynthesis of other connective tissue components including elastin, fibronectin, proteoglycans, bone matrix, and elastin-associated fibrillin. Two enzymes along with iron are required in carnitine synthesis; and 3 enzymes, dopamine--hydroxylase, peptidyl-glycine monooxygenase, and 4-hydroxyphenylpyruvatedioxygenase, are required in hormone and amino acid biosynthesis. Vitamin C is an effective antioxidant because of its ability to donate electrons and its antioxidant effect operates
Deficiency State
Breastfed infants of strict vegan mothers, children receiving macrobiotic diets, and the elderly are at risk for B12 deficiency as are individuals with the absence of intact stomach, ileum, pancreatic exocrine function or intrinsic factor. 55 Chronic use of proton pump inhibitors increases the risk for B12 deficiency by inhibition of intragastric proteolysis, thereby inhibiting the release of B12 from food prior to binding to haptocorrin and also inhibiting B12 binding to gastric intrinsic factor. 56 Autoantibodies against parietal cell H+K+adenosine triphosphate causing loss of gastric parietal cells or blocking the B12 binding site for intrinsic factor result in B12 deficiency. Genetic defects that involve deletions or defects of methylmalonic acid-CoA mutase, TCII, or enzymes in the pathway of cobalamin adenosyllation have been reported to be associated with B12 deficiency. 57 Clinical manifestations of B12 deficiency include macrocytic megaloblastic anemia and neurological problems. The latter include ataxia, muscle weakness, spasticity, incontinence, vision problems, dementia, psychosis, and mood disturbance. Impaired cognitive function has been demonstrated in adolescents with marginal cobalamin. 58 Decreased plasma B12 and elevated plasma and urine methylmalonic acid and plasma homocysteine are
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in the aqueous phase both intra- and extracellularly. It participates in redox reactions with many other dietary and physiological compounds including glutathione, tocopherol, flavonoids, and the trace metals iron and copper. Antioxidation activities at the tissue level include protection of the eye, neutrophils, and sperm DNA among many other tissues. In the circulation, it protects against oxidation of plasma low-density lipoprotein (LDL). Ascorbate also provides antioxidant protection indirectly by regenerating other biological antioxidants such as glutathione and -tocopherol back to their active state. Ascorbic acid functions as a reducing agent for mixed function oxidases in the microsomal drug-metabolizing system that inactivates a wide variety of substrates, such as endogenous hormones or xenobiotics including drugs, pesticides, or carcinogens that are foreign to humans. The vitamin is involved in the biosynthesis of corticosteroids and aldosterone and in the microsomal hydroxylation of cholesterol to bile acids. 5 One form of hereditary methemoglobinemia is reported to be responsive to vitamin C.62
Both the 1- and 2-electron oxidation products of the vitamin are readily reduced back to ascorbic acid in vivo chemically and enzymaticallyby glutathione, NADH, and NADPH dependent reductases and relatively small amounts of the vitamin are lost through catabolism. Vitamin C is actively secreted in human gastric juice. Proton pump inhibitor therapy lowers the concentration of vitamin C in gastric juice and may reduce the bioavailability of ingested vitamin C. The kidney is capable of reabsorption of ascorbate but renal excretion of ascorbate is greater with increased intake. Aspirin may increase urinary ascorbate.6 Due to homeostatic regulation, the biological half-life of ascorbate varies widely from 8 to 40 days and is inversely related to the ascorbate body pool. A body pool of < 300 mg is associated with scurvy while maximum body pools are estimated to be about 2 g.
Deficiency State
In developed countries, population surveys show serum vitamin C concentrations are significantly lower in smokers and low-income persons, presumably reflecting the increased oxidative stress of smokers and low dietary consumption of vitamin C foods.63 Clinical manifestation of vitamin C deficiency is quite rare but has been reported in children with severely restricted diets related to food faddism, psychiatric or developmental problems, 64 or in children with end-stage organ disease with severely compromised nutrition.65 It also has been reported in young children who ingest only well-cooked foods, few fruits and vegetables, and are supplemented with ultra heat-processed milk.66 The primary clinical manifestation of vitamin C deficiency is scurvy and reflects deterioration of elastic tissues. Clinical features include follicular hyperkeratosis, petechiae, ecchymoses, coiled hairs, inflamed and bleeding gums, perifollicular hemorrhages, and impaired wound healing. Refusal to walk, with or without joint effusions and arthralgia, dyspnoea, edema, weakness, fatigue, depression and Sjogren syndrome (dry eyes and mouth) also can occur. In experimental subjects, gingival inflammation and fatigue were among the most sensitive markers of deficiency without being frankly scorbutic. Impaired bone growth, disturbed ossification, and subperiosteal hemorrhage may be present. Scurvy usually occurs at a plasma concentration of < 0.2 mg/dL (11 mol/L) although leukocyte ascorbate concentration is considered a better measure of tissue reserve than plasma ascorbate concentration and is the preferred indicator of vitamin C status.67
Source
Almost 90% of vitamin C in the typical diet comes from fruits and vegetables. Citrus fruits, tomatoes, tomato juice, and potatoes are major sources. Other sources include brussel sprouts, cauliflower, broccoli, strawberries, cabbage, and spinach. Vitamin C content of foods can vary with growing condition, season, stage of maturity, cooking practice, and storage time prior to consumption. 22

Some 70% to 90% of usual dietary intake of ascorbic acid is absorbed via a sodium-dependent active transport at low gastrointestinal ascorbate concentrations, while passive diffusion occurs at high concentrations. With large intakes of vitamin C, unabsorbed ascorbate is degraded in the intestine, a process that may account for the diarrhea and intestinal discomfort. Dehydroascorbic acid is the form of vitamin that primarily crosses the membranes of blood and intestinal cells, after which it is reduced intracellularly to ascorbic acid and localized mostly in the cytosol. Cellular transport of ascorbic acid and dehydroascorbic acid is mediated by tissue-specific cellular transport systems which allow for wide variation of tissue ascorbate concentrations. High levels are maintained in the pituitary and adrenal glands, leukocytes, eyes, and the brain, while low levels are found in plasma and saliva. Both intracellular and plasma vitamin C exist predominantly in the free reduced form as ascorbate monoanion.
69
Supplementation
Gastrointestinal disturbances such as nausea, abdominal cramps, and diarrhea have been reported at vitamin C intake of > 3 g/d probably as a result of the osmotic effect of unabsorbed vitamin C.68 In vivo data do not clearly show a causal relationship between excess vitamin C intake by apparently healthy individuals and other adverse effects2 although increased urine oxalate excretion and development of oxalate stones may be possible. However, individuals with hemochromatosis, glucose-6-phosphate dehydrogenase deficiency, and renal disorders may be more susceptible to adverse effects of excess vitamin C intake, which include excess iron absorption, pro-oxidant effects, and kidney (oxalate) stone formation. There is also risk for reduced vitamin B12 and copper levels, increased oxygen demand, dental enamel erosion, allergic response,2 and blocking the action of warfarin.6 Vitamin C intake of 250 mg/d or higher has been associated with false negative result for stool and gastric occult blood.69 High-dose vitamin C supplement should be stopped before these laboratory tests.
pathway end products, CoA and acyl-CoA. CoA is hydrolyzed to pantothenic acid in a multiple-step reaction and is excreted intact in the urine in proportion to dietary intake.
Deficiency State
Deficiency has been reported only with feeding semisynthetic diets70 or an antagonist to the vitamin, -methyl pantothenic acid.71 Clinical manifestations may be nonspecific and include irritability, restlessness, fatigue, apathy, malaise, sleep disturbances, nausea, vomiting and abdominal cramps, numbness, paresthesia, and staggering gait, and increased sensitivity to insulin. Historically, pantothenic acid was implicated in the burning feet syndrome that affected prisoners of war in Asia during World War II.72 There are no data to support the use of whole blood, plasma, or red cell concentrations as a marker of deficiency state. Urinary excretion of pantothenic acid is strongly dependent on dietary pantothenic acid.70
Supplementation
There are no subgroups of population who are distinctly susceptible to adverse effects of excess pantothenic acid.
Pantothenic Acid (Vitamin B5)

Pantothenic acid is a component of coenzyme A (CoA) which is involved in more than 70 enzymatic pathways. CoA, in forms such as acetyl-CoA and succinyl-CoA, plays an important role in the tricarboxylic acid cycle and in the synthesis of fatty acids and membrane phospholipids, amino acids, steroid hormones, vitamins A and D, porphyrin and corrin rings, and neurotransmitters, and acetylation and acylation of proteins and the synthesis of -tubulin.
Biotin (Vitamin B7)

Biotin is a cofactor for 5 mammalian carboxylases. These carboxylases catalyze the carboxylation of pyruvate to oxaloacetate which serves as an intermediate in the tricarboxylic acid cycle, of propionyl-CoA to form D-methylmalonylCoA, then undergoes isomerization to succinyl-CoA and enters into the tricarboxylic acid cycle, of acetyl-CoA to malonyl-CoA, which serves as a substrate for fatty acid elongation; and in the degradation of leucine.
Source
Pantothenic acid is widely distributed in foods and found in high concentrations in organ meats, yeast, egg yolk, fresh vegetables, whole grains, and legumes. Intestinal microflora can synthesize pantothenic acid but its contribution in humans has not been quantified.
Source
Biotin is widely distributed in natural food stuffs but its concentration varies substantially with liver having the highest content; fruits and most meats contain small amounts. The contribution of biotin synthesized by intestinal microflora to the bodys needs has not been defined.

CoA in the diet is hydrolyzed in the intestinal lumen to dephospho-CoA, phosphopantethine, and pantethine, with the latter subsequently hydrolyzed to pantothenic acid. Intestinal absorption of pantothenic acid occurs through a saturable sodium-dependent active transport at low intakes, while passive diffusion occurs at high intakes. Tissue CoA synthesis is regulated primarily by panto thenate kinase, an enzyme feedback inhibited by the

Most dietary biotin is protein bound although it also exists in free form. Biotinase releases the free vitamin from the protein for absorption primarily in the proximal small intestine but some occurs at the proximal colon. Absorption is by active transport at low concentrations and passive diffusion at high concentrations. Avidin, a protein found
70
in appreciable amounts in raw egg white, binds to biotin and prevents its absorption. Specific receptors are probably involved in tissue uptake of biotin. About half of biotin undergoes metabolism to bisnorbiotin and biotin sulfoxide before excretion. In human urine and plasma, they are present in molar proportions of ~3:2:1. Two additional minor metabolites, bisnorbiotin methyl ketone and biotin sulfone, are also present in urine. The urinary excretion and serum concentrations of biotin and its metabolites increase roughly in the same proportion in response to either intravenous or oral administration of large doses of biotin.73 During normal breakdown of cellular proteins, biotin-containing enzymes are degraded to biocytin (-N-biotinyl-L-lysine) or short oligopeptides containing biotin-linked lysyl residues. Biotin is released from these oligopeptides by biotinidase and the biotin is reused.74
Supplementation
Intakes of biotin at > 10 mg/d in a variety of subjects at different life stages was not associated with documented adverse effects.
Choline
Choline is the major source of methyl groups in the diet. It is a precursor for acetylcholine, phospholipids, and the methyl donor betaine. Functionally, it plays a critical role in the structural integrity of cell membranes, methyl metabolism, cholinergic neurotransmission, transmembrane signaling, and lipid and cholesterol transport and metabolism.
Source
Choline in the diet is available as free choline or is bound as water-soluble (phosphocholine, glycerophosphocholine) or lipid soluble (sphingomyelin, phosphotidylcholine) esters. It is widely distributed in foods with most in the form of phosphatidylcholine in membranes. Foods especially rich in choline compounds are milk, liver, eggs, and peanuts. Lecithin, a phosphatidylcholine-rich fraction prepared during commercial purification of phospholipids, is often used interchangeably with phosphatidylcholine, and is frequently added to food as an emulsifying agent and may be a significant source of choline. Endogenous synthesis of choline occurs via sequential methylation of phosphatidylethanolamine catalyzed by the enzyme phosphatidylethanolamine N-methyltransferase and with S-adenosylmethionine as the methyl donor. However, it is insufficient to compensate for the lack of dietary choline.
Deficiency State
Clinical deficiency of biotin is uncommon but has been reported in individuals who consumed raw egg whites over long periods75 or received total parenteral nutrition before biotin supplementation.76 Infantile seizures either alone or with other neurological or cutaneous findings, particularly in the presence of ketolactic acidosis and organic aciduria, are typical of biotinidase deficiency.77 Infants manifest rash around the mouth, nose, and eyes as biotin deficiency facies after several months of biotin-free total parenteral nutrition. This rash may extend to ears and perineal orifices. Alopecia totalis, hypotonia, lethargy, developmental delay, and withdrawn behavior also may occur. Similar manifestations including ataxia and paresthesia may occur in older children and adults. The list of inborn errors of metabolism that result in biotin dependency and various degrees of neurological and dermatologic abnormalities now extends to holocarboxylase synthetase deficiency and a defect in biotin transport.78 Biochemically, urine excretion of biotin is decreased and 3-hydroxyisovaleric acid is increased.79 Plasma biotin is not a sensitive indicator of inadequate biotin intake. Reduced expression of SLC19A3, a potential biotin transporter, in leukocytes may prove to be a useful indicator of marginal biotin deficiency.80 Biotinidase deficiency results in a relative biotin deficiency through lack of adequate digestion of protein-bound biotin. It is treated with free (unbound) biotin at the estimated typical dietary intake of 50 to 150 mcg/d.81

Choline can be absorbed as lipid-soluble esters through the lymph or as free choline into portal circulation. Pancreatic enzymes can liberate choline from its ester forms. The absorption through the small intestinal mucosa is by transporter proteins, which are probably unique for choline. Some choline may be metabolized by intestinal bacteria to form betaine (which may be absorbed and used as a methyl donor) and methyl amines (which are not methyl donors). Choline, folate, and B12 metabolism interactions are required for methyl transfer from MTHF to homocysteine to form methionine and tetrahydrofolate with the enzyme methionine synthase. Thus, the need for choline is modified by methionine, folic acid, and vitamin B12 .
71
All tissues accumulate choline by diffusion and mediated transport and a specific carrier mechanism transports free choline across the blood-brain barrier at a rate proportional to the serum choline concentration. The liver and kidney also readily take up choline where a large proportion is oxidized to betaine. The methyl groups of betaine can be scavenged and reused in single-carbon metabolism.
Deficiency State
Though many foods contain choline, there is at least a twofold variation in dietary intake in humans. When deprived of dietary choline, most men and postmenopausal women developed signs of organ dysfunction (fatty liver or muscle damage), while less than half of premenopausal women developed such signs.82 Individuals receiving total parenteral nutrition devoid of choline but adequate for methionine and folate developed hepatic steatosis and elevated alanine aminotransferase. These abnormalities resolved in some individuals when a source of dietary choline was provided.83 In addition to the gender influence, there also appears to be genetic polymorphism and epigenetics influence for susceptibility to choline deficiency. 82 Fasting plasma, erythrocyte, and tissue content of choline and phosphatidylcholine can be used as markers of choline status.
3. Niacin can be synthesized from: A. Valine B. Threonine C. Tryptophan D. Methionine E. Linoleic acid 4. Excess folate intake may exacerbate clinical manifestation of deficiency in: A. Iron B. Vitamin B6 C. Thiamin D. Vitamin B12 E. Choline 5. Inherited metabolic defects in water-soluble essential micronutrients may present in the neonate as: A. Intractable seizures B. Nutritional deficiency rickets C. Bleeding tendency D. Cataract E. Blindness See p. 487 for answers.
References
Supplementation
The critical adverse effect from high intake of choline is hypotension, with corroborative evidence on cholinergic side effects (eg, sweating and diarrhea, and fishy body odor).1
1. Bioavailability of water-soluble essential micronutrients is usually not affected by: A. Temperature and duration of cooking B. Storage C. Exposure to light D. Source from food or supplement E. Maturity of the plant 2. Clinical status of water-soluble essential micronutrients may be affected by all of the following except: A. Dietary intake B. Intact pancreatic function C. Intact stomach D. Intact small bowel E. Intact large bowel
1. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 1998. 2. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academy Press; 2000. 3. American Academy of Pediatrics Policy. In: Kleinman RE, ed. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009. 4. Northwestern University. Fact sheet: Nutrients and diet regimens. www.feinberg.northwestern.edu/nutrition. Accessed May 28, 2009. 5. Drugs, Supplements, and Herbal Information, Medline Plus, National Institutes of Health. http://www.nlm.nih.gov/ medlineplus/druginformation.html. Accessed June 25, 2009. 6. Micronutrient Information Center, Linus Pauling Institute, Oregon State University. http://lpi.oregonstate.edu/infocenter/vitamins.html. Accessed May 28, 2009. 7. USDA Agriculture Research Service. Nutrient data laboratory. http://www.nal.usda.gov/fnic/foodcomp/search/. Accessed September 23, 2009. 8. Department of Health and Human Services. Food and Drug Administration. Parenteral multivitamin products. Federal Register. 2000;65:2120021201 9. Drug Facts and Comparisons 2009. St Louis, MO: Wolters Kluwer Health.
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10. Picciano MF, Dwyer JT, Radimer KL, et al. Dietary supplement use among infants, children and adolescents in the United States, 1999 2002. Arch Pediatr Adol Med. 2007;161:978985. 11. Basu TK, Donaldson D. Intestinal absorption in health and disease: micronutrients. Best Pract Res Clin Gastroenterol. 2003;17:957979. 12. Rudatsikira E, Muula AS, Siziya S. Current cigarette smoking among in-school American youth: results from the 2004 National Youth Tobacco Survey. Int J Equity Health. 2009 Apr 3;8:10 13. Seo DC, Jiang N. Associations between smoking and extreme dieting among adolescents. J Youth Adolesc. 2009;38:13641373. 14. National Center for Chronic Disease Prevention and Health Promotion. Healthy youth! Alcohol and drug use. http:// w w w.cdc.gov/HealthyYouth/alcoholdrug/index.htm. Accessed September 25, 2009. 15. Ganapathy V, Smith SB, Prasad PD. SLC19: the folate/thiamine transporter family. Pflugers Arch. 2004;447:641646. 16. Singleton CK, Martin PR. Molecular mechanisms of thiamine utilization. Curr Mol Med. 2001;1:197207. 17. Ariaey-Nejad MR, Balaghi M, Baker EM, Sauberlich HE. Thiamin metabolism in man. Am J Clin Nutr. 1970;23:764778. 18. Mehta S, Fawzi W. Effects of vitamins, including vitamin A, on HIV/AIDS patients. Vitam Horm. 2007;75:355383. 19. Allen LH, Peerson JM, Olney DK. Provision of multiple rather than two or fewer micronutrients more effectively improves growth and other outcomes in micronutrient-deficient children and adults. J Nutr. 2009;139:10221030. 20. Malik ZA, Abadi J, Sansary J, Rosenberg M. Elevated levels of vitamin B12 and folate in vertically infected children with HIV-1. AIDS. 2009;23:403407. 21. Nevado J, Tenbaum SP, Castillo AI, Snchez-Pacheco A, Aranda A. Activation of the human immunodeficiency virus type I long terminal repeat by 1 alpha, 25-dihydroxyvitamin D3. J Mol Endocrinol. 2007;38:587601. 22. Ball GFM. Vitamins in Foods: Analysis, Bioavailability, and Stability. Boca Raton, FL: Taylor and Francis; 2006. 23. Specker BL, Black A, Allen L, Morrow F. Vitamin B-12: low milk concentrations are related to low serum concentrations in vegetarian women and to methylmalonic aciduria in their infants. Am J Clin Nutr. 1990;52:10731076. 24. Hahn JS, Berquist W, Alcorn DM, Chamberlain L, Bass D. Wernicke encephalopathy and beriberi during total parenteral nutrition attributable to multivitamin infusion shortage. Pediatrics. 1998;101:E10. 25. Luxemburger C, White NJ, ter Kuile F, et al. Beri-beri: the major cause of infant mortality in Karen refugees. Trans R Soc Trop Med Hyg. 2003;97:251255. 26. Davis RA, Wolf A. Infantile beriberi associated with Wernickesencephalopathy. Pediatrics. 1958;21:409420. 27. Fattal-Valevski A, Kesler A, Sela BA, et al. Outbreak of life-threatening thiamine deficiency in infants in Israel caused by a defective soy-based formula. Pediatrics. 2005;115:e233e238.
28. Kornreich L, Bron-Harlev E, Hoffmann C, et al. Thiamine deficiency in infants: MR findings in the brain. Am J Neuroradiol. 2005;26:16681674. 29. Talwar D, Davidson H, Cooney J, St JOReilly D. Vitamin B(1) status assessed by direct measurement of thiamin pyrophosphate in erythrocytes or whole blood by HPLC: comparison with erythrocyte transketolase activation assay. Clin Chem. 2000;46:704710. 30. Bayoumi RA, Rosalki SB. Evaluation of methods of coenzyme activation of erythrocyte enzymes for detection of deficiency of vitamins B1, B2, and B6. Clin Chem. 1976;22:327335. 31. Fattal-Valevski A, Azouri-Fattal I, Greenstein YJ, Guindy M, Blau A, Zelnik N. Delayed language development due to infantile thiamine deficiency. Dev Med Child Neurol. 2009;51:629634. 32. Fattal-Valevski A, Bloch-Mimouni A, Kivity S, et al. Epilepsy in children with infantile thiamine deficiency. Neurology. 2009;73:828833. 33. Powers HJ. Riboflavin (vitamin B-2) and health. Am J Clin Nutr. 2003;77:13521360. 34. Jusko WJ, Levy G. Absorption, metabolism, and excretion of riboflavin-5-phosphate in man. J Pharm Sci. 1967;56:5862. 35. Erlich SD. Possible interactions with vitamin B2 (riboflavin). (2007). www.umm.edu/altmed/articles/vitamin-b2-000989. htm. Accessed May 28, 2009. 36. Amin HJ, Shukla AK, Snyder F, Fung E, Anderson NM, Parsons HG. Significance of phototherapy-induced riboflavin deficiency in the full-term neonate. Biol Neonate. 1992;61:7681. 37. Drake VJ, Jacobson EL (2007) Niacin. Micronutrient Information Center, Linus Pauling Institute, Oregon State University. http://lpi.oregonstate.edu/infocenter/vitamins/ niacin. Accessed May 28, 2009. 38. Gregory JF 3rd. Nutritional Properties and significance of vitamin glycosides. Annu Rev Nutr. 1998;18:277296. 39. Hegyi J, Schwartz RA, Hegyi V. Pellagra: dermatitis, dementia,and diarrhea. Int J Dermatol. 2004;43:15. 40. Coburn SP. Location and turnover of vitamin B6 pools and vitamin B6 requirements of humans. Ann N Y Acad Sci. 1990;585:7685. 41. Coursin DB. Convulsive seizures in infants with pyridoxinedeficient diet. J Am Med Assoc. 1954;154:406408. 42. Bessey OA, Adam DJ, Hansen AE. Intake of vitamin B6 and infantile convulsions: a first approximation of requirements of pyridoxine in infants. Pediatrics. 1957;20:3344. 43. Kretsch MJ, Sauberlich HE, Newbrun E. Electroencephalographic changes and periodontal status during short-term vitamin B-6 depletion of young, nonpregnant women. Am J Clin Nutr. 1991;53:12661274. 44. Gospe SM Jr. Pyridoxine-dependent seizures: new genetic and biochemical clues to help with diagnosis and treatment. Curr Opin Neurol. 2006;19:148153. 45. Lui A, Lumeng L, Aronoff GR, Li TK. Relationship between body store of vitamin B6 and plasma pyridoxal-P clearance: metabolic balance studies in humans. J Lab Clin Med. 1985;106:491497. 46. Schaumburg H, Kaplan J, Windebank A, et al. Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N Engl J Med. 1983;309:445448.
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47. Parry GJ, Bredesen DE. Sensory neuropathy with low-dose pyridoxine. Neurology. 1985;35:14661468. 48. Stover PJ. Physiology of folate and vitamin B12 in health and disease. Nutr Rev. 2004;62:S3S12. 49. McDowell MA, Lacher DA, Pfeiffer CM, et al. Blood folate levels: the latest NHANES results. NCHS Data Brief. 2008 May;(6):18. 50. Weir DG, McGing PG, Scott JM. Folate metabolism, the enterohepatic circulation and alcohol. Biochem Pharmacol. 1985;34:17. 51. Tonetti C, Burtscher A, Bories D, Tulliez M, Zittoun J. Methylenetetrahydrofolate reductase deficiency in four siblings: a clinical, biochemical, and molecular study of the family. Am J Med Genet. 2000;91:363367. 52. Ramaekers VT, Rothenberg SP, Sequeira JM, et al. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med. 2005;352:19851991. 53. Wuerges J, Geremia S, Fedosov SN, Randaccio L. Vitamin B12 transport proteins: crystallographic analysis of beta-axial ligand substitutions in cobalamin bound to transcobalamin. IUBMB Life. 2007; 59:722729. 54. Amin S, Spinks T, Ranicar A, Short MD, Hoffbrand AV. Long-term clearance of [57Co]cyanocobalamin in vegans and pernicious anaemia. Clin Sci (Lond). 1980;58:101103. 55. Allen LH. How common is vitamin B-12 deficiency? Am J Clin Nutr. 2009;89:693S696S. 56. Termanini B, Gibril F, Sutliff VE, Yu F, Venzon DJ, Jensen RT. Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with Zollinger-Ellison syndrome. Am J Med. 1998;104:422430. 57. Kapadia CR. Vitamin B12 in health and disease: part I-inherited disorders of function, absorption, and transport. Gastroenterologist. 1995;3:329344. 58. Louwman MW, van Dusseldorp M, van de Vijver FJ, et al. Signs of impaired cognitive function in adolescents with marginal cobalamin status. Am J Clin Nutr. 2000;72:762769. 59. Vidal-Alaball J, Butler CC, Cannings-John R, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev. 2005;(3):CD004655. 60. Andrs E, Dali-Youcef N, Vogel T, Serraj K, Zimmer J. Oral cobalamin (vitamin B12) treatment. An update. Int J Lab Hematol. 2009;31:18. 61. Shepherd G, Velez LI. Role of hydroxocobalamin in acute cyanide poisoning. Ann Pharmacother. 2008;42:661669. 62. Jamal A. Hereditary methemoglobinemia. J Coll Physicians Surg Pak. 2006;16:157159. 63. Schleicher RL, Carroll MD, Ford ES, Lacher DA. Serum vitamin C and the prevalence of vitamin C deficiency in the United States: 2003-2004 National Health and Nutrition Examination Survey (NHANES). Am J Clin Nutr. 2009; Aug 12 [Epub ahead of print]. 64. Willmott NS, Bryan RA. Case report: scurvy in an epileptic child on a ketogenic diet with oral complications. Eur Arch Paediatr Dent. 2008;9:148152. 65. Samonte VA, Sherman PM, Taylor GP, et al. Scurvy diagnosed in a pediatric liver transplant patient awaiting combined kidney and liver retransplantation. Pediatr Transplant. 2008;12:363367.
66. Ratanachu-Ek S, Sukswai P, Jeerathanyasakun Y, Wongtapradit L. Scurvy in pediatric patients: a review of 28 cases. J Med Assoc Thai. 2003;86:S734740. 67. Thurnham DI. Micronutrients and immune function: some recent developments. J Clin Pathol. 1997;50:887891. 68. Wandzilak TR, DAndre SD, Davis PA, Williams HE. Effect of high dose vitamin C on urinary oxalate levels. J Urol. 1994;151:834837. 69. Gogel HK, Tandberg D, Strickland RG. Substances that interfere with guaiac card tests: implications for gastric aspirate testing. Am J Emerg Med. 1989;7:474480. 70. Fry PC, Fox HM, Tao HG. Metabolic response to a pantothenic acid deficient diet in humans. J Nutr Sci Vitaminol (Tokyo). 1976;22:339346. 71. Hodges RE, Bean WB, Ohlson MA, Bleiler R. Human pantothenic acid deficiency produced by omega-methyl pantothenic acid. J Clin Invest. 1959;38:14211425. 72. Glusman M. The syndrome of burning feet (nutritional melagia) as a manifestation of nutritional deficiency. Am J Med. 1947;3:211223. 73. Wolf B, Grier RE, Secor McVoy JR, Heard GS. Biotinidase deficiency: a novel vitamin recycling defect. J Inherit Metab Dis. 1985;8 (suppl 1):5358. 74. Mock DM, Heird GM. Urinary biotin analogs increase in humans during chronic supplementation: the analogs are biotin metabolites. Am J Physiol. 1997;272:E8385. 75. Baugh CM, Malone JH, Butterworth CE Jr. Human biotin deficiency. A case history of biotin deficiency induced by raw egg consumption in a cirrhotic patient. Am J Clin Nutr. 1968;21:173182. 76. Mock DM, Baswell DL, Baker H, Holman RT, Sweetman L. Biotin deficiency complicating parenteral alimentation: diagnosis, metabolic repercussions, and treatment. J Pediatr. 1985;106:762769. 77. Wolf B, Heard GS, Weissbecker KA, McVoy JR, Grier RE, Leshner RT. Biotinidase deficiency: initial clinical features and rapid diagnosis. Ann Neurol. 1985;18:614617. 78. Mardach R, Zempleni J, Wolf B, et al. Biotin dependency due to a defect in biotin transport. J Clin Invest. 2002;109:16171623. 79. Mock NI, Malik MI, Stumbo PJ, Bishop WP, Mock DM. Increased urinary excretion of 3-hydroxyisovaleric acid and decreased urinary excretion of biotin are sensitive early indicators of decreased biotin status in experimental biotin deficiency. Am J Clin Nutr. 1997;65:951958. 80. Vlasova TI, Stratton SL, Wells AM, Mock NI, Mock DM. Biotin deficiency reduces expression of SLC19A3, a potential biotin transporter, in leukocytes from human blood. J Nutr. 2005;135:4247. 81. Wolf B, Heard GS, McVoy JR, Raetz HM. Biotinidase deficiency: the possible role of biotinidase in the processing of dietary protein-bound biotin. J Inherit Metab Dis. 1984;7 (suppl 2):121122. 82. Zeisel SH. Gene response elements, genetic polymorphisms and epigenetics influence the human dietary requirement for choline. IUBMB Life. 2007;59:380387. 83. Buchman AL, Dubin MD, Moukarzel AA, et al. Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Hepatology. 1995;22:13991403.
Fat-Soluble Vitamins
Winston Koo, MBBS, FACN, CNS, May Saba, PharmD, BCNSP, Mirjana Lulic-Botica, BSc, BCPS, and Judith Christie, RN, MSN
8
Learning Objectives
1. Understand the physiological basis for the function and requirement for fat-soluble vitamins, as a group or for each vitamin individually. 2. Understand the common risk factors and special considerations in the predisposition to develop fatsoluble vitamin deficiency states. 3. Understand the common manifestations and diagnosis of deficiency states for these fat-soluble vitamins. 4. Understand the potential risks of excessive intake of fat-soluble vitamins.
CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 Vitamin A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .76
Biochemistry and Physiology Sources Absorption and Metabolism Deficiency Adverse Effects
Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Introduction
Vitamin E. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Vitamin K . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Achievement of adequate status for fat-soluble vitamins (A, D, E, and K) depends on adequate intake, intestinal digestion and absorption, cellular uptake, and metabolism. Vitamins D and K are produced endogenously in substantial, but variable, amounts. Fortification of some vitamins (eg, vitamin D) is widely practiced because of their limited distribution in commonly consumed natural foods. However, a varied dietary intake generally assures an adequate supply of fatsoluble vitamins meeting the dietary reference intake (DRI) values in the normal population (Table 8-1). Fat-soluble vitamins have metabolic interactions with one another, and with other nutrients. These interactions may affect the requirements for and biological actions of fatsoluble vitamins. For example, other antioxidants including vitamin C, glutathione, and ubiquinols, can affect the regeneration of -tocopherol and the requirement for vitamin E; zinc, energy, and protein metabolism affect vitamin A status through their effect on production of retinol-binding protein (RBP) and transthyretin; novel ligands (eg, secondary bile acids and long-chain polyunsaturated fatty acids) can
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FAT-SOLUBLE VITAMINS
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activate vitamin D receptors leading to additional potential biological function for vitamin D. Thus nutrient requirements and functions of fat-soluble vitamins should not be considered in isolation; they must be considered as part of total nutrition support.
Table 8-1 Dietary Reference Intake for Fat-Soluble Vitamins1-4
Life stage Vitamin A mcg RAE (1 mcg = 3.3 IU) VITAMIN D* IU (1 mcg = 40 IU) VITAMIN E mg VITAMIN K* mcg
06 mo* 712 mo* 13 y 48 y 913 y MALES 1418 y FEMALES 1418 y PREGNANCY 1418 y LACTATION 1418 y UL
400 (600) 500 (600) 300 (600) 400 (900) 600 (1700) 900 (2800) 700 (2800) 750 (2800)
400 (1000) 400 (1000) 400 (2000) 400 (2000) 400 (2000) 400 (2000) 400 (2000) 400 (2000)
4 5 6 (200) 7 (300) 11 (600) 15 (800) 15 (800) 15 (800) 19 (800)
2.0 2.5 30 55 60 75 75 75 75 NA
1200 (2800) 400 (2000)
For the individual: * Adequate intake (AI) = observed or experimentally determined estimates of nutrient intake by a group or groups of healthy people. Applicable for all ages for vitamins D and K. Recommended dietary allowance (RDA) = average daily dietary intake sufficient to meet the requirement of 97% to 98% of healthy individuals in a life stage and gender group. RDA = EAR + 2SDEAR or 1.2 EAR or 1.3 EAR. For a group: Estimated average requirement (EAR) = daily intake of a nutrient estimated to meet the nutrient requirement of half of the healthy individuals in a life stage and gender group. Dose response assessment UL = Upper limit for each life stage is indicated in parenthesis. NA = not available
Consideration of special circumstances including the effect of medication is warranted. Chronic glucocorticoid and phenobarbital therapy affects vitamin D metabolism. Alternately, marked alteration in vitamin K intake can adversely affect coumarin anticoagulant therapy. Treatment of extreme obesity with increasingly severe dietary restriction and bariatric surgery can result in decreased intake and absorption of fat-soluble vitamins and other nutrients. The use of bile salt or fat sequestrants, such as cholestyramine and orlistat, as adjunct therapy for hypercholesterolemia, hepatobiliary disorders, or extreme obesity has the potential
to decrease the absorption of all fat-soluble vitamins and predisposes an individual to a deficiency state. Mineral oil and other nonabsorbable lipids interfere with absorption of fat-soluble vitamins. The adverse effects are potentially greater during periods of increased metabolic demands (eg, pediatric age ranges). Certain groups of individuals are at risk for fat-soluble vitamin deficiency. Individuals with any disease state that impairs biliary and pancreatic secretions, intestinal mucosal function, micelle formation, uptake into enterocytes, and chylomicron secretion can impair the digestion and absorption of all fat-soluble vitamins. Thus, severe hepatobiliary disorders, cystic fibrosis, and Whipples disease are some of the diseases that predispose the individual to fatsoluble vitamin deficiency. Increasingly, inherited defects in absorption or metabolism of various vitamins are documented to contribute to deficiency states in an individual. Deficiency states from limited intake are more common for vitamins A and D than for vitamins E and K. Restrictions in the variety of foods due to limited financial resources or fad diets is a risk factor for deficiency states. Concomitant deficit in other nutrients is also common in these circumstances. The at-risk life stages include the very young and adolescence. For example, prolonged exclusively breastfed infants living at higher latitudes are at risk for vitamin D deficiency. This is the result of lack of endogenous production from inadequate sunlight exposure and poor exogenous intake because of the low vitamin D content of breast milk. Pregnancy and lactation result in added demands to the bodys nutritional requirements. In certain disease states, supplementation of fat-soluble vitamins under medical supervision is appropriate. Bioavailability of the enteral supplement may be improved with the water miscible form or with alteration in the physical form, 5 although parenteral supplementation still may be needed in some patients. In healthy populations, ingestion of fatsoluble vitamins, often in some combination of multiple vitamins, is a common practice among adults and children.13,6 Supplementation in amounts similar to the daily requirements (ie, doubling the intake to twice the daily recommendation), is unlikely to result in any adverse effect, although there is also no consistent benefit. Adverse effects from consumption of fat-soluble vitamins naturally occurring in foods has been reported for vitamin A.7 Chronic exposure to excess intake of vitamins A and D is well known to have toxic effects affecting many organ systems. In some cases, single exposure to large doses of some fat-soluble vitamins may be toxic and occasionally may be lethal. Certain individuals (eg, those with chronic
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alcohol abuse and liver dysfunction) may be at greater risk for adverse effects of excess intake or deficiency in fat-soluble vitamins and other nutrients. Cigarette consumption increases the demand on antioxidants in addition to its other adverse effects.
Vitamin A
Vitamin A, or retinoids, refers to retinol and its derivatives including synthetic analogs that have the same -ionone ring and similar biological activities. They also include provitamin A carotenoids that are the dietary precursor of retinol. The all-trans isomer is the most common and stable form although many cis isomers also exist. Retinoids are critical to the maintenance of proper vision in the signal transmission of images to the visual cortex. They are necessary for cell differentiation and integrity of epithelial cells throughout the body including normal differentiation of the cornea and conjunctival membranes, as well as for the photoreceptor rod and cone cells of the retina. Other critical functions include maintenance of immune function, expression of various genes that encode for structural- and extracellular matrix-proteins, enzymes, RBPs and receptors, and embryonic development of hindbrain, eyes, ears, heart, and limbs. Provitamin A carotenoids must be converted to retinoids to exert vitamin A function. In addition, carotenoids are excellent antioxidants and may have other biological properties unrelated to their vitamin A activity.
green and yellow vegetables, oils, and fruits. Ripe, colored fruits and cooked, yellow tuber vegetables are more efficiently converted to vitamin A compared to dark green leafy vegetables. 3 Current estimates of vitamin A intake from vegetable sources is about 26% to 34% based on retinol activity equivalent (RAE). 3 Supplements are available as retinol, retinyl esters (palmitate, acetate, and N-formyl aspartamate), retinaldehyde or -carotene, either alone or in a multivitamin, and in oral and parenteral forms.11,12 Vitamin A activity is expressed as RAEs (1 mcg RAE = 1 mcg all-trans-retinol = 2 mcg supplemental all-trans-carotene = 12 mcg dietary all-trans--carotene = 24 mcg other dietary provitamin A carotenoids = 3.3 IU of vitamin A activity). 3 The bioconversion of dietary provitamin carotenoids to RAE is estimated to be 12:1 (mcg:mcg) based on the relative absorption efficiency of -carotene from food and the functional carotene:retinol equivalency ratio. One RAE for dietary provitamin A carotenoids other than -carotene is lower and set at 24 mcg. 3 The use of mcg RAE is preferred to mcg retinol equivalent (RE) or International Units when calculating and reporting the amount of total vitamin A in mixed foods or assessing the amount of dietary and supplemental vitamin A consumed. RE was based on the earlier erroneous two times higher estimate of bioconversion of dietary carotenoids. 3
Absorption and Metabolism

The efficiency of absorption of preformed vitamin A is about 70% to 90%. Vitamin A supplements, particularly -carotene, are generally better absorbed than the dietary vitamin sources. There may be a maturation lag in the ability to absorb vitamin A in the preterm infant13 and the only effective means to elevate plasma retinol concentrations in preterm infants is via parenteral route.14 Dietary retinyl esters are freed by acidic digestion and emulsified by bile salts to form micelles. These micelles are transported to the intestinal cells, where the retinyl ester is moved across the mucosal membrane and hydrolyzed, re-esterified, and then incorporated into chylomicrons within the cell and secreted into lymph. At physiological concentrations, cellular uptake and efflux of unesterified retinol by enterocytes is mediated by lipid transporters and saturable, whereas at high pharmacological doses, the absorption of retinol is nonsaturable.15 Portal route of absorption is possible under some circumstances. Carotenoids are solubilized into micelles, from which they are absorbed into duodenal mucosal cells. Absorption of carotenoids is by passive diffusion and by a facilitated
Sources
Vitamin A is present in the diet as retinyl esters derived almost exclusively from animal sources (liver and fish liver oils, dairy products, kidney, and eggs). Most of the vitamin A in breast milk is in the form of retinyl palmitate in milk fat and is in greatest concentration in colostrum and transition milk. The vitamin A content of breast milk is generally lower in vitamin A deficient populations but is still sufficient to prevent subclinical deficiency in exclusively breastfed infants during the first 6 months. 8 Cows milk has relatively lower vitamin A content than human milk and averages ~40 International Units (IU)/g fat.9 The U.S. Food and Drug Administration encourages dairy producers to fortify reduced fat milk to 2000 IU/L.9 Infant formulas are fortified with vitamin A at 250 to 750 IU/100 kcal.10 Hightemperature sterilization of milk increases isomerization of trans- to cis-retinol by as much as 34%. 3 Provitamin A carotenoids (mainly -carotene) are distributed widely in
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process that requires, at least for lutein, the class B-type1 scavenger receptor (SR-B1).16 The intestine, liver, lung, adipose, and other tissues possess ,-carotene 15,15 monooxygenase activity that allows the central cleavage of the -carotene to form 2 molecules of retinal. The latter can be converted to other retinoids. Eccentric cleavage of carotenoids by other enzymes is also possible. The absorption efficiency of -carotene has wide inter-individual variation and is usually < 20%. 3,16 It is higher in the presence of dietary fat, from homogenized, juiced, or cooked vegetables which allow the release of carotenoids, and during poor vitamin A status. It is lower in the presence of intestinal infections or infestations, and at high dietary carotenoid intake.17 -carotene significantly reduces lutein absorption when given simultaneously. 3 Retinyl esters and carotenoids are transported to the liver in chylomicron remnants. Apoprotein E and several specific hepatic membrane receptors are required for the uptake of chylomicron remnants by the liver. Retinyl esters are hydrolyzed to retinol then bound to RBP for release into the circulation. In the blood, holo-RBP associates with transthyretin to form a trimolecular complex with retinol in a 1:1:1 molar ratio for delivery to peripheral tissues. Retinoic acid, nuclear retinoic acid receptor and retinoid X receptors, cellular retinol, and retinoic acid binding proteins I and II are critical to the function of retinoids. Carotenoids are incorporated into very low density lipoproteins and exported from the liver into the blood. They enter peripheral tissues via receptor uptake of lipoproteins and undergo further metabolism. Retinoids are stored in the liver and other tissues including adipose tissue, bone marrow, lung, eye, kidney, and other organs. When vitamin A intake is adequate, >90% of total body vitamin A is present in the liver. Vitamin A concentration of at least 20 mcg/g of liver in adults is suggested as the minimal acceptable reserve.18 Regeneration of retinyl esters to form local storage pools (eg, in the retinal pigment epithelium) also occurs. Typically, the majority of vitamin A metabolites are excreted in the urine and almost all of the excreted metabolites are biologically inactive. Thus elevated plasma concentrations of retinol, RBP, and transthyretin can occur in chronic renal disease. Some retinoid metabolites are conjugated with glucuronic acid or taurine in the liver for excretion in bile.
health and survival of infants, young children, and pregnant and lactating women. These life-stage groups represent periods when both nutrition stress is high and the diet is likely to be chronically deficient in vitamin A. There are numerous clinical effects of vitamin A deficiency (Table 8-2) but the most specific manifestation is xerophthalmia. In developed countries, risk factors for vitamin A deficiency include fat malabsorption conditions, strict vegan diets, fad diets, and severely restricted preformed- or provitamin A. Ethanol decreases liver vitamin A stores by increasing release of hepatic retinol independent of dietary intake and decreasing conversion of -carotene to retinol, thus promoting vitamin A deficiency. 3
Table 8-2 Clinical Effects of Vitamin A Deficiency3,19,20 Xerophthalmia* XN: Impaired dark adaptation (from slowed regeneration of rhodopsin) to night blindness XCj: Conjunctival dryness (xerosis), XB: keratinization (Bitots spot) XCo: Corneal xerosis, XU/K: Corneal ulceration and/or keratomalacia of any part, XSc: Corneal scar in central part, XSp: Corneal scar in peripheral part XF: Xerophthalmia fundus Generalized dysfunction of cellular and humoral immunity withincreased morbidity and mortality especially from measlesanddiarrhea Impairs iron mobilization from stores Defects in lung function Follicular hyperkeratosis * Classification according to reference 19.
Deficiency
Vitamin A deficiency is an endemic nutrition problem throughout much of the developing world and affects the
The level of retinol in the blood is under homeostatic control over a broad range of body stores and reflects body stores only when these are very low or very high. 8 In addition, low plasma retinol concentration can result from an inadequate supply of dietary protein, energy, or zinc because of decreased rate of synthesis of RBP; or from acute or chronic infection because of decreases in the concentrations of the negative acute phase proteins, RBP and transthyretin, even when liver retinol is adequate. 3 Changes over time in plasma retinol concentration distributions within a population can be helpful to determine vitamin A status.8 Plasma retinol at < 0.70 mol/L (1 mol/L = 28.6 mcg/dL) reflects vitamin A inadequacy and at < 0.35 mol/L is considered as indicative of vitamin A deficiency.20 Simultaneous measurement of plasma RBP is helpful to assess the vitamin A status.4 Other measures of vitamin A status such as the relative dose response (RDR) and modified relative dose response (MRDR), immune function tests, conjunctival impression cytology, dark adaptation test, pupillary response test,
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and total liver reserve by isotope dilution, are abnormal in clinical vitamin A deficiency. However, none of the above measures have sufficient data relating to the usual dietary intakes of individuals or populations to allow adequate determination of the vitamin A status. Some of these tests (eg, RDR and MRDR) are subjected to other factors such as RBP production that can influence the outcome. 3,8,21 Night blindness significantly improved in a majority of affected persons with vitamin A or -carotene supplementation.22 Vitamin A supplementation reduces the risk of mortality among infants, young children, and pregnant and postpartum women in developing countries. Intramuscular vitamin A supplement has a modest effect on reduction in oxygen requirement at 36 weeks postmenstrual age in those with birth weights < 1 kg.14 Deficiency in other nutrients also should be treated as they also may detrimentally affect vitamin A status. For example, zinc deficiency decreases the synthesis and secretion of RBP and transthyretin, and synthesis of rhodopsin. There is no evidence for a certain percentage of provitamin A carotenoids to meet the vitamin A requirement. However, in view of the health benefits of consumption of fruits and vegetables, 5 servings of fruits and vegetables daily could provide 5.2 to 6 mg/d of provitamin A which is ~50% to 65% of the mens RDA for vitamin A. 3
Adverse Effects
There are substantial data on the adverse effects of high vitamin A intake.18,23 Individuals with pre-existing liver disease, hyperlipidemia, severe protein malnutrition, or high alcohol intake, may be distinctly susceptible to the adverse effects of preformed vitamin A intake. Short-term large doses and even a single dose > 150,000 mcg in adults24 and proportionately lower in children can result in acute toxicity characterized by nausea, vomiting, headache, vertigo, blurred vision, muscular incoordination, and raised intracranial pressure. In infants, there is also bulging of fontanels.18,25 Animal studies demonstrated that a similarly large single dose of vitamin A can be lethal.26 Chronic toxicity is usually associated with ingestion of large doses > 30,000 mcg/day for months or years. Clinical manifestations of chronic toxicity are varied and non-specific and may include irritability, anorexia, skin desquamation, and liver abnormalities including elevated liver enzymes, fibrosis, and cirrhosis. In infants, additional non-hepatic manifestations include bulging fontanel, craniotabes, and laboratory findings of cortical hyperostosis, hypercalcemia, and hyperphosphatemia, and metastatic calcifications may occur at an intake between 5,500 to 6,750 mcg/d for 1 to
3 months. 3,25 In adults, there are inconsistent findings for bone mineral loss and fractures. 3 Ethanol, while promoting a deficiency of vitamin A, also enhances vitamin A hepatotoxicity.27 Care is needed with vitamin A supplementation in patients with renal dysfunction to avoid vitamin A toxicity because the kidney is the main route of excretion of vitamin A and its metabolites. Both acute and chronic vitamin A toxicity are associated with increased plasma retinyl ester concentrations. 28 In humans, teratogenic effects, particularly neural crest defects, from naturally occurring metabolites of vitamin A (trans-retinoic acid, 13-cis retinoic acid, and their oxoderivatives) are well documented in women exposed during the first trimester. There are limited data to link teratogenic effects to high-dose preformed vitamin A (retinol and retinyl esters) and insufficient data to determine the presence of toxic non-teratogenic developmental effects. 29 Adolescents using vitamin A or derivatives for the treatment of acne must be informed of the potential teratogenic effects and counseled on the need to avoid pregnancy during this therapy. High -carotene intake has not been shown to cause hypervitaminosis A but carotenodermia (a yellowish discoloration of the skin from hypercarotenemia) has been reported30,31 and is reversed when the intake is discontinued. Clinical intervention trial of -carotene supplement based on its antioxidant activity has resulted in a significant increase in the rate of lung cancer in smokers. This would suggest that excessive intake of the provitamin A carotenoids may have unintended consequences on the complex and intricately balanced natural antioxidant defense system. 32 Also, the combination of excess -carotene and ethanol may result in hepatotoxicity. 3
Vitamin D
Vitamin D (calciferol) refers to two fat-soluble seco-sterols: cholecalciferol (vitamin D3) photosynthesized in the skin of vertebrates, and ergocalciferol (vitamin D2) from the yeast and plant sterol. The term vitamin D without the subscript is frequently used generically to describe vitamins D2 and D3 and, correspondingly, their metabolites. The parent vitamin D compounds are biologically inert and require two obligatory hydroxylation steps primarily in the liver and kidney to 25 hydroxyvitamin D (25 OHD) and 1,25 dihydroxyvitamin D (1,25 (OH)2D), respectively. Quantitatively, 25 OHD is the major circulating metabolite. It is a good marker of vitamin D status as it reflects the cumulative
79
effects of exposure to sunlight and dietary intake of vitamin D. 33 At physiological concentrations, 1,25 (OH)2D is the metabolite responsible for most, if not all, biological functions of vitamin D. The classic actions of vitamin D include the maintenance of calcium homeostasis and bone mineralization in the prevention of rickets in children and osteomalacia in adults. These effects are mediated primarily through 1,25 (OH)2D binding of nuclear vitamin D receptor (VDR) and from participation in various feedback loops involving parathyroid hormone, calcitonin, and fibroblast growth factor (FGF)-23. There is also 1,25 (OH)2D3 -mediated gene regulation for several bone anabolic and resorbing factors. VDR is widely distributed in numerous organ systems and 1,25 (OH)2D3 -VDR effects at the local level include immunomodulation, antimicrobial action, detoxification, cell proliferation, apoptosis regulation, insulin secretion, skin integrity and -oxidation. 34 VDR stimulation independent of1,25 (OH)2D3 controls hair cycling and brain development. Novel ligands other than 1,25 (OH)2D3 including lithocolic acid, curcumin, -tocotrienol, and essential fatty acid derivatives may play additional specific roles in physiological functions. 35 Despite the numerous physiological functions mediated by VDR, the evidence for major dysfunction from vitamin D deficiency other than the classic actions of mineral homeostasis and bone mineralization islimited. Biological activity of vitamin D is expressed in International Units based on bioassay using cholecalciferol. The biological activity of 1 mcg of vitamin D is 40 IU and 1 mcg 25 OHD is 200 IU (ie, 5 times more potent than cholecalciferol).1 Both forms of vitamin D undergo the same metabolic fate and function similarly at least for the classic actions in the clinical prevention and treatment of rickets and osteomalacia. 36,37 The role of vitamin D2 in other actions is not well defined.
individuals, endogenous synthesis of vitamin D is possible although the rate of production is lower than less pigmented individuals. In any case, adequate endogenous production of vitamin D3 is not assured for all populations because of multiple factors that affect its endogenous synthesis. Foods naturally rich in vitamin D are limited to the flesh of fatty fish and fish liver oil, and the liver and fat from aquatic mammals (eg, seals and polar bears). Thus, dietary intake of vitamin D from foods comes primarily from fortified milk products and other fortified foods such as breakfast cereals.41,42 The average intake of vitamin D is about 200 to 400 IU per day with children tending to have greater intake than adults.41 Human milk and cows milk have very low vitamin D content (< 50 IU/L). In the United States, a vast majority of natural milk and all infant formulas are fortified with vitamin D3 at 400 IU (10 mcg)/L9 and 40 to 100 IU/100 kcal,10 respectively. The amounts of vitamin D added to the milk products were erratic during the early 1990s but more recent testing of samples indicates that vitamin D fortification is more uniform.9 Vitamin D supplements as vitamin D2 or D3 are available either alone or as multivitamins in oral preparations. The parent vitamin D compound is available in parenteral form only as part of a multivitamin. The more potent vitamin D analog or hydroxylated vitamin D metabolites are available in the oral and parenteral forms and are most often used as part of the management of specific medical conditions. For example, there are vitamin D analogs with minimal or no calcemic effects that are used for their antiproliferative and pro-differentiation actions.11,12

Intestinal absorption of vitamin D and its metabolites requires normal bile and pancreatic secretions. Once absorbed from the intestine, it is incorporated into chylomicrons and transported through the lymphatic system. Both the endogenously synthesized and absorbed dietary vitamin D and its metabolites are transported in the circulation primarily by specific vitamin D binding protein and also by albumin to the various tissues. Structural differences in the parent vitamin D3 and vitamin D2 and their metabolites alter their binding to the carrier protein vitamin D binding protein (DBP) and their metabolism. Data on bioavailability of vitamin D3 versus D2 is controversial with respect to the maintenance of circulating 25 OHD concentrations.43,44 Circulating parent vitamin D is short-lived as it is either stored in the fat or metabolized in the liver.45 In the hepatic mitochondria, vitamin D 25 hydroxylase is regulated by vitamin D and its metabolites. The half-life of circulating
Sources
Endogenous synthesis of vitamin D3 requires exposure to sunlight or irradiation in the ultraviolet B range. It is extremely effective and a 10- to 15-minute whole-body exposure to peak summer sun will generate and release up to 20,000 IU vitamin D3 into the circulation. 38,39 However, prolonged sunlight exposure increases the conversion of previtamin D3 to inactive metabolites. Cutaneous production of vitamin D3 is substantially diminished by decreased exposure to sunlight from seasonal changes, or time of day, clouds, aerosols, thick ozone, higher latitude, aging, clothing, sunscreen use, and melanin pigmentation.40 In dark-skinned
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25 OHD is 10 days to 3 weeks.46 Subsequent hydroxylation at the 1-carbon position to 1,25 (OH)2D in the kidney is tightly regulated, principally through the action of parathyroid hormone in response to calcium and phosphorus levels. The half-life of 1,25 (OH)2D is ~4 to 6 hours.47 It is possible that activated macrophages, some lymphoma cells, and cultured skin and bone cells also make 1,25 (OH)2D and exert paracrine or autocrine actions. Excessive unregulated production of 1,25 (OH)2D by activated macrophages and lymphoma cells is responsible for hypercalciuria and hypercalcemia. Enterohepatic circulation of vitamin D and its metabolites is present but probably has a limited role in their conservation.48 Further hydroxylation at the 24-carbon of 25 OHD and 1,25 (OH)2D is the initial step in the metabolic degradation of these 2 vitamin D metabolites, with the major metabolite (calcitroic acid) excreted in the urine.49
Deficiency
Clinical deficient states can result from lack of cutaneous production of vitamin D3 with inadequate intake, impaired absorption or metabolism of vitamin D to its active form 1,25 (OH)2D, or impaired recognition of 1,25 (OH)2D by its receptor. Drugs such as glucocorticoids inhibit vitamin D dependent calcium absorption. Phenobarbital and phenytoin can alter the metabolism and circulating halflife of vitamin D metabolites. Chronic therapy with these medications predisposes patients to the effects of vitamin D deficiency. Vitamin D deficiency results in inadequate mineralization, or demineralization, of the skeleton with occurrence of rickets in the developing skeleton and osteomalacia in adults. Rickets is characterized by widening at the ends of long bones, rachitic rosary, deformations include bowed legs and knock-knees, and frontal bossing of the skull. In addition, secondary hyperparathyroidism occurs as a homeostatic response to prevent a decrease in circulating ionized calcium from vitamin D deficiency. Parathyroid hormone mobilizes calcium from the skeleton resulting in porotic bones, and conserves renal calcium but increases phosphorus excretion as reflected by low or absent urine calcium and increased urine phosphorus. Thus, vitamin D deficiency is characterized by a low circulating concentration of 25 OHD, normal fasting circulating calcium with low or low normal phosphorus, and elevated parathyroid hormone, although hypocalcemia can occur in chronic vitamin D deficiency. Increased bone turnover with vitamin D deficiency is reflected by elevated bone alkaline phosphatase, collagen, and non-collagenous bone proteins
including hydroxyproline, pyridinoline, deoxypyridinoline, N- and C-teleopeptides, and osteocalcin in the circulation and/or urine. Based on the traditional Gaussian distribution, the lower limit of serum or plasma 25 OHD is considered to be in the range of 10 to 15 ng/mL (1 nmol/L = 0.4 ng/mL). However, the lower limit in adults is recommended to be ~80 nmol/L (32 ng/mL) based on changes in biomarkers such as parathyroid hormone, calcium absorption, and bone mineral density38 and in children to be ~60 nmol/L (24 ng/mL).4 Low circulating 25 OHD is common in children50 and adults.42 Non-calcium and non-bone related clinical outcomes including cancer risk and immune defects from population-based studies in vitamin D status are not well defined. The widespread occurrence of low circulating 25OHD concentrations in children and the occasional clinical manifestation of rickets in non-supplemented infants have prompted the recommendation to raise the daily vitamin D intake to 400 IU.4 However, beneficial effects of having values of serum or plasma 25 OHD concentrations higher than the current recommended levels remain undefined.
Adverse Effects
Vitamin D toxicity from prolonged exposure to natural sunlight has not been reported. Increased sunlight exposure leads to a decrease in endogenous production of vitamin D3 by conversion of previtamin D3 to inactive metabolites, inhibition of 25-hydroxylase enzymes results in decreased production of 25 OHD3, and stimulation of 24-hydroxylase enzyme results in increased metabolic degradation of vitamin D metabolites. These processes contribute to the prevention of hypervitaminosis D and vitamin D toxicity. Excessive vitamin D intake from supplements can result in hypervitaminosis D and is characterized by a considerable increase in plasma 25 OHD in the range of 400 to 1250 mol/L (160500 ng/mL). 51,52 Other vitamin D metabolites are also elevated although the increase in 1,25 (OH)2D is generally elevated to a much lower extent. 52 Clinical toxicity is manifested through hypercalcemia and its multiple debilitating effects include polyuria, polydipsia, depression, and metastatic calcification of soft tissues including the kidney, blood vessels, heart, and lung. These effects generally are seen with chronic supplementation in excess of 20,000 IU daily53 although toxicity can occur at lower doses. Toxicity from chronic intake of ergocalciferol appears to require significantly higher doses. 54 It is possible that this lower toxicity may be a result of its relatively low bioactivity compared to cholecalciferol.
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Vitamin E
There are 8 naturally occurring forms of vitamin E with 4 (-, -, -, and -) tocopherols, all in the RRR- form, and 4 (-, -, -, and -) tocotrienols. The RRR- form of -tocopherol is maintained in human plasma and occurs naturally in foods. Eight different stereoisomers in equal amounts are found in synthetic vitamin E (all rac-tocopherol): RRR-, RSR-, RRS-, RSS-, SRR-, SSR-, SRS-, and SSS- forms with structural differences at the side chain and at the ring/tail junction. The various forms of vitamin E are not interconvertible in the human. The plasma concentration and biological activity of different forms of vitamin E are dependent primarily on the affinity of -tocopherol transfer protein (-TTP) for them. RRR--tocopherol has the highest affinity for -TTP. Other forms of vitamin E stereoisomers have much lower binding affinity to -TTP.2 They may have some biological functions55,56 and their intake are reported as -tocopherol equivalent.2 Vitamin E functions primarily as a non-specific chainbreaking antioxidant acting as a peroxyl radical scavenger that prevents the propagation of free radical reaction and lipid peroxidation. 57 Vitamin E also may play important roles in cell proliferation and differentiation, cell adhesion and arachidonic acid cascade through inhibition of protein kinase C activity, downregulating expression of intercellular cell adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1), and upregulating expression of cytosolic phospholipase A 2 and cyclooxygenase-1.2 Current recommendations for vitamin E intake include only the 2R-stereoisomeric forms of -tocopherol (RRR-, RSR-, RRS-, RSS-) since they are maintained in human plasma or tissue. Data on intakes from current surveys and nutrient content of foods are presented as -tocopherol equivalents (-TE) and include all 8 naturally occurring forms of vitamin E, after adjustment for bioavailability using previously determined equivalency. For example, -tocopherol is estimated to have only 10% of the bioactivity of -tocopherol. Based on the NHANES III (Third National Health and Nutrition Examination Survey 1988 to 1994) data, ~80% of the -TE from foods is contributed by foods containing -tocopherol. Thus, the intake of -TE is usually greater than the intake of -tocopherol alone.2 Milligrams of -tocopherol in a meal including fortified food or multivitamins is based on the following conversion factors:
= mg -TE in a meal 0.8 and/or = IU of the RRR--tocopherol compound 0.67 = IU of all rac--tocopherol compound 0.45 If diets vary considerably from what might be considered typical in the United States or Canada, a conversion factor other than 0.8 might be more appropriate.2 All forms of supplemental -tocopherol are used to establish the tolerable upper intake level for vitamin E as all forms of vitamin E are absorbed.2
Sources
The main dietary sources of vitamin E are edible vegetable oils. All of the -tocopherol present in natural foods is in the RRR--tocopherol form. Oils from wheat germ, sunflower, safflower, canola, olive, and cottonseed contain > 50% of the tocopherol as -tocopherol. Soybean and corn oils contain ~10 times as much -tocopherol as -tocopherol. Palm and rice bran oils contain high proportions of -tocopherol, as well as various tocotrienols. Meat, poultry, fish, dairy products, nuts, grains and fruit, especially the oils or fatty portions, are other sources of -tocopherol. 2 Colostrum and breast milk are rich sources of vitamin E. 58 Infant formulas are fortified with a minimum of 0.7 IU/100 kcal.10 Infant formulas fortified with the natural form of -tocopherol have better bioavailability compared to the synthetic forms. 59 Estimation of dietary intake of vitamin E is difficult because the source of oil is not always known with certainty and most nutrient databases, as well as nutrition labels, do not distinguish among the different tocopherols in food. Food preparation, such as deep frying using vegetable oil, leads to chemical structure modification and may result in functional discrepancy. 56 Vitamin E esters usually as acetate of either natural RRR- or the synthetic mixture (all rac-) of -tocopherol are used in food fortification, supplements, and pharmacological agents. Vitamin E supplements are available alone or as multivitamins in oral preparation. Vitamin E is available in parenteral form only as part of a multivitamin.11 A water-miscible formulation of vitamin E, tocopheryl polyethylene glycol succinate 1000 (TPGS), is absorbed, metabolized, and reverses signs of vitamin E deficiency in children60 with severe fat malabsorption.

Reports of vitamin E absorption from the intestinal lumen vary widely from 21% to 86%. In healthy humans, the esters are hydrolyzed and absorbed as efficiently as -tocopherol. The absorption of various forms of vitamin E is independent and shows similar apparent efficiency. 2 Efficiency of
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absorption depends upon biliary and pancreatic secretions, micelle formation, uptake into enterocytes, and chylomicron secretion. 2 Vitamin E absorption is facilitated by dietary fat and is lowered following vitamin E supplementation.61 During chylomicron catabolism, some vitamin E is distributed to all of the circulating lipoproteins. Chylomicron remnants, containing newly absorbed vitamin E, are taken up by the liver. The high affinity of hepatic -TTP to -tocopherol over all other vitamin E isomers is responsible for the preferential secretion of -tocopherol with very low-density lipoprotein from the liver, 62 which is the main determinant of plasma vitamin E concentrations. Adipose tissue and muscle are other major storage sites for vitaminE. Vitamin E rapidly transfers between lipoproteins and between lipoproteins and cell membranes, which may enrich cell membranes with vitamin E. The human plasma phospholipid transfer protein accelerates this process.63 The RRR-stereoisomer has roughly twice the availability of the all-rac forms. Tissue -tocopherol concentrations largely reflect changes in plasma concentrations of -tocopherol.64 The 4 tocopherols are ultimately degraded by omegaoxidation and subsequent beta-oxidations followed by the elimination of the metabolites in the bile and in the urine. Excess -tocopherol as well as forms of vitamin E not preferentially used is excreted unchanged in the stool and in bile. The decreased intestinal absorption and increased excretion of urinary vitamin E metabolites may limit the rise in plasma -tocopherol (~ threefold) and vitamin E supplements providing > 150 to 200 mg daily may not promote higher tissue concentrations.65 When vitamin E intercepts a radical, -tocopherol is oxidized to the tocopheryl radical, a 1-electron oxidation product. A tocopherol radical can be reduced (ie, to regenerate -tocopherol) by other antioxidants including vitamin C, glutathione, and ubiquinols. The tocopherol radical can undergo further metabolism and is excreted in urine. It also may act as a prooxidant in the absence of a water-soluble antioxidant and oxidize other lipids in vitro. Whether this occurs in vivo is inconclusive. Vitamin E compounds other than RRR--tocopherol are preferentially metabolized and excreted.2
Deficiency
Vitamin E requirements increase with increased intake of polyunsaturated fatty acids, high-level physical activity, and cigarette smoking. However, the extent of increased requirement and the compensatory effects of other antioxidants are not defined. Intake of plant phenolic compounds and
flavonoids may add to the total antioxidant pool. Cellular redox cycling is coupled to the energy status of the organism. Thus dietary deficiencies of niacin or riboflavin might result in insufficient reducing equivalents for recycling oxidized products.2 Clinical deficiency from low dietary intake of vitamin E in normal individuals without undue oxidative stresses has not been reported.2 Clinical vitamin E deficiency occurs with fat malabsorption syndromes or with genetic defect in -TTP or abetalipoproteinemia where there is decreased hepatic reserve and circulating vitamin E. Vitamin E deficiency causes axonal degeneration of the large myelinated axons and results in posterior column and spinocerebellar symptoms. Peripheral neuropathy is initially characterized by areflexia, with progression to ataxic gait, and by decreased vibration and position sensations. Ophthalmoplegia, skeletal myopathy, and pigmented retinopathy also may occur.60 Neurological symptoms can progress if untreated and may be reversed if treated early. Increased erythrocyte fragility in vitro and hemolytic anemia with vitamin E deficiency are reversible with adequate replacement of vitamin E. Plasma -tocopherol is decreased in vitamin E depleted subjects and a level > 12 mol/L (0.5 mg/dL; 1 mol/L = 0.042 mg/dL) is consistent with vitamin E adequacy. 2 In subjects with elevated serum lipids, for example in cholestasis, a ratio of serum -tocopherol to serum total lipids of < 0.6 mg/g indicates vitamin E deficiency regardless of serum -tocopherol concentrations. In subjects with normal serum lipid concentrations (328573 mg/dL), corrections are not necessary to assess whether -tocopherol concentrations are within the normal range. 60,66 Hydrogen peroxide induced hemolysis and lipid peroxidation biomarkers in plasma, urine, or breath are elevated during vitamin E depletion and are normalized upon vitamin E repletion. However, these markers are non-specific and may vary with intake of other antioxidants. Routine supplementation of vitamin E is recommended for specific disorders. However, there are no conclusive data to support a high intake of vitamin E in the management of chronic illnesses involving the cardiovascular system, diabetes mellitus, cancer, central nervous system, cataracts, or immune function.2
Adverse Effects
All forms of vitamin E are absorbed and could contribute to vitamin E toxicity although not all forms are maintained in plasma. Normal adults appear to tolerate oral tocopherol intake of 100 to 800 mg/d67 but adverse effects from the
83
consumption of vitamin E as a supplement, food fortifier, or pharmacological agent are possible. There are contradictory reports in humans on hemorrhagic complications from high vitamin E intake. It is possible that individuals deficient in vitamin K or on anticoagulant therapy are at an increased risk for coagulation defects. 2 Preterm infants with birth weights < 1.5 kg with elevated plasma vitaminE at a mean of 5.1 mg/dL have an increased incidence of sepsis and necrotizing enterocolitis.68 Plasma -tocopherol concentrations are not informative for assessing adverse effects because they plateau at ~3 to 4 times the values for non-supplemented individuals. 2
prevalent in margarines, infant formulas, and prepared foods. Long-chain menaquinones are produced in substantial amounts endogenously but are probably insufficient to meet the daily requirement for vitamin K.72 Vitamin K is present in low concentrations in breast milk (< 5 mcg/L). Commercial infant formulas are fortified with vitamin K (50100 mcg/L) based on a minimum of 4 mcg/100 kcal.10 Intravenous fat emulsions are another source of vitamin K although the content varies with composition of the fat emulsion and manufacturing process.73 Vitamin K supplement is available alone or as part of many, but not all, multivitamin preparations in oral and parenteral forms.
Vitamin K
There are 2 naturally occurring compounds with vitamin K activity: phylloquinone (vitamin K1) from plants and long-chain menaquinones (vitamin K 2) synthesized from intestinal bacteria. Menadione (vitamin K 3) is chemically synthesized and has better water solubility than the 2 natural forms. Structural differences in the isoprenoid side chain govern many facets of the metabolism of K vitamins, including the way they are transported, taken up by target tissues, and subsequently excreted.69 Vitamin K in its reduced form is a cofactor for gammaglutamyl carboxylase enzymes responsible for the posttranslational conversion of specific glutamic acid (Glu) residues to -carboxyglutamyl (Gla) residues in a subclass of proteins known as vitamin K dependent proteins (also known as -carboxylated proteins or Gla-proteins). The major Gla proteins include certain proteins of the blood coagulation system: prothrombin (coagulation factor II), factors VII, IX, and X, protein C, protein S, and protein Z; and proteins expressed in mineralized tissues: osteocalcin and matrix Gla-protein.70,71 Other putative non-cofactor functions of vitamin K include suppressing inflammation, preventing brain oxidative damage, and playing a role in sphingolipid synthesis. 3,71

Phylloquinone absorption in the jejunum is dependent on the presence of bile and pancreatic secretions and is enhanced by dietary fat. Free phylloquinone is almost completely absorbed but absorption of vitamin K from food sources is much lower and is generally < 20%. 3 Absorbed phylloquinone is secreted into lymph and enters the circulation. In the postprandial state, phylloquinone is transported mainly by triglyceride-rich lipoproteins (TRLs) and longchain menaquinones mainly by low-density lipoproteins. Liver uptake and turnover of phylloquinone is rapid. TRLborne phylloquinone uptake by some extrahepatic tissues (eg, osteoblasts) is an apoE-mediated process with the LRP1 receptor playing a predominant role. Both phylloquinone and menaquinones activate the steroid and xenobiotic receptor that initiates their catabolism. Vitamin K is excreted primarily in bile and also in urine after oxidative degradation of the phytyl side chain followed by glucuronide conjugation. The liver has the highest concentration of phylloquinone and significant amounts are also present in the heart and other tissues. Hepatic reserve is rapidly depleted from restricted dietary intake.
Deficiency
Individuals at risk for vitamin K deficiency include those with severe fat malabsorption conditions (eg, hepatobiliary disorders) or after bariatric surgery, especially those with severe diet restriction. Prolonged use of broad-spectrum antibiotics may decrease vitamin K synthesis by intestinal bacteria. Long-term differences in dietary vitamin K intake modulate the response to coumarin anticoagulants, which act by blocking the vitamin K recycling. Elevated intake of vitamin E antagonizes vitamin K action probably through its effect on vitamin K absorption and metabolism.2,74 The classic sign of vitamin K deficiency is an increase in
Sources
Vitamin K content in most foods is very low (< 10 mcg/ 100 g), and the majority is obtained from a few leafy green vegetables and 4 vegetable oils (soybean, cottonseed, canola, and olive) that contain high amounts. Hydrogenation of plant oils to form solid shortenings results in some conversion of phylloquinone to 2,3-dihydrophylloquinone but it is uncertain whether these forms are metabolically and functionally identical. These forms of vitamin K are most
84
prothrombin time, and in severe cases, a hemorrhagic event. Both abnormalities are responsive to vitamin K. However, other than the exclusively breastfed infant without vitamin K prophylaxis therapy, it is almost impossible to achieve this level of deficiency by simple restriction of vitamin K intake in any nutritionally adequate, self-selected diet in healthy individuals. The role of vitamin K in matrix-Gla formation would support its physiological activity in the metabolism of multiple organ systems but to date its role in chronic diseases such as osteoporosis and atherosclerosis remains to be defined. Prothrombin time, vitamin K dependent factors II, VII, IX, and X, plasma phylloquinone and menaquinone concentrations, and proteins induced in vitamin K deficiency such as under--carboxylated prothrombin (PIVKA-II) and osteocalcin (ucOC), respond to alterations in dietary vitamin K and are helpful to assess relative changes in vitamin K status. However, prothrombin time is the only indicator of vitamin K status associated with adverse clinical effects. Vitamin K prophylaxis is recommended in newborn infants75 and in conditions that predispose the patient to fatsoluble vitamin deficiency states.
Adverse Effects
Vitamin K toxicity is rare. Parenteral administration of a large amount of water-soluble synthetic vitamin K (vitamin K 3) has been associated with hemolytic anemia, hyperbilirubinemia, and kernicterus4 and with liver damage. 3 No adverse effects associated with other vitamin K supplements or from food have been reported in healthy individuals although high dietary intake or supplemental vitamin K can inhibit the anticoagulation effect of vitamin K antagonists.
D. Carotenoids have a different extent of vitamin A activity. E. Retinoids and carotenoids have similar potency for bioactivity. 3. All of the following statements on endogenous synthesis of vitamin D are correct except: A. It occurs following exposure to sunlight. B. A brief period of sunlight exposure can generate a large amount of vitamin D. C. Dark-skinned individuals cannot produce vitamin D. D. Vitamin D toxicity does not occur following chronic sunlight exposure. E. Sunscreen, clothing, and winter can decrease the capacity to produce vitamin D. 4. Which of the following statements concerning vitamin E is correct? A. Various forms of vitamin E are interconvertible. B. Natural RRR--tocopherol has similar biopotency to all other naturally occurring vitamin E stereoisomers. C. Synthetic (all-rac-tocopherol) vitamin E has greater biopotency than the natural RRR--tocopherol. D. Soybean and safflower oils have much higher content of -tocopherol versus -tocopherol. E. Vegetable oils are poor sources of vitamin E. 5. Which of the following may interfere with vitamin K action? A. Chronic antibiotic therapy B. Cholestyramine C. Orilstat D. Coumarin E. All of the above See p. 487 for answers.
1. Human milk is a good source of which fat-soluble vitamins? A. A and E B. D and A C. E and D D. K and D E. K and A 2. All of the following statements about vitamin A are correct except: A. Absorption increases with presence of dietary fat. B. Vitamin A metabolizes into various forms with biological action. C. Vitamin A activity of carotenoids is mediated through its conversion to retinoids.
References
1. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press; 1997. 2. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academy Press; 2000. 3. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press; 2001.
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4. American Academy of Pediatrics, Committee on Nutrition. Kleinman RE, ed. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009. 5. Papas KA, Sontag MK, Pardee C, et al. A pilot study on the safety and efficacy of a novel antioxidant rich formulation in patients with cystic fibrosis. J Cyst Fibros. 2008;7:6067. 6. Picciano MF, Dwyer JT, Radimer KL, et al. Dietary supplement use among infants, children and adolescents in the United States, 1999 2002. Arch Pediatr Adol Med. 2007;161:978985. 7. Mahoney CP, Margolis MT, Knauss TA, Labbe RF. Chronic vitamin A intoxication in infants fed chicken liver. Pediatrics. 1980;65:893897. 8. World Health Organization. Brown E, Akre J, eds. Indicators for Assessing Vitamin A Deficiency and Their Application in Monitoring and Evaluating Intervention Programmes. Geneva: World Health Organization; 1996. http://www.who.int/nutrition/ publications/micronutrients/vitamin_a_deficieny/WHO_ NUT_96.10/en/index.html. Accessed July 25, 2009. 9. Murphy SC, Whited LJ, Rosenberry LC, Hammond BH, Bandler DK, Boor KJ. Fluid milk vitamin fortification compliance in New York state. J Dairy Sci. 2001;84:28132820. 10. U.S. Food and Drug Administration. Code of Federal Regulations Title 21. Infant formula nutrient specifications. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFR Search.cfm?fr=107.100&SearchTerm=infant%20 formula. Accessed August 2, 2009. 11. Drug Facts and Comparisons 2009. St. Louis, MO: Wolters Kluwer Health. 12. Drugs, Supplements, and Herbal Information. Medline Plus, National Institutes of Health. http://www.nlm.nih.gov/ medlineplus/druginformation.html. Accessed June 25, 2009. 13. Koo WWK, Krug-Wispe S, Succop P, Tsang RC, Neylan M. Effect of different vitamin A intakes in very low birth weight infants. Am J Clin Nutr. 1995;62:12161220. 14. Darlow BA, Graham PJ. Vitamin A supplementation to prevent mortality and short and long-term morbidity in very low birthweight infants. Cochrane Database Syst Rev. 2007;4:CD000501. 15. Harrison EH. Mechanisms of digestion and absorption of dietary vitamin A. Annu Rev Nutr. 2005;25:87103. 16. Borel P, Drai J, Faure H, et al. Recent knowledge about intestinal absorption and cleavage of carotenoids. Ann Biol Clin. (Paris) 2005;63:165177. 17. Tang G, Qin J, Dolnikowski GG, Russell RM. Vitamin A equivalence of beta-carotene in a woman as determined by a stable isotope reference method. Eur J Nutr. 2000;39:711. 18. Olsen JA. Adverse effects of large doses of vitamin A and retinoids. Semin Oncol. 1983;10:290293. 19. Singh K. Modified classification of xerophthalmia. Indian J Ophthalmol. [serial online] 1991 [cited November 24, 2009]; 39:105107. http://www.ijo.in/text.asp?1991/39/3/105/24460. 20. World Health Organization. Global prevalence of vitamin A deficiency in populations at risk 19952005. WHO Global Database on Vitamin A Deficiency. Geneva: World Health Organization; 2009. http://whqlibdoc.who.int/publications/ 2009/9789241598019_eng.pdf. Accessed July 25, 2009.
21. Wasantwisut E. Application of isotope dilution technique in vitamin A nutrition. Food Nutr Bull. 2002; 23(3 Suppl):103106. 22. World Health Organization, United Nations Childrens Fund, VACG Task Force. Vitamin A Supplements: A Guide to Their Use in the Treatment and Prevention of Vitamin A Deficiency and Xerophthalmia. 2nd ed. Geneva: World Health Organization; 1997. http://www.who.int/nutrition/publications/micronutrients/vitamin_a_deficieny/9241545062/en/index.html. Accessed July 25, 2009. 23. Penniston KL, Tanumihardjo SA. The acute and chronic toxic effects of vitamin A. Am J Clin Nutr. 2006;83:191201. 24. Bendich A, Langseth L. Safety of vitamin A. Am J Clin Nutr. 1989;49:358371. 25. Persson B, Tunell R, Ekengren K. Chronic vitamin A intoxication during the first half year of life; description of 5 cases. Acta Paediatr Scand. 1965;54:4960. 26. Macapinlac MP, Olson JA. A lethal hypervitaminosis A syndrome in young monkeys (Macacus fascicularis) following a single intramuscular dose of a water-miscible preparation containing vitamins A, D2 and E. Int J Vitam Nutr Res. 1981;51:331341. 27. Leo MA, Lieber CS. Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity. Clin Nutr. 1999;69:10711085. 28. Krasinski SD, Russell RM, Otradovec CL, et al. Relationship of vitamin A and vitamin E intake to fasting plasma retinol, retinol-binding protein, retinyl esters, carotene, alpha-tocopherol, and cholesterol among elderly people and young adults: increased plasma retinyl esters among vitamin A-supplement users. Am J Clin Nutr. 1989;49:112120. 29. World Health Organization, The Micronutrient Initiative. Safe Vitamin A Dosage During Pregnancy and Lactation. Geneva: World Health Organization; 1998. http://www.who. int/nutrition/publications/micronutrients/vitamin_a_deficieny/WHO_NUT_98.4/en/index.html. Accessed July 25, 2009. 30. Lascari AD. Carotenemia. A review. Clin Pediatr. 1981;20:2529. 31. Bendich A. The safety of beta-carotene. Nutr Cancer. 1988;11:207214. 32. Black HS. Reassessment of a free radical theory of cancer with emphasis on ultraviolet carcinogenesis. Integr Cancer Ther. 2004;3:279293. 33. Haddad JG Jr, Hahn TJ. Natural and synthetic sources of circulating 25-hydroxyvitamin D in man. Nature. 1973;244:515517. 34. Jurutka PW, Bartik L, Whitfield GK, et al. Vitamin D receptor: key roles in bone mineral pathophysiology, molecular mechanism of action, and novel nutritional ligands. J Bone Miner Res. 2007;22 Suppl 2:v210. 35. Haussler MR, Haussler CA, Bartik L, et al. Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention. Nutr Rev. 2008;66 (10 Suppl 2):S98112. 36. Gordon CM, Williams AL, Feldman HA, et al. Treatment of hypovitaminosis D in infants and toddlers. J Clin Endocrinol Metab. 2008;93:27162721.
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37. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med. 2009;169:551561. 38. Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr. 2005;135:317322. 39. Lehmann B. The vitamin D3 pathway in human skin and its role for regulation of biological processes. Photochem Photobiol. 2005;81:1246 1251. 40. Engelsen O, Brustad M, Aksnes L, Lund E. Daily duration of vitamin D synthesis in human skin with relation to latitude, total ozone, altitude, ground cover, aerosols and cloud thickness. Photochem Photobiol. 2005;81:12871290. 41. Calvo MS, Whiting SJ, Barton CN. Vitamin D fortification in the United States and Canada: current status and data needs. Am J Clin Nutr. 2004;80:1710S6S. 42. Yetley EA. Assessing the vitamin D status of the US population. Am J Clin Nutr. 2008;88:558S564S. 43. Holick MF, Biancuzzo RM, Chen TC, et al. Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. J Clin Endocrinol Metab. 2008;93:677681. 44. Armas LA, Hollis BW, Heaney RP. Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab. 2004;89:53875391. 45. Mawer EB, Backhouse J, Holman CA, Lumb GA, Stanbury SW. The distribution and storage of vitamin D and its metabolites in human tissues. Clin Sci. 1972;43:413431. 46. Mawer EB, Schaefer K, Lumb GA, Stanbury SW. The metabolism of isotopically labeled vitamin D3 in man: the influence of the state of vitamin D nutrition. Clin Sci. 1971;40:3953. 47. Kumar R. The metabolism and mechanism of action of 1,25-dihydroxyvitamin D3 . Kidney Int. 1986;30:793803. 48. Clements MR, Chalmers TM, Fraser DR. Enterohepatic circulation of vitamin D: a reappraisal of the hypothesis. Lancet. 1984;1:13761379. 49. DeLuca HF. Evolution of our understanding of vitamin D. Nutr Rev. 2008;66 (10 Suppl 2):S73S87. 50. Rovner AJ, OBrien KO. Hypovitaminosis D among healthy children in the United States: a review of the current evidence. Arch Pediatr Adolesc Med. 2008;162:513519. 51. Jacobus CH, Holick MF, Shao Q , et al. Hypervitaminosis D associated with drinking milk. N Engl J Med. 1992;326:11731177. 52. Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr. 2008;88:582S586S. 53. Heaney RP. Vitamin D: criteria for safety and efficacy. Nutr Rev. 2008;66 (10 Suppl 2):S178S181. 54. Stephenson DW, Peiris AN. The lack of vitamin D toxicity with megadose of daily ergocalciferol (D2) therapy: a case report and literature review. South Med J. 2009;102:765768. 55. Sen CK, Khanna S, Roy S. Tocotrienols: vitamin E beyond tocopherols. Life Sci. 2006;78:20882098. 56. Cornwell DG, Ma J. Studies in vitamin E: biochemistry and molecular biology of tocopherol quinones. Vitam Horm. 2007;76:99134.
57. Traber MG, Atkinson J. Vitamin E, antioxidant and nothing more. Free Radic Biol Med. 2007;43:415. 58. Debier C. Vitamin E during pre- and postnatal periods. Vitam Horm. 2007;76:357373. 59. Stone WL, LeClair I, Ponder T, Baggs G, Barrett Reis B. Infants discriminate between natural and synthetic vitamin E. Am J Clin Nutr. 2003;77:899906. 60. Sokol RJ, Butler-Simon N, Conner C, et al. Multicenter trial of d-alpha-tocopheryl polyethylene glycol 1000 succinate for treatment of vitamin E deficiency in children with chronic cholestasis. Gastroenterology. 1993;104:17271735. 61. Lodge JK, Hall WL, Jeanes YM, Proteggente AR. Physiological factors influencing vitamin E biokinetics. Ann N Y Acad Sci. 2004;1031:6073. 62. Traber MG, Burton GW, Hamilton RL. Vitamin E trafficking. Ann N Y Acad Sci. 2004;1031:112. 63. Kostner GM, Oettl K, Jauhiainen M, Ehnholm C, Esterbauer H, Dieplinger H. Human plasma phospholipid transfer protein accelerates exchange/transfer of alpha-tocopherol between lipoproteins and cells. Biochem J. 1995;305:659667. 64. Burton GW, Traber MG, Acuff RV, et al. Human plasma and tissue alpha-tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E. Am J Clin Nutr. 1998; 67: 669684. 65. Schultz M, Leist M, Petrizika M, Gassmann B, BrigeliusFlohe R. A novel urinary metabolite of -tocopherol, 2,5,7,8-tetramethyl-2(2carboxyethyl)-6-hydroxychroman, as an indicator of adequate vitamin E supply? Am J Clin Nutr. 1995;62:1527S1534S. 66. Sokol RJ, Heubi JE, Iannaccone ST, Bove KE, Balistreri WF. Vitamin E deficiency with normal serum vitamin E concentrations in children with chronic cholestasis. N Engl J Med. 1984;310:12091212. 67. Farrell PM, Bieri JG. Megavitamin E supplementation in man. Am J Clin Nutr. 1975;28:13811386. 68. Johnson L, Bowen FW Jr, Abbasi S, et al. Relationship of prolonged pharmacologic serum levels of vitamin E to incidence of sepsis and necrotizing enterocolitis in infants with birth weight 1,500 grams or less. Pediatrics. 1985;75:619638. 69. Shearer MJ, Newman P. Metabolism and cell biology of vitamin K. Thromb Haemost. 2008;100(4):530547. 70. Suttie JW. Synthesis of vitamin K dependent proteins. FASEB J. 1993;7:445452. 71. Benzakour O. Vitamin K dependent proteins: functions in blood coagulation and beyond. Thromb Haemost. 2008;100:527529. 72. Booth SL, Suttie JW. Dietary intake and adequacy of vitamin K. J Nutr. 1998;128:785788. 73. Chambrier C, Bannier E, Lauverjat M, Drai J, Bryssine S, Boultreau P. Replacement of long-chain triglyceride with medium-chain triglyceride/long-chain triglyceride lipid emulsion in patients receiving long-term parenteral nutrition: effects on essential fatty acid status and plasma vitamin K1 levels. J Parenter Enteral Nutr. 2004;28:712. 74. Traber MG. Vitamin E and K interactions a 50-year-old problem. Nutr Rev. 2008;66:624629. 75. American Academy of Pediatrics Policy Statement. Committee on Fetus and Newborn. Controversies concerning vitamin K and the newborn. Pediatrics. 2003;112:191192.
Fluids and Electrolytes

Gerald L. Schmidt, PharmD, BCNSP
CONTENTS
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Fluid Distribution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Fluid Regulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Hypervolemia Hypovolemia
Learning Objectives
Fluid Considerations/Requirements inChildren. . . . . . . . 89 Treatment of Fluid Imbalances. . . . . . . . . . . . . . . . . . . . . . 90 Electrolyte Assessment. . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

Sodium
1. Describe factors that influence movement of fluid and electrolytes between the intracellular and extracellular fluid compartments. 2. Recommend appropriate treatments for fluid and electrolyte abnormalities. 3. Describe the differences in the treatment of acute and chronic electrolyte abnormalities.
Background
Potassium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Hyperkalemia Hypokalemia
Magnesium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Hypermagnesemia Hypomagnesemia
Calcium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Hypercalcemia Hypocalcemia
Phosphorus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
Hyperphosphatemia Hypophosphatemia
Water is the most abundant and probably the most important substance in the body. It is essential for digestion, absorption, transport, and utilization of nutrients as well as the excretion of waste products. The regulation of fluids and electrolyte balance is maintained by an elaborate system of interrelated regulatory systems to ensure proper cell function. Unfortunately, fluid and electrolyte imbalances are common, and when severe, these imbalances can have a detrimental effect on major organ systems. This chapter will focus on fluid and electrolyte homeostasis as well as commonly encountered fluid and electrolyte abnormalities and the treatment of these disorders.
Fluid Distribution
Water, being the most abundant component of the body, makes up a large portion of total body weight. The actual percentage of total body water (TBW) varies depending on age, weight, gender, and body fat percentage. Adipose tissue is the least hydrated body tissue; therefore, obese patients will have a lower percentage of TBW content.13 Water accounts for about 80% of total body weight in premature infants and this proportion decreases slowly to 55% to 60% of total body weight by age 18 years.4,5 TBW is divided into
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3 separate compartments: intracellular fluid (ICF) (32% 52% of total body weight), transcellular fluid (1.5%2.5% of total body weight), and extracellular fluid (ECF) (16%26% of total body weight). The ECF is further divided into the interstitial space (12%19% of total body weight) and the intravascular space (4%6% of total body weight).6 Relative percentages in each compartment at various ages can be found in Table 9-1. The primary factor that determines the water distribution between the ICF and ECF compartments is osmotic pressure. Sodium is the predominant extracellular osmotic agent, and potassium is the predominant intracellular osmotic agent. The sodium-potassium-adenosine triphosphatase (Na+-K+-ATPase) pump maintains the sodium and potassium gradient in normal conditions by pumping 3 sodium ions extracellularly for every 2 potassium ions it pumps intracellularly. A disruption in the function of the Na+-K+-ATPase pump can have a significant effect on fluid distribution between the compartments. 3 Fluid composition also plays an important role in fluid dynamics between the ICF and ECF. For example, when 100 mL of 5% dextrose (a solute-free solution) is administered intravenously to a patient, the dextrose is metabolized and the resultant water gets distributed proportionally to all compartments. Approximately 65% of the fluid volume (65 mL) would go into the ICF, 32% (32 mL) would remain in the ECF, and 3% (3 mL) would go into the transcellular fluid compartment. Of the 32 mL that remained in the ECF, 25% (8 mL) would remain in the intravascular space and 75% (24 mL) would be in the interstitial space. If 100 mL of 0.9% sodium chloride were given, all 100 mL would stay in the ECF: 25% (25 mL) in the intravascular space and 75% (75 mL) in the interstitial space.7,8 The administration of a hypertonic solution (eg, 3% sodium chloride) has a different effect on fluid distribution. The increased tonicity of the 3% sodium chloride would create an osmotic gradient, pulling fluid into the ECF from the ICF. Thus, the ECF
Table 9-1 Distribution of Total Body Water as a Percent of Total Body Weight
Age/Life Stage Total Body Water
volume would increase as would the ECF and ICF osmolality. However, the ICF volume would decrease due to the fluid shift caused by the hypertonic fluid. The volume of the ECF increase would be determined by the tonicity and the volume of the hypertonic solution given.7 The balance between the ECF and ICF is important in fluid homeostasis, but these are not the only compartments that must be maintained. The ECF components, the intravascular space and the interstitial space, are maintained by Starling forces. Starling forces consist of plasma oncotic pressure and hydrostatic pressure. When fluid moves from the plasma to the interstitial space, edema occurs.9 As vascular permeability increases, albumin leaks from the plasma to the interstitial space. This capillary leak causes a reduction in plasma oncotic pressure which in turn causes fluid to move from the plasma to the interstitial space. If this happens quickly, and the plasma volume is not replaced, intravascular volume depletion can occur resulting in hypotension and poor perfusion.
Fluid Regulation
The primary source of fluid intake is usually the diet, although some water will be generated from the oxidation of carbohydrates, proteins, and fat. 3,10 The majority of fluid losses are through urinary output, but fluid losses also occur via the skin and the respiratory and gastrointestinal (GI) tracts. Sodium and fluid balance are closely intertwined. Disturbances of water balance lead to changes in plasma osmolarity and sodium balance, and changes in sodium balance result in changes in plasma osmolarity and fluid volume. In order to maintain a relatively normal serum osmolarity (290 5 mOsm/L), the sodium-to-TBW ratio must be maintained in a relatively narrow range. When a fluid deficit or excess occurs, physiological feedback mechanisms are activated to either increase or decrease renal water excretion or to increase or decrease thirst, thereby influencing fluid intake.1115 An abnormality in either of
Intracellular
Extracellular
Transcellular
Premature infant 3-month-old infant 6-month-old infant 10- to 18-year-old child/adolescent Elderly patient
80% 70% 60% Male 59% Female 57% 50%
52% 46% 39% 38% 36% 32%
26% Intravascular 6% Interstitial 19% 22% Intravascular 5.5% Interstitial 16.5% 19% Intravascular 5% Interstitial 14% 18% Intravascular 4.5% Interstitial 13.5% 16% Intravascular 4% Interstitial 12%
2.5% 2% 1.8% 1.7% 1.5%
FLUIDS AND ELECTROLYTES
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these 2 mechanisms can have a significant effect on water and sodium balance. The treatment of a fluid deficit or a fluid excess requires the identification of the condition that caused the abnormality and determination of the time frame during which the abnormality occurred. Acute disturbances, changes occurring in 48 hours or less, are more frequently associated with signs and symptoms and can be corrected acutely. Chronic disturbances developing over a longer period of time are typically asymptomatic and should be replaced less aggressively.16 When assessing or treating fluid and electrolyte imbalances, the patients volume status must be assessed to determine if he or she is euvolemic, hypervolemic, or hypovolemic. Patients who are euvolemic usually have the ability to self-regulate fluid status and require little more than maintenance fluids and electrolyte supplementation. Patients who are either hyperor hypovolemic require additional assessment and may require additional treatment as well.
increases the permeability of water in the collecting tubule, resulting in water reabsorption in the collecting tubule (ie, water retention). The resultant water retention will result in a more concentrated urine.20,21 Signs and symptoms of hypovolemia include thirst, altered mental status, weakness, fatigue, neuromuscular irritability, agitation, seizures, and coma.22 Other conditions that may lead to hypovolemia include GI hemorrhage, vomiting, diarrhea, excessive sweating, burns, diabetes insipidus, and excessive diuresis.23 The fluid deficit can be calculated by using the following equation:
Fluid deficit = {(Patient serum sodium 140) body weight in kilograms} 140
Fluid Considerations/Requirements inChildren
Hypervolemia
Hypervolemia, or increased TBW, causes a decreased serum osmolarity resulting in dilute urine by suppressing the levels of circulating antidiuretic hormone (ADH). The precise mechanism by which plasma osmolarity suppresses ADH is unclear, but it probably is related to specialized cells that sense osmolarity changes and send messages to the neuroendocrine cells located in the hypothalamus or the organum vasculosum.17 In most cases, the thirst response will be suppressed, ADH will be suppressed, and the excess water will be excreted by the kidneys. However, in conditions where the low plasma osmolarity fails to inhibit ADH secretion (such as in severe low-output congestive heart failure), cell expansion, hypervolemia, and hyponatremia continue to progress.18 Symptoms include headache, nausea, vomiting, muscle twitching, convulsion, and if severe, death.19 Other conditions that may result in hypervolemia include kidney or liver failure with ascites, sepsis, cardiac failure, and syndrome of inappropriate antidiuretic hormone (SIADH).
Normal daily fluid requirements can be estimated in a variety of ways. One of the most common ways, the Holliday-Segar formula, is a weight-based method (Table 9-2).24,25 For example, using this method, a child weighing 27 kg would require a minimum of 1640 mL of fluid per day. This method is commonly used to estimate fluid requirements; however, it does not address fluid requirements in abnormal circumstances such as kidney failure or congestive heart failure.
Table 9-2 Calculating Estimated Fluid Requirements (Holliday-Segar Formula)
Body Weight Daily Fluid Requirement Fluid Requirements
10 kg > 10 kg to 20 kg > 20 kg
100 mL/kg 1000 mL + 50 mL/kg for wt > 10 kg 1500 mL + 20 mL/kg for wt > 20 kg
4 mL/kg/h 40 mL/h + 2 mL/kg/h > 10 kg 60 mL/h + 1 mL/kg > 20 kg
Hypovolemia
Hypovolemia is a condition where TBW is decreased significantly enough to result in symptoms. The body can correct the problem by stimulating the thirst response, increasing ADH release, or both. When the plasma osmolarity is increased or when the blood volume or pressure is reduced, the thirst response is stimulated.17 In hypovolemia, the serum osmolarity increases and the blood volume decreases, which results in the release of ADH. The presence of ADH
There are a number of conditions that require adjustments in fluid intake in order to provide optimal care. After birth, a contraction of the ECF compartment takes place due to the loss of interstitial fluid, which results in a 5% to 10% weight loss in healthy neonates, possibly more in premature infants.2631 Prematurity affects fluid balance. Premature infants may require as much as 200 mL/kg/d to maintain fluid balance due to their large insensible fluid losses. These losses are due partially to the large skin-to-body surface area ratio and partially to the immaturity of the skin which leads to increased evaporative fluid loss. 32,33 In addition, phototherapy and radiant warmers increase water losses, often as much as 20 to 40 mL/kg/d. 3437 Insensible fluid losses may remain greater than 100 mL/kg/d for weeks in neonates
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weighing less than 750 g. In patients weighing between 750 g and 1000 g, insensible fluid losses can decrease to 60 mL/ kg over the first week of life, and in those neonates weighing between 1001 g and 1250 g, insensible fluid losses usually decrease to 35 mL/kg over the first week. 38 This decrease in insensible fluid losses is due mainly to maturation and thickening of the skin shortly after birth. Antenatal steroids that help progress lung maturation will also affect skin thickening, which reduces fluid losses via the skin. Therefore, premature infants whose mothers did not receive antenatal steroids prior to birth may have excessive fluid losses for an extended period of time. 37 Other conditions that increase insensible water loss include omphalocele, gastroschisis, tachypnea, and administration of non-humidified oxygen. Conditions that may require fluid restriction due to decreased fluid losses include but are not limited to kidney and lung dysfunction and heart failure. One relatively simple way to assess fluid balance is by assessing daily weights. It is important to use the same scale and to make sure that the patient has the same equipment attached to accurately assess daily weights. Rapid weight changes typically reflect changes in water balance. Another useful indicator for assessing fluid status is serum sodium concentrations. An increase in the serum sodium concentration with little weight gain or weight loss typically indicates dehydration, whereas a low serum sodium concentration along with weight gain typically indicates fluid overload. Conditions that affect the serum sodium concentration will affect fluid balance. Likewise, conditions that affect fluid balance will have an effect on the serum sodium concentration. When addressing fluid issues, assessing trends in the serum sodium concentration is essential to making the appropriate adjustment. Whenever possible the underlying cause of the electrolyte disturbance should be treated, rather than just treating the serum sodium concentration. Dilutional hyponatremia (one form of hypervolemia) can occur from conditions where fluid accumulates, such as in sepsis, and in kidney or liver dysfunction, especially when ascites is present. 39 In general, chronic fluid disturbances take longer than 48 hours to develop, and patients typically do not exhibit signs and symptoms unless the fluid overload is severe, resulting in a very low serum sodium concentration (typically less than 120 mEq/L). Overzealous diuresis or administration of hypertonic saline can result in an osmotic demyelination syndrome, causing brain injury if serum sodium is increased (or decreased) faster than 0.5mEq/L/h or by more than 10 mEq/L in 24 hours.19 The
treatment of significant hypovolemia (dehydration) will be covered in the Hypernatremia section of this chapter.
Electrolyte Assessment
Treatment of Fluid Imbalances
Changes in the ECF compartment are responsible for the signs and symptoms associated with fluid and electrolyte imbalances. Therefore, it is the ECF compartment that must be corrected to alleviate those signs and symptoms. There are 5 basic steps or criteria that are essential in the assessment and treatment of fluid and electrolyte abnormalities (Table 9-3). The first step is to determine the cause of the electrolyte imbalance. For example, is the hypokalemia a result of chronic diuretic therapy or is it the result of an intracellular shift secondary to a large dextrose infusion? Once the cause has been identified, the second step is to classify the event as either acute or chronic. The prescriber can then determine whether a supplemental infusion or a change in the maintenance solution (step 3) is a more appropriate intervention to correct the abnormality. Acute problems should usually be treated with supplemental infusions whereas chronic problems should usually be treated with maintenance solutions. The next step is to determine the therapeutic index of the electrolyte to be corrected. If treating a severe hypokalemia, it is typically safer to administer a relatively moderate potassium infusion and then recheck the serum potassium concentration before repeating the dose rather than giving one large potassium supplemental infusion. If the deficit was inappropriately assessed and the single supplementation was too high, the patient could develop hyperkalemia and its associated consequences. In a patient with severe hypomagnesemia, overestimating the magnesium supplementation will have little clinical impact on the patient. Therefore the prescriber can be more aggressive when supplementing magnesium and phosphate versus potassium. The final step or criterion is to assess the acuity of the electrolyte imbalance. If the serum electrolyte concentration is critical or life-threatening, then the problem should be treated acutely. After initial treatment, then the maintenance solution can be adjusted, if necessary.
Table 9-3 Five Steps or Criteria for Correcting Electrolyte Abnormalities 1. Determine the cause of the electrolyte abnormality. 2. Classify the electrolyte abnormality as acute or chronic. 3. Determine whether a supplemental infusion (bolus) or an increase in the maintenance infusion or intake is appropriate for treatment. 4. Determine the therapeutic index of the electrolyte. 5. If the serum electrolyte concentration is critical or life-threatening, treat acutely, then determine if an adjustment is needed in the maintenance fluid intake.
91
Reference values for normal serum electrolyte concentrations based on age appear at the beginning of each electrolyte section below. These values are included to illustrate the differences in electrolyte concentrations for various age groups. Laboratory reference values will vary from institution to institution, and practitioners should use the reference values listed at their individual institutions for adjusting serum electrolyte values.
Sodium
Preterm: Older Infants: Children and Adolescents: 130140 mEq/L 133146 mEq/L 135145 mEq/L
Sodium is the most abundant extracellular cation in the body. It has 2 primary functions: fluid balance and maintenance of the membrane potential of cells. The body maintains sodium homeostasis primarily by the reninangiotensin-aldosterone system and ADH secretion. Other systems involved in sodium maintenance include the sympathetic nervous system, atrial natriuretic peptide, the kallikrein-kinin system, various intrarenal mechanisms, and other factors that regulate renal and medullary blood flow.40 The body maintains cell membrane potential by the Na+-K+-ATPase pump. Three sodium ions are pumped out of the cell for every 2 potassium ions that are pumped into the cell, which produces the negative charge in the cells necessary for normal functioning of nerves and muscle cells and the active transport of nutrients, such as glucose and amino acids.41 In normal situations the bodys sodium losses match the bodys sodium intake. The kidney has the ability to reabsorb up to 99% of the sodium presented to the renal tubules, so in times of a sodium intake deficit, serum sodium concentrations can be maintained. Daily sodium losses in these instances may be only a few milliequivalents. Medications can also affect sodium balance. Lactulose, normal saline, and hypertonic saline can cause hypernatremia, and medications such as chlorpropamide, demeclocycline, and
Table 9-4 Oral Electrolyte Requirements by Age (mg)
Age Sodium Potassium Age
loop diuretics can cause hyponatremia. Diuretics can also cause sodium imbalances. Loop diuretics cause a hypo volemic hypernatremia due to increased water loss relative to sodium loss, and overzealous use of thiazide diuretics causes a hypovolemic hyponatremia. Sodium requirements vary depending on age group and also vary from patient to patient. In general, parenteral requirements for sodium are about 2 to 5 mEq/kg in term infants, children, and adolescents. In preterm infants, as little as 1 mEq/kg of sodium may maintain sodium concentrations, but in general 3to4mEq/kg is recommended for the first week of life and then 3 to 6 mEq/kg in preterm infants less than 28 weeks gestation.42,43 Oral sodium requirements vary with age (Table 9-4). Hypernatremia Hypernatremia is defined as serum sodium concentration greater than 145 mEq/L. Hypernatremia usually develops under conditions of low or normal total body sodium but it can also develop with an increase in total body sodium. Hypernatremia is typically a result of net water loss or hypotonic fluid loss. Causes of hypernatremia include lack of oral hydration, diarrhea, vomiting, overzealous diuresis, fever, and the inability to express a need for water (eg, infants, children, or patients who have an altered mental status). An algorithm for the evaluation and treatment of hypernatremia can be found in Figure 9-1. If the hypernatremia is due to sodium intake, then intake must be decreased. If the hypernatremia is associated with dehydration, then rehydration should be started immediately. If the dehydration is mild and asymptomatic, then rehydration can be addressed by simply altering the oral fluid intake. If the dehydration is moderate to severe or if the patient is symptomatic, aggressive treatment should begin immediately. In order to treat the patient appropriately, classifying dehydration as mild, moderate, or severe is helpful. Mild dehydration can be identified by the presence of dry mucous membranes with normal hemodynamic parameters. Moderate dehydration can be defined as the presence
Magnesium Age Calcium Phosphorus
00.5 y 0.51 y 12 y 25 y 69 y 10 y or older
120 200 225 300 400 500
500 700 1000 1400 1600 2000
00.5 y 0.51 y 13 y 48 y 913 y > 13 y (M) > 13 y (F)
30 75 80 130 240 400 360
00.5 y 0.51 y 13 y 48 y 8 y or older
210 270 500 800 1300
100 275 460 500 1250
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of changes in hemodynamic parameters suggesting intravascular depletion like tachycardia, mild hypotension, and orthostasis. Severe volume depletion is defined by the presence of more profound hemodynamic compromise, such as moderate to severe hypotension, tachycardia, and poor perfusion. Clinical symptoms of mild, moderate, and severe dehydration generally correspond to a 5%, 10%, and 15% weight loss in infants, respectively, which can be detected if pre- and post-dehydration weights are available. In teenagers, mild, moderate, and severe dehydration correspond to a 3%, 5%, and 7% loss in body weight, respectively.44 Fluid therapy must include replacement of the deficit as well as provision of maintenance fluids. There are various methods used for correcting volume depletion, but 3 principles always apply: (1) the fluid deficit must be replaced with an appropriate fluid; (2) maintenance fluids must be provided on an ongoing basis; and (3) if there are continued ongoing losses (eg, gastric drainage, vomiting, diarrhea), these losses must be replaced on an ongoing basis to prevent further fluid deficits. For example, an infant weighing 5 kg has a 500 mL (10%) fluid deficit. Given the degree of fluid deficit (10% or more), an isotonic fluid bolus (20 mL/kg or 2% of the patients body weight = 100 mL) would be indicated initially. After this bolus, the remaining deficit (8% or 400 mL) would be replaced as follows: 50% (200 mL) over the next 8 hours and 50% (200 mL) over the subsequent 16 hours. In addition to the deficit
Figure 9-1 Hypernatremia
replacement, usual maintenance fluids (Column 3 in Table 9-2) must be administered. If severely volume depleted, the patient will require more than one 20 mL/kg fluid bolus to resolve the tachycardia, hypotension, and other symptoms. Once the tachycardia and hypotension have resolved, the fluid deficit and maintenance requirements can be calculated. In a teenager, the fluid deficit associated with mild, moderate, and severe dehydration is generally about 50% of that seen in an infant; therefore the initial bolus is generally 10 mL/kg rather than 20 mL/kg. Alternatively, as in adults, a fluid bolus of 500 mL to 1000 mL is given initially and repeated based on hemodynamic response. Hypertonic dehydration (hypernatremia) must be managed differently. In hypertonic dehydration, the fluid from the ICF compartment is drawn into the intravascular space. Rapid administration of fluid as described above may cause rapid fluid shifts that can result in cerebral edema and intracranial bleeding. In hypertonic dehydration, the fluid volume deficit is calculated and gradually replaced (usually over 48 hours).45 The need for a fluid bolus as described above is based on hemodynamic parameters. If the patient is hemodynamically compromised (hypotension, severe tachycardia), then a 10 to 20 mL/kg bolus of an isotonic fluid is imperative to restore perfusion and normalize hemodynamic parameters. When correcting severe symptomatic hypovolemic hypernatremia, the underlying cause of the hypernatremia should be treated. In general, to prevent
Adapted from Matarese LE, Gottschlich MM, eds. Contemporary Nutrition Support Practice: A Clinical Guide. Whitmire SJ. Fluids and electrolytes, p. 130. Copyright 1998 with permission from Elsevier.
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cerebral edema, the serum sodium should not be corrected at a rate that exceeds 0.5mEq/L/h or more than 10 mEq/L in 24 hours. Hyponatremia Hyponatremia is defined as a serum sodium concentration less than 135 mEq/L. It is one of the most common electrolyte disturbances found in the hospitalized patient. Signs and symptoms include headache, nausea, vomiting, muscle cramps, lethargy, restlessness, disorientation, and depressed reflexes and are more commonly seen with an acute decrease in the serum sodium concentration typically
Figure 9-2 Hyponatremia
below 125 mEq/L. Severe acute hyponatremia is life-threatening; fortunately the more common type of hyponatremia seen in hospitalized patients is slow-developing and less severe. The 2 most common causes of hyponatremia include hypervolemic hyponatremia where the total body sodium is normal to high and TBW is high, and hyponatremia due to actual sodium and water losses. In kidney failure, liver failure with ascites, hyperaldosteronism, and congestive heart failure, the body accumulates sodium and fluid, resulting in hypervolemic hyponatremia, sometimes referred to as dilutional hyponatremia. Diarrhea and other GI losses such as gastric suction, enterocutaneous fistulas, or necrotizing
Adapted from Matarese LE, Gottschlich MM, eds. Contemporary Nutrition Support Practice: A Clinical Guide. Whitmire SJ. Fluids and electrolytes, p. 129. Copyright 1998 with permission from Elsevier.
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enterocolitis; thiazide diuretic-induced hyponatremia; and salt-wasting nephropathy are examples of conditions that cause hypovolemic hyponatremia. In premature neonates, the salt-wasting nephropathy can be severe, often requiring delivery of sodium equal to 6 mEq/kg or more daily to maintain sodium and fluid balance.27 An algorithm for the evaluation and treatment of hyponatremia can be found in Figure 9-2. Treatment with hypertonic saline may be indicated if the serum sodium concentration is below 125 mEq/L or if the patient is symptomatic. The sodium deficit is calculated by using the equation:
sodium deficit (mEq) = TBW wt (Nadesired Naactual) where TBW is the percentage of the body weight found in Table 9-1 divided by 100, and weight is in kg.
solutions or maintenance intravenous (IV) fluids should start at about 2 to 4 mEq/kg and may increase depending on kidney function, GI losses, and medication use.42, 44 Oral potassium requirements vary with age (Table9-4).
Table 9-5 Medications Affecting Potassium and Magnesium
Hyperkalemia Hypokalemia
Typically no more than 50% of the sodium deficit should be replaced over 12 hours. In general, the serum sodium should not be corrected at a rate that exceeds 0.5 mEq/L/h or more than 10 mEq/L in 24 hours in order to prevent the development of central pontine myelinolysis.46
Potassium-sparing diuretics Nonsteroidal anti-inflammatory drugs Angiotensin converting enzyme inhibitors Angiotensin-II receptor blockers Trimethoprim Pentamidine Cyclosporine Tacrolimus Heparin Penicillin G potassium -blockers Succinylcholine
Hypermagnesemia
Loop diuretics Thiazide diuretics Fludrocortisones High-dose glucocorticoids High-dose penicillins Phenolphthalein Sodium polystyrene sulfonate Sorbitol 2adrenergic agonists Tocolytic agents Theophylline Caffeine Insulin/dextrose
Hypomagnesemia
Potassium
Newborn: Infant: Children and Adolescents: 3.75.9 mEq/L 4.15.3 mEq/L 3.44.7 mEq/L
Tocolytic agents Magnesium-containing antacids Magnesium-containing enemas
Cisplatinum Foscarnet Amphotericin B Aminoglycosides Thiazide diuretics
Potassium is the primary ICF cation. Potassium is essential for cell metabolism and maintenance of resting membrane potential. Intracellular potassium concentrations are approximately 140 mEq/L (ICF potassium concentrations equal ECF sodium concentrations due to the action of the Na+-K+-ATPase pump).47 Other factors that affect potassium distribution include those affecting the Na+-K+-ATPase pump, such as insulin, catecholamines, and ECF pH; exercise; and cell breakdown. 3,48,49 Potassium is primarily excreted via the kidney. Potassium excretion varies based on serum potassium concentrations and the release of aldosterone and angiotensin II. A lack of aldosterone causes potassium retention, whereas an excess causes potassium depletion. 50 In times of a potassium deficit, urinary excretion drops significantly, but not entirely. If potassium intake significantly increases, urinary potassium excretion will increase as well as potassium excretion via non-renal mechanisms (GI tract), a process known as potassium adaptation. In chronic kidney insufficiency, GI potassium losses may increase to 30% to 50% of the ingested potassium. 5153 Medications that affect potassium concentrations can be found in Table 9-5. Supplementation in parenteral nutrition (PN)
Hyperkalemia
Hyperkalemia is defined as a serum potassium concentration greater than 4.7 to 5.9 mEq/L, depending on the patients age. Signs and symptoms of hyperkalemia include muscle twitching, cramping, weakness, ascending paralysis, electrocardiogram (ECG) changes (eg, peaked T-waves, prolonged PR interval), and dysrhythmias (eg, bradyarrhythmias, ventricular fibrillation, and asystole). Hyperkalemia is one of the most dangerous electrolyte imbalances that develop in premature infants. The immaturity of the kidneys results in a reduced glomerular filtration rate, urinary potassium excretion, acidosis, and immature renal tubular response to aldosterone. 54 Hyperkalemia can occur from excessive potassium intake in the presence of altered kidney excretion or metabolic acidosis caused by conditions such as diabetic ketoacidosis and renal tubular acidosis. Metabolic acidosis causes hyperkalemia by causing a shift of potassium from the ECF to the ICF in order to balance the excess hydrogen ions that are moving into the ICF. Clinically significant hyperkalemia can also develop as a result of cell lysis (hemolysis) or tissue injury and death
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(eg, burns, rhabdomyolysis) in vivo due to the release of the ICF potassium into the serum. Treatment of hyperkalemia depends on both the severity and the cause. All sources of potassium intake should be discontinued immediately and, if feasible, any medication that may contribute to hyperkalemia should be stopped or the dose reduced. If the potassium is significantly elevated or if the patient is symptomatic, IV calcium chloride should be administered immediately to reduce the excitability of the cardiac muscle. (Note: Calcium gluconate is generally not recommended in emergency situations.) There are two basic mechanisms used to treat hyperkalemia: shifting potassium into the ICF and removing potassium from the body. Insulin in combination with glucose, 2-adrenergic agonists, and sodium bicarbonate will shift the potassium into the ICF. Loop and thiazide diuretics (loop to a greater extent than thiazide), cation exchange resins like sodium polystyrene, and dialysis all reduce potassium concentrations by directly removing potassium from the body (exchange resins and dialysis) or by increasing renal potassium excretion (diuretics). Serum potassium concentrations should be monitored frequently during treatment, especially in patients being treated with dextrose and insulin, 2-adrenergic agonists, and sodium bicarbonate because once these therapies are discontinued, potassium will shift back to the ECF compartment. Potassium concentrations should be monitored for at least 12hours after the hyperkalemia has resolved to ensure that equilibration of potassium between the ICF and ECF is complete. 3 Pseudohyperkalemia is common in infants and young children and can occur when red blood cells break down during the blood-drawing process. In other words, the serum potassium detected in the sample is higher than the actual serum potassium concentration due to hemolysis of the red blood cells during the blood-drawing process or while in the collection tube. This form of hyperkalemia is the most common form detected in pediatric patients with normal kidney function. If pseudohyperkalemia is suspected, and if the patient is asymptomatic and has normal kidney function, the serum potassium concentration should be repeated (avoiding rapid aspiration and use of narrow gauge needles if possible) before starting any treatment for hyperkalemia.
catecholamines, and inadequate intake. Signs and symptoms are non-specific but include dysrhythmias, paralysis, muscle necrosis, and possibly death. The treatment of hypokalemia depends on both the severity and the cause of the hypokalemia. Oral potassium supplements are available as a variety of salts, and the choice of agent depends on other concomitant electrolyte imbalances, cost, and patient preference. In an asymptomatic patient with mild to moderate hypokalemia, oral supplementation is preferred because of safety reasons (eg, there is no risk for potassium extravasation). Oral supplementation also reduces the risk of overcorrection causing hyperkalemia and too rapid correction causing dysrhythmias. Oral potassium can be irritating to the GI tract. For mild to moderate potassium depletion, doses of 2 to 5 mEq/kg/d in divided doses, not to exceed 1 to 2 mEq/kg as a single dose, taken with plenty of water, are recommended. 55,56 Serum potassium should be rechecked approximately 2 hours after the initial dose is completed, and additional doses given, if needed. The use of IV potassium supplementation should be reserved for patients who are symptomatic, who have severe hypokalemia, or when administration via the GI tract is contraindicated. Dosages range from 0.5 to 1 mEq/kg depending on the severity of the hypokalemia and kidney function. Generally, infusion rates should not exceed 0.5 mEq/kg/h, unless continuous cardiac monitoring is available. Potassium can be caustic to the vein, so to minimize irritation, the concentration for administration through a peripheral vein should not exceed 0.06mEq/mL. 56,57 When administering IV potassium supplementation, co-administration with dextrose may worsen the hypokalemia by stimulating insulin release, which promotes the intracellular shift of potassium. Concurrent hypomagnesemia may result in refractory hypokalemia due to increased renal potassium losses due to the kidneys attempt to conserve magnesium and impairment of the Na+-K+-ATPase pump. 58 As such, it is important to correct a low magnesium level while treating hypokalemia. Serum potassium should be rechecked approximately 2 hours after the initial dose is completed, and additional doses given, if needed.
Magnesium
All Age Groups: 1.62.3 mg/dL
Hypokalemia
Hypokalemia is defined as a serum potassium concentration less than 3.4 mEq/L. It is a common electrolyte abnormality seen in clinical practice. Causes of hypokalemia include medications, metabolic alkalosis, abnormal GI losses, hyperaldosteronism, hypomagnesemia,
Magnesium is an essential cofactor in more than 300 enzymatic reactions, including those involved in glucose metabolism, fatty acid synthesis and breakdown, and DNA and protein metabolism. Magnesium plays a critical role in the functioning of the Na+-K+-ATPase pump, thus affecting
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neuromuscular transmission, cardiovascular excitability, vasomotor tone, and muscle contraction. Magnesium is also an integral component of bone and parathyroid hormone (PTH) secretion. 59,60 More than 50% of the magnesium in the body resides in bone. Magnesium is found primarily in the ICF with only about 2% of total body stores found in the ECF. About 61% of serum magnesium is physiologically active in the ionized form, 33% protein bound, and 5% complexed to phosphate, citrate, and other compounds. Magnesium homeostasis is maintained and regulated by the GI tract, kidney, and bone via PTH. Healthy individuals absorb between 30% and 40% of ingested magnesium. Magnesium is absorbed in the distal jejunum and ileum, and absorption is inversely proportional to the magnesium intake. Magnesium is primarily excreted via the kidneys with about 35% of ingested magnesium excreted in the urine. In the presence of high magnesium intake, renal excretion increases to maintain normal serum magnesium concentrations. Very little magnesium (1%2%) is excreted via the feces. Bone is very important to the homeostasis of serum magnesium concentrations. If a patient becomes magnesium depleted, the mineral is leached from the bone to maintain ECF magnesium concentrations. ECF magnesium is then sacrificed to the ICF to maintain normal metabolic functions.61 Medications that affect magnesium concentrations are listed in Table 9-5. IV magnesium supplementation in PN solutions ranges from 0.25 mEq/kg to 0.5mEq/kg daily but may be higher in patients with abnormal magnesium losses. Oral magnesium requirements vary with age (Table 9-4).
Hypermagnesemia occurs primarily in the setting of kidney insufficiency in combination with continued magnesium intake. In the premature infant, the most common cause of hypermagnesemia results from placental transfer of magnesium during the treatment of premature labor contractions with magnesium sulfate. The effect that hypermagnesemia has on the ability to relax smooth muscle makes magnesium a viable treatment due to the low risk of harm to the neonate. The neonate with hypermagnesemia will have poor muscle tone, which will return to normal as the serum magnesium concentration decreases over approximately 2 to 5 days, depending on the severity of the initial hypermagnesemia.66
Hypomagnesemia
Hypomagnesemia is defined as serum magnesium concentration less than 1.3 mg/dL. It is a common condition seen in hospitalized patients. Signs and symptoms include apathy, depression, psychosis, muscle weakness, vertigo, ataxia, seizures, confusion, leg cramps, hyperactive tendon reflexes, anorexia, nausea, vomiting, paresthesias, Chvosteks and Trousseaus sign, spontaneous carpal-pedal spasm, and cardiac complications including dysrhythmias.67 Hypomagnesemia can also cause other electrolyte abnormalities. Hypomagnesemia may result in refractory hypokalemia because of increased renal potassium losses due to the kidneys attempt to conserve magnesium and impairment of the Na+-K+-ATPase pump. 58 Hypomagnesemia may also result in hypocalcemia. Magnesium deficiency can impair parathyroid function, and hypomagnesemia accompanied by hypoparathyroidism is a common cause of neonatal hypocalcemia.68,69 Hypomagnesemia can be caused by decreased intake, increased excretion, or intracellular shifts of magnesium.70 Excessive renal losses may occur in patients with acute tubular necrosis, renal tubular acidosis, Bartter syndrome, or hyperaldosteronism, or may be induced by medications such as amphotericin, cisplatin, cyclosporine, aminoglycosides, and foscarnet.71 Intracellular shifts can be caused by dextrose and/or insulin administration. Because only about 1% to 2% of total body magnesium is found in the ECF, serum concentrations are not a good reflection of total body magnesium stores. Treatment of hypomagnesemia is therefore empirical. The IV route is preferred in patients with moderate to severe hypomagnesemia because of the GI intolerance generally seen with large oral doses. Recommended doses are 0.2 to 0.4 mEq/kg (2550 mg/kg), up to 2 mEq (2 g) every 8 to 12 hours for 2 to 3 doses.72 There is a renal magnesium threshold for magnesium reabsorption;
Hypermagnesemia
Hypermagnesemia is defined as serum magnesium greater than 2.4 mg/dL. Hypermagnesemia is usually well tolerated but can affect neurological, neuromuscular, and cardiac function when magnesium concentrations exceed 3 mg/dL.62,63 Physical findings include nausea, vomiting, diaphoresis, flushing, depressed mental function, drowsiness, muscular weakness, hypotension, and bradycardia. If patients with severe hypermagnesemia are symptomatic, IV calcium chloride should be administered immediately to reduce the excitability of the cardiac muscle. (Note: Calcium gluconate is generally not recommended in emergency situations.) Hemodialysis may be required to reduce the magnesium concentration to a safer value. Treatments for hypermagnesemia in an asymptomatic patient include dietary magnesium restriction, administration of a loop diuretic, and possibly hemodialysis if kidney dysfunction is present.64, 65
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thus up to 50% of an individual magnesium dose can be eliminated via the kidneys if the magnesium is not distributed intracellularly.73,74 In asymptomatic adults, a maximum infusion rate of 1 g (8 mEq)/h is recommended. 3,75 This infusion rate would equate to about 0.1 mEq/kg/h in children. Supplemental magnesium doses may be reduced by 50% in patients with kidney dysfunction to lessen the risk of hypermagnesemia. However, reducing the dose by 50% may not be necessary in all cases because, if only a one-time dose is given, the magnesium will not continue to accumulate, and mild hypermagnesemia is well tolerated. Serum magnesium should be rechecked approximately 2 hours after the infusion is completed, and additional boluses given, if needed.
the calcium bound to albumin, and the free or ionized calcium. Therefore, if the serum albumin is low, the serum total calcium also will be low. Although not completely reliable in critically ill patients, serum calcium concentrations can be corrected for the degree of hypoalbuminemia using the equation:
Corrected calcium = measured total calcium (mg/dL) + 0.8 [4 albumin (g/dL)]
Calcium
Age Group Total Calcium Age Group Ionized (SI Units)
Preterm Full Term
6.211 mg/dL 7.610.4 mg/dL
10 d 2 y 212 y > 12 y
911 mg/dL 8.810.8 mg/dL 8.610 mg/dL
Preterm Full Term < 36 h Full Term 3684 h > 84 h
1.752 mmol/L 1.051.37 mmol/L 1.11.42 mmol/L 1.21.38 mmol/L
Alternatively, if the patients albumin is low, then the serum ionized calcium should be checked as this is the most accurate laboratory test for assessing the physiologically active calcium status. The serum pH and the phosphorus and albumin concentrations affect the amount of calcium that is ionized.7779 Supplementation of calcium in PN solutions ranges from 1 to 4 mEq/kg. Oral calcium requirements vary with age and can be found in Table 9-4.
Hypercalcemia
Hypercalcemia is most often seen in patients with hyperparathyroidism or cancer with bone metastases. It can also occur with toxic serum concentrations of vitamin A or vitamin D, chronic ingestion of milk and/or calcium carbonate-containing antacids in the setting of kidney insufficiency, immobility, tuberculosis, and medications. Clinical signs and symptoms include fatigue, nausea, vomiting, constipation, anorexia, and confusion. In severe cases, cardiac dysrhythmias may be present. Mild hypercalcemia typically responds to fluid and ambulation. In severe hypercalcemia, immediate treatment should be started to prevent acute kidney failure, obtundation, ventricular dysrhythmias, coma, and death. If a loop diuretic and IV fluid are used to treat hypercalcemia (eg, to increase calcium excretion), IV hydration with 0.9% sodium chloride should be started immediately to prevent dehydration. Hemodialysis may be necessary for patients with life-threatening hypercalcemia or those with kidney failure. 80
Calcium is one of the most abundant ions in the body. It accounts for 1% to 2% of total body weight. Calcium is necessary for many physiological functions including neuromuscular activity, preservation of the integrity of cell membranes, regulation of endocrine secretory activities, blood coagulation, activation of the complement system, and bone metabolism. Serum calcium concentrations are controlled by the parathyroid gland. When serum calcium is low, PTH secretion is stimulated, which increases bone resorption, augments renal calcium conservation, and activates vitamin D, which increases calcium absorption from the GI tract. When serum calcium is increased, the thyroid releases calcitonin, which acts to inhibit bone resorption and increase renal calcium excretion. Generally, serum calcium concentrations are maintained by either renal excretion of excess calcium or leaching of calcium from the bone.76 About 99% of the bodys calcium is found in teeth and bone, with only 1% found in the serum. There are 3 forms of calcium in the body: complexed, protein-bound, and ionized. Complexed calcium is that combined with nonprotein anions such as phosphate, carbonate, and citrate. It is not available for physiological activity. Slightly less than half of the serum calcium is bound to protein, primarily albumin. The serum calcium measures total serum calcium,
Hypocalcemia
Measured hypocalcemia is commonly encountered in patients with hypoalbuminemia but does not require treatment unless the corrected calcium or ionized calcium is found to be low. Signs and symptoms of hypocalcemia include hypotension, decreased myocardial contractility, prolonged QT interval, paresthesias, Chvosteks and Trousseaus signs, muscle cramps, tetany, and seizures. Causes of hypocalcemia include vitamin D deficiency or the inability to activate vitamin D, hyperphosphatemia,
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pseudohypoparathyroidism, decreased PTH activity, sepsis, rhabdomyolysis, and massive blood transfusions.81 Medications can also cause hypocalcemia. Of particular importance to the premature infant are furosemide, phenobarbital, and phenytoin. 82 Sulfur-containing amino acids (eg, cysteine) also increase renal calcium excretion. The increased renal calcium excretion seen with cysteine supplementation in PN solutions is counterbalanced by the increased solubility of calcium and phosphorus in PN solutions supplemented with cysteine hydrochloride due to the lower pH of the solution after cysteine is added.83, 84 Patients with severe hypocalcemia or acute symptomatic hypocalcemia require immediate treatment. IV calcium comes in two salt forms: chloride and gluconate. Calcium chloride contains 13.6 mEq of elemental calcium per gram; calcium gluconate contains 4.65 mEq of elemental calcium per gram. Because there is 3 times the elemental calcium in calcium chloride compared to calcium gluconate, calcium chloride is associated with a higher incidence of tissue necrosis if extravasation occurs. 85 For hypocalcemic tetany, 0.5 to 1 mEq/kg of calcium chloride infused over 5 to 10 minutes may be used; this dose may be repeated in 6 hours or followed with a continuous infusion with 2.5 mEq/kg/d of calcium chloride.86, 87 If hypomagnesemia is present, magnesium supplementation should be given to facilitate correction of hypocalcemia. In cases of hypocalcemia secondary to hyperphosphatemia, treating with a phosphate binder should be considered prior to giving IV calcium to prevent calcium/phosphate precipitation in soft tissues.
destruction and acidosis cause a shift to the ECF.77 Intravenous phosphorus requirements are 1 to 2.5 mmol/kg in premature infants and 0.5 to 1 mmol/kg/d in term infants and children up to 18 years of age. Oral phosphorus requirements vary with age (Table 9-4).
Hyperphosphatemia
Hyperphosphatemia is defined as a serum phosphate concentration greater than 4.5 to 9 mg/dL, depending on the patients age. Most patients are asymptomatic, but signs and symptoms may include anorexia, nausea, vomiting, dehydration, and neuromuscular irritability. The biggest concern with hyperphosphatemia is metastatic calcification from elevated serum concentrations of calcium and phosphate.91 Although various equations for predicting metastatic calcification are used, the equations are not accurate because of the variety of factors that determine in vivo calcium/phosphate solubility. Ionized calcium is much more reactive than phosphate, so hypercalcemia with a mild hyperphosphatemia has a higher probability of causing metastatic calcification than hyperphosphatemia with slightly increased serum calcium. With the newer phosphate-binding agents available, aluminum-containing antacids are no longer recommended for the treatment or prevention of hyperphosphatemia in patients with kidney insufficiency because of the anemia, osteomalacia, and central nervous system toxicity experienced with the use of aluminum-containing agents in this patient population.92
Hypophosphatemia
Hypophosphatemia can be defined as a serum phosphorus concentration below 2.7 mg/dL to 4.5 mg/dL, depending on the patients age.47 Hypophosphatemia is common in critical illness, malnutrition, alkalosis, and in patients receiving phosphate binders (eg, aluminum- , magnesium- , and calcium-containing products, sevelamer, or sucralfate). Signs and symptoms of hypophosphatemia include neurological, neuromuscular, cardiopulmonary, and hematologic dysfunction.8890 Primary causes of hypophosphatemia include inadequate intake of phosphate or the administration of large amounts of dextrose solutions in malnourished patients who are at risk for developing refeeding syndrome (Chapter 19). Treatment of hypophosphatemia varies, depending on the serum phosphorus concentration and the presence of signs and symptoms. Mild asymptomatic hypophosphatemia can be treated with oral phosphate supplements, assuming that the GI tract is functional. However, oral supplements are not well absorbed and often cause diarrhea.
Phosphorus
Newborn: 10 days2 years: 212 years: > 12 years: 4.59 mg/dL 4.56.7 mg/dL 4.55.5 mg/dL 2.74.5 mg/dL
Phosphorus, mainly in the form of phosphate, is the primary intracellular anion in the body. It has many important functions including bone and cell membrane composition, maintenance of normal pH, and provision of energy-rich bonds (adenosine triphosphate, or ATP), and it is needed in all cellular functions that require energy. Phosphorus is required for glucose utilization, glycolysis, 2,3-diphosphoglycerate synthesis, neurological function, and muscular function.88-90 Phosphorus homeostasis is maintained by GI absorption, renal excretion, PTH, and distribution between the ICF and ECF. Glucose and insulin, catecholamines, and alkalosis all cause intracellular shifts of phosphorus. Cell
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Patients with symptomatic or moderate to severe hypophosphatemia should be treated with IV phosphate. Two salt forms are available for replacing phosphate: sodium phosphate and potassium phosphate. Sodium phosphate provides 4 mEq sodium for every 3 mmol phosphate, and potassium phosphate provides 4.4 mEq potassium for every 3 mmol phosphate. When ordering phosphate, the dose should be ordered in millimoles of phosphate rather than milliequivalent of the sodium or potassium component of the salt. Common recommendations for replacing phosphate provide up to 0.32 mmol/kg of phosphate for serum phosphorus levels < 1.5 mg/dL. This dose is often inadequate and may require multiple boluses to reach normal phosphorus levels.93,94 Higher doses have been recommended for phosphorus replacement in adults, and the higher supplemental doses have been used successfully in pediatric patients (Table 9-6). Serum phosphate levels should be checked 2 hours after the infusion is completed and the patient should be redosed if needed. Phosphate should be replaced no faster than 0.1 to 0.2 mmol/kg/h to allow the phosphate time to move intracellularly and to prevent possible hypocalcemia.95 If potassium phosphate is used to replace the phosphate, the infusion rate should be based on the potassium infusion rate. ECG monitoring should accompany infusion of individual doses greater than 0.5 mEq/kg/h. Sodium phosphate is the preferred salt for phosphate supplementation.
Table 9-6 Phosphate Replacement in Adults Mild Depletion (2.33 mg/dL) Moderate Depletion (1.62.2 mg/dL) Severe Depletion (< 1.5 mg/dL) 0.16 mmol/kg 0.32 mmol/kg 0.64 mmol/kg
1. The intravenous administration of 100 mL of 0.9% sodium chloride to a patient will: A. Increase the intracellular fluid (ICF) compartment by 100 mL but will not increase the extracellular fluid (ECF) compartment. B. Increase the ECF compartment by 100 mL, with a 75 mL increase in intravascular volume. C. Increase the ECF compartment by 100 mL, with a 25 mL increase in intravascular volume. D. Increase the ICF compartment by 50 mL, with a 25mL increase in intravascular volume. 2. A 1340-g neonate is placed on IV fluids/nutrition at 160 mL/kg/d. Over the next 5 days the weight decreased to 1250 g due to the contraction of the ECF seen after
birth. On day 7, the patients serum sodium concentration is 137 mEq/L. The patient continues to receive 160 mL/kg/d of IV fluids that contain 3 mEq/kg/d of sodium. Over the next 3 days, the patients serum sodium concentration has decreased to 129 mEq/L. The patient does not appear to be fluid overloaded, septic, or suffering from necrotizing enterocolitis. The patients weight has remained around 1250 g. What is the most appropriate way to correct the serum sodium concentration? A. Increase the sodium concentration in the IV solution because the current sodium intake is inadequate to keep up with the renal and GI sodium losses. B. Decrease the maintenance IV fluid rate by 25% because the decrease in the serum sodium concentration is probably due to fluid overload. C. Give sodium chloride orally to replace the sodium deficit. D. Decrease the maintenance IV fluid by 25% and give sodium chloride orally because the decrease in the serum sodium concentration is probably due to fluid overload, but the serum sodium concentration is a critical value; thus treatment must begin immediately. 3. An 8-year-old child who weighs 27 kg is admitted for nausea, vomiting, and failure to thrive. The patient is started on maintenance IV fluids containing D5W/0.2 NaCl with 20 mEq KCl per liter. The following morning, the serum phosphorus concentration is 1.2 mg/dL and the serum potassium concentration is 3.4 mEq/L. What is the most appropriate way to correct the serum phosphorus concentration? A. Add sodium phosphate 1 mmol/kg to the maintenance IV fluid. B. Add potassium phosphate 1 mmol/kg to the maintenance IV fluid. C. Give sodium phosphate 27 mmol (36 mEq sodium) intravenously over 8 hours. D. Give potassium phosphate 27 mmol (40 mEq potassium) intravenously over 8 hours. See p. 487 for answers.
References
1. Steijaert M, Deurenberg P, Van Gaal L, De Leeuw I. The use of multi-frequency impedance to determine total body water and extracellular water in obese and lean female individuals. Int J Obes Relat Metab Disord. 1997;21(10):930934.
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2. Sartorio A, Malavolti M, Agosti F, Marinone PG, Caiti O, Bedogni G. Body water distribution in severe obesity and its assessment from eight-polar bioelectrical impedance analysis. Eur J Clin Nutr. 2005;59(2):155160. 3. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders. 5th ed. New York, NY: McGraw-Hill; 2001. 4. Whitmire SJ. Fluids and electrolytes. In: Gottschlich MM, ed. Science and Practice of Nutritional Support: A Case-Based Core Curriculum. Dubuque, IA: Kendall/Hunt; 2001:5384. 5. Bhatia J. Fluid and electrolyte management in the very low birth weight neonate. J Perinatol. 2006;26(Suppl 1):S19S21. 6. Bakris GL, Stein JH. Sodium metabolism and maintenance of extracellular fluid volume. In: Arieff AI, DeFronzo RA, eds. Electrolyte and Acid-Base Disorders. 2nd ed. New York, NY: Churchill Livingstone; 1995:2950. 7. Soheyl B, Klaus Z, Zoltan S, et al. Small-volume fluid resuscitation with hypertonic saline prevents inflammation but not mortality in a rat model of hemorrhagic shock. Shock. 2006; 25(3):283289. 8. Mange K, Matsuura D, Cizman B, et al. Language guiding therapy: the case of dehydration versus volume depletion. Ann Int Med. 1997; 127(9):848853. 9. Hansen M. Fluid balance. In: Hansen M, ed. Pathophysiology: Foundations of Disease and Clinical Intervention. Philadelphia, PA: Saunders; 1998:160175. 10. Toney GM, Chen QH, Cato MJ, Stocker SD. Central osmotic regulation of sympathetic nerve activity. Acta Physiol Scand. 2003; 177(1):4355. 11. Sutsch G, Bertel O, Rickenbacher P, et al. Regulation of aldosterone secretion in patients with chronic congestive heart failure by endothelins. Am J Cardiol. 2000; 85(8):973976. 12. Quinn SJ, Williams GH. Regulation of aldosterone secretion. Annu Rev Physiol. 1988; 50:409426. 13. Weber KT. Aldosterone in congestive heart failure. N Engl J Med. 2001;345(23):16891697. 14. Thomson CJ, Bland J, Burd J, Baylis PH. The osmotic thresholds for thirst and vasopressin release are similar in healthy man. Clin Sci. 1986;71:651656. 15. Robertson GL. Thirst and vasopressin function in normal and disordered states of water balance. J Lab Clin Med. 1983;101(3):351371. 16. Langley G. Fluid, electrolytes, and acid-base disorders. In: Gottschlich MM, DeLegge MH, Mattox T, Mueller C, Worthington P, eds. The A.S.P.E.N. Nutrition Support Core Curriculum: A Case-Based Approach The Adult Patient. Silver Spring, MD: American Society for Parenteral and Enteral Nutrition; 2007:104128. 17. Zimmerman EA, Ma LY, Nilaver G. Anatomical basis of thirst and vasopressin secretion. Kidney Int. 1987; 21:S14S19. 18. Uretsky BF, Verbalis JG, Generalovich T, Valdes A, Reddy PS. Plasma vasopressin response to osmotic and hemodynamic stimuli in heart failure. Am J Physiol. 1985;248(3):H395H402. 19. Sterns RH, Spital A. Disorders of water balance. In: Kokko JP, Tannen RL, eds. Fluids and Electrolytes, 2nd ed. Philadelphia, PA: Saunders; 1990:139194.
20. Knepper MA, Rector CF. Urinary concentration and dilution. In: Brenner BM, Rector FC, eds. The Kidney. 4th ed. Vol 1. Philadelphia, PA: Saunders; 1991:445482. 21. Mange K, Matsuura D, Cizman B, et al. Language guiding therapy: the case of dehydration versus volume depletion. Ann Intern Med. 1997;127(9):848853. 22. Heitz U, Horne M. Pocket Guide to Fluid, Electrolytes, and AcidBase Balance. 5th ed. St Louis, MO: Mosby-Year Book; 2004. 23. Mirtallo J, Canada T, Johnson D, et al. Safe practices for parenteral nutrition. J Parenter Enteral Nutr. 2004;28(6):S39S70. 24. Holliday MA, Segar WE. The maintenance need for water in parenteral fluid therapy. Pediatrics. 1957;19:823832. 25. Choong K, Bohn D. Maintenance parenteral fluids in the critically ill child. J Pediatr (Rio J). 2007;83(2 Suppl):S3S10. 26. Lorenz JM, Kleinman LI, Ahmed G, et al. Phases of fluid and electrolyte homeostasis in the extremely low birth weight infant. Pediatrics. 1995;96(3):484489. 27. Modi N. Sodium intake and preterm babies. Arch Dis Child. 1993;69:8791. 28. Bauer K, Bovermann G, Roithmaier A, Gotz M, Proiss A, Versmold HT. Body composition, nutrition and fluid balance during the first two weeks of life in preterm neonates weighing less than 1500 grams. J Pediatr. 1991;118(4):615620. 29. Sankar MJ, Agarwal R, Mishra S, Deorari AK, Paul VK. Feeding of low birth weight infants. Indian J Pediatr. 2008;75(5):459469. 30. Shaffer SG, Brandt SK, Hall RT. Postnatal changes in total body water and extracellular volume in the preterm infant with respiratory distress syndrome. J Pediatr. 1986;109(3):509514. 31. Tang W, Ridout D, Modi N. Influence of respiratory distress syndrome on body composition after preterm birth. Arch Dis Child Fetal Neonatal Ed. 1997;77(1):F28F31. 32. Rutter N, Hull D. Water loss from the skin of term and preterm babies. Arch Dis Child. 1979;54(11):858868. 33. Costarino AT, Baumgart S. Modern fluid and electrolyte management of the critically ill premature infant. Ped Clin North Am. 1986;33(1):153178. 34. Kjartansson S, Hammarlund K, Sedin G. Insensible water loss from the skin during phototherapy in term and preterm infants. Acta Paediatr. 1992;81(10):764768. 35. Grunhagen DJ, de Boer MG, de Beaufort AJ, Walther FJ. Transepidermal water loss during halogen spotlight therapy in preterm infants. Pediatr Res. 2002;51(3):402405. 36. Maayan-Metzger A, Yosipovitch G, Hadad E, Sirota L. Trans epidermal water loss and skin hydration in preterm infants during phototherapy. Am J Perinatol. 2001;18(7):393396. 37. Hartnoll G. Basic principles and practical steps in the management of fluid balance in the newborn. Semin Neonatal. 2003;8(4): 307313. 38. Davis ID, Avner ED. Neonatal-perinatal medicine: diseases of the fetus and infant. In: Fanaraff AA, Martin RJ, eds. Fluid and Electrolyte Management. 7th ed. St. Louis, MO: CV Mosby; 2002:619627. 39. Kumar V, Cotran RS, Robbins SL. Disorders of vascular flow and shock. In: Kumar V, Cotran RS, Robbins SL, eds. Basic Pathology. 5th ed. Philadelphia, PA: Saunders; 1992:6191.
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40. Pincus MR, Preuss HG, Henry JB. Evaluation of renal function, water, electrolytes, acid-base balance and blood gasses. In: Henry JB, ed. Clinical Diagnosis and Management by Laboratory Methods. 19th ed. Philadelphia, PA: Saunders; 1996:139149. 41. Hwai-Ping S. Sodium, chloride, and potassium. In: Stipanuk M, ed. Biochemical and Physiological Aspects of Human Nutrition. Philadelphia, PA: Saunders; 2000:686710. 42. Wilkins BH. Renal function in sick very low birthweight infants: 3. Sodium, potassium, and water excretion. Arch Dis Child. 1992; 67(10):11541161. 43. Hartnoll G, Betremieux P, Modi N. Randomised controlled trial of postnatal sodium supplementation on body composition in 25 to 30 week gestational age infants. Arch Dis Child Fetal Neonatal Ed. 2000;82(1):F24F28. 44. Roberts KB. Fluids and electrolytes: parenteral fluid therapy. Pediatr Rev. 2001;22(11):380387. 45. Finberg L. Hypernatremic (hypertonic) dehydration in infants. N Engl J Med. 1973;289(4):823832. 46. Holliday MA, Kalayci MN, Harrah J. Factors that limit brain volume changes in response to acute and sustained hyper- and hyponatremia. J Clin Invest. 1968;47(8):19161928. 47. Robertson J. Blood chemistries and body fluids. In: Robertson J, Shilkofski N, eds. The Harriet Lane Handbook. 7th ed. Philadelphia, PA: Elsevier Mosby; 2006:661672. 48. Horisberger J, Lemas V, Kraehenbuhl J, Rossier BC. Structure-function relationship of Na,K-ATPase. Annu Rev Physiol. 1991;53:565584. 49. Rodriguez-Soriano J. Potassium homeostasis and its disturbance in children. Pediatr Nephrol. 1995;9(3):364374. 50. Ganguly A. Primary aldosteronism. N Engl J Med. 1998;339(25):18281834. 51. Kelvay LM, Bogden JD, Aladjem M, et al. Renal and gastrointestinal potassium excretion in humans: new insight based on new data and review and analysis of published studies. J Am Coll Nutr. 2007;26(2):103110. 52. Mathialahan T, Sandle GI. Dietary potassium and laxatives as regulators of colonic potassium secretion in end-stage renal disease. Nephrol Dial Transplant. 2003;18(2):341347. 53. Brown RS. Extrarenal potassium homeostasis. Kidney Int. 1986;30(1):116127. 54. Subramanian S, Agarwal R, Deorari AK, Paul VK, Bagga A. Acute renal failure in neonates. Indian J Pediatr. 2008;75(4):385391. 55. Strom BL, Carson JL, Schinnar R, et al. Upper gastrointestinal tract bleeding from oral potassium chloride. Comparative risk from microencapsulated vs wax matrix formulations. Arch Intern Med. 1987;147(5):954957. 56. Potassium chloride. In: Taketomo CK, Hodding JH, Kraus DM, eds. Pediatric Dosage Handbook. 15th ed. Hudson, OH: Lexi-Comp; 2008:14321435. 57. Potassium chloride. In: Phelps SJ, Hak EB, Crill CM, eds. The Teddy Bear Book: Pediatric Injectable Drugs. 8th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:368369.
58. Whang R, Whang DD, Ryan MP. Refractory potassium repletion. A consequence of magnesium deficiency. Arch Intern Med. 1992;152(1):4045. 59. Reinhart RA. Magnesium metabolism. A review with special reference to the relationship between intracellular content and serum levels. Arch Intern Med. 1988;148(11):24152420. 60. Zaloga GP, Roberts PR. Calcium, phosphorus, and magnesium disorders. In: Ayres SM, Grenvik NA, Holbrook PR, Shoemaker WC, eds. Textbook of Critical Care. 4th ed. Philadelphia, PA: Saunders; 2000:905928. 61. Quamme GA. Laboratory evaluation of magnesium status. Renal function and free intracellular magnesium concentration. Clin Lab Med. 1993;13(1):209223. 62. Teng RJ, Wu TJ, Sharma R, Garrison RD, Hudak ML. Early neonatal hypotension in premature infants born to preeclamptic mothers. J Perinatol. 2006;26(8):471475. 63. Whang R, Ryder KW. Frequency of hypomagnesemia and hypermagnesemia. Requested vs routine. JAMA. 1990; 263(22):30633064. 64. Reinhart RA. Magnesium metabolism. A review with special reference to the relationship between intracellular content and serum levels. Arch Intern Med. 1988;148:(11)24152420. 65. Van Hook JW. Endocrine crises. Hypermagnesemia. Crit Care Clin. 1991;7(1):215223. 66. Ramsey PS, Rouse DJ. Magnesium sulfate as a Tocolytic agent. Semin Perinatol. 2002;25(4):236247. 67. Weisinger JR, Bellorin-Font E. Magnesium and phosphorus. Lancet. 1998;352(9125):391396. 68. Lee CT, Tsai WY, Tung YC, Tsau YK. Transient pseudohypoparathyroidism as a cause of late-onset hypocalcemia in neonates and infants. J Formos Med Assoc. 2008;107(10):806810. 69. Desai TK, Carlson RW, Geheb MA. Prevalence and clinical implications of hypocalcemia in acutely ill patients in a medical intensive care setting. Am J Med. 1988;84(2):209214. 70. Ryzen E, Wagers PW, Singer FR, Rude RK. Magnesium deficiency in a medical ICU population. Crit Care Med. 1985;13(1):1921. 71. Dacey MJ. Hypomagnesemic disorders. Crit Care Clin. 2001;17(1):155173, viii. 72. Magnesium sulfate. In: Taketomo CK, Hodding JH, Kraus DM, eds. Pediatric Dosage Handbook. 15th ed. Hudson, OH: Lexi-Comp; 2008:10901092. 73. Topf MJ, Murray PT. Hypomagnesemia and hypermagnesemia. Rev Endocr Metab Disord. 2003;4(2):195206. 74. Oster JR, Epstein M. Management of magnesium depletion. Am J Nephrol. 1988;8(5):349354. 75. Herbert P, Mehta N, Wang J, Hindmarsh T, Jones G, Cardinal P. Functional magnesium deficiency in critically ill patients identified using a magnesium-loading test. Crit Care Med. 1997;25(5):749755. 76. Chattopadhyay N, Mithal A, Brown EM. The calciumsensing receptor: a window into the physiology and pathophysiology of mineral ion metabolism. Endocrinol Rev. 1996;17(5):289307.
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77. Popovtzer MM. Disorders of calcium, phosphorus, vitamin D, and parathyroid hormone activity. In: Schrier RW, ed. Renal and Electrolyte Disorders. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:216277. 78. Jain A, Agarwal R, Sankar MJ, Deorari AK, Paul VK. Hypocalcemia in the newborn. Indian J Pediatr. 2008;75(2):165169. 79. Bushinsky DA, Monk RD. Electrolyte quintet: Calcium. Lancet. 1998; 352(9124):306311. 80. Zivin JR, Gooley T, Zager RA, Ryan MJ. Hypocalcemia: a pervasive metabolic abnormality in the critically ill. Am J Kidney Dis. 2001;37(4):689698. 81. Guise TA, Mundy GR. Clinical review 69: Evaluation of hypocalcemia in children and adults. J Clin Endocrinol Metab. 1995;80(5):14731478. 82. Schmidt GL, Baumgartner TG, Fischlschweiger W, Sitren HS, Thakker KM, Cerda JJ. Cost containment using cysteine HCl acidification to increase calcium/phosphate solubility in hyperalimentation solutions. J Parenter Enteral Nutr. 1986;10(2):203207. 83. Wood RJ, Sitrin MD, Cusson GJ, Rosenberg IH. Reduction of total parenteral nutrition-induced urinary calcium loss by increasing the phosphorus in the total parenteral nutrition prescription. J Parenter Enteral Nutr. 1986;10(2):188190. 84. Semple P, Booth C. Calcium chloride; a reminder. Anaesthesia. 1996;51(1):93. 85. Calcium chloride. In: Phelps SJ, Hak EB, Crill CM, eds. The Teddy Bear Book: Pediatric Injectable Drugs. 8th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:7071. 86. Calcium chloride. In: Taketomo CK, Hodding JH, Kraus DM, eds. Pediatric Dosage Handbook. 15th ed. Hudson, OH: Lexi-Comp; 2008:290291.
87. Davis KD, Attie MF. Management of severe hypercalcemia. Crit Care Clin. 1991;7(1):175190. 88. Peppers MP, Geheb M, Desai T. Endocrine crises. Hypophosphatemia and hyperphosphatemia. Crit Care Clin. 1991;7(1):201214. 89. Knochel JP. The pathophysiology and clinical characteristics of severe hypophosphatemia. Arch Intern Med. 1977;137(2):203220. 90. Worley G, Claerhout SJ, Combs SP. Hypophosphatemia in malnourished children during refeeding. Clin Pediatr. 1998;37(6):347352. 91. Clark Cl, Sacks GS, Dickerson RN, Kudsk KA, Brown RO. Treatment of nutrition support using a graduated dosing scheme: results from a prospective clinical trial . Crit Care Med. 1995;23(9):15041511. 92. Sperschneider H, Gunther K, Marzoll I, Kirchner E, Stein G. Calcium carbonate (CaCO3): an efficient and safe phosphate binder in haemodialysis patients? A 3-year study. Nephrol Dial Transplant. 1993;8(6):530534. 93. Potassium phosphate. In: Phelps SJ, Hak EB, Crill CM, eds. The Teddy Bear Book: Pediatric Injectable Drugs. 8th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:370371. 94. Goodman WG, Goldin J, Kuzion BD, et al. Coronaryartery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342(20):14781483. 95. Ritz E. The clinical management of hyperphosphatemia. J Nephrol. 2005;18(3):221228.
PART II
AGE-SPECIFIC NUTRITION FOR GROWTH AND DEVELOPMENT
10. Nutrition and Early Development . . . . . . . . . . . . . . 105 Russell J. Merritt, MD, PhD, FAAP Barbara Marriage, PhD, RD Ricardo Rueda, MD, PhD 11. Human Milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 Jacqueline J. Wessel, RD, CNSD 12. Infant Formulas and Complementary Feeding. . . . 129 Kelly Green Corkins, MS, RD, CNSD Timothy Sentongo, MD 13. Growth Assessment and Monitoring . . . . . . . . . . . 143 Timothy Sentongo, MD 14. Obesity and Metabolic Disorders. . . . . . . . . . . . . . 149 Michelle Battista, BS, PhD Candidate Robert Murray, MD 15. Lipid Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 Shirley Huang, MD Melanie Katrinak, RD, CSP, LDN 16. Use of Fad and Popular Diets. . . . . . . . . . . . . . . . . 169 Catherine Christie, PhD, RD Julia A. Watkins, PhD, MPH Judith C. Rodriguez, PhD, RD 17. Sports Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 Jackie Buell, PhD, RD, LD, ATC, LAT Diane L. Habash, PhD, RD, LD
Nutrition and Early Development

Russell J. Merritt, MD, PhD, FAAP, Barbara Marriage, PhD, RD, and Ricardo Rueda, MD, PhD
10
CONTENTS
Nutrition Physiology of Pregnancy . . . . . . . . . . . . . . . . . . 105 Impact of Maternal Dietary Deficiencies onthe Fetus. . 107
Macronutrients Calcium Iron Folic Acid and Vitamin B12 Vitamin E Multiple Micronutrients
Learning Objectives
Impact of Nutrition and Other Stresses on Fetal Metabolism, Organ Growth, andDevelopment . . . . . . . . 109 History and Epidemiology of the Fetal Originsof Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Hypothesis Expansion to Postnatal Growth Period
1. Achieve familiarity with the normal physiology and metabolism of the fetus and know nutrient deficiencies associated with adverse pregnancy outcomes. 2. Know common late adverse manifestations of early programming observed in epidemiologic and animal studies. 3. Be aware of potential mechanisms involved in late and transgenerational effects of early life programming.
Nutrition Physiology of Pregnancy
Integration of Pre- and Postnatal Programming Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

Early Programming in the Premature Infant
Animal Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

Animal Models of Dietary Manipulation Animal Models Induced by Glucocorticoid Exposure Animal Models Induced by Surgical Manipulation
Third and Future Generation Effects . . . . . . . . . . . . . . . . Implications for Future Health . . . . . . . . . . . . . . . . . . . . . Implications for Current Practice. . . . . . . . . . . . . . . . . . . Future Research Needs. . . . . . . . . . . . . . . . . . . . . . . . . . .
114 115 115 116
Pregnancy proceeds from fertilization to implantation through development and maturation of the placenta (of fetal origin) and the fetus. A healthy pregnancy is dependent on maternal nutrition status at conception, adequate oxygen delivery (blood-flow dependent) to the placenta and fetus, and the availability of appropriate amounts of nutritional substrates in the hormonal matrix that facilitates development of the placenta and the fetus. Early in gestation, placental mass is high relative to that of the fetus, and in later gestation this ratio declines. Initially, placental transport is largely dependent on increases in placental size, but later in pregnancy, both placental transport function and placental size must increase to meet the needs of the rapidly growing fetus. The uterus and placenta are perfused by the maternal uterine arteries, and the placenta transfers nutrients and gasses bi-directionally across the microvillous maternalfacing membranes and fetal-facing baso-lateral membranes of the syncytiotrophoblast and into the fetal venous circulation. The placenta has a relatively higher glucose requirement than the fetus to perform its important functions of substrate regulation, transport, and hormone
105
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secretion. In intrauterine growth restriction (IUGR) pregnancies, placental weight is reduced more than fetal weight. In contrast, the placenta may be increased in mass in gestational diabetes.1 Much of what we know about fetal substrate metabolism comes from extensive studies of the late gestation ovine fetus initiated by Battaglia and many other investigators associated with the Perinatal Research Center at the University of Colorado School of Medicine.28 The umbilical vein transports oxygen and nutrients to the fetus toward the fetal liver and ductus venosus, which variably shunts blood around the liver to the fetal heart and brain. Until the time of birth, when the lungs expand and pulmonary artery resistance increases, the lungs are also partly bypassed. This increases oxygenated blood flow to the fetal brain via the ductus arteriosus that connects the pulmonary artery and the aorta. Blood containing amino acids, metabolites, and carbon dioxide (CO2) returns to the placenta by way of the 2 umbilical arteries. The major energy source for the fetus is glucose, which normally all comes from maternal transport to the fetus and placenta.2 It also uses lactate produced in the placenta and endogenously.9 Glucose uptake by placental and fetal tissues and fetal growth are proportional to glucose delivery. 2 The fetal pancreas secretes insulin by mid-gestation and responds to variations in the glucose delivery rate. Normally the fetal liver is not active in gluconeogenesis. Fetal tissue glucose transporters and intracellular downstream metabolic regulators are modulated by glucose and insulin levels in the fetus. Insulin-responsive fetal tissues include the heart, liver, skeletal muscle, and adipose tissue. Placental glucose uptake is not regulated by insulin. When fetal glucose supply is limited, fetal glucose oxidation is maintained by virtue of increased uterine artery/umbilical vein glucose gradient and gluconeogenesis from amino acids in the fetus: the fetus develops with mechanisms that tend to keep its energy metabolism relatively constant, while growth is, at times of deficient energy supply, expendable.3 Amino acids are the second most important macronutrient in the fetus with at least 14 complex amino acid transporter systems on both of the syncytiotrophoblast membranes.10 The large neutral and branched-chain amino acids are transported most directly proportional to their maternal concentration. 5 Because of shared transporters and competition among amino acids for specific transporters, an increase in delivery of multiple amino acids sharing the same transporter to the uterine artery may have a different effect than an increase of a single amino acid on the uptake and transport of a specific amino acid. All amino
acids except tryptophan are in much higher concentration in the placenta than in maternal blood. Leucine appears to have specific trophic effects on the placenta and the fetus, possibly because of its impact on mammalian target of rapamycin (mTOR), which is a critical regulator of protein synthesis. IUGR fetuses have reduced fetal enrichment of leucine relative to the maternal circulation.4 Other specific amino acids such as arginine have not only nutrient, but, similarly, regulatory and developmental effects.10 The fetal liver makes glutamate (largely from glutamine), aspartate, and serine; the flux of glutamate and serine is in the direction of the placenta, where they are metabolized, the glutamate oxidized to CO2 . Serine is important to the onecarbon pool for nucleotide biosynthesis and as a precursor for glycine and gluconeogenesis. 5 When there is reduced oxygen, glucose, and amino acid availability to the fetus by virtue of reduced umbilical vein blood flow (associated with placental transport insufficiency), fetal weight gain slows. There are compensatory increases in fetal amino acid catabolism such that changes in fetal blood amino acid concentrations are minimized. This situation is associated with altered substrate distribution and changes in relative organ growth. When glucose (and other substrate) supply is limited and the fetus is relatively hypoglycemic, growth of the brain, kidney, and adrenals is relatively maintained. Growth of the spleen, liver, pancreas, and lung are reduced in excess of the (primate) body weight decrement.11 More blood is shunted through the ductus venosus, reducing splanchnic substrate availability. This leads to slower growth and altered fetal liver metabolism and reduced pancreatic beta cell mass or function, depending on the stage of pregnancy. The most common cause of IUGR is placental transport insufficiency (oxygen, glucose, amino acids), which may be related to local uterine factors, maternal malnutrition, advanced maternal diabetes, hypertension, or other maternal or placental pathology.12,13 Central metabolic mediators for regulatory hormone and metabolic changes in the fetus are fetal insulin, cortisol (increased levels of which are associated with reduced glucose uptake, increased gluconeogenesis, and slower fetal growth),14 and insulin-like growth factors (IGFs), which are critical for placental development and function and protein synthesis in fetal tissues.15,16 The increased insulin levels seen in response to acute hyperglycemia (in sheep) diminish with sustained hyperglycemia, and glucose transporters in liver, muscle, and adipose tissue decline, although total fetal glucose uptake remains elevated. The liver volume may beincreased. Many of these fetal adaptations may persist,
NUTRITION AND EARLY DEVELOPMENT
107
alter postnatal substrate metabolism, and determine the metabolic response to postnatal and later diet. Specific common metabolic/hormonal derangements that influence organ growth and metabolic development of the fetus include hypoglycemia, hyperglycemia, maternal or gestational diabetes, and activation of the fetal hypothalamic-pituitary-adrenal (HPA) axis (summarized by McMillen17) by a variety of intrauterine insults. The fetus and its uteroplacental support system are highly adaptive to their vascular supply, oxygenation state, and metabolic substrate availability. In this formative stage of life, thousands of responses at the fetal, organ, tissue, membrane, cytosolic, and nuclear levels determine the survival, health, and function of the fetus. These responses are regulated at the enzyme substrate level, others at the level of messenger ribonucleic acid (mRNA) transcription, and some at the nuclear level by way of epigenetic modification. Some of these adaptations are transient and others, particularly with prolonged exposure, appear to be permanent. Epigenetic changes involve gene regulation effects that are inherited from one cell generation to the next. These gene expression modifications do not change the deoxyribonucleic acid (DNA) sequence.18 Examples of epigenetic mechanisms include DNA methylation, histone modification, and alterations in noncoding RNAs.19 Epigenetic modifications of cells in specific organs help determine the final metabolic phenotype, which is a product of both genetic inheritance and developmental environmental influences on gene expression. Vulnerability to environmental and dietary influences appears to continue well past the time of birth. Fetal and early postnatal plasticity allows survival, but may also set the stage for later maladaptive metabolic responses, particularly to metabolic environments different from that experienced early in development (eg, food surfeits versus scarcity).20
placental synthesis of nitric oxide, a major vasodilator and angiogenesis factor, and polyamines, key regulators of DNA and protein synthesis, may provide an explanation for IUGR in response to the 2 extremes of nutrition problems with the same pregnancy outcome. Placental and fetal growth is most vulnerable to maternal nutrition status during the peri-implantation period and the period of rapid placental development (the first trimester of gestation). There has been extensive clinical research, using both observational and interventional study designs, that allows some quantification of the effects of maternal anthropometric indices, dietary intake in pregnancy, and nutritional supplements with respect to measures of fetal size and maturity at birth. Overall, these studies find a strong positive association between maternal pre-pregnancy nutrition status and the ability of a mother to nourish her growing fetus. Recent evidence also suggests that periconceptional undernutrition, as well as pregnancy undernutrition, are important determinants of the length of gestation. Gestational weight gain and nutritional interventions during pregnancy appear able to modify this association by altering the rate of fetal growth, although the extent of the modification appears to be dependent on maternal baseline nutrition status, and is modest.23 Current estimates of nutrition needsare provided in Table 10-1.
Macronutrients
In terms of maternal macronutrient status, there is some evidence that balanced protein/energy supplementation may be beneficial for decreasing rates of low birth weight (LBW) and small for gestational age (SGA) deliveries, especially in populations where women have chronically marginal nutrition status prior to pregnancy.15 However, overall analysis of the available evidence suggests that maternal supplementation with balanced or high-protein diets had no beneficial effects on fetal growth. There is limited evidence that protein supplementation adversely affected fetal growth rate (as measured by mean birth weight) and therefore potentially increased LBW deliveries. The effect of energy/protein restriction has been also evaluated in women who were classified as obese pre-pregnancy or had rapid early gestational weight gain. In women who were obese before pregnancy, there have been no benefits to fetal growth of restricting energy and protein during gestation, although evidence from controlled trials is limited. 23 It has also been reported that high intakes of protein and fat during pregnancy may impair development of the fetal pancreatic beta cells and lead to insulin deficiency in theoffspring.16
Maternal nutrition during pregnancy can exert long-lasting effects on the health of the offspring.21 These effects may be due to undernutrition or deficit of specific nutrients, or to an excess of energy or nutrients. Epidemiological and animal studies suggest that fetal adaptive responses to the intrauterine environment, including maternal malnutrition, overnutrition, or diabetes, may increase the risk of many chronic diseases in adulthood, including Type 2 diabetes and coronary heart disease (CHD).22 Animal studies also show that both maternal undernutrition and overnutrition reduce placental-fetal blood flow and slow fetal growth. Impaired
Impact of Maternal Dietary Deficiencies onthe Fetus
108
On the other hand, very recent studies have demonstrated that a low-protein diet in utero had a deleterious effect on bone development in the offspring that persisted into adulthood.24 The offspring displayed significant differences in bone structure and density at various sites. These differences are indicative of significantly altered bone turnover.25
Table 10-1 Recommended Daily Nutrient Intakes During Pregnancy Water Energy Carbohydrate Total fiber Linoleic acid Linolenic acid Protein Vitamin A Vitamin C Vitamin D Vitamin E Vitamin K Thiamin Riboflavin Niacin Vitamin B6 Folate Vitamin B12 Pantothenic acid Biotin Choline Calcium Chromium Copper Fluoride Iodine Iron Magnesium Manganese Molybdenum Phosphorus Selenium Zinc Potassium Sodium Chloride 3L Varies by age, pregnancy stage, BMI, activity 175 g 28 g 13 g 1.4 g 71 g 750770 mcg* 8085 mg/d* 5 mcg 15 mg 7590 mcg* 1.4 mg 1.4 mg 18 mg 1.9 mg 600 mcg 2.6 mcg 6 mg 30 mcg 450 mg 10001300 mg* 2930 mcg* 1000 mcg 3 mg 220 mcg 27 mg 350400 mg* 2 mg 50 mcg 7001250 mg* 60 mcg 1112 mg* 4.7 g 1.5 g 2.3 g
Calcium
In terms of specific micronutrients, maternal calcium supplementation may have a beneficial effect on fetal growth, particularly in women with low calcium status at the outset of pregnancy or who were classified as being at risk of gestational hypertension. Calcium supplementation during pregnancy can be linked directly to increased bone density and bone length of neonates.26 The effects on fetal growth appeared to come partly from a reduction in preeclampsia and resultant lengthened gestation.23
Iron
Some studies have reported that iron deficiency anemia early in pregnancy was associated with greater than a twofold increase in the risks of LBW and preterm delivery.21 In addition, reduced iron availability for brain iron accretion is associated with persisting developmental and behavioral changes. A number of conditions associated with fetal growth retardation or macrosomia such as diabetes, placental insufficiency, and smoking restrict iron availability during gestation and predispose to later iron deficiency. 27 In well-nourished populations, folic acid needs are usually met by dietary intake. However, in some countries (eg, the United States), it is recommended that pregnant women consume 600 mcg of folic acid per day to reduce the risk of neural tube defects (Table 10-1). A dietary deficiency of folate interferes with the growth of the fetus. Low maternal folate intake (< 240 mcg/d) has been associated with a greater than threefold increase in the risk of LBW and preterm delivery. A metabolic effect of folate deficiency is elevation of homocysteine, and women with high homocysteine levels are more likely to have a reproductive history of preeclampsia, preterm delivery, LBW, or fetal growth restriction.21 A recent study carried out in India has highlighted that dietary methyl donors including B12 and folate seem to play a major role in fetal programming. Maternal low B12 status along with normal to high folate status predicted later adiposity and insulin resistance in children. Thus, 1-C (methyl) metabolism seems to play a key role in fetal programming.28
Folic Acid and Vitamin B12
* Varies by age group. Adapted from U.S. Dietary Reference Intakes (www.nap.edu).
Vitamin E
The plasma concentration of -tocopherol, the most common isomer of vitamin E, was positively related to fetal growth (birth weight for gestation), reduced small-forgestation births, and increased risk of large-for-gestation births. Concentrations of -tocopherol were positively
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related to the use of prenatal multivitamins before and during pregnancy and to vitamin E in the maternal diet. Emerging evidence suggests that the effect of vitamin E on fetal growth may be via increased blood flow and nutrient supply to the fetus.21
Multiple Micronutrients
There have been few studies published to examine whether multiple micronutrient supplements might be more beneficial than single micronutrients. There is evidence of interactions of several micronutrients at the metabolic level. Little is yet known about the significance of these interactions for pregnancy outcomes, especially in developing countries where nutrient deficiencies rarely occur in isolation and multiple micronutrient deficiencies are common. 29 A meta-analysis of global multinutrient supplementation studies found a small effect on birth weight between ironfolate supplementation or placebo. 30
Deprivation of nutrients and/or oxygen in utero alters fetal metabolism in a manner that changes body growth and the development of individual fetal tissues. 31 The effects of varying nutrient availability on fetal metabolism depend on the specific nature of the nutrition variation and on the duration, severity, and gestational age at onset of the insult. Deprivation of oxidative substrates such as glucose produces a different metabolic response in the fetus from that seen from oxygen deprivation alone or when there is combined oxygen and substrate deficiency. These different nutrition challenges also have different effects on the uteroplacental tissues and on the fetal hormonal environment, both of which influence the availability and metabolic fate of specific nutrients in the fetus. 32 Many of the nutritionally induced alterations in fetal metabolism and growth are likely to be mediated by hormonal changes in either the mother or the fetus. Dietary restriction is known to alter maternal concentrations of growth hormone (GH), insulin-like growth factors (IGFs), insulin, glucocorticoids, leptin, thyroid hormones, and placental lactogen. 31 These hormones alter maternal metabolite concentrations that in turn influence fetal substrate availability, particularly for those metabolites crossing the placenta against a concentration gradient. In general, reducing fetal delivery of oxygen and nutrients lowers anabolic hormones (eg, insulin, IGFs, and thyroid hormones) and increases catabolic hormone concentrations
Impact of Nutrition and Other Stresses on Fetal Metabolism, Organ Growth, andDevelopment
(eg, cortisol, catecholamines, glucagons, and GH). The anabolic hormones tend to increase the uptake and utilization of glucose and reduce the oxidation of amino acids. They also enhance protein accretion by stimulating protein synthesis, by reducing proteolysis, or both. The catabolic hormones tend to increase fetal glucose production by activating hepatic gluconeogenesis. They also reduce protein accretion and fetal uptake of amino acids. The fetal HPA axis is particularly vulnerable to changes in the intrauterine environment. In humans, most brain and HPA development occurs in utero. However, in species often used as models of in utero manipulation that give birth to immature offspring (eg, rodents), most brain development occurs in the early postnatal days. 33,34 Prenatal stress has a profound effect on neuroendocrine development and function. Exposure of the fetus to elevated glucocorticoids appears to be the central link between prenatal stress and modification of HPA axis development and function. There is evidence that antenatal stress/ anxiety has a programming effect on the fetus that lasts at least until mid-childhood and results in higher rates of behavioral and emotional problems. 35 Cognitive and behavioral modifications have also been linked to alterations in HPA axis activity and prenatal glucocorticoid exposure. Prenatal stress has been associated with changes in memory and behavior, and with depression, anxiety, chronic fatigue syndrome, and schizophrenia. 33 These alterations in HPA axis function, behavior, and cognition as a result of prenatal stress have been related to changes in brain corticosteroid receptor populations and alterations in hippocampal and hypothalamic neuronal development. 36 Numerous studies in animals and humans have demonstrated that synthetic glucocorticoid administration can also promote HPA hyperactivity. Synthetic glucocorticoids are poorly catabolized by placental 11-hydroxysteroid dehydrogenase type 2 (11HSD2), and readily pass to the fetus. 37 Fetal glucocorticoid exposure alters the expression of glucocorticoid receptors, and impacts every level of the HPA axis. Synthetic glucocorticoids are often administered to women threatened with preterm delivery to enhance fetal lung maturation to reduce morbidity and mortality at a time in gestation when endogenous fetal cortisol levels would normally be quite low. Due to recent clinical observations and animal studies of this practice, concerns have been voiced by international expert groups. In spite of these concerns, administration of repeated doses of antenatal corticosteroids to pregnant patients continues to be common clinical practice. 33 Programming of the fetal HPA axis appears to play a
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central role in the link between fetal growth and long-term disease in adulthood (Figure 10-1). Stress-induced prenatal programming of HPA axis function can increase the risk of developing cardiovascular and metabolic diseases. On another front, evidence is also accumulating rapidly that chronic stimulation of the HPA axis and resulting excess glucocorticoid exposure may play a role in the development of visceral obesity. Because regulation of energy and food intake under stress is important for survival, it is not surprising that the HPA axis is not only the conductor of appropriate stress responses, but also tightly intertwined with the regulation of appetite. 38
History and Epidemiology of the FetalOriginsof Disease

Hypothesis
Early nutrition programming is the concept that nutrition experiences in early life can program an individuals metabolism and development and influence later health outcomes. In 1962, McCance39 observed that the size of a weanling rat varied inversely with the number of littermates suckled by the dam. Further experimental work in both rats and pigs illustrated that the earlier in life the animal was
exposed to food restriction, the more permanent the effects on adult size, despite attempts to obtain catch-up growth.40 Competition among fetuses for intrauterine food supply or littermates for milk can lead to periods of undernutrition during critical periods of development. The fetus or neonate adapts by slowing the rate of cell division in certain organs in such a way as to permanently change or program metabolism and growth potential. Barker and colleagues proposed the developmental or fetal origins of adult disease in humans in 1986. The hypothesis was based on observations that the highest rates of CHD in a geographical region of England were associated with increased infant mortality in the same population decades earlier.41 Further epidemiological evidence was provided from 2 large studies of males from Hertfordshire and Sheffield, England, that demonstrated a strong correlation between LBW, low weight for length at 1 year, and small head circumference with death from CHD.42,43 It is of interest to note that the relationship between LBW and CHD was related to slow fetal/infant growth rather than prematurity. The association between reduced size at birth and risk factors for CHD including obesity, hypertension, hyperlipidemia, and non-insulin-dependent diabetes mellitus (NIDDM) has been confirmed from cohort
Figure 10-1 Scheme of the role that programming of the fetal hypothalamic-pituitary-adrenal (HPA) axis during development plays in the link between fetal growth and long-term disease in adulthood. Gc: Glucocorticoids; Dex: Dexamethasone.
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studies in various countries.4449 A systematic review of 80 studies found that there was a 2-mmHg decrease in systolic blood pressure per kilogram increase in birth weight.48 A review of 48 papers examining the relationship of birth weight and later glucose and insulin metabolism demonstrated that LBW was correlated with adverse glucose and insulin metabolism, possibly related to insulin resistance.49 Fetal overnutrition in infants of diabetic mothers may also cause an increased risk of glucose intolerance and NIDDM in later life. 50 A study in Pima Indians demonstrated a U-shaped relationship between birth weight and prevalence of NIDDM with high birth weight explained by the presence of gestational diabetes. 51
Expansion to Postnatal Growth Period

Although nutrition effects during fetal life have been shown to be important determinants of susceptibility to later health effects, postnatal events modify the influence of prenatal growth. In evaluating the fetal origins of disease hypothesis it has been recognized that it is important to adjust for early weight gain and current body size. Numerous epidemiological studies show that the highest risk for cardiovascular disease (CVD) and associated disorders is in adults who were small at birth and became overweight or obese during childhood or adulthood.44,5255 The thrifty phenotype hypothesis proposed by Hales and Barker postulates that the fetus selectively distributes nutrients to certain organs during periods of undernutrition, leading to permanent metabolic changes that enhance its chance of survival during periods of limited postnatal nutrition. 56 If adequate food becomes available postnatally, the prenatal metabolic adaptations to undernutrition are detrimental in that obesity and related metabolic disorders may develop. 57 Lucas and colleagues proposed the term programming to explain the mechanism whereby an early stimulus or insult occurring at a critical or sensitive period results in a permanent or long-term change. 58 Current research seeks to identify critical periods during prenatal and postnatal life when nutrition deficiencies or excesses may influence the risk of chronic adult disease. Recent evidence suggests that rapid weight gain during infancy may be associated with an increased incidence of childhood or adult obesity and cardiovascular risk factors. The majority of the studies show consistent associations between LBW and rapid weight gain in infancy with increased risk of CHD. In addition, an observational study from Helsinki demonstrated that slow weight gain during infancy followed by a rapid weight gain after 1 year of age increased the risk of coronary disease, irrespective of birth
size. 54 A systematic review of 15 studies examining the role of rapid growth in infancy and childhood on later obesity found 13 publications that demonstrated a significant association of early rapid growth with obesity prevalence in later life. 59 Another systematic review that evaluated both size at birth and rate of growth in infancy concluded that infants who are at the highest end of the distribution for weight, or who grew rapidly during infancy, are at increased risk of subsequent obesity.60 Although controversy exists as to the specific periods of infancy and childhood that predict later adiposity, several observational studies have indicated that weight gain in the first half of infancy may be a critical period.6163 In formula-fed infants in whom repeated measures of infant weight gain were available, Stettler and colleagues showed that rapid weight gain in the first week of life was associated with risk of overweight in adulthood.64 Several reviews have demonstrated that breastfeeding may reduce the risk of later obesity. It has been suggested that the benefits of breastfeeding may be due to slower growth in the breastfed compared to the formula-fed infant. The differences in growth rate between breastfed and formula-fed infants are greatest in the first few weeks of life, a critical period for programming of obesity.64 Observational studies support the hypothesis that early postnatal nutrition plays an important role in the development of obesity and related cardiovascular risk factors, but limited clinical evidence exists on the effects of early nutrition programming in term infants. In a recent study, SGA term infants randomly assigned to a nutrient-enriched formula at birth had higher diastolic blood pressure at 6 to 8 years.65 In a secondary analysis, the diastolic blood pressure was greater in children who had more rapid weight gain from birth to 9 months.65 Support for the growth acceleration hypothesis in term infants was demonstrated in a study that utilized multiple measurements of growth from birth to 5 years in relation to blood pressure.66 Rapid increases in weight in the first 6 months of life predicted elevated diastolic blood pressure in adults, independent of fetal growth.66 LBW and rapid postnatal growth are associated with later elevated blood pressure indicating the importance of both prenatal and postnatal factors in the programming of later health effects. Improved maternal nutrition and prevention of rapid percentile-crossing weight gain in infants could have a substantial impact on the development of adult chronic diseases.
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Integration of Pre- and Postnatal Programming Effects
Gluckman and colleagues use the term developmental plasticity (defined as the ability of an organism to develop in various ways, depending on the particular environment or setting) to provide a framework for the observations on the impact of early growth on later health.20 The first models to explain the developmental origins of health and disease (DOHaD) idea were the thrifty phenotype and the fetal salvage hypothesis in which a fetus adapts to survive a deprived intrauterine environment. 56,67 These theories were later expanded to include the postnatal environment and termed a predictive adaptive response.68 The risk of disease is increased when the postnatal environment does not match what is predicted prenatally. Animal studiesin which nutritional, endocrinologic, or surgical manipulation from conception to weaning have been used to induce permanent changes in the offspringprovide biological support for the concept of developmental plasticity and its role as a key determinant in the risk of later chronic disease.
Early Programming in the Premature Infant

Prospective interventional studies performed by Singhal, Lucas et al in preterm infants have demonstrated the importance of early nutrition for long-term health outcomes.69 More than 900 preterm infants were randomly assigned in 2 parallel trials to receive (a) banked breast milk or preterm formula or (b) standard term formula or preterm formula. The preterm infants fed breast milk for a period of 4 weeks had improved lipid profiles,70 lower blood pressure,71 lower leptin concentrations, and decreased insulin resistance72,73 at 13 to 16 years compared to the infants fed preterm (nutrient-enriched) formula. The lipoprotein profile, C-reactive protein (a marker for the low-grade inflammatory response associated with the atherosclerotic process), and blood pressure did not differ significantly between infants randomized to standard infant formula and those fed preterm formula.70,71 The ratio of leptin to fat mass (a marker of obesity) was significantly higher in children fed the preterm formula compared to the children who received breast milk or standard term formula.72 Fasting 32-33 proinsulin concentration (a marker of insulin resistance) was significantly higher in children who received preterm formula, and further analysis demonstrated that differences in weight gain (or loss) in the first 2 weeks of life was the only factor related to later proinsulin concentrations, irrespective of size at birth.73 These landmark studies provide the first experimental clinical evidence that faster postnatal
growth and a nutrient-dense diet may be a risk factor for later CVD. Although slower growth in preterm infants may have benefits for later health outcomes,69 the risks of adverse consequences on cognition must be considered. Numerous studies have demonstrated that growth restriction in preterm infants is associated with long-term short stature and cognitive deficits. Preterm infants fed standard formula compared to nutrient-enriched formula demonstrated a significant reduction in intelligence quotient (IQ ) and neurocognitive impairment at 7 to 8 years of age.74 Higher bone mineralization and improved linear growth in childhood has been reported in preterm infants fed a preterm formula versus unfortified breast milk or standard formula.75,76 There are clear benefits for the use of specialized formulas in preterm infants relative to term formulas to support brain development that outweigh the later risks of cardiovascular disorders. Short-term advantages of dietary supplementation of at-risk infants have also been demonstrated in developing countries where more rapid weight gain up to 2 years of age was associated with decreased hospital admissions and reduced mortality.77 Further research is needed to determine optimal growth to achieve cognitive benefits (in preterm infants) and short-term health benefits in at-risk populations while minimizing the longer-term risk of chronic disease.
Animal Models
Animal models of early growth restriction have been used to better understand its relationship with adult human disease and to provide insight into underlying molecular mechanisms. Nutritional, hormonal, and surgical insults during pregnancy have been shown to result in growth restriction in various species.78
Animal Models of Dietary Manipulation

Dietary manipulation by global caloric restriction, reduction of dietary protein content, iron restriction, or dietary fat supplementation have all been studied in rodents and ovine models. The most common model is the pregnant rat subjected to malnutrition. However, a limitation of the rodent model is that the rat is an altricial animal, born with a poorly developed central nervous system and autocrine system, with significant maturation during weaning. The guinea-pig may be a more relevant model as these animals are precocial and born with well-developed central nervous, endocrine, and cardiovascular systems. Because of the polytocous nature of rats and guinea-pigs, there may be considerable variability in fetal and neonatal nutrient
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supply to individual offspring within a litter. In contrast, sheep pregnancies are usually singleton or twin.79 In the maternal low-protein animal models there are striking parallels with the development of type 2 diabetes and/or the metabolic syndrome. In this model, rats are fed a low-protein (5%-8%) diet during pregnancy that restricts the growth of the offspring. If such offspring are cross-fostered to mothers fed a control diet (20% protein) during lactation, they gain weight rapidly and, by weaning (21 days of age), have similar body weights to controls. However, this catch-up growth has a detrimental effect on longevity. Permanent growth restriction results if maternal protein restriction is continued during lactation, even after the offspring are weaned to a control diet. Maternal protein restriction has been shown to have long-term effects on the structure and function of individual organs. Beta-cell proliferation and islet size were significantly reduced in the pancreas. However, a functional defect in glucosestimulated insulin secretion from islets of adult low-protein offspring is only observed when an additional dietary insult such as high fat or sucrose feeding is introduced post natally.80 Maternal protein restriction has also been shown to have long-term effects on insulin-sensitive tissues. There are structural and functional changes in the liver. Skeletal muscle is more sensitive to insulin in terms of its ability to stimulate glucose uptake. Adipocytes have an elevated basal and insulin-stimulated glucose uptake and increased levels of insulin receptors.78 Nutrition restriction is also one of the most common experimental methods of fetal insult used for investigation into the mechanisms of programmed hypertension. This was one of the first methods to demonstrate that the timing of the insult is critical to the programming response. A reduction of nephron number was observed when the nutrition insult coincided with the nephrogenic period. Slow fetal growth also leads to alterations in the normal regulatory systems involved in the long-term control of blood pressure regulation. The pathogenesis of hypertension programmed by in utero insult is multi-factorial and appears to involve intrinsic intrarenal defects and alterations in extrarenal regulatory systems critical to renal sodium excretion. A role for sex steroids was also demonstrated.81 Severe food restriction (to only 30% of ad libitum intake) during pregnancy has also been shown to induce severe intrauterine growth restriction in rats. In addition to expressing hypertension in adulthood, these offspring have increased fasting plasma insulin compared to control offspring. They also have increased food intake, consistent with findings in humans suggesting early growth restriction
is associated with adult central adiposity.82 Less severe food restriction (to 50% of ad libitum intake) from day 15 of pregnancy to weaning has been shown to result in insulinopenia and an age-dependent loss of glucose tolerance in 12-month-old male offspring.83 Iron Feeding rats and sheep iron-deficient diets during pregnancy leads to anemia and growth restriction of the fetus. The offspring have decreased iron concentrations in brain tissue that cannot be normalized by iron treatment after weaning. In addition, behavioral differences and alterations in cardiovascular development have been noted.78 Gestational conditions that compromise fetal iron status include maternal iron deficiency, diabetes mellitus, and hypertension. Animal models have demonstrated that early iron deficiency affects neuronal and glial energy metabolism, monoamine metabolism, and myelination.19 It also induces genomic changes coding for signal transduction, dendritic structure, and energy metabolism that last well into adulthood, in spite of later iron repletion. Early iron sufficiency may be critical for long-term neurologic health.19 Animal models are also used to study early life influences on appetite and feeding behavior. Studies of rodent models indicate that fetal undernutrition determines adult adiposity. It is unclear whether the increase in central adiposity is related to increased food intake or reduced energy expenditure, although evidence exists to suggest that both may be involved. Rats subjected to intrauterine protein restriction exhibited increased preference for highfat foods. Feeding of energy-dense foods to rats that were undernourished in utero promoted a greater degree of obesity than noted in animals with adequate nutrition in fetal life. Programming of appetite may stem from remodeling of hypothalamic structures that control feeding and programming of the expression of genes involved in responses to orexigenic hormones. Recent work has defined circuitry in the hypothalamus that appears to mediate many of the effects of the adipocyte-derived hormone leptin on feeding and glucose homeostasis. Evidence accumulated primarily in mice indicates that these circuits develop as projections from the arcuate nucleus of the hypothalamus. Leptin appears to play a crucial neurotrophic role governing development of these pathways that regulate food intake and adiposity.84 Early programming of appetite and obesity is a complex phenomenon and the understanding of how maternal nutrition determines later energy balance is at a very early stage.85
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Animal Models Induced by Glucocorticoid Exposure

Several animal studies have shown that prenatal glucocorticoid excess, either from endogenous overproduction from maternal stress or through exogenous administration to the mother or fetus, reduces birth weight and causes hypertension, hyperglycemia, and behavioral abnormality in the offspring. These effects are transmitted across generations without further exposure to glucocorticoids, an observation that supports an epigenetic mechanism.86 Rat offspring that have been exposed to excess prenatal glucocorticoids undergo catch-up growth postnatally and normalize body weight by weaning. Outcomes from such offspring when they are adults are consistent with the hypothesis that rapid postnatal catch-up growth is deleterious to health.78 There are also accumulating data in rodents to suggest that prenatal glucocorticoid overexposure programs an adverse adult cardiovascular, metabolic, neuroendocrine, and behavioral phenotype. The phenotypic outcome is similar to that of the low-protein model. Fetal glucocorticoid overexposure may be a common mechanism for mediating fetal growth retardation and metabolic programming. This suggestion is based on the observation that dietary protein restriction during rat pregnancy reduces 11-HSD2 activity. This enzyme, as mentioned earlier, serves as a placental barrier to maternal glucocorticoids by rapidly metabolizing maternal glucocorticoids to inert 11-keto forms to minimize fetal exposure to glucocorticoids.78 HPA regulation can be programmed by nutrient restriction. In fetal rats nutrient restriction results in blunted diurnal patterns of adrenocorticotropic hormone (ACTH) at 4 weeks postnatal age, alterations in basal plasma corticosterone in adulthood, and altered basal HPA axis activity. 33 Normally, the presence of 11-HSD2 in the placental syncytiotrophoblasts protects the fetus from maternally derived glucocorticoids. Maternal glucocorticoid levels are much higher than fetal levels for most of pregnancy, so a relative deficiency in placental 11-HSD2 would put the fetus at great risk of increased glucocorticoid exposure. 87 In some studies, a strong positive correlation has been reported between placental 11-HSD2 activity and fetal weight at term and birth weight in preterm infants. Maternal protein restriction in rodents reduces the activity of 11-HSD2 in the placenta. 11-HSD2 activity is influenced by multiple maternal environmental factors and its modulation may be a mechanism through which a variety of environmental insults exert their programming effects. 86
Animal Models Induced by Surgical Manipulation

Reduction in placental blood flow and consequent restriction of oxygen, nutrient transport, and fetal growth can be produced in the rat by uterine artery ligation in late gestation, uterine and umbilical artery embolism, or carunclectomy.78,79 At 2 weeks of age, growth-retarded offspring in this model have reduced nephron number. This nephron deficit was associated with impaired renal function at 2 weeks of age despite compensatory hypertrophy of remaining nephrons. Also, molecular analysis of skeletal muscle from fetuses and 21-day-old offspring following uterine artery ligation revealed that this mode of growth restriction is associated with changes in both mitochondrial gene expression and function. In female offspring, after uterine artery ligation, growth restriction was associated with increased fasting blood glucose levels and with impaired glucose tolerance and lower insulin secretion during a glucose tolerance test.78 Adverse events during pregnancy can affect not only the offspring of the pregnancy but also the next generation. In a UK study examining the relationship of adult blood pressure to the mothers fetal growth and size at birth, it was demonstrated that reduced fetal growth was associated with raised blood pressure in the next generation. 88 The researchers concluded that if the growth of a female fetus is restricted, there are changes in her physiology and metabolism that lead to elevated blood pressure in the next generation. Adults who were born during the Dutch famine and whose mothers had inadequate nutrition during the first 2 trimesters of pregnancy were more likely to be obese and have abnormal lipid profiles than adults whose mothers had poor nutrition during the third trimester. 89 Infants born to mothers who were malnourished during the third trimester were leaner but had impaired glucose tolerance. Infants who were of normal birth weight born to severely malnourished mothers went on to deliver smaller babies in the next generation. One explanation for the intergenerational effects on birth weight is that the hormonal environment of the uterus of the undernourished mother may affect the reproductive tract of the fetus. A possibly similar transgenerational transmission of longevity propensity has been identified for males in epidemiologic studies of food supply during early spermatogenesis.90 Although the mechanisms behind these relationships are poorly understood, epigenetic dysregulation of the insulin-like growth factor 2 (IGF-2) gene has been proposed. IGF-2 is a key factor in human development and growth and is maternally imprinted. Individuals
Third and Future Generation Effects
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who were prenatally exposed to malnutrition during the Dutch famine had less DNA methylation of the IGF-2 gene compared with their unexposed same-sex siblings 6 decades later.91 These data support the hypothesis that early life environmental conditions cause epigenetic changes in humans that persist throughout life.
Implications for Future Health
Dietary inadequacy, imbalance, or excess can all impact fetal development. Some of these changes persist throughout life or leave the individual vulnerable to later environmental and dietary conditions that can adversely impact health and longevity. Underlying fetal morphological and functional changes related to pregnancy, postnatal diet, and various stressors and their adult consequences have been delineated. Now we are beginning to understand the molecular determinants of these changes and the dietary and environmental factors controlling them. Both over- and undernutrition in utero and in early life can increase risks for adverse metabolic outcomes including type 2 diabetes, CVD, and obesity. The seriousness of these events is amplified by evidence that certain potentially adverse epigenetic effects induced in the female fetus may persist through at least an additional generation. Current agricultural production and food distribution and changes in diet and activity patterns are associated with a historically high prevalence of obesity, diabetes, and their complications. As many as a third of todays children in some states are destined to become diabetic, given obesity rates and genetic predisposition. In developed countries, many of these may now be in the second or third generation of families expressing this phenotype. Many come from environments with a history of food and micronutrient scarcity. In many parts of the world, these contrasting nutrition states coexist contemporaneously. In the course of a lifetime, individuals can be expected to pass from one dietary camp to the other, magnifying the potential adverse developmental impacts inherent to both. In India we now have the phenomenon of the thin, fat Indian that has given India the distinction of the worlds highest rate of diabetes, despite a lower ranking for obesity. Based on what is emerging from the DOHaD literature and the investigation of epigenetics, we can expect the consequences of dietary scarcity and surfeit and their coexistence to exert their adverse effects in future generations in the absence of fresh insights on how to intervene to break this cycle. An inability to meet potential major population increases in health care costs related to morbidity patterns associated with DOHaD-associated conditions could itself become
a driver of morbidity and mortality, as well as a potential source of economic and political instability. Already, it is estimated that todays children in the United States will, for the first time in generations, not live longer than their parents. The most frequent of the DOHaD-associated conditions include hypertension, diabetes, coronary artery disease, and the complications of obesity. For each of these conditions, primary prevention is far preferable to, and far less expensive than, treatment and secondary or tertiary preventive measures. However, medical treatments have developed far faster than the behavioral, cultural, and social changes required to alter the trajectory of the development of these conditions. In light of this, medical solutions should be sought along with the broader public health initiatives that will be required to improve the quality of life for the developing fetus and neonate.
Implications for Current Practice
What implications can be drawn from current knowledge in this area for nutrition advice in the practice of obstetrics, pediatrics, neonatology, and public health? Given that preconceptual nutrition status is at least as important as nutrition status during pregnancy, planned pregnancies in mature women with good nutrition status is a highly desirable starting point. This requires approaches to maximizing nutrition status of fertile women of childbearing age beyond an exclusive focus on pregnancy and lactation, especially where pregnancies are unlikely to be planned. During pregnancy, adequate energy, protein, and micronutrients, including methyl donors, can be expected to have a salutary effect on developmental outcomes related to fetal nutrition status. There is some evidence to indicate excesses of fat and protein during pregnancy are to be avoided, and long-chain n-3 fatty acids, especially docosahexaneoic acid, may have beneficial impact on mental, visual, and behavioral development. Monitoring fetal growth, maternal weight gain, and maternal blood sugar can detect deviations from expected developmental patterns. For term infants, it appears to be desirable to continue on a relative growth trajectory (percentile) similar to that experienced in utero. Traditionally, normalizing the growth of in utero growth-retarded infants has been accepted as the de facto goal of good nutrition. Based on more recent findings, these children may be metabolically more suited to a slower rate of growth. Percentile crossing in infancy, and later, appears to increase risk of the DOHaDassociated conditions. In the first 2 weeks of life and after about 4 months of age, breastfeeding may lead to less weight
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gain than formula feeding and can be viewed as particularly beneficial in this population. An important medical concern in such infants is to support brain development, but most of the data on the importance of early nutrition for brain development come from studies of premature infants. It remains largely unknown if nutritional supplementation and growth acceleration are beneficial in this regard for term growth-retarded infants. For infants in underdeveloped countries who develop extrauterine growth retardation later in infancy and early childhood, short-term nutritional supplementation has been found to reduce acute morbidity and mortality (as well as progression of their malnutrition). Premature infants, especially extremely low birth weight (ELBW) infants, are at high risk of extrauterine growth retardation. Their nutrition requirements exceed those of term infants, given their immature development and body composition. In these infants, developmental achievement and reduced neurological complications are associated with higher growth rates. Premature infants, both in-hospital and following hospital discharge, are very responsive to nutritional supplementation. Data from Lucas and Singhal have been taken by some to demonstrate that rapid growth should not be encouraged for this population, based on higher blood pressure, leptin, blood lipids, and split proinsulin values in premature infants when fed premature formula compared to term formula or human milk. However, in their studies, these markers of cardiovascular risk were not elevated above those for typical term infants. These same investigators demonstrated developmental disadvantages in these infants at least through childhood from receiving standard term formulas versus more nutrientrich premature formula. Interestingly, while premature infants fed premature formula grew faster than breastfed infants, their neuro-developmental status was not better than that of breastfed infants. Bone mineralization is improved in premature infants given mineral-rich premature and post-discharge formulas compared to standard term formulas. However, this may not persist into adulthood.92 Human milk with human milk fortifier is the current recommended approach for small premature infants as it can preserve the beneficial nutrition and immunologic effects of human milk while providing additional energy, protein, minerals, and other micronutrients. For formula-fed premature infants, premature, not term, formula is recommended. However, there is no evidence postdischarge formulas have improved developmental outcomes versus infants fed standard term formulas after hospital discharge. However, in the smallest infants, they have been observed to enhance head
growth. The recent U.S. data from Ehrenkranz on the positive developmental outcome of encouraging early growth in premature infants dictates against any go-slow approach for these infants to possibly reduce markers of future cardiovascular risk (to below values observed in healthy term infants).93
Future Research Needs
This is a rich area for potential investigation at all levels of biological research. At the molecular level, we need specific descriptions of the molecular changes underlying the DOHaD phenomenon in various organs and the mechanisms controlling these molecular changes, including nutrition influences. In physiology, there remain opportunities to explore the developmental impact of organ-specific effects of general and nutrient-specific under- and overnutrition at various stages of fetal and infant development.94 Beardsall et al lists opportunities for studies of glucose control in the fetus relative to body composition, pancreatic development, and in utero programming of glucose control.94 The epidemiologists, who did much to initiate this field of research, can tell us more about the similarities and differences of effects of different stressors (eg, gestational malnutrition versus diabetes) on the expression of the DOHaD-related morbidity. More remains to be done to elucidate the relation of intrauterine and postnatal effects (and their interaction). Clinical investigators can prospectively study the developmental impact of growth acceleration in various populations and age groups of infants and young children looking at infection and immune outcomes, cardiovascular and metabolic risk factors, bone health, and neurodevelopment. There may be better versus worse times or target populations for catchup growth. There appears to be great potential in exploring very early or later drug or hormonal interventions to reverse the underlying molecular basis of some DOHaD-associated conditions. For example, administration of leptin (a pleomorphic hormone during gestation) in late gestation or shortly after birth may reverse the development of the expected postnatal phenotype of the growth-retarded fetus or alter the development of appetite regulation.95,96 There is also the potential to alter the epigenetic phenotype through controlled exposure to methyl donors or other agents directly affecting epigenetic mechanisms.97,98
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1. The dominant fuel source for the healthy fetus is: A. Fatty acids because they are the richest source of energy B. Amino acids because they promote rapid growth C. Galactose, because the fetus cannot utilize glucose D. Glucose transported from the maternal circulation 2. Nutrition programming is a process that: A. Is specific to the fetus B. Occurs only in animals C. Occurs early in life and may extend beyond a single generation D. Is a transient response to nutrient availability 3. Upward growth percentile-crossing in infancy and early childhood: A. Reduces short-term infectious mortality and leads to lower adult blood pressure B. Has been associated with increased risk for development of features of the metabolic syndrome C. Helps prevent subsequent rebound obesity D. Improves glucose control later in life See p. 487 for answers.
References
1. Pardi G, Cetin I. Human fetal growth and organ development: 50 years of discoveries. Am J Obstet Gynecol. 2006;194(4):10881099. 2. Hay WW Jr. Placental-fetal glucose exchange and fetal glucose metabolism. Trans Am Clin Climatol Assoc. 2006;117:321340. 3. Hay WW Jr. Recent observations on the regulation of fetal metabolism by glucose. J Physiol. 2006;572(pt 1):1724. 4. Battaglia FC. Clinical studies linking fetal velocimetry, blood flow and placental transport in pregnancies complicated by intrauterine growth retardation (IUGR). Trans Am Clin Climatol Assoc. 2003;114:305313. 5. Battaglia FC. In vivo characteristics of placental amino acid transport and metabolism in ovine pregnancy--a review. Placenta. 2002;23(Suppl A):S3S8. 6. Battaglia FC, Wilkening R, Meschia G. Unique organ specific characteristics of amino acid metabolism in early development. Trans Am Clin Climatol Assoc. 1995;106:141149. 7. Barry JS, Anthony RV. The pregnant sheep as a model for human pregnancy. Theriogenology 2008;69(1):5567. 8. Regnault TR, Friedman JE, Wilkening RB, Anthony RV, Hay WW Jr. Fetoplacental transport and utilization of amino acids in IUGR--a review. Placenta. 2005;26(Suppl A):S52S62. 9. Sparks JW, Hay WW Jr, Bonds D, Meschia G, Battaglia FC. Simultaneous measurements of lactate turnover rate and umbilical lactate uptake in the fetal lamb. J Clin Invest. 1982;70(1):179192.
10. Grillo MA, Lanza A, Colombatto S. Transport of amino acids through the placenta and their role. Amino Acids. 2008;34(4):517523. 11. Myers RE, Hill DE, Holt AB, Scott RE, Mellits ED, Cheek DB. Fetal growth retardation produced by experimental placental insufficiency in the rhesus monkey. I. Body weight, organ size. Biol Neonate. 1971;18(5):379394. 12. Howarth C, Gazis A, James D. Associations of Type 1 diabetes mellitus, maternal vascular disease and complications of pregnancy. Diabet Med. 2007;24(11):12291234. 13. Kanaka-Gantenbein C, Mastorakos G, Chrousos GP. Endocrine-related causes and consequences of intrauterine growth retardation. Ann N Y Acad Sci. 2003;997:150157. 14. Ward JW, Wooding FB, Fowden AL. Ovine feto-placental metabolism. J Physiol. 2004; 554(Pt 2):529541. 15. de Onis M, Villar J, Gulmezoglu M. Nutritional interventions to prevent intrauterine growth retardation: evidence from randomized controlled trials. Eur J Clin Nutr. 1998;52(Suppl 1):S83S93. 16. Shiell AW, Campbell DM, Hall MH, Barker DJ. Diet in late pregnancy and glucose-insulin metabolism of the offspring 40 years later. BJOG 2000;107(7):890895. 17. McMillen IC, MacLaughlin SM, Muhlhausler BS, Gentili S, Duffield JL, Morrison JL. Developmental origins of adult health and disease: the role of periconceptional and foetal nutrition. Basic Clin Pharmacol Toxicol. 2008;102(2):8289. 18. Wu G, Bazer FW, Cudd TA, Meininger CJ, Spencer TE. Maternal nutrition and fetal development. J Nutr. 2004;134(9):21692172. 19. Georgieff MK. The role of iron in neurodevelopment: fetal iron deficiency and the developing hippocampus. Biochem Soc Trans. 2008;36(pt 6):12671271. 20. Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008;359(1):6173. 21. Scholl TO. Maternal nutrition before and during pregnancy. Nestle Nutr Workshop Ser Pediatr Program. 2008;61:7989. 22. Martin-Gronert MS, Ozanne SE. Maternal nutrition during pregnancy and health of the offspring. Biochem Soc Trans. 2006;34(pt 5):779782. 23. Morton SMB. Maternal nutrition and fetal growth and development. In: Gluckman P, Hanson M, eds. Developmental 24. Lanham SA, Roberts C, Cooper C, Oreffo RO. Intrauterine programming of bone. Part 1: alteration of the osteogenic environment. Osteoporos Int. 2008;19(2):147156. 25. Lanham SA, Roberts C, Perry MJ, Cooper C, Oreffo RO. Intrauterine programming of bone. Part 2: alteration of skeletal structure. Osteoporos Int. 2008; 19(2):157167. 26. Thomas M, Weisman SM. Calcium supplementation during pregnancy and lactation: effects on the mother and the fetus. Am J Obstet Gynecol. 2006;194(4):937945. 27. Rao R, Georgieff MK. Iron in fetal and neonatal nutrition. Semin Fetal Neonatal Med. 2007;12(1):5463. 28. Yajnik CS, Deshmukh US. Maternal nutrition, intrauterine programming and consequential risks in the offspring. Rev Endocr Metab Disord. 2008;9(3):203211.
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29. Ramakrishan U, Manjrekar R, Rivera J, Gonzales-Cossio T. Micronutrients and pregnancy outcome : A review of the literature. Nutr Res. 1999;19:103159. 30. Shah PS, Ohlsson A. Effects of prenatal multimicronutrient supplementation on pregnancy outcomes: a meta-analysis. CMAJ. 2009;180(12):E99108. 31. Fowden AL, Ward JW, Forhead A. Control of fetal metabolism: relevance to developmental origins of health and disease. In: Gluckman P, Hanson M, eds. Developmental Origins of Health and Disease. UK: Cambridge University Press; 2006:143158. 32. Fowden AL, Forhead A. The role of hormones in intrauterine development. In: Barker DJP, ed. Fetal Origins of Cardiovascular and Lung Disease. New York, NY: Marcel Dekker Inc; 2000:199228. 33. Sloboda D, Newnham J, Moss T, Challis J. The fetal hypothalamic-pituitary-adrenal axis: relevance to developmental origins of health and disease. In: Gluckman P, Hanson M, eds. Developmental Origins of Health and Disease. UK: Cambridge University Press; 2006:191-205. 34. Dobbing J, Sands J. Comparative aspects of the brain growth spurt. Early Hum Dev. 1979;3(1):7983. 35. OConner TG, Heron J, Golding J, Glover V. Maternal antenatal anxiety and behavioural/emotional problems in children: A test of a programming hypothesis. J Child Psychol Psychiatry. 2003;44:10251036. 36. Welberg L, Seckl J. Prenatal stress, glucocorticoids and the programming of the brain. J Neuroendocrinol. 2001;13(2):113128. 37. Seckl JR, Holmes MC. Mechanisms of disease: glucocorticoids, their placental metabolism and fetal programming of adult pathophysiology. Nat Clin Pract Endocrinol Metab. 2007;3(6):479488. 38. Adam TC, Epel ES. Stress, eating and the reward system. Physiol Behav. 2007;91(4):449458. 39. McCance RA. Food, growth, and time. Lancet. 1962;2(7258):671676. 40. Widdowson EM, McCance RA. A review: new thoughts on growth. Pediatr Res. 1975;9(3):154156. 41. Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet. 1986;1(8489):10771081. 42. Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet. 1989;2(8663):577580. 43. Barker DJP, Osmond C, Simmonds SJ, Wield GA. The relation of small head circumference and thinness at birth to death from cardiovascular disease in adult life. Br Med J. 1993;306:422426. 44. Frankel S, Elwood P, Sweetnam P, Yarnell J, Smith GD. Birthweight, body-mass index in middle age, and incident coronary heart disease. Lancet. 1996; 348(9040):14781480. 45. Stein CE, Fall CH, Kumaran K, Osmond C, Cox V, Barker DJ. Fetal growth and coronary heart disease in south India. Lancet. 1996;348(9037):12691273. 46. Leon DA, Lithell HO, Vagero D, et al. Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15,000 Swedish men and women born 191529. BMJ. 1998;317(7153):241245.
47. Forsen T, Osmond C, Eriksson JG, Barker DJ. Growth of girls who later develop coronary heart disease. Heart. 2004;90(1):2024. 48. Huxley RR, Shiell AW, Law CM. The role of size at birth and postnatal catch-up growth in determining systolic blood pressure: a systematic review of the literature. J Hypertens. 2000;18(7):815831. 49. Newsome CA, Shiell AW, Fall CH, et al. Is birth weight related to later glucose and insulin metabolism?A systematic review. Diabet Med. 2003;20(5):339348. 50. Dabelea D, Pettitt DJ. Intrauterine diabetic environment confers risks for type 2 diabetes mellitus and obesity in the offspring, in addition to genetic susceptibility. J Pediatr Endocrinol Metab. 2001;14(8):10851091. 51. McCance DR, Pettitt DJ, Hanson RL, et al. Birth weight and non-insulin dependent diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype? BMJ. 1994;308(6934):942945. 52. Fall CH, Osmond C, Barker DJ, et al. Fetal and infant growth and cardiovascular risk factors in women. BMJ. 1995;310(6977):428432. 53. Eriksson JG, Forsen T, Tuomilehto J, Winter PD, Osmond C, Barker DJ. Catch-up growth in childhood and death from coronary heart disease: longitudinal study. BMJ. 1999;318(7181):427431. 54. Eriksson JG, Forsen T, Tuomilehto J, Osmond C, Barker DJ. Early growth and coronary heart disease in later life: longitudinal study. BMJ. 2001;322(7292):949953. 55. Rich-Edwards JW, Kleinman K, Michels KB, et al. Longitudinal study of birth weight and adult body mass index in predicting risk of coronary heart disease and stroke in women. BMJ. 2005;330(7500):1115. 56. Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992;35(7):595601. 57. Ozanne SE, Hales CN. Early programming of glucose-insulin metabolism. Trends Endocrinol Metab. 2002;13(9):368373. 58. Lucas A. Programming by early nutrition in man. Ciba Found Symp. 1991;156:3850. 59. Monteiro PO, Victora CG. Rapid growth in infancy and childhood and obesity in later lifea systematic review. Obes Rev. 2005;6(2):143154. 60. Baird J, Fisher D, Lucas P, et al. Being big or growing fast: systematic review of size and growth in infancy and later obesity. BMJ. 2005;331(7522):929. 61. Stettler N, Zemel BS, Kumanyika S, Stallings VA. Infant weight gain and childhood overweight status in a multicenter, cohort study. Pediatrics. 2002;109(2):194199. 62. Stettler N, Kumanyika SK, Katz SH, Zemel BS, Stallings VA. Rapid weight gain during infancy and obesity in young adulthood in a cohort of African Americans. Am J Clin Nutr. 2003;77(6):13741378. 63. Dennison BA, Edmunds LS, Stratton HH, Pruzek RM. Rapid infant weight gain predicts childhood overweight. Obesity. 2006;14(3):491499. 64. Stettler N, Stallings VA, Troxel AB, et al. Weight gain in the first week of life and overweight in adulthood: a cohort study of European American subjects fed infant formula. Circulation. 2005;111(15):18971903.
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65. Singhal A, Cole TJ, Fewtrell M, et al. Promotion of faster weight gain in infants born small for gestational age: is there an adverse effect on later blood pressure? Circulation. 2007;115(2):213220. 66. Ben Shlomo Y, McCarthy A, Hughes R, Tilling K, Davies D, Smith GD. Immediate postnatal growth is associated with blood pressure in young adulthood: the Barry Caerphilly Growth Study. Hypertension. 2008;52(4):638644. 67. Cianfarani S, Germani D, Branca F. Low birthweight and adult insulin resistance: the catch-up growth hypothesis. Arch Dis Child. Fetal Neonatal Ed. 1999;81(1):F71F73. 68. Gluckman PD, Hanson MA. The consequences of being born smallan adaptive perspective. Horm Res. 2006;65(Suppl 3):514. 69. Singhal A, Lucas A. Early origins of cardiovascular disease: is there a unifying hypothesis? Lancet. 2004;363(9421):16421645. 70. Singhal A, Cole TJ, Fewtrell M, Lucas A. Breastmilk feeding and lipoprotein profile in adolescents born preterm: follow-up of a prospective randomised study. Lancet. 2004;363(9421):15711578. 71. Singhal A, Cole TJ, Lucas A. Early nutrition in preterm infants and later blood pressure: two cohorts after randomised trials. Lancet. 2001;357(9254):413419. 72. Singhal A, Farooqi IS, ORahilly S, Cole TJ, Fewtrell M, Lucas A. Early nutrition and leptin concentrations in later life. Am J Clin Nutr. 2002;75(6):993999. 73. Singhal A, Fewtrell M, Cole TJ, Lucas A. Low nutrient intake and early growth for later insulin resistance in adolescents born preterm. Lancet. 2003;361(9363):10891097. 74. Lucas A, Fewtrell MS, Morley R, et al. Randomized trial of nutrient-enriched formula versus standard formula for postdischarge preterm infants. Pediatrics. 2001;108(3):703711. 75. Chan GM. Growth and bone mineral status of discharged very low birth weight infants fed different formulas or human milk. J Pediatr. 1993;123(3):439443. 76. Fewtrell MS, Prentice A, Jones SC, et al. Bone mineralization and turnover in preterm infants at 8-12 years of age: the effect of early diet. J Bone Miner Res. 1999;14(5):810820. 77. Victora CG, Barros FC, Horta BL, Martorell R. Short-term benefits of catch-up growth for small-for-gestational-age infants. Int J Epidemiol. 2001;30(6):13251330. 78. Ozanne SE. Metabolic programming in animals. Br Med Bull. 2001;60:143152. 79. Armitage JA, Khan IY, Taylor PD, Nathanielsz PW, Poston L. Developmental programming of the metabolic syndrome by maternal nutritional imbalance: how strong is the evidence from experimental models in mammals? J Physiol. 2004;561(Pt 2):355377. 80. Desai M, Crowther NJ, Lucas A, Hales CN. Organ-selective growth in the offspring of protein-restricted mothers. Br J Nutr. 1996;76(4):591603. 81. Ojeda NB, Grigore D, Alexander BT. Developmental programming of hypertension: insight from animal models of nutritional manipulation. Hypertension. 2008; 52(1):4450.
82. Vickers MH, Breier BH, Cutfield WS, Hofman PL, Gluckman PD. Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. Am J Physiol Endocrinol Metab. 2000;279(1):E83E87. 83. Woodall SM, Johnston BM, Breier BH, Gluckman PD. Chronic maternal undernutrition in the rat leads to delayed postnatal growth and elevated blood pressure of offspring. Pediatr Res. 1996;40(3):438443. 84. Bouret SG, Simerly RB. Developmental programming of hypothalamic feeding circuits. Clin Genet. 2006;70(4):295301. 85. Langley-Evans SC, Bellinger L, McMullen S. Animal models of programming: early life influences on appetite and feeding behaviour. Matern Child Nutr. 2005;1(3):142148. 86. Drake AJ, Tang JI, Nyirenda MJ. Mechanisms underlying the role of glucocorticoids in the early life programming of adult disease. Clin Sci. (Lond) 2007;113(5):219232. 87. Fowden AL, Forhead AJ. Endocrine mechanisms of intrauterine programming. Reproduction. 2004;127(5):515526. 88. Barker DJ, Shiell AW, Barker ME, Law CM. Growth in utero and blood pressure levels in the next generation. J Hypertens. 2000;18(7):843846. 89. Stein AD, Lumey LH. The relationship between maternal and offspring birth weights after maternal prenatal famine exposure: the Dutch Famine Birth Cohort Study. Hum Biol. 2000;72(4):641654. 90. Pembrey ME, Bygren LO, Kaati G, et al. Sex-specific, maleline transgenerational responses in humans. Eur J Hum Genet. 2006;14(2):159166. 91. Heijmans BT, Tobi EW, Stein AD, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci. USA 2008;105(44):1704617049. 92. Fewtrell MS, Williams JE, Singhal A, Murgatroyd PR, Fuller N, Lucas A. Early diet and peak bone mass: 20 year follow-up of a randomized trial of early diet in infants born preterm. Bone. 2009;45(1):142149. 93. Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole WK. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics. 2006;117(4):12531261. 94. Beardsall K, Diderholm BM, Dunger DB. Insulin and carbohydrate metabolism. Best Pract Res Clin Endocrinol Metab. 2008; 22(1):4155. 95. Alexe DM, Syridou G, Petridou ET. Determinants of early life leptin levels and later life degenerative outcomes. Clin Med Res. 2006;4(4):326335. 96. Palou A, Pico C. Leptin intake during lactation prevents obesity and affects food intake and food preferences in later life. Appetite. 2009;52(1):249252. 97. Stocker CJ, Cawthorne MA. The influence of leptin on early life programming of obesity. Trends Biotechnol. 2008;26(10):545551. 98. Zeisel SH. Nutrigenomics and metabolomics will change clinical nutrition and public health practice: insights from studies on dietary requirements for choline. Am J Clin Nutr. 2007;86(3):542548.
Human Milk
Jacqueline J. Wessel, RD, CNSD
11
Learning Objectives
120 121 122 122 123 123 123 124 125
CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Breastfeeding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Preterm Breast Milk. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fortification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Banked Human Milk. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Growth of Breastfed Infants. . . . . . . . . . . . . . . . . . . . . . . Breast Milk Safety and Administration . . . . . . . . . . . . . . Breast Milk and Maternal Medications . . . . . . . . . . . . . .
1. List 3 benefits of the use of human milk for the infant. 2. Describe the 10 steps to successful breastfeeding. 3. State the American Academy of Pediatrics recommendation for the use of vitamin D with an exclusively human milk fed infant. Breastfeeding is advocated throughout the world. The American Academy of Pediatrics (AAP), the Canadian Pediatric Society, the International Pediatric Association, the World Health Organization (WHO), and others all have policies that recommend breastfeeding as the preferred method of feeding for infants.14 The Healthy People 2010 goals proposed by the United States Surgeon General include breastfeeding initiation rates of 75% and continued breastfeeding rates of 50% at 6 months and 25% at 12 months5 which are close to being achieved nationally although significant state-to-state variability remains.6 The advantages of breastfeeding are numerous and include nutritional, immunologic, bonding, and societal benefits (Table 11-1). Some of this may be attributed to the establishment of beneficial bacteria in the gastrointestinal tract of the infant through the use of breast milk which contains probiotics, especially Bifidobacterium bifidum and Lactobacillus. Breastmilk also contains growth factors, including oligosaccharides, that promote the growth of these bacteria and are generally called probiotics.7 The bifidus flora of the breastfed infant is thought to activate the immune system and defend against pathogens.8 The colonization of breastfed infants gastrointestinal tracts has been different than that of formula-fed infants. This may be changing as prebiotics and probiotics have now been added to some infant formulas in an effort to duplicate this benefit.9
Introduction
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Table 11-1 Benefits of Breastfeeding Improved mother-infant bonding More rapid uterine involution Mother Postpartum weight loss Decreased incidence of premenopausal breast cancer Decreased incidence of ovarian cancer May protect against development of osteoporosis Antibacterial factors: Secretory IgA, IgM, IgG, IgD, Bifidobacterium growth factor, lactoferrin, complement C1-9, factor binding proteins, lysozyme, lactoperoxidase, macrophages, neutrophils, B and T lymphocytes, lipid, growth factors, nucleotides, vitamins A, E, C1,10,11 Infant Decreased incidence of gastrointestinal illness, respiratory illness, otitis media, urinary tract infections, sudden infant death syndrome1217 Lower incidence of allergies, even with a family history of atopy1822 May have lower incidence of later chronic diseases such as Crohns disease, lymphoma, specific genotypes of diabetes mellitus type 12326 Society Reduced time off work for mothers of breastfed infants for infants illness Reduced health care costs1
Table 11-2 Ten Steps to Successful Breastfeeding3

Every facility providing maternity services and care for newborn infants should:
1. Have a written breastfeeding policy that is routinely communicated to all health care staff. 2. Train all health care staff in skills necessary to implement this policy. 3. Inform all pregnant women about the benefits and management ofbreastfeeding. 4. Help mothers initiate breastfeeding within 30 minutes after birth. 5. Show mothers how to breastfeed and how to maintain lactation even if they should be separated from their infants. 6. Give newborn infants no food or drink other than breast milk, unlessmedically indicated. 7. Practice rooming inallow mothers and infants to remain together24 hours a day. 8. Encourage breastfeeding on demand. 9. Give no artificial teats or pacifiers (also called dummies or soothers) to breastfeeding infants. 10. Foster the establishment of breastfeeding support groups and refer mothers to them on discharge from the hospital or clinic. Reprinted with permission from Baby-Friendly USA Web site, http://www.babyfriendlyusa.org. Accessed December 31, 2009.
For the premature infant the use of breast milk may offera particular advantage in decreasing the incidence of necrotizing enterocolitis (NEC).2729 Research by MeinzenDerr suggested a dose-related association of breast milk feeding with a reduction in risk of NEC or death in extremely low birthweight infants.28 However, in a randomized trial of extremely premature infants, there was no difference in the incidence of NEC between the group of infants fed donor human milk and those fed preterm formula. 30 Kleinman, Walker, and Schanler have suggested a protective effect against infection in premature infants who are fed their own mothers milk. 31,32
Breastfeeding
In 1991 the WHO and United Nations International Childrens Fund (UNICEF) established an international program to promote breastfeeding, the Baby Friendly Hospital Initiative (BFHI).3 This incorporated a 10-step program to promote and support breastfeeding (Table 11-2).
The management of the breastfeeding dyad requires skill and knowledge to achieve a successful outcome for both the mother and infant. Unfortunately, there are still reports of hypernatremic dehydration among exclusively breastfed neonates due to inadequate intake with potentially devastating consequences. The recommendation from analyses of these reports is for close and regular follow-up of breastfed infants by a health care provider. 3335 Evidence-based guidelines from the Academy of Breastfeeding Medicine are available that provide recommendations for best practice in the management of term, near-term (3537 week), and premature infants. 3638 Late preterm (near-term) infants with gestational ages between 3436 6/7 weeks are at particular risk for lactation problems as these infants may appear to be competent early in breastfeeding when they are not and may fool even experienced mothers. These infants may have difficulty extracting milk and stimulating the mother to produce an adequate milk supply. 39 Late preterm infants are more likely to require rehospitalization in the first 2 weeks after birth and have poor lactation outcomes such as early cessation of breastfeeding, jaundice, dehydration, and poor growth.40 Their mothers are also at risk for delayed lactogenesis.40 Meier et al. and Wight describe strategies to work with the motherinfant dyad in establishing and maintaining maternal milk supply and adequate intake for the infant. 39,40
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The mothers of premature or sick term infants have the challenge of pumping breast milk. Strategies to facilitate pumping are available.41 A discussion of these is beyond the scope of this chapter and interested readers are referred to the book by Wight et al and to several works by Paula Meier PhD RN. She has written extensively on the promotion of lactation in an inner-city newborn intensive care unit (NICU) setting,42 evaluation of the efficiency of different breast pumps,43 and the role of nipple shields in facilitating milk transfer for preterm infants.44 Breast milk from mothers of preterm infants often may have increased amounts of protein, sodium, chloride, and iron for 3 weeks45 to approximately 1 month after delivery.46 For optimal growth preterm infants need augmentation of breast milk due to their increased needs for protein, phosphorus, calcium, and zinc.4749 Previously it was thought that, at least in terms of bone mineralization, as infants born prematurely grew into childhood their bone density would normalize. A new study by Chan et al demonstrated that premature infants, < 1.5 kg at birth, continue to show lower bone mineral content and density and tend to be significantly smaller for age than their term counterparts when studied at 5 to 9 years of age. 50 Fortification is an acceptable method of augmenting breast milk for a premature infant.27,47,48 There are different methods of fortification that can be utilized including powdered human milk fortifier or mixing higher calorie (30 calorie) premature formula in a 1:1 mixture or other ratios with breast milk. The final nutrient content can vary significantly depending on the fortifier selected (Table 11-3). Many prefer human milk fortifier in order to use the maximal amount of human milk. There is an increase in osmolality when the fortifier is added to breast milk, 51 but there appears to be no difference in the incidence of side effects,48 NEC, 52 or altered gastric emptying. 53 A liquid fortifier, Prolact+4 H 2MF, is made from human milk and comes as +6, +8, and +10 with increasing amounts of calories and protein. 54 This product is much more expensive than traditional human milk fortifiers.
Table 11-3 Nutrient Composition of Human Milk and Fortified Human Milk Based on Intake of 150 mL/kg5459
Calories Protein Calcium Phosphorus
Preterm Breast Milk
Preterm Milk Term Milk Preterm milk with Enfamil Human Milk Fortifier with iron Preterm milk with Similac Human Milk Fortifier Preterm/term milk 1:1 with Similac Special Care 30 cal/oz Prolact+4 H2MF Recommended Intake for preterm infants
101 cal/kg 102 cal/kg mixed to 120 cal/kg 120 cal/kg
2.1 g/kg 1.5 g/kg 3.75 g/kg
37.5 mg/kg 19.5 mg/kg 42 mg/kg 21 mg/kg 172.5 mg/ kg 207 mg/kg 94.5 mg/kg
3.6 g/kg
117 mg/kg
4.35 g/kg preterm milk 125 cal/kg 174 mg/kg 95.6 mg/kg 3.75 g/kg term milk Fortifies up Added Added 120 cal/kg minerals to 3.45 g/kg minerals 120 cal/kg 3-4 g/kg/d 120-230 mg/kg 60-140 mg/ kg
Fortification
Sometimes due to a disease process a term infant cannot tolerate full volume feedings. In this case higher calorie human milk can be made, but not using the same products that are used for the preterm infant as the levels of calcium and phosphorus may be too high. An individualized approach is necessary based on the prescribed volume and the calorie, protein, and mineral needs for that infant. Term infant formula may be used to augment breast milk to keep a good protein, carbohydrate, and lipid ratio. A concept sometimes called lacto engineering may also be used to increase calories, using the higher calorie hind milk to augment the caloric content of the milk. This will not alter the need for fortification for a preterm infant, but it can help supply additional calories. A creamatocrit is a measurement for estimating the fat content and therefore the caloric content of a human milk sample. A microhematocrit tube is filled with milk and spun in a centrifuge. The layer of fat is measured as with a blood hematocrit.60,61 Regression equations are as follows: Fresh breast milk: Energy(kcal/dL) = 5.99 creamatocrit (%) + 32.5 and Frozen breast milk: Energy (kcal/dL) = 6.20 creamatocrit (%) + 35.1.62 Research is being conducted on the content of hind milk. There appear to be no significant differences in creamatocrit values of the milk of mothers of preterm, small for gestational age, and term infants.63 The creamatocrit values appear to increase until 16 weeks postpartum and then
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decline.63 The circadian variation of fat content in human milk has been evaluated, and although spot values may be misleading, consistent sampling does show a trend in 2 studies for samples expressed at night to have greater fat content.64,65 The vitamin A and E levels also appear to be 1.6 times higher in hind than foremilk, something to consider when planning fortification.66 Medela has a commercial, easy-to-use creamtocrit instrument that also computes the calories per ounce and fat grams.67 Validation studies and tests using creamatocrit measurements performed by mothers have also been done.6870 There has been controversy concerning the effect of iron as one of the ingredients in human milk fortifiers on the antimicrobial properties of human milk. A reduced antimicrobial effect of human milk with an iron-containing fortifier has been demonstrated against Escherichia coli (E. coli), Staphylococcus, Enterobacter sakazakaii (E. sakazakaii), and Group B streptococcus in one study,71 and against E. coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans in a second study 72 when these organisms were added to human milk. A proposed explanation is the effect of iron on the antibacterial effects of lactoferrin, which is diminished when lactoferrin is saturated with iron.71 In another study, no effect was seen in the counts of resident flora and E. sakazakaii using fortifiers added to fresh milk in a time span of 6 hours.73 The human milk-derived fortifier when added to breast milk did not affect the antimicrobial properties of the milk.74
Banked Human Milk
Banked donor pasteurized human milk is used in many nurseries, either as a bridge to feed early if the mothers own milk is not yet in, or as a substitute for the mother who cannot supply sufficient milk or who has chosen not to pump. Some nurseries use donor milk in the first few weeks after delivery as that is the peak time for contracting NEC. Donor milk may be collected from preterm or term mothers; obviously there is a much greater pool available from mothers of term infants. The pasteurization in particular alters some of the properties of human milk.46 If donor-banked term milk is used for a preterm infant, there will be increased needs for supplemental protein, calcium, and phosphorus as the levels of these nutrients are lower in donor term milk than in preterm milk.75 The latest statement regarding vitamin D from the AAP is to supplement with 400 International Units per day beginning soon after birth.76 This replaces the 2003 statement that recommended 200 International Units
beginning in the first 2 months after birth.77 Rickets, an example of extreme vitamin D deficiency, continues to be reported in the United States and other Western countries, predominantly in the breastfed population and in infants with darker skin pigmentation.78,79 Historically we relied upon the effect of sunlight on our skin to stimulate synthesis of vitamin D from cholesterol as our main source. There is normally very little vitamin D in breast milk. In a lactating mother supplemented with 400 International Units of vitamin D, the vitamin content of her own milk ranges from < 25 to 78 International Units/L.80 There is some research on providing women with very large doses of vitamin D, thereby increasing the content of their milk. At this time there is a need for research concerning the safety and efficacy of this method prior to recommendation to a larger population.80 There is also now concern about the age at which direct sunlight exposure is initiated, with the current recommendation that infants under 6 months be kept out of direct sunlight.81 In following these guidelines, vitamin D supplementation is necessary. More vitamin D-only products are now made and are included in the new paper on vitamin D.76 The iron content in human milk is very low, although more bioavailable compared to iron in iron-fortified infant formula.82 Iron needs in the first 6 months of life for a breastfed infant rely on the infants stores at birth. 82 In healthy breastfed term infants iron deficiency before 6 months of age is observed but uncommon. Typically at 4 to 6 months, iron-rich complementary foods are added, although the newer guidelines are for exclusive breastfeeding for 6 months.83 Premature infants do not have the same iron stores as term infants, and infants who are hospitalized may have blood sampled for testing, further depleting their iron stores. Premature infants typically receive iron supplementation due to their low stores at birth and beneficial effect has been documented in the literature.84 Iron deficiency in infants is concerning as it appears to lead to developmental delay, which is irreversible.84 Infants who are breastfed exclusively for 6 months may be at increased risk of iron deficiency. 82 Ziegler et al studied the effect of early (at 1 month) iron administration on breastfed term infants. 85 Early supplementation was feasible and well tolerated by most infants. 86
Vitamin D
Growth of Breastfed Infants
Growth of breastfed infants differs from formula-fed infants. The WHO has published a growth curve87 based on infant growth data from one site in the United States as well as sites in Brazil, Ghana, India, Norway, and Oman.
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The intention was to choose sites where breastfeeding was commonly practiced and provide lactation support to mothers to help them comply with the feeding standards required to construct this growth curve. The factors were: exclusive or predominate breastfeeding for the first 4 months, introduction of complementary food between 4 and 6 months, and partial breastfeeding to be continued until at least 12 months.88 Comparing the 2000 Centers for Disease Control and Prevention (CDC) growth curve to the WHO curve, there are notable differences in the growth trajectory of breastfed infants, with breastfed infants growing more rapidly in the first 2 months and less rapidly from 3 to 12 months in relation to the CDC curve. Linear growth is higher until 4 months. The growth trajectories show that infants in the CDC curve are heavier and shorter than the WHO reference population.89 In 2001, a powdered infant formula, Portagen (which was not a standard formula for preterm infants), was used and prepared in a NICU for preterm infants. A 33-week infant became ill and died; the cerebral spinal culture grew E. sakazakaii. Because this is a rare cause of neonatal meningitis, the state health board and the CDC became involved. In the investigation it was shown that not only opened cans of the formula contained the bacteria but also the unopened cans as well. This launched an investigation into the bacterial counts of powdered formula, for unlike liquid concentrate or ready to feed, it is not sterile.90,91 In the guidelines issued by the CDC in 2002, it stated that formula products should be based on nutrition needs with alternatives to powder forms used whenever possible; and hang times limited to 4 hours.90 The Food and Drug Administration issued a letter to professionals with similar recommendations.92 This has implications for the use of powdered human milk fortifiers as well as the use of expressed breast milk. Safety remains a paramount concern in the provision of any nutrition to the preterm or term infant. Detailed guidelines published by the American Dietetic Association (ADA) have been established for the collection, labeling, transporting, storage, and administration of expressed breast milk.93 The Human Milk Banking Association of North America also published guidelines for the handling of breast milk in hospitals, daycare settings, and the home.94 The following are some of the ADA key points: Mothers are encouraged to express milk ideally as soon as possible after birth (or breastfeed if the infant is able).93 Mothers are encouraged to pump every 2 to 3 hours or at least 8 times in 24 hours using a hospital grade pump, using a double kit to not only save time but also
Breast Milk Safety and Administration
increase hormone levels, leading to increased milk production.9395 Breast milk should be stored in sterile or aseptic food grade plastic or glass containers that are built to withstand long-term freezing. They need to have close-fitting caps that provide an airtight closure; a nipple is not an acceptable cap.93 Labels should include the name of the contents: expressed breast milk, infants name, medical record or identification number, date and time of milk expressed, medications or supplements taken by the mother, whether the milk is fresh or frozen, date and time of milk thawed, and expiration. The expiration will depend on whether the milk is fresh or frozen. Labels should be made of a material that the writing on the label can still be read after freezing and moisture.93 Frozen milk should not be transported in ice as ice is warmer than frozen milk and could thaw the milk. Blue ice containers freeze at a colder temperature and are acceptable for use.93 Length of time milk may be stored at different storage temperatures93:
Temperature Length of Time Recommended
Storage Method
Room temperature Cooler with ice packs Refrigerator, thawedmilk Refrigerator, fortified milk Refrigerator, fresh milk Freezer, home unit Freezer Freezer
25C, 75F 15C, 59F 4C, 39F 4C, 39F 4C, 39F 20C, 4F 70C, 94F
<4h 24 h 24 h feeding when possible 24 hours 48 h 3 mo 612 mo > 12 mo
As breast milk is not homogenized, separation of fat may occur when breast milk is used in tube feedings. Research has shown a 17% fat loss in intermittent feeding but a 34% loss in a continuous tube feeding.95 While some nurseries never use human milk in a continuous feeding setup due to the losses, others believe that although it is not ideal it is the best therapy for the infant and they will accept, and try to minimize, the losses via the tube. These techniques include using a shortened tubing length and tilting the feeding pump syringe upward,96 as well as transitioning to bolus feedings when possible.93 The hang time for breast milk should be 4 hours and the syringe and tubing should be changed every 4 hours aswell.93
HUMAN MILK
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Only the milk to be given per feed should be warmed. Excessive heat could harm the infant and destroy factors such as IgA and enzymes. Any milk left in a bottle should be discarded.93 Hospitals should have policies to cover the misadministration of breast milk. Unfortunately this continues to be a problem in nurseries, and strategies have been employed to decrease the incidence of misadministration.9799 A thorough schematic is presented in the ADA manual.93 In addition to concerns about bacterial contamination, cytomegalovirus (CMV) in breast milk has been addressed. Freezing at 20C has been discussed as a method of decreasing the viral load of CMV in breast milk. Freezing at this temperature does not appear to decrease secretory IgA, lysozyme, lactoferrin, C3 complement, or the function of cells in breast milk.100 While freezing at 20C for various time periods does appear in studies to decrease viability of CMV, it is not certain what freezing time period is safe for high viral loads and what would be necessary to achieve 100% inactivity. A full discussion of this issue is beyond the scope of this article, and a review of the topic is available.101 Health professionals are often asked questions about the use of medications in mothers who are lactating. Riordan and Auerbach state that there are 3 knowns about medications and breast milk: (1) most drugs pass into breast milk; (2) almost all medication appears in only small amounts, usually less than 1% of the maternal dosage; and (3) very few drugs are contraindicated for breastfeeding women.102,103 That does not mean, however, that caution should not be taken when prescribing medications to lactating women. Hales Medications and Mothers Milk is a useful reference that is updated regularly and compiles the known data about medications, assigning a risk code.104 The evaluation of the safety of medications for premature infants depends on 3 factors according to Hale: the amount of medication in the milk, the oral bioavailability of the medication, and the ability of the infant to clear the medication.105 Some of the drugs of concern in general are the chemotherapeutic agents, radioactive isotopes, drugs of abuse, lithium, ergotamine, and drugs that suppress lactation. Antihistamines may reduce milk supply.105
1. Why is the late preterm infant at particular risk for lactation problems? A. The infant may be mislabeled as a term infant and treated as such. B. The infant may have difficulty extracting milk sufficiently. C. The infant appears competent at breastfeeding when he or she is not. D. The mothers of these infants are at risk for delayed lactogenesis. E. All of the above. 2. Can the use of higher calorie hind milk from the use of lactoengineering replace fortification in a preterm infant? A. Yes B. No 3. Could there be nutrition problems affecting growth with the use of donor banked human milk for preterm infants? A. Yes B. No See p. 487 for answers.
Breast Milk and Maternal Medications
References
1. American Academy of Pediatrics, Committee on Nutrition. Kleinman RE, ed. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:55. 2. Canadian Paediatric Society Nutrition Committee, American Association of Pediatrics Committee on Nutrition. Breastfeeding; a commentary in celebration of the international year of the child.1979. Pediatrics. 1978;65:591601. 3. International Pediatric Association: Recommendations for action programmes to encourage breastfeeding. Acta Paediatr Scand. 1976;65:275277. 4. WHO/UNICEF. Protecting, promoting, and supporting breastfeeding; the special role of maternity services, a joint WHO/UNICEF statement. Geneva Switzerland 1989, World Health Organization. 5. US Department of Health and Human Services. Healthy People 2010: Understanding and Improving Health and Objectives for Improving Health. Vols. 1, 2. 2nd ed. Washington, DC: US Dept of Health and Human Services; 2000. 6. Centers for Disease Control and Prevention. Breastfeeding Report Card, United States: Outcome Indicators. http://www. cdc.gov/breastfeeding/data/report_card2.htm.Accessed November 12, 2009. 7. Lawrence RA, Lawrence RM. Breastfeeding: A Guide for the Medical Profession. 6th ed. St. Louis, MO: Mosby; 2005:187.
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8. Fanaro S, Vigi V. Infant formulas supplemented with prebiotics: intestinal microbiota and immune responses. Minerva Pediatr. 2008;60:327335. 9. Hatakka K, Savilahti E, Ponka A, et al. Effect of long-term consumption of probiotic milk on infections in children attending day care centres: double blind, randomized trial. BMJ. 2001;322:1327. 10. May JT. Microbial contaminants and antimicrobial properties of human milk. Microbiol Sci. 1988;5:4246. 11. Goldman AS, Garza C, Nichols BJ, et al. Immunologic factors in human milk during the first year of lactation. J Pediatr. 1982;100:563. 12. Howie PW, Forsyth JS, Ogston SA, et al. Protective effect of breastfeeding against infection. BMJ. 1990;336:92. 13. Duncan B, Ey J, Holberg CJ, Wright AJ, et al. Exclusive breastfeeding for at least 4 months protects against otitis media. Pediatrics. 1993;91:867872. 14. Aniansson G, Alni B, Andersson A, et al. A prospective cohort study on breastfeeding and otitis media in Swedish infants. Pediatr Infectious Dis J. 1994;12:183188. 15. Paradise JL, Elster BA, Tan L. Evidence in infants with cleft palate that breast milk protects against otitis media. Pediatrics. 1994;94:853860. 16. Pisacane A, Grazione L, Mazzarella G, et al. Breastfeeding and urinary tract infections. J Pediatr. 1992;120:8789. 17. Vennemann MM, Bajanowski T, Brinkman B, et al. Does breastfeeding reduce the risk of sudden infant death syndrome? Pediatrics. 2009;123:e406e410. 18. Saarinen IJM, Kajosaari M, Backnman A, et al. Prolonged breastfeeding as prophylaxis for atopic disease. Lancet. 1979;2:163166. 19. Kramer MS. Does breastfeeding help protect against atopic disease? Biology, methodology and a golden jubilee of controversy. J Pediatr. 1988;112:181190. 20. Thygarejan A, Burks AW. American Academy of Pediatrics recommendations on the effect of early nutritional interventions on the development of atopic disease. Curr Opin Pediatr. 2008;20:698702. 21. Greer FR, Sicherer SH, Burks W, et al. Effects of nutritional interventions on the development of atopic disease in infants and children; the role of maternal diet restriction, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics. 2008;121:183190. 22. Hanson LA, Adlerberth I, Carlsson B, et al. Host defense of the neonate and the intestinal flora. Acta Peadiatric Scand. 1989; 351(suppl):122125. 23. Koletzko S, Sherman P, Corey M, et al. Role of infant feeding practices in development of Crohns disease in childhood. BMJ. 1989;298:16171618. 24. Gerstein HC. Cows milk exposure and type I diabetes mellitus. Diabetes Care. 1994;17:1319. 25. Savilahti E, Saarinen KM. Early infant feeding and type I diabetes. Eur J Nutr. 2009;48(4):243249. 26. Davis MK, Savitz DA, Graubard BI. Infant feeding and childhood cancer. Lancet. 1988;2:365368. 27. Schanler RJ. The use of human milk for premature infants. Pediatr Clin N Am. 2001;48:207219.
28. Meinzen-Derr J, Poindexter B, Wrage L, et al. Role of human milk in extremely low birth weight infants risk of necrotizing enterocolitis or death. J Perinatol. 2009;29:5762. 29. Sisk PM, Lovelady CA, Dillard RG, et al. Early human milk feeding is associated with a lower risk of necrotizing enterocolitis in very low birth weight infants. J Perinatol. 2007;27428433. 30. Schanler RJ, Lau C, Hurst NM, et al. Randomized trial of donor human milk versus preterm formula as substitutes for mothers own milk in the feeding of extremely low birthweight infants. Pediatrics. 2005;116:400406. 31. Schanler RJ. Mothers own milk, donor human milk, and preterm formulas in the feeding of extremely premature infants. J Pediatr Gastroenterol Nutr. 2007;48:S175S177. 32. Kleinman RE, Walker WA. The enteromammary immune system. Dig Dis Sci. 1979;24:876882. 33. Wang AC, Chen SJ, Yuh YS. Breastfeeding associated neonatal hypernatremic dehydration in a medical center: a clinical investigation. Acta Paediat Taiwan. 2007;48:186190. 34. Unal S, Arhan E, Kara N, et al. Breastfeeding associated hypernatremia: retrospective analysis of 169 term newborns. Pediatr Int. 2008;50:2934. 35. Yaseen H, Salem M, Darwich M. Clinical presentation of hypernatremic dehydration in exclusively breastfed neonates. Indian J Pediatrics. 2004;71:10591062. 36. Academy of Breastfeeding Medicine. Guidelines for hospital discharge of the breastfeeding term newborn and mother. Going home protocol. 2007, Sep 2 (3)158165. http://www.guideline.gov/summary/summary.aspx?doc_ id=11556&nbr=5987&ss=15. Accessed November 12, 2009. 37. Academy of Breastfeeding Medicine. Breastfeeding the near term infant (35 to 37 weeks gestation). 2004 Aug 22. http:// www.guideline.gov/summary/summary.aspx?ss=15&doc_ id=11227&nbr=5874. Accessed November 12, 2009. 38. Academy of Breastfeeding Medicine. Transitioning the breastfeeding/breastmilk-fed premature infant from the neonatal intensive care unit to home. 2004 Sep 17. http://www.guideline.gov/summary/summary.aspx?doc_id=11229. Accessed November 12, 2009. 39. Wight N. Breastfeeding the borderline near term infant. Pediatric Ann. 2003;32:329336. 40. Meier PP, Furman LM, Deenhardt M. Increased lactation risk for late preterm infants and mother: evidence and management strategies to protect breastfeeding. J Midwifery Womens Health. 2007;52:579587. 41. Wight NE, Morton JA, Kim JH. Best Medicine Human Milk in the NICU. Amarillo, TX: Hale Publishing, LP; 2008. 42. Meier PP, Engstrom JL, Mingolelli SS, et al. The Rush Mothers Milk Club: Breastfeeding interventions for mothers with very-low-birthweight infants. J Obstet Gynecol Neonatal Nurs. 2004;33:164172. 43. Meier PP, Engstrom JL, Hurst NM, et al. A comparison of the efficiency, comfort and convenience of two hospital-grade electric breast pumps for mothers of very low birth weight infants. Breastfeed Med. 2008;3:141120. 44. Meier PP, Brown LP, Hurst NN, et al. Nipple shields for preterm infants: effect on milk transfer and duration of breastfeeding. J Hum Lact. 2000;16:106114.
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45. Chazpak N, Ruiz JG, KMC Team. Breast milk composition in a cohort of preterm infants mothers followed in a ambulatory program in Colombia. Acta Paediatr. 2007;96:17351739. 46. Lawrence RA, Lawrence RM. Breastfeeding: A Guide for the Medical Profession. 6th ed. St. Louis, MO: Mosby; 2005:445. 47. Morales Y, Schanler RJ. Human milk and clinical outcomes in VLBW infants: how compelling is the evidence of benefit? Semin Perinatol. 2007;31:8388. 48. Mukhopadhyay K, Narang A, Mahajan R. Effect of human milk fortification in appropriate for gestation and small for gestation preterm babies: a randomized trial. Indian Pediatrics. 2007;44:286290. 49. Carey DE, Rowe JS, Goetz CA, et al. Growth and phosphorus metabolism in premature infants fed human milk, fortified human milk, or special premature formula. Am J Dis Child. 1987;141:511. 50. Chan GM, Armstrong C, Moyer-Mileur L, et al. Growth and bone mineralization in children born prematurely. J Perinatol. 2008; 28:619623. 51. Janjindami W, Chotsampancharoen T. Effect of fortification on the osmolality of human milk. J Med Assoc Thai. 2006; 99:14001403. 52. Bhat BA, Gupta B. Effects of human milk fortification on mortality factors in very low birthweight infants. Ann Saudi Med. 2003;23:2831. 53. Yigit S, Akgoz A, Memisoglu A, et al. Breast milk fortification: effect on gastric emptying. J Matern Fetal Neonatal Med. 2008;21;843846. 54. Prolacta Web site. http://www.Prolacta.com. Accessed January 2009. 55. Sapsford A. Composition of human milk and selected enteral products. In: Groh Wargo S, Thompson M, Cox J, eds. Nutritional Care for High Risk Newborns. 3rd ed. Chicago, IL: Precept Press; 2000:664 56. Abbott Nutrition Web site. http://www.abbottnutrition.com/ products. Accessed January 2009. 57. MeadJohnson Nutrition Web site. http://www.mjn.com. Accessed January 2009. 58. Groh Wargo S. Recommended enteral nutrient intakes. In: Groh Wargo S, Thompson M, Cox J, eds. Nutritional Care for High Risk Newborns. 3rd ed. Chicago, IL: Precept Press; 2000:234. 59. Ziegler EE. Protein requirements of very low birth weight infants. J Pediatric Gastroenterol Nutr. 2007;45:S170S174. 60. Lawrence RA, Lawrence RM. Breastfeeding: A Guide for the Medical Profession. 6th ed. St. Louis, MO: Mosby; 2005:693. 61. Lucas A, Gibbs JAH, Lyster RLI, et al. Creamatocrit: simple clinical technique for estimating fat concentration and energy value of human milk. Br Med J. 1978;1:1018. 62. Wang CD, CHU PS, Mellen BG, et al. Creamatocrit and the nutrient composition of human milk. J Perinatol. 1999;19:343346. 63. Chatterjee R, Chatterjee S, Datta T, et al. Longitudinal study of human milk creamatocrit and weight gain in exclusively breastfed infants. Indian Pediatrics. 1997; 34:901904. 64. Lubetsky R, Mimouni FB, Dollberg S, et al. Consistent circadian variations in creamatocrit over the first 7 weeks of lactation: a longitudinal study. Breastfeed Med. 2007;2:1518.
65. Weber A, Loui A, Jochum F, et al. Breast milk from mothers of very low birthweight infants: variability in fat and protein content. Acta Paediatr. 2001;90:772775. 66. Bishara R, Dunn MS, Merko SE, et al. Nutrient composition of hindmilk is produced by mothers of very low birth weight infants born at less than 28 weeks gestation. J Hum Lact. 2008;24:159167. 67. Medala Web site. http://www.medelabreastfeedingus.com/ for-professionals/lc-information. Accessed February 2009. 68. Meier PP, Engstrom JL, Zuleger JL, et al. Accuracy of a userfriendly centrifuge for measuring creamatocrit on mothers milk in a clinical setting. Breastfeed Med. 2006;1:7987. 69. Griffith TL, Meier PP, Bradford LP, et al. Mothers performing creamatocrit measures in the NICU: accuracy, reactions, and cost. J Obstet Gynecol Neonatal Nurs. 2000;29:249257. 70. Meier PP, Engstrom JL, Murtaugh MA, et al. Mothers milk feedings in the neonatal intensive care nursery: accuracy of the creamatocrit technique. J Perinatol. 2002; 22:646649. 71. Chan GM. Effect of powdered human milk fortifier on the antibacterial actions of human milk. J Perinatol. 2003;23:620623. 72. Ovali F, Ciftci I, Cetinkaya Z, et al. Effects of human milk fortifier on the antimicrobial properties of human milk. J Perinatol. 2006;26:761763. 73. Telang S, Berseth CL, Ferguson PW, et al. Fortifying fresh human milk with commercial human milk fortifiers does not affect the bacterial growth during 6 hours at room temperature. J Am Diet Assoc. 2005;105:567572. 74. Chan GM, Lee MI, Rechman DJ. Effects of a human milkderived human milk fortifier on the antibacterial actions of human milk. Breastfeed Med. 2007;2:205208. 75. Wojcik KY, Rechtman DJ, Lee, ML, et al. Macronutrient analysis of a nationwide sample of breast milk. J Am Diet Assoc. 2009; 109:137140. 76. Wagner CL, Greer FR; American Academy of Pediatrics Section on Breastfeeding; American Academy of Pediatrics Committee on Nutrition. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 2008:122:11421152. 77. Gartner LM, Greer FR; American Academy of Pediatrics Section on Breastfeeding; American Academy of Pediatrics Committee on Nutrition. Prevention of rickets and vitamin D deficiency: new guidelines for vitamin D intake. Pediatrics. 2003;111:908910. 78. Kreiter SR, Schwartz RP, Kirkman HN, et al. Nutritional rickets in African American breastfed infants. J Pediatr. 2000;137:153157. 79. Ward LM. Vitamin D deficiency in the 21st century: a persistent problem among Canadian infants and mothers. CMAJ. 2005;172:769770. 80. Wagner CL, Hulsey TC, Fanning D, et al. High dose vitamin D supplementation in a cohort of breastfeeding mothers and their infants; a six month follow-up pilot study. Breastfeed Med. 2006;1:5970. 81. American Academy of Pediatrics, Committee on Environmental Health. Ultraviolet light: a hazard to children. Pediatrics. 1999;104:328333.
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82. American Academy of Pediatrics, Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics. 2005;115:496506. 83. Chantry CJ, Howard CR, Auinger P. Full breastfeeding duration and risk for iron deficiency in U.S. infants. Breastfeeding Med. 2007;2:6373. 84. Steinmacher J, Pohlandt F, Bode H, et al. Randomized trial of early versus late enteral iron supplementation in infants with a birth weight of less than 1301 grams: neurocognitive development at 5.3 years corrected age. Pediatrics. 2007;120:538546. 85. Ziegler EE, Nelson SE, Jeter JM. Iron supplementation of breastfed infants from an early age. Am J Clin Nutr. 2009;89(2):525532. 86. Lozoff B, Jimenez E, Hagen J, et al. Poorer behavioral and developmental outcome more than 10 years after treatment for iron deficiency. Pediatrics. 2000;105:E51. 87. World Health Organization. The WHO Child Growth Standards. www.who.int/childgrowth/standards/en. Accessed January 30, 2009. 88. WHO Multicentre Growth Reference Study Group. Breastfeeding in the WHO Multicentre Growth Reference Study. Acta Paediaticia. 2006;(Suppl)450:1626. 89. de Onis M, Onyango AW. The Centers for Disease Control and Prevention 2000 growth charts and the growth of breastfed infants. Acta Paediatrica. 2003;92:413419. 90. Enterobacter sakazakaii infections associated with the use of powdered infant formulaTennessee 2001. MMWR Weekly. April 12, 2002;298300. 91. Bowen AB, Braden CR. Invasive Enterobacter sakazakaii disease in infants. Emerging Infectious Diseases. August 2006. http://www.cdc.gov/ncidod/EID/vol12no08/05-1509.htm. Accessed November 12, 2009. 92. Food and Drug Administration. Health professionals letter on Enterobacter sakazakii infections associated with use of powdered (dry) infant formulas in neonatal intensive care units. April 11, 2002, revised October 10, 2002.
93. Sapsford A, Lessen R. Expressed human milk. In: Robbins ST, Beker LT, eds. Infant Feedings: Guidelines for Preparation of Formula and Breastmilk in Health Care Facilities. Chicago, IL: American Dietetic Association; 2004. 94. Human Milk Banking Association of North America. 2006 Best Practice for Expressing, Storing and Handling of Mothers Own Milk in Hospital and at Home. Raleigh, NC: Human Milk Banking Association of North America; 2006. 95. Martinez FE, Desai ID, Davidson AGF, et al. Ultrasonic homogenization of expressed human milk to prevent fat loss during tube feeding. J Pediatr Gastroenterol Nutr. 1987;6:593. 96. Narayan I, Singh B, Harvey D. Fat loss during feeding of human milk. Arch Dis Child. 1984; 59:475477. 97. Zeilhofer UB, Frey B, Zandee J, Bernet V. The role of critical incident monitoring in detection and prevention of breast milk confusions. Eur J Pediatr. 2009;168(10):12771279. 98. Dougherty D, Giles V. From breast to bottle: quality assurance for breast milk management. Neonatal Network. 2000; 19:2125. 99. Drenckpohl D, Bowers L, Cooper B. Use of the six signs methodology to reduce incidence of breast milk administration errors in the NICU. Neonatal Network. 2007; 26:161166. 100. Lawrence RA. Storage of human milk and the influence of procedures on immunological components of human milk. Acta Paediatr Suppl. 1999;88:1418. 101. Lawrence RM. Cytomegalus in human breast milk: risk to the premature infant. Breastfeeding Med. 2006;1:99107. 102. Riordan J. Drugs and breastfeeding. In: Riordan J, Auerbach K, eds. Breastfeeding and Human Lactation. 2nd ed. Sudbury, MA: Jones and Bartlett; 1998,163219. 103. American Academy of Pediatrics, Committee on Nutrition. Kleinman RE, ed. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:71. 104. Hale T. Medications and Mothers Milk. 13th ed. Amarillo, TX: Hale Publishing, LP; 2008. 105. Hale T. Medication in breastfeeding mothers of preterm infants. Pediatric Ann. 2003;337347.
Infant Formulas and ComplementaryFeeding

Kelly Green-Corkins, MS, RD, CNSD and Timothy Sentongo, MD
12
CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 Types of Infant Formulas. . . . . . . . . . . . . . . . . . . . . . . . . . 130
Standard Milk-Based Term Infant Formulas Term Formulas Designed for Symptoms of Intolerance Premature or Low Birth Weight Formulas Premature Discharge Formulas Specialized Infant Formulas
Learning Objectives
Functional Ingredients in Infant Formulas. . . . . . . . . . . . 135

DHA/ARA
1. Explain the basis for and regulation of infant formulas. 2. Discuss reasons for functional ingredients in infant formulas. 3. Differentiate infant formulas and target populations. 4. Describe how increased caloric concentrations may influence tolerance. 5. Summarize reasoning behind current guidelines for introducing complementary foods to an infants diet. The World Health Organization recommends human milk as the sole source of nutrition for healthy full-term infants birth to 6 months of age.1 Breastfeeding provides benefits to the infant that infant formula can not. Breastfeeding promotes gastrointestinal development and function, immune support, and neurodevelopment. 2 It is not always possible for a mother to breastfeed, or a mother may choose not to breastfeed due to cultural, social, or health reasons. Iron-fortified infant formulas are appropriate substitutes for human milk. No matter what the choice or reason for not breastfeeding, a mother should be supported in her decision. 3 Because human milk is the optimal source of nutrition for an infant, infant formulas are designed to be similar to human milk and/or to promote a similar response as seen in the breastfed infant.4 Even with the latest functional ingredients added (docosahexaenoic acid [DHA] and arachidonic acid [ARA], nucleotides, probiotics, prebiotics), infant formulas are still not able to provide the hormones, immunoglobulins, enzymes, and live cells that are in human milk. 3 Infant formulas are designed using cows milk or soy as a base. Although infant formula manufacturers will
129
Forms of Infant Formula and Mixing Guidelines . . . . . . . 137 Introducing Complementary Foods to the Infants Diet. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 Toddler Formulas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Introduction
130
never be able to completely replicate human milk, research continues and there are modifications to improve the quality of infantformulas. 3 An infant formula is defined by the Federal Food, Drug, and Cosmetic Act (FDCA) as a food which purports to be or is represented for special dietary use solely as a food for infants by reason of its simulation of human milk or its suitability as a complete or partial substitute for human milk.5 Infant formulas designed to meet a specific medical need (ie, premature infant formulas) are considered exempt because the nutrition requirements of infants with certain medical conditions differ from those of healthy infants. Exempt formulas are not exempt from monitoring or regulation and need to meet certain criteria. All infant formula manufacturers must begin with safe ingredients that are approved for use in infant formulas, or are generally recognized as safe (GRAS). 5 The Infant Formula Act of 1980 (revised 1986), an amendment to the FDCA, was developed due to an incident involving inadequate chloride in a soy-based formula that resulted in metabolic acidosis in several infants.6 The Food and Drug Administration (FDA) is responsible for monitoring the manufacturers that make infant formulas. There are federal regulations on quality control, labeling, nutrient levels, formula recall, new product notification, and exempt products. There are established levels for 29 nutrients and maximum levels for 9 nutrients. Manufacturers are required to declare on the label the levels of each nutrient provided, and the manufacturer must analyze each batch of formula to ensure the declared levels of all essential nutrients are being provided. The FDA reviews the analysis records and will perform tests on the formula to monitor the manufacturers. 5 The concentration of nutrients in infant formula is higher than in human milk because of the decreased bioavailability in infant formula. 3,7
Table 12-1 Infant Formula Manufacturer Web Sites

Manufacturer Product Line Web Site
Regulation
Abbott Nutritionals Mead Johnson Nestle Gerber Nutricia PBM Nutritionals Vitaflo
Similac Enfamil GOOD START Neocate and other products Bright Beginnings Parents Choice some modulars
www.abbottnutrition.com www.meadjohnson.com www.gerber.com www.nutricia-na.com www.pbmproducts.com www.vitaflousa.com
Standard Milk-Based Term Infant Formulas

Standard milk-based infant formulas (Table 12-2) are designed to meet the needs of healthy infants birth to 1 year of age. The protein source is cows milk, which is iron-fortified. Most formula-fed infants will consume one of these products. A subgroup of the standard infant formulas is organic. In order to be labeled organic, the formula ingredients must be certified organic and meet U.S. Department of Agriculture regulations. Ingredients must be produced without pesticides, added growth hormones, or antibiotics.
Term Formulas Designed for Symptoms of Intolerance

Formulas designed for symptoms of intolerance (Table 12-3)are milk-based and are appropriate for the full-term infant. Modifications include partial hydrolysis of the protein, reduced lactose or lactose-free, and added rice starch. Partially Hydrolyzed Protein Formulas containing partially hydrolyzed protein are not considered hypoallergenic and are not intended to be used for treatment of any allergic condition or disease. Partially hydrolyzed formulas contain reduced or no lactose and each product is different in the type of protein hydrolyzed and degree of hydrolysis. Therefore, assumptions can not be made that all partially hydrolyzed protein formulas offer identical benefits.8 The benefits of partially hydrolyzed 100% whey protein have been studied and research demonstrates that it may decrease the risk of atopic dermatitis in infants with a family history of allergic disease. 8 The product containing the partially hydrolyzed 100% whey protein is considered a routine milk-based infant formula. Another product on the market contains partially hydrolyzed whey and casein. This product is marketed for intolerances but does not have research to suggest the
Types of Infant Formulas
Information included in this section and the accompanying tables is up-to-date as of the time of publication. For the most current information, please visit the manufacturers Web sites (Table12-1).
INFANT FORMULAS AND COMPLEMENTARYFEEDING
131
Table 12-2 Standard Milk Based Infant Formulas (per 100 calories) The standard dilution for these products is 0.67 kcal/mL (20 kcal/oz).
Product (Manufacturer) Protein g (% kcal) Source CHO g (% kcal) Source Fat g (% kcal) Source Na mg K mg Ca Phos Fe mg mg mg Osmolal- Comments ity mOsm
Bright Beginnings Milk-based (PBM Nutritionals) Bright Beginnings Organic (PBM Nutritionals)
2.2 (9%) 10.9 (43.6%) nonfat milk, whey lactose protein concentrate 2.2 (9%) organic reduced minerals whey, nonfat milk 2.1 (8.5%) (liquid): reduced minerals whey, nonfat milk (powder): whey protein concentrate, nonfat milk 2.1 (8.5%) whey, nonfat milk 10.6 (42%) lactose
Enfamil LIPIL w/iron (Mead Johnson)
10.9 (43.5%) lactose
5.3 (47.7%) 27 108 82 palm olein, soy oil, coconut oil, high oleic safflower or sunflower oil 5.3 (48%) 23 84 63 organic palm or palm olien, high oleic safflower or sunflower oil, coconut oil, soy oil 5.3 (48%) 27 108 78 palm olein, soy oil, coconut oil, high oleic sunflower oils
43 1.8
added nucleotides
42 1.8
added nucleotides, DHA 17 mg, ARA 34 mg
43 1.8
300
DHA 17 mg, ARA 34 mg PRSL 18.9/100 cals
Enfamil PREMIUM (Mead Johnson)
11 (43.5%) 5.3 (48%) 27 108 78 lactose, galacto- palm olein, soy oil, oligosaccharides coconut oil, high oleic sunflower oils 11.2 (45%) lactose, corn maltodextrin 5.1 (46%) palm olein, soy oil, coconut oil, high oleic safflower or sunflower oil 5.1 (46%) palm olein, soy oil, coconut oil, high oleic safflower or sunflower oil 5.1 (46%) palm olein, soy oil, coconut oil, high oleic safflower or sunflower oil 27 108 67
43 1.8
300
GOOD START Gentle PLUS (Nestle/Gerber)
GOOD START Nourish PLUS (Nestle/Gerber)
GOOD START Protect PLUS (Nestle/Gerber)
5.3 (47.7%) 27 108 palm olein, soy oil, coconut oil, high oleic safflower or sunflower oil Parents Choice Organic 2.2 (9%) 10.6 (42%) 5.3 (48%) 23 84 (PBM Nutritionals) organic reduced organic lactose organic vegetable mineral whey oils (palm or palm olein, high oleic safflower or sunflower, coconut, soy) Similac Advance 2.07 (8%) 11.2 (43%) 5.4 (49%) 24 105 EarlyShield nonfat milk, whey lactose, high oleic safflower (Abbott Nutritionals) protein concentrate galactose oligo- oil, soy oil, coconut saccharides oil (GOS) Similac Organic 2.07 (8%) 10.56 (42%) 5.49 (49%) 24 105 (Abbott Nutritionals) organic nonfat dry organic corn organic high oleic milk maltodextrin, sunflower oil, organic lactose, organic soy oil, organic sugar organic coconut oil
Parents Choice Milk Formula DHA & ARA (PBM Nutritionals)
2.2 (9%) whey protein concentrate (enzymatically hydrolyzed, reduced in minerals) 2.2 (9%) whey protein concentrate (enzymatically hydrolyzed, reduced in minerals) 2.2 (9%) whey protein concentrate (enzymatically hydrolyzed, reduced in minerals) 2.1 (8.4%) nonfat milk, whey protein concentrate
38 1.5
250
added nucleotides 28 mg/L, DHA 17 mg, ARA 34 mg PRSL 19.1/100 cals added prebioticgalactooligosaccharide (GOS) 46 mg added nucleotides, DHA 0.32%, ARA 0.64% PRSL 19.5/100 cals 5 mg added nucleotides PRSL 19.5/100 cals No DHA and ARA
11.2 (45%) lactose, corn maltodextrin
27 108 67
38 1.5
250
11.2 (45%) lactose, corn maltodextrin
27 108 67
38 1.5
250
46 mg added nucleotides, DHA 0.32%, ARA 0.64% PRSL 19.5/100 cals DHA, ARA
10.9 (43.6%) lactose
78
43 1.8
63
42 1.8
DHA, ARA
78
42 1.8
310
added nucleotides, DHA 0.15%, ARA 0.40% PRSL 18.7/100 cals added prebiotics, GOS DHA 0.15%, ARA 0.40% PRSL 18.8/100 cals unmodified whey:casein 18:82
78
42 1.8
225
132
Table 12-3 Infant Formulas for Symptoms of Intolerance (per 100 calories) Standard dilution is 0.67 kcal/mL (20 kcal/oz).
Product (Manufacturer) Protein g (% kcal) Source CHO g (% kcal) Source Fat g (% kcal) Source Na mg K mg Ca mg Phos mg Fe mg Osmolal- Comments ity mOsm
Bright Beginnings Gentle (PBM Nutritionals)
2.3 (9%) 10.8 (43%) nonfat milk, whey corn syrup solids, protein hydrolysate lactose
5.3 (48%) palm olein, coconut oil, soy oil, high oleic safflower or sunflower oil 5.1 (46%) palm olein, soy oil, cocnut oil, high oleic sunflower oil 5.3 (48%) palm olein, soy oil, coconut oil, high oleic sunflower oil
32 108 82
46
1.8
added nucleotides, DHA, ARA
Enfamil AR LIPIL (Mead Johnson)
2.5 (10%) nonfat milk
11 (44%) lactose, rice starch, maltodextrin 10.8 (43%) corn syrup solid, lactose
40 108 78
53
1.8 240 RTU 230 Powder 1.8 220
DHA 17 mg, ARA 34 mg PRSL 22/100 cals DHA 17 mg, ARA 34 mg PRSL 20/100 cals
Enfamil Gentlease LIPIL (Mead)
2.3 (9%) partially hydrolyzed nonfat milk and whey protein concentrate
32 108 82
46
Parents Choice Gentle (PBM Nutritionals)
2.3 (9%) 10.8 (43%) nonfat milk, whey corn syrup solids protein hydrolysate
5.3 (48%) palm olein, cocnut oil, soy oil, high oleic safflower or sunflower oil 5.3 (48%) palm olein, coconut oil, soy oil, high oleic safflower or sunflower oil 5.3 (48%) palm olein, coconut oil, soy oil, high oleic safflower or sunflower oil 5.46 (49%) soy oil, cocnut oil 5.4 (49%) high oleic safflower oil, soy oil, coconut oil 5.4 (49%) high oleic safflower oil, soy oil, coconut oil
32 108 82
46
1.8
DHA, ARA
Parents Choice Lactose Free with Lipids (PBM Nutritionals) Parents Choice Sensitivity (PBM Nutritionals)
2.3 (9%) whey protein concentrate, milk protein isolate 2.6 (10%) milk protein isolate
10.8 (43%) corn syrup solids
32 108 82
46
1.8
DHA, ARA
10.5 (42%) corn syrup solids, sucrose
36 130 195 130
DHA, ARA
Similac Isomil DF 2.66 (11%) 10.1 (40%) (Abbott Nutritionals) soy protein isolate, corn syrup solids, L-methionine sucrose Similac Sensitive 2.14 (9%) (Abbott Nutritionals) milk protein isolate Similac 2.14 (9%) Sensitive RS milk protein (Abbott Nutritionals) isolate 10.7 (43%) corn maltodextrin, sugar 10.7 (43%) corn syrup, rice starch, sugar
44 108 105 75
1.8 240
no DHA or ARA, soy protein DHA 0.15%, ARA 0.40% PRSL 19.9/100 cals DHA 0.15%, ARA 0.40% PRSL 19.9/100 cals
30 107 84
56
1.8 200
30 107 84
56
1.8 180
same potential benefits as the partially hydrolyzed 100% wheyprotein. Lactose-free Lactose is only present in mammalian milk. Lactosefree formulas have similar calorie, protein, fat, and micronutrient content as standard milk-based formulas. Lactose-free formulas, including soy formulas, may be indicated in infants with suspected transient lactase deficiency secondary to gastroenteritis or protracted diarrhea. Parents with lactose intolerance may assume their infants are also
lactose intolerant. However, most babies make adequate amounts of lactase and congenital lactase deficiency is extremely rare. Milk-based lactose-free formulas are not indicated in galactosemia. Added Rice Starch Added rice starch formulas are standard milk-based infant formulas designed to thicken in the acidic environment of the stomach to decrease spitting-up episodes.9 Rice starch is added as part of the carbohydrate content; therefore, the macronutrient distribution remains consistent with
133
Table 12-4 Soy-Based Infant Formulas (per 100 calories) Standard dilution for soy-based formulas is 0.67 kcal/mL (20 kcal/oz).
Enfamil ProSobee 2.5 (10%) 10.6 (42%) LIPIL soy protein isolate, corn syrup solid L-methionine (Mead Johnson) 2.5 (10%) enzymatically hydrolyzed soy protein isolate, L-methionine Similac Isomil 2.45 (10%) Advance soy protein isolate, (Abbott Nutritionals) L-methionine Bright Beginnings 2.5 (10%) Soy soy protein isolate, L-methionine (PBM Nutritionals) Parents Choice Soy DHA and ARA (PBM Nutritionals) 2.5 (10%) soy protein isolate GOOD START Soy PLUS (Nestle/Gerber) 11 (44%) corn maltodextrin, sucrose 10.3 (41%) corn syrup solids, sugar 10.6 (42%) corn syrup solids
10.6 (42%) corn syrup solids
5.3 (48%) palm olein, soy oil, coconut oil, high oleic sunflower oil 5.1 (46%) palm olein, soy oil, coconut oil, high oleic safflower or sunfloweroil 5.46 (49%) high oleic safflower oil, soy oil, cocnut oil 5.3 (48%) palm olein, coconut oil, soy oil, high oleic safflower or sunflower oil 5.3 (48%) palm olein, coconut oil, soy oil, high oleic safflower or sunfloweroil
36
120 105 69
1.8 liquid 200 DHA 34 mg, powder ARA 17 mg 170 PRSL 23/100 cals 1.8 180 DHA, ARA PRSL 22.9/100 cals
40
116 105 63
44 36
108 105 75 120 105 83
1.8 200 1.8
DHA 0.15%, ARA 0.40% PRSL 22.8/100 cals DHA 17 mg, ARA 34 mg PRSL
36
120 105 69
1.8
DHA, ARA PRSL 22.9/100 cals
standard milk-based infant formulas. Rice cereal may be added to standard infant formula to achieve a similar effect; however, it increases the caloric density and may result in clogged nipples. Added rice starch formulas are not substitutes for thickened formula indicated for risk of aspiration. Currently there are 2 added rice starch products on the market; one of the products is lactose-free while the other has reduced lactose. Each product has studies to support that the added rice starch decreases episodes of spitting up.9,10 Soy-Based Formulas Soy-based formulas (Table 12-4) are designed to meet the needs of healthy infants birth to 1 year of age. The protein source is soy, supplemented with methionine to make it a complete protein source. These formulas are fortified with iron and are lactose-free. It is estimated that about 25% of infants consuming formula will consume a soy-based formula. Soy-based infant formulas have higher calcium and phosphorus than standard cows milk-based formulas because of reduced bioavailability secondary to phytates.11 Soy-based formulas offer no advantage over cows milkbased formulas except for a few indications. Indications for soy-based formula are infants with galactosemia or hereditary lactase deficiency (rare), or if a vegetarian human milk substitute is requested.12 Soy-based formulas are not recommended for premature infants as they are not designed to meet the premature
infants specific needs.12 Soy milk protein is no less allergenic than cows milk protein. 3 Infants with documented cows milk allergy should not be given a soy formula because 10% to 14% of these babies will also have a sensitivity to soy protein.13,14 Infants with acute gastroenteritis who were previously well can be managed with rehydration and continued use of human milk or their usual cows milkbased formula at the standard dilution.12
Premature or Low Birth Weight Formulas

Premature or low birth weight (LBW) formulas (Table 12-5) come in ready-to-feed nurser bottles that are available for hospital use only. These formulas are milk-based and designed to meet the special nutrition needs of preterm infants (born less than 37 weeks gestation) and/or infants born less than 1500 g (which is considered very low birth weight [VLBW]) while in the hospital, if human milk is not available. The unique characteristics of this group of formulas include increased protein, carbohydrate blends of lactose and glucose polymers, fat blends containing a portion of fat as medium-chain triglycerides (MCTs) to promote fat absorption, and increased calcium and phosphate to promote net mineral retention and bone mineralization.15,16 Premature infant formulas are available with low iron or iron-fortified. One of the 3 formulas available has partially hydrolyzed 100% whey protein. The other 2 formulas contain intact whey and casein proteins.
134
Premature Discharge Formulas

Premature discharge formulas (Table 12-6) are designed to meet the nutrition needs of the infant born prematurely or the LBW infant who is transitioning home. These formulas are milk-based with higher levels of calcium and phosphorus than standard term infant formulas. They provide a nutrient intake that is between a preterm and term formula. The American Academy of Pediatrics (AAP) supports the use of preterm discharge formulas to postnatal age of 9 to12 months corrected age or until weight for length is maintained above the 25th percentile. 3
acids and small peptides. The fat content is made up of longchain triglycerides (LCTs), varying amounts of MCTs, and polyunsaturated vegetable oils to supply essential fatty acids (EFAs). These formulas are lactose-free and because of the hydrolyzed protein have a higher osmolarity. Protein hydrolysates are recommended in infants intolerant of cows milk and soy proteins, and those with significant malabsorption due to gastrointestinal or hepatobiliary disease (eg, cystic fibrosis, short gut syndrome, biliary atresia, cholestasis, protracted diarrhea). 3,17 Amino Acid Based Amino acid-based infant formulas (Table 12-8) are indicated in extreme protein hypersensitivity or when intolerance symptoms persist on an extensively hydrolyzed formula.18 Approximately 2% to 10% of infants with cows milk protein allergy develop persistent symptoms despite therapy with partially hydrolyzed formula and thus require an amino acid-based formula.19 There is no additional benefit to using an amino acid-based formula if an extensively hydrolyzed casein formula is effective. Other indications for the amino
Specialized Infant Formulas

Extensively Hydrolyzed Protein Formulas containing extensively hydrolyzed protein (Table 12-7) are considered hypoallergenic according to AAP and FDA standards, meaning that most children with cows milk protein sensitivity will not have an allergic reaction to these formulas. The protein in these formulas is extensively hydrolyzed by heat or enzymes, resulting in free amino
Table 12-5 Premature Infant Formulas (per 100 calories) Standard dilution varies and can be 0.67 kcal/mL (20 kcal/oz) or 0.8 kcal/mL (24 kcal/oz).
Enfamil Premature LIPIL 20 cal/oz (low iron or iron fortified) (Mead Johnson) Enfamil Premature LIPIL 24 cal/oz (low iron or iron fortified) (Mead Johnson) GOOD START Premature 24 cal/oz (Nestle/Gerber) Similac Special Care 20 cal/oz (low iron oriron fortified) (Abbott Nutritionals) Similac Special Care 24 cal/oz (low iron oriron fortified) (Abbott Nutritionals) Similac Special Care 30 cal/oz (Abbott Nutritionals)
3 (12%) 11 (44%) non-fat milk, whey corn syrup solids, protein concentrate lactose 3 (12%) 11 (44%) non-fat milk, whey corn syrup solids, protein concentrate lactose
5.1 (44%) MCT oil, soy oil, high oleic vegetable oil 5.1 (44%) MCT oil, soy oil, high oleic vegetable oil
58
98
165 83
0.5 240 1.8
58
98
165 83
0.5 300 1.8
DHA 17 mg, ARA 34mg, PRSL 27/100 cals, nucleotides 28mg/L, Ca:Phos ratio 2:1 DHA 17 mg, ARA 34mg, PRSL 27/100 cals, nucleotides 34mg/L, Ca:Phos ratio 2:1 Ca:Phos ratio 1.9:1
3 (12%) enzymatically hydrolyzed whey protein isolate (from cows milk) 3 (12%) nonfat milk, whey protein concentrate
10.5 (42%) corn maltodextrin, lactose 10.3 (41%) corn syrup solids, lactose
5.2 (46%) MCT oil, soy oil, high oleic safflower or sunflower oil 5.43 (47%) MCT, soy oil, coconutoil 5.43 (47%) MCT, soy oil, coconutoil 6.61 (57%) MCT, soy oil, coconutoil
55
120 164 85
1.8 275
43
129 180 100
0.37 235 1.8
DHA 0.25%, ARA0.40%, PRSL 27.8/100 cals DHA 0.25%, ARA0.40%, PRSL 27.8/100 cals DHA 0.25%, ARA0.40%, PRSL 27.8/100 cals
10.3 (41%) 3 (12%) nonfat milk, whey corn syrup solids, protein concentrate lactose 3 (12%) 7.73 (31%) nonfat milk, whey corn syrup solids, protein concentrate lactose
43
129 180 100
0.37 280 1.8
43
129 180 100
1.8 325
135
Table 12-6 Premature Discharge Infant Formulas (per 100 calories) Standard dilution for these formulas is 0.73 kcal/mL (22 kcal/oz).
Enfamil EnfaCare LIPIL (Mead Johnson)
10.4 (42%) powder: lactose, corn syrup solids RTU: maltodextrin, lactose 10.1 (40%) Similac NeoSure 2.8 (11%) (Abbott Nutritionals) nonfat milk, whey corn syrup solids, protein concentrate lactose
2.8 (11%) whey protein concentrate, nonfatmilk
5.3 (47%) high oleic sunflower or safflower oil, soy oil, MCT, coconut oil 5.5 (49%) soy oil, coconut oil, MCT
35
105 120 66
42 mg added 1.8 powder nucleotides, DHA 260 liquid 250 17mg, ARA 34 mg, PRSL 24/100 cals 1.8 250 DHA 0.15%, ARA0.40%, PRSL 25.2/100 cals
33
142 105 62
acid-based formulas include eosinophilic gastrointestinal disorders and transitioning from parenteral to enteral feedings and short bowel syndrome (SBS).19 Carbohydrate Free These formulas (Table 12-9) are designed for the management of carbohydrate metabolism disorders and carbohydrate malabsorption issues (eg, glucose-galactose malabsorption).20 The physician or healthcare professional prescribes a carbohydrate to be added to the formula and it is usually titrated up to make the formula 20 kcal/oz.21 Reduced Fat/Modified Fat These reduced or modified fat formulas (Table 12-10) can be used in conditions of decreased bile salts, fat malabsorption, defective lymphatic transport of fat, chylothorax, or long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Due to the risk of essential fatty acid deficiency (EFAD), these formulas should only be used under the supervision
Table 12-7 Extensively Hydrolyzed Protein Infant Formulas (per 100 calories)
Product (Manufacturer) Protein g (% kcal) Source CHO g (% kcal) Source Fat g (% kcal) Source
of a physician. Evaluation of triene:tetraene ratio may be needed to detect EFAD, and addition of EFAs at a volume of 3% to 5% of total kilocalories may be indicated with some of the formulas with lower levels of the long-chain fatty acids. Reduced Mineral The mineral content of this formula (Table 12-11) is close to the mineral content of human milk and is designed to treat calcium disorders.21 The formula may also be used for infants with impaired renal function. An additional source of iron may need to be considered. Infants consuming this formula should be monitored by a medical professional.
Functional Ingredients in Infant Formulas

DHA/ARA
Long-chain polyunsaturated fatty acids (LCPUFAs) in infant feeding refer to docosahexaenoic acid (DHA) and arachidonic acid (ARA). DHA and ARA are synthesized
Na mg
K mg
Ca mg
Phos mg
Fe mg
Osmolal- Comments ity mOsm
Nutramigen LIPIL (Mead Johnson)
Nutramigen with Enflora LGG (Mead Johnson) Pregestimil LIPIL (Mead Johnson)
10.2 (41%) corn syrup solids, dextrose, modified corn starch RTU-no dextrose Similac Alimentum 2.75 (11%) 10.2 (41%) Advance casein hydrolysate, sugar, modified (Abbott Nutritionals) L-cystine, L-tyrosine, tapioca starch L-tryptophan
2.8 (11%) extensively hydrolyzed casein, L-cystine, L-tyrosine, L-tryptophan 2.8 (11%) extensively hydrolyzed casein, L-cystine, L-tyrosine, L-tryptophan 2.8 (11%) casein hydrolysate, amino acids
10.3 (41%) corn syrup solids, modified corn starch 10.3 (41%) corn syrup solids, modified corn starch
5.2 (48%) 47 palm olein, soy oil, coconut oil, high oleic sunflower oil 5.3 (48%) 47 palm olein, soy oil, coconut oil, high oleic sunflower oil 47 5.6 (48%) MCT, soy oil, corn oil, high oleic safflower or sunflower oil RTU-no corn oil 5.54 (48%) 44 high oleic safflower oil, MCT, soy oil
1.8 liquid 320 DHA 17 mg, ARA34mg, powder PRSL 25/100 cals, 300 lactose and sucrose free 110 94 52 1.8 300 DHA 17 mg, ARA 34 mg, PRSL 16.8/100 cals, *added probiotic Lactobacillus GG 110 pwdr pwdr 1.8 RTU 280 DHA 17 mg, 94 52 ARA 34 mg pwdr, RTU RTU PRSL 25/100 cals, 115 75 RTU - PRSL 26/100cals 110 94 52 118 105 75 1.8 370 DHA 0.15%, ARA0.40%, PRSL 25.3/100 cals
136
Table 12-8 Free Amino Acid Infant Formulas (per 100 calories)
Similac EleCare (Abbott Nutritional) Neocate Infant DHA & ARA (Nutricia)
3.1 (15%) free L-aa 3.1 (12%) free aa
10.7 (43%) corn syrup solids 11.7 (47%) corn syrup solids
Nutramigen AA LIPIL 2.8 (11%) (Mead Johnson) free amino acids
10.3 (41%) corn syrup solids, modified tapioca starch
4.8 (42%) 45 150 116 84.2 1.5 350 high oleic safflower oil, MCT oil, soy oil 4.5 (41%) 37.3 155.1 124 93.1 1.85 375 refined vegetable oil (soy oil, coconut oil, high oleic sunflower oil) 5.3 (48%) 47 110 94 52 1.8 350 palm olein, soy oil, coconut oil, high oleic sunflower oil
DHA, ARA PRSL 28/100 cals available without DHA & ARA also
DHA 17 mg, ARA 34 mg, PRSL 16.8/100 cals
Table 12-9 Carbohydrate-Free Formulas (per 100 calories)

RCF* 3.0 (12%) 10.1 (40%) 5.3 (48%) 44 (Abbott Nutritionals) soy protein isolate, selected by high oleic safflower L-methionine physician or health oil, coconut oil, soy oil care professional 3232A 2.8 (11%) 13.5 (54%) 4.2 (35%) 43 (Mead Johnson) extensively choice by physician, MCT, corn oil hydrolyzed casein, modified tapioca L-cystine, L-tyrosine, starch as stabilizer L-tryptophan *based on 100 calories when 52 gm of CHO are added to 13 oz of concentrate
108 105 75
1.8 168
no DHA/ARA PRSL 25.8/100cals 59 gm CHO added to 1 quart prepared product, PRSL 25/100 cals
109 94
63
1.88 type of CHO will influence
from the dietary EFAs alpha-linolenic acid (-3) and linoleic acid (-6), respectively. Endogenous synthesis of LCPUFAs begins in the first days of life.22 DHA and ARA are present in human milk. Breastfed infants have higher plasma and erythrocyte lipid concentrations of DHA and ARA compared to infants fed formula without DHA and ARA.23 Furthermore, DHA and ARA are the major fatty acids in neural tissues and DHA is a major component of photoreceptor cells.24 The major supply of LCPUFAs to the fetus during development is from maternal plasma.25 Therefore, the clinical significance of this seems to be more prominent for the preterm infant as compared to the term infant.22 Nucleotides Nucleotides are compounds formed of phosphoric acid, a sugar, and a purine or pyrimidine base that are synthesized, degraded, and salvaged in the body. This continuous process takes place to a larger degree in the gut and immune system than the rest of the body because cells are more rapidly turning over.26 Dietary nucleotides are thought to have effects on intestinal growth and development, healing
the intestinal mucosa, and may contribute to the pool of nucleotides available to the proliferation of lymphocytes.27 A source of dietary nucleotides may be important for infants whose tissue turnover rates may be higher (eg, the preterm infant or infants with chronic diarrhea).26 There is still a question as to what the appropriate level of dietary nucleotides should be and which ones should be used. The levels and types of nucleotides that are currently being provided in infant formulas have not shown any deleterious effects.28 Prebiotics and Probiotics Prebiotics are complex dietary carbohydrates present in breast milk and several foods that are not digestible or absorbable by the human gastrointestinal tract.29,30 They include fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS). Prebiotics become the fuel for beneficial bacteria in the gut and stimulate their growth. This gives the beneficial bacteria a competitive advantage over the other bacteria in the gut. 31 Probiotics are defined as non-pathogenic organisms in the food supply that provide a benefit to the host. 32 Bifidobacteria is the most prevalent species that colonizes
137
the intestines of breastfed infants. 33,34 It is thought that the higher percentage of bifidobacteria may be associated with some health benefits. 35 Bifidobacteria lactis added to infant formula has been shown to be safe and increases the percentage of bifidobacteria in the microflora. 35 Lactobacillus GG (rhamnose) is another species of bacteria prevalent in the intestines of healthy infants. Studies suggest that an extensively hydrolyzed protein formula with supplemented LGG may be more effective in the treatment of cows milk protein allergy than the same formula without supplementation. 36
Infant formula is available in 3 forms: ready-to-feed, liquid concentrate, and powder. All forms are nutritionally complete and are regulated. There are small differences between the 3 forms for technical reasons.7 Liquid concentrate and powder forms require the addition of potable water to reconstitute and can be mixed to various caloric dilutions according to the special need of the infant. Ready-to-feed is the most commonly used form in hospitals as it is considered commercially sterile. It is convenient and limits opportunity for contamination. The
Forms of Infant Formula and Mixing Guidelines
manufacturers provide many different formulas in standard caloric dilution and some formulas at higher caloric concentrations in convenient ready-to-feed nurser bottles. Consumers can purchase ready-to-feed formula at standard dilution in quart-sized bottles or single-serving nurser bottles. Ready-to-feed formula is the most expensive form as the consumer is paying for the convenience. Liquid concentrate is also considered commercially sterile, but because it needs to be mixed with water to make a standard dilution, it offers more opportunity for potential contamination than ready-to-feed. Liquid concentrate is the second choice in hospitals and can be used to make highercaloric concentrations. It is easy to mix for consumers and offers some financial savings over ready-to-feed. Powder is not sterile and must be mixed with water. Because it is not sterile, it may contain pathogenic bacteria. 37 Powder formula has been associated with Enterobacter sakazakii contamination in immunocompromised neonates in healthcare facilities.38 Because of the population that they serve, hospitals only use powder when there is no other option available.39 Reconstituted powder formulas have been safely consumed by millions of infants worldwide over the past half century, so parents of healthy newborns should continue to feel comfortable using powder infant formulas. The
Table 12-10 Modified Fat Formulas (per 100 calories)

Enfamil Enfaport LIPIL (Mead Johnson)
3.5 (14%) 10.2 (41%) calcium caseinate, corn syrup solids sodium caseinate
5.4 (45%) MCT (84%), soy oil
30
115 94
52
1.8 280 (30 cal/oz)
Monogen (Nutricia) Lipistart (vitaflo)
2.7 (11%) whey protein concentrate, L-amino acids 3 (12%)
16 (64%) corn syrup solids 12 (47%)
2.8 (25%) 48 MCT (as fractionated coconut oil), walnut oil 4.6 (41%) 55
86
62
48
108 105 77
250-22 cal/oz 370-30 cal/oz 180-22 cal/oz 205-24 cal/oz 272-30 cal/oz
DHA, ARA PRSL 29/100 cals *comes in RTU, 30 cal/oz. Water can be added to dilute to lower concentrations essential fatty acid ratio n6:n3 of 4.6:1 *for > 1 y old *for > 1 y old
Table 12-11 Reduced Mineral Infant Formula (per 100 calories)

Similac PM 60/40 2.2 (9%) (Abbott Nutritionals) whey protein concentrate, sodium caseinate
10.2 (41%) lactose
5.6 (50%) 24 high oleic safflower oil, soy oil, coconut oil
80
56
28
0.7 280
no DHA & ARA PRSL 18.3/100 cals
138
ESPGHAN (European Society for Pediatric Gastroenterology, Hepatology, and Nutrition) Committee on Nutrition recommends that in the home powder infant formulas should be freshly prepared for each feeding and any remaining milk discarded to minimize potential risk of contamination.40 Consumers choose it because it is the least expensive form and can be quickly mixed at any location when needed. Water Tap water or boiled and cooled water is adequate to use when preparing formula for healthy infants with a normal immune system and who are fed orally.41 Municipal tap water is more regulated than bottled water. Municipal tap water is fluoridated whereas most bottled water is not. Bottled water or infant fluoridated bottled water may be a good choice when tap water is from a well because well water may contain high levels of certain minerals. In hospitals only chilled, sterile water is recommended in formula preparation.42 Infants consuming either human milk or infant formula exclusively do not have a need for additional water in their diets. Human milk or infant formula provides adequate free water for hydration in hot or dry climates and if the infant is febrile.3 Standard Dilution When mixing formulas, healthcare professions should suggest that parents read the manufacturer instructions on the can as instructions may vary by manufacturer and by product. In powdered formulas, only use the scoop that comes with that particular formula because scoop sizes are different for each formula. Standard dilution for term infant formulas is 20 kcal/oz, or 0.67 kcal/mL, and can be made by mixing 1 scoop of powder for each 2 oz of water, or by mixing a 13-oz can of concentrate with 13 oz of water. Increasing Caloric Concentration For special feeding situations, both powdered infant formula or infant formula concentrate can be reconstituted (Table 12-12) to provide formula with more concentrated calories than standard dilution. 21 Concentrated liquids from all manufacturers contain 40 kcal/oz, so the same instructions for preparation and caloric concentration can be used forall.
Table 12-12 Increasing Caloric Concentration of Term Infant Formulas with Standard Dilution of 20 kcal/oz or 0.67 kcal/mL
Concentration Amount of Powder/Liquid Water (oz)
4 scoops powdered formula* 8 13 oz liquid concentrate 13 5 scoops powdered formula* 8 24 kcal/oz (0.8 kcal/mL) 13 oz liquid concentrate 9 5.5 scoops powdered 8 27 kcal/oz (0.9 kcal/mL) formula* 13 oz liquid concentrate 6 *Use only the scoop provided with the specific formula. Scoop sizes vary from product to product.
20 kcal/oz (0.67 kcal/mL)
Modular Macronutrients Modular macronutrients can be used to increase caloric concentration. Modulars are available as protein, carbohydrate, fat, and combinations of macronutrients. The fat and/or carbohydrate modulars may not add as significantly to the potential renal solute load (PRSL) and osmolality as concentrating the formula with less water, and fat and/or carbohydrate modulars should be considered when concentrating calories higher than 24 calories per ounce. Modular macronutrients will not increase the concentration of micronutrients like concentrating just the formula powder or concentrate. This may be desirable in some situations (renal insufficiency) and not desirable in other situations (increased calcium and phosphorus needs in prematurity). Modulars can be added to the formula when mixing or they can be mixed with water and delivered as a bolus through the tube separate from formula. To boost caloric intake of formula, some common food products or ingredients may also be used (eg, table sugar, vegetable oil, or corn starch). These ingredients may not be ideal, but they are much less expensive than the manufactured modulars. Increasing Concentration of Breast Milk Infants born prematurely often have caloric and nutrient deficits, even at discharge, and although breast milk is the best choice for feeding these infants, it may not meet all of the caloric and nutrient needs of the infant with significant comorbidities.43 Expert opinion and studies show that preterm infants discharged from the hospital at suboptimal weight being fed breast milk should continue to be supplemented to assure adequate nutrient intake.44,45 Some healthcare professionals suggest adding premature infant formula or infant formula powder to expressed breast milk to increase the caloric and nutrient density. There is no evidence for or against this practice, and there is a great potential for error. Close medical monitoring is suggested.46
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The AAP recommends exclusive breastfeeding for a minimum of 4 months, but preferably 6 months. There is no nutrition indication to start complementary foods any earlier than 4 to 6 months of age, and starting solids as early as 4 months of age has not shown any adverse effects on growth.3 Each infant develops at his or her individual rate. An infant is usually ready for solid foods when birth weight has doubled, there is truncal stability to sit with support, and neuromuscular maturation has been achieved.2 Other signs may include frequently putting things in the mouth, leaning forward and opening the mouth to indicate a desire for food, and consuming more than 32 ounces of human milk or formula each day.2 There is no evidence to support the introduction of foods in any certain order. The general rule is to add 1 single-ingredient food at a time and wait about 3 to 5 days before introducing a new food, watching for possible intolerances or allergic reactions. 3 Some parents want to make their own baby foods. Parents should cook the food until soft and put it in a baby food grinder or blender until the desired consistency is reached. For infants just starting on solid foods, the consistency should be a smooth puree. Older infants can tolerate small consistent-sized bits in their food. Parents should avoid adding salt or sugar. 3 A good time to advance textures is when the infant starts teething. Parents should be aware that rub on teething medications can interfere with chewing and swallowing because muscles in the throat can become numb. Careful observation is advised. Juice After 6 months of age fruit juice can be introduced in a cup and should be limited to 4 to 6 oz/d. 3 Only 100% fruit juice should be offered. Fruit juice displaces the more nutrientdense human milk or infant formula and therefore should be used in limited amounts. Infants should not be offered juice in a bottle or in a cup that can be carried around and should not consume juice just before bed because of the increased risk for dental caries. Overconsumption of juice can lead to osmotic diarrhea due to the high fructose and sorbitol content. 3 Milk Milk (whole, 2%, 1%, skim, goat), other than infant formula, should be avoided during the first year of life. Milk is lower in iron and has a higher renal solute load due to the higher
Introducing Complementary Foods to the Infants Diet
amounts of protein, sodium, potassium, and chloride. Milk is also limited in EFAs, zinc, and vitamin E. 3 Foods to Avoid the First Year Foods that are difficult to chew or can easily choke a child or be aspirated should be avoided up to about 4 years of age. Foods to avoid include, but are not limited to, hotdogs, nuts, grapes, raisins, raw carrots, popcorn, and rounded candies. 3 Honey is another food to avoid during the first year of life. Honey contains a bacteria that results in botulism. The infants developing immune system is not able to adequately protect against the bacteria. Botulism is potentially very serious and can result in death if not diagnosed and treated properly in the infected infant. 3
Toddler Formulas
Toddlers consuming adequate amounts of nutrients, especially iron, from solid foods do not need formula. Whole cows milk is appropriate after 1 year of age. Toddler formulas (Table 12-13) contain higher amounts of iron, vitamin C, and vitamin E than cows milk and contain nutrients such as zinc that cows milk does not contain. The calcium and phosphorus levels of the toddler formulas are higher than infant formulas to match the needs of the growing toddler. Toddler formulas contain DHA and ARA.
140
Table 12-13 Toddler Formulas (per 100 calories) Standard dilution for these products is 0.67 kcal/mL (20 kcal/oz).
GOOD START Gentle PLUS 2 (Nestle/Gerber)
2.2 (9%) 11.2 (45%) whey protein lactose, corn concentrate maltodextrin (from cows milk, enzymatically hydrolyzed, reduced in minerals) 2.2 (9%) 11.2 (45%) whey protein lactose, corn concentrate maltodextrin (from cows milk, enzymatically hydrolyzed, reduced in minerals) 2.6 (10%) non-fat milk
5.1 (46%) 27 palm olein, soy oil, coconut oil, high oleic safflower or sunflower oil
108 190 106
265
DHA 0.32%, ARA 0.64%, PRSL 146/L
GOOD START Protect PLUS 2 (Nestle/Gerber)
5.1 (46%) 27 palm olein, soy oil, coconut oil, high oleic safflower or sunflower oil
108 190 106
265
DHA 0.32%, ARA 0.64%, PRSL 146/litre *added probiotics, Bifidobacteria lactis DHA 17 mg, ARA 34 mg, PRSL 26/100cals DHA 0.15%, ARA 0.40%, PRSL 20/100 cals DHA 17 mg, ARA 34 mg, PRSL 26/100cals DHA 17 mg, ARA 34 mg, PRSL 26/100cals * with added prebiotic, FOS DHA, ARA
Enfagrow Premium NextStep (Mead Johnson)
10.5 (42%) 5.3 (48%) 36 lactose, corn syrup palm olein, soy oil, solids coconut oil, high oleic sunflower oils 5.49 (49%) high oleic safflower oil, soy and coconut oils 5.3 (48%) vegetable oils 5.3 (48%) vegetable oils 24
130 195 130
270
Similac Go & Grow 2.07 (8%) 10.56 (43%) Milk-based non-fat milk, whey lactose (Abbott Nutritionals) protein concentrate Bright Beginnings 2 2.6 (10%) non-fat milk (PBM Nutritionals) Bright Beginnings 2 2.6 (10%) with prebiotics non-fat milk (PBM Nutritionals) 10.5 (42%) corn syrup solids, lactose 10.5 (42%) corn syrup solids, lactose
105 150 81
300
36
130 195 130
36
130 195 130
Parents Choice Stage 2 Formula (PBM Nutritionals) GOOD START Soy Plus 2 (Nestle/Gerber)
2.6 (10%) non-fat milk
10.5 (42%) corn syrup solids, lactose 10.9 (44%) corn maltodextrin, sucrose
5.3 (48%) 36 palm olein, soy oil, coconut oil, high oleic safflower oil 5.0 (45%) 40 palm olein, soy oil, coconut oil, high oleic safflower or sunflower oil 5.46 (49%) 49 high oleic safflower oil, soy oil, coconut oil 4.4 (40%) 36 palm olein, soy oil, coconut oil, high oleic sunflower oils
130 195 130
2.8 (11%) enzymatically hydrolyzed soy protein isolate
116 190 106
180
DHA 0.32%, ARA 0.64%, PRSL 175/liter
Similac Go & Grow 2.45 (10%) 10.3 (41%) Soy-based soy protein isolate, corn syrup solids, (Abbott Nutritionals) L-methionine sugar Enfagrow Soy Next Step (Mead Johnson) 3.3 (13%) 11.8 (47%) soy protein isolate, corn syrup solids L-methionine
108 150 100
200
DHA 0.15%, ARA 0.40%, PRSL 23.7/100 cals DHA 17 mg, ARA 34 mg, PRSL 30/100 cals
120 195 130
230
1. Which formula(s) is indicated for transient lactose intolerance? A. Enfamil AR LIPIL B. Parents Choice Gentle C. Similac Sensitive D. B and C
2. What is the standard dilution of term infant formulas? A. 15 kcal/oz B. 20 kcal/oz C. 25 kcal/oz D. 30 kcal/oz
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3. According to the Federal Food, Drug, and Cosmetic Act, infant formulas that meet a specific medical need . are considered A. Exempt B. GRAS (generally recognized as safe) C. Specialized D. Medical foods 4. Prebiotics are: A. Oligosaccharides B. Complex dietary carbohydrates that are not digestible by humans C. The fuel for beneficial bacteria in the gut D. All of the above See p. 487 for answers.
References
1. World Health Organization. The World Health Organizations infant feeding recommendation. http://www.who.int/nutrition/topics/infantfeeding_recommendation/en/. Accessed December 15, 2008. 2. American Academy of Pediatrics, Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics. 1997;100:10351039. 3. American Academy of Pediatrics, Committee on Nutrition. Kleinman RE, ed. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009. 4. Aggett PJ, Agostini C, Goulet O, et al. The nutritional and safetyassessment of breast milk substitutes and other dietary products for infants: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2001;32:256258. 5. Federal Food, Drug, and Cosmetic Act, 412, Title 21 Code of Federal Regulations 106, 107. 6. Infant metabolic acidosis and soy-based formula United States. MMWR . November 15, 1996:45(45);985988. http:// www.cdc.gov/mmwr/preview/mmwrhtml/00044475.htm. Accessed December 1, 2008. 7. Klish, WJ. Special infant formulas. Pediatrics in Review. 1990;12:5562. 8. VonBerg A, Koletzko S, Filipiak B, et. al. Certain hydrolyzed formulas reduce the incidence of atopic dermatitis but not that of asthma; three year results of the German Infant Nutrition Intervention Study. J Allergy Clin Immunol. 2007;119(3):71187125. 9. Vanderhoof JA, Moran JR, Harris CL, et.al. Efficacy of a prethickened infant formula: a multicenter double blind, randomized, placebo controlled parallel group trial in 104 infants with symptomatic gastroesophageal reflux. Clin Pediatr. 2003;41:483495. 10. Among healthy 2-month-old infants compared to a standard formula. Data on file, AJ68, May 2007. Ross Products Division, Abbott Laboratories, Columbus, Ohio.
11. Mimouni F, Campaigne B, Naylan M, Tsang RC. Bone mineralization in the first year of life in infants fed human milk, cow-milk formula or soy-based formula. J Pediatr. 1993;122(3):348354. 12. Bhatia J, Greer F and the Committee on Nutrition. Use of soy-based formulas in infant feeding. Pediatrics. 2008;121;10621068. 13. Zeigler RS, Sampson HA, Bock SA, et al. Soy allergy in infant and children with IgE-associated cows milk allergy. J Pediatr. 1999;134(5):614622. 14. Klemola T, Vanto T, Juntunen-Blackman K, Kalimo K, Korpela R, Verjonen E. Allergy to soy formula and to extensively hydrolyzed whey formula in infants with cows milk allergy: a prospective, randomized study with a follow-up to the age of 2 years. J Pediatr. 2002;140(2):219224. 15. Picaud JC, Decullier E, Plan O, et al. Growth and bone mineralization in preterm infants fed preterm formula or standard term formula after discharge. J Pediatr. 2008;153:616621. 16. Klein CJ. Nutrient requirements for preterm infant formulas. J Nutr. 2002;132(Suppl 16-I):1395S1577S. 17. American Academy of Pediatrics Committee on Nutrition. Hypoallergenic infant formulas. Pediatrics. 2000;106:346349. 18. Sicherer SH, et al. Hypoallergenicity and efficacy of an amino acid-based formula in children with cows milk and multiple food hypersensitivities. J Pediatr. 2001;138:688693. 19. Hill DJ, Murch SH, Rafferty K, et al. The efficacy of amino acidbased formulas in relieving symptoms of cows milk allergy: A systematic review. Clin Exp Allergy. 2007;37:808822. 20. Wright EM. Glucose galactose malabsorption. Am J Physiol. 1998;275(5):G87982. 21. Joeckel RJ, Phillips SK. Overview of infant and pediatric formulas. Nutr Clin Prac. 2009;24:356362. 22. Agostoni C, Riva E. Role and function of long-chain polyunsaturated fatty acids in infant nutrition. In: Raiha NC, Rubaltelli FF, eds. Infant Formula: Closer to the Reference. Nestle Nutrition Workshop Series. Pediatric Program. Vol 47 Suppl. Philadelphia, PA: Lippincott Williams & Wilkins; 2002. 23. Makrides M, Neumann MA, Simmer K, Gibson RA. Erythrocyte fatty acids of term infants fed either breastmilk, standard formula, or formula supplemented with long-chain polyunsaturates. Lipids. 1995;30(10):941948. 24. Martinez M. Tissue levels of polyunsaturated fatty acids during early human development. J Pediatr. 1992;120:S129S138. 25. Berghaus TM, Demmelmair H, Koletzko B. Fatty acid composition of lipid classes in maternal and cord plasma at birth. Eur J Pediatr. 1998;157:763768. 26. Boza JJ, Martinez-Augustin O. Role and function of nucleotides in infant nutrition. In: Raiha NC, Rubaltelli FF, eds. Infant Formula: Closer to the Reference. Nestle Nutrition Workshop Series. Pediatric Program. Vol 47 (Suppl) Philadelphia, PA: Lippincott Williams & Wilkins; 2002. 27. Carver JD. Advances in nutritional modifications of infant formulas. Am J Clin Nutr. 2003;77:1550S1554S.
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28. Koletzko B, Baker S, Cleghorn G, et al. Global standard for the composition of infant formula: recommendations of an ESPGHAN coordinated international expert group. J Pediatr Gastroenterol Nutr. 2005;41:584599. 29. Arslanoglu S, Moro GE, Boehm G. Early supplementation of prebiotic oligosaccharides protects formula-fed infants against infections during the first 6 months of life. J Nutr. 2007;137:24202424. 30. Roberfroid M. Prebiotics: the concept revisited. J Nutr. 2007;137(Suppl 2):830S837S. 31. Kullen MJ, Bettler J. The delivery of probiotics and prebiotics to infants. Current Pharmaceutical Design. 2005;11:5574. 32. Saavedra JM. Clinical applications of probiotic agents. Am J Clin Nutr. 2001;73:1147S1151S. 33. Harmsen HJ, Wildeboer-Veloo AC, Raangs GC, et al. Analysis of intestinal flora development in breast-fed and formulafed infants by using molecular identification and detection methods. J Pediatr Gastroenterol Nutr. 2000;30:6167. 34. Yoshioka H, Iseki K, Fujita K. Development and differences of intestinal flora in the neonatal period in breast-fed and bottlefed infants. Pediatrics. 1983;72:317321. 35. Saavedra JM. Use of probiotics in pediatrics: rationale, mechanisms of action, and practical aspects. Nutr Clin Pract. 2007;22:351365. 36. Baldassarre M, Laforgia N, Grosso R, et al. Lactobacillus GG improves recovery from cow milk protein allergy colitis compared to extensively hydrolyzed formula alone. Dig Liv Dis. 2008;40:A82. 37. Drudy D, Mullane NR, Quinn T, Wall PG, Fanning F. Enterobacter sakazakii: an emerging pathogen in powdered infant formula. Clin Infect Dis. 2006;42:9961002.
38. Enterobacter sakazakii infections associated with the use of a powdered infant formulaTennessee 2001. MMWR Weekly. April 12, 2002:51(14);298300. http://www.cdc.gov/mmwr/ preview/mmwrhtml/mm5114a1.htm. Accessed March 20, 2009. 39. Whaley T, Robbins S. Strategies for Implementing the Guidelines for Handling of Infant Feeding. Building Block for Life. 2004:27(3). 40. ESPGHAN Committee on Nutrition. Preparation and handling of powdered infant formula: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2004;39(4):320322. 41. Mueller C, Nestle M. Regulation of medical foods: toward a rational policy. NCP. 1995;10:815. 42. Robbins ST, Beker LT. Infant feedings; Guidelines for preparation of formula and breastmilk in health care facilities. Chicago, IL: American Dietetic Association; 2004. 43. Groh-Wargo S, Sapsford A. Enteral nutrition support of the preterm infant in the neonatal intensive care unit. NCP. 2009;24(3):363376. 44. Aggett PJ, Agostoni C, Axelsson I, et al. Feeding preterm infants after hospital discharge: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2006;42(5):596603. 45. OConnor DL, Khan S, Weishuhn K, et al. Growth and nutrient intakes of human milk fed preterm infants provided with extra energy and nutrients after hospital discharge. Pediatrics. 2008;121:766776. 46. Academy of Breastfeeding Medicine. Clinical Protocol #12, Transitioning the breastfeeding/breastmilk-fed premature infant from the neonatal intensive care unit to home. September 17, 2004. www.bfmed.org. Accessed October 8, 2009.
Growth Assessment and Monitoring

Timothy Sentongo, MD
13
CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143 Growth Assessment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Weight Height (Length/Stature) Head Circumference Weight-for-Length Failure to Thrive Body Mass Index (BMI) Ideal Body Weight (IBW)
Learning Objectives
1. Understand the importance of growth assessment in pediatrics. 2. Learn appropriate techniques and parameters for assessing growth. 3. Employ growth charts in the assessment of growth disorders. 4. Understand limitations of growth charts.
Interpretation of Growth Charts and Percentiles . . . . . . 146

Assessing Linear Growth Potential
Introduction
Limitations of Growth Charts as a Diagnostic Tool. . . . . 147
Normal growth and development from infancy through adolescence to adulthood is the ultimate goal of pediatric care. Growth is most rapid during infancy, decelerates during childhood, and has a final increase in velocity during puberty. The relative protein and energy requirements of infants, children, and adolescents mirror the growth phase. Effective nutrition support requires assessment of nutrition status; protein, energy, fluid, and electrolyte requirements; and monitoring response to intervention. These objectives are accomplished through careful and repeated measurements of growth, nutrition status, and biochemical parameters over time. The growth parameters most easily obtained are weight (kg), length/height (cm), head circumference (cm), and body mass index (BMI) (kg/m 2). Other equally informative but less frequently obtained parameters include skinfold measurements, extremity circumferences, and limb lengths. The Centers for Disease Control and Prevention (CDC) has published reference charts (www.cdc.gov/growthcharts) for monitoring growth in North American children aged from birth to 20 years. In 2006 the World Health Organization (WHO) published international weight, length/height, and BMI-for-age growth standards for children aged from birth
143
144
to 5 years. The data used to derive WHO growth standards were based on healthy breastfed infants and young children representing all continents. Free download of these charts is available at www.who.int/childgrowth/standard/cht. Later in 2007 the WHO also published height- and BMIfor-age growth charts for children aged 5 to 19 years, and weight-for-age growth standards for children aged 5 to 10 years (http://www.who.int/childgrowth/en/). After age 2 years the linear growth in most healthy children stabilizes along a percentile channel that projects to a final height within 2 standard deviations (SDs) (8.5cm) of the calculated mid-parental height.1 Likewise BMI after age 2 years can now be linked to adolescent and adult BMI, thus providing a window of opportunity for early intervention to prevent obesity. Thus growth charts are important road maps for assessing growth status, response to nutrition intervention, and detection of growth disorders. Every pediatric clinician should become familiar with use and interpretation of childhood growth charts.
Table 13-1. Recommended Time Intervals for Monitoring Short- and Long-Term Growth in Children3,4,11
Measurement Age Group Short-Term Long Term Follow-Up
Pre-term infants Birth to 6 mo Weight (kg) 636 mo 220 y Pre-term infants Length (cm) Birth to 6 mo 636 mo Height (cm) 220 y Birth to 6 mo Head circumference (cm) 636 mo BMI (kg/m2) 220 y Soft tissue measurements Mid-arm circumference (mm) Triceps skinfold (mm)
Daily 12 wk 14 wk 28 wk 4 wk 36 mo 4 wk
Weekly 2 mo 6 mo 12 mo 4 wk 2 mo 6 mo 612 mo 2 mo 6 mo 12 mo 312 mo 112 mo
4 wk 4 wk
Growth Assessment
Proper instruments, accurate measurement techniques, and appropriate reference data are essential for meaningful assessment and interpretation of growth status. Appropriate time intervals between measurements should be used when monitoring short- and long-term growth. Weight measurements, which are easy to obtain and associated with the least measurement error, should be made frequently. Length/height increments occur more slowly. Length/height is more reliably assessed over longer intervals because even with good technique, measurements may be associated with an inter-observer measurement error of 0.5 cm.2 Middle upper arm circumference and triceps skinfold thickness are more difficult to measure reliably and reproducibly; however, they correlate well with nutrition status.3 See Table 13-1 for suggested time intervals. Pubertal status based on the Tanner system for growth of pubic hair in both sexes, breast development in girls, and genital development in boys should also be assessed for the purposes of interpreting growth velocity during later childhood and adolescence. 5
The updated 2000 CDC age- and gender-based weightfor-age growth reference charts for children aged birth to 36months and 2 to 20 years should be used (see Chapter 33). Individualized weight-for-age percentiles and SD scores (z scores) may be computed using the free access CDC Epi Info nutrition calculator and statistics program. 6 Diseasespecific growth charts are available for Down syndrome,7 achrondroplasia, 8 and other genetic disorders. 3
Height (Length/Stature)
Linear growth status (cm) is influenced by hereditary factors, nutrition, chronic disease, and genetic disorders. Correct equipment and measuring technique are important for obtaining reliable assessments. Accuracy is improved by repeating the measurements and obtaining an average. Serially obtained growth measurements should be plotted on age- and gender-appropriate CDC growth reference charts. Length (supine) is measured to the nearest 0.1 cm in children younger than 3 years or older children who cannot stand. Length should be assessed using a length board (stadiometer) or firm surface. It requires 2 measurers: one to position the head and the other to stretch and straighten the legs so that the knees are flat and feet at a 90-degree angle with the footboard. 3 Standing height is measured to the nearest 0.1 cm. It is obtained after age 2 years in children able to support their weight evenly on both feet. Subjects should stand barefooted with heels, buttocks, shoulders, and back of head against the measuring device and eyes looking straight ahead. 3 The updated 2000 CDC age- and gender-based
Weight
Infants should be undressed to the diaper and older children measured in light clothing using an age-appropriate scale. Measurements should be in metric units (kg) and rounded off to 1 decimal point.
GROWTH ASSESSMENT AND MONITORING
145
combined growth reference charts for children aged birth to 36 months and 2 to 20 years, respectively, should be used. Individualized length/height for age percentiles and SD scores (z scores) can be computed using the free access CDC Epi Info nutrition calculator and statistics program.6 Disease-specific growth charts are available for Down syndrome, achondroplasia, and other genetic disorders. 3,7,8 Tanner-Whitehouse height velocity charts may be used to monitor rate of height gain in girls aged 1 to 16 years and boys aged 1 to 19 years.9 Height below the 5th percentile indicates short stature. Height velocity below the 5th percentile suggests severely stunted growth that warrants assessment of pubertal status, screening for familial short stature, constitutional growth delay, and evaluation for chronic illness (eg, chronic inflammatory diseases, endocrinopathy, and skeletal and genetic disorders). Children with musculoskeletal deformities (eg, cerebral palsy, spinal kypho-scoliosis, and extremity contractures) that prevent accurate measurement of stature may be assessed using upper-arm and lower-limb lengths. Obtaining these measurements requires training in anthropometry and special instruments (anthropometers). Growth reference charts are available for upper-arm and lower-limb extremity lengths for girls aged 3 to 16 years and boys aged 3 to 18 years.10
length percentile suggests there is a non-nutrition etiology for impaired linear growth (eg, growth hormone deficiency and other endocrine, genetic, and skeletal disorders). Decreased weight-for-length (< 5th percentile) is consistent with nutrition failure to thrive (FTT). Impaired growth in children with nutrition FTT is characterized by weight more severely impaired than length and head circumference. FTT may be secondary to organic factors (ie, illness impairing food intake, digestion, absorption, or utilization). Non-organic FTT refers to factors external to the child (eg, food deprivation). Mixed organic and non-organic FTT may occur following infections, gastroenteritis, or any illnesses associated with prolonged inadequate calorie intake secondary to inappropriate food restrictions or behavioral feeding problems.
Failure to Thrive
The term FTT is not a diagnosis or specific disease entity but denotes weight gain or linear growth that is less than expected for age. FTT may be referred to as wasting when weight is disproportionately affected vs. stunting when length/height is significantly impaired. Wasting may occur following an acute illness. The growth changes are: weight-for-length percentile or BMI percentile < 5th percentile (~2 SD) or involuntary lack of weight gain or loss resulting in dropping below any 2 major percentile channels (95th, 90th, 75th, 50th, 25th, 10th, and5th). Stunting occurs following chronic inadequate caloric intake, disease, or endocrinopathy. The diagnostic growth findings are: length or height < 5th percentile (~2 SD) or consecutive height measurements dropping below any 2major percentile channels. Marasmus is moderate-to-severe FTT without edema. Kwashiorkor is moderate-to-severe FTT in association with hypoalbuminemia and edema. The WHO classifies FTT as moderate or severe using criteria of weight-for-length/height and length/height-for-age SD scores and presence or absence of edema (Table 13-2).
Table 13-2 World Health Organization Classification of Malnutrition12
Classification Moderate Severe
Head Circumference
Brain growth occurs most rapidly from birth to age 36 months and thereafter slows down. Head circumference (cm) must be routinely measured using a non-stretchable measuring tape. Anteriorly the tape is placed just superior to the eyebrows and posteriorly it is placed so that the maximum circumference is measured. 3 Impaired brain growth and size is a rare complication of chronic malnutrition and is not characteristic of primary skeletal disorders. Therefore, children with disproportionately sized heads should be evaluated for other disorders impacting brain or skull size.
Weight-for-Length
Weight-for-length percentiles provide a means of assessing a childs weight while taking into account his or her length. They are used to screen overweight and underweight in children aged < 36 months. See 2000 CDC weight-forlength growth reference charts for children aged birth to 36months. Increased weight-for-length percentile > 90% indicates overweight.11 When associated with significantly decreased length percentile (< 5%), increased weight-for-
Edema
No
Yes (Edematous malnutrition)
Weight-for-length 3 to 2 < 3 (wasting) z score* Height-for-age z score* 3 to 2 < 3 (stunting) *Growth channels of WHO international growth charts are along z scores 3; 2; 1; 0; 1; 2 and 3.
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Body Mass Index (BMI)

BMI is a composite index used to relate appropriateness of body weight for height. It is computed by dividing body weight in kilograms by height in meters squared (weight (kg)/height (m)2). It is very useful for screening and classifying overweight and obesity. However, BMI does not distinguish between overweight from excess body fat, increased muscle mass, or even increased weight attributed to large bones in tall people. Therefore, additionally estimating body fat stores by physical exam or measuring triceps skinfold thickness is essential for interpreting BMI. The normal range of BMI substantially changes with age in children. BMI is initially low at birth and then rapidly increases during infancy to peak at age ~1 year. BMI values then gradually decline, reaching a nadir between ages 2 to 4 years. It then rebounds at age ~7 years as children begin to accrue gender unique body fat patterns (adiposity rebound) and steadily increases throughout puberty and adolescence. Early occurrence of BMI rebound (before age 5.5 years) is associated with a longer period of accumulating body fat and thus greater risk for persistent overweight throughout childhood, adolescence, and into adulthood.13 The importance of BMI is its strong correlation with risk for cardiovascular disease and morbidity. Growth charts correlating BMI values of children and adolescents with adulthood BMI have been available since 2000. Therefore, BMI is very useful for screening and monitoring overweight and obesity in children and adolescents. The definition of overweight is BMI for age 85th and < 95th percentile. The terminology obesity denotes excess body fat and the associated health risks. The cutoff for obesity in youth is defined as BMI for age 95th percentile or calculated BMI 30 kg/m2 , whichever is lower.11 BMI for age < 10th percentile may be used to assess underweight or risk for underweight. However, BMIs correlation with risk for morbidity is less sensitive for underweight patients. CDC age- and gender-based BMI growth reference charts for 2000 are available for children and adolescents aged 2 to 20 years.6 Computing BMI z score is also available online using the free access CDC Epi Info nutrition calculator.6
wasting; 70% to 80% moderate wasting; 60% to 70% severe wasting, and < 60% as severe wasting14 approaching incompatibility with survival.15 IBW changes more rapidly than BMI. Therefore it may be used to monitor short-term response to nutrition support or weight reduction therapy. Computing IBW requires a growth chart and several steps unlike BMI, which is a simple calculation with known cutoff values that correlate with morbidity.
Interpretation of Growth Charts and Percentiles
A percentile value represents the proportion of children at a given age with growth parameters similar to or less than the measured value. The most effective way to use growth charts diagnostically is through serial measurements. The major percentile channels are labeled lines extending on the growth chart. They correspond with the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles. The 50th percentile corresponds to the median/mean measurement for the growth parameter at a specific age. The 5th and 95th percentiles correspond to ~2 SDs away from mean value. Growth measurements further than 2 SDs from the mean are significantly deviated from normal and thus require evaluation for disease. Serially obtained growth measurements that rise or drop below 2 major percentile channels represent accelerated or decelerated growth, respectively. This calls for verifying accuracy of the growth plot and in-depth evaluation if confirmed. Growth measurements falling below the 5th percentile or exceeding the 95th percentile (~2 SDs) cannot be assigned a percentile value. This is because distribution of measurements above or below the 5th and 95th percentiles is skewed. Therefore comparison of growth measurements that fall outside the 2-SD range is best assessed by using z scores (SD scores) (Table 13-3). SD scores for any growth measurement can be computed using Web-based Epi-Info Nutrition anthropometric software (CDC Epi Info nutrition calculator).6
Table 13-3 Comparison of Percentiles and SD Scores (z scores)
Percentile Corresponding z score
Ideal Body Weight (IBW)

This is a method to compare the patients actual weight with the median weight for stature. It is calculated as follows: [Patients measured weight (kg)/50th percentile weight (kg) for patients height] 100. A variation of 10% is considered within normal. A value > 120% corresponds to significant overweight. The Waterlow criteria classify 80% to 90% mild
0.1 3rd 16th 50th 84th 97th 99.9th
3 2 1 0 1 2 3
GROWTH ASSESSMENT AND MONITORING
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Assessing Linear Growth Potential

The childs height percentile before pubertal growth should fall within 2 SDs (8.5 cm) of the mid-parental height determined as follows1: Boys ([Fathers height (cm) + mothers height (cm) + 13 cm]/2) 8.5 Girls: ([Fathers height (cm) + mothers height (cm) 13 cm]/2) 8.5 Pubertal stage should always be assessed because of its significant impact on interpretation of weight and height gain in females > 8 to 9 years and males > 12 to 13 years. Validated self-assessment figures for pubertal status are available.
Limitations of Growth Charts as a Diagnostic Tool

The reliability of growth charts as an assessment tool depends on accuracy of growth measurements. Therefore the nutrition specialist should be trained in proper nutrition assessment technique. The specificity of growth charts in detecting growth disorders is higher with serially obtained measurements (longitudinal data). Interpretation of growth disorders should not be based on a single growth measurement. Growth charts are important for detecting extreme deviations from normal. Thus milder deviations (< 2 SDs) may be overlooked. Growth charts are a screening tool and not diagnostic. Growth charts do not replace careful history, physical examination, and diagnostic tests. BMI is a ratio of weight corrected for height. It correlates very well with body fat and risk for cardiovascular disease. However, weight is composed of body fat and fat-free mass (organs, muscle, and bones). Tall and/or muscular people tend to have high BMI values unrelated to body fat (ie, increased weight attributed to large bones and muscle mass). Obesity specifically refers to excess body fat and the associated medical risks. Therefore BMI alone is inadequate for diagnosing obesity. Diagnosis of obesity additionally requires estimation of excess body fat by either physical exam or skinfold anthropometry.11
3. The CDC recommends terminology of obesity in children with BMI > 95th percentile. A. True B. False 4. Diagnosis of FTT or wasting is based on each of the following except: A. Length < 3rd percentile B. Weight-for-length or BMI < 3rd percentile C. Change in weight percentile from 90th to 50th D. Change in weight percentile from 50th to 25th 5. The 50th percentile weight, height, or BMI for age corresponds with the following z score: A. 2 B. 1 C. 0 D. 1 E. 2 6. Which of the following is incompatible with survival? A. BMI < 3rd percentile B. Change in weight percentile from 75th to 5th percentile C. Height z score 5 D. 60% of ideal body weight 7. Length measurements in an 18-month-old toddler are obtained with the child standing upright. A. True B. False See p. 487 for answers.
References
1. BMI at age 18 months is correlated with BMI in adolescence. A. True B. False 2. Diagnosis of obesity is based on BMI for age > 85th percentile. A. True B. False
1. Tanner JM, Goldstein H, Whitehouse RH. Standards for childrens height at ages 2-9 years allowing for heights of parents. Arch Dis Child. 1970;45(244):755762. 2. Ulijaszek SJ. Measurement error. In: Ulijaszek SJ, Johnston FE, Preece MA, eds. The Cambridge Encyclopedia of Human Growth and Development. Cambridge, UK: Cambridge University Press; 1998:28. 3. Zemel BS, Riley EM, Stallings VA. Evaluation of methodology for nutritional assessment in children: anthropometry, body composition, and energy expenditure. Annu Rev Nutr. 1997;17:211235. 4. Owen GM. The assessment and recording of measurements of growth of children: report of a small conference. Pediatrics. 1973;51(3):461466. 5. Tanner JM. Normal growth and techniques of growth assessment. Clin Endocrinol Metab. 1986;15(3):411451. 6. Centers for Disease Control and Prevention. Epi Info Downloads. http://www.cdc.gov/epiinfo/downloads.htm. Accessed November 12, 2009. 7. Myrelid A, Gustafsson J, Ollars B, Anneren G. Growth charts for Downs syndrome from birth to 18 years of age. Arch Dis Child. 2002;87(2):97103.
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8. Hoover-Fong JE, McGready J, Schulze KJ, Barnes H, Scott CI. Weight for age charts for children with achondroplasia. Am J Med Genet A. 2007;143A(19):22272235. 9. Tanner JM, Davies PS. Clinical longitudinal standards for height and height velocity for North American children. J Pediatr. 1985;107(3):317329. 10. Spender QW, Cronk CE, Charney EB, Stallings VA. Assessment of linear growth of children with cerebral palsy: use of alternative measures to height or length. Dev Med Child Neurol. 1989;31(2):206214. 11. Barlow SE; Expert Committee. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics. 2007;120(Suppl 4):S164S192.
12. World Health Organization G. The management of severe malnutrition: A manual for physicians and other senior health workers. 1999:47. http://whqlibdoc.who.int/hq/1999/ a57361.pdf. Accessed November 12, 2009. 13. Whitaker RC, Pepe MS, Wright JA, Seidel KD, Dietz WH. Early adiposity rebound and the risk of adult obesity. Pediatrics. 1998;101(3):E5 14. Waterlow JC. Classification and definition of protein-calorie malnutrition. Br Med J. 1972;3(5826):566569. 15. Cahill GF Jr. Starvation in man. N Engl J Med. 1970;282(12):668675.
Obesity and Metabolic Disorders

Michelle Battista, BS, PhD Candidate and Robert Murray, MD
14
CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 What Is the Metabolic Syndrome in Adults? . . . . . . . . . . 150 Metabolic Syndrome Controversies AmongAdults . . . . . 150
Cut-points Etiology Synergistic Risk and Treatment
Learning Objectives
What Is the Metabolic Syndrome in Children? . . . . . . . . 151

Select Metabolic Syndrome Controversies in Children
1. Identify the components that comprise the metabolic syndrome diagnosis in the adult population. 2. Describe the most common reasons why the metabolic syndrome, as a diagnosable entity, has not been accepted in the pediatric population. 3. Learn about the Expert Committee Recommendations in pediatric practice. Since the early 1900s evidence has suggested the coexistence of chronic disorders associated with diabetes mellitus and coronary heart disease (CHD).1 It wasnt until the years between 1980 and 1990 that scientists developed an understanding of the mechanisms underlying the connection between obesity, hypertension, hyperlipidemia, and type 2 diabetes mellitus and its relationship to increased cardiovascular disease (CVD) risk. Metabolic syndrome was a term first used to describe how environmental and genetic factors work together to produce this constellation of chronic metabolic disorders.1 However, it was the earlier work of Gerald Reaven2 that set the precedent for how the metabolic syndrome is applied within the clinical world today. In 1988, Reavens Banting Lecture described the relationship between hyperinsulinemia, glucose intolerance, hypertension, and free-fatty acid metabolism and their association with CVD. Reaven hypothesized that the state of insulin resistance was the driver for metabolic change and represented the common pathophysiological link between these otherwise unrelated metabolic events.2 Through the 1990s, distinct perspectives on the etiology of metabolic syndrome began to emerge, coupled with the inclusion of additional biomarkers such as measures
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Applying the Metabolic Syndrome Cluster toaPediatric Population . . . . . . . . . . . . . . . . . . . . . . . . . 153 A Clinical Approach to the Identification of the Metabolic Syndrome and Its Attendant Cardiovascular Disease Risks. . . . . . . . . . . . . . . . . . . . . . 153
Establishing a Risk Factor Profile: Expert Committee Recommendations Role of Socioeconomic Status and Ethnicity Nutrition and Physical Activity Behaviors Acanthosis Nigricans
Introduction
Expert Committee Recommendations . . . . . . . . . . . . . . . 155

BMI Percentile The Family Health History Behaviors A Focused Review of Systems and TargetedPhysicalExamination Laboratory Analysis
The Element of Time. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 The Role of Weight Reduction, Proper Nutrition, and Physical Activity. . . . . . . . . . . . . . . . . . . . . 157 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
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of insulin resistance and markers of pro-inflammation to augment the original components. This newfound knowledge resulted in several monikers being applied: syndrome X, the deadly quartet, and the insulin resistance syndrome. However, in 1999 the term metabolic syndrome reappeared, now evolved from a hypothesis to a clinical entity. It is an emerging diagnosis applied to the adult population and, to a lesser extent, pediatrics. The diagnosis of metabolic syndrome has been subject to criticism, as much remains unknown about the cumulative risk of its components and the utility of making this diagnosis. 3,4 Despite these criticisms, identification of metabolic syndrome and its component disorders among adults or children offers useful information about the patients metabolic risk, particularly that associated with future cardiovascular morbidity and mortality. 5
diagnosable entity. The controversy begins with the criteria used. Currently, there are 3 sets of diagnostic criteria widely accepted for the metabolic syndrome. These include definitions from the National Cholesterol Education Program, Adult Treatment Panel III (NCEP-ATP III),6 the World Health Organization,7 and the International Diabetes Federation (IDF).8 Each of their components, etiological perspectives, and intervention strategies can be summarized (Table 14-1). Fundamentally, the components that comprise each of the metabolic syndrome definitions are similar. They feature a measure of body fatness, hypertension, triglycerides, high-density lipoprotein (HDL) cholesterol, and some measure of glucose intolerance. Yet, it is important to note the distinctive arrangement of diagnostic criteria and the management focus of the 3 definitions.
What Is the Metabolic Syndrome in Adults?
The early work of Hanefield and Reaven described the metabolic syndrome as a constellation of metabolic risk factors including obesity, hypertension, dyslipidemia, and glucose intolerance, all of which are associated with increased cardiovascular mortality. However, today the metabolic syndrome is no longer viewed as a novel concept, but has surfaced as a
Metabolic Syndrome Controversies AmongAdults
Lack of a single set of criteria for the metabolic syndrome in adults has created confusion among practitioners. Such inconsistencies hamper determinations of the specificity and sensitivity of the metabolic syndrome diagnosis, as well as its prevalence.9 Experts offer several reasons why a
Table 14-1 Etiology and Diagnostic Criteria of the Metabolic Syndrome in Adults
Diagnostic Criteria Etiological Underpinnings Recommendations
National Cholesterol Education Program, Adult Treatment Panel III (NCEPATP III)6 World Health Organization (WHO)7
International Diabetes Federation (IDF)8
Three or more of the following: 1) Abdominal Obesity 2) Elevated Triglycerides 3) Low HDL-Cholesterol 4) Hypertension 5) Raised Fasting Plasma Glucose A measure of glucose intolerance characterized by: 1) Impaired Glucose Tolerance 2) Impaired Fasting Glucose 3) Diabetes 4) Insulin Resistance Plus 2 or more of the following: 4) Abdominal Obesity 5) Elevated Triglycerides 6) Low HDL- Cholesterol 7) Hypertension 8) Microalbuminuria A measure of body fatness characterized by: 1) Abdominal Obesity Plus 2 or more of the following: 2) Elevated Triglycerides 3) Low HDL-Cholesterol 4) Hypertension 5) Raised Fasting Plasma Glucose
The etiological perspective focuses on risk for cardiovascular disease which is attributed to environmental and genetic causes. The etiological perspective focuses on ameliorating risk for type 2 diabetes mellitus which is attributed to the state of insulin resistance.
To control risk, NCEP-ATP III recommends weight control and physical activity as target therapeutic interventions. To control risk, WHO recommends weight control, physical activity, and the use of insulin sensitizing agents as target therapeutic interventions.
The etiological perspective focuses on the need to establish a universally accepted definition for metabolic syndrome in research and clinical practice.
Similar to the NCEP-ATP III, IDF recommends lifestyle changes including reducing calorie intake, increasing physical activity, and altering dietary habits to mitigate risk.
OBESITY AND METABOLIC DISORDERS
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consensus definition for the metabolic syndrome has not been reached.
Synergistic Risk and Treatment

Is the risk of metabolic syndrome greater than the sum of its parts? In other words, is it truly a syndrome? Even Gerald Reaven challenged the idea that the diagnosis of the metabolic syndrome was itself a clinical entity of greater value than its individual components. From a clinical standpoint, the influence of the metabolic syndrome suggests to the practitioner the presence of CVD risk and therefore should be fully evaluated and aggressively treated.4 Evidence implies that after adjusting for each of its individual components, the metabolic syndrome is no longer associated with early CVD mortality.18 In an analysis of diabetics and non-diabetics with the presence or absence of the metabolic syndrome, those with diabetes and the metabolic syndrome had the highest prevalence (19.2%) of CHD mortality, followed by individuals with metabolic syndrome only (13.9%). Despite this significant association of the metabolic syndrome and CVD mortality, multivariate analysis confirmed the presence of elevated blood pressure, diabetes, and low HDL cholesterol, not the metabolic syndrome, were significant predictors for CHD.19 Similarly, the evaluation of metabolic syndrome and the 11-year risk of incident CVD confirmed that when all 5 metabolic syndrome parameters are considered, metabolic syndrome as a whole does not incur greater CVD risk when compared with the sum of the individual components.20 Even though data suggest that the entity of the metabolic syndrome does not incur risk greater than the sum of its parts, it has been shown that individuals diagnosed with the cluster of disorders that comprise the metabolic syndrome suffer greater cardiovascular morbidity and mortality when compared with individuals without the syndrome. According to the NCEP-ATP III Framingham Risk Score, approximately one-third of individuals with the metabolic syndrome are classified as high risk. 21 As demonstrated in the Framingham Offspring and San Antonio Heart Study, the predicted risk of CHD in individuals with the metabolic syndrome was significant (11.8% and 9.8%, respectively) when compared with individuals without the metabolic syndrome (7% and 6.8%, respectively). Studies looking at incident CVD mortality indicate a twofold increase among individuals having the metabolic syndrome compared to those without the syndrome.19,20,22
Cut-points
Evidence has failed to identify appropriate cut-point values for any given metabolic component. Worldwide adoption of Westernized eating and physical activity behaviors has resulted in an increased prevalence of obesity, diabetes, stroke, and heart disease in what were once healthy populations. Researchers have learned that the degree of metabolic risk associated with developing CVD is distinct among people with diverse ethnic backgrounds. One good example is the differences of dyslipidemias among various ethnic groups. In the African American population, the standard cutoff values for triglycerides and HDL-cholesterol predicted insulin resistance is only 17%.10 Furthermore insulin resistance and triglycerides were found to be inverselycorrelated (ie, as insulin levels rose with insulin resistance, triglycerides fell). In this way markers for dyslipidemia within the range of normal may prove insensitive and fail to identify individuals, particularly African Americans, who are insulin resistant and at risk for cardiovascular damage.11 Furthermore, ethnic differences in metabolic risk have been reported for measures of waist circumference and hypertension among African Americans, Hispanics, Caucasians, Iranians, and Asians.9,1215 These findings justify the need to assess the obese patient with a tailored approach to capture global metabolic risks.
Etiology
Controversy around the metabolic syndrome has surrounded the criteria utilized to make the diagnosis. Because the etiological underpinnings of the metabolic syndrome are substantially altered by ethnic variability it is difficult to build a single, all-inclusive definition.1,4,9 Since Reaven, the basic connecting point uniting the various components has been insulin resistance. Yet even in this there is controversy. Some believe that the primary pathway leading to the metabolic syndrome is the result of glucose intolerance and diabetes9 whereas others suggest that glucose has no direct role in the metabolic syndrome or insulin resistance.16,17 These individuals promote the surprising hypothesis that it is disordered fat metabolism, not glucose metabolism, which is the etiologic prime mover for development of insulin resistance and, as a result, the metabolic syndrome. Although the current research has not yet detailed the sequence of events leading to the insulinresistant state that precedes the metabolic syndrome, mounting evidence supports the role of abnormal fat metabolism.16,17
What Is the Metabolic Syndrome in Children?
Similar to the adult classification of the metabolic syndrome, no consensus definition in the pediatric population exists, despite begin widely studied among adolescents. This has created further controversy in the utility of the metabolic
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syndrome in children. A recent review23 published in 2008 reported 40 unique definitions characterizing pediatric metabolic syndrome, most emanating from the NCEP definition for adults. 23 Depending on the criteria used to classify the syndrome, prevalence among obese children and adolescents ranges from 26% to 49.7%. 2426 However, there are a few fundamental problems with the metabolic syndrome in children and adolescents. 27 Lack of consensus on etiology, age, and developmentally appropriate cut-point measures for components of the metabolic syndrome in children, the effects of growth stage, puberty, and ethnicity as well as emerging evidence on the role of non-traditional risk factors, all need to be considered. This discussion will focus briefly on issues such as cut-points, puberty, and nontraditional risk factors including the pro-inflammatory state and anatomical changes to the vasculature. Brambilla et al 27 offers a more complete review of the major and minor concerns with the metabolic syndrome in children and adolescents. Furthermore, a scientific statement from the American Heart Association (AHA) was released in 2009. In this update to the 2003 report, the AHA provides a more comprehensive synopsis of the current advancements, challenges, and limitations to applying the metabolic syndrome to the child and adolescent populations. 28
standardized protocol has been accepted for obtaining its measurement in clinical practice. 34 Puberty Perhaps the greatest confounding factor for the application of metabolic syndrome in pediatrics is the change of the bodys metabolic milieu that occurs during the years of puberty. The combined metabolic effects of growth hormone and insulin-like growth factor 1 (IGF-1) are associated with a normal state of mild insulin resistance, which follows the onset of puberty. 35 Furthermore, this phenomenon appears to be independent of body fat. 36 Thus, from the standpoint of the metabolic syndrome, puberty-induced insulin resistance complicates the task of attributing insulin resistance to the normal pubertal changes versus the metabolic consequences of overweight and obesity. Non-Traditional Cardiovascular Risk Factors Insults to the cardiovascular system are associated with obesity and insulin resistance in childhood and adolescence. Formation of plaques and fatty streaks, deposited in the blood vessel walls, are associated with abnormal lipids and high blood pressure. All of these abnormalities have been found among obese children and adolescents. For example, excess body weight drives metabolic change resulting in insulin resistance and even vascular dysfunction. Over time anatomical changes to the arterial wall begin to develop and by some are thought to be the earliest indicators of risk for CVD. 37,38 Further damage to the blood vessel wall compromises arterial distensibility. At this point the ability for the blood vessel to contract and relax is compromised. Vascular resistance rises and high blood pressure ensues. 37 Disruption of the anatomical and physiological integrity of the vascular system appears to develop silently during childhood, even as young as age 5. The persistence of these anatomical vascular changes signifies a new wave of non-traditional cardiovascular risk factors that, like hypertension and dyslipidemia, need to be evaluated and treated aggressively. Happily the evidence demonstrates that through physical activity and proper nutrition these changes can be reversed. 37 Since Reavens lecture in 1988, another major finding has occurred that has expanded our perspective on the metabolic syndrome. Chronic inflammation has been found not only to be closely associated with obesity in adults, children, and adolescents but also connected with each element of the metabolic syndrome. 3942 This interconnectedness shapes the development of CVD. Among a number of actions, chronic inflammation, as identified by the biomarker highsensitivity C-reactive protein (hs-CRP), promotes platelet
Select Metabolic Syndrome Controversies in Children

Cut-point Pediatric-specific cut-points that are sensitive to age, gender, and ethnicity have not been adapted for the majority of the metabolic syndrome components,27,29,30 thus making it difficult to classify the syndrome as a diagnosable entity in the pediatric population. Wide variations in pediatric-specific cut-points have been found across studies23 with many assigning arbitrary threshold values with no proven basis to predict future health risk. 31 One example that is subject to much debate is the value of waist circumference to substantiate metabolic syndrome risk in children. Some argue that measurements of visceral fat, when compared with other measures of body fatness, are the single most predictive anthropometric value of the metabolic syndrome. 32 However, in children, percentile values for waist circumference are poorly established across age groups. Furthermore, the currently established cut-point references for waist circumference in children are not suitable for all ethnic populations, as most guidelines result from studies conducted in white, European descendents. 33 Even if the appropriate, age-specific cut-points were established for children, the value of waist circumference is arbitrary, as no
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adhesion, a critical step in the expansion of atherosclerotic plaques. Further, in CVD the atherosclerotic lesion is expanded and made unstable by the influx of inflammatory cells, resulting in heart disease and stroke.43 This link between the immune-inflammatory system and the bodys metabolism is a consequence of cytokines secreted from excess adipose tissue. Far from being a passive storage site for triglycerides, the adipocyte produces a vast array of chemokines with paracrine and endocrine functions.44,45 Among them are several pro-inflammatory cytokines. Not all adipocytes are the same. Visceral fat is far more inflammatory than peripheral fat, explaining why waist circumference, as a proxy for visceral fat, is such a key sign when assessing risk in obese patients.46,47 Such adipokines released from metabolically active adipose tissue include tumor necrosis factor-alpha (TNF-), C-reactive protein, and interleukin-6 (IL-6), all of which have been implicated in accelerating the atherosclerotic process.44,45 Obesity and the subsequent pro-inflammatory state are suspected as the underlying mechanisms responsible for the progression of insulin resistance. Consequently, the triad of obesity, inflammation, and insulin resistance is associated with the metabolic syndrome in children. Children and adolescents who are morbidly obese are more insulin resistant and present with higher levels of inflammatory biomarkers including IL-6, intracellular adhesion molecule-1 (ICAM), and E-selectin, compared to lean counterparts.42,46 In obese children and adolescents, the presence of traditional metabolic syndrome components is associated with non-traditional risk factors such as CRP and IL-6.4750 Furthermore, early functional and morphological changes to cardiovascular function, measured by intima-media thickness and flow-mediated dilation, are present with markers of inflammation and the metabolic syndrome. 39,43,51 Non-alcoholic fatty liver disease (NAFLD) has also been implicated as an adverse consequence of carrying excess weight in childhood. In general it is estimated that 38% of obese children have NAFLD. 52 Diagnosis is confirmed by liver biopsy. The relationship between NAFLD and the presence or development of the metabolic syndrome is less understood, particularly in the pediatric population. However, evidence shows a positive correlation between increased levels of aminotransferases and the number of metabolic syndrome risk factors present among children diagnosed with NAFLD. 53 Schwimmer et al54 demonstrated that children with NAFLD have significantly more CVD risk factors associated with the metabolic syndrome than children without NAFLD. 54 Although
more studies are needed to determine the pathophysiology, natural history, and treatment of NAFLD, 55 an expert committee recognizes that the biomarkers for liver function, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are reasonable markers for NAFLD and are an important part of the laboratory assessment of the obese child. 56 The Expert Committee recommendations appear later in this chapter (Table 14-2).
Applying the Metabolic Syndrome Cluster toaPediatric Population
Irrespective of the ability to make a formal diagnosis of the metabolic syndrome in the pediatric population, evidence of the clustering of the metabolic syndrome components in children and adolescents suggests (1) that the bodys metabolic milieu is adapting to the presence of excess body fat, (2) that the clustering of metabolic risk factors infer greater risk for CVD mortality compared with peers who do not present with the metabolic syndrome phenotype, and (3) that the collective and individual metabolic risks represent a high-risk finding among children and adolescents. Developing metabolic risk at a young age implies that the health burden of cardiovascular damage will be greatly amplified by time the child ages into adulthood. The imperative raised in the original concept of the metabolic syndrome remains, which was to identify insulin-resistant individuals at greatest risk for CVD and in most urgent need for lifestyle intervention.4 The overweight pediatric patient represents the leading edge of cardiovascular risk. A comprehensive approach to the assessment of metabolic syndrome and its components allows the pediatrician to observe the development of metabolic risk at its earliest stages and intervene to arrest the prospect of lifelong CVD risk.
A Clinical Approach to the Identification of the Metabolic Syndrome and Its Attendant Cardiovascular Disease Risks
Establishing a Risk Factor Profile: Expert Committee Recommendations56
Essentially, risk is defined as someone or something in a state of high susceptibility. Factors indicating future risk for disease are evident at a young age. The clinical utility of the metabolic syndrome to establish a childs risk profile may be greatly enhanced when combined with other clinical practice tools that help identify disease risk. Family history, race, socioeconomic status, and eating and physical activity behaviors all contribute to the future health risk of the child. For example, children having a first-degree
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relative with type 2 diabetes mellitus double their risk for developing the disease. 57 Furthermore, the components of the metabolic syndrome are documented to track across generations. In the Northern Manhattan Family Study, 58 the heritability of metabolic syndrome components was strikingly significant. 58 Among overweight and obese Hispanic youth, genetic determinants appear to predict the components of metabolic syndrome, as 68% and 60% of children, respectively, reported a family history of diabetes and cardiovascular disease. 59
Role of Socioeconomic Status and Ethnicity

Low socioeconomic status is highly associated with the development of overweight and obesity among American children.6062 Lower cumulative family income is significantly associated with the onset of health conditions that limit childhood activities and require treatment by a pediatrician.61 However, in other countries lower socioeconomic class does not necessarily indicate higher prevalence of health risk. In fact, Chinese and Russian children from upper-level income groups are reported to have a higher incidence of overweight and obesity compared with middle and lower socioeconomic groups, an indication of access to a more Western lifestyle.62 Furthermore, when socioeconomic status is a factor along with race/ethnicity, the risk for obesity is even greater. For example, Hispanic and black children from lower socioeconomic groups are significantly at greater risk for obesity than their Caucasian counterparts.63
study looking at Saturday morning TV broadcasts, more than 50% of the commercials featured promoted food items and over 90% of these food-oriented commercials featured high-sugar/salt and high-fat foods.66 As Halford67,68 et al found, overweight and obese children respond to such advertisements by consuming more calories and choosing more snack foods after viewing such broadcasts.65,66 In light of the sedentary behaviors that children and adolescents are displaying today, recent national recommendations emphasize that children participate in at least 1 hour of moderate to vigorous physical activity each day. 56 These recommendations are based on evidence from a systematic review that highlights the effects of physical activity on health and behavioral outcomes.69 Children who participate in higher levels of physical activity are leaner. For those children who are overweight and obese, physical activity has been shown to reduce total body fat provided these children are physically active for 30 to 60 minutes 3to7 days per week. When examining variables of cardiovascular health, a consistent level of physical activity improves high-density lipoprotein (HDL) cholesterol and triglycerides in high-risk children. Changes to the cardiovascular risk profile have been found to occur irrespective of any significant changes in weight reduction.69
Acanthosis Nigricans
Insulin resistance and subsequent hyperinsulinemia initiate a series of cascading metabolic events signaling total body changes in metabolism. Ultimately the clustering of metabolic parameters, as seen in the metabolic syndrome, brings attention to the serious health risks that are associated with insulin resistance and obesity. Furthermore, such metabolic changes identify individuals in most urgent need for lifestyle intervention. Essentially, identifying certain physical signs may alert clinicians early in the clinical course. Risk associated with family history, socioeconomic status, and nutrition and physical activity behaviors may be effective screening tools for prevention activities. However, as evidence suggests, a substantial number of children and teens already have acquired the first signs of metabolic changes, which will with time place a serious health burden on their cardiovascular system. Unlike family history, ethnicity, lifestyle, behavior, and body mass index (BMI) that predict future health burdens, the skin sign of acanthosis nigricans represents a physical manifestation of existing metabolic change. Several studies indicate that acanthosis nigricans is relatively common among children and adolescents, particularly those who are obese. In a broad population
Nutrition and Physical Activity Behaviors

A recent review by the members of the American Dietetic Association examined the relationship between eating and sedentary behaviors on the development of overweight and obesity in childhood.64 Consuming large amounts of sugarsweetened beverages and fruit juices was found to increase caloric intake and displace more nutritious foods from the diet. Although at this time evidence is lacking to support the relationship between sugar-sweetened beverages, fruit juices, and increased adiposity, epidemiological evidence has suggested that fruit and vegetable consumption may be protective against the development of childhood obesity.64 Sedentary lifestyle behaviors have also been implicated as a potential cause of pediatric overweight and obesity. A recent study showed that 35% of boys and 25% of girls watch 4 or more hours of television (TV) each day.65 Irrespective of socioeconomic status and race, children who watch more TV are less physically active and are more overweight.63 Furthermore, TV watching also influences appetite, particularly if the child is already overweight or obese. In one
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the prevalence of acanthosis nigricans among African American, Hispanic, and Caucasian youth is 19.4%, 23.1%, and 4.9%, respectively.70 However, when overweight and obese sub-populations are examined specifically, rates of acanthosis nigricans are much higher. Among an ethnically diverse sample of obese children, acanthosis nigricans was seen in 46%. With rates of obesity beyond the 99th percentile, children present with acanthosis nigricans 70% of the time.70 National directives have recognized acanthosis nigricans screening as a non-invasive tool to identify burgeoning changes in metabolism that are associated with numerous risk factors for CVD, including abnormal lipid and glucose metabolism.7174 Pediatricians are urged to obtain laboratory tests on overweight and obese children who present with acanthosis nigricans including a complete fasting lipid profile, fasting glucose, and markers of liver function. 56
The Family Health History

Family health history is a strong indicator of future health risk for a child, particularly if the risk is identified in a firstdegree relative. However, unlike the other health risks, family health history is not modifiable. It does, however, represent an important context for a discussion about a childs risk for chronic diseases that are fueled by excess body weight.
Behaviors
A targeted history should capture information about nutrition and physical activity habits of the overweight or obese child and the family. This information should serve as the baseline and basis for prevention and intervention counseling directed both at the child and the family.
Expert Committee Recommendations56
A Focused Review of Systems and TargetedPhysicalExamination

The focused review of systems and targeted physical examination of the child should be comprehensive in nature and include, but not be limited to, the presence of anxiety, polyuria/dipsia, headaches, sleep problems, abdominal pain (a focused review of systems); acanthosis nigricans, the presence of dysmorphic features, hirsutism and extreme acne, tonsillar hypertrophy, abdominal tenderness, unexpected rates of linear growth, and undescended testicles. A crucial part of the childs physical exam should be the blood pressure, but it must be obtained using the correct cuff size at rest. The results are then assessed using tables comparing systolic and diastolic readings against normals for the childs height percentile to ascertain at risk values over the 90th percentile and hypertensive values above the 95th percentile.76
Due to the lack of a standard definition to diagnose the metabolic syndrome in the adult and pediatric populations, the best course of treatment for individuals with the syndrome remains to be determined. Experts disagree on whether the metabolic syndrome should be treated differently from the treatment prescribed for the individual components of the syndrome. Some counsel a more comprehensive approach to treatment for patients with the metabolic syndrome. Yet what we do know is the chronic disease components that derive the metabolic syndrome are a direct result of excess adiposity and subsequent insulin resistance. Therefore, national directives established by an expert committee may be used as a guideline to assess overweight and obese children and adolescents for health risks and mediate with the appropriate lifestyle and treatment interventions. These evidence-supported guidelines were published as a supplement to Pediatrics in December 2007, titled the Expert Committee Recommendations Regarding the Prevention, Assessment, and Treatment of Child and Adolescent Overweight and Obesity.56 There are 6 steps to consider when assessing a childs health risk in a practice-based setting:
Laboratory Analysis
More invasive testing is required for overweight and obese children to identify health risks that may be otherwise hidden. It is important to note that Expert Committee56 guidelines on further laboratory testing mirror most of the components that comprise the metabolic syndrome. Table 14-2 lists what labs should be drawn at what degree of obesity and at what age. The physician also should explore concerns raised during the history and physical exam, investigated fully along with the testing recommended for all overweight children. The above have been described by the Expert Committee56 more explicitly and provide the pediatrician with practice-ready guidelines to assess the global health risk of the overweight or obese child. Furthermore, these
BMI Percentile
At least annually, but ideally at each well child visit, the childs height and weight should be measured and the BMI percentile value should be calculated and plotted on the growth chart. The pediatrician should be looking for BMI percentile trends that show an increasing weight-for-height trajectory and classify the child as underweight, normal weight, overweight, or obese. 56,75
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Table 14-2 Laboratory Testing Guidelines Based on Age, BMI Percentile, and Risk Factors Present
Laboratory Testing Parameters Fasting Lipid Profile (Cholesterol, HDL,LDL, and Triglycerides) Fasting Glucose (Every 2 years) Hepatic Function (ALT and AST; Every 2years)
Age 29 years BMI % 85th95th (with no additional risk factors*) BMI % > 85th95th (with additional risk factors*) BMI % > 95th99th (with or without additional risk factors*) BMI % > 99th (with or without additional risk factors*) Age 1018 years BMI % 85th95th (with no additional risk factors*) BMI % > 85th95th (with additional risk factors*) BMI % > 95th99th (with or without additional risk factors*) BMI % > 99th (with or without additional risk factors*)
X X X X
X X X X X X X X X X
*Risk factors refer to those risks found during the assessment of family history and physical examination. The laboratory guidelines recommended by the Expert Committee are merely baseline recommendations. Any concerns found during the assessment of the family history and/or physical examination should be evaluated and monitored.
recommendations emphasize the need for risk identification to occur sooner in the childs life, rather than later, as identification of these health risks ultimately leads to the establishment of an intervention program targeted at reducing obesity-related comorbidities and controlling body weight. CVD morbidity and mortality is the ultimate outcome of individuals who carry metabolic risk. The younger the child is when metabolic risk is acquired, the higher the likelihood of tracking these components into adulthood.7779 For example, if overweight status continues past their first decade of life, excess body weight tracks into adulthood for 80% of them.77,80 On examining the metabolic syndrome, metabolic predictors also track quite well across childhood, through young adulthood and into adulthood.78,79 The diagnosis of the metabolic syndrome in childhood increases the odds of developing the metabolic syndrome and type 2 diabetes mellitus in adulthood 9-fold and 11-fold, respectively.79 Examining metabolic changes associated with the metabolic syndrome among elementary age children reveals a startling trend. When adult definitions are adjusted to reflect the pediatric-specific cut-points, the prevalence of metabolic syndrome among pre-pubescent overweight and obese children ranges from 39% to 59%.81 Even more sobering is the number of children who exhibit at least
The Element of Time
1 metabolic abnormality secondary to obesity. In urban Mexico, among obese school-aged children screened for metabolic syndrome risk, 90% had insulin resistance based on the homeostasis model assessment (HOMA). In addition, 14% of all children screened were at risk for or already frankly hypertensive.82 In eastern Kansas, 18% and 37% of elementary school children had elevated blood pressure or triglycerides, respectively.83 The most common metabolic abnormalities among overweight school-aged children from urban Chicago screening were impaired fasting glucose (21%), raised triacylglycerols (11%), and elevated blood pressure (11%).84 Fortunately in pediatrics, the elements of time and growth are on our side. Yet, time is a double-edged sword for overweight children. Left untreated, the morbidity associated with the array of comorbidities is magnified over time. So, children identified with risk factors in their first decade will face health challenges even in their young adulthood and middle age. Yet, data indicate that the cardiovascular consequences of metabolic dysfunction are reversible if detected early and corrected with appropriate management, including a highly nutritious diet and improved fitness. 37 Therefore, the call to healthcare providers is to focus on mitigating risks in very young children, especially because the metabolic syndrome is unreliable in the pubescent population. Recent national recommendations on lipid screening85 recognized the long-term consequences of obesity on
157
children in their first decade of life. The committee recommends screening children with risk factors beginning at the age of 2 years with close follow-up, particularly where there is a strong family history.85
The underlying driver of metabolic dysfunction is excess adipose tissue. Therefore, fundamentally, the initial treatment is optimal nutrition, increased physical activity/ physical fitness, and weight maintenance. Evidence shows that for the obese patient a modest reduction in excess body weight of as little as 5% to 7% induces significant health benefits, including a decrease in triglycerides, LDL, and VLDL cholesterols; raised HDL cholesterol; lowered blood pressure; and improvements in insulin action with improved glucose status.86,87 Optimal nutrition, particularly a diet rich in fruits, vegetables, and low-fat dairy (as described in the DASH diet) has been shown to prevent increases in blood pressure during early childhood. 88 The DASH diet significantly improved measures of systolic and diastolic blood pressure among adolescents with documented hypertension.89 Physical activity alone is documented to alter CVD risk. In the prevention of coronary artery disease, individuals who are more physically active cut their risk in half, compared with sedentary individuals. In adults, comprehensive lifestyle interventions that include physical activity result in modest reductions in body fat, 5% to 7%, and demonstrate significant health benefits, starting with a lowered insulin resistance. 86,87 Irrespective of weight loss, exercise alone still demonstrates improvement of CVD outcomes. Among individuals with established CVD, exercise-only interventions significantly reduce cardiac mortality and total mortality by 31% and 27%, respectively.90 The physiological and functional changes to the vasculature develop silently during childhood and are fueled by obesity. As mentioned, the damage is amenable if detected early and intervention is administered. For obese children and adolescents already presenting with early CVD risk the use of exercise training has been supported as one management strategy. Irrespective of significant reductions in weight, exercise training demonstrates marked improvementin endothelial dysfunction. Worsening endothelial dysfunction, measured by flow-mediated dilation, is a predictor of future adverse cardiovascular events and correlates with measures of body fatness. Children who perform exercise training,
The Role of Weight Reduction, ProperNutrition, and Physical Activity
particularly high-intensity exercise training, show marked improvement in vascularfunction.9193 Mounting evidence in support of optimal nutrition, physical activity, and weight maintenance to ameliorate obesity and therefore lessen CVD risk, has prompted the Expert Committee56 to establish 9 core messages for pediatricians to reinforce as preventive and treatment strategies, applicable both for low-risk and high-risk children. Evidence-informed prevention and treatment goals should focus on: 1) Limiting sugar-sweetened beverages 2) Encouraging a healthful diet with at least 9 servings of fruits and vegetables 3) Limiting television and screen time to 2 hours a day or less 4) Eating breakfast daily 5) Limiting eating out away from home 6) Encouraging family meals 7) Limiting portion sizes 8) Engaging in 1 hour or more of moderate to vigorous physical activity each day 9) Breastfeeding exclusively until 6 months of age For some high-risk children, optimal nutrition, physical activity, and weight maintenance efforts are ineffective at controlling weight and reducing the burden of comorbidities. A more aggressive intervention is required. Lipid-lowering drug therapies, particularly statins, have been approved for use in children, as young as 8 years of age at the highest risk.85 It is important to emphasize that pharmacological treatments have demonstrated safety and effectiveness among high-risk children and adolescents only94 and are not recommended for children presenting with moderate lab values or risk. Similarly, bariatric weight-loss surgery has been used in the United States as a treatment option for morbidly obese adolescents. Bariatric weight loss in this population is proven to be successful at mitigating the comorbidities of excess body weight.95 However, an expert panel of pediatricians and surgeons has recommended that candidates demonstrate certain physical and psychological readiness before receiving bariatric surgery.95 Therefore, whether the treatment for the obese child includes pharmacological or surgical intervention, it is crucial for the practitioner to assess the risk status of the child. Utilizing practice-ready tools and guidelines provided by the Expert Committee on the Assessment, Prevention and Treatment of Child and Adolescent Overweight and Obesity56 can assist the practitioner in evaluating risk and making decisions on the appropriate treatment course for the obese child or adolescent.
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In the decade following Reavens Banting Lecture in 1988, 2 the metabolic syndrome evolved from a concept to a diagnosis. Despite providing useful information on metabolic risk and the susceptibility for developing CVD, the clinical utility of the metabolic syndrome diagnosis remains controversial among researchers in adult and pediatric medicine. Among children and adolescents, the lack of consensus on the definition of the metabolic syndrome is compounded by (1) the inability to define metabolic thresholds using pediatric-specific cut-points, (2) the role of natural metabolic changes during puberty, and (3) the application of emerging, non-traditional CVD risk factors in the metabolic syndrome definition. But the very presence of the metabolic syndrome in the pediatric population suggests that a shift in metabolism fueled by excess body weight is underway. Further, the presence of risk factors in early childhood means that damage to the cardiovascular system has begun. When metabolic risk factors present in a cluster, the clinical course and health outcomes for that child are compromised, unless interventions are undertaken. The Expert Committee on the Assessment, Prevention and Treatment of Child and Adolescent Overweight and Obesity56 underscored the role of the clinician to identify metabolic risk factors at the earliest stage possible, institute treatment, and follow up closely. Identification of metabolic risk in a child may prove beneficial for several reasons: (1) the threat of evolving cardiovascular damage throughout the lifespan can be reversed, if identified early and coupled with aggressive lifestyle changes, and (2) weight management is easier due to growth, along with the potential to influence home and school environments. Practice-ready guidelines emphasize a 6-step approach to assessing health risk in practice. For children at any risk level, the Expert Committee56 recommends evidence-based counseling supported by the 9 core messages for prevention and treatment. For children presenting with substantial health risks associated with the metabolic syndrome, pediatricians should focus on a comprehensive intervention strategy, including optimal nutrition, physical activity, weight maintenance, and, when appropriate, pharmacological and/or surgical intervention.
Summary
1. Which factors are most restrictive in the diagnosis of the metabolic syndrome in pediatrics? A. Puberty B. Ethnicity C. Gender D. Established cut-points E. Lack of consensus on the clinical component disorders of the metabolic syndrome 2. Which of the following was not an original intention of the metabolic syndrome as a conceptual entity? A. To identify the most at-risk individuals for cardiovascular disease B. To establish the clinical cluster as a diagnosable entity C. To explain the connection between otherwise unrelated metabolic events D. To identify an individual in most urgent need of lifestyle intervention 3. After identifying a 5-year-old child with a body mass index > the 95th percentile, what would be the most inappropriate next steps in the childs care? A. Obtain a detailed family history B. Discuss lifestyle behaviors C. Perform a targeted physical exam and review of systems D. Obtain a laboratory analysis E. Refer to sub-specialty care F. Simply monitor the childs weight over the next 12 months See p. 487 for answers.
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54. Schwimmer JB, Pardee PE, Lavine JE, Blumkin AK, Cook S. Cardiovascular risk factors and the metabolic syndrome in pediatric non-alcoholic fatty liver disease. Circulation. 2008;15:277283. 55. Barshop NJ, Sirlin CB, Schwimmer JB, Lavine JE. Review article: epidemiology, pathogenesis and potential treatment of paediatric non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2008;28:1324. 56. Barlow SE; Expert Committee. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics. 2007;120:S164S192. 57. Dallo FJ, Weller SC. Effectiveness of diabetes mellitus screening recommendations. Proc Natl Acad Sci. 2003;100:1057410579. 58. Lin HF, Boden-Albala B, Juo SH, Park N, Rundek T, Sacco RL. Heritabilities of the metabolic syndrome and its components in the Northern Manhattan study. Diabetologia. 2005;48:2006-2012. 59. Butte NF, Comuzzie AG, Cole SA, et al. Quantitative genetic analysis of the metabolic syndrome in Hispanic children. Pediatr Res. 2005;58:12431248. 60. Goodman E. The role of socioeconomic status gradients in explaining differences in US adolescents health. Am J Public Health. 1999;89:15221528. 61. Chen E, Martin AD, Matthews KA. Trajectories of socioeconomic status across childrens lifetime predict health. Pediatrics. 2007;120:e297e303. doi:10.1542/peds.20063098. 62. Wang Y. Cross national comparison of childhood obesity: The epidemic and the relationship between obesity and socioeconomic status. Int J Epidemiol. 2001;30:11291136. 63. Singh SG, Kogan MD, Van Dyck PC, Siahpush M. Racial/ ethnic, socioeconomic, and behavioral determinants of childhood and adolescent obesity in the United States: analyzing independent and joint associations. Ann Epidemiol. 2008;18:682695. 64. American Dietetic Association. Factors associated with childhood overweight. http://www.adaevidencelibrary.com/topic. cfm?cat=2792. Accessed December 3, 2008. 65. Marshall SJ, Gorely T, Biddle SJH. A descriptive epidemiology of screen-based media use in youth: a review and critique. J Adolesc. 2006;29:333349. 66. Kotz K, Story M. Food advertisements during childrens Saturday morning television programming: are they consistent with dietary recommendations? J Am Diet Assoc. 1994;29:12961300. 67. Halford JC, Gillespie J, Brown V, Pontin EE, Dovey TM. Effect of television advertisements of foods on food consumption in children. Appetite. 2004;42:221225. 68. Halford JC, Boyland EJ, Hughes GM, Stacey L, McKean S, Dovey TM. Beyond brand-effect of television food advertisements on food choice in children: the effects of weight status. Public Health Nutr. 2008;11:897904. 69. Strong WB et al. Evidence based physical activity for schoolage youth. J Pediatr. 2005;146:732737.
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85. Daniels SR, Greer FR, and the Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics. 2008;122:198208. 86. McBride PE, Einerson JA, Grant H, et al. Putting the diabetes prevention program into practice: a program for weight loss and cardiovascular disease reduction with metabolic syndrome or type 2 diabetes mellitus. J Nutr Health Aging. 2008;12:745s749s. 87. Racette SB, Weiss EP, Hickner RC, Holloszy JO. Modest weight loss improves insulin action in African Americans. Metabolism. 2005;54:960965. 88. Moore LL, Singer MR, Bradlee ML, et al. Intake of fruits, vegetables and dairy products in early childhood and subsequent blood pressure changes. Epidemiol. 2005;16:411. 89. Couch SC, Saelens BE, Levin L, Dart K, Falciglia G, Daniels S. The efficacy of a clinic based behavioral nutrition intervention emphasizing a DASH-type diet for adolescents with elevated blood pressure. J Pediatr. 2008;152:494502. 90. Thompson PD, Buchner D, Pina IL, et al. American Heart Association Council on Clinical Cardiology Subcommittee on Exercise, Rehabilitation, and Prevention; American Heart Association Council on Nutrition, Physical Activity, and Metabolism Subcommittee on Physical Activity. Exercise and Physical Activity in the Prevention and Treatment of Atherosclerotic Cardiovascular Disease: A Statement from the Council of Clinical Cardiology and the Counsel on Nutrition, Physical Activity and Metabolism. Circulation. 2003;24:31093116. 91. Hopkins ND, Stratton G, Tinken TM, et al. Relationships between measures of physical fitness, physical activity, body composition, and vascular function in children. Atherosclerosis. 2009; 204:244249. 92. Meyer AA, Kundt G, Lenschow U, Schuff-Werner P, Kienast W. Improvement of early vascular changes and cardiovascular risk factors in obese children after a six-month exercise program. J Am Coll Cardiol. 2006;7:18651870. 93. Watts K, Beye P, Siafarikas A, et al. Exercise training normalizes vascular dysfunction and improves central adiposity in obese adolescents. J Am Coll Cardiol. 2004;19:18231827. 94. McCrindle BW, Urbina EM, Dennison BA, et al. American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee; American Heart Association Council of Cardiovascular Disease in the Young; American Heart Association Council on Cardiovascular Nursing. Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing. Circulation. 2007;115:19481967. 95. Spear BA, Barlow SE, Ervin C, et al. Recommendations for treatment in children and adolescents with overweight or obesity. Pediatrics. 2007;120:S254S288.
Lipid Disorders
Shirley Huang, MD, and Melanie Katrinak, RD, CSP, LDN
15
Learning Objectives
1. Understand cardiovascular disease risk and the etiologies of lipid disorders. 2. Describe how to screen for lipid disorders and interpret lab results. 3. Discuss the role of dietary factors and physical activity in treating lipid disorders.
CONTENTS
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 Types of Lipid Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Genetic Polygenic Other
Screening and Lab Interpretation. . . . . . . . . . . . . . . . . . . 163

Dietary Cholesterol Dietary Fats Simple Carbohydrates Fiber Plant Sterols/Stanols Omega-3 Fatty Acids Soy Protein Garlic Antioxidants Physical Activity
Background
Pharmacologic Intervention . . . . . . . . . . . . . . . . . . . . . . . 167
Cardiovascular disease (CVD) remains the leading cause of death and morbidity in the United States.1 Risk factors for CVD include family history of early heart disease, abnormal serum cholesterol levels, high blood pressure, insulin resistance, diabetes mellitus, physical inactivity, obesity, cigarette smoking, and certain medications. The specific abnormal serum cholesterol levels include a high concentration of low-density lipoprotein (LDL) cholesterol, a low concentration of high-density lipoprotein (HDL) cholesterol, and high triglycerides. While CVD is considered an adult disease, research has shown that the process of arthrosclerotic CVD begins early in life and is progressive throughout the lifespan.24 High cholesterol in childhood accelerates the atherosclerotic process and places the child at risk for CVD as an adult. Children with high LDL cholesterol are also likely to have high levels as adults. 5 With increasing rates of obesity in children over the past 3 decades, the rates of obesity-related lipid disorders have also risen.6,7 Nutrition intervention during childhood plays a critical role in CVD prevention and dyslipidemia treatment to reduce the risk of CVD.
162
LIPID DISORDERS
163
Types of Lipid Disorders

Genetic
Two of the most common genetic lipid disorders will be described. These disorders are unique and require an individualized diet and treatment plan with a lipid specialist and registered dietitian or other skilled clinician. Familial Hypercholesterolemia There are 2 types of familial hypercholesterolemia (FH): homozygous FH and heterozygous FH. Homozygous FH is rare, with an occurrence of approximately 1 in 1 million, with total cholesterol levels ranging from 600 to 1000 mg/dL. Skin xanthomas (cholesterol plaques) may also be found in these patients at birth or before 6 years of age. Angina pectoris and myocardial infarction can occur before 6years of age. Heterozygous FH has an occurrence from 1 in 200 to 1 in 500, with total cholesterol levels exceeding 230 mg/dL and LDL cholesterol exceeding 160 mg/dL. No other clinical symptoms are present in the first decade of life, but by the second decade, tendon xanthomas of the hands may be found in 10% to 15% of the children.8 Nearly all patients with FH require medications in addition to lifestyle behavior interventions to normalize, or at least improve, their LDLlevels.1 Lipoprotein Lipase Deficiency Lipoprotein lipase (LPL) deficiency results in high levels of triglycerides, which presents in infancy with abdominal pain and hypertriglyceridemia.8 Because LPL deficiency involves a specific metabolic abnormality or defect, dietary intervention requires only restriction in fat and not simple carbohydrates (compared to polygenic hypertriglyceridemia which responds to a restriction of simple carbohydrates). Treatment requires long-term weight control and a diet of 20 g of fat daily. The diet can be supplemented with medium-chain triglycerides (MCTs), which will not increase triglyceride levels, to provide another source of fat and calories.
triglyceride levels, low HDL levels, abdominal obesity, high blood pressure, insulin resistance, and fatty liver increases the risk of CVD and diabetes mellitus.6,9,10 In children who are obese with a body mass index 95th percentile for age and gender, 52% have high triglycerides, and 50% have low HDL levels.6 Children with polygenic hypercholesterolemia often respond well to nutrition and lifestyle behavioral interventions.
Other
Other causes of lipid disorders include medications and certain disease states. Medications such as progestins, anabolic steroids, glucocorticoids, psychotherapeutic drugs, and retinoic acid acne treatment can cause abnormal lipid levels. In addition, diseases such as untreated hypothyroidism, renal disease, polycystic ovarian syndrome (PCOS), or liver disease may also cause dyslipidemias.11
Screening and Lab Interpretation
Tables 15-1 and 15-2 indicate who should be screened for lipid disorders and the screening procedure. Interpretation of the resultant fasting lipid profile is delineated in Table 15-3.
Table 15-11
Who to screen?
Any patient > 2 years of age with any of the following CVD risk factors: A parent, grandparent, aunt, or uncle with cardiovascular disease < 55 years (male) or < 65 years (female). Cardiovascular disease includes: myocardial infarction, sudden cardiac death, coronary bypass surgery, balloon angioplasty, angina pectoris, coronary atherosclerosis, peripheral vascular disease, or stroke or A parent with a total cholesterol > 240 mg/dL or A family history that is not available (adopted child) or Other cardiovascular risk factors: obesity (BMI > 95th percentile), sedentary lifestyle, smoking, hypertension, diabetes, congenital heart disease, renal disease or Treatment with retinoid acid, anticonvulsants, or oral contraceptives Table 15-21
Polygenic
Of all types of lipid disorders, polygenic hypercholesterolemia (nonfamilial) is the most common. Lifestyle factors such as diet, weight, and physical inactivity combined with a genetic susceptibility are the cause of this form of dyslipidemia. High triglycerides and low HDL levels are often seen with obesity and/or a diet with food and drinks high in simple carbohydrates. In the metabolic syndrome (Chapter 14), a constellation of findings including high
How to screen?
After a 9-12 hour fast, obtain a fasting lipid profile that includes: Total cholesterol (TC) High-density lipoprotein cholesterol (HDL) Triglycerides (TG) Low-density lipoprotein cholesterol (LDL), calculated* If TG > 400 mg/dL, a Direct LDL needs to be ordered
* Calculated LDL = TC(HDL-TG/5) (if TG < 400 mg/dL)
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Figure 15-1
*A more conservative HDL cut-point is chosen here. HDL > 40 mg/dL is a cut-point used in pediatric and adult metabolic syndrome.1,6 The American Heart Assocation recommends HDL > 35 mg/dL in pediatrics.20
Adapted from The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).1
Nutrition Management
The emphasis on a healthy diet and lifestyle is key in the prevention of CVD and treatment of abnormal lipid levels.12 To prevent CVD in all children 2 years old, recommendations include a daily diet with total fat < 30% total calories, saturated fat < 10% of total calories, trans fat < 1% of total calories, and dietary cholesterol < 300 mg.1 Furthermore, CVD prevention also includes increasing consumption of fruits, vegetables, fish, whole grains, and reduced-fat dairy products while reducing the intake of fruit juice, sugarsweetened beverages and foods, and salt.13 For children 2 years old at risk for CVD, the daily diet should be further restricted to saturated fat < 7% of total calories and dietary cholesterol to < 200 mg.1 For children between 12 months and 2 years of age who are overweight, obese, or have a family history of obesity, dyslipidemia, or CVD, reduced fat milk is now considered safe and appropriate.1 Additional dietary management for high-risk patients should always be tailored based on individual lipid profile and involve counseling with a lipid specialist and registered dietitian or other skilled clinician to ensure effective nutrition intervention while maintaining appropriate growth and development.
Dietary Cholesterol
Dietary cholesterol is found in animal-based foods and can be reduced by limiting foods such as butter, egg yolk, high-fat meat, beef, poultry with skin, and whole milk dairy products. Although limiting dietary cholesterol has less of a serum lipid lowering effect and has a more variable response among individuals than limiting saturated and trans fats, it is still important because cholesterol and saturated fat are found together in most foods.9,14 In general, LDL may be decreased by 3% to 5% if dietary cholesterol is restricted to < 200 mg daily. In addition, an increase of 100 mg/d of dietary cholesterol increases total serum cholesterol by 2 to 3 mg/dL.
Dietary Fats
Saturated Fats Limiting saturated fats can help to lower LDL levels.14 Saturated fat is found more in animal- than plant-based foods. A major source of saturated fat is red meat, but dairy products are also commonly overlooked as a source of saturated fat in childrens diets. Plant-based sources of saturated fat
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are mainly found in tropical oils (coconut, palm, and palm kernel), which are often used in commercially baked goods. To reduce saturated fat intake, whole milk dairy products may be replaced with low-fat or non-fat (skim) dairy products, and leaner cuts of meat may be recommended. Low-fat, reduced fat, and baked cookies, crackers, and other baked goods should be consumed instead of full-fat versions. Using additional saturated fat in the cooking process should be limited. Low-fat cooking methods such as broiling, grilling, steaming, microwaving, poaching, or baking are preferable to frying. Saturated fats should be limited to < 7% total calories in children with high cholesterol. Trans Fats Trans fats, or hydrogenated fats, are produced when fat is hydrogenated to make it solid at room temperature. In the process of hydrogenation, bonds in the cis position are switched to the trans position, which has been shown to increase LDL and decrease HDL cholesterol. Trans fats are found mostly in stick margarine, high-fat baked goods, shortening, commercial frying oils, and fried snack foods. Examples of these foods are doughnuts, pastries, crackers, cookies, potato and tortilla chips, french fries, and other bakery and snack foods. Trans fats should be limited to < 1% of total calories for all children 2 years old.1 Nutrition labels are allowed to list zero grams of fat per serving if the product contains less than 0.5 g of trans fat per serving. Therefore, to ensure a food is completely free of trans fat, it is important to check the ingredients for hydrogenated and/ or partially hydrogenated oils. Monounsaturated and Polyunsaturated Fats Children with dyslipidemia are encouraged to replace saturated and trans fats with the healthier monounsaturated and polyunsaturated fats, which decrease LDL cholesterol.1,15 Monounsaturated fats are found in avocados, many nuts and seeds, and vegetable oils such as olive, canola, peanut, and sesame oil.13 Polyunsaturated fats are found in most nuts and seeds, fatty fish (salmon, tuna, mackerel, herring, and trout) and vegetable oils like soybean, corn, safflower, and sunflower oils.16 It is important to note that while these fats are healthy, they are still calorically dense and should be limited as recommended by the Dietary Guidelines for Americans,13 especially for weight maintenance or loss.
hypertriglyceridemia, other than LPL deficiency, primarily need to limit their intake of simple carbohydrates. Simple sugars and carbohydrates, found in foods such as sweetened beverages, desserts, snacks, and white breads and other refined starches, raise triglycerides more than saturated and trans fats. For children who are overweight or obese with high triglycerides, limiting dietary fat, especially saturated and trans fats, and increasing physical activity should also be recommended in addition to limiting simple carbohydrates because obesity will have a direct effect on triglyceride levels.13
Fiber
Fiber combined with a low-fat diet may help to improve cholesterol levels further. Soluble fiber such as oat bran, psyllium, pectin, and guar gum decreases LDL cholesterol primarily, and has some effect on increasing HDL cholesterol.17 An increase in soluble fiber of 5 to 10 g/d may reduce LDL by 3% to 5%.9 One study found that children who consumed 6.4 g of soluble fiber as psyllium decreased their LDL by 7%.18 Fiber binds to bile acids and decreases cholesterol absorption. Specific guidelines for the suggested amount of fiber intake for children with dyslipidemia currently do not exist, and remain controversial. However, general guidelines for estimating adequate fiber intake in children are found in the dietary reference intake (DRI) and are generally much higher than most children and adolescents consume.19 Another commonly used method is adding 5 to the childs age to obtain the recommended daily intake of fiber in grams, up to 20 g/d (for example, a 6-year-old child should consume approximately 11 g of fiber), although there is limited supporting evidence for this calculation.17,20
Plant Sterols/Stanols
Plant sterols and stanols are essential components of cell membranes in plants that are structurally similar to cholesterol. Plant stanols are saturated sterols and have no double bonds. Their action is to inhibit absorption of dietary cholesterol and to decrease re-absorption of cholesterol from bile. Plant sterols or stanol esters have been incorporated into margarine/butter spreads, granola bars, yogurt drinks, oatmeal, cereal, and some other foods and are also available in caplets. A randomized control study in children using 2 g of plant sterol in margarine per day decreased LDL by 8%.21 Plant sterols are considered safe for children at recommended doses of 2 g/d to lower LDL levels. However, they may theoretically have the potential to decrease levels of fat-soluble vitamins such as vitamin A (beta carotene)
Simple Carbohydrates
For the general population, current recommendations encourage choosing mostly complex carbohydrates with a limited intake of simple carbohydrates.13 Patients with
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or vitamin E (alpha tocopherol), which can typically be prevented by increasing intake of food sources of both. A multivitamin may be considered if additional risk factors for vitamin deficiency are present. 21
benefits of soy remain controversial, soy can provide polyunsaturated fatty acids, fiber, vitamins, and minerals beneficial for cardiovascular and overall health.17
Omega-3 Fatty Acids

The omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are found in fish oils and ocean fish (herring, mackerel, salmon, and sardines), and lower triglycerides by inhibiting very low-density lipoprotein (VLDL) and apolipoprotein B (apoB) synthesis. 22 While fish intake has been shown to be cardioprotective, it has no effect on total cholesterol, LDL, or HDL and has only been shown to lower triglycerides. Still, the American Heart Association (AHA) and American Academy of Pediatrics (AAP) recommend increasing fish consumption for CVD prevention; no specific guidelines exist for pediatrics, but the recommendation for adults is 2 servings per week.23 DHA and EPA may be synthesized from alphalinolenic acid, which is found in flaxseed oil, canola oil, soy oil, and walnuts. A total of 2 to 4 g of DHA/EPA may be recommended for triglycerides > 500 mg/dL.24,25 This level of intake, in general, cannot be achieved by seafood intake alone and requires supplementation or medication. It should be noted that over-the-counter fish oil supplements are often dosed with the total grams of fish oil, but one should pay attention to total grams of combined DHA and EPA, and not total grams of fish oil, in dosing supplements for the treatment of high triglycerides.
Garlic
Garlic may have beneficial cardiovascular effects such as lowering LDL cholesterol, lowering blood pressure, reducing platelet aggregation, and acting as an antioxidant and anti-inflammatory agent.24 However, the mechanism of garlics actions are unclear. Other studies have shown no cardiovascular effect in children.20 At this time, there are no recommendations regarding the use of garlic for lowering cholesterol in children.
Antioxidants
Antioxidants have been raised as a possible treatment for high cholesterol because oxidized LDL is implicated in plaque development. Although daily supplementation of vitamins C and E may improve endothelial function, largescale clinical trials have not shown any benefit related to the primary or secondary prevention of CVD. 24,27 Studies in children are limited, and antioxidant vitamin supplementation is not currently recommended to manage dyslipidemia.27
Physical Activity
Physical activity is beneficial for children and adolescents with dyslipidemia, due to its effects on raising HDL and decreasing triglyceride levels. Improvement of LDL levels and insulin resistance have also been documented.28,29 In addition, physical activity plays a critical role in maintaining an appropriate weight, which also affects cholesterol levels. Physical activity should be encouraged in all patients with dyslipidemia unless another medical condition contraindicates this. New physical activity guidelines recommend that children have at least 60 minutes of moderate to vigorous physical activity daily, including vigorous physical activity at least 3 days per week. 30 Nutrition and physical activity recommendations for specific lipid abnormalities are summarized in Table 15-3.
Soy Protein
The effect of soy on lowering cholesterol remains controversial. While some studies show soy isoflavones can decrease LDL and triglycerides and increase HDL, others show little or no effect. Although a daily intake of 25 g of soy in adults may decrease total and LDL cholesterol from 1.5% to 4.5%, this may be related more to the use of soy as a substitute for foods high in saturated fat.22,24,26 No recommendations have been made for children. While the cholesterol-lowering
TABLE 15-3 Summary of Nutrition and Physical Activity Recommendations for Specific Lipid Abnormalities
Lipid Abnormality Fiber Simple Carbohydrates Dietary Cholesterol Trans Fat Saturated Fat Omega-3 Fats Physical Activity
High LDL High TG Low HDL
Increase DGA DGA
DGA Decrease DGA
< 200 mg < 200 mg < 200 mg
< 1% total kcal < 1% total kcal < 1% total kcal
< 7% total kcal < 7% total kcal < 7% total kcal
DGA Increase DGA
Increase Increase Increase
DGA = Dietary Guidelines for Americans 2005.

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Medications may be considered in conjunction with nutrition and physical activity interventions for patients 8 years and older with an LDL 190 mg/dL (or 160 mg/dL with a family history of early heart disease or 2 additional risk factors present, or 130 mg/dL or > 100 mg/dL depending if Type 1 diabetes mellitus or other high-risk conditions exist).1,31 HMG CoA-reductase inhibitors, or statins, are the recommended class of medications to lower LDL levels in pediatrics. Statins have been shown to be safe and effective in lowering cholesterol in a number of clinical trials, though they have generally been short-term. 3236 Patients, however, need to be monitored closely for liver and muscle side effects. Niacin and bile acid-binding resins are other classes of cholesterol-lowering medications but are not routinely recommended in pediatrics due to limited effectiveness and poor compliance. Cholesterol-absorption inhibitors are the newest class that are often combined with other medications such as statins, but have not yet been extensively studied in children.
Pharmacologic Intervention
References
1. Which of the following values is least important in assessing a fasting lipid profile? A. Triglycerides B. Total cholesterol C. LDL D. HDL 2. What percentage of trans fats is recommended by the American Heart Association? A. < 5% total calories/day B. < 10% total calories/day C. < 30% total calories/day D. < 1% total calories/day 3. In which lipid profile would omega-3 fats be beneficial for a pediatric patient? A. LDL 200 mg/dL, triglycerides 80 mg/dL, HDL 50 mg/dL B. LDL 110 mg/dL, triglycerides 550 mg/dL, HDL 25 mg/dL C. LDL 120 mg/dL, triglycerides 150 mg/dL, HDL 25 mg/dL D. LDL 180 mg/dL, triglycerides 100 mg/dL, HDL 30 mg/dL See p. 487 for answers.
1. Daniels SR, Greer FR; Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics. 2008;122:198208. 2. Newman WP III, Freedman DS, Voors AW, et al. Relation of serum lipoprotein levels and systolic blood pressure to early atherosclerosis: the Bogalusa Heart Study. N Engl J Med. 1986;314(3):138144. 3. Berenson GS, Srinivasan SR, Bao W, Newman WP III, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and the early development of atherosclerosis. The Bogalusa Heart Study. N Engl J Med. 1998;338(23):16501656. 4. McGill HC Jr, McMahan CA, Malcom GT, Oalmann MC, Strong JP; for the PDAY Research Group. Effects of serum lipoproteins and smoking on atherosclerosis in young men and women. Aterioscler Thromb Vasc Biol. 1997:17(1):95106. 5. Webber LS, Osganian V, Luepker RV, et al. Cardiovascular risk factors among third grade children in four regions of the United States. The CATCH Study: Child and Adolescent Trial for Cardiovascular Health. Am J Epidemiol. 1995;141(5):428439. 6. Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988-1994. Arch Pediatr Adolesc Med. 2003;157:821827. 7. Ogden CL, Carroll MD, Flegal KM. High body mass index for age among US children and adolescents, 2003-2004. JAMA. 2008;299(20):24012405. 8. Kwiterovich PO. Diagnosis and management of familial dyslipidemia in children and adolescents. Pediatr Clin North Am. 1990;37:14891523. 9. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:24862497. 10. Schwimmer JB, et al. Cardiovascular risk factors and the metabolic syndrome in pediatric nonalcoholic fatty liver disease. Circulation. 2008;118:277283. 11. Kwiterovich PO. Recognition and management of dyslipidemia in children and adolescents. J Clin Endocrinol Metab. 2008;93(11):4200-4209. 12. Rose G. Sick individuals and sick populations. Int J Epidemiol. 1985;14(1):3238. 13. US Department of Health and Human Services. 2005 dietary guidelines for Americans. http://www.healthierus.gov/ dietaryguidelines. Accessed November 12, 2009. 14. Howell WH, McNamara DJ, Tosca MA, Smith BT, Gaines JA. Plasma lipid and lipoprotein responses to dietary fat and cholesterol: a meta-analysis. Am J Clin Nutr. 1997;65:17471764. 15. American Academy of Pediatrics Policy Statement. Cholesterol in Childhood. (RE9805) Pediatrics. 1998;101:141147.
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16. American Heart Association. Face the Fats. http://www. americanheart.org/presenter.jhtml?identifier=3046074 Accessed November 12, 2009. 17. Dalidowitz C. Nutrition management of dyslipoproteinemia. In: Nevin-Folino NL, ed. Pediatric Manual of Clinical Dietetics. 2nd ed. Chicago, IL: American Dietetic Association; 2003:319340. 18. Davidson MH, Dugan LD, Burns JH, Sugimoto D, Story K, Drennan K. A psyllium enriched cereal for the treatment of hypercholesterolemia in children: a controlled, double-blind, cross-over study. Amer J Clin Nutr. 1996;63:96102. 19. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). Washington DC: National Academy Press; 2005. 20. Kavey RE, Daniels SR, Lauer RM, et al. American Heart Association guidelines for primary prevention of atherosclerotic cardiovascular disease beginning in childhood. Circulation. 2003;107(11):15621566; copublished in J Pediatr. 2003;142(4):368372. 21. Tammi A, Ronnemaa T, Miettinen TA, et al. Effects of gender, apolipoprotena E phenotype and cholesterol-lowering by plant stanol esters in children: the STRIP study. Special Turku Coronary Risk Factor Intervention Project. Acta Paediatr. 2002;91(11):11551162. 22. Krummel D. Nutrition in cardiovascular disease. In: Mahan LK, Escott-Stump S, eds. Krauses Food, Nutrition, and Diet Therapy. 10th ed. Philadelphia, PA: WB Saunders Co; 2000:571. 23. Nutrition Committee of the American Heart Association. AHA Dietary Guidelines. Circulation. 2000:2296. 24. Fletcher B, Berra K, Ades P, et al. Managing abnormal blood lipids: a collaborative approach. Circulation. 2005;112:31843209. 25. Kris-Etherton PM, Harris WS, Appel LJ; American Heart Association Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106:27472757. 26. Erdman JW Jr. AHA Science Advisory. Soy protein and cardiovascular disease: a statement for healthcare professionals from the Nutrition Committee of the AHA. Circulation. 2000;102:25552559. 27. Engler MM, Engler MB, Malloy MJ, et al. Antioxidants vitamins C and E improve endothelial function in children with hyperlipidemia: Endothelial Assessment of Risk From Lipids in Youth (EARLY) Trial. Circulation. 2003;108:10591063.
28. Maron BJ, Chaitman BR, Ackerman MJ, et al. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation. 2004;109(22):28072816. 29. Strong WB, Malina RM, Blimkie CJ, et al. Evidencebased physical activity for school-age youth. J Pediatr. 2005;146(6):732737. 30. US Department of Health and Human Services. 2008 physical activity guidelines for Americans. http://www.health.gov/ paguidelines. Accessed November 12, 2009. 31. Kavey R, Aladda V, et al. Cardiovascular Risk Reduction in High-Risk Patients: A Scientific Statement From the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: Endorsed by the American Academy of Pediatrics. Circulation. 2006;114:27102738. 32. de Jongh S, Ose L, Szamosi T, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized double-blind, placebo-controlled trial with simvastatin. Circulation. 2002;106(17):22312237. 33. Lambert M, Lupien PJ, Gagne C, et al. Treatment of familial hypercholesterolemia in children and adults: effect of lovastatin. Canadian Lovastatin in Children Study Group. Pediatrics. 1996;97(5):619628. 34. McCrindle BW, Ose L, Marais AD. Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial. J Pediatr. 2003;143(1):7480. 35. de Jongh S, Lilien MR, opt Roodt J, et al. Early statin therapy restores endothelial function in children with familial hyper cholesterolemia. J Am Coll Cardiol. 2002;40(12):21172121. 36. Wiegman A, Hutten BA, de Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA. 2004;292(3):331337.
Use of Popular and Fad Diets

Catherine Christie, PhD, RD, Julia A. Watkins, PhD, MPH, and Judith C. Rodriguez, PhD, RD
16
CONTENTS
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Approach to the Overweight/Obese Child or Adolescent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Use of Fad and Popular Diets . . . . . . . . . . . . . . . . . . . . . . Lifelong Weight Management. . . . . . . . . . . . . . . . . . . . . . Types of Fad and Popular Diets. . . . . . . . . . . . . . . . . . . . .
Behavioral Weight-Loss Plans Food-Focused Weight Loss Plans Reduced Macronutrient Content Plans Food Group Guides/Exchange Systems Food Timing/Meals and Snacks Combinations Commercial Meal/Snack Replacements Other Plans 169 170 170 171 171
Learning Objectives
1. Describe the importance of weight maintenance versus weight loss recommendations when working with children and adolescents. 2. Critique one of the discussed popular/fad diets for use with children. 3. Critique another popular/fad diet discussed for use with adolescents. 4. Assess the efficacy of a balanced macronutrient low-kilocalorie diet for use with children.
Background
Diets Designed for Use with Children. . . . . . . . . . . . . . . . 174

Balanced Macronutrient Low-Kilocalorie Diets Traffic Light Diet Food Guide Pyramid Multidisciplinary Behavior Change Programs
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
The incidence and prevalence of childhood overweight and obesity is increasing worldwide.1 This increase is associated with multiple health risks and adverse effects in childhood as well as later in life such as sleep problems, endocrine disorders, respiratory problems, gastrointestinal problems, skin conditions, orthopedic disorders, and cardiovascular risk factors.2 Dietary intake data are also of concern. Less than 40% of U.S. youth meet the U.S. Dietary Guidelines for saturated fat, which is related to risk for heart disease and diabetes.3 According to the Youth Risk Behavior Surveillance (YRBS) survey, 80% of adolescents do not eat fruits and vegetables 5 or more times per day, which impacts on the findings that only 39% of youth 2 to 17 years meet the U.S. Department of Agricultures recommendations for fiber.4,5 There is a need for successful, scientifically sound weightloss measures with dietary, physical activity, and social support components to assist youth. According to the YRBS survey, a large number of adolescents use unhealthy methods to lose or maintain weight, evidenced by the finding that during the 30 days preceding the survey, 12.3% of students went without eating for 24 hours or more, 4.5% had vomited or taken
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laxatives; and 6.3% had taken diet pills, powders, or liquids without a doctors advice.4 Systematic reviews of childhood obesity and expert committee recommendations have emerged over the last several years69 and all agree that child and adolescent obesity treatment should: be directed at motivated families in which the child and/or parents perceive obesity to be a problem and appear willing to make lifestyle changes be directed at the entire family rather than just the overweight/obese child aim for weight maintenance unless body mass index (BMI) is > 99th percentile be more intensive than has been the norm combine changes in diet plus changes in physical activity and/or reduction in sedentary behavior The current definitions state that if BMI is greater than or equal to the 95th percentile, the child is obese, and if BMI is between the 85th and 94th percentiles, the child is overweight (Table 16-1).
Table 16-1 Weight Recommendations According to Age and BMI Percentile9
Age Target
Clinical Approach to the Overweight/Obese Child or Adolescent
25 years BMI of 85th to 94th percentile BMI of 95th percentile
Weight maintenance until BMI of < 85th percentile or slowing of weight gain, as indicated by downward deflection of BMI curve. Weight maintenance until BMI of < 85th percentile; however, if weight loss occurs with healthy, adequate energy diet, then it should not exceed 1 lb/mo. If greater loss is noted, then patient should be monitored for causes of excessive weight loss. Weight maintenance until BMI of < 85th percentile or slowing of weight gain, as indicated by downward deflection of BMI curve. Weight maintenance until BMI of < 85th percentile or gradual weight loss of ~1 lb/mo. If greater loss is noted, then patient should be monitored for causes of excessive weight loss. Weight loss not to exceed average of 2 lb/wk. If greater loss is noted, then patient should be monitored for causes of excessive weight loss.
The American Dietetic Association evidence-based analysis of pediatric overweight literature on intervention programs reported positive effects from 2 specific kinds of interventions: (1) multi-component, family-based programs for children between the ages of 5 and 12 and (2) multicomponent school-based programs for adolescents. The components included were behavioral counseling, promotion of physical activity, parent training/modeling, dietary counseling, and nutrition education.10 Interventions should be based on the familys readiness to change and include the following recommendations9: consumption of 5 servings of fruits and vegetables per day minimization or elimination of sugar-sweetened beverages limits of 2 hours of screen time per day, no television in the room where the child sleeps, and no television if the child is < 2 years of age 1 hour of physical activity per day In addition, parents and family members should be counseled to facilitate the following eating behaviors: eating breakfast daily limiting meals outside the home, including at fast-food venues and other restaurants eating family meals at least 5 or 6 times per week allowing the child to self-regulate his or her meals and avoiding overly restrictive behaviors Parents of overweight or obese children may be overweight themselves and often look to popular diets as a means of losing weight. Because these diets are often adopted by the family and modified for children or adolescents, a discussion of the use of popular diets for pediatric patients is warranted. Family-friendly popular diets include elements of healthy eating that are applicable or can be easily modified to safely include children. Popular diets can be categorized into 7 major types: behavioral, food-focused, reduced macronutrient content, food group guides or exchange systems, food timing or specific combinations of meals and snacks, commercial meal or snack replacements, and an other category for plans that do fit in any previous category.11 Within each category of weight-loss diets, many are effective in reducing weight because regardless of the plan or claim, they principally lower caloric intake by prescribing limits on food intake. However, the scientific evidence consistently concludes that successful weight loss should be
611 years BMI of 85th to 94th percentile BMI of 95th to 98th percentile BMI of 99th percentile 1218 years BMI of 85th to 94th percentile
Use of Fad and Popular Diets
Weight maintenance until BMI of < 85th percentile or slowing of weight gain, as indicated by downward deflection of BMI curve. BMI of 95th to Weight loss until BMI of < 85th percentile, no 98th percentile more than average of 2 lb/wk. If greater loss is noted, then patient should be monitored for causes of excessive weight loss. BMI of 99th Weight loss not to exceed average of 2 lb/wk. percentile If greater loss is noted, then patient should be monitored for causes of excessive weight loss. Reproduced with permission from Pediatrics, Vol. 120, page 254, copyright 2007 by the American Academy of Pediatrics.
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coupled with a plan that enables the dieter to manage weight over a lifetime.11 The more extreme the plan, the more difficult it is to follow over the long term. The key for lifelong weight management is following a plan individualized to each persons needs. Kilocalorie- and portion-controlled diets seem to be more conducive to long-term compliance than fat- and carbohydrate-restricted diets.12 According to the Weight Control Registry,13 adults who are successful at losing weight and keeping it off individualize their changes in lifestyle to include eating and exercise behaviors that they can sustain for a lifetime. Therefore, when considering any diet plan individuals should consider nutrition, food variety, moderate intake, food portions, rate of including these into their lifestyle, ways to continue them for an extended time, and how to add physical activity. For many, the term diet evokes thoughts of something temporary. The resultant on-off mindset produces short-term change only and does not address the underlying behaviors that created the need to diet in the first place. Successful weight-reduction programs reduce body weight and body fat gradually by decreasing caloric intake and increasing caloric expenditure. An increase in physical activity builds or maintains muscle mass and, together with aerobic activity, determines the utilization of body fat reserves and thus the metabolic rate or the rate of kilocalories being burned. Diets that promise immediate or fast weight loss are not recommended as they defy the scientific basis for metabolism, particularly in children as normal growth may be inhibited. Such claims are at best misleading and at worst, potentially harmful. The calculation of energy balance reveals that fat loss occurs at the rate of 1 to 2 pounds per week, even when a person severely restricts caloric intake. To lose 1 pound of body fat per week, a negative caloric deficit of 3500 kilocalories or 500 kilocalories for 7 days must occur. Weight loss greater than the recommended 1 to 2 pounds per week can only occur by losing muscle and water in addition to fat.14 It is important for families to set a reasonable and reachable goal for weight loss with their physician and a registered dietitian before undertaking a diet. When planning a change in diet for the family, the plan should first be evaluated to see if it is compatible with their lifestyle and health needs. It should be a plan that the family can foresee continuing indefinitely. A lifestyle change is required to prevent periods of on and off dieting and regression to the previous habits which initially caused weight gain. On and off dieting results in weight regain, which could negatively impact health and affect disease progression.
Lifelong Weight Management
The following 5 steps to lifelong weight management are helpful for families who are considering a change in their diet for weight loss of any family member11: 1. Eat food in appropriate portion sizes. A. Meat, poultry, and fish servings should be the size of a deck of cards or a bar of soap. B. Pasta, rice, and other grains should not be larger than the size of a tennis ball. C. Legumes should be about half the size of a tennis ball. D. A piece of cheese should be about the size of four dice. 2. Focus on slow, gradual weight loss or weight maintenance in children through regular eating and physical activity. Skipping meals has not been shown to help weight loss. Breakfast is particularly important for children and adolescents. 3. Eat a variety of foods with an emphasis on whole grains, fruits, vegetables, low-fat dairy products, lean meats, poultry, fish, legumes, nuts, and seeds. 4. Drink water and avoid sweetened caloric beverages. 5. Limit fats, added sugars, and refined foods.
Types of Fad and Popular Diets
Although there are a myriad of fad and popular diets, most share some common claims or principles that enable them to be grouped into a few categories.
Behavioral Weight-Loss Plans

A recent example of a behavioral weight-loss plan is the French Women Dont Get Fat15 diet. This diet makes the following basic recommendations: Avoid the extremes of either going hungry or feelingstuffed. Avoid obsessing about eating and dieting. Do not skip meals or induce feelings of deprivation. Eat nuts as snacks or sprinkled over foods. Eat the real thing in moderation instead of using substitutes. Eat 3 daily meals that include carbohydrates, proteins, and fats. Do not replace regular meals with beverages such as shakes or smoothies. Eat yogurt with active cultures. Eat without stuffing yourself or feeling guilty. Enjoy high-quality bread and chocolate in moderate amounts. Enjoy fresh foods and flavorful fruits and vegetables in season.
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Enjoy different seasonings by using either fresh or dried herbs and spices. Focus on small portions of high-quality foods. If you relapse, simply get back on track. Make physical activity an integral part of your day. Plan what to eat in advance. Savor meals, slow down, relax, and stop what you are doing to eat. Take pleasure in eating and focus on the good not bad things to eat. While not exclusive to this diet, behavioral approaches to weight loss that include portion control, regular physical activity, self-efficacy and self-regulation, and the monitoring of eating and weight have been shown to be effective for successful long-term weight management in adults.12 These principles are also recommended for children and adolescents.9 Behavioral strategies to help overweight children and their families include establishing a regular meal and snack pattern; eating smaller portions at meals and snacks; limiting second helpings to fresh fruit and non-starchy vegetables; selecting lower-fat dairy products; eating more foods that are baked, broiled, grilled, or boiled instead of fried; selecting healthful snacks that include low-fat protein along with fresh fruit, vegetables, or whole grain bread and cereals; and when eating out, selecting more healthful options or splitting larger servings to share with other family members or peers.8
Food-Focused Weight Loss Plans

One of the oldest and most well-known examples of a foodfocused weight-loss plan is the grapefruit diet. Although grapefruit is credited with containing a special fat-burning enzyme, no scientific evidence exists to substantiate that claim. Weight loss is achieved through limited food selection, reduced caloric intake, and loss of fluid. Complex carbohydrates and snacks between meals are forbidden, while most vegetables and all meat and fish are allowed. Meals comprise eggs, meat or fish, salads, vegetables, skim milk, tomato juice, and unlimited amounts of black coffee or tea. Each meal is accompanied by half a grapefruit or half a cup of unsweetened grapefruit juice. If no behavioral or lifestyle changes are instituted, it is likely that weight lost will be regained over time.11 This type of plan would not be recommended for children or adolescents due to the potential for nutrient deficiencies, severely restricted caloric intake, and excessive weight loss.
Reduced Macronutrient Content Plans

The best known of the low-carbohydrate plans may be the Atkins Diet16 followed by the South Beach Diet.17 The
most recent Atkins diet promotes 5 nutrition rules: a high consumption of protein and fiber, substantial vitamin and mineral intake, low amounts of sugar, and the elimination of trans fats. Although physical activity is encouraged with the diet plan, the main focus is on high-protein, low-carbohydrate eating. Short-term research studies tracking the progress of adults on the diet have reported high levels of satiety, a temporary improvement in blood lipids and glucose levels, some loss of body fat, and the sparing of muscle protein.18,19 In a recent 2-year trial, researchers concluded Mediterranean-style diets that are not necessarily lower fat but focus on healthier fats and low-carbohydrate diets may be effective alternatives to low-fat diets. The more positive effects on lipids with the low-carbohydrate diet and on glycemic control with the Mediterranean-style diet indicate that diets should be tailored to individual preferences and health risks.20 Whereas reducing intake of simple sugars may be appropriate for children and adolescents, lowcarbohydrate plans should not be recommended due to the potential low intake of fiber, nutrients, and kilocalories to support growth and development. The South Beach Diet17 is a variation on the carbohydrate-restricted diet divided into 3 phases. Phase I allows lean meats, chicken, egg or egg substitutes, fish, olive oil, vegetables, salads, nuts, and some low-fat milk. Phase II introduces lower glycemic-index carbohydrates in limited amounts. Fruits are recommended for lunch or dinner, but not breakfast. Whole grain bread, sweet potatoes, and brown or wild rice in modest portions replace white bread, white potatoes, and white rice. Mashed, steamed cauliflower replaces mashed potatoes. Sandwiches are replaced by fillings in lettuce wraps. This phase lasts for 2 weeks or until the desired weight is lost. If overindulgence occurs during this phase, the recommendation is to return to Phase I for 1 week. Phase III is the lifelong maintenance phase where the emphasis is on the good carbohydrates and fats with restriction of the bad carbohydrates and fats. This lowkilocalorie, high-protein, lower-carbohydrate plan allows healthy fats, high-fiber foods, and selected carbohydrates in moderate amounts. The evidence suggests that moderate intake of carbohydrates, proteins, and healthy fats facilitates weight management in adults.10 This plan is adaptable for use with children particularly in Phase III. However, the entire family should be committed to focusing on > 5 fruits and vegetables per day, minimizing sweetened beverages, increasing physical activity, and reducing sedentary behaviors as well as eating breakfast daily, limiting meals outside the home including at fast-food venues and other restaurants, eating family meals at least 5 or 6 times per
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week, allowing the child to self-regulate his or her meals, and avoiding overly restrictive behaviors.9 The Pritikin Diet21 and the Dean Ornish Diet22 are the most well-known of the low-fat diets. Both diets were originally developed for the prevention and treatment of heart disease and also became popular as weight-loss diets. The Pritikin plan comprises a total caloric breakdown of 10% fat, 10% to 15% protein, and 75% to 80% carbohydrates with 35 g of fiber, less than 100 mg of cholesterol, and 600 mg of sodium. Exercise and stress management are integral to the plan. Encouraged as a life-long commitment, this restrictive, very low-fat, high-fiber plan requires extensive menu planning and may be difficult to implement as it entails careful label reading and product comparison.11 In addition, there are no studies that have evaluated the use of this diet in children or adolescents. Like the Pritikin plan, the Dean Ornish Diet22 allows only 10% of kilocalories from fat. It also limits sugar and honey. The restriction on fat and simple sugars prevents individuals from consuming excess kilocalories and the high-fiber content contributes to a feeling of fullness. In addition, the diet promotes whole foods and a high intake of phytochemicals from vegetarian-based foods and forbids meat, nuts, seeds, avocados, white flour, white rice, and fried foods. The diet also advocates a comprehensive lifestyle change including stress management training, smoking cessation, meditation, and moderate exercise. There is strong scientific evidence to support the plans claim to reverse the risk of heart disease in adults, and the resulting weight loss is due to the caloric restriction.22 However, there are no studies that have evaluated the use of this diet in children or adolescents.
and managing cues to overeating, stress management, and making a plan to handle setbacks. There are no forbidden foods and treats are allowed as long as the predominant eating style is low-kilocalorie density. There is strong scientific evidence that reducing caloric intake combined with exercise and behavior management produces weight loss in adults.12 There are no studies that have evaluated the use of this diet in children or adolescents however it does contain many of the elements recommended (eg, focusing on > 5 fruits and vegetables per day, minimizing sweetened beverages, increasing physical activity and reducing sedentary behaviors as well as eating breakfast daily, limiting meals outside the home including at fast-food venues and other restaurants, and allowing the child to self-regulate his or her meals and avoiding overly restrictive behaviors).9
Food Timing/Meals and Snacks Combinations

A recent example of this category is the Suzanne Somers Diet.24 According to this diet, eating fat does not cause weight gain, sugar is more fattening than fat, and carbohydrates are not essential in the diet. According to Ms. Somers, weight gain is caused by hormonal imbalances and successful weight loss depends on keeping insulin stable following digestion. This is achieved by eating certain foods in specific combinations, cutting carbohydrate intake, and eliminating sugars and refined carbohydrates, starchy foods, white flour, caffeine, and funky foods. Meals should not be skipped and after eating fruit, the dieter should wait 20 minutes before consuming other foods. There are 2 levels to this diet. Level 1 is the most restrictive and is designed to initiate weight loss. Level 2 is the maintenance phase and introduces some protein, fat, and carbohydrate combinations. The rationale for the diets effectiveness is not substantiated by scientific data; however weight loss may be achieved due to the many food restrictions and the total caloric intake of the structured meals.11 This type of plan would not be recommended for children or adolescents due to the lack of scientific validity in the premise, the potential for nutrient deficiencies, and severely restricted caloric intake.
Food Group Guides/Exchange Systems

One example of a food group or exchange plan is the Volumetrics Weight-Control Plan.23 Food choices are based on kilocalorie density. Fat, fiber, protein, and water content of foods all affect energy or kilocalorie density. By eating predominantly filling, low-kilocalorie, dense foods, smaller portions of a few high-kilocalorie, dense foods can be included and the person will still lose weight due to the overall kilocalorie restriction. Low-energy, dense foods include fruits and vegetables, skim milk, broth-based soups, fat-free salad dressings, pasta, cooked high-fiber grains, potatoes, legumes, low-fat meats, salads, low-fat soups, low-fat cheeses, cottage cheese, frozen yogurt, and nonkilocalorie beverages. This diet is complemented by regular exercise and behavior management, which includes keeping a food and exercise log, not skipping meals, identifying
Commercial Meal/Snack Replacements

One of the largest commercial weight-loss programs is WeightWatchers.25 WeightWatchers, International, Inc. has more than 1.5 million members attending one of its 50,000 weekly meetings around the world. WeightWatchers was one of the first to incorporate a walking program and emphasize physical activity as a necessary part of dieting. The POINTS Weight-Loss System assigns a point value to activities and food which is determined by the number of
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kilocalories, total fat, and dietary fiber in a defined serving. Each person is given a daily POINTS target that will lead to a caloric deficit that translates into 1 to 2 pounds per week weight loss. A second plan called the Core Plan focuses on choosing foods with low energy density. By routinely monitoring hunger cues and with an allowance for periodic indulgences, the Core Plan has been shown to produce weight losses equal to the POINTS system. There is strong evidence to support a lifestyle plan that includes regular monitoring and support systems using commonly available foods. The emphasis on portion control and low energy density foods can be translated to many food settings, and the recipes help teach dieters to prepare dishes lower in kilocalories. Members do pay a fee for the weight-loss services including those on the Internet and for WeightWatchers-branded food items.11 WeightWatchers does not recommend its plan for children and instead discusses childrens needs in terms of 2 goals: ensuring the child grows and develops normally and helping the child reach a healthy weight. Weight maintenance strategies are recommended for children as young as 3 years of age26 and weight gain in overweight young children should be limited to 2 pounds for every inch of growth.25 Over age 4, it is recommended that the child maintain weight until the BMI drops down into the normal range, below the 85th percentile. 27
and reducing health risks in the environment are integrated into each plan. However, there is no scientific validity to the idea that diet should be defined by blood type. By limiting specific foods and sometimes food groups, those who follow the diet can lose weight, but the elimination of specific foods and groups is based on a premise without adequate scientific evidence.11 This diet plan is not recommended for children or adolescents.
Diets Designed for Use with Children

Balanced Macronutrient Low-Kilocalorie Diets
Evidence does suggest that short- and long-term reduced energy (less than 1200 kcal) may be an effective part of a multi-component weight-management program in children 6 to 12 years of age.29 In the adolescent population, the use of reduced energy (not less than 1200 kcal) is generally effective for short-term weight loss but without continuing dietary intervention, weight is regained. 29
Traffic Light Diet

The Traffic Light Diet was designed to promote weight loss, provide adequate kilocalories and nutrients for growth and development, and be easy to follow. 30 The diet divides foods into 11 categories, with the foods in each category then separated into 3 color groups: green, yellow, and red. These colors correspond to the colors of a traffic light and signify GO (green), eat as much as you like; approach with CAUTION (yellow), eat in moderate amounts; and STOP (red), do not eat. Green foods are those foods that contain less than 20 kcal per average serving and are found only in the vegetable and free foods categories. Yellow foods are foods that are within 20 kcal per average serving of the caloric value of the average food within that food group. Yellow foods are items from the 4 basic food groups, which a child should eat in recommended amounts in order to obtain adequate nutrition. Red foods are foods that exceed the caloric value of a yellow food, thereby lowering the nutrient density of the food. In addition, red foods include any food that is made to resemble red food, as low-kilocalorie lasagna, which might not be a red food in terms of kilocalories, but is labeled a red food because a person will not break the habit of eating lasagna if often substituting low- for high-kilocalorie lasagna. Participants are limited to 4 red foods per week. Results showed a clear superiority of the parent and child intervention including diet and self-monitoring by both parent and child (Group I) over diet and self-monitoring by the child alone (Group II) and the control group
Other Plans
Eat Right for Your Type28 was on the New York Times bestseller list and remains a popular diet plan today. The book provides 4 diets based on the Blood Types O, A, B, and AB. People with Type O blood are described as hunters, who need a diet with high protein, lean, chemical-free meat, poultry, and fish with limited grains, beans, and legumes. Those with type A blood, the cultivators, need to eat predominantly vegetarian with fish and an emphasis on vegetables, tofu, grains, beans, legumes, and fruit. Type B, the nomads, should eat meat (no chicken), dairy, grains, beans, legumes, vegetables, and fruit. Type AB, the enigma, can eat a mixed diet in moderation including meat, seafood, dairy, tofu, beans, legumes, grains, vegetables, and fruit. Each blood type has a long list of forbidden foods including specific meats and poultry, seafood, dairy, eggs, oils and fats, nuts and seeds, beans, legumes, cereals, breads, muffins, grains, pasta, vegetables, fruit, juices, fluids, spices, condiments, herbal teas, and other beverages. Each of the blood-type diets consists of whole, unprocessed foods and all recommend the consumption of vegetables, which provide fiber, health-promoting nutrients, and phytochemicals. Physical activity, stress management,
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with no diet or self-monitoring (Group III). After 8months and 21 months of treatment, the results for children in the 3 treatment groups were similar. Childrens weight decreased by 16.6%, 18.6%, and 16.1% in Groups I, II, and III, respectively. However, after 5 years, the children in Group I maintained their relative weight change (-13.6%), while children in Group II were at baseline (+3.3%) and the children in Group III were heavier (+7%). 31
Food Guide Pyramid

The Food Guide Pyramid was designed as a general guide for diet and exercise in adults; however it was used as a dietary component in childhood weight management in one study of adolescents. The results found that the adolescents using the Food Guide Pyramid actually gained weight over the course of the study compared with adolescents who ate a balanced macronutrient low-kilocalorie diet. 32
Multidisciplinary Behavior Change Programs

Two examples of multidisciplinary behavior change programs for overweight children and their families are SHAPEDOWN and Kidshape. Both were developed in academic medical centers and are offered in community settings such as hospitals or clinics with interdisciplinary teams of health professionals. They often include the disciplines of nutrition, exercise physiology, endocrinology, psychology, family therapy, adolescent medicine, family medicine, and/or behavioral and developmental pediatrics. SHAPEDOWN incorporates behavioral techniques to address underlying issues of the childs or adolescents weight. Included are problem solving, communication, and parenting skills (eg, limit setting and nurturing). In addition, cognitive therapy, stress management techniques, and body image therapies are used. 33 SHAPEDOWN was shown to produce significant long-term outcomes in a controlled study of 66 adolescents followed for 15 months who were randomly assigned to experimental or control groups. There were no significant differences between groups in any of the variables studied at the beginning of the study. The SHAPEDOWN group at the end of the treatment (3 months) and at 1 year follow-up (15 months) significantly decreased relative weight and significantly improved weight-related behavior, self-esteem, depression, and knowledge. The control group made no significant improvement in any of these variables except self-esteem. 34 KidShape is a 9-week comprehensive family-based pediatric weight management program for overweight children and their families. Classes are divided into 3 major parts including a registered dietitian teaching adults and
kids together about healthy eating for weight loss, separate meetings for adults and children with a mental health professional to learn to change habits and behaviors and receive group support, and meetings for adults to discuss their specific questions while kids participate in 30 minutes of aerobic exercise; during 2 weeks adults and kids exercise together. 35 Program effectiveness was evaluated in a study of 1,022 families from 24 community-based and hospital-based sites in Pennsylvania and California from 2004 through 2006. Food records, activity logs, program questionnaires, and participant BMIs were obtained at the beginning and the end of the program. Statistically significant improvements in BMI, eating, physical activity, and self-esteem were reported. 36 A follow-up study looked at a convenience sample of 86 children at 3 months, 88 children at 6 months, 30 children at 12 months, and 15 children at 18 to 24 months after completion of the KidShape program. Graduates of the program maintained a significant change in BMI up to 24 months after the program and reported continued improvement in eating and physical activity. 37
Conclusion
There are many diets that will result in weight loss or weight maintenance in adults and children because they control and lower caloric intake. The scientific evidence is strong that a successful weight-loss or weight-maintenance plan for children and adolescents should include reduced kilocalorie intake though consumption of 5 servings of fruits and vegetables per day and minimization or elimination of sugar-sweetened beverages (which are both present in a balanced macronutrient reduced kilocalorie diet and the Traffic Light Diet) as well as the behavioral components (eg, eating breakfast daily, limiting meals outside the home including at fast-food venues and other restaurants, eating family meals at least 5 or 6 times per week, allowing the child to self-regulate his or her meals and avoiding overly restrictive behaviors). Long-term weight management happens when a plan is individualized to a familys needs and preferences. Kilocalorie- and portion-controlled diets such as the balanced macronutrient low-calorie diets and the Traffic Light Diet have been studied over time and may be more conducive to long-term compliance in families than fat- and carbohydrate-restricted diets. Reviewing the various categories of popular and fad diets indicates that all have strengths and weaknesses and have the potential to result in weight loss in adults. However, for children and adolescents, these diets have not been studied due to potential risks for growing children and adolescents from elimination of key food groups, greater-than-recommended
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caloric restriction, adverse behavioral patterns of eating, and/ or lack of scientific evidence for the basis of the diets recommendations. The key requirement for dietary treatment of overweight children and adolescents is to initiate and maintain lifelong healthy eating habits that focus on unhealthy weight in the short term and foster improved health outcomes in the long term. Family involvement, and particularly parental involvement in weight control, weight maintenance, and weight-loss interventions, is associated with weight loss in children, and the use of behavior change techniques as an integral part of the program improves weight outcomes for both children and parents.38
B. Greater than recommended caloric restriction C. Promotion of an adverse eating pattern D. Adequate scientific data for use in children for the diet/plan See p. 487 for answers.
References
1. According to the American Dietetic Association Evidence Analysis Library, which of the following clinical approaches had positive effects when working with overweight/obese children ages 5 to 12? A. Multi-component, school-based B. Behavioral, family-based C. Multi-component, family-based D. Diet, family-based 2. The parents of an 8-year-old child have decided to implement changes that will promote healthier lifestyle habits among all the family members. Which of the following changes is in line with changes recommended when there is readiness to change? A. Adding a salad or vegetable to lunch and dinner meals B. Substituting the dinner soda with a caffeine free beverage C. Limiting family television viewing time to 3 hours a day D. Taking the family for a 30-minute walk after dinner 3. Diets that have been studied for use with children or adolescents include: A. The Food Guide Pyramid and The (Childrens) Atkins Plan B. The Traffic Light Diet and the Food Guide Pyramid C. The Traffic Light Diet and the Pritikin Plan D. The Volumetrics and the Exchange Plans 4. Many of the popular/fad diets commonly used by adults are generally not recommended for children for all of the following reasons except: A. Their potential negative risks to a growing child related to the elimination or decrease of a key food group
1. World Health Organization. Diet, Nutrition and the Prevention of Chronic Diseases. WHO TRS 916. Geneva: WHO/FAO; 2003. 2. Weiss R, Dziurra J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med. 2004;350:23622374. 3. US Department of Agriculture. Continuing Survey of Food Intakes by Individuals 199496. US Dept. of Agriculture, Agricultural Research Service; 1998. 4. Centers for Disease Control and Prevention. Youth Risk Behavior SurveillanceUnited States, 2005. Morbidity & Mortality Weekly Rep. 2006;55(SS-5):1108. 5. Lin BH, Guthrie J, Frazao E. American childrens diets not making the grade. Food Rev. 2001;24(2):817. 6. Washington, R. Overview of the expert recommendations for the assessment, prevention, and treatment of child and adolescent overweight and obesity. Obes Manage. 2008;2:20-23. 7. Barlow SE and the Expert Committee. Expert committee recommendations on the assessment, prevention, and treatment of child and adolescent overweight and obesity. Pediatrics. 2007;120 (suppl4):S163S288. 8. Kirk S, Scott BJ, Daniels SR. Pediatric obesity epidemic: treatment options. J Am Diet Assoc. 2005;105:S44S51. 9. Spear BA, Barlow SE, Ervin C, et al. Recommendations for treatment of child and adolescent overweight and obesity. Pediatrics. 2007;120;S254S288. 10. Position of the American Dietetic Association: individual-, family-, school-, and community-based interventions for pediatric overweight. J Am Diet Assoc. 2006;106:925945. 11. Rodriguez J. The Diet Selector. Philadelphia, PA: Running Press; 2007. 12. American Dietetic Association. Adult Weight Management Evidence Based Nutrition Practice Guideline. ADA Evidence Library. 2008. http://www.adaevidencelibrary.com/topic. cfm?cat=2798. Accessed July 28, 2008. 13. National Weight Control Registry. http://www.nwcr.ws/ Research/default.htm. Accessed May 27, 2008. 14. Evans SA, Parsons AD, Overton JM. Homeostatic responses to caloric restriction: influence of background metabolic rate. J Appl Physiol. 2005;99(4):13361342. 15. Guiliano M. French Women Dont Get Fat. New York, NY: Random House; 2005. 16. Atkins RC. Atkins New Diet Revolution. New York, NY: M. Evans & Co; 2002. 17. Agatson A. The South Beach Diet. New York, NY: Random House; 2003.
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18. Sharman MJ, Gomez AL, Kraemer WJ, Volek JS. Very low-carbohydrate and low-fat diets affect fasting lipids and postprandial lipemia differently in overweight men. J. Nutr. 2004;134:880885. 19. Brehm BJ, Seeley RJ, Daniels SR, et al. A randomized trial comparing a very low carbohydrate diet and a kilocalorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women. J Clin Endocrinol Metab. 2003;88(4):16171623. 20. Shai I, Schwarzfuchs D, Henkin Y, et al. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med. 2008;359:229241. 21. Pritikin R. The New Pritikin Program. New York, NY: Simon & Schuster; 2000. 22. Ornish D. Eat More Weight Less. New York, NY: Harper Collins; 1993. 23. Rolls B, Barnett RA. The Volumetrics Eating Plan. New York, NY: Harper Collins; 2005. 24. Somers S. Eat Great, Lose Weight. New York, NY: Random House; 1999. 25. WeightWatchers. www.weightwatchers.com. Accessed December 10, 2008. 26. Barlow S, Dietz W. Obesity evaluation and treatment: expert committee recommendations. Pediatrics. 1998;102(3). 27. Daniels SR, Arnett DK, Eckel RH, et al. Overweight in children and adolescents: pathophysiology, consequences, prevention and treatment. Circulation. 2005;111:19992012. 28. DAdamo P, Whitney C. Eat Right for Your Type. New York, NY: GP Putnam & Sons; 1996. 29. American Dietetic Association. Pediatric Weight Management Evidence Based Nutrition Practice Guidelines. ADA Evidence Library. www.adaevidenceanalysislibrary.com. Accessed December 10, 2008.
30. Epstein LH, Valoski A, Wing RR, McCurley J. Ten-year follow-up of behavioral, family based treatment for obese children. JAMA. 1990;264:25192523. 31. Epstein LH, Valoski A, Wing RR, McCurley J. Ten-year outcomes of behavioral family-based treatment for childhood obesity. Health Psychol. 1994;13:373383. 32. Saelens BE, Sallis WF, Wilfley DE, Patrick K, Cella JA, Buchta, R. Behavioral weight control for overweight adolescents initiated in primary care. Obes Res. 2002;10:22-32. 33. SHAPEDOWN information and description. http://www. shapedown.com/SD_About.html. Accessed August 4, 2009. 34. Mellin LM, Slinkard LA, Irwin CE Jr. Adolescent obesity intervention: validation of the SHAPEDOWN program. J Am Diet Assoc. 1987;87:333338. 35. KidShape information and description. http://www. kidshape.com/. Accessed August 7, 2009. 36. Rivard CW, Neufeld N. A comprehensive outcome analysis of a multi-site, multi state family-based pediatric weight management program. J Am Diet Assoc. 2007;107(8):A-11. 37. Rivard CW, Neufeld N. A long-term comprehensive evaluation of a family based pediatric weight management program implemented in multiple community based and hospital based sites. J Am Diet Assoc. 2008;109(9):A-94. 38. McLean N, Griffin L, Toney K, Hardeman W. Family involvement in weight control, weight maintenance and weight-loss interventions: a systematic review of randomized trials. Int J Obesity. 2003;27:9871005.
Sports Nutrition
Jackie Buell, PhD, RD, LD, ATC, LAT and Diane L. Habash, PhD, RD, LD
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Learning Objectives
1. Outline the distribution and quantity of macronutrients in the diet of the child/adolescent athlete, and with attention to timing around sport. 2. Discuss differences in adult and youth heat dissipation, and suggest fluid intake to help protect the young athlete from heat injury and poor performance due to dehydration. 3. Describe to young athletes how to think about fueling (food) relative to the timing of sport to maximize muscle glycogen (pre-event) and encourage muscle growth/ strength (post-event). 4. Provide young athletes and their supporters with educational Web sites and professional organizations to locate current information and resources.
CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
Carbohydrates Protein
Fat. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vitamins and Minerals. . . . . . . . . . . . . . . . . . . . . . . . . . . . Timing to Sport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recovery Nutrition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bedtime Nutrition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nutrition Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nutrition Resources. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
181 181 182 182 183 183 183 183
Introduction
The drive to improve and perfect performance is not new to athletes of any age. As a result of the desire to excel, athletes train harder and longer, and may look for dietary supplements or other nutrition advantages. Depending on the sport, athletes perceive that they can gain a further edge over competitors by changing their body weight or composition. Young athletes who are highly motivated in their sport and performance may not be well educated about the potential impact of proper nutrition or dietary supplements. Research suggests they obtain most of their information from teachers and parents, followed by trainers, friends, and Web sites.1 These athletes are ripe for information in this teaching opportunity for the healthcare professional, and the following conversation points2 may make the greatest impact: tips focused on sports performance with some attention to body image and weight issues since these are likely significant motivators for the athlete;
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a positive approach and reinforcement counseling with goal setting; inclusion of the family when appropriate; suggestions for recipes, shopping, and cooking tips when family is included; encouragement for the athlete to take responsibility for food choices, eating behaviors, and some preparation and packing of foods; and involvement of the athlete in diet evaluation and subsequent goal determinations and goal evaluations. The spectrum of young athletes, from child through young adult, undoubtedly differs from other groupsincluding those of different ages, less active peers, and adultsin terms of nutrition needs. Research on this young cohort spectrum is sparse. Working to evaluate or improve the diet of a young athlete likely involves using the (non-athletic) life-stage dietary reference intake (DRI) peer standards with extrapolation on how exercise, motion inefficiency, or growth/development might influence the standards. In addition to the life-stage DRI energy (kilocalories) and protein recommendations to support growth, young athletes need to consume enough additional calories to cover the needs of sport if the desire is to remain in energy balance and fuel the muscle for growth and performance. Because more research exists for adult populations, it is tempting to apply adult recommendations to identify sports nutrition goals for young individuals. It is wise to remember that children and youth are different, such as their degree of motion inefficiency, 3 and this may invalidate the adultto-child extrapolation. Nonetheless, due to a lack of data on broad groups of child or adolescent athletes, this chapter will extrapolate from peer and adult cohort recommendations. Achieving the desired caloric balance is the starting nutrition consideration and calculation for athletes of all ages. Athletes with significant caloric imbalances may demonstrate undesired weight gain or weight loss, and this is the usual reason for nutrition intervention with a young athlete. The best starting number is to use the life-stage energy needs as outlined in the current DRIs according to activity level.4 Be aware that many child/adolescent athletes may exceed the very active physical activity category within the DRI, and consider increasing the estimated calories accordingly to achieve the desired weight maintenance or gain goals. This is particularly true with adolescents during the growth spurt engaged in high-intensity sports (eg, basketball, soccer, lacrosse, etc.) who usually desire to gain lean mass. Such athletes may need upwards of 6000 calories daily to tip the energy balance to favor muscle mass accretion, and these same athletes would lose weight consuming
4500 calories daily. Estimating energy needs and monitoring for desirable changes is necessary to confirm the accuracy of the energy prescription.
Carbohydrates
The most obvious dietary need within the calories allotted for the young athlete should be carbohydrate to fuel the muscle. It has long been accepted that carbohydrate is the primary fuel for human muscle as intensity of activity increases, and this is well confirmed in adult athletes. It is suggested that children may be able to use even more carbohydrate as substrate than adults5; thus, fueling the muscle to at least the adult mass-dependent recommendation is prudent. In adults, carbohydrate has been demonstrated to be supportive before, during, and after endurance exercise when enough calories are consumed overall. 6 Ensuring 5 g of carbohydrate per kilogram body weight is the basic starting point for all athletes.7,8 The need for carbohydrate increases as the time and intensity of activity increases. The more serious athlete who practices daily for 1 to 2 hours might increase this fueling to 7 g/kg up through 11 to 12 g/kg for 3 to 4 hours of intense exercise per day.7,8 It is not as simple as asking the frequency and length of practices; to apply these guidelines it is important to gauge the actual time spent in high-intensity activity. Most sport practice sessions include periods of inactivity and rest. Including the downtime of sessions would overestimate fueling needs. Consuming too much simple carbohydrate may increase dental cariesespecially when the choices include sticky and fermentable sourcesand there is a high degree of variability in how humans tolerate high carbohydrate. It is prudent to consider the athletes preferences, tolerance, and performance enhancement when fine-tuning the carbohydrate in the diet. Awareness of the underlying health benefits of the source of carbohydrate should also be emphasized in this cohort as a strategy to encourage lifelong healthy habits. Carbohydrate in the diet comes mostly from the grains, fruit, and milk food groups with smaller contributions from the vegetable group. Overall encouragement to use whole grains over refined products will improve the fiber content and nutrient density of the diet and may confer long-term health benefits. The value of fruit in the diet is uncontested, and the child or adolescent athlete needs 4 servings of milk/dairy daily for skeletal health. Even though vegetables provide a minimal contribution, promoting them for carbohydrate advantages may encourage better consumption in this young population. Another potential advantage of encouraging healthier carbohydrate sources
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in this population is the carryover it might extend to the athletes family unit. The use of high-carbohydrate recommendations for individuals who do not tolerate carbohydrate well due to allergies or metabolic issues (such as diabetes) should be approached with caution and attention to tolerance. In general, there is very little nutrition value in the use of sugar-sweetened beverages, and the evaluating clinician should be vigilant for overuse of these products and the amount of sugar and empty calories they contribute to the overall diet. The current DRI would accept up to 25% of the diet in simple sugars.4 An exception where consumption of sugar-sweetened drinks may actually be desirable and helpful is the appropriate use of commercial sports drinks designed to help the athlete maintain hydration and blood glucose levels with timing around and during practice orevents.9
Practical application: Athletes weight 2.2 = kg body weight,
multiply by 5 g/kg to recommend minimal daily carbohydrate intake. Consuming 0.5 to 1 g/kg within the hour prior to exercise, with a predilection for liquid sources for those unable to eat right before practice or events, may better prepare the muscle for high-intensity work. For events lasting longer than 90 minutes, consumption of a formulated glucose-electrolyte solution may help maintain blood glucose and glycogen stores to delay fatigue. Recovery nutrition would also include 1 g/kg taken immediately after exercise if the next meal is not immediately available. Note the fraction of the total daily carbohydrate that is suggested to surround the competition to keep the muscle fueled. This nutrient timing is novel to many athletes and is simply a snack-planning issue for desired results. See Table 17-1 to help translate the grams to actual foods.
Table 17-1 Translation of Gram Recommendations to Foods

Primary Foods Portion Grams Per Portion
Carbohydrates Grains (4 kcal/g) Fruits Milk Vegetables Protein Meat (4 kcal/g) Milk Beans Peanut Butter Fats (9 kcal/g) saturated polyunsaturated
monounsaturated
1 oz equivalent, cup starchy beans 1 medium fruit 8 oz milk, 6 oz yogurt 1/2 cup cooked, 1 cup raw 1 oz equivalent 8 oz milk, 6 oz yogurt, 1oz cheese 1/2 cup starchy 1 TBSP counts as 1 fat and 1 protein 1 tsp equivalent of animal fat (butter, bacon, cream, shortening, sourcream) 1 tsp plant oil (corn, safflower, soy) 1 TBSP regular salad dressing (2 TBSP reduced fat) 1 tsp mayonnaise (1TBSP reduced fat) 1 TBSP sunflower seeds 1 tsp oil (canola, olive, peanut) 2 TBSP or 1/6 medium avocado, 8 large black olives or 10 green 6 nuts of most nuts 1 TBSP sesame seeds
15 15 12 5 7 8 7 7 5 5
Protein
Protein is not typically viewed as energy for sport, but is critical for growth and development. The amount of protein needed in the athletes diet remains controversial in all populations.10,11 The DRI for protein, without consideration of athletic activity, ranges from the adult recommended dietary allowance (RDA) of 0.8 g/kg/d to the child adolescent recommendation of 1.05 g/kg/d,4 and this current protein DRI excludes additional protein possibly available for muscle fueling or metabolism. It is well-documented that adult athletes are able to utilize more than these DRIrecommended amounts to support the muscle protein turnover and energy demands of varying activities.12 In general, nutrition recommendations for adult athletes encompass a range of about 1 to 1.7 g/kg/d.13 Bulk-seeking strength athletes top the recommendation chart at 1.7 g/ kg/d as the extrapolated upper threshold that nitrogen balance studies have demonstrated can physiologically be used for lean mass accretion.14 It is intuitive that the upper threshold for the child or adolescent athlete may be slightly higher than these adult values due to compounded growth and
development needs in addition to the usual lean mass goals. It has become an easy-to-remember recommendation for adult athletes to consume 1 g/lb (2.2 g/kg) of body weight, and this would likely be an appropriate recommendation for youth as well when it is desirable to assure that the athlete has more than adequate protein for lean mass accretion and muscle metabolism. Phillips article is helpful in understanding the argument over adequate (required) versus advantageous protein, and addresses the potential fat loss associated with high-protein diets as well as the metabolic inefficiency of using protein for energy.11 It should be emphasized that consuming more than about 2 g/kg/d is not necessary for muscle growth and may actually suppress muscle protein synthesis.15 Protein conversations often include debates around the safety of high-protein diets, but examination of the literature finds little evidence of liver or kidney function issues in healthy adult athletes.16 There is no research on high-protein diets in child, preadolescent, or adolescent athletes, but error on the side of safety where the ceiling is defined as 2.2 g/kg would be prudent. High-protein diets will displace carbohydrate from the diet and that is not in the best interest of performance.
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The quality of protein in the athletes diet should also be assessed. The protein in animal products should contain all the essential amino acids, and the essential amino acids have been demonstrated most important to the muscle during and after exercise.17 Athletes who rely on plant proteins need to ensure a wide variety and adequate amount of plant protein sources to provide sufficient essential amino acids consumed over the course of a day.18 The use of processed protein supplements, especially among males, is quite popular in the form of wheybased protein powders, shakes, and energy bars. Reminding the athlete that there is no formal (ie, Food and Drug Administration) oversight for these food products to ensure label accuracy, purity, and lack of adulteration should be part of the educational conversation. The protein literature demonstrates that strength19 and endurance20 athletes can easily consume this higher level of protein within the habitual diet without using supplements. It is critical to remember that high-protein diets will unduly tax the unhealthy liver and kidneys, but is not proven to be an issue for healthy livers or kidneys in adults.16
Practical application: Athletes body weight in pounds is equal
to grams of total protein for maximal muscle support such as heavy endurance exercise or muscle-building training phases. Athletes not engaged in endurance exercise or muscle-building phases of training would likely fare well with 1.1 to 1.4 g/kg. The growth phase of the athlete must always be taken into consideration for protein needs where periods of increased growth place the athlete at a higher protein need. For best muscle recovery, athletes should strive to consume about 15 g of good-quality protein (along with adequate carbohydrate) immediately after exercise to support a positive growth environment. See Table 17-1 to help translate the grams to actual foods.
Practical application: Fat should provide 20% to 35% of daily
energy. The total energy recommendation multiplied by 0.2 and 0.35 will yield a range of calories of fat, and dividing the calories by 9 calories per gram will calculate the grams of fat desired. It is standard to derive the needed protein and carbohydrate first, then ensure the suggested fat is within this caloric range for the athlete.
The ideal amount and type of fat in the diet remains as controversial for athletes as it is in general. The current acceptable macronutrient distribution range from the DRIs calls for 20% to 35% of the calories be taken as fat. Prudent heart health recommendations encourage incorporation of mono- and polyunsaturated fats to displace many of the typical saturated fats in the Western diet.21 When athletes are struggling to maintain body mass during the competitive season, it is imperative to encourage calorie-dense foods which typically include a higher fat proportion. The hormonal milieu in the body is undoubtedly supported by an adequate fat intake and calorie balance. Recent literature has addressed fat loading as a method of supporting fueling for sub-maximal endurance exercise, but the studies thus far demonstrate a loss of high gear or reduced ability to reach or sustain high intensity,22 and there is no research on how these diets may influence body composition or cardiovascular health (in child athletes).
Fat
Ensuring adequate hydration is a safety concern as well as a performance advantage.2325 Dehydration may contribute to a decrement in aerobic performance at as little as 2% per body weight in adults, and may be life-threatening to adults at levels of 7% to 8% per body weight depending on the athlete.25 Children do not adapt as well as adults to heat extremes or thirst mechanism, and differ from adults in production of metabolic heat and sweat capacity26 demonstrating the likely difference in heat balance at any given intensity or environment. Research in young male populations by the Bar-Or group demonstrates reduced aerobic capacity and increased core temperature at 1% dehydration.26 Additionally, the American Academy of Pediatrics outlines the physiological differences in sweating and heat dissipation in children and adolescents.23 The research on youth hydration and physiology convince the sports nutrition practitioner to ensure hydration awareness in young athletes. Young athletes have been demonstrated to be less aware of fluid needs (thirst) and need strong encouragement and guidance from the parent, coach, and/or athletic trainer to consume fluids as often as the weather and activity dictate.9 Professional organization guidance statements (Table 17-2) call for ensured pre-hydration, evaluation of the practice environment (heat, humidity, available shade, clothing modifications), adequate fluid breaks every 15 to 20 minutes during activity, and intentional rehydration after activity.
Table 17-2 Professional Organization Guidance Statements on Hydration American Academy of Pediatrics (2000)23 Athlete should begin well-hydrated. During activity, periodic drinking should be enforced with 5 oz of water or salted beverage for 88-lb child or 9 oz for 132-lb adolescent (with inferred volume adjustment for body size differences). Pre-hydrate 34 hr before with 1720 oz, then 710 oz 1020 minutes immediately before; consume 710 oz during activity; post-exercise hydration aims to provide 125%150% losses. Slowly consume 57 mL/kg at least 4 hr prior; if urine is concentrated consume 35 mL/kg 2 hours before; event hydration focuses on individual sweat rate and tolerance.
Hydration
National Athletic Trainers Association (2000)24
American College of Sports Medicine (2007)25
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The recommendation for consumption of plain water versus commercially prepared sports drinks containing carbohydrate, sodium, and/or potassium likely depends on voluntary fluid consumption, the length of the athletic session, pre-event carbohydrate status, and the sodium loss of the individual. Athletes who sweat profusely and lose a lot of sodium are best to also be aware of their sodium needs alongside fluid needs. Bar-Or has demonstrated the flavor and sodium content of a drink to be important to voluntary consumption by young athletes. 27,28 Foods helpful in replacing sodium include soup, pretzels, or liberal salt shaker use. The use of sugar-flavored milk products has become common in recovery nutrition,29 and it is notable that an 8 oz glass of milk typically contains 120 to 170 mg of sodium (depending on brand and type), which would also contribute to fluid balance.2931 Shirreffs and Maughan have nicely demonstrated the value of sodium in the rehydration plan. 32 When discussing additional sodium intake, advice should be tailored to the likely salt loss of the athlete.
Heavy sodium loss indicators: Eyes burn when sweat gets in them, workout shirts appear to have rings of salt around sweat areas, granular feeling to skin after workout at the side of face where sideburns would be.
Overdrinking can lead to hyponatremia, but this is usually limited to smaller athletes who drink large amounts of water (hypotonic) over a period of hours while engaged in endurance exercise. Use of a sports drink for activities lasting longer than 60 to 90 minutes may help avoid this life-threatening condition. Teaching children and adolescents to drink an appropriate amount is an important task for safe participation and good health.
Vitamins and Minerals
If the practitioner is able to estimate energy expenditure, it is relatively simple to suggest a daily drinking plan to provide 1 mL/kcal of fluid as a starting point. It is common practice to screen for dehydration risks by weighing athletes before and after practice, and to encourage consumption of 150% of the fluids (weight) lost (approximately 3 cups or 24 oz per pound lost). Evaluation of urine osmolality, refractometry, and bioelectrical impedance are among the current trends for evaluation of hydration status, 33 but likely the most practical to teach is evaluation of urine color. For athletes with significant sweat losses and muscle-cramping issues, it is helpful to calculate a personalized sweat rate to formulate the strongest hydration plan.
Practical application: Hydration should be a continuous process
throughout the athletes day, but routine hydration with respect to exercise should also be habit. Athletes should ensure pre-hydration with 5 to 7 mL/kg of fluids at least 4 hours before events; this leaves enough time for the body and kidneys to produce urine for evaluation of hydration status. If urine is still concentrated (color and smell), consume an additional 3 to 5 mL/kg 2 hours prior. Fluid breaks every 15 to 20 minutes during activity should provide about 5 oz for the smaller child (88 lb) and 9 oz for the adolescent (132 lb). Rehydration is best achieved with consuming fluid equal to 150% of the weight lost during activity. This means drinking about 24 oz of fluid per pound lost. Co-ingestion of sodium will help replenish lost sodium, which is critical to maintaining hydration.
Athletes or their parents often ask if a vitamin-mineral supplement is necessary or protective. Athletes consuming at least 1800 calories per day within a diet that includes a wide variety of foods from all food groups do not likely need to supplement the vitamins and minerals. Athletes who restrict food choices like red meat (iron), milk (calcium), and carbohydrates (B vitamins) from the diet may benefit from supplementation. The inclusion of a generalized multivitamin where the label reflects 100% to 200% Daily Value for most contained nutrients is likely harmless when the supplement is a known and reputable brand. There is no evidence that consuming supplements containing large amounts of antioxidants protects the body. In fact, there is evidence in adults that this sort of therapy may actually oppose the goals of the supplement. 34 In general, a one-aday style vitamin-mineral supplement should not be seen as a substitution for a balanced and variety-filled diet, but may be a low-risk answer for parents or athletes worried about dietary adequacy.
Timing to Sport
A common pattern seen in some young athletes is to eat sparse calories early in the day with the bulk of energy consumption later in the day. It is a positive health habit to distribute energy consumption throughout the day, and this habit has the added benefit for athletes of providing the muscle with more consistent access to storage fuels as well. Athletes who wait to eat most of their calories late in the day are usually so hungry that it is hard to make positive decisions about which foods to eat and how much should be consumed. It may be better for hunger levels, metabolism, body composition, and muscle fueling to eat multiple small meals throughout the day (every 2 to 4 hours) to achieve energy balance instead of imploding the body with too many calories late in the day. An athlete cannot underestimate the importance of breakfast on a daily basis. On non-competition days, a mixed breakfast supplying ample carbohydrate and about 25% of the daily calories will refuel the muscle and liver
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from the overnight fast and should be consumed before practices. On competition days when breakfast is the pre-event meal, the athlete should consider that the carbohydrate will pre-fuel the muscle while the protein and fat of the meal will determine the satiety during competition. Finding the timing of consumption and mixture of foods to promote high-intensity competition along with a comfortable gastrointestinal system is the task to practice and master during non-competition sessions. Most athletes do well with a fairly high carbohydrate meal (at least 1 g/ kg body weight (BW)) and about 3 oz of lean protein with 1 or 2 fat portions (Table 17-3) 2 to 3 hours (no more than about 4 hours) before competition. Some athletes perform well when they further top off the muscle carbohydrate by consuming 40 to 60 g of carbohydrate within 1 hour of competition. An athlete needs to experiment with various foods to know what works best; some athletes will prefer fluid sources of carbohydrate for gut comfort this close to intense exercise. Consumption of high-fiber, high-fat, or high-sugar foods can cause abdominal distress in some individuals resulting in abdominal cramping, gas, and/or diarrhea. Table 17-4 provides examples of fueling ideas for the day of the competition.
fat any differently than other eating throughout the day assuming the calorie consumption matches calories needed. It is the overall calorie balance that is important. As long as the nighttime snack is within the daily calorie needs of the individual, the timing is not important. It is common to suggest the use of dairy products (eg, low-fat milk or yogurt) late in the evening for the possible positive influence on fat metabolism38 and continued anabolic support to the muscle.
Nutrition Challenges
Common nutrition-related issues that young athletes may experience are listed in Table 17-5. Young athletes are often serious about their bodies and sports, and a healthcare practitioners respect and guidance can help them through nutrition-related challenges.
Nutrition Resources
Recovery Nutrition
Recovery nutrition has become one of the hottest recommendation topics in recent years of sports nutrition.17,35 Consuming an appropriate recovery snack immediately after exercise should become habit for athletes who do not have at least 24 hours to recover the muscle nutritionally. A recovery snack should be a priority for multiple-event athletes or when the daily routine demands multiple practices close together. An appropriate recovery snack for adult athletes suggests 40 to 60 g of carbohydrate and 15 to 20g of good-quality protein to provide the essential amino acids. The carbohydrate for recovery has demonstrated a more rapid period of glycogen restoration, and the additional calories in protein stimulate the muscle to set up an anabolic environment.15,36 The current research supports essential amino acids as the stimulus for this anabolic change and leucine (a branched-chain essential amino acid) is likely important to the response. 37
Many resources are available that can provide greater depth across the field of sports nutrition. In a field that is subject to popular opinion and media-sensitized measures of performance, the information given to athletes, caregivers, and coaches should be grounded in and supported by evidencebased science. See Table 17-6 for resources suggested by the authors. (All Web sites accessed January 20, 2009.)
Bedtime Nutrition
Bedtime nutrition is another recommendation that serious athletes should consider. Concerns about eating after a certain time of the evening and if a protein supplement should be taken are commonplace in adult populations. Bedtime snacking does not necessarily convert to body
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Table 17-3 Examples of Meals and Snacks Used With Timing Around Sport Description Pre-game Target is high carbohydrate within mixed diet (34 hr prior) 2 cups whole wheat pasta with 1 cup sauce and 3 oz lean meat, 1 Pasta meal cup of salad, 1 piece garlic bread, and 1 cup 2% milk Fast food Wendys grilled chicken with baked potato with broccoli cheesesauce Larger athletes might add a small Frosty to above to bring total to Pre-event Target is well-tolerated carbohydrates (2060 min prior) 12 oz sweet tea with 1 oz animal crackers 20 oz sports drink 2 oz pretzels with water During event Sports drink only warranted if longer than 90 minutes of intense (48 oz every activity (otherwise water is great) 1520 min) Per 8 oz Gatorade G Gatorade G2 series Powerade Powerade Zero Accelerade (incl 4 g protein) Recovery (within 45 min) Target is intentional mix of carbohydrate and good-quality protein
kcal
g CHO
g pro
g fat
797 780 1080 kcal 231 160 200 kcal 50 25 60 0 80 kcal Target 200300
120 117 143 g CHO 48 40 47 g CHO 14 7 17 0 15 g CHO Target 4060
54 44 59 g pro 2 0 6 Na (mg) 110 110 55 55 120 g pro Target 1015 11 20 18 11 10 10
18 16 31 g fat 4 0 0 K (mg) 30 30 30 33 15 g fat Target low 1.5 10 3 2.5 2 2
1 cup ready-to-eat cereal (eg, multi-grain Cheerios) with 1 cup 250 50 skim milk and 1 medium banana Peanut butter (1 TBSP) and jelly (1 TBSP) sandwich on 2 slices 368 52 whole wheat bread with 1 cup milk Turkey sandwich with 2 slices bread and about 2 oz turkey with 12 300 50 oz sports drink 1 cup lowfat chocolate milk with 1 oz pretzels 259 50 1 mozzarella string cheese stick, 1 cup green grapes, 1 medium 215 44 orange with water PowerBar and water 247 48 kcal = calories, g CHO = grams of carbohydrate, g pro = grams of protein, g fat = grams fat, Na = sodium, K = potassium
Table 17-4 Fueling Ideas for the Day of Competition

Timing Nutrition Goals Example (always relative to athlete size and energy needs)
Breakfast at least 34 hr from event Pre-event snack 12 hr before During event if high intensity lasts longer than 90 minutes After event within 45 minutes if multiple events (Recovery snack) Snacks between meals not as close to event
Balanced meal heavy on carbohydrate High carbohydrate Liquid carbohydrate 3060 g/hr Carbohydrate and good-quality protein (3:1 or 4:1 ratio of carbohydrate to protein) Carbohydrate with little protein and little fat
Whole grain or fruit pancakes with syrup, 8 oz milk, side of fresh fruit, 2oz lean meat, 16 oz water after meal will begin hydration on right path 12 oz sports drink, piece of fruit or pretzels; if urine is strong, morewater 48 oz of sports drink every 1520 minutes 8 oz chocolate milk with peanut butter (limit to 1 TBSP) and jelly sandwich on whole grain bread Trail mix with 2 TBSP dried cranberries or raisins, 1 tsp peanuts, and 1 oz mozzarella cheese stick -ORTurkey or ham sandwich with 2 oz meat, 2 slices whole grain bread, tomato/lettuce as tolerated, with glass of water Plate surface divided as 1/4 meat, 1/4 whole grain, 1/2 brightly colored fruits and vegetables with glass of milk
Meals not close to time of event
Balanced with carbohydrate, adequate protein, and fat
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Table 17-5 Common Issues for Athlete Nutrition

Issue Possible Indicators and Concerns Solutions
Limited nutrition knowledge related to sports performance
Cannot describe desirable pre-game meals or recovery eating Has no hydration plan
Provide reputable Web sites Suggest easy-to-read books Stress planning and organization for having foods and beverages available Practice having all the foods and beverages needed for sport Note timing of events and fuel/hydrate accordingly Note travel impact on eating and hydrating opportunities and on performance Identify community partners (eg, a Certified Specialist in Sports Dietetics(CSSD)) Educate on advantages of diet with varied food groups to include performance advantages of carbohydrate foods Encourage athlete to bring foods that she or he likes so the athlete is at leastfueling Encourage practice for fuel/hydration Discuss planning strategies for foods typically afforded Buy in bulk and separate/store in pantry/freezer Help athlete understand correct amount of protein to prevent undernutritionoroverspending Cook in bulk and freeze for later access Buy generic for most foods Buy fruits and vegetables in season Ensure family is not eligible for federal food assistance program Stress that normal physical activity and adequate nutrition optimize growth Educate that growth has genetic and environmental components Consider that intense exercise may be associated with delayed growth Check and reinforce appropriate athlete vs parent expectations of lean massaccretion; use growth charts Explain puberty progression and risks of stifling puberty When in doubt, suggest evaluation by psychological professional and dietitian Early intervention may avoid Female Athlete Triad outcome (see below)
Picky eater
Low variety in habitual diet Does not like entire food groups
Eating on a budget Eating 1 or 2 meals per day or low income Eating little meat and lots of bread and pasta
Male athlete with high growth expectations
Questions about how much protein needed or what supplements will work overt in desire to be bigger Usually
Weight control expectations (typically females)
Secondary sex characteristics not desirable to somefemale athletes Underfueling to avoid gaining weight; poor performanceand health detriments may result Poor self-esteem and/or self-image Overt comments about not liking body parts (eg,bellyor thighs) Unhealthy control methods (eg, diet pills, smoking,vomiting, laxatives, or starvation) Often occurs in young females who want to lose weight Can be due to perceptions that meat has too much fat and calories
Vegetarianism
Educate about optimal protein-alternative foods (dairy, legumes) or how to combine foods to ensure complete proteins Alert athlete to consume adequate nutrients such as iron, calcium, and zinc Inquire about why this lifestyle is appealing to the athlete to ensure answer isconsistent with balanced decision Encourage eating a diet with a wide variety of foods that will fuel the muscle foroptimal performance When in doubt, suggest evaluation by psychological professional and dietitian Intervene early to increase chances for recovery
The Female Athlete A combination of 3 disorders (or spectrums) that includes low energy availability (ie, expend more Triad calories than consume), amenorrhea, and low bonedensity May be related to disordered eating, poor body image, unrealistic body weight goals, and weightloss expectations Often undetectable or not considered until stress fracture occurs Exists in all sports but especially in those with weight or appearance requirements Critical read for this area of evaluation is ACSM Position Statement39 Use of May be related to athletes desire to excel but oftennot supported by evidence performanceenhancing Often used by athlete as a substitute for supplements (legal adequatenutrition and illegal) Could be related to peer pressure and media influences
There are no pediatric evidence-based clinical trials on the use or the adverse effects of some supplements (herbals, ergogenic aids, etc.) Recent review of supplement studies shows anabolic steroid use ranges from 1% to 11.1% of adolescents surveyed and creatine use in reviewed studies ranged from5.6% to 30%40 Supplements sought frequently for improving speed, decreasing weight, or increasing size/bulk of athlete Use of one multivitamin/mineral supplement daily has been suggested for all individuals, not just athletes Seek advice of certified sports dietitian (CSSD)
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Table 17-6 Additional Exercise and Nutrition Resources

Topic Resources
To find a Registered Dietitian (RD) certified to work with athletes; known as a Certified Specialist in Sports Dietetics (CSSD) General Sports Nutrition Information
General Exercise Physiology Information
Supplement Information
Digital Athlete Resources
American Dietetic Association (ADA) list of RDs www.eatright.org ADA Dietetic Practice Group for Sports, Cardiovascular, and Wellness Nutritionists (SCAN) list of CSSD RDs www.scandpg.org Position Papers: American Dietetic Association41 www.eatright.org American College of Sports Medicine25,41 www.acsm.org National Athletic Trainers Association www.nata.org/statements/ Books/Web sites: Sports Nutrition; A Practice Manual for Professionals. 4th ed. Chicago, IL: American Dietetic Association; 2006 http://www.scandpg.org/cssd_promotion.php Gatorade Sports Science Institute* www.gssiweb.com American College of Sports Medicine www.acsm.org NISMAT Exercise Physiology Corner* www.nismat.org/physcor/index.html Australian Institute of Sport* www.ausport.gov.au/ais/nutrition Gatorade Sports Science Institute* www.gssiweb.com Drug Free Sport* www.drugfreesport.com/ IBIDS database ods.od.nih.gov/Health_INformation/IBIDS.aspx Natural Medicines Database www.naturaldatabase.com Consumer Labs third party quality testing www.ConsumerLabs.com *Many of the above Web sites have companion athlete links or at an appropriate level for athletes.
1. How much carbohydrate as a minimum should the young athlete include in the daily diet? A. This is not important. It is the overall calories that count. B. 5 g/kg body weight C. 15 g/kg body weight D. Athletes only need about 35% of their diet as carbohydrate. 2. When, relative to a strength-training session, is the timing and amount of protein intake the most important for a young athlete trying to gain lean mass? A. Protein should be the primary focus. B. Carbohydrate only; no protein needed C. 3:1 or 4:1 ratio of carbohydrate to protein D. Athletes should not eat within 30 to 45 minutes of exercise.
3. How much fluid should an athlete who requires 3500 kcal/d be aiming to consume? A. 3.5 L along with evaluation of urine color for hydration B. Athletes should let thirst be their guide. C. Athletes need 8 to 10 glasses of water per day. D. All athletes should consume an electrolyte sports drink during activities in the heat. 4. Which of the following are included spectrums of the female athlete triad? A. Amenorrhea or delayed menarche B. Poor bone mineral acquisition compared with age cohort C. Low energy availability D. All of the above See p. 487 for answers.
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References
1. Hoffman JR, Faigenbaum AD, Ratamess NA, Ross R, Kang J, Tenenbaum G. Nutritional supplementation and anabolic steroid use in adolescents. Med Sci Sports Exerc. 2007;40(1):1524. 2. Andrew K. Practice tips (in children and young athletes). In: L. Burke, V. Deakin, eds. Clinical Sports Nutrition. 3rd ed. Sydney: McGraw Hill; 2006:620. 3. Walker JL. The energy cost of horizontal walking and running in adolescents. Med Sci Sports Exerc. 1999;31(2):311. 4. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). Washington, DC: National Academy Press; 2005:12. 5. Bass S, Inge K. Nutrition for special populations: children and young athletes. In: L. Burke, V. Deakin, ed. Clinical Sports Nutrition. 3rd ed. Sydney: McGraw Hill; 2006:605. 6. Jacobs K, Sherman W. The efficacy of carbohydrate supplementation and chronic high carbohydrate diets for improving endurance performance. Int J Sports Nutr. 1999;9:92115. 7. Burke L, Cox G, Cummings N, Desbrow B. Guidelines for daily carbohydrate intake: Do athletes achieve them? Sports Med. 2001;31:267299. 8. Dunford M. Sports Nutrition: A Practice Manual for Professionals. 4th ed. Chicago, IL: American Dietetic Association; 2006:547. 9. Ali A, Williams C, Nicholas CW, Foskett A. The influence of carbohydrate-electrolyte ingestion on soccer skill performance. Med Sci Sports Exerc. 2007;39(11):19691976. 10. Tipton KD, Witard OC. Protein requirements and recommendations for athletes: relevance of ivory tower arguments for practical recommendations. Clin Sports Med. 2007;26(1):1736. 11. Phillips SM. Dietary protein for athletes: from requirements to metabolic advantage. Appl Physiol Nutr Metab. 2006;31(6):647654. 12. Lemon PW. Beyond the zone: protein needs of active individuals. J Am Coll Nutr. 2000;19(5):513S521S. 13. Tarnopolsky MA. Protein and amino acid needs for training and bulking up. In: L. Burke, V. Deakin, eds. Clinical Sports Nutrition. 3rd ed. Sydney: McGraw Hill; 2006:95. 14. Lemon PW. Effects of exercise on dietary protein requirements. Int J Sport Nutr. 1998;8(4):426447. 15. Bolster DR, Pikosky MA, Gaine PC, et al. Dietary protein intake impacts human skeletal muscle protein fractional synthetic rates after endurance exercise. Am J Physiol Endocrinol Metab. 2005;289(4):E678E683. 16. Martin WF, Cerundolo LH, Pikosky MA, et al. Effects of dietary protein intake on indexes of hydration. J Am Diet Assoc. 2006;106(4):587589. 17. Borsheim E, Tipton KD, Wolf SE, Wolfe RR. Essential amino acids and muscle protein recovery from resistance exercise. Am J Physiol Endocrinol Metab. 2002;283(4):E648E657. 18. American Dietetic Association, Dietitians of Canada. Position of the American Dietetic Association and Dietitians of Canada: vegetarian diets. J Am Diet Assoc. 2003;103(6):748765.
19. Phillips SM. Protein requirements and supplementation in strength sports. Nutrition. 2004;20(7-8):689695. 20. Tarnopolsky M. Protein requirements for endurance athletes. Nutrition. 2004;20(7-8):662668. 21. Position of the American Dietetic Association and Dietitians of Canada: Dietary fatty acids. J Am Diet Assoc. 2007;107(9):15991611. 22. Stellingwerff T, Spriet LL, Watt MJ, et al. Decreased PDH activation and glycogenolysis during exercise following fat adaptation with carbohydrate restoration. Am J Physiol Endocrinol Metab. 2006;290(2):380388. 23. American Academy of Pediatrics: Climatic heat stress and the exercising child and adolescent. Committee on Sports Medicine and Fitness. Pediatrics. 2000;106(1):158159. 24. Casa DJ, Armstrong LE, Hillman SK, et al. National Athletic Trainers Association position statement: Fluid replacement for athletes. J Athl Train. 2000;35(2):212. 25. American College of Sports Medicine. American College of Sports Medicine position stand. Exercise and fluid replacement. Med & Sci Sports & Exerc. 2007;39(2):377390. 26. Bar-Or O. Temperature regulation during exercise in children and adolescents. In: C. Gisolfi, DR Lamb, eds. Perspectives in Exercise Sciences and Sports Medicine. Indianapolis, IN: Benchmark Press; 1989:335367. 27. Wilk B, Bar-Or O. Effect of drink flavor and NaCl on voluntary drinking and hydration in boys exercising in the heat. J Appl Physiol. 1996;80(4):11121117. 28. Wilk B, Kriemler S, Keller H, Bar-Or O. Consistency in preventing voluntary dehydration in boys who drink a flavored carbohydrate-NaCl beverage during exercise in the heat. Int J Sport Nutr. 1998;8(1):19. 29. Karp JR, Johnston JD, Tecklenburg S, Mickleborough TD, Fly AD, Stager JM. Chocolate milk as a post-exercise recovery aid. Int J Sport Nutr Exerc Metab. 2006;16(1):7891. 30. Bauman DE, Mather IH, Wall RJ, Lock AL. Major advances associated with the biosynthesis of milk. J Dairy Sci. 2006;89(4):12351243. 31. Roy BD. Milk: The new sports drink? A review. J Int Soc Sports Nutr. 2008;5:15. 32. Merson SJ, Maughan RJ, Shirreffs SM. Rehydration with drinks differing in sodium concentration and recovery from moderate exercise-induced hypohydration in man. Eur J Appl Physiol. 2008;103(5):585594. 33. Stuempfle KJ, Drury DG. Comparison of 3 methods to assess urine specific gravity in collegiate wrestlers. J Athl Train. 2003;38(4):315319. 34. Knez WL, Jenkins DG, Coombes JS. Oxidative stress in half and full Ironman triathletes. Med Sci Sports Exerc. 2007;39:283288. 35. Baty JJ, Hwang H, Ding Z, et al. The effect of a carbohydrate and protein supplement on resistance exercise performance, hormonal response, and muscle damage. J Strength Cond Res. 2007;21(2):321329. 36. Ivy JL, Goforth HWJ, Damon BM, McCauley TR, Parsons EC, Price TB. Early postexercise muscle glycogen recovery is enhanced with a carbohydrate-protein supplement. J Appl Physiol. 2002;93(4):13371344.
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37. Tipton K, Sharp C. The response of intracellular signaling and muscle-protein metabolism to nutrition and exercise. Eur J Sport Sci. 2005;5(3):107121. 38. Zemel MB, Donnelly JE, Smith BK, et al. Effects of dairy intake on weight maintenance. Nutr & Metab. 2008;5:28. 39. Nattiv A, Loucks AB, Manore MM, et al. American College of Sports Medicine position stand. The female athlete triad. Med Sci Sports Exerc. 2007;39(10):18671882.
40. Castillo EM, Comstock RD. Prevalence of use of performanceenhancing substances among United States adolescents. Pediatr Clin N Am. 2007;54:663675. 41. American Dietetic Association; Dietitians of Canada; American College of Sports Medicine, Rodriguez NR, Di Marco NM, Langley S. American College of Sports Medicine position stand. Nutrition and athletic performance. Med Sci Sports Exerc. 2009;41(3):709731.
PART III
DISEASE STATES AND NUTRITION
18. Developmental Delay . . . . . . . . . . . . . . . . . . . . . . . 191 Kathleen J. Motil, MD, PhD 19. Eating Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 204 Christina Fitzgerald, MS, RD, LDN Betsy Hjelmgren, MS, RD, LDN, CSP 20. Food Allergies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 Mary Beth Feuling, MS, RD, CD, CNSD Michael B. Levy, MD Praveen S. Goday, MBBS, CNSP 21. Diabetes Mellitus and Other Endocrine Disorders. . . . . . . . . . . . . . . . . . . 226 Diane Olson, RD, CNSD, CSP, LD W. Frederick Schwenk II, MD 22. Inborn Errors of Metabolism . . . . . . . . . . . . . . . . . 232 Bridget Reineking, MS, RD, CD Sandy van Calcar, PhD, RD, CD 23. Cardiac Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . 247 Anupama Chawla, DCH(UK), MD, CNSP Janice Antino, RD, MS, CNSD, CSP Mindy Freudenberg, RD, MS, CNSD 24. Renal Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256 Christina L. Nelms, MS, RD, CSP, CNSC, LD Marisa Juarez, MPH, RD, LD Bradley A. Warady, MD 25. Gastrointestinal Disease . . . . . . . . . . . . . . . . . . . . 283 Donald George, MD Elizabeth Bobo, MS, RD, LDN, CNSD 26. Hepatic Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . 302 Samuel A. Kocoshis, MD Renee A Wieman, RD, CSP, LD, CNSD
27. Intestinal Failure . . . . . . . . . . . . . . . . . . . . . . . . . . 311 Robert H. Squires, Jr., MD 28. Pulmonary Disorders . . . . . . . . . . . . . . . . . . . . . . . 323 Allison Mallowe, RD, LDN Suzanne Michel, MPH, RD, LDN Maria Mascarenhas, MBBS 29. Organ Transplantation . . . . . . . . . . . . . . . . . . . . . . 337 Anita Nucci, PhD, RD, LD Sharon Strohm, MBA, RD, LDN Neelam Katyal, MS, RD, LDN Beth Lytle, RD, LDN 30. Oncology, Hematopoietic Transplant, andSurvivorship. . . . . . . . . . . . . . . . . . . . . . . . . . . 349 Nancy Sacks, MS, RD, LDN Elizabeth Wallace, RD, CNSC, LDN Seema Desai, MS, RD, LDN, CNSD Vinod K. Prasad, MD, MRCP (London) David Henry, MS, BCOP Virginia Guzikowski, MSN, CRNP Liesje Nieman Carney, RD, CNSD, LDN Beth Bogucki Wright, MS, RD, CSP, LDN Susan Rheingold, MD 31. Trauma and Burns . . . . . . . . . . . . . . . . . . . . . . . . . 378 Arlet G. Kurkchubasche, MD 32. Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 Arlet G. Kurkchubasche, MD
Developmental Delay
Kathleen J. Motil, MD, PhD
18
Learning Objectives
1. Identify the nutrition problems frequently diagnosed in children with developmental delay. 2. Assess the nutrition status of the child with developmental delay. 3. Understand the approach to provide oral and enteral support to the child with developmental delay.
CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 Nutrition Problems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
Undernutrition, Growth Failure, and Overweight Micronutrient Deficiencies Osteopenia
Nutrition Assessment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

Medical History Growth and Anthropometric Measurements Physical Examination Meal Observation Diagnostic Studies
Nutrition Support. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

Nutrition Requirements Positioning and Oral Feeding Behavioral Modification Enteral Tube Feeding Feeding Intolerance Ethical Considerations
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
Undernutrition, growth failure, overweight, micronutrient deficiencies, and osteopenia are nutrition comorbidities that affect the child with developmental delay regardless of the specific neurological disability. The epidemiology, pathogenesis, assessment, and treatment of these disorders in neurologically impaired children have been reviewed elsewhere.13 This chapter examines further the principles and practices associated with the nutrition management of children with developmental disabilities that are characterized primarily by gross and fine motor dysfunction and with or without cognitive or speech delay. Early involvement by a multidisciplinary team of physicians, nurses, dietitians, feeding therapists, psychologists, and social workers is essential to prevent the adverse outcomes associated with poor nutrition status in the child with developmental delay. Undernutrition and overweight lead to more frequent hospital admissions and physician visits and diminished participation in home and school activities.4 Adequate nutrition support may restore linear and ponderal growth, improve health and quality of life, reduce the frequency of hospitalization, enhance neurological function and developmental progress, support wound healing and peripheral circulation, decrease the frequency of aspiration, and ameliorate gastroesophageal reflux in
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Introduction
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these children. 59 Careful evaluation and monitoring of children with severe disabilities is warranted because of the risk of nutrition-related morbidity and mortality.10
Inappropriate dietary intake
Nutrition Problems
Undernutrition, Growth Failure, and Overweight
Prevalence The true prevalence of undernutrition, growth failure, and overweight in children with developmental delay is unknown. Estimates are limited to disorders such as cerebral palsy, myelodysplasia, spina bifida, spinal cord injury, and Rett syndrome.1120 Undernutrition, based on weight-forheight and triceps skinfold thickness, has been documented in 29% to 46%, linear stunting in 23%, and overweight in 8% to 40% of individuals with these disorders. The prevalence of undernutrition increases with increasing age, lower intelligence, and increased severity of neurological impairment.17 Pathophysiology Non-nutrition factors including the type and severity of neurological disability, ambulatory status, and cognitive ability contribute to growth failure in children with developmental delay.21 Children with seizures or spastic quadriplegia and those who are non-ambulatory have lower height z scores than children who lack these disabilities.18 Children with spastic hemiplegia have smaller measures of breadth and length on the affected side, suggesting that neurological impairment influences growth.21 Inherent genetic factors may be associated with permanent linear stunting.22 Height-for-age z scores may decrease with advancing age independently of weight-for-age z scores in individuals affected with scoliosis or contractures.18 Nutrition factors contribute to growth failure in children with developmental delay based on correlations between height and weight z score deficits.23 Nutrition status explains 10% to 15% of the variability of linear growth in children with cerebral palsy. 23 Nutrition status has a stronger effect on linear growth in younger than in older children, attesting to the irreversible effects of longterm undernutrition on growth. Inappropriate dietary intake relative to nutrient needs, oral motor dysfunction, increased nutrient losses, and altered energy expenditure may account for the poor nutrition status of children with developmental delay.
Inappropriate dietary energy intake is the primary cause of undernutrition, growth failure, and overweight in the neurologically impaired child.2428 Children with cerebral palsy and myelomeningocele consume less dietary energy and nutrients than unaffected children. They may be unable to communicate hunger, food preferences, and satiety, leaving caretakers responsible for regulating their dietary intake. Caretakers often overestimate the childs energy intake and underestimate the time spent feeding the child.26,29 Because the task of feeding may be difficult and time-consuming, the amount of food provided may be insufficient to meet the childs growth needs. When adequate dietary energy is provided by enteral tube feedings, nutritional therapy leads to weight gain and linear growth.22 Careful monitoring may be necessary to avoid overfeeding, and consequently overweight, in these children. 30
Oral motor dysfunction
Feeding problems associated with oral motor dysfunction occur frequently in children with developmental delay.12,29 In one study, 90% of preschool children with cerebral palsy had oral motor dysfunction during the first year of life; 57% had sucking problems, 38% had swallowing problems, and 80% were fed non-orally at least once as infants. Severe feeding difficulties preceded the diagnosis of cerebral palsy in as much as 60% of patients. Poor suck, difficulty breastfeeding, problems with the introduction of solid foods, difficulty drinking liquids, difficulty biting or chewing solids, and coughing and choking with meals were common parental complaints. Dependency on a caretaker and the inefficiency of the feeding process, including the amount of food spilled and the time required for feeding, influence the childs nutrition status.12,16,29 Children with cerebral palsy take 2 to 12 times longer to swallow pureed food and up to 15 times longer to chew and swallow solids than unaffected children. 31 In one report, 28% of parents required more than 3 hours daily to feed their child and 3% required more than 6 hours daily. 32 Longer mealtimes may not compensate for feeding inefficiency. 31 Parents may perceive mealtime as a stressful, unpleasant experience. 32 Parents perceptions of mealtime are important because 60% of children with cerebral palsy are totally dependent on a caretaker for feeding.29 Oral motor dysfunction usually correlates with the severity of motor impairment.16,3335 Children may present with inadequate lip closure, drooling, and persistent tongue thrust, resulting in food loss through spillage. Bolus formation may be difficult to accomplish because of abnormal
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oral sensation, uncoordinated or involuntary tongue movements, or delayed development of age-appropriate oral motor skills. Initiation of the swallowing reflex may be delayed, resulting in food accumulation in the vallecula or pyriform sinuses and subsequent aspiration. Neurologically impaired children with these findings have lower height-, weight-, and weight-for-height z scores, body fat, and arm muscle area than unaffected children.16,34,35 Children with more severe impairment who are unable to lift their heads or feed themselves have a higher risk of aspiration. 36 Early, persistent, and severe feeding difficulties are markers of subsequent poor health, nutrition status, and growth and identify children who may benefit from gastrostomy feedings. 35,37
Increased nutrient losses
clinical features. Altered body composition and reduced physical activity make formulas used to calculate energy needs in healthy children invalid for children with developmental delay. Clinical Features Height-for-age and weight-for-age growth standards of children with developmental delay are lower than those of the reference population.11,12,23,4648 The median height-for-age and weight-for-age for children with spastic quadriplegic cerebral palsy and Rett syndrome range between the 5th and 10th percentiles for the National Center for Health Statistics (NCHS) reference population. The differences between the observed growth pattern of children with spastic quadriplegic cerebral palsy or Rett syndrome and the NCHS reference population become greater with increasing age. Developmental impairment may adversely affect linear growth even in the absence of undernutrition because of the underlying genetic or medical condition. As a consequence, growth failure may not be corrected completely by nutritional therapy.22 Children with developmental delay may have progressive weight deficits due to fat loss, while muscle and visceral proteins are maintained. Some children lack weight gain in the presence of linear growth, while others have progressive muscle atrophy unresponsive to nutritional intervention. Although children with developmental delay may be shorter and weigh less than unaffected children, others may be overweight based on weight-for-height, triceps skinfold thickness, or underwater weighing1113 or have features consistent with the metabolic syndrome (Chapter 14).19 The prevalence of overweight may be underestimated because weight-for-height gains are overlooked in the presence of a small body size or an aberrant distribution of body fat. Weight-for-height comparisons may be monitored less frequently than weight alone because of the difficulty obtaining accurate height measurements.
Children with developmental delay who feed themselves may have poor hand-to-mouth coordination, leading to loss of nutrients as a result of excessive spillage. The use of adaptive utensils may enhance movement performance and minimize food spillage in these individuals. 38 Gastroesophageal reflux, which affects 75% of developmentally impaired children, and delayed gastric emptying may result in a loss of nutrients because of frequent emesis.
Abnormal energy expenditure
Children with spastic quadriplegic cerebral palsy and myelodysplasia may grow adequately with average energy intakes as low as 50% to 61% of the dietary reference intake (DRI) for age and gender because their lean body mass, and hence resting energy expenditure (REE), is lower than that of unaffected children.14,26,39,40 REE in children with myelomeningocele is 96% of predicted, but total daily energy expenditure is lower than predicted because of a reduction in physical activity.41,42 Children with diplegia, hemiplegia, and spina bifida have higher rates of energy expenditure while walking compared with unaffected children.43 Dietary energy needs of children with cerebral palsy who ambulate or have athetosis are higher than those who do not.44 REE correlates poorly with body cell mass in some developmentally impaired children, suggesting that central nervous system injury may affect energy regulation. 39 REE in well-nourished, non-ambulatory children with cerebral palsy is lower than that predicted from equations based on age, gender, and weight in healthy children. 39,45 The DRI for energy in healthy children overestimates the energy needs of children with spastic quadriplegic cerebral palsy in whom a value of REE 1.1 may be sufficient.26 The ability to estimate dietary energy needs of children with developmental delay is difficult because of the heterogeneity in their
Micronutrient Deficiencies
Vitamin, trace element, and essential fatty acid (EFA) deficiencies have been documented in children with developmental delay who have reduced dietary intakes.4951 Iron, selenium, zinc, EFAs, and vitamins C, D, and E were reported to be deficient in 15% to 50% of the children.4952 Some may develop nutrient deficiencies because enteral formulas provide adequate amounts of micronutrients only when volumes that meet their age-related DRI for energy are consumed. 53 Because many children with developmental delay require lower energy intakes, their micronutrient
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intakes are correspondingly lower. Replacement therapy reverses these abnormalities. Complementary and alternative medicine is administered frequently to children with chronic medical conditions. 54 The use of dietary supplements, including vitamins, minerals, herbs, or other botanicals, was reported by 6% of families with children who have cerebral palsy. 55 Concerns have been raised because of potential interactions between complementary or alternative medicines and antiepileptic drugs and consequently modification of seizure risk. 56
itself may remain stable, manifestations of the disorder may change over time and require periodic reassessment. Medications A review of medications is important because drugs prescribed for gastroesophageal reflux, drooling, constipation, seizures, and spasticity may influence the childs eating pattern. Gastric acid inhibitors and laxatives often minimize gastrointestinal discomfort and reverse feeding refusal. Valproic acid, gabapentin, topiramate, zonisamide, and felbamate may affect appetite and result in weight gain or loss. Many anticonvulsants impact the level of consciousness, thereby reducing oral motor skills and airway protection. Glycopyrrolate may reduce pooling of oral secretions, but may aggravate constipation. Baclofen and trihexyphenidyl may reduce spasticity, and consequently, energy expenditure. Review of Systems The review of systems identifies clinical problems that may influence the type of nutritional intervention prescribed. Respiratory and gastrointestinal problems impact all aspects of nutrition support. Emesis, food refusal, anemia, and intestinal blood loss suggest gastroesophageal reflux and esophagitis. Acid reflux tends to be more frequent in children with severe disabilities and those with scoliosis. Irritability, infrequent bowel movements, and abdominal distention suggest constipation. Chronic cough, poorly controlled asthma, or recurrent pneumonia raises the possibility of aspiration. Growth History Birth weight and length and previous weight and length measurements, when recorded on NCHS growth charts, may be compared with the reference population to determine if growth faltering or abnormal weight gain or loss has occurred. Height measurements may be erroneous if the child has difficulty standing. The heights of the biological parents may provide insight regarding the childs genetic growth potential. Social History The child with developmental delay requires a considerable amount of care, a factor that impacts the parents ability to work and the familys social activities. Scheduled activities, such as school or physical therapy, and the siblings school and parents work schedules require consideration when planning nutritional interventions. Financial issues,
Osteopenia
Osteopenia is prevalent in developmentally impaired children. 52,5759 Weight z score is the best correlate of bone mineral density z score in children with developmental delay. 58 Dietary calcium, vitamin D, and phosphorus intakes are lower than the DRI in 50% to 80% of these children. 24,60 Non-ambulatory children have lower bone mineral content than those who ambulate independently. 58 Limited ambulation, increased duration of anticonvulsant therapy, and reduced sun exposure contribute to the pathogenesis of osteopenia. 5760 Osteopenia is associated with an increased fracture risk in developmentally impaired children. 5759 Supplemental calcium improves bone mineral density by 5% over 4 years in healthy children, but the effect of dietary calcium in children with developmental delay is unknown.61 The use of bisphosphonates increased bone mineral density by 89% over 18 months in children with cerebral palsy. 62 However, the relation between bisphosphonate use and fracture risk or frequency in these children is unknown. The use of bisphosphonates is limited because their indications in childhood diseases are not well defined and their longterm effects on bone remodeling in children are unknown.
Nutrition Assessment
Nutrition assessment of the child with developmental delay includes a thorough medical history, accurate growth and anthropometric measurements, a complete physical examination, meal observation and food record review, and selected diagnostic studies.
Medical History
The medical history includes information about the etiology, duration, and severity of neurological impairment and its expected course. These factors correlate with the risk of undernutrition and may affect the type of nutritional intervention required. Although the neurological condition
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medical insurance, and the availability of home care require exploration. All individuals involved in the care and feeding of the child and all settings in which feeding occurs require consideration to ensure that nutritional interventions can be integrated into the family or institutional routines.
Growth and Anthropometric Measurements

Growth measures reflect the childs nutrition status.17 Accurate measures of height, length, or a proxy if these measurements are not reliable, and weight are obtained, using standardized techniques and equipment, at every medical encounter. Length is obtained supine in children less than age 2 years or in older children unable to stand. Alternative measures such as upper arm length (UAL) or lower leg length (LLL) may be used to estimate body length in children who have contractures or scoliosis. Reference standards are available for UAL and LLL in children age 2 years and older.63 Standing height, without shoes and braces, is obtained in all other children. Weight is measured with the child wearing little or no clothing. Children with severe disabilities may be weighed while being held by a parent, while seated in a wheelchair, or on a table scale. Body mass index (BMI) can be calculated from height and weight measurements of children age 2 years and older. Although the inability to measure standing height theoretically invalidates the calculation of BMI, estimates derived from LLL serve as a practical alternative in the clinical setting. Weight-for-length is determined for children less than age 2 years. Head circumference may be of limited use in the presence of microcephaly. Height (length), weight, BMI, and weight-for-length, when properly measured and plotted on gender- and age-appropriate growth charts (http://www. cdc.gov/growthcharts), can be compared with previous measures and the reference population. Condition-specific growth charts may be available, but often have limited use because of small data sets that contributed to their formation. Any height or weight measurement that falls below the 5th percentile, is greater than the 95th percentile, or crosses 2 growth channels is considered to represent an abnormal growth pattern. Serial measurements are obtained to determine if the growth pattern is truly abnormal or if these findings represent constitutional short stature or the re-channeling of the genetic growth potential in children with neurological disabilities. Radiographic studies of bone age may help to clarify the presence of abnormal growth patterns because chronic undernutrition is one of the causes of delayed bone maturation, and hence, delayed linear growth.64
The BMI-for-age may be used to screen children with neurological disabilities for underweight and overweight. Children are classified as underweight if their BMI-for-age is less than the 5th percentile, overweight if their BMI-forage is between the 85th and 95th percentile, and obese if their BMI-for-age is greater than the 95th percentile. The use of BMI-for-age may be problematic because of decreased muscle mass, increased regional and total body fat, and/or skeletal deformities in children with neurological disabilities. Nevertheless, an estimate of the BMI-for-age serves as a useful guide for the approach to nutritional intervention. Thus, nasogastric or gastrostomy tube feedings may be indicated if the BMI-for-age is less than 11 to 13 kg/m 2 because of the increased morbidity and mortality associated with these values.65 Conversely, an energy-deficit diet may be implemented if the BMI-for-age is greater than 30 kg/m 2 , whereas a more restrictive diet such as a protein-sparing modified fast may be necessary for a BMI-for-age greater than 40 kg/m 2 .66 Body fat and arm muscle area can be estimated from mid-upper arm circumference and triceps skinfold thickness.11 Reliability is improved when the same observer obtains the measurements. The values for triceps skinfold thickness and arm muscle area may be compared to reference standards.67 Body fat usually is reduced at all sites, with the triceps being affected more than the subscapular skinfold thickness in children with developmental delay.11,23 Measures of triceps skinfold thickness rather than weightfor-height percentiles may better identify those children with undernutrition. Decreased triceps skinfold thickness identifies 96% of children with depleted fat stores, while weight-for-height less than the 10th percentile identifies only 55%.46 Waist circumference may serve as an alternative indicator of adiposity because this measure correlates well with truncal fat.19
Physical Examination
Physical examination focuses on signs of undernutrition, linear stunting, overweight, and specific nutrient deficiencies. Muscle tone, activity level, and the presence of athetoid movement are relevant because they influence dietary energy needs. Contractures and scoliosis are noteworthy for positioning during meals. Abnormal breath sounds may be suggestive of chronic respiratory problems associated with aspiration. Abdominal distention in conjunction with palpable masses suggests constipation. Examination of the skin may reveal the presence of decubitus ulcers. Pallor, skin rashes, smooth tongue, gingival bleeding, petechiae, bone deformities, or pedal edema may suggest other micronutrient deficiencies.
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Meal Observation
A 24-hour recall of habitual food intake or a 3-day record of food consumption reflects the adequacy of dietary energy and nutrient intake. 34 Meal observation, with emphasis on the childs ability to feed independently and the efficiency of the feeding process, may reveal a reason for poor weight gain.12,16,29,30 An evaluation of oral motor skills, including inadequate lip closure, drooling, a persistent extrusion reflex, gagging and delayed swallowing, or coughing and choking during meals reflects poor feeding capabilities. Limited texture tolerance may indicate poor oral ability to manage food, resulting in self-restricted eating patterns, reduced nutrient intake, and poor weight gain.68,69 Consumption of inappropriate food textures may result in aspiration. Fatigue and lethargy during meals may suggest hypoxemia.70 Meal observation shows that children with developmental delay may be offered less, consume less, and spill more food than unaffected children. Classification systems based on measures of growth and patterns of food consumption, such as eating efficiency and oral motor feeding skills, may be helpful to assess the effectiveness of oral feeding interventions.71,72
Diagnostic Studies
Although isolated nutrient deficiencies may be present in children with developmental delay, extensive laboratory evaluation is not necessary.4951 A complete blood count and serum ferritin may document anemia or iron deficiency. Serum electrolytes and blood urea nitrogen (BUN) reflect hydration status; however, BUN may be low because of poor protein intake and low muscle mass. Serum albumin and prealbumin, factors that correlate strongly with the risk of morbidity and mortality, are less reliable indicators of nutrition status.73 Abnormal serum phosphorus, alkaline phosphatase, and 25-hydroxyvitamin D levels may coincide with poor bone mineral status. Bone densitometry may be considered in children who have pathologic fractures. Bone quantitative ultrasonography may be more easily performed than bone densitometry; however, normative data for children are not yet available.74 Additional diagnostic studies may be helpful, depending on the childs symptoms and the need for permanent enteral access. A videofluoroscopic assessment of chewing and swallowing function, using different food and beverage textures, determines the degree of oral motor dysfunction and risk of aspiration. Positioning the child during the evaluation is important because some children may not aspirate when placed upright, but do so in a reclined position. A swallowing function study may demonstrate silent
aspiration in the absence of choking and coughing during meals. Assessment of swallowing function at the end of a meal is informative because feeding fatigue may lead to aspiration. A swallowing function study may provide guidance for appropriate food textures and therapeutic feeding techniques. Gastroesophageal reflux may be apparent based on symptoms of vomiting, chest or abdominal pain, feeding refusal, or irritability. A 24-hour esophageal pH probe study may be helpful if the diagnosis of acid reflux is not obvious. A gastric emptying scan may detect delayed gastric emptying which indirectly may contribute to gastroesophageal reflux and aspiration. An upper gastrointestinal series may detect gastroesophageal dysmotility or superior mesenteric artery syndrome, both of which may interfere with feeding. Episodic reflux occurring during the study may not be diagnostic of acid reflux disease. An abnormal location of the stomach in the thorax of children with severe scoliosis may influence the type of intervention used for enteral access. The child with symptoms suggestive of chronic aspiration may require a chest x-ray and an evaluation by a pulmonologist, especially if surgical intervention for enteral access is considered. Monitoring O2 saturation during a meal may be important because children with developmental delay may have hypoxemia with feedings.70 Modifying food textures and liquid consistencies with thickening agents may help to reduce aspiration risk.
Nutrition Support
Nutrition support is provided enterally rather than parenterally, assuming competency of the gastrointestinal tract. Enteral tube feedings are essential in children who cannot meet their energy and nutrient needs orally.75 Evidence of oral motor feeding difficulties, undernutrition (weight-forheight < 80% of expected, BMI < 5th percentile), growth failure (height-for-age < 90% of expected), overweight (BMI > 85th percentile), and individual nutrient deficiencies indicate the need for nutritional intervention.1
Nutrition Requirements
Energy requirements of children with developmental delay vary with the severity of their neurological disability, their mobility, the presence of feeding difficulties, altered body composition, and the need for weight gain or loss and catchup growth. Dietary energy needs for the maintenance of body weight may be estimated from either the DRI standards for basal energy expenditure (http://www.nal.usda. gov/fnic/etext/000105.html), indirect calorimetry,76 or height77 (Table 18-1). Dietary energy needs for catch-up
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growth may approximate the DRI for basal energy expenditure 1.5. Monitoring the rate of weight gain or loss and change in BMI is the best way to determine the adequacy of diet in the child with developmental delay. Adequate provision of dietary protein, vitamins, and minerals is mandatory when energy intakes are modified to obtain the desired rate of weight change. In the absence of evidence-based nutrient allowances for children with developmental delay, the DRIs for protein, vitamins, and minerals in healthy children are recommended (http://www.nal.usda.gov/fnic/ etext/000105.html). Multivitamin and mineral supplements may be prudent for children with developmental delay who rely primarily on table foods and beverages to meet their nutrient needs, particularly in relation to the need for improved vitamin D status.78
Table 18-1. Methods to Determine Dietary Energy Needs in Neurologically Impaired Children Dietary Reference Intake Standards for Basal Energy Expenditure (http://www.nal.usda.gov/fnic/etext/000105.html) Energy intake (kcal/d) = Basal Energy Expenditure (BEE) x 1.1 Age (y) Basal Energy Expenditure (kcal/d) Boys Girls 38 1035 1004 913 1320 1186 1418 1729 1361 Indirect Calorimetry76 Energy intake (kcal/d) = [basal energy expenditure (BMR) x muscle tone x activity] + growth where: BMR (kcal/d) = body surface area (m2) x metabolic rate (kcal/m2/h) x 24 h Muscle tone = 0.9 if decreased, 1 if normal, and 1.1 if increased Activity = 1.1 if bedridden, 1.2 if wheelchair dependent or crawling, and 1.3 if ambulatory Growth = 5 kcal/g of desired weight gain (normal and catch-up growth) Height77 15 kcal/cm in children without motor dysfunction 14 kcal/cm in children with motor dysfunction who are ambulatory 11 kcal/cm in children who are non-ambulatory
of the neck, has been used; however, improved feeding efficiency in children has not been documented. 80 Periodic reassessment of oral feeding skills is important to determine the potential for continued oral feeding.
Behavioral Modification
Behavioral therapy initiated by a skilled child psychologist may improve the quantity of food consumed, the feeding efficiency, and the range of textures accepted, as well as the quality of feeding interactions between the caretaker and the child.81
Enteral Tube Feeding

Oral feedings can be maintained in children with adequate oral motor skills who have a low risk of aspiration. Adequate positioning and adjustment of food and beverage consistency with thickening agents may improve feeding efficiency. Increasing the energy density of food maximizes energy intake. If oral intake is insufficient to promote weight gain, linear growth, and adequate hydration, if the amount of time to feed the child is excessive because of chewing and swallowing dysfunction, or if aspiration is a risk, enteral tube feedings may be considered. The type of enteral access selected will depend upon the nutritional and clinical status of the child and the anticipated duration of enteral feedings. Parents will be concerned about the childs loss of oral feeding skills, the risks and benefits of enteral tube feeding, and the manner in which alternative feeding methods fit the familys lifestyle. Enteral feeding regimens that preserve oral feeding skills while providing adequate nutrient intakes facilitate the transition back to oral feeds when safe or after catch-up growth has been achieved. Enteral Access Nasogastric or nasojejunal tube feedings are minimally invasive methods that may be used for short-term nutrition support in undernourished children or in those with acid reflux or aspiration who are awaiting gastrostomy placement. Nasogastric or nasojejunal tubes are not used long-term because they may be dislodged easily, may stiffen and cause intestinal perforation, or may result in nasal congestion, sinusitis, otitis media, and skin and mucosal irritation. Bedside placement of nasojejunal tubes can be achieved by allowing the tube to migrate spontaneously or in conjunction with a prokinetic drug. 8284 Newer techniques such as pH-assisted tube placement are available. 85 Fluoroscopic or endoscopic tube placement may be required if these approaches are unsuccessful. Gastrostomy feedings provide an option for children
Positioning and Oral Feeding

The feeding therapist can assist with oral motor skills, correct positioning of the child, and the use of appropriate chairs and adapted utensils during meals. Therapy to improve oral motor skills may be attempted, especially before age 5 years. Oral feeding interventions may enhance oral motor function, but are not effective in promoting feeding efficiency and weight gain.79 VitalStim, a device that administers electrical stimulation to the musculature
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with severe feeding problems who have poor weight gain, although evidence-based practice guidelines with attendant risks and benefits are lacking.6,7 A gastrostomy tube or button device is recommended for long-term enteral nutrition (EN) because it is more comfortable for the child and is less easily dislodged than a nasogastric tube. Gastrostomy feedings may promote weight gain, improve the childs health, and reduce the time spent feeding the child.68,22 The best clinical response is seen in children with the shortest time between the neurological insult and gastrostomy placement. Children who have a gastrostomy placed within the first year of life are more likely to exceed the 5th percentile for height and weight. Gastrostomy feedings initiated within 1 year of the neurological insult are associated with improved weight-for-age, weight-for-length, and lengthfor-age. Nutritional intervention initiated 8 years after the neurological insult does not normalize length-for-age, despite improvement in weight-for-age. 86 Percutaneous endoscopic gastrostomy (PEG) placement, a minimally invasive non-surgical procedure, involves little discomfort and the feeding device can be used within a few hours of installation. 87 The higher death rate in children fed by gastrostomy may reflect the severity of their neurological disability compared with those fed orally.7,88 The risk of acid reflux or esophagitis after PEG placement in developmentally impaired children without previous symptoms is increased.8993 Medical therapy for pre-existing acid reflux often will be required after PEG placement. 88 An evaluation for acid reflux before PEG placement may be warranted because 5% of developmentally impaired children who have a normal pH probe study eventually require an anti-reflux procedure compared with 29% to 58% of those who have an abnormal pH probe study.88,89 Acid reflux may improve in some children after PEG placement and nutritional rehabilitation. Further evaluation with upper endoscopy and esophageal biopsy does not predict clinical outcome after PEG placement in children.94 Surgical gastrostomy placement is a safe alternative to enteral access in the child with developmental delay. Laparoscopic gastrostomy placement is associated with less morbidity, permits earlier EN, and has a cost advantage compared with the open technique. Laparoscopic or open surgical fundoplication may be required in as much as 25% of neurologically impaired children.88,89,93,95,96 Although pyloroplasty improves gastric emptying, dumping syndrome may occur and require long-term continuous infusions until bolus feeds are tolerated.97,98 The risk of feeding difficulty, gas bloat, or dumping syndrome, and recurrence of acid reflux after a fundoplication, varies in children with
developmental delay.95,98,99 Retching may be a disturbing symptom after a fundoplication, but generally can be controlled by slowing the rate of formula administration.100 Surgical gastrojejunostomy or jejunostomy tube placement may be required in children who do not tolerate gastric feeds, have severe gastroesophageal reflux, are at risk for aspiration, are poor candidates for fundoplication, or are high-risk for failure of a second anti-reflux procedure. A surgical or laparoscopic loop or Roux-en-Y jejunostomy is reserved for selected children in whom other options have failed.101 Image-guided, retrograde or antegrade, percutaneous placement of gastrostomy or gastrojejunostomy tubes is an alternative, minimally invasive fluoroscopic method for enteral feeding.102 The retrograde percutaneous technique has a higher rate of successful placement than the PEG method and has a lower rate of major complications than PEG or surgical gastrostomy placement. Formula Administration The choice of enteral formula depends on the childs age, medical condition, energy requirement, and mode of enteral access. Standard, age-appropriate, infant or pediatric, casein-based formulas are administered routinely. Whey-based formulas may be better tolerated because they enhance gastric emptying.103 Children who manifest symptoms associated with cows milk protein sensitivity may require a protein hydrolysate or amino acid formula. Nutrient deficiencies may occur as a consequence of enteral feedings.2,6,17 Adult formulas may prevent hypoalbuminemia during periods of catch-up growth, but care should be taken to avoid iron, vitamin D, calcium, and phosphorus deficiency.24 If high energy density (1.5 or 2 kcal/mL) formulas are used, monitoring hydration status and protein and micronutrient intake is necessary. A fiber-containing formula may ameliorate constipation, but may aggravate intestinal gas bloating if the volume is increased rapidly. Bolus formula feedings are preferred in children who do not have acid reflux or delayed gastric emptying because they mimic the physiologic responses associated with meals, allow a more flexible feeding schedule, and are more convenient in ambulatory children. Continuous formula infusions may be used throughout the day or night in children who do not tolerate bolus feeds or have formula administered directly into the jejunum. When large volumes are required, bolus feeds can be combined with continuous nocturnal infusions of formula. Continuous nocturnal infusions avoid interruptions during daytime activities, but may interfere with sleep.104
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Feeding Intolerance
Feeding intolerance may be associated with recurrent acid or non-acid reflux, delayed gastric emptying, diarrhea, or constipation.105 In the absence of progression of the neurological disorder, intercurrent infection, or intestinal obstruction, the quality and quantity of the feeding regimen requires periodic re-evaluation. Changing the feeding schedule from bolus to continuous infusion, decreasing the rate of infusion, concentrating the formula to decrease the volume of feeds, or selecting an alternative formula may ameliorate symptoms. If symptoms persist, medical treatment of acid reflux or delayed gastric emptying may be instituted before exploring laparoscopic or surgical procedures. Medical management of acid reflux and delayed gastric emptying consists of using whey hydrolysate formulas and medications that promote acid suppression (histamine antagonists, proton pump inhibitors) and motility (bethanechol, metoclopramide, erythromycin, cisapride). Although the availability of cisapride is restricted because of safety concerns, its use in neurological disorders associated with QT wave abnormalities (eg, Rett syndrome) is cautioned. Medical management of constipation consists of single or multiple laxative agents with stool-softening and stimulatory effects (polyethylene glycol-electrolyte solution, magnesium hydroxide, senna extract, lactulose, bisacodyl). Rectal inertia may require local treatment with suppositories (bisacodyl) or enemas.106
Acknowledgments
The authors thank V. Moore for secretarial support. This chapter is a publication of the USDA/ARS Childrens Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, and has been funded in part with federal funds from the U.S. Department of Agriculture, Agricultural Research Service, under Cooperative Agreement Number 58-6250-1-003. The contents herein do not necessarily reflect the views or policies of the U.S. Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.
Ethical Considerations
Many families find the idea of a feeding gastrostomy difficult to accept.107 Caregivers believe that they have failed to adequately care for the child when physicians insist on gastrostomy placement. Starvation, quality of life, prolongation of life, and meaningful family interrelationships constitute a framework for discussion. Although medical opinions generally prevail, parental wishes should be considered and respected.
Conclusion
Nutrition support is essential for the care of the child with developmental delay. After a thorough evaluation, an individualized intervention plan that accounts for the childs nutrition status, feeding ability, and medical condition may be determined. Nutrition assessments may be performed at least annually in the older child and more frequently in the infant and toddler to document adequate growth and nutrient intakes. The goal of nutrition assessment and intervention is to optimize the childs health, functional status, and quality of life, while maintaining adequate growth and nutrition status.
1. Which anthropometric measurements are most useful to determine nutrition status of the child with developmental delay? A. Height, length, and triceps skinfold B. Weight, head circumference, and arm circumference C. Head circumference, body mass index, and triceps skinfold thickness D. BMI, weight, and height 2. What are the most common reasons for poor weight gain in the child with developmental delay? A. Inadequate dietary intake and constipation B. Increased basal metabolic rate C. Chewing and swallowing dysfunction and inadequate dietary intake D. Athetoid or repetitive motor movements and aspiration 3. The best way to determine the adequacy of the diet for children with developmental delay is to: A. Calculate dietary energy needs based on the DRI standards for basal energy expenditure. B. Monitor the rate of weight gain or loss and change in BMI. C. Measure hemoglobin concentration and serum albumin levels. D. Provide a protein hydrolysate or amino acid formula as the main source of nutrients. See p. 487 for answers.
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72. Gisel EG. Effect of oral sensorimotor treatment on measures of growth and efficiency of eating in the moderately eating-impaired child with cerebral palsy. Dysphagia. 1996;11(1):4858. 73. Fuhrman MP, Charney P, Mueller CM. Hepatic proteins and nutritional assessment. J Am Diet Assoc. 2004;104(8):12581264. 74. Hartman C, Brik R, Tamir A, Merrick J, Shamir R. Bone quantitative ultrasound and nutritional status in severely handicapped institutionalized children and adolescents. Clin Nutr. 2004; 23(1):8998. 75. Axelrod D, Kazmerski K, Iyer K. Pediatric enteral nutrition. J Parenter Enteral Nutr. 2006;30(1 Suppl):S21S26. 76. Krick J, Murphy PE, Markham JF, Shapiro BK. A proposed formula for calculating energy needs of children with cerebral palsy. Dev Med Child Neurol. 1992;34(6):481487. 77. Culley WJ, Middleton TO. Caloric requirements of mentally retarded children with and without motor dysfunction. J Pediatr. 1969;75(3):380384. 78. Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics. 2008;122(2):398417. 79. Gisel EG, Applegate-Ferrante T, Benson JE, Bosma JF. Effect of oral sensorimotor treatment on measures of growth, eating efficiency and aspiration in the dysphagic child with cerebral palsy. Dev Med Child Neurol. 1995;37(6):528543. 80. Chetney R, Waro K. A new home health approach to swallowing disorders. Home Health Nurse. 2004;22(10):703707. 81. Linscheid TR. Behavioral treatments for pediatric feeding disorders. Behav Modif. 2006;30(1):623. 82. Kalliafas S, Choban PS, Ziegler D, Drago S, Flancbaum L. Erythromycin facilitates postpyloric placement of nasoduodenal feeding tubes in intensive care unit patients: randomized, double-blinded, placebo-controlled trial. J Parenter Enteral Nutr. 1996;20(6):385388. 83. Kittinger JW, Sandler RS, Heizer WD. Efficacy of metoclopramide as an adjunct to duodenal placement of small-bore feeding tubes: a randomized, placebo-controlled, doubleblind study. J Parenter Enteral Nutr. 1987;11(1):3337. 84. Davies AR, Bellomo R. Establishment of enteral nutrition: prokinetic agents and small bowel feeding tubes. Curr Opin Crit Care. 2004;10(2):156161. 85. Krafte-Jacobs B, Persinger M, Carver J, Moore L, Brilli R. Rapid placement of transpyloric feeding tubes: a comparison of pH-assisted and standard insertion techniques in children. Pediatrics. 1996;98(2 Pt 1):242248. 86. Sanders KD, Cox K, Cannon R, et al. Growth response to enteral feeding by children with cerebral palsy. J Parenter Enteral Nutr. 1990;14(1):2326. 87. Gauderer MW. Percutaneous endoscopic gastrostomy: a 10-year experience with 220 children. J Pediatr Surg. 1991;26(3):288292. 88. Catto-Smith AG, Jimenez S. Morbidity and mortality after percutaneous endoscopic gastrostomy in children with neurological disability. J Gastroenterol Hepatol. 2006;21(4):734738.
89. Sulaeman E, Udall JN, Brown RF, et al. Gastroesophageal reflux and Nissen fundoplication following percutaneous endoscopic gastrostomy in children. J Pediatr Gastroenterol Nutr. 1998;26(3):269273. 90. Khattak IU, Kimber C, Kiely EM, Spitz L. Percutaneous endoscopic gastrostomy in paediatric practice: complications and outcome. J Pediatr Surg. 1998;33(1):6772. 91. Behrens R, Lang T, Muschweck H, Richter T, Hofbeck M. Percutaneous endoscopic gastrostomy in children and adolescents. J Pediatr Gastroenterol Nutr. 1997;25(5):487491. 92. Grunow JE, al-Hafidh A, Tunell WP. Gastroesophageal reflux following percutaneous endoscopic gastrostomy in children. JPediatr Surg. 1989;24(1):4244. 93. Isch JA, Rescorla FJ, Scherer LR 3rd, West KW, Grosfeld JL. The development of gastroesophageal reflux after percutaneous endoscopic gastrostomy. J Pediatr Surg. 1997;32(2):321322. 94. Heikenen JB, Werlin SL. Esophageal biopsy does not predict clinical outcome after percutaneous endoscopic gastrostomy in children. Dysphagia. 2000;15(3):167169. 95. Cameron BH, Blair GK, Murphy JJ 3rd, Fraser GC. Morbidity in neurologically impaired children after percutaneous endoscopic versus Stamm gastrostomy. Gastrointest Endosc. 1995;42(1):4144. 96. Heine RG, Reddihough DS, Catto-Smith AG. Gastrooesophageal reflux and feeding problems after gastrostomy in children with severe neurological impairment. Dev Med Child Neurol. 1995;37(4):320329. 97. Farrell TM, Richardson WS, Halkar R, et al. Nissen fundoplication improves gastric motility in patients with delayed gastric emptying. Surg Endosc. 2001;15(3):271-274. 98. Bufler P, Ehringhaus C, Koletzko S. Dumping syndrome: a common problem following Nissen fundoplication in young children. Pediatr Surg Int. 2001;17(56):351355. 99. Pimpalwar A, Najmaldin A. Results of laparoscopic antireflux procedures in neurologically impaired children. Semin Laparosc Surg. 2002;9(3):190196. 100. Friedman JN, Ahmed S, Connolly B, Chait P, Mahant S. Complications associated with image-guided gastrostomy and gastrojejunostomy tubes in children. Pediatrics. 2004;114(2):458461. 101. Richards CA, Milla PJ, Andrews PL, Spitz L. Retching and vomiting in neurologically impaired children after fundoplication: predictive preoperative factors. J Pediatr Surg. 2001;36(9):14011404. 102. Neuman HB, Phillips JD. Laparoscopic Roux-en-Y feeding jejunostomy: a new minimally invasive surgical procedure for permanent feeding access in children with gastric dysfunction. J Laparoendosc Adv Surg Tech A. 2005;15(1):7174. 103. Fried MD, Khoshoo V, Secker DJ, Gilday DL, Ash JM, Pencharz PB. Decrease in gastric emptying time and episodes of regurgitation in children with spastic quadriplegia fed a whey-based formula. J Pediatr. 1992;120(4 Pt 1):569572. 104. Holden CE, Puntis JW, Charlton CP, Booth IW. Nasogastric feeding at home: acceptability and safety. Arch Dis Child. 1991;66(1):148151.
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105. Del Buono R, Wenzl TG, Rawat D, Thomson M. Acid and nonacid gastro-oesophageal reflux in neurologically impaired children: investigation with the multiple intraluminal impedance procedure. J Pediatr Gastroenterol Nutr. 2006;43(3):331335. 106. Leibold S, Eckmark E, Adams RC. Decision-making for a successful bowel continence program. Eur J Pediatr Surg. 2000;10(Suppl. 1):2630. 107. Isaacs D, Kilham HA, Somerville HM, OLoughlin EV, Tobin B. Nutrition in cerebral palsy. J Paediatr Child Health. 2004;40(56):308310.
Eating Disorders
Christina Fitzgerald, MS, RD, LDN and Betsy Hjelmgren, MS, RD, LDN, CSP
19
Learning Objectives
1. Discuss the basic macro- and micronutrient needs in the eating-disordered patient. 2. Summarize the rationale for providing oral nutrition versus enteral nutrition or parenteral nutrition in patients with eating disorders. 3. Identify patients at risk for refeeding syndrome and identify key monitoring parameters in its prevention and treatment. An eating disorder is an elusive disease that afflicts many adolescents and young adults. It can be difficult to detect and can go undiagnosed for extended periods while wreaking havoc on the young growing body. Unfortunately, eating disorders, specifically anorexia nervosa, have the highest premature fatality rate of all mental illnesses.1 In the United States alone, more than 10 million females and 1 million males are battling an eating disorder such as anorexia nervosa or bulimia nervosa. Of those females afflicted, approximately 5 million are American girls.2 However, this disease is not specific to the female gender; approximately 10% of those afflicted are males. Once thought of as a white upper-class disease, eating disorders are seen across all cultures and all socioeconomic classes. Robinson et al found that among the leanest 25% of sixth- and seventhgrade girls, Hispanics and Asians reported significantly more body dissatisfaction than did Caucasians. 3 This chapter reviews the classification, diagnosis, and etiology of eating disorders; describes nutrition therapy and monitoring of interventions for eating disorders; defines and describes the pathogenesis of refeeding syndrome; and discusses prevention and treatment of refeeding syndrome.
CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 Classification and Diagnosis of Eating Disorders. . . . . . 205
Physical Presentation Etiology of Eating Disorders
Nutrition in Eating Disorders. . . . . . . . . . . . . . . . . . . . . . . 206

Nutrition Requirements Laboratory Assessment
Nutrition Support in Eating Disorders . . . . . . . . . . . . . . . 208

Oral Nutrition and Meal-Planning Guidelines Enteral Nutrition Support and Route of Feeding Parenteral Nutrition Monitoring Nutrition Interventions
Introduction
Refeeding Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

Definition and Incidence Pathophysiology and Characteristics of StarvationandRefeeding Prevention and Therapy
204
EATING DISORDERS
205
Anorexia nervosa, bulimia nervosa, binge-eating disorder, and eating disorder not otherwise specified are eating disorders with the commonalities of extreme emotion and behaviors around food and body image. The American Psychiatric Association recommends using a multiaxial system in assessing and diagnosing mental disorders and now lists the subcategories Anorexia Nervosa, Bulimia Nervosa, Binge-Eating Disorder, and Eating Disorder Not Otherwise Specified in its Diagnostic and Statistical Manual of Mental Disorders (DSM) (Figures 19-119-4). These subcategories are diagnosed and classified on Axis 1 of the multiaxial system.4 Of note, amenorrhea (ie, the absence of at least 3 consecutive menstrual cycles) is one of the diagnostic criteria for anorexia nervosa listed in the DSM. However, this may not be useful in the assessment of adolescent patients as healthy adolescent females may normally have episodes of amenorrhea during the first 1 to 2 years after the onset of menarche. 5 Psychiatric comorbidities, such as obsessive-compulsive disorder and affective disorder, are common and should be treated alongside the eating disorder.6 Major depression
Classification and Diagnosis of Eating Disorders
is the most common comorbid disease among persons with anorexia nervosa7 and substance abuse prevalence is estimated at 30% to 70% in persons with bulimia. 8 It is often these psychiatric comorbidities or other medical problems, such as continued dizziness or fatigue, that are presented to the physician prior to the eating disorder detection.
Physical Presentation
Physical presentation of a person with anorexia nervosa includes lanugo-type hair, muscle wasting, dry skin, cyanosis of extremities, bradycardia less than 60 beats/min, and cachexia. When anorexia develops in childhood, the first clinical sign may be failure to make weight gains while continuing to grow in height as opposed to documented weight loss. Growth charts should be evaluated for typical growth patterns of the individual.9 Physical signs and symptoms of a person with bulimia nervosa are more difficult to detect but may include parotid gland enlargement, scarring of the hand used to stimulate gag reflux (referred to as Russells sign), erosion of dental enamel with increased dental caries, and sore red throat
Figure 19-2 American Psychiatric Association Diagnostic Criteria for 307.51 Bulimia Nervosa
Figure 19-1 American Psychiatric Association Diagnostic Criteria for 307.1 Anorexia Nervosa A. Refusal to maintain body weight at or above a minimally normal weight for age and height (ie, weight loss leading to maintenance of body weight less than 85% of that expected; or failure to make expected weight gain during period of growth, leading to body weight less than 85% of that expected). B. Intense fear of gaining weight or becoming fat, even though underweight. C. Disturbance in the way in which ones body weight or shape is experienced, undue influence of body weight or shape on selfevaluation, or denial of the seriousness of the current low body weight. D. In postmenarcheal females, amenorrhea, ie, the absence of at least three consecutive menstrual cycles. (A woman is considered to have amenorrhea if her periods occur only following hormone, eg, estrogen, administration.) Restricting Type: During the current episode of anorexia nervosa, the person has not regularly engaged in binge-eating or purging behavior (ie, self-induced vomiting or the misuse of laxatives, diuretics, or enemas). Binge-Eating/Purging Type: During the current episode of anorexia nervosa, the person has regularly engaged in binge-eating or purging behavior (ie, self-induced vomiting or the misuse of laxatives, diuretics, or enemas).
Reprinted with permission from: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 2000.
A. Recurrent episodes of binge eating. An episode of binge eating is characterized by both of the following: 1. Eating, in a discrete period of time (ie, within any 2-hour period), an amount of food that is definitely larger than most people would eat during a similar period of time and under similar circumstances; 2. A sense of lack of control over eating during the episode (ie, a feeling that one cannot stop eating or control what or how much one is eating). B. Recurrent inappropriate compensatory behavior in order to prevent weight gain, such as self-induced vomiting; misuse of laxatives, diuretics, enemas, or other medications; fasting; or excessive exercise. C. The binge eating and inappropriate compensatory behaviors both occur, on average, at least twice a week for 3 months. D. Self-evaluation is unduly influenced by body shape and weight. E. The disturbance does not occur exclusively during episodes of anorexia nervosa. Purging Type: During the current episode of bulimia nervosa, the person has regularly engaged in self-induced vomiting or the misuse of laxatives, diuretics, or enemas. Nonpurging Type: During the current episode of bulimia nervosa, the person has used other inappropriate compensatory behaviors, such as fasting or excessive exercise, but has not regularly engaged in selfinduced vomiting or the misuse of laxatives, diuretics, or enemas.
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secondary to excessive purging.10 Dependent on the degree of purging, and if any restriction is utilized, the patient with bulimia nervosa may meet all expected weight gains and track normally along the growth chart percentiles.
Nutrition in Eating Disorders
Etiology of Eating Disorders

The etiology of eating disorders is complex but appears to originate from not only predisposed genetic factors but also serotonin dysfunction and psychological factors surrounding childhood abuse and/or trauma.11 A 17-year longitudinal study of 800 children found that eating conflicts, struggles with food, and unpleasant meals were additional risk factors for the development of an eating disorder in this population.12 The role of heredity is still unclear, as twin studies, often utilized to differentiate between genetic factors and environment in familial studies, have reported mixed data, with some demonstrating a strong correlation while others little correlation.13
Figure 19-3 Research Criteria for Binge-Eating Disorder A. Recurrent episodes of binge eating. An episode of binge eating is characterized by both of the following: 1. Eating, in a discrete period of time (ie, within any 2-hour period), an amount of food that is definitely larger than most people would eat in a similar period of time under similar circumstances; 2. A sense of lack of control over eating during the episode (ie, a feeling that one cannot stop eating or control what or how much one is eating). B. The binge-eating episodes are associated with three (or more) of the following: 1. Eating much more rapidly than normal, 2. Eating until feeling uncomfortably full, 3. Eating large amounts of food when not feeling physically hungry, 4. Eating alone because of being embarrassed by how much one is eating, 5. Feeling disgusted with oneself, depressed, or very guilty after overeating. C. Marked distress regarding binge eating is present. D. The binge eating occurs, on average, at least 2 days a week for 6months. Note: The method of determining frequency differs from that used for bulimia nervosa; future research should address whether the preferred method of setting a frequency threshold is counting the number of days on which binges occur or counting the number of episodes of binge eating. E. The binge eating is not associated with the regular use of inappropriate compensatory behaviors (ie, purging, fasting, excessive exercise) and does not occur exclusively during the course of anorexia nervosa or bulimia nervosa.
Although nutritional rehabilitation and weight stabilization are essential components in the treatment of and recovery from eating disorders, research continues to be limited in this population. The following recommendations should be used as guidelines and not definitive treatment.
Macronutrients
Energy Requirements
Initial energy requirements for anorexia nervosa are 30 to 40 kcal/kg of current body weight.4 An elevated dietinduced thermogenesis (DIT) has been reported in anorexia nervosa.14 In patients with an elevated DIT or patients who are extremely anxious, energy requirements may be as high as 80 to 100 kcal/kg before weight gain can be achieved.4 If higher energy needs are required in a patient with anorexia nervosa due to poor weight gain, the patient should be evaluated for manipulation of intake. In patients with bulimia nervosa or binge-eating disorder, initial energy requirements for weight maintenance may start at 1.2 to 1.3 measured resting energy expenditure (REE) for sedentary activity.15 It is recommended to avoid caloric levels that promote weight loss until an eating pattern is stabilized, because a restriction in calories in such a patient may trigger a binging episode.
Figure 19-4 American Psychiatric Association Diagnostic Criteria for 307.50 Eating Disorder Not Otherwise Specified A. For females, all of the criteria for anorexia nervosa are met except that the individual has regular menses. B. All the criteria for anorexia nervosa are met except that, despite significant weight loss, the individuals current weight is in the normal range. C. All of the criteria for bulimia nervosa are met except that the binge eating and inappropriate compensatory mechanisms occur at a frequency of less than twice a week or for duration of less than 3 months. D. The regular use of inappropriate compensatory behavior by an individual of normal body weight after eating small amounts of food (ie, self-induced vomiting after the consumption of two cookies). E. Repeatedly chewing and spitting out, but not swallowing, large amounts of food. F. Binge-eating disorder: recurrent episodes of binge eating in the absence of the regular use of inappropriate compensatory behaviors characteristic of bulimia nervosa.
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Protein Requirements
Recommended protein intake is the recommended dietary allowance (RDA) in g/kg ideal body weight for age (0.81.5 g/kg) or 15% to 20% of total calories from a high biologic value source.4,15
Fat Requirements
anorectic patients with thiamin and magnesium in addition to addressing any other found deficiencies.17 At onset of intervention, provide a 100% RDA multivitamin with minerals.15
Laboratory Assessment
A detailed laboratory assessment is recommended at time of initial assessment. Although a complete blood count (CBC) and chemistry profile is recommended, these traditional tests are typically normal and may underestimate the physical damage and degree of malnutrition. More targeted and sensitive tests are recommended, including zinc, iron, prealbumin, transferrin, ferritin, 25-OH vitamin D, thiamin, and complement 3 (C3) level.18 Refer to Figure 19-5 for a complete recommendation of laboratory tests. Despite these normal CBC panels, elevated serum cholesterol and abnormal lipoprotein profiles are often found in an anorectic patient regardless of consumption of extremely low-fat and low-cholesterol diets. Arden et al postulates that mild hepatic dysfunction, decreased bile acid secretion, and/or hypothalamic dysfunction may contribute to these abnormalities.19
Recommended fat intake is 25% to 30% of total daily calories from fat, with appropriate sources of essential fatty acids.4,15
Micronutrients
A number of micronutrient deficiencies occur in patients with eating disorders. In both anorexia nervosa and bulimia nervosa, zinc deficiency is common and documented as resultant from suboptimal intake attributed to severe caloric restriction, avoidance of red meat, and/or the adoption of an inadequate vegetarian lifestyle.16 Additionally, riboflavin, thiamin, calcium, B-vitamin, and magnesium deficiencies are well documented and are of concern in both anorexia nervosa and bulimia nervosa.11 It is recommended to routinely screen and subsequently supplement
Figure 19-5 Recommended Laboratory Tests Standard Complete Blood Count (CBC) with differential Urinalysis Complete Metabolic Profile: Sodium, Chloride, Potassium, Glucose, Blood Urea Nitrogen, Creatinine, Total Protein, Albumin, Globulin, Calcium, Carbon Dioxide, AST, Alkaline Phosphates, Total Bilirubin Serum magnesium Thyroid Screen (T3, T4, TSH) Electrocardiogram (ECG) Special Circumstances 15% or more below ideal body weight (IBW) Chest X-Ray Complement 3 (C3) 24 Creatinine Clearance Uric Acid 20% or more below IBW or any neurological sign Brain Scan 20% or more below IBW or sign of mitral valve prolapse Echocardiogram 30% or more below IBW Skin Testing for Immune Functioning Weight loss 15% or more below IBW lasting 6 months or longer at any time during course of eating disorder Dual Energy X-Ray Absorptiometry (DEXA) to assess bone mineral density Estradiol Level (or testosterone in males) Adapted from http://www.nationaleatingdisorders.org/p.asp?WebPage_ID=758#Table1. Accessed January 2, 2009. Copyright 2008 National Eating Disorders Association. www.nationaleatingdisorders.org.
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Nutrition Support in Eating Disorders

Oral Nutrition and Meal-Planning Guidelines
In all eating disorders, the ultimate nutrition treatment goals include non-restrictive eating that incorporates variety and nutritional adequacy, and absence of purging behaviors.20 In bulimia, purging efforts are utilized in attempts to lose weight, and patients will often request assistance during treatment in achieving this goal. For patients suffering from either bulimia or binge-eating disorder, although longterm weight loss may be reasonable and/or recommended, the immediate goal should be interruption of the binge or binge-purge cycle with stabilization of weight.9 For all eating disorder types, plan 4 to 6 eating opportunities per day. Allow no more than 4 hours between eating opportunities in order to prevent hypoglycemia, extreme hunger, and/or the temptation to binge.20 Each meal and snack should contain a balance of sufficient carbohydrates to prevent craving, and adequate protein and fat to promote satiety.9 For patients with binge-eating disorder or bulimia, the initial meal plan should not include any foods that the patient is unwilling or unable to keep from vomiting. Provide support to the patient during and after meals while encouraging expression of feelings. Additionally, encourage the patient to remain out of the bathroom for up to an hour after meal consumption.20
easily purged.15 For the anorectic patient, several options are appropriate: bolus feed appropriate supplemental calories only at mealtimes, bolus feed only uneaten calories to meet mealtime goal, or nighttime continuous feed of uneaten or excessive calories.20 When EN is utilized, an isotonic, fiber-containing, polymeric formula is usually sufficient for nutritional repletion, unless impaired digestion or absorption indicates use of an elemental- or peptide-based product. Due to the high risk of refeeding syndrome (discussed below) in an anorectic patient, the initial infusion should not exceed 25 to 50 mL/h and should be gradually increased 10 to 25 mL every 8 to 24 hours as tolerated until goal feeds are achieved.20 Manipulation behaviors may arise when utilizing EN in the eating-disordered individual. Precautions need to be taken. Sample behaviors used in tube feeding manipulation include18: lowering the delivery rate on the feeding pump; using sharp objects to poke holes in the feeding tube; filing the tube to reduce thickness, then bending the tube at that point to spill the feeding; removing the feeding bag from its hanging pole and swinging it to create air pockets to clog the tube; purging through the surgical opening of a percutaneous endoscopic gastrostomy tube; and placing the nasogastric tube in another place (in a plant, out the window, in the mattress).
Enteral Nutrition Support and Route of Feeding

The decision to initiate enteral nutrition (EN) in a person with an eating disorder is a complex one and should take into account not only the patients immediate physical health but also his or her psychological health. EN support is indicated if a patient is refusing any oral intake, rapid weight loss continues despite improved oral intake, or the patient is hypermetabolic and unable to meet nutritional needs orally. When choosing a route for EN, the nasogastric route is preferred for the relative ease of administration; however, a nasojejunal placement may alleviate discomfort from delayed gastric emptying.15 If long-term enteral support is needed, it is recommended that the tube ending be placed in the duodenum to avoid problems with gastric reflux and purging by the patient.18 When utilizing EN in an eating-disordered patient, it is encouraged to provide the supplementation in a manner that will continue to promote the persons ability to identify natural hunger cues. In a patient with bulimia nervosa, a continuous drip tube feeding is often recommended because a bolus feeding may cause involuntary vomiting and is more
Parenteral Nutrition
Parenteral nutrition (PN) is only indicated in cases of digestive inability as it leads to a continued loss of hunger cues in the eating-disordered individual. 20 When PN is initiated in severely malnourished patients, caution needs to be taken due to the possibility that refeeding syndrome might occur. Refer to the Refeeding Syndrome section in this chapter for definitions and guidelines.
Monitoring Nutrition Interventions

The anthropometric status of patients with eating disorders should be assessed and monitored regularly. Rehydration and replenished glycogen stores contribute to weight gain during the initial refeeding; thereafter, weight gain results from increased lean and fat stores.9 In hospitalized patients in whom weight restoration is a goal, 2 to 3 pounds per week is reasonable.9 The hospitalized individual should be weighed daily, gowned, preprandial and postvoid. Baseline height and growth history should be obtained and monitored every 1 to 2 months in patients who still have growth potential.
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Baseline anthropometric measurements (skinfolds, midarm circumference, and midarm muscle circumference) should be obtained at onset of intervention and monitored as medically indicated.9,15
Refeeding Syndrome
Definition and Incidence
Refeeding syndrome can be described as a cascade of potentially fatal complications caused by shifts in fluid and electrolytes as nutrition is reintroduced into the body, taxing wasted and weakened tissues and demanding more nutrients than are readily available.21,22 It is manifested in an assemblage of symptoms that result from rapidly and inappropriately refeeding (via oral, enteral, or parenteral route) individuals who have been malnourished or starved for a period of time, usually exceeding 7 to 10 days. 23 Other symptoms of refeeding syndrome include cardiac dysfunction, edema, and neurological changes.24 Hypophosphatemia is the hallmark clinical sign of refeeding syndrome, but hypomagnesemia and hypokalemia are also common indicators. Glucose intolerance and thiamin deficiency are often present as well.25 The exact incidence of refeeding syndrome is unknown, due in part to the lack of a universal definition 21 and also poor recognition of the condition. It is known that 30% to 38% of previously unfed patients receiving PN containing phosphorus experience hypophosphatemia, 26 and 100% of these patients develop hypophosphatemia when no phosphorus has been added to the PN solution. It has also been documented that when patients were vigorously refed, 80% experienced hypokalemia, hypomagnesemia, and/or hypophosphatemia.27
Pathophysiology and Characteristics of StarvationandRefeeding

In a normal, fed state, glucose and fatty acids are the preferred energy substrates for the human body. During periods of starvation exceeding 3 to 5 days, the body shifts glucose metabolism to fat and protein metabolism and enters a state of ketosis. The brain switches from glucose to ketones as an energy source. The liver visceral protein stores and vital organs, adipose tissue, and fluids also become depleted. The wasting of muscle affects vital organ function, including both respiratory capacity and cardiac mass and output.21,24 During starvation, the kidneys role is to decrease the excretion of minerals as the bodys stores become depleted. Serum electrolyte levels are maintained by decreased excretion through the kidneys and by volume constriction as
fluid shifts from extracellular to intracellular spaces.21 In addition, because electrolytes, especially phosphorus, play a major role in glucose metabolism, electrolyte demands are diminished during ketosis and starvation.28 As nutrition is reintroduced to the body, a rapid spike of insulin accompanies the introduction of carbohydrate, which seems to be the driving force of refeeding syndrome.1 Insulin promotes the uptake of glucose, water, and electrolytes by the cells, and thus glycogen, protein, and fat synthesis resume. Water and sodium are retained causing extracellular fluid overload, which can lead to pulmonary edema and cardiac decompensation.22 Hyperglycemia may result from excess carbohydrate administration and inadequate insulin output. Hyperglycemic complications include osmotic diuresis, dehydration, metabolic acidosis, and ketoacidosis.21 Anabolism is triggered by macronutrient intake and places demands on the body for a myriad of other nutrients including phosphorus, potassium, magnesium, and water-soluble vitamins. These nutrients are now in short supply due to their depletion during the prolonged period of fasting, and the bodys remaining stores are exhausted quickly.21 Thus, hypophosphatemia, hypokalemia, hypomagnesemia, and thiamin deficiency may clinically present. Phosphorous is involved in the intracellular processes and structural integrity of all the cells.21 It is also required for the production of energy in the form of adenosine triphosphate (ATP), and is a structural component of 2,3-diphosphoglycerate (2,3-DPG).25 Hypophosphatemia may cause clinical symptoms when serum levels reach 1.5 mg/dL, and severe hypophosphatemia ( 1 mg/dL) can have devastating effects on multiple systems.22 Serum phosphorus levels typically reach a nadir around 2 to 3 days of refeeding.1 Cardiovascularly, ATP depletion and cardiac atrophy contribute to hypocontractility and ventricular arrhythmia, which is complicated by volume overload. Skeletal muscle weakness and sarcolema disruption lead to rhabdomyolysis. Myopathy causes difficulty with ambulation and may additionally contribute to respiratory dysfunction due to accessory muscle and diaphragmatic weakness/catabolism. Hypophosphatemia affects the hemo-immunologic system by inducing bone marrow dysfunction, which can lead to decreased immune function evidenced by hemolytic anemia, thrombocytopenia, hemolysis, and decreased oxygen delivery to peripheral tissue. Hypophosphatemia influences the nervous system via inadequate 2,3-DPG and/or ATP deficiency, which may contribute to the incidence of delirium, coma, hallucinations, seizures, tetany, weakness, and parasthesias. 25
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Hypokalemia may result as anabolism resumes and cells take up potassium during fluid and electrolyte shifts. Serum potassium levels < 2.5 mg/dL may cause devastating paralysis, respiratory dysfunction, rhabdomyolysis, muscle necrosis, and changes in myocardial contraction and signal conduction.22 Serum magnesium levels < 1 mg/dL can cause electrocardiographic changes, tetany, convulsions, and seizures.29 Patients experiencing refeeding syndrome may present with hypophosphatemia, hypokalemia, and/or hypomagnesemia, thus illustrating the importance of close electrolyte monitoring. All vitamins may be deficient as a result of long-term inadequate nutritional intake. However, due to its role in carbohydrate metabolism, thiamin is of particular importance. Thiamin (vitamin B1) is a structural component of nervous system membranes30 and thus its deficiency may present with symptoms of beriberi such as parasthesia, hypoesthesia, anesthesia, and lower extremity weakness,4 or as Wernickes encephalopathy (ocular abnormalities, ataxia, confusion, hypothermia, coma) or Korsakoffs psychosis (retrograde and anterograde amnesia, confabulation). 31
Prevention and Therapy

Prevention of refeeding syndrome is the most effective factor in its management, therefore an awareness and ability to identify high-risk patients is key.22 Patients with a weight loss of 10% within 2 to 3 months or those at or below
70% ideal body weight are at the greatest risk.22 Categories of patients who may meet these criteria include those with anorexia nervosa, alcoholism, cancer, uncontrolled diabetes, marasmus, malabsorptive syndrome (eg, pancreatitis, cystic fibrosis, short bowel), prolonged fasting, morbid obesity with profound weight loss, prolonged antacid use (due to binding of phosphorus), and long-term diuretic use (due to electrolyte losses), as well as postoperative patients, the elderly, and patients allowed nothing by mouth for greater than 5 to 7 days.21 If a patient meets the preceding high-risk criteria for refeeding syndrome, there are several acceptable approaches for preventing or treating refeeding (Table 19-1). Importantly, baseline electrolytes (including potassium, phosphorus, magnesium, and calcium) should be obtained and corrected if low prior to the initiation of feeds.1 Electrolyte monitoring should continue 1 to 4 times per day depending upon the severity of malnutrition, for the first 3 days.24 During this time, calories may be introduced at 50% of goal, not to exceed 20 to 25 kcal/kg/d.1,21,22,24 Macronutrient distribution should limit carbohydrate intake to 2 to 3 g/kg/d based on actual body weight. No restriction is necessary for protein or fat intake, and common recommendations for each are 1 to 1.5g/kg/d1,22,24 and 1 g/kg/d, respectively.1 Fluid should be restricted to 800 to 1000 mL/d due to the potential risk of fluid overload and cardiac decompensation.22,24
TABLE 19-1 Timeline for Prevention and Therapy of Refeeding Syndrome1,21,22,24,25,32,33

Days 13 Days 47 Days 814
Calories Carbohydrate Protein Fat Fluid Phosphorus
50% of goal, or 1520 kcal/kg/d 23 g/kg/d 11.5 g/kg/d 1 g/kg/d 8001000 mL/d 0.30.6 mmol/kg/d for normal serum levels. Correct low serum levels aggressively with 918 mmol over 212 hours as indicated 24 mmol/kg/d. Correct low serum levels as necessary 0.2 mmol/kg/d. Correct moderately low serum levels with 0.5 mmol/kg x 24 hours. Correct severely low levels with 24 mmol over 6 hours 200300 mg daily Multivitamin/mineral supplement daily
Advance by 200300 kcal if electrolytes stable Advance to meet daily calorie adjustments 11.5 g/kg/d 1 g/kg/d Advance with calories if electrolytes stable and no clinical signs of fluid overload 0.30.6 mmol/kg/d. Continue to correct low serum levels as necessary 24 mmol/kg/d. Correct low serum levels as necessary 0.2 mmol/kg/d if stable. 0.25 mmol/kg/d for patients who have been hypomagnesemic 200300 mg daily Multivitamin/mineral supplement daily
Advance every 3 days by 200300 kcal if electrolytes remain stable Advance to meet daily calorie adjustments 11.5 g/kg/d 1 g/kg/d Advance with calories if electrolytes stable and no clinical signs of fluid overload 0.30.6 mmol/kg/d. Continue to correct low serum levels as necessary 24 mmol/kg/d. Correct low serum levels as necessary 0.2 mmol/kg/d
Potassium Magnesium
Thiamin Other vitamins/minerals
200300 mg daily until day 10 Multivitamin/mineral supplement daily
EATING DISORDERS
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During these first few days of renourishment, electrolytes, if low, should be corrected aggressively. Potassium phosphate preferably, or sodium phosphate in the presence of normal serum potassium, can be given intravenously for moderate to severe hypophosphatemia.25 Different references recommend infusing 9 to 18 mmol over anywhere from 2 to 12 hours.21,25,32 For orally fed patients with mild to moderate hypophosphatemia, cows milk is an excellent source of both phosphorus and potassium,25 and can be used to treat mild electrolyte derangements. Oral sodium phosphate can also be used, at 500 mg 4 times per day until serum phosphorus is stable, then decreased to 250 mg 3 times per day for maintenance.22 Mild to moderate hypomagnesemia can be treated with an initial dose of 0.5 mmol/kg over a 24-hour infusion, then maintained at 0.25 mmol/kg/d for the next 5 days to maintain serum levels.21 For severe hypomagnesemia, infuse 24 mmol over 6 hours, then follow with 0.25 mmol/kg/d for the next 5 days as above.21 In addition to the attention paid to macronutrients and electrolytes, patients at risk of refeeding should receive a daily multivitamin/mineral supplement. Any signs or symptoms of thiamin deficiency can be treated with 200 to 300 mg of oral thiamin daily for 10 days to correct deficiency. 21 After electrolytes have stabilized and the patient has received 72 hours of nutrition at 50% of goal, calories can gradually be increased every 3 days by 200 to 300 kcal. 22,24,33 Continue to monitor and correct electrolytes as feedings progress for the duration of the first 2 weeks of feeding. 21 With awareness and proper monitoring, refeeding syndrome can be prevented or managed appropriately to prevent serious complications and the potential of death. Monitoring and correction of electrolytes, supplementation of nutrients, and conservative administration of carbohydrate and fluid can save lives of those at highest risk forrefeeding.
2. In an eating-disordered individual, parenteral nutrition is only indicated A. If the person is unwilling to consume food orally B. In cases of digestive inability C. If the person is < 75% of ideal body weight D. If the person is manipulating the enteral tube 3. Persons at greatest risk for refeeding syndrome include: A. Weight loss 10% within 2 to 3 months or those at or below 70% ideal body weight B. Weight loss 10% within 6 to 8 months or those at or below 70% ideal body weight C. Weight loss 7% within 2 to 3 months or those at or below 75% ideal body weight D. Weight loss 7% within 2 to 3 months or those at or below 70% ideal body weight See p. 487 for answers.
References
1. The following are common physical signs and symptoms of anorexia nervosa: A. Lanugo-type hair, cyanosis of the extremities, and erosion of the dental enamel B. Cyanosis of the extremities, erosion of the dental enamel, and Russells sign C. Cachexia, cyanosis of the extremities, and muscle wasting D. Cachexia, Russells sign, and sore red throat
1. Skipper A, ed. Dietitians Handbook of Enteral and Parenteral Nutrition. 2nd ed. Gaithersburg, MD: American Society for Parenteral and Enteral Nutrition; 1998. 2. Crowther JH, Wolf EM, Sherwook N. Epidemiology of bulimia nervosa. In: Crowther M, Tannenbaum DL, Hobfoll SE, Stephens MAP, eds. The Etiology of Bulimia Nervosa: The Individual and Familial Context. Washington, DC: Taylor + Francis; 1992:126. 3. Robinson T, Killen J, Litt I, et al. Ethnicity and body dissatisfaction: are Hispanic and Asian girls at increased risk for eating disorders? J Adolesc Health. 1996;19(6):384393. 4. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Eating Disorders. 2nd ed. Washington, DC: APA Press; 2000b. 5. Fischer M, Golden NH, Katzman DK, et al. Eating disorders in adolescents: a background paper. J Adolesc Health. 1995;16:420 437. 6. Carney CP, Andersen AE. Eating disorders. Guide to medical evaluation and complications. Psychiatr Clin North Am. 1996;19:657679. 7. Herzog DB, Nussbaum KM, Marmor AK. Comorbidity and outcome in eating disorders. Psychiatr Clin North Am. 1996;19:843859. 8. Vastag B. Whats the connection? No easy answers for people with eating disorders and drug abuse. JAMA. 2001;285:10061007. 9. Mahan LK, Escott-Stump S. Krauses Food, Nutrition, & Diet Therapy. 11th ed. Philadelphia: WB Saunders Co; 2004. 10. Russell GFM. The changing nature of anorexia nervosa. J Psychiatr Res. 1985;19:101109. 11. Patrick L. Eating disorders: a review of the literature with emphasis on medical complications and clinical nutrition Eating Disorders. Alternative Med Rev. FindArticles.com Web site. http://findarticles.com/p/articles/mi_m0FDN/is_3_7/ ai_88823869/pg_3/ Accessed January 3, 2009.
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12. Kotler LA, Cohen P, Davies M, Pine DS, Walsh BT. Longitudinal relationships between childhood, adolescent, and adult eating disorders. J Am Acad Child Adolesc Psychiatry. 2001;40(12):14341440. 13. Fairburn CG, Cowen PJ, Harrison PJ. Twin studies and the etiology of eating disorders. Int J Eat Disord. 1999;26:349358. 14. de Zwaan M, Aslam Z, Mitchell JE. Research on energy expenditure in individuals with eating disorders: a review. Int J Eating Disord. 2002;32:127134. 15. The Royal College of Psychiatrists. Guidelines for the nutritional management of anorexia nervosa. http://www.rcpsych. ac.uk/files/pdfversion/cr130.pdf. Accessed December 15, 2008. 16. Bakan R, Birmingman CL, Aeberhardt L, Goldner EM. Dietary zinc intake of vegetarian and nonvegetarian patients with anorexia nervosa. Int J Eating Disord. 1993;13:229233. 17. Winston AP, Jamieson CP, Madira W, et al. Prevalence of thiamin deficiency in anorexia nervosa. Int J Eat Disord. 2000;28:451454. 18. Woosley M. Eating Disorders: A Clinical Guide to Counseling and Treatment. Chicago, IL: American Dietetic Association; 2002. 19. Arden MR, Weiselberg EC, Nussbaum MP, et al. Effect of weight restoration on the dyslipoproteinemia of anorexia nervosa. J Adolesc Health. 1990;11:199202. 20. Setnick JS. The Eating Disorders Clinical Pocket Guide: Quick Reference for Healthcare Professionals. Snack Time Press; 2005. 21. Mehanna HM, Moledina J, Travis J. Refeeding syndrome: What it is, and how to prevent and treat it. BMJ. 2008;336:14951498.
22. Tresley J, Sheean PM. Refeeding syndrome: recognition is the key to prevention and management. J Am Diet Assoc. 2008;108:21052108. 23. Lagua RT, Claudio VS. Nutrition and Diet Therapy Reference Dictionary. 4th ed. New York, NY: Chapman and Hall; 1996. 24. McCray S, Walker S, Parrish CR. Much ado about refeeding. Practical Gastroenterology. 2005;23:2644. 25. Marinella MA. The refeeding syndrome and hypophosphatemia. Nutr Rev. 2003;61:320323. 26. Sacks GS, Walker J, Dickerson RN, et al. Observations of hypophosphatemia and its management in nutrition support. Nutr Clin Pract. 1994;9:105108. 27. Yantis M, Velander R. How to recognize and respond to refeeding syndrome. Nursing. 2008;38:3439. 28. Brody T. Nutritional Biochemistry. San Diego, CA: Academic Press; 1994. 29. Kraft MD, Btaiche IF, Sacks GS. Review of the refeeding syndrome. Nutr Clin Prac. 2005;20:625633. 30. Itokaiva Y, Schulz RA, Cooper JR. Thiamine in nerve membranes. Biochem Biophys Acta. 1972;266:293299. 31. Reuler JB, Girard DE, Cooney TG. Wernickes encephalopathy. N Engl J Med. 1985;312:10351039. 32. Dwyer K, Barone JE, Rogers JF. Severe hypophosphatemia in postoperative patients. Nutr Clin Pract. 1992;7:279283. 33. Klein CJ, Stanek GS, Wiles CE. Overfeeding macronutrients to critically ill adults metabolic complications. J Am Diet Assoc. 1998;98:795806.
Food Allergies
Mary Beth Feuling, MS, RD, CD, CNSD, Michael B. Levy, MD, and Praveen S. Goday, MBBS, CNSP
20
Learning Objectives
213 213 214 215 215 215
CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Major Food Allergens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Presentation. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
IgE-Mediated Diseases Mixed IgE and Non-IgE Mediated Diseases Non-IgE Mediated Disease
1. Understand the epidemiology, pathophysiology, clinical presentation, and recognition of pediatric food allergies. 2. Describe the nutrition assessment of children with food allergies. 3. Summarize the nutrition management of children with food allergies. 4. Understand the food and non-food allergy issues that may impact the provision of nutrition support.
Allergy Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 Management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216

Clinical and Laboratory Assessment Nutrition Intervention Nutritionally Complete Formulas Milk Substitutes Dietary Allowance Versus Dietary Restrictions
Introduction
Micronutrient Supplementation . . . . . . . . . . . . . . . . . . . . 221

Two Special Scenarios Prognosis and Follow-Up
Adverse reactions to foods are a growing public health concern in the Western world. Food allergies are a greater problem in children than in adults, with significant food allergies being associated with poorer nutrition outcomes in children. This chapter discusses the epidemiology, pathophysiology, clinical presentation, management, and prognosis of children with food allergies.
Food Allergies and Nutrition Support. . . . . . . . . . . . . . . . 223

Enteral Nutrition Parenteral Nutrition
Definitions
Several terms may be used when defining adverse reactions to foods. An abnormal response to a food may include allergy, hypersensitivity, or intolerance. Tolerance usually refers to the ability to consume a food that may have the potential for allergy or a food that previously caused allergy and is now consumed without sequelae. Adverse reactions to foods may occur within a spectrum of reactions ranging from immunoglobulin E (IgE) to non-IgE mechanisms. Generally speaking, allergy or hypersensitivity refers to IgE-mediated events and intolerance refers to non-IgE events. Other important definitions that will be used in this chapter are outlined in Table 20-1.
213
214
Table 20-1 Definitions of Common Terms That Are Frequently Used in Association with Food Allergies
Term Definition
Adverse food reaction Allergen Anaphylaxis Antibodies Antigen Atopic dermatitis (eczema) Atopy Elimination diet Food allergy (hypersensitivity) Food challenge Food and symptom diary Food intolerance Mast cells Skin prick test Tolerance
Any undesired response to a food regardless of mechanism. Substance foreign to the body that, on interaction with the immune system, causes an allergic reaction. An acute, often severe, and sometimes fatal immune response that may affect one or more organ systems. Immunoglobulins produced in response to an antigen or allergen. Any substance (as a toxin or enzyme) that stimulates an immune response in the body (especially the production of antibodies). A disease characterized by chronic inflammation of the skin which is atopic, hereditary, and non-contagious. Tendency toward the development of allergic diseases, determined genetically. An eating plan that omits one or more foods suspected to cause an adverse food reaction. An adverse food reaction that is mediated by an immunologic mechanism; the reaction occurs consistently after consumption of a particular food and causes functional changes in target organs; IgE-mediated food hypersensitivity, gluten sensitivity. Administration of a food in increasing amounts performed in order to establish whether a patient is orally tolerant. This may be performed in an open, single-blind, or double-blind fashion. A subjective tool for recording food and drink consumed and onset, intensity, and duration of symptoms. An adverse reaction to a food caused by toxic, pharmacologic, metabolic, or idiosyncratic reactions to the food or chemical substances in the food. Tissue cells that release histamine and other mediators that cause allergic symptoms. A test in which an antigen is applied directly to the skin and is pricked with a specifically designed device. The localized histamine and mediator release correlates to the presence of specific IgE. Ability to consume a food that may have the potential for allergy or a food that previously caused allergy and is now consumed without sequelae.
For many clinicians, defining a food reaction as IgE-mediated or non-IgE mediated has great utility. IgE reactions have been well understood and chemically described as a cascade of events which involves a process that results from mast cell or basophil degranulation at mucosal surfaces or the skin. Because IgE can be quantitatively measured, levels of food-specific IgE may aid in the diagnosis of IgEmediated food allergy and serial food-specific IgE levels may be followed to help determine the development of clinical tolerance. Non-IgE food intolerance may include immunologic and non-immunologic reactions due to the effects of other components within food (eg, lactose, seafood toxins, or naturally occurring pharmacologically active compounds such as tyramine). These substances may cause an adverse reaction, but are differentiated from true food allergy because they do not involve the IgE cascade.
Gastrointestinal diseases related to foods also may be caused by IgE and non-IgE mechanisms. Some diseases such as eosinophilic esophagitis may have both an IgE and a non-IgE component. These diseases are characterized in Table 20-2.
Epidemiology
Adverse reactions to foods have been reported in up to 15% to 20% of the population with the highest prevalence in infancy and childhood. In 2007, the Centers for Disease Control and Prevention (CDC) reported that an estimated 3 million children under age 18 years (3.9%) had a reported food allergy. Higher rates were seen in children under age 5, as compared with children 5 to 17 years of age with boys and girls showing similar rates of food allergy. Interestingly, Hispanic children had lower rates than non-Hispanic black or non-Hispanic white children.1
Table 20-2 Clinical Food Allergy Syndromes Associated with IgE or Non-IgE Mechanisms
IgE-Mediated Syndromes Mixed IgE & Non-IgE-Mediated Syndromes Non-IgE-Mediated Syndromes
Oral allergy syndrome Anaphylaxis Urticaria Angioedema
Eosinophilic esophagitis Eosinophilic gastritis Eosinophilic gastroenteritis Atopic dermatitis
Protein-induced enterocolitis Protein-induced enteropathy Food protein-induced enterocolitis syndrome (FPIES) Dermatitis herpetiformis, gluten enteropathy
FOOD ALLERGIES
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There has been a significant rise in atopic conditions in westernized countries over the past 20 years. Results from the third National Health and Nutrition Examination Survey (NHANES III), which measured the prevalence of positive skin prick test responses to common allergens in the U.S. population from 19881994, showed a significant rise in allergy skin prick test reactivity from the NHANES II study of 19761980.2 In 2007, the reported food allergy rate among all children younger than 18 years was 18% higher than in 1997. During the 10-year period of 1997 to 2006, food allergy rates increased significantly among both preschoolers and older children. In addition, from 2004 to 2006, there were approximately 9,500 hospital discharges per year with a diagnosis related to food allergy among children under age 18 years.1 Most studies suggest that 6% to 8% of the pediatric population and up to 1% to 3% of adults may have true food allergy based on skin prick tests. The true prevalence in the population is probably lower because of false-positive skin prick tests and this fact has also been noted using random telephone surveys. 3 Sicherer et al determined the prevalence of peanut and tree nut allergy to be 0.7% adults and 0.4% children in a New York telephone survey. 3,4 Children with food allergies are more likely to have other allergic conditions including asthma and atopic dermatitis when compared to children without food allergies. Asthma has been reported in 29% of children with food allergies (12% in children without food allergies); respiratory allergy is noted in over 30% versus 9% without food allergies while eczema is seen in 27% as compared with 8% of children without food allergies.2 Patients with a peanut allergy have asthma and atopic dermatitis prevalence rates of 46% and 50%, respectively. 5
ingestion, inhalation of airborne residue (eg, steam droplets carrying antigen), or by skin contact. The allergenic properties of foods may be affected by product processing (eg, heating or enzymatic digestion), which may affect changes in the antigenic epitope conformation. This may render a food more or less allergenic. The allergen threshold dose, which is the dose that triggers a systemic allergic reaction in the host, involves many factors and is an area of current research interest. IgE-mediated degranulation of effector cells occurs after the food allergen contacts the food-specific IgE antibodies. Cross-linking of the IgE antibodies present on the surface of these cells results in mediator release of histamine, leukotrienes, and prostaglandins. These mediators cause the clinical manifestations of immediate hypersensitivity reactions including pruritus, vasodilatation, smooth muscle contraction, mucus production, and inflammatory cell recruitment to tissues.6
Major Food Allergens
Almost every major food allergen identified is a protein or glycoprotein. They tend to resist denaturation by heat or acid and may be more or less common depending on the society or ethnicity of the population observed. In the United States, milk, soy, egg, wheat, peanut, tree nut, fish, and seafood are the most common allergens noted. However, other legumes, sesame, poppy seed, sunflower seed, pine nuts, and spices are allergens of increasing importance.
Clinical Presentation
IgE-Mediated Diseases
The major IgE-mediated allergic diseases are oral allergy syndrome, anaphylaxis, urticaria, and angioedema. The pollen-associated oral allergy syndrome presents with pruritus of the lips, palate, tongue, and oropharynx following oral mucosal contact with fresh fruits and vegetables. The reaction usually does not occur following a cooking process because the cross-reactive allergen is very heat sensitive. These symptoms usually resolve without treatment and generally do not progress to cause more systemic involvement. Cross-reactivity between plant pollens and fruits is responsible for the clinical syndrome. Specifically, patients with ragweed sensitivity may have these symptoms after ingesting watermelon, cantaloupe, banana, or honeydew while patients sensitive to birch pollen may notice symptoms with apple, pear, celery, carrot, or peach. Food-induced anaphylaxis is the most severe form of
Pathophysiology
The production of IgE antibody may develop in the genetically predisposed individual through mechanisms that involve multiple factors. Once allergen-specific IgE is produced, binding to the high-affinity IgE receptor which is present on mast cells and basophils occurs. Low-affinity IgE receptors are present on eosinophils, monocytes, and macrophages.6 There are multiple host, antigen, and allergen factors that may be involved in the IgE-sensitization cascade which may result in the subsequent development of clinical allergy. These factors include the genetics of the host, immunologic competence at the mucosal level, and allergen presentation by intact antigen-processing cells, as well as the route of exposure to the allergen. Sensitization may occur via
216
immediate hypersensitivity reaction. Symptoms may include hypotension, urticaria, angioedema, respiratory compromise including laryngeal edema, and gastrointestinal symptoms of pain, vomiting, and diarrhea; although, food-induced anaphylaxis can occur without any skin manifestations. Near-fatal and fatal reactions often occur in the teenage to 35-year age range and are associated with a patient history of asthma, an accidental ingestion of a known allergen, and the delayed administration of epinephrine. The foods implicated are usually peanut, tree nut, or seafood.7
on the clinical history and presentation, and removal of the offending food serves as a simple and effective therapy. The age at which oral tolerance develops varies. Allergy skin prick testing is commonly used by the practicing allergist-immunologist to determine the presence of IgE to specific foods. Clinical correlation of the patient history to the testing results is important. The skin prick technique is highly reproducible and extracts for these tests are commercially available for hundreds of airborne and food allergens. These tests are performed by applying the extracts by a prick or puncture technique to the palmar surface of the forearm or upper back. The allergy prick test is actually a localized mediator-release phenomenon which occurs following allergen presentation to skin mast cells. The reaction is a nearly immediate wheal and flare reaction characteristic of IgE-mediated allergy. The test is read within 20 minutes and correlates closely with the presence of specific IgE to the suspected allergen. Positive tests indicate the presence of IgE but not clinical reactivity with an estimated false positive rate of approximately 50%. A negative test has high negative predicted value of nearly 95%, thus excluding the role of IgE.13 In-vitro radioallergosorbent tests (RAST) are blood tests that are available for the determination of serumspecific IgE with close correlation to skin prick testing results. The Pharmacia ImmunoCAP system has been studied with food challenge results showing a greater than 95% predictive value for reactions to peanut, egg, and milk. There are a small number of false negative ImmunoCAP tests for peanuts. The established values can be utilized by clinicians to determine when a food challenge may be safe to perform in the patient with IgE-mediated food allergy.14
Allergy Testing
Mixed IgE and Non-IgE Mediated Diseases

The gastrointestinal eosinophilic disorders listed in Table 20-2 have features that may best be described as mixed IgE and non-IgE disorders. There may be evidence of IgE present (eg, positive skin prick tests or serologic in vitro IgE to the offending food) but other mechanisms may be involved. These disorders are characterized by eosinophilic infiltration of the esophageal, gastric, or intestinal mucosa. These patients often present with vomiting, abdominal pain, weight loss, or failure to thrive. Diagnosis is confirmed with endoscopic examination and biopsy. Eosinophilic esophagitis is discussed later in this chapter.
Non-IgE Mediated Disease

Efforts to define the mechanisms underlying the non-IgE mediated diseases listed in Table 20-2 have shown varying results. These conditions are thought to be caused by other immunologic mechanisms not involving IgE. Typical symptoms may include recurrent vomiting or diarrhea. In infancy, this is most commonly related to cows milk or soy protein. This condition is discussed in detail below. Food protein-induced enterocolitis syndrome (FPIES) is classified as a non-IgE mediated allergic disorder, triggered by the ingestion of certain food proteins.8 Children usually present at less than 12 months of age with vomiting and/or diarrhea within hours of ingestion of the causative food. The symptoms should mimic IgE-mediated anaphylaxis, however the clinical picture lacks the usual cutaneous signs of urticaria, angioedema, or respiratory compromise. Some children present in a moribund state, with shock and metabolic acidosis.9 Typically, the offending food is either cows milk or soy10,11 although meats, vegetables, and grains have also been implicated.9 Tests for food-specific IgE by either skin prick testing or serologic in-vitro methods are negative.12 Awareness of the entity is important as the clinical presentation can be confused with other life-threatening conditions. Multiple presentations before the true diagnosis is established are the norm. Early diagnosis should be based
Management
There is currently no cure available for the food allergic individual. Strict avoidance of the allergy-causing food is the only way to prevent a reaction. Future treatment horizons may include anti-IgE monoclonal antibody which has already been trialed in peanut allergy, as well as newer forms of allergen immunotherapy.15 Trials in oral desensitization have been recently published and have shown efficacy in inducing tolerance.16 Exclusion of foods may lead to nutrition problems that require the expertise of a qualified dietitian. All patients with anaphylaxis to foods (or other allergens) and patients with severe food allergies should be educated regarding the use of injectable epinephrine, which may be lifesaving in the
FOOD ALLERGIES
217
event of accidental exposure. Practically, all children with multiple food allergies should be co-managed by an allergist and a dietitian. Because avoidance is the only proven treatment,17 children with food allergies need to avoid the foods to which they are allergic. The goals of the dietitian are twofold: to provide families and patients with guidelines, education, and suggestions for avoiding the allergenic foods and to monitor the child to ensure a nutritionally adequate diet that will promote appropriate weight gain and growth. There must be a multidisciplinary approach that is adopted in conjunction with the allergist with accurate diagnosis of causative foods, assessment of nutrition status, institution of a diet that eliminates the offending foods (elimination diet), prevention of adverse reactions, development of proper emergency treatment with an action plan in place, and treatment of associated atopic
disorders. There should be ongoing care by both the allergist who periodically determines whether the child has developed tolerance to any of the offending foods and the dietitian who continues to monitor the nutrition status and growth of the child. An algorithm for the management of the food-allergic child is proposed in Figure 20-1.
Restriction of a childs diet due to the diagnosis of food allergies may have a severe impact on his or her nutrition intake. This section provides a practical approach to identifying the risk factors that can lead to nutrition deficiencies, undernutrition, and poor growth while providing guidelines for a comprehensive nutrition assessment. Because strict avoidance of the causative food is necessary, it is critical to clearly define the avoidance list. The
Figure 20-1: Algorithm for the Evaluation of Suspected Food Reactions
218
nutrition risk increases as the number of foods avoided increases. This compounds the challenge for providing a nutritionally complete diet. Any additional problems associated with feeding further compound the risk. It is crucial to collaborate with the allergist and the family to clearly define the foods to be avoided and prevent any unnecessary restrictions. The degree of nutrition risk can be ascertained by methods outlined in Table 20-3.
Table 20-3 Questions That Need To Be Asked To Determine the Degree of Nutrition Risk in Children with Food Allergies
How many foods need to be avoided?
requirements for healthy children. Occasionally they will require increased caloric intake to provide catch-up growth due to poor growth often associated with allergen restriction. In addition, children with moderate to severe atopic dermatitis may have higher caloric and protein needs based on the degree of skin involvement. The more medically complex allergic child may have other nutrition needs due to his or her other medical diagnoses and these are discussed elsewhere in this book.
Clinical and Laboratory Assessment

Nutrient intake and growth are affected in children with food allergies. Children with greater than 2 food allergies have a lower height, weight, and body mass index (BMI) than those with 1 food allergy.19 Diagnosis of food allergies often results in poor growth due to lack of caregiver knowledge, inadequate intake due to lack of guidance for substitutions to meet nutrition needs, and increased anxiety associated with feeding. Failure to achieve normal growth rates or growth velocity definitely suggests the need for medical nutrition therapy but a multidisciplinary approach involving a dietitian at the time of diagnosis of food allergy may be able to prevent or attenuate problems associated with growth. Accurate anthropometric data and use of growth charts is critical to the evaluation of these children. Based on the diet and feeding history, the clinician must review the risk of micronutrient deficiency. Table 20-5 summarizes the micronutrients provided by the top 8 allergens and provides the most common food alternatives that can be used when these foods need to be avoided. Many children with multiple food allergies are at high risk for inadequate essential amino acids and essential fatty acids. Refer to Chapter 3 (Carbohydrates) and Chapter 4 (Fats) for a complete discussion of the goals for the pediatric population. Often protein hydrolysate-based and/or amino acid-based formulas can be used to supplement the diet to meet these nutrition needs. Patients who present after being on prolonged significantly restricted diets without concomitant multivitamin-multimineral use and patients who present with significant malnutrition should be considered for laboratory tests of micronutrient adequacy. The clinical scenario should guide which laboratory tests are obtained (eg, a vegetarian child who is sustained on rice milk should be tested for anemia, zinc deficiency, essential fatty acid deficiency, and vitamin D deficiency). Most patients in the United States with minimal dietary restrictions can be managed through judicious use of a multivitamin-multimineral supplement and without laboratory testing.
Risk increases with more foods being/needing to be avoided

What is the impact on nutrients?
Risk increases with more of the following nutrients being impacted orfewer nutrients being severely impacted Calories Protein Fat Micronutrients
Are there other concerns about food intake?
Risk increases with other medical and psychological diagnoses affecting intake Swallowing/chewing difficulties Psychological diagnoses affecting intake Feeding disorder
When a diagnosis of food allergy has been made, medical nutrition therapy with scheduled follow-up visits can provide a way to monitor the overall health effects of food elimination. Identifying individuals at risk may protect and possibly improve the patients nutrition and overall health status. Medical nutrition therapy with appropriate food substitution(s) provides the tools necessary, giving the food-allergic patient the specific focus needed for improved nutrition self-care and food allergen avoidance.18 Table 20-4 provides a case scenario where 3 toddler diets are presented. The first diet is a typical unrestricted diet. Once the toddler is diagnosed with food allergies to milk, egg, and peanut, the second diet that needs to be followed puts him at a high risk for malnutrition and micronutrient deficiencies. The third diet provides the vital food substitutions (for the foods that the child must avoid) to ensure adequate nutrition. Nutrient intake needs change over time throughout the life cycle. This includes all of the macronutrient, micronutrient, and fluid needs, all of which play a key role in a developing child. These intake guidelines can be found in other chapters of this book. Nutrient requirements for infants and children with food allergies are the same as the
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Table 20-4 Case Scenario

Diet 1 Breakfast Lunch Dinner Diet 2 Breakfast Lunch Dinner Diet 3 Breakfast Lunch Dinner
Whole milk Cereal Banana
Whole milk Peanut butter & jelly sandwich Cooked carrots with butter Strawberries
Whole milk Meatloaf Peas
Whole milk Cereal Banana
Whole milk Peanut butter & jelly sandwich Cooked carrots with butter Strawberries
Whole milk Meatloaf Peas
Enriched soymilk Cereal Banana
Mashed potatoes Roll with butter
Mashed potatoes Roll with butter
Enriched soymilk Soynut butter and jelly sandwich Cooked carrots with milk-free margarine Strawberries
Enriched soy milk Milk-free, egg-free meatloaf Peas
Mashed potatoes made with chicken broth Milk-free roll with milk-free margarine
SNACK
SNACK
SNACK
SNACK
SNACK
SNACK
SNACK
SNACK
SNACK
Granola bar Juice
Yogurt drink Oatmeal cookie
Ice cream
Granola bar Juice
Yogurt drink Oatmeal cookie
Ice cream
Teddy Grahams Juice
Soy yogurt FAAN Oatmeal cookie*
Soy ice cream
*Food Allergy and Anaphylaxis Network recipe (can be found at http://www.foodallergy.org/recipes.html)
Nutrition Analysis of Diet 1 Nutrient % Goal**
Calories Protein Fat Calcium Vitamin D Iron Zinc
1490 kcal 47 g 55 g 1100 mg 203 IU 9.9 mg 8.9 mg
> 100 360 33% of totalkcal 221 101 141 297
305 kcal 5g 2g 98 mg 20 IU 4 mg 2.6 mg
25 41 6% of totalkcal 20 10 59 87
1360 kcal 42 g 49 g 754 mg 285 IU 10 mg 6 mg
> 100 321 32% of totalkcal 151 285 147 201
**Based on DRI for age.20 Legend: D iet 1: Sample menu for an 18-month-old child prior to diagnosis of food allergy. Diet 2: Nutritionally depleted sample menu for the same child who has been diagnosed with milk, egg, and peanut allergy. Diet 3: Revised nutritionally adequate menu for the child with acceptable food substitutions.
Table 20-5 Key Micronutrients Provided by the Most Common Food Allergens and Alternative Food Sources That Can Serve as Food Substitutes for the Allergenic Foods
Allergenic Foods Micronutrients Provided Appropriate Food Substitutes
Milk Egg Soy Wheat Peanut/Tree nut Fish/Shellfish
vitamin A, vitamin D, riboflavin, pantothenic acid, vitamin B12, calcium, phosphorus vitamin B12, riboflavin, pantothenic acid, biotin, selenium thiamin, riboflavin, pyridoxine, folate, calcium, phosphorus, magnesium, iron, zinc thiamin, riboflavin, niacin, iron, folate if fortified vitamin E, niacin, magnesium, manganese, chromium vitamin B6, vitamin E, niacin, phosphorus, selenium, omega-3 fatty acids, folate, copper, zinc, potassium
meats, legumes, whole grains, nuts, fortified foods/ beverages (with B vitamins, calcium, and vitamin D) meats, legumes, whole grains meats, legumes alternative fortified grains (barley, rice, oat, corn, rye, quinoa, soy) and potatoes whole grains, vegetable oils whole grains, meats, oils, soybean, flaxseed, nuts
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Nutrition Intervention
Education provides a family and patient the pathway for success with an elimination diet. This includes education regarding dietary avoidance and consideration of nutrition deficiencies that may result. In addition, they must receive education regarding the nutrition goals for the patient in order to avoid nutrition consequences of food allergies. They must also be educated about resources for obtaining additional information regarding living with food allergies (eg, support groups, local retail establishments that sell allergen-free foods, cookbooks, and other helpful tips for the elimination diet). A list of food allergy resources is provided in Table 20-6. Each food-allergic child/family must be given a list of substitutions in order to be successful with strict avoidance of the food allergens. In addition, a nutritionally complete formula or beverage, if possible, should be encouraged. This type of information assists the patient and family in living a normal and well-nourished life despite having food allergies. Without education, the recommendation of an elimination diet can be overwhelming and unsuccessful as families struggle to find accurate and useful information.
Table 20-6 Food Allergy Resources
Resource Website
the small fraction of children who are also allergic to the protein hydrolysates. Both of these types of formulas are generally less palatable than standard formulas and are considerably more expensive. Significant advances in the flavor and acceptability of the formulas have been made which has improved the adherence to incorporating these formulas as supplemental nutrition. The major categories of formulas are enumerated in Table 20-7.
Table 20-7 Major Pediatric Formulas
Formula Protein Examples Infant formulas
Cows Milk
Casein, whey
Similac Advance Early Shield Enfamil Premium

Formulas for older children
PediaSure Lactose-free
Infant formulas
Similac Sensitive
PediaSure Soy Soy
Infant formulas
Enfamil ProSobee Similac Isomil Advance

Bright Beginnings Soy Pediatric Drink Hydrolysate http://www.foodallergy.org http://www.aaaai.org http://www.eatright.org http://www.aafa.org http://www.apfed.org http://www.acaai.org Elemental Peptides, amino acids
Infant formulas
Food Allergy & Anaphylaxis Network American Academy of Allergy, Asthma& Immunology American Dietetic Association Asthma and Allergy Foundation ofAmerica American Partnership For Eosinophilic Disorders American College of Allergy, Asthma& Immunology
Nutramigen Similac Alimentum

Vital jr Peptamen Jr Amino acids
Infant formulas
Neocate EleCare Nutramigen AA

older children (ELEMENTAL)
Neocate Jr EleCare EO28 Splash
Nutritionally Complete Formulas

Identification of formulas is dependent upon the known food allergens. Most standard formulas are free of wheat, egg, peanut, tree nut, fish, and shellfish. It is common to substitute a soy protein-based formula for the cows milk protein-allergic patient. In patients who are allergic to both cows milk and soy, a protein hydrolysate or elemental formula is recommended. These formulas exploit the concept that intact proteins are allergenic and with increasing breakdown of the intact protein, the allergenicity can be reduced. Protein hydrolysates are made by hydrolysis of proteins into mostly di- and tri-peptides and can be tolerated by the vast majority (80% 90%) of patients with allergies to milk and soy. Elemental formulas are made up of individual amino acids and are tolerated by
Most children with food allergies can be managed through judicious food substitutions. When faced with an extensive array of food allergies that span multiple food groups, protein hydrolysate and elemental formulas become the primary option. Infants under the age of 4 to 6 months usually accept these less-palatable formulas without difficulty but with increasing age acceptability of these formulas becomes a problem. In toddlers or preschool children, when elemental formulas are the sole or major source of nutrition and the patient will not consume enough to sustain nutrition, tube feeding may become necessary. Patients who are extremely malnourished at presentation may need to be admitted to the hospital to monitor for refeeding syndrome (Chapter 19); otherwise, most patients
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with food allergies can be managed in the outpatient setting.
Milk Substitutes
Milk substitutes must be used in combination with nutrition assessment and monitoring. There are many different milk products in the marketplace that continue to provide alternatives for the allergic patient. However, each product should only be used with careful consideration of the nutritional quality of the milk product. Many provide adequate micronutrients such as vitamin D, calcium, and B vitamins; however most provide minimal fat and protein. Children under the age of 2 are at high risk for malnutrition if one of the incomplete milk substitutes is used in place of whole cows milk. See Table 20-8 for a list of the nutritional constituents of various milk substitutes.
Dietary Allowance Versus Dietary Restrictions

The diagnosis of food allergy impacts the patient and family in many different ways including grocery shopping, cooking, socializing, travel/vacations, eating out, and family relationships. It is essential to provide education regarding all of these topics. One of the cornerstones of management is education about reading food labels.21 Labels must be read every time a food product is purchased as the ingredients may change without warning. Labels must also be read for
Table 20-8 Nutrition Comparisons of Various Milk Substitutes with Whole Milk
Nutrient per 8 oz. Rice Milk, Non-Enriched Rice Milk, Enriched, Refrigerated Soy Milk, Enriched
supplements, medications, bath products, lotions, pet foods, and cosmetics as young children may accidentally or voluntarily consume these products. The Food Allergen and Consumer Protection Act (FALCPA), which became effective in January 2006, mandates that foods (including spices and flavorings) identify the 8 major allergens on the food label. Voluntary allergen advisories or may contain statements are also appearing on an increasing number of products. 22 These statements are voluntary; companies elect when to use the statements and what language to use. The statements are used by some companies to indicate there may be a risk of cross-contact with an allergen in another product. Recent efforts to increase public awareness and strides made in labeling of food products are encouraging. However, there is also a concern that food companies may choose to make voluntary statements regarding cross-contamination in an attempt to avoid accidental exposures to allergens. If this practice does occur, it may decrease food choices for patients with food allergies. Table 20-9 provides some examples of hidden food allergens in common foods.
Micronutrient Supplementation
The benefit of early intervention is to avoid micronutrient deficiency by recommending adequate substitutions and supplementation. The DRIs20 for vitamins, minerals, and
Whole Milk
PediaSure
Almond Milk
Hazelnut Milk
Oat Milk
Multigrain Milk
Calories 120 120 130 150 237 70 110 7.1 2 2 Protein (g) 1 1 7 8 Carbohydrate (g) 25 25 17 11 26 11 18 11.8 2.5 3.5 Fat (g) 2 2 4 8 3.5 3 7.4 2.5 3.5 Unsaturated fat (g) 2 2 0.5 5 3.1 0 0 Saturated fat (g) 0 0 Calcium (mg) 20 300 300 294 230 300 300 1.8 0.1 3.3 0.36 0.36 Iron (mg) NS NS Zinc (mg) 0.29 0.29 0.6 1 2.8 5.4 Selenium (mcg) NS NS 9 NS 0.12 0.15 0.107 0.64 NS Thiamin-B1 (mg) NS 0.07 0.447 0.5 0.5 0.5 Riboflavin-B2 (mg) Niacin-B3 (mg) 0.8 0.8 0.8 0.261 4 NS 0.23 0.4 0.883 2.4 NS Pantothenic acid-B5 (mg) NS 1.5 60 12 88 NS Folate (mcg) 1.5 1.5 3 1.07 1.4 NS Vitamin B12 (mcg) Vitamin A ( IU) NS 500 500 300 610 500 500 Vitamin D (IU) NS 100 100 100 120 100 100 NS Not a significant source Legend: These are typical nutrition values for various milk substitutes. Individual brands may have varying amounts of nutrients.
130 4 24 2.5 2.5 0 300 0.36 0.5 500 100
160 5 30 2 2 0 300 1.08 0.5 500 100
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Table 20-9 Common Sources of Hidden Food Allergens

Egg Milk Nuts Soy Wheat Rice
Pasta Bread/bread crumbs Egg Beaters Candy/chocolate Marshmallows Waffles
Bread/bread crumbs Breakfast cereals Frozen desserts Candy/chocolate Canned tuna Processed meats
Breakfast cereals/ granola bars Egg rolls Cakes/cookies Frozen desserts Nut butters Sauces/chili
Bread/bread crumbs Waffles Crackers Chicken hot dogs/ low-fat beef franks Cakes/muffins Bouillon cubes
Cereals Gluten-free products Chicken hot dogs/ low-fat beef franks Soy sauce Barbecue-flavored potato chips Modified food starch
Baby food Bread/bread crumbs Cake/muffin mixes Waffles Soups
trace elements can be used for children with food allergies because the vast majority of these children are normal except for their food allergies and atopic problems. Chapter 6 (Minerals), Chapter 7 (Water-Soluble Essential Micronutrients), and Chapter 8 (Fat-Soluble Vitamins) discuss these topics. Recommendations for supplementations should be made based on foods that need to be eliminated and the patients nutrition status. There are several hypo-allergenic multivitamin-multimineral supplements that are appropriate for children with food allergies (Table 20-10).
Table 20-10 Allergen-Free Multivitamins
All of these products are free of milk, soy, egg, wheat, peanut, tree nut, fish, and shellfish.
One-A-Day Kids Scooby-Doo! Complete Multivitamin One-A-Day Bugs Bunny Complete Multivitamin Flintstones Complete-Childrens Chewable Multivitamin NanoVM (13 yrs and 48 yrs)*# Multivitamin Natures Plus Animal Parade Childrens Chewable Multivitamin *This product is only available online. # This is the only allergen-free vitamin that contains selenium. Note: Products can change at any time and labels should be read beforeuse.
and respiratory symptoms (allergic rhinoconjunctivitis, asthma).24 This condition can also develop when an infant is exclusively breastfed, through the passage of the offending antigens from food consumed by the mother through the breast milk. The diagnosis is usually made through the history of clinical symptoms in young infants that develop soon after birth or shortly after starting cows milk-based formula in an infant with a family history of atopy. If the reaction is IgE-mediated, then the specific IgE levels may be elevated. Up to 80% to 90% of these infants will do well with a protein hydrolysate and the rest will require an elemental formula.25 In breastfed infants, the mother should initially avoid cows milk; if there is no improvement, she may also need to exclude some of the other common food allergens. These children, particularly infants with gastrointestinal symptoms, have a good prognosis. Approximately 50% of infants are able to tolerate cows milk by the age of 1 year and the vast majority remits by the age of 3 years.23 Eosinophilic esophagitis Eosinophilic esophagitis (EE) is a disorder of the esophagus characterized by upper gastrointestinal tract symptoms in association with esophageal mucosal eosinophilia. 26 EE tends to be a chronic disease with persistent or relapsing symptoms and appears to be becoming more prevalent. Children under the age of 5 years commonly present with food refusal, regurgitation, and emesis. Abdominal pain and failure to thrive may also be seen. Dysphagia and food impaction tend to be increasingly common with age. There is a strong association between EE and allergic rhinitis, asthma, and eczema as well as food allergies. All patients with EE must be managed with coordinated care between a gastroenterologist, allergist, and dietitian. Systemic and topical corticosteroids effectively resolve acute features of EE; however, when discontinued, the
Two Special Scenarios

Cows Milk-Protein Allergy Cows milk-protein allergy (CMPA) is the most common food allergy in early childhood with an incidence of 2% to 3% in the first year of life.23 Most infants with CMPA develop symptoms before 1 month of age, often within a week after introduction of cows milk-based formula. The majority have 2 or more symptoms with symptoms from 2 or more organ systems: cutaneous symptoms (urticarial rash, atopic eczema), gastrointestinal symptoms (blood in the stool, diarrhea, vomiting, protein-losing enteropathy),
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disease generally recurs. Three types of nutrition intervention have met with varying degrees of success in EE. First, specific food elimination can be based on allergy testing and clinical history.27 Even when allergy testing does not reveal specific food allergens, elimination diets can be used. Simply removing the 8 most common allergenic foods (milk, soy, egg, wheat, peanut, tree nut, fish, and seafood) from the diet has significant efficacy.28 Finally, a 100% amino acid-based formula diet can be utilized, thus removing all potential food allergens; this approach has been extremely effective.29,30 Hence, medical nutrition therapy should be considered as an effective treatment in all children diagnosed with EE. When deciding on the use of a specific nutrition therapy, the patients lifestyle and family resources also need to be considered. This requires comprehensive education and nutrition monitoring by a dietitian.
commencement of nutrition support.
Enteral Nutrition
Enteral nutrition support of children presenting with food allergies can be straightforward. Because most enteral formulas contain cows milk protein, children with cows milk protein allergies can be managed with soy-based, protein hydrolysate, or elemental formula using the principles outlined earlier in this chapter. Some of the formula intolerances that occur in young children receiving nutrition support are probably secondary to food allergies and are usually not recognized at the first instance. Since one of the management strategies for formula intolerances during nutrition support includes a transition to a protein hydrolysate/elemental formula, the acute situation usually resolves. Often, food allergy is diagnosed retrospectively when the child cannot be transitioned back to a more standard formula.
Prognosis and Follow-Up

There is a good possibility that many young children diagnosed with allergies to foods such as milk, egg, wheat, and soybeans will outgrow the sensitivity after several years. 31 There is a trend for non-IgE-mediated milk allergy to be outgrown more quickly than IgE-mediated allergy with both forms of the allergy having a good prognosis. 31 Children who develop a food allergy after 3 years of age are less likely to lose the food reactions over a several-year period. 25 Peanut allergy is a lifelong disorder for most but not all patients. 31 Individuals with allergies to foods such as tree nuts, fish, and seafood seem likely to retain their allergic sensitivity for a lifetime. 31 Follow-up visits with the allergist-immunologist are important for the management of food allergies. Because pediatric patients have the potential for outgrowing a food allergy, the follow-up visits can re-assess the allergic status and determine if any food allergens may be re-introduced. Re-introduction of a food allergen should only be considered if managed and directed by the allergist. Introduction of previously avoided allergens may increase food options, decrease cost if the patient is drinking a specialty formula and/or eating specialty allergen-free foods, and decrease the stress around preparing meals for the child.
There are minimal data on PN support in children with documented allergies to foods. Egg allergy can be a cause for concern because these proteins can be found in intravenous lipid solutions. In patients with documented allergies to eggs, 3 options could be consideredconsultation with an allergist who may or may not do a skin prick test, lipidfree PN, or the use of Liposyn II. 32 There is a theoretical risk with extremely soy-allergic patients needing PN. Most of these patients probably tolerate intravenous lipid, but the first 2 options outlined above should be considered. A variety of allergies to PN have been described through case reports in the literature. 3238 As with other allergies, they appear to be more common in children. 3638 Skin rashes appear to be the most common manifestation. However, they can present with dyspnea, cyanosis, nausea, vomiting, headache, flushing, fever, and chest pain. Anaphylaxis can occur. 3739 All of these reactions can occur at the first administration, after several days of administration, or after reinstitution following a hiatus. These reactions have been attributed to intravenous lipid preparations, 32,34 crystalline amino acid solutions, 37 and multivitamin mixtures (either due to stabilizers and emulsifiers in the M.V.I. Pediatric or due to vitamin K). 3537,39 When these reactions occur, PN needs to be stopped and appropriate drug treatment for the allergic reaction started. If the reaction is severe and the patient is going to continue to require PN, a multidisciplinary approach utilizing an allergist, pharmacist, nutrition-support physician, and/
Food Allergies and Nutrition Support
There are two possible scenarios wherein food allergies are associated with nutrition support. The first is when a child with known food allergies requires nutrition support and the second is where allergies to formula or parenteral nutrition (PN) components become apparent only after the
224
or dietitian should be pursued. Two approaches may be considered when the reaction is mild and resolves after PN is discontinued. The first is to have skin prick testing of the lipid, multivitamin, and amino acid components and removal of the offending agent(s) before PN is restarted. The other approach has been to identify the offending agent through trial and error. One micronutrient that may be added to PN solutions and cause significant allergic reactions is intravenous iron. All 3 parenteral iron compoundsiron dextran, sodium ferric gluconate complex in sucrose, and iron sucrose can be associated with allergic reactions.40,41 It appears that iron sucrose is associated with the lowest risk of allergy.41 Iron dextran is the least expensive preparation, and a test dose should always be given with the thought of routinely pre-treating patients with diphenhydramine and acetaminophen to minimize adverse events. Both sodium ferric gluconate and iron sucrose offer safe alternatives to patients intolerant of iron dextran but at a higher cost.40,41 Iron dextran-sensitive patients and patients with multiple allergies who receive one of the newer preparations should receive test doses prior to therapy.
does not drink a milk substitute. All of the following must be done or considered at this visit EXCEPT: A. Assessment of growth and nutrient intake B. Suggesting an age-appropriate beverage C. Recommending follow-up with allergist as patient is tolerating milk and soy D. Suggesting food challenge of peanut butter at home 4. A 6-month-old breastfed infant has significant vomiting and diarrhea within hours of being given a bottle of cows milk-based formula. His mother reports that this has happened each time he has been fed the formula. She denies any skin rashes. RAST testing for IgE directed against cows milk protein is negative. All of the following are true about this child EXCEPT: A. This is consistent with IgE-mediated anaphylaxis. B. This is most likely food protein-induced enterocolitis syndrome. C. Cows milk protein must be eliminated from the childs diet. D. In addition to breastfeeding, a protein hydrolysate formula may be appropriate. See p. 487 for answers.
1. A 7-year-old boy with an enterocutaneous fistula develops an urticarial rash the day that he is started on parenteral nutrition. All of the following constituents of his parenteral nutrition could cause the rash EXCEPT: A. Intravenous lipid B. Amino acid solution C. Pediatric multivitamin solution D. Dextrose 2. An 18-month-old vegetarian girl with presumed milk and soy protein allergy is drinking 32 ounces of enriched rice milk per day. She also eats rice, wheat, corn, fruits, and vegetables but does not consume any egg or meat products. She does not receive any vitamin or mineral supplementation. You are concerned about her intake of all of the following EXCEPT: A. Fat B. Vitamin D C. Energy D. Zinc 3. A 6-year-old Asian boy is seen by a dietitian for followup nutrition assessment and education. His parents report he is allergic to milk, soy, and peanuts. He has a history of anaphylaxis while eating peanut butter one year ago. His current intake includes tofu stir-fry and milk chocolate candy bars. Parents report he eats these foods at least once a week without any problems. He
References
1. Branum AM, Lukacs SL. Food allergy among U.S. children: trends in prevalence and hospitalizations. NCHS data brief, no 10. Hyattsville, MD: National Center for Health Statistics; 2008. 2. Arbes SJ Jr, Gergen PJ, Elliott L, Zeldin DC. Prevalences of positive skin test responses to 10 common allergens in the US population: results from the third National Health and Nutrition Examination Survey. J Allergy Clin Immunol. 2005;116(2):377383. 3. Sicherer SH, Muoz-Furlong A, Burks AW, Sampson HA. Prevalence of peanut and tree nut allergy in the US determined by a random digit dial telephone survey. J Allergy Clin Immunol. 1999;103(4):559562. 4. Sicherer SH, Muoz-Furlong A, Sampson HA. Prevalence of seafood allergy in the United States determined by a random telephone survey. J Allergy Clin Immunol. 2004;114(1):159165. 5. Sicherer SH, Furlong TJ, Burks AW, Sampson HA. A voluntary registry for peanut and tree nut allergy: characteristics of the first 5149 registrants. J Allergy Clin Immunol. 2001;108(1):128132. 6. Sampson HA, Burks AW. Mechanisms of food allergy. Annu Rev Nutr. 1996;16:161177. 7. Bock SA, Muoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol. 2001;107(1):101103. 8. Sicherer SH. Food protein-induced enterocolitis syndrome: clinical perspectives. J Pediatr Gastroenterol Nutr. 2000;30 Suppl:S4549.
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9. Sicherer SH, Eigenmann PA, Sampson HA. Clinical features of food protein-induced enterocolitis syndrome. J Pediatr. 1998;133(2):214219. 10. Powell GK. Milk- and soy-induced enterocolitis of infancy. Clinical features and standardization of challenge. J Pediatr. 1978;93(4):553560. 11. Burks AW, Casteel HB, Fiedorek SC, Williams LW, Pumphrey CL. Prospective oral food challenge study of two soybean protein isolates in patients with possible milk or soy protein enterocolitis. Pediatr Allergy Immunol. 1994;5(1):4045. 12. Nowak-Wegrzyn A, Sampson HA, Wood RA, Sicherer SH. Food protein-induced enterocolitis syndrome caused by solid food proteins. Pediatrics. 2003;111(4)Pt 1:829835. 13. Bock SA, Lee WY, Remigio L, Holst A, May CD. Appraisal of skin tests with food extracts for diagnosis of food hypersensitivity. Clin Allergy. 1978;8(6):559564. 14. Sampson HA. Utility of food specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol. 2001;107(5):891896. 15. Burks W, Bannon G, Lehrer SB. Classic specific immunotherapy and new perspectives in specific immunotherapy for food allergy. Allergy. 2001;56(Suppl 67):121124. 16. Jones SM, Pons L, Roberts JL, et al. Clinical efficacy and immune regulation with oral peanut immunotherapy. J Allergy Clin Immunol. 2009;124:292230. 17. Sicherer SH. Diagnosis and management of childhood food allergy. Curr Probl Pediatr. 2001;31(2):3557. 18. Hubbard S. Nutrition and food allergies: the dietitians role. Ann Allergy Asthma Immunol. 2003;90(6 Suppl 3):115116. 19. Christie L, Hine RJ, Parker JG, Burks W. Food allergies in children affect nutrient intake and growth. J Am Diet Assoc. 2002;102(11):16481651. 20. Food and Nutrition Board, Institute of Medicine. Dietary reference intakes: recommended intakes for individuals; 2009 (2/5):7. http://iom.edu/en/Global/News%20Announcements/~/media/Files/Activity%20Files/Nutrition/DRIs/ DRISummaryListing2.ashx. Accessed November 23, 2009. 21. Joshi P, Mofidi S, Sicherer SH. Interpretation of commercial food ingredient labels by parents of food-allergic children. J Allergy Clin Immunol. 2002;109(6):920922. 22. Food Allergy Issues Alliance. Food Allergen Labeling Guidelines. Washington, DC: National Food Processors Association; 2001. 23. Hst A. Frequency of cows milk allergy in childhood. Ann Allergy Asthma lmmunol. 2002;89(Suppl):3337. 24. Hst A. Cows milk protein allergy and intolerance in infancy. Some clinical, epidemiological and immunological aspects. Pediatr Allergy Immunol. 1994;5(Suppl):136. 25. Atkins D. Food allergy: diagnosis and management. Prim Care. 2008;35(1):119140. 26. Furuta GT, Liacouras CA, Collins MH et al. First International Gastrointestinal Eosinophil Research Symposium (FIGERS) Subcommittees. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133(4):13421363.
27. Spergel JM, Andrews T, Brown-Whitehorn TF, Beausoleil JL, Liacouras CA. Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests. Ann Allergy Asthma Immunol. 2005;95(4):336343. 28. Kagalwalla AF, Sentongo TA, Ritz S et al. Effect of sixfood elimination diet on clinical and histologic outcomes in eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2006;4(9):10971102. 29. Kelly KJ, Lazenby AJ, Rowe PC, Yardley JH, Perman JA, Sampson HA. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology. 1995;109(5):15031512. 30. Markowitz JE, Spergel JM, Ruchelli E, Liacouras CA. Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents. Am J Gastroenterol. 2003;98(4):777782. 31. Wood RA. The natural history of food allergy. Pediatrics. 2003;111(6):16311637. 32. Buchman AL, Ament ME. Comparative hypersensitivity in intravenous lipid emulsions. J Parenter Enteral Nutr. 1991;15(3):345346. 33. Nagata MJ. Hypersensitivity reactions associated with parenteral nutrition: case report and review of the literature. Ann Pharmacother. 1993;27(2):174177. 34. Weidmann B, Lepique C, Heider A, Schmitz A, Niederle N. Hypersensitivity reactions to parenteral lipid solutions. Support Care Cancer. 1997;5(6):504505. 35. Scolapio JS, Ferrone M, Gillham RA. Urticaria associated with parenteral nutrition. J Parenter Enteral Nutr. 2005;29(6):451453. 36. Bullock L, Etchason E, Fitzgerald JF, McGuire WA. Case report of an allergic reaction to parenteral nutrition in a pediatric patient. J Parenter Enteral Nutr. 1990;14(1):98100. 37. Pomeranz S, Gimmon Z, Ben Zvi A, Katz S. Parenteral nutrition-induced anaphylaxis. J Parenter Enteral Nutr. 1987;11(3):314315. 38. Market AD, Lew DB, Schropp KP, Hak EB. Parenteral nutrition-associated anaphylaxis in a 4-year-old child. J Pediatr Gastroenterol Nutr. 1998;26(2):229231. 39. Andersen HL, Nissen I. Presumed anaphylactic shock after infusion of Lipofundin. Ugeskr Laeger. 1993;155(28):22102211. 40. Silverstein SB, Rodgers GM. Parenteral iron therapy options. Am J Hematol. 2004;76(1):7478. 41. Bailie GR, Clark JA, Lane CE, Lane PL. Hypersensitivity reactions and deaths associated with intravenous iron preparations. Nephrol Dial Transplant. 2005;20(7):14431449.
Diabetes Mellitus and Other Endocrine Disorders

Diane Olson, RD, CNSD, CSP, LD and W. Frederick Schwenk II, MD
21
CONTENTS
Diabetes Mellitus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
Type 1 Diabetes Mellitus Type 2 Diabetes Mellitus CF-Related Diabetes Mellitus
Learning Objectives
Consequences of Hyper/Hypoglycemia in the CriticallyIll Child. . . . . . . . . . . . . . . . . . . . . . . . . . . 227 Glucose Control in Healthy Children with Diabetes. . . . .228
Short-Term Implications Long-Term Complications
Glucose Control in Children with Diabetes Mellitus on Parenteral Nutrition. . . . . . . . . . . . . . . . . . . . 228

Choice of Dextrose Solution Use of an Insulin Infusion Addition of Insulin to Parenteral Nutrition Solutions
1. Define the different types of diabetes mellitus that occur in childhood. 2. Relate how to create a parenteral formulation or choose an enteral formula in a child with diabetes mellitus receiving nutrition support. 3. Report the optimal way to administer insulin in a child with diabetes on parenteral or enteral nutrition support. 4. State how to prevent hypo- or hypernatremia in a child with central diabetes insipidus on nutrition support.
Diabetes Mellitus
Glucose Control in Children with Diabetes Mellitus onEnteral Nutrition. . . . . . . . . . . . . . . . . . . . . . . 229

Choice of Formula Administration of Insulin
Nutrition Support in CF-Related Diabetes . . . . . . . . . . . . 229

Choice of Formula Control of Blood Glucose
Diabetes mellitus is one of the most common chronic illnesses in the pediatric-aged population. It results from an absolute or relative lack of insulin, with or without insulin resistance. While there are a number of different causes of diabetes in children, all untreated forms of diabetes mellitus are associated with elevated plasma glucose and lipid concentrations.
Nutrition Support in Other Endocrine Conditions . . . . . . 229

Central Diabetes Insipidus Panhypopituitarism
Definitions
Type 1 Diabetes Mellitus
The most common form of diabetes in children remains type 1 diabetes mellitus. This disorder is usually an autoimmune destruction of the beta cells of the pancreas, resulting in an absolute deficiency of insulin.14 Incidence of type 1 diabetes mellitus in the United States and other western countries has been increasing. In the United States, the prevalence of type 1 diabetes mellitus at 18 years of age is 2 to 3 per 1000.1 The incidence of type 1 diabetes mellitus is about 1.5 times greater in the American non-Hispanic white
Future Research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
226
DIABETES MELLITUS AND OTHER ENDOCRINE DISORDERS
227
population than in African Americans or Hispanic Americans. Children with type 1 diabetes mellitus are at risk for developing ketoacidosis and require insulin to prevent hyperglycemia.2 Because of a risk for developing low blood glucose concentrations, current recommendations from the American Diabetes Association (ADA) are to keep target blood glucose goal ranges in children somewhat higher than what is recommended for adults.2,4
Type 2 Diabetes Mellitus

In the last 20 years, there has been an epidemic of childhood obesity in developed countries. 5 Associated with this increase in childhood obesity has been a marked increase in the incidence of children with type 2 diabetes mellitus. 69 The etiology of type 2 diabetes remains to be established, but appears to be caused not only by a relative insufficiency of insulin secretion by the pancreas but also by insulin resistance. In the United States, depending upon the geographic location, between 8% and 43% of new-onset cases of diabetes are type 2 diabetes mellitus. Children with type 2 diabetes mellitus rarely develop ketoacidosis.8 Optimal treatment of children with type 2 diabetes mellitus remains controversial.9 The incidence of type 2 diabetes mellitus varies by ethnic group, with higher rates (in order) in Native Americans, African Americans, Hispanic Americans, and Pacific Islanders/Asian children.9
CF-Related Diabetes Mellitus

Children with cystic fibrosis (CF) and pancreatic insufficiency are at increased risk of developing CF-related diabetes.1013 The prevalence of this condition in children with CF and pancreatic insufficiency less than 18 years of age has been reported to be between 5% and 15%, while in similar adults the prevalence may be as high as 50%.12,13 These children do not typically develop ketoacidosis and may have increased insulin resistance, particularly at time of intercurrent illness.10,14 Children with CF-related diabetes may not exhibit the classic symptoms of polyuria and polydipsia associated with other types of diabetes mellitus.15
Hyperglycemia appears to be common in pediatric intensive care units (ICUs) regardless of whether the child has known diabetes mellitus.1619 In one retrospective study involving 152 children in a pediatric ICU, blood glucose concentrations greater than 125 mg/dL were observed in over half of the patients within 24 hours of admission and
Consequences of Hyper/Hypoglycemia in the CriticallyIll Child
in almost 90% of the patients sometime during the admission.16 In a second retrospective study, almost 70% of 192 critically ill children had blood glucose concentrations greater than 120 mg/dL within 24 hours of admission to a pediatric ICU.17 Hyperglycemia has been linked to poor outcome. In a study of 184 children less than 1 year of age who had undergone cardiac surgery, hyperglycemia in the postoperative period was associated with increased mortality and morbidity.18 However, in a fourth retrospective study of 1094 admissions to a pediatric intensive care unit, the risk of having a blood glucose value over 200 mg/dL was less than the risk of having a blood glucose value less than 65 mg/dL.18 Furthermore, the risk of dying was 6 times greater if the child had a blood glucose less than 110 mg/dL than if all blood glucose values were greater than 110 mg/dL.19 There are many reasons why hyperglycemia might affect mortality and morbidity in critically ill patients. In vitro, high glucose concentrations have been shown to cause abnormalities in several aspects of immune function, including intracellular killing, complement function, granulocyte adhesion, chemotaxis, phagocytosis, and respiratory burst function.20 Glucose attaches itself to the third component of complement, affecting this components ability to attach itself to microbes and impairing opsonization of the microbe.21 On the other hand, it is not difficult to understand why low blood sugars might affect mortality and morbidity in critically ill children. More than 60% of the basal metabolic rate in an infant is estimated to be related to brain metabolism, compared with less than 30% in an adult.22 Numerous studies in adult patients with diabetes have shown increased morbidity and mortality associated with hyperglycemia.23,24 These studies formed the backdrop for a large retrospective study in surgical patients showing that intensive insulin therapy reduced in-hospital mortality rates by 34% and had a profound effect on a variety of morbidities.21 A similar retrospective study in non-surgical patients also showed reductions in mortality and morbidity, although the results were not as striking.25 These reports led many intensive care units to modify their management of hyperglycemia in diabetic and non-diabetic patients. Since those initial studies, there have been a plethora of additional reports, with varying conclusions.26,27 Additional studies have focused on the increased morbidity and morality associated with hypoglycemia in adult hospitalized patients,28,29 consistent with the findings in children. The optimal control of blood glucose in the adult hospitalized patient with or without diabetes remains controversial. There are very limited data in children. While one recent
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randomized, prospective study of intensive insulin therapy in critically ill children did show improved morbidity and mortality in a subgroup of patients,30,31 near normal plasma glucose concentrations, regardless of whether the child has pre-existing diabetes, are not set as goals by many pediatric practitioners.
Glucose Control in Children with Diabetes Mellitus on Parenteral Nutrition

Choice of Dextrose Solution
There are no data to suggest that children with diabetes require a special formulation for parenteral nutrition (PN). The composition of the PN solution should be determined independent of whether the patient has diabetes. This includes the choice of the final concentration of dextrose. However, it should be noted that many children with diabetes have hyperlipidemia,4 so that the triglyceride levels in children with diabetes on PN need to be monitored carefully.
Glucose Control in Healthy Children with Diabetes

Short-Term Implications
The current recommendations of the ADA are that target blood glucose concentrations be individualized for each child with diabetes.4 In general, children less than the age of 7 years often have a form of hypoglycemic unawareness due to limited cognitive ability and immature counterregulation, making them more susceptible to severe hypoglycemia.4 Children less than 5 years of age appear to be at risk for permanent cognitive impairment after episodes of severe hypoglycemia. 3234 In addition, severe hypoglycemia occurs in younger children most frequently during sleep. 35 Consequently, blood glucose targets for younger children are usually higher than for adolescents or adults.2,4,36 While ketoacidosis continues to be a concern in undiagnosed children with type 1 diabetes mellitus, it is rarely a problem in children known to have type 1 diabetes mellitus unless inadequate or no insulin is given.4 Overall, the incidence of short-term adverse events in children, such as hospitalization and severe hypoglycemia, is high. 37
Use of an Insulin Infusion

When an infusion containing a high concentration of dextrose is given intravenously in a child (or adult) with diabetes, blood glucose concentrations are most safely controlled using a separate intravenous (IV) insulin infusion.43 If insulin is given intravenously, the infusion can easily be changed if the rate of IV glucose administration is changed. In adults, insulin is often directly added to the PN, beginning with a dose of 0.1 units of regular insulin per gram of dextrose in the infusate (eg, 10 units/L of 10% dextrose; 20 units/L of 20% dextrose).43 Additional subcutaneous regular insulin or an IV insulin infusion may be needed to supplement the insulin in the PN. This ratio of insulin to dextrose is unlikely to cause hypoglycemia and minimizes the need to discard a bag of PN because it contains too much insulin.43 While a similar protocol may be used in children, a strong case can be made to control blood glucose concentrations using a separate infusion of insulin. Using a syringe pump, the insulin infusion can be directly piggy-backed into the IV line. A reasonable rate to begin such an infusion would be 0.05 units of regular insulin per kilogram body weight per hour. The rate of insulin administration can be changed to optimize blood glucose control. As mentioned previously, there is no consensus as to how tightly to control the plasma glucose concentration in a critically ill child, with or without a previous diagnosis of diabetes. However, most practitioners would suggest that blood glucose concentrations between 100 mg/dL and 200 mg/dL might be a reasonable goal, preventing both hypoglycemia and ketoacidosis. Whatever method is chosen to administer the IV insulin, blood glucose concentrations need to be checked frequently. This is often done at least hourly in children on an insulin infusion until there appears to be stability in the blood glucose concentrations. Blood glucose concentrations
Long-Term Complications
In contrast to some older children with type 2 diabetes, children with type 1 diabetes rarely have complications at the time of diagnosis.38 A large prospective, randomized study called the Diabetes Control and Complications Trial (DCCT) established that the major risk factor for microvascular complications is glycemic control.3941 What appears to be important is the exposure to elevated glucose concentrations over time.38 However, despite marked improvement in treatment options, 12 years after diagnosis more than 50% of patients with type 1 diabetes had developed complications or comorbities.39,42 Persistently high blood glucoses over time also appear to increase the risk of macrovascular complications, but these rarely occur in childhood.
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are easiest to control if the PN is given as a continuous infusion, rather than being cycled. It should also be mentioned that even if the IV infusion of dextrose is stopped, patients with type 1 diabetes mellitus will continue to need some insulin to inhibit hepatic gluconeogenesis and prevent the child from developing ketoacidosis.
in adults that patients who develop CF-related diabetes have lower body mass indices and are more likely to require enteral feedings from 2 years prior to diagnosis compared to adults who do not develop CF-related diabetes.48
Control of Blood Glucose

Blood glucose concentrations in children with CF and CF-related diabetes receiving EN support can usually be managed with subcutaneous insulin.1013 However, with intercurrent illness, children with CF have increased insulin resistance, requiring larger doses than the typical 1 unit of insulin per kilogram body weight per day requirements of children with type 1 diabetes mellitus.10,14
Addition of Insulin to Parenteral Nutrition Solutions

If a separate IV insulin infusion is used to control blood glucose concentrations and both the rate of insulin infusion and blood glucose concentrations have remained stable over 24 hours, the separate insulin infusion can be discontinued and insulin added directly to the PN. In such cases, one can easily calculate the amount of insulin that is required to control blood glucose concentrations during the administration of the PN by totaling the amount of insulin infused with the separate infusion. Previously, albumin was also added to the PN to prevent the insulin from binding to the bag and tubing being used to administer the PN. However, adequate blood glucose control can be obtained without such an addition.44
Nutrition Support in Other Endocrine Conditions

Central Diabetes Insipidus
Central or neurogenic diabetes insipidus is a relatively rare condition in children resulting from an inability to secrete active vasopressin from the posterior pituitary gland.49 While genetic defects in vasopressin synthesis have been described, the usual etiology of this condition is a hypothalamic or posterior pituitary lesion.49 There are multiple causes of this condition including tumors, inflammatory lesions, vascular diseases, and cranial malformations.49 Outpatient treatment for this condition in children with intact thirst sensation involves giving an analogue of vasopressin either orally or intranasally. Such children are allowed to drink to thirst. Fluid intake in children without an intact thirst mechanism must be monitored carefully to prevent hypo- or hypernatremia. There do not appear to be any published guidelines as to how to manage a child with central diabetes insipidus who might require PN or EN. Because of the large volumes of fluid associated with such therapy, the child is at risk for both hypo- and hypernatremia. One option for managing such a patient is to use a low-dose IV infusion of aqueous vasopressin, as has been described for use in children who are receiving additional fluid as part of a chemotherapy regimen. 50 To maintain adequate hydration and serum sodium concentrations, a dilute infusion of aqueous vasopressin is given at a starting rate of 0.08 to 1 mU/kg/h. During the infusion, fluid intake, urine output, body weight, urine specific gravity, and serum electrolyte concentrations are monitored carefully.
Glucose Control in Children with Diabetes Mellitus onEnteral Nutrition

Choice of Formula
The use of enteral formulas designed for patients with diabetes has not been studied in children with diabetes. Therefore, the current recommendations are to use a standard age-appropriate formula.45
Administration of Insulin
Blood glucose concentrations in children with diabetes on enteral nutrition (EN) support can usually be adequately controlled by using subcutaneous injections of insulin. Guidelines for adults have been published for the administration of insulin at the initiation of tube feedings, as the rate of tube feedings increases, and for continuous intermittent and nocturnal feeding schedules.44 By dosing the insulin on a per kilogram body weight basis, these recommendations can also be utilized in children. Of course, careful monitoring of blood glucose concentrations is required.
Nutrition Support in CF-Related Diabetes

Choice of Formula
PN support is rarely required in children with CF.46 If EN support is being considered, no evidence suggests that one enteral formulation is superior to another.47 There are data
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Panhypopituitarism
Another relatively uncommon endocrine condition that might affect nutrition support is panhypopituitarism. Again, no guidelines exist for how to manage nutrition support in such patients. Children with panhypopituitarism are unable to secrete a number of anterior pituitary hormones, including growth hormone and corticotropin. This condition can be the result of intracranial surgery, but can also be idiopathic. Children with this condition often present with hypoglycemia and are at continuing risk for low blood sugars. The hypoglycemia is due to an inability to counterregulate. 51 To prevent hypoglycemia in a critically ill child with this condition, additional glucocorticoids are administered. In such patients, a strong case can also be made for administering nutrition support as a constant infusion, rather than giving enteral feeds as boluses or cycled PN.
4. Serum sodium concentrations can be safely maintained in a child with diabetes insipidus on EN or PN support by: A. Limiting oral fluids B. Administering a vasopressin analogue orally C. Doubling the patients usual dose of a vasopressin analogue D. Using an intravenous drip of aqueous vasopressin See p. 487 for answers.
References
Future Research
Research in children is difficult, not only because they cannot give informed consent but also because mortality is quite low, requiring large numbers of patients to do outcome studies. Consequently, many of the above recommendations are extrapolated from adult recommendations. Future studies will hopefully answer what is the optimal blood glucose concentration for a critically ill child. It is also hoped that new strategies will be developed to help children with diabetes mellitus achieve improved blood glucose control when they are receiving PN or EN.
1. When creating a parenteral formulation to use in a child with diabetes mellitus, the dextrose concentration should be: A. Kept to a minimum B. No greater than 15% C. At least 20% D. Chosen without regard to whether the child has diabetes mellitus 2. To prevent hyperglycemia, hospitalized children with CF-related diabetes mellitus and acute infections may require: A. An increased amount of insulin B. A decreased amount of insulin C. Their usual doses of insulin D. Frequent doses of short-acting insulin 3. In children with diabetes mellitus on EN, insulin should usually be: A. Discontinued B. Given parenterally C. Given subcutaneously D. Given enterally
1. Cooke DW, Plotnick L. Type 1 diabetes mellitus in pediatrics. Pediatr Rev. 2008;29:374 385. 2. Silverstein J, Klingensmith G, Copeland K, et al. Care of children and adolescents with Type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care. 2005;28(1):186212. 3. American Diabetes Association. Diagnosis and classification of diabetes. Diabetes Care. 2006;20(suppl 1):S4S25. 4. American Diabetes Association. Clinical Practice Recommendations 2009. Diabetes Care. 2009;32(suppl 1):S13S61. 5. American Academy of Pediatrics, Committee on Nutrition. Pediatric obesity. In: Kleinman RE, ed. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:733782. 6. American Academy of Pediatrics, Committee on Nutrition. Pediatric dietary management of diabetes mellitus in children. In: Kleinman RE, ed. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:673697. 7. Sinha R, Fisch G, Teague B, et al. Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med. 2002;346(22):802810. 8. American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes Care. 2000; 23(3):381389. 9. Kaufman F. Type 2 diabetes in youth: rate, antecedents, treatment, problems and prevention. Pediatr Diabetes. 2007:8(suppl 9):46. 10. Moran A, Hardin D, Rodman, et al. Diagnosis, screening and management of cystic fibrosis related diabetes mellitus: a consensus conference report. Diabetes Res Clin Pract. 1999;45(1):6173. 11. Hardin DS, Moran A. Diabetes mellitus in cystic fibrosis. Endocrinol & Metab Clin North Am. 1999;28(4):787800. 12. Solomon MP, Wilson DC, Corey M, et al. Glucose intolerance in children with cystic fibrosis. J Pediatr. 2003;142(2):128132. 13. Moran A, Doherty L, Wang X, Thomas W. Abnormal glucose metabolism in cystic fibrosis. J Pediatr. 1998;133(1):1017. 14. Brennan AL, Geddes DM, Gyi KM, Baker EH. Clinical importance of cystic fibrosis-related diabetes. J Cyst Fibros. 2004;3(4):209222. 15. American Academy of Pediatrics, Committee on Nutrition. Nutrition in cystic fibrosis. In: Kleinman RE, ed. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:10011020.
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16. Srinivasan V, Spinella PC, Drott HR, Roth CL, Helfaer MA, Nadkarni V. Association of timing, duration, and intensity of hyperglycemia with intensive care unit mortality in critically ill children. Pediatr Crit Care Med. 2004;5(4):329336. 17. Faustino EV, Apkon M. Persistent hyperglycemia in critically ill children. J Pediatr. 2005;146(1):57. 18. Yates AR, Dyke PC 2nd, Taeed R, et al. Hyperglycemia is a marker for poor outcome in the postoperative pediatric cardiac patient. Pediatr Crit Care Med. 2006;7(4):351355. 19. Wintergerst KA, Buckingham B, Gandrud L, Wong BJ, Kache S, Wilson DM. Association of hypoglycemia, hyperglycemia, and glucose variability with morbidity and death in the pediatric intensive care unit. Pediatrics. 2006;118(1):173179. 20. Van den Berghe G, Wouters P, Weeker F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345(19):13591367. 21. McMahon MM, Bistrian BR. Host defenses and susceptibility to infection in patients with diabetes mellitus. Infect Dis Clin North Am. 1995;9(1):19. 22. Haliday MA. Metabolic rate and organ size during growth from infancy to maturity and during late gestation and early infancy. Pediatrics. 1971;47(1):167179. 23. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyper glycemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet. 2000:355(9206):773778. 24. Capes SE, Hunt D, Malmberg K, Pathak P. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke . 2001;32(10):24262432. 25. Van den Berghe G, Wilmer A, Hermans C, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;345(5):449461. 26. Inzucchi Se, Slegel MD. Glucose control in the ICUhow tight is too tight? N Engl J Med. 2009;360(13):13461349. 27. The NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):12831297. 28. Turchin A, Matheny ME, Shubina M, et al. Hypoglycemia and clinical outcomes in patients with diabetes hospitalized in the general ward. Diabetes Care. 2009;32(7):11531157. 29. Arabi Y, Tamim HM, Rishu AH. Hypoglycemia with intensive insulin therapy in critically ill patients: Predisposing factors and association with mortality. Crit Care Med. 2009;37(9):25362544. 30. Vlasselaers D, Milants I, Desmet L, et al. Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomized controlled study. Lancet. 2009;373(9663):547556. 31. Agus MSD, Hirshberg EL. Pediatrics: Intensive insulin therapy in critically ill children. Nature Rev Endo. 2009;5(7):360362. 32. Northam EA, Anderson PJ, Werther GA, Warne GL, Adler RG, Andrewes D. Neuropsychological complications of IDDM in children 2 years after disease onset. Diabetes Care. 1998;21(3):379384. 33. Rovet J, Alvarez M. Attentional functioning in children and adolescents with IDDM. Diabetes Care. 1997;20(5):803810.
34. Bjorgaas M, Gimse R, Vik T, Sand T. Cognitive function in type 1 diabetic children with and without episodes of sever hypoglycaemia. Acta Paediatr. 1997;86(2):148153. 35. Ryan C, Gurtunca N, Becker N. Hypoglycemia: a complication of diabetes therapy in children. Pediatr. Clin North Am. 2005;52(6):17051733. 36. Ryan CM, Becker DJ. Hypoglycemia in children with type 1 diabetes mellitus. Pediatr Endocrinol. 1999;28(4):883900. 37. Levine B, Anderson BJ, Butler DA, et al. Predictors of glycemic control and short-term adverse outcomes in youth with type 1 diabetes. J Pediatr. 2002;139(2):197203. 38. Gallego PH, Wiltshire E, Donaghue KC. Identifying children at particular risk of long-term diabetes complications. Pediatric Diabetes. 2007;8(suppl 6):4048. 39. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977986. 40. Diabetes Control and Complications Trial Research Group. Effect of intensive therapy on the microvascular complication of type 1 diabetes mellitus. JAMA. 2002;287(19):25632569. 41. Writing Team for the DCCT and EDIC Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA . 2003;290(16):21592167. 42. Danne T, Kordonouri O. Current challenges in children with type 1 diabetes. Pediatr Diabetes. 2007;8(Suppl 6):35. 43. McMahon MM. Diabetes mellitus. In: Merritt T, ed. A.S.P.E.N. Nutrition Support Practice Manual. 2nd ed. Silver Spring, MD: American Society for Parenteral and Enteral Nutrition. 2005:317323. 44. Weber SS, Wood WA, Jackson EA. Availability of insulin from parenteral nutrient solutions. Am J Hosp Pharm. 1977;34:353357. 45. American Diabetes Association. Nutrition principles and recommendations in diabetes. Diabetes Care. 2004;27(Suppl 1):S3646. 46. Jelalian E, Stark LJ, Reynolds L, Seifer R. Nutrition intervention for weight gain in cystic fibrosis: a meta analysis. J Pediatr. 1998;132(3 Pt 1):486492. 47. Erskine JM, Lingard C, Sontag M. Update on enteral nutrition support in cystic fibrosis. Nutr Clin Pract. 2007;22(7):223232. 48. White H, Pollard K, Etherington C, et al. Nutritional decline in cystic fibrosis related diabetes: the effect of intensive nutritional intervention. J Cyst Fibros. 2009;8(3):179185. 49. Ghirardello S, Garre ML, Rossi A, Maghnie M. The diagnosis of children with central diabetes insipidus. J Pediatr Endocrinol Metab. 2007;20(3):359375. 50. Bryant WP, OMarcaigh AS, Ledger GA, Zimmerman D. Aqueous vasopressin infusion during chemotherapy in patients with diabetes insipidus. Cancer. 1994;74(9):25892592. 51. Bolli GB, Fanelli CG. Physiology of glucose counterregulation to hypoglycemia. Endocrinol Metab Clin North Am. 1999;28(3):467493.
Inborn Errors of Metabolism

Bridget Reineking, MS, RD, CD and Sandy van Calcar, PhD, RD, CD
22
CONTENTS
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 Phenylketonuria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
Natural History Maternal Phenylketonuria Acute Management Chronic Management
Learning Objectives
Methylmalonic Acidemia. . . . . . . . . . . . . . . . . . . . . . . . . . 237

Natural History Acute Management Chronic Management
Ornithine Transcarbamylase Deficiency. . . . . . . . . . . . . . 239

1. Understand the basic principles of treating inborn errors of metabolism. 2. Understand the biochemistry and medical nutrition therapy for phenylketonuria. 3. Understand the biochemistry and medical nutrition therapy for methylmalonic acidemia. 4. Understand the biochemistry and medical nutrition therapy for ornithine transcarbamylase deficiency. 5. Understand the biochemistry and medical nutrition therapy for very long-chain acyl Co-A dehydrogenase deficiency. 6. Understand the biochemistry and medical nutrition therapy for classic galactosemia.
Very Long Chain Acyl-CoA Dehydrogenase Deficiency. . . 240

Background
Galactosemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
Inborn errors of metabolism (IEM) are genetic disorders caused by deficient production or function of specific enzymes, transport proteins, or enzyme cofactors in protein, lipid, carbohydrate, or micronutrient metabolism. The deficiency in enzyme activity results in accumulation of various abnormal metabolites that can cause detrimental symptoms. Presentation of disease varies greatly depending on the disorder, but severe forms of many disorders can include overwhelming illness in the newborn period with hypotonia, seizures, and coma associated with poor feeding (Table 22-1). Many of these disorders can be fatal or cause profound developmental delay if not treated promptly and aggressively.
232
INBORN ERRORS OF METABOLISM
233
Table 22-1 Various Signs and Symptoms of Inborn Errors of Metabolism Overwhelming illness in the newborn period Recurrent vomiting Poor growth Failure to thrive Developmental delay Mental retardation Loss of previously acquired skills Hypotonia Hypertonia Seizures Infantile spasms Unusual odor Episodes of rhabdomyolysis with intense exercise Cardiomyopathy
devoid of the amino acid(s) that cannot be fully metabolized, but will provide all other amino acids, carbohydrates, fat sources, vitamins, and minerals. Medical foods often provide a significant portion of a childs nutrition needs. 35
Figure 22-1 Basic Principles of Nutrition Management of Inborn Errors ofMetabolism
Newborn screening is an important public health program that can detect many IEM in the neonate, which allows for early diagnosis and initiation of treatment.1 Newborn screening was initiated in the 1960s with detection of phenylketonuria (PKU). PKU is often referred to as the model for newborn screening because the methodology is reliable and cost-effective and there are clear benefits from early intervention with medical nutrition therapy. With the recent introduction of tandem mass spectrometry, more than 30 IEM can now be detected from blood spots collected at 24 to 48 hours of age.1 The number of screened disorders varies by state, although a national uniform panel has been recommended.2 Infants with abnormal screening results are referred to specialized clinics with medical geneticists, metabolic dietitians, and genetic counselors to assure prompt clinical evaluation and confirmatory testing. When the diagnosis is confirmed, appropriate medical and nutrition management is initiated. The overall goal of treatment for IEM is to improve and maintain metabolic homeostasis. Medical nutrition therapy plays a large role to achieve this goal. The basic principles of medical nutrition therapy for IEM include prevention of catabolism with adequate caloric intake, restriction of the offending substrate, supplementation of deficient products, and/or supplementation with the enzymes cofactor (Figure 22-1). In order to meet nutrient needs but prevent excessive intake of substrates, specialized formulas, which are termed medical foods, have been developed for treatment of numerous IEM. Medical foods do not contain the substrate(s) that cannot be metabolized. For instance, a medical food designed for an amino acidopathy will be
In disorders where the blocked substrate is an essential amino acid, a limited but sufficient quantity of substrate must be provided to allow for growth and protein maintenance. This is accomplished by providing a source of intact protein from regular infant formula or, for some disorders, a limited quantity of breast milk is allowed. However, excessive intake of the substrate(s) results in elevations in the offending metabolites and can lead to detrimental symptoms. Careful laboratory monitoring and proper nutrition education is essential to treat IEM. 35 This chapter provides a basic overview of 5 disorders to illustrate different types of IEM and their nutrition management. Various references are available that provide detail about the biochemistry and treatment of the wide range of IEM. 57 For any IEM, different phenotypes are possible and treatment can vary greatly depending on the severity of the disorder. Presentation of a disorder can occur in infancy, childhood, or for some disorders, in adults. The patients age, growth, and other clinical factors influence the nutrition prescription. For many of these disorders, lifelong monitoring and treatment changes are required. The involvement of a metabolic dietitian trained to manage IEM is imperative for successful treatment of these conditions.
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Phenylketonuria
Natural History
PKU is an inborn error of phenylalanine (phe) metabolism caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH), which catalyses the hydroxylation of phe to tyrosine (Figure 22-2). PKU is an autosomal recessive disorder with a carrier frequency of 1 in 50 and incidence of approximately 1 in 10,000 to 15,000 births in those of European ancestry. More than 500 mutations have been identified in the PAH gene, but genotype/phenotype correlations have not proven to predict outcome. 8
Figure 22-2 Phenylketonuria (PKU) results from a deficiency of phenylalanine hydroxylase (PAH) with elevated phenylalanine concentrations and tyrosine deficiency. PAH requires the cofactor tetrahydrobiopterin (BH4).
which 211 subjects with PKU were randomized at age 6 to continue or discontinue the PKU diet.9 Results from this study demonstrated that individuals with PKU who discontinued the diet developed significant reductions in IQ and academic performance by age 12 years.9 A follow-up study of 70 adults who participated in the PKU Collaborative Study found significantly fewer adverse medical, cognitive, and psychological outcomes in those who were randomized to remain on diet compared with those who stopped diet treatment at age 6.12 Conclusions from these and other studies led to the recommendation of life-long treatment for PKU.1315
Maternal Phenylketonuria
Phenylalanine is a known teratogen and in utero exposure to elevated phe concentrations interferes with embryonic development.16 Infants born to women with uncontrolled phe levels during pregnancy are at risk for low birth weight, microcephaly, congenital abnormalities, and mental retardation. The National Maternal PKU Collaborative Study (19842000) found that these detrimental effects to the fetus could be prevented if maternal plasma phe concentrations remained below 6 mg/dL prior to conception and throughout pregnancy.17,18 Education about the risks of elevated phe concentrations during pregnancy should begin early in adolescence for all females with PKU.
Adapted from Acosta PB, Yannicelli S. The Ross Metabolic Formula System Nutrition Support Protocols. 4th ed. Columbus, OH: Ross Products Division/Abbott Laboratories; 2001. Copyright 2001 with permission from Abbott Nutrition.
Acute Management
Initial Presentation When an infant with PKU is identified by newborn screening, treatment should be initiated as soon as possible. Depending on the degree of elevation in plasma phe, dietary phe is eliminated or greatly reduced in the diet until blood phe levels decrease to the treatment range of 2 to 6 mg/dL. This can be accomplished by feeding exclusively a phe-free, but otherwise nutritionally complete, medical food. Once plasma phe concentrations are reduced to < 6 mg/dL, a limited quantity of an intact protein is added to the medical food to meet minimum phe needs for growth and protein maintenance (Table 22-2). 35 The intact protein source can be provided by a standard infant formula or breast milk. Phe concentrations may increase during times of illness or severe injury. Prevention of catabolism can minimize these elevations. During illness, individuals with PKU are encouraged to reduce phe intake but continue to consume the phe-free medical food. If gastrointestinal symptoms develop, the medical food can be discontinued and carbohydrate-based beverages can be provided to increase caloric intake to help slow catabolism. 3 Efforts should be made to
PKU is often classified based on the degree of phe elevation in blood prior to initiation of treatment. Those with classic PKU show blood phe elevations > 20 mg/dL (normal phe is < 2 mg/dL). Untreated classic PKU results in profound mental retardation, seizures, and autistic-like behavior. Treatment with a phe-restricted diet ameliorates this outcome and those with classic PKU can have similar intelligence quotient (IQ ) and developmental potential as their unaffected siblings.9 On the other end of the spectrum, phe elevations in those with mild hyperphenylalaninemia (HPA) remain < 10 mg/dL and may not require any diet modification. 35 Treatment recommendations for PKU have evolved since diet treatment was first described in the 1950s.10 Initially, metabolic specialists discontinued the phe-restricted diet at 6 years of age because it was felt that brain development was complete and continuation of the diet could cause nutrition deficiencies.11 This practice was formally evaluated in the National PKU Collaborative Study (19681984) in
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select medications that are phe-free. The source of phe in pediatric medications is typically in the flavoring agents which may contain aspartame (Nutrasweet) as the sweetener. Aspartame is a dipeptide derived from aspartic acid and phenylalanine.19
TABLE 22-2 Recommended Daily Nutrient Intakes for Phenylketonuria Age Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr 19 yr Men 11 to < 15 yr 15 to < 19 yr 19 yr 225 900 3.38 5.50 55 65 70 2,700 (2000 3700) 2,800 (2100 3900) 2,900 (2000 3300) 250 750 230 700 220 700 3.45 5.00 3.45 5.00 3.75 5.00 50 55 60 2,200 (1500 3000) 2,100 (1200 3000) 2,100 (1400 2500) 25 70 20 45 15 35 10 35 (mg/d) 200 400 210 450 220 500 120 (145 95) 120 300 350 3.50 3.00 (145 95) 110 250 300 3.00 2.50 (135 80) 105 250 300 3.00 2.50 (135 80) (g/d) (g/d) (kcal/d) 1,300 1.72 3.00 30 (900 1800) 1,700 2.25 3.50 35 (1300 2300) 2,400 2.55 4.00 40 (1650 3300) 300 350 3.50 3.00 PHE (mg/kg) Nutrient TYR Protein (mg/kg) (g/kg) Energy (kcal/kg)
Figure 22-3. Calculating a Low-Phe Formula An infant weighing 3.6 kg is diagnosed with PKU with an initial blood phe concentration of 15 mg/dL. Determine an appropriate formula for this infant. Answer: Provide a phe-free formula until phe concentrations are < 6 mg/dL. Then add an intact protein source to meet nutrition needs. Determine Needs 1) Determine Phe Requirement Using Table 22-2. 3.6 kg 45 mg of phe*/kg = 162 mg of phe per day *Phe requirements range from 25-70 mg/kg. Given the moderate elevation in blood phe of 15 mg/dL, phe requirements are estimated at 45 mg/kg. 2) Determine Tyrosine (Tyr) Requirement 3.6 kg 325 mg of tyr/kg = 1170 mg 3) Determine Protein (Pro) Requirement 3.6 kg 3.2 g of pro/kg = 1112 g of pro 4) Determine Calorie (kcal) Requirement 3.6 kg ~ 120 kcal/kg = 430450 kcal Calculate Formula 1) Determine the Amount of Infant Formula Needed to Meet Phe Needs Infant formula A contains 330 mg of phe in 100 g 162 mg of phe needed per day 100 g of infant formula 330 mg of phe = 49 g of Infant Formula A Needed
2) Determine Amount of Kcals and Protein in Infant Formula Infant formula A contains 10.8 g of protein and 518 kcal in 100 g 49 g infant formula A 10.8 g protein 100 g of infant formula 49 g of infant formula A 518 kcal 100 g of infant formula = 5.3 g of protein = 254 kcals
295 1100 4.42 6.50 290 1200 4.35 6.50
3) Determine Amount of Phe-Free Medical Food B Needed to Meet Protein Needs Phe-free medical food B contains 15 g of protein in 100 g 11.5 g total protein needs 5.3 g of protein from Infant formula A = 6.2 or ~6 g of protein needed 6 g of protein needed 100 g of medical food B 15 g of protein 4) Determine Kcal from Phe-Free Medical Food B 40 g of medical food B 480 kcal 100 g of phe free medical food Final Recipe
Product Amount Phe (mg) Pro (g) Calories
= 40 g of phe-free medical food
Chronic Management
The goal of chronic management for PKU is restriction of dietary phe to maintain blood phe concentrations within the recommended treatment range of 2 to 6 mg/dL from infancy to age 12 years and 2 to 10 mg/dL in adolescents.14 However, with the concern of maternal PKU, adolescent girls should be encouraged to maintain levels below 6 mg/dL. Additional treatment goals include maintenance of adequate growth velocity and weight gain, prevention of protein deficiency, and achieving adequate macro- and micronutrient status. 35
= 192 kcal
Infant Formula A Phe-free medical food B Total
49 g 40 g
162 mg 0 mg 162 mg
5g 6g 11 g
254 kcal 192 kcal 446 kcal
Volume required at 20 kcal/oz = 22 fl oz (625 mL)
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Dietary phe must be quantified to achieve blood phe control. Phe needs vary between individuals and change with age, weight, and growth velocity (Table 22-2). In infancy, the phe requirement is supplied by a standard infant formula or breast milk (Figure 22-3). Adjustments in the phe prescription are based on frequent monitoring of blood phe concentrations. If blood phe concentrations are elevated above the treatment range, the amount of intact protein must be decreased incrementally until phe concentrations are within the treatment range. 35 Breastfeeding is possible in the treatment of PKU; metabolic control in infants allowed to breastfeed is similar to those consuming a regular infant formula as their phe source.20,21 To maintain phe concentrations within the treatment range, adjustments are made in the prescribed volume of phe-free medical food to effectively increase or decrease the infants intake of breast milk. Medical food may be provided prior to each breastfeeding or feedings of medical food and breastfeeding may be alternated.20,21 The average phe content of breast milk is known and is higher in colostrum than mature milk by approximately 60%.22,23 Total protein needs for infants and children with PKU may be greater than protein needs for the general population (Table 22-2) because of rapid amino acid absorption and utilization when free amino acids rather than an intact protein are given as the source of protein. 24 Caloric requirements should be determined using dietary reference intake (DRI) estimates and adjusted based on frequent growth measurements.25 An individuals phe requirement is the same regardless of the source of intact protein consumed (formula, breast milk, or solid food). When an infant transitions to solids, the infant formula or breast milk is decreased and replaced by an equivalent amount of phe from foods. Caregivers are instructed to count milligrams of phe or use an exchange system (1 exchange = 15 mg phe). References are available that list the phe content of various foods and beverages.3,26,27 Accuracy in measuring medical food, infant formula, and foods is imperative for successful management of PKU. The use of a gram scale is recommended because small measurement errors can lead to significant changes in blood phe concentrations. Phe is found in any food containing protein. Meat, legumes, nuts, and dairy products are too high in phe and are not allowed in the phe-restricted diet. Grains, fruits, and vegetables must be precisely measured and the phe content carefully calculated to ensure proper blood phe control (Table 22-3). For the PKU diet, free foods and beverages are those that contain no protein (and no phe) such as sugars and fats. 3,27
Table 22-3 Example of Daily Meal Plan for Classic Phenylketonuria Age: 3 years, 9 months Weight: 15.2 kg Height: 101 cm Sex: Female Medical Food Prescription: 125 g of Phenex-2 unflavored + 18 fl oz of water = 20 fl oz total volume Daily Phenylalanine Prescription from Foods: 200 mg Estimated Needs: Protein: > 30 g/d Kcal: 900 1800 kcal/d
Meal Food or Liquid Offered Amount Eaten Phe Protein Calories
Breakfast
Lunch
Snack
Dinner
Snack
Medical Food Froot Loops Crackles Low-Protein Cereal Blueberries, fresh Medical Food French Fries, Ore-Ida Golden Fries Broccoli, cooked Thousand Island Dressing Peaches, canned Cantaloupe, fresh Medical Food Sweet Potato, with skin, baked Green beans, canned Pears, canned Zoo Animal Crackers, Farleys Sorbet, strawberry
6 oz 6g 30 g 32 g 7 oz 56 g 28 g 16 g 57 g 27 g 7 oz 22 g 28 g 90 g 22 g 122 g
0 mg 17 mg 7 mg 8 mg 0 mg 50 mg 14 mg 6 mg 8 mg 8 mg 0 mg 25 mg 14 mg 8 mg 20 mg 15 mg 200 mg 0%
11 g 0.4 g 0.2 g 0.2 g 13 g 1.4 g 0.6 g 0.1 g 0.3 g 0.2 g 13 g 0.4 g 0.4 g 0.2 g 1.6 g 0.4 g 43.4 g 85.3%
154 kcal 25 kcal 120 kcal 18 kcal 179 kcal 80 kcal 6.0 kcal 59 kcal 42 kcal 9 kcal 179 kcal 23 kcal 6 kcal 66 kcal 94 kcal 119 kcal 1179 kcal 43.4%
Total % from medical food
Low-protein food products, made primarily from wheat starch (instead of wheat flour), are available to increase variety and meet the caloric needs of individuals with PKU. Products include low-protein baking mixes, bread, rice, pasta, peanut butter, cereals, and snack chips. Some food companies also market low-protein specialty items such as chicken nuggets,
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hamburgers, egg replacers, and cheese. Several lowprotein cookbooks for PKU are also available.28,29 In PKU, decreased PAH activity reduces the production of tyrosine; thus, tyrosine becomes an essential amino acid for this population (Figure 22-2). Medical foods for PKU are supplemented with tyrosine and additional tyrosine supplementation is indicated only if the combination of intact protein and medical food does not meet tyrosine requirements. Plasma tyrosine concentrations should be routinely monitored in individuals with PKU. 3,4 Some micronutrients may be insufficient in the low-phe diet, particularly in those consuming a suboptimal amount of medical food. Inadequate intake of iron, folate, vitamin B12 , calcium, and vitamin D has been reported. 3032 Dietary intake should be analyzed for micronutrient content and additional supplementation prescribed as needed. 33 In addition, intake of essential fatty acids (EFAs) may be low even with sufficient intake of medical food and erythrocyte EFA profiles should be routinely assessed. 3436 If low concentrations are found, vegetable oils such as canola or walnut oil or a docosahexaenoic acid (DHA) supplement can be added to the diet. Some medical formulas designed for PKU are now supplemented with arachidonic acid (ARA) and DHA. Large neutral amino acids (LNAAs): Phenylalanine and other LNAAs (leucine, valine, isoleucine, methionine, tyrosine, tryptophan, and threonine) share common transporters at the blood-brain barrier and intestinal mucosa. In PKU, competitive inhibition from high concentrations of phe reduce the transport of other LNAAs into the cerebral cells, which may reduce synthesis of various neurotransmitters. 37 Supplementation with high doses of LNAAs can reduce both blood and brain concentrations of phe; improved executive function skills have been measured in those with poor dietary control who were treated with LNAA supplements. 38,39 Several LNAA formulations are now commercially available. Cofactor supplementation: A newer therapy for the treatment of PKU is supplementation with a synthetic form of tetrahydrobiopterin, the cofactor for the PAH enzyme (sapropterin dihydrochloride, Kuvan) (Figure 22-2). For some individuals, administration of sapropterin can improve PAH activity and, thus, lower blood phe levels.40,41 In a phase III randomized, placebo-controlled, double-blind study, 44% of those taking sapropterin for 6 weeks showed a reduced phe concentration of 30% or greater.40 Response to sapropterin needs to be individually assessed as not all individuals with PKU will respond to supplementation and the degree of response to the drug varies. Supplementation with sapropterin rarely allows for complete liberalization of
the low-phe diet or eliminates the need for medical food.42 Continued involvement of a trained dietitian and geneticist is imperative.
Methylmalonic Acidemia
Natural History
Methylmalonic acidemia (MMA) is an inborn error of isoleucine (ile), methionine (met), threonine (thr), valine (val), and odd-chain fatty acid metabolism caused by a deficiency of the enzyme methylmalonyl-CoA mutase, which converts methymalonyl CoA to succinyl-CoA with eventual oxidation in the citric acid cycle (Figure 22-4). In MMA, methylmalonyl CoA is not metabolized and leads to accumulation of various methylmalonate metabolites. The degree of deficiency in the mutase enzyme affects the clinical outcome of this disorder.6,7,43 Those classified with mut-deficiency have some residual activity and often a less severe clinical course than those with mut0 deficiency who have no remaining enzyme activity.43,44 Methylmalonyl-CoA mutase requires the cofactor 5-dehydroxyadenosylcobalamin, which is produced from vitamin B12 . Defects in the production of the cobalamin cofactor can also cause MMA. The estimated prevalence of MMA is 1 in 80,000 births.45,46 Infants with classic MMA caused by a severe deficiency of the mutase enzyme often present in the first week of life with overwhelming illness. Symptoms include poor feeding, failure to thrive, hypotonia, vomiting, and dehydration with ketosis, acidosis, hyperammonemia, and hypoglycemia.43,44 Acute episodes are often fatal without aggressive management. Screening for MMA is now included in the expanded newborn screening panel, which is expected to improve early diagnosis and clinical outcomes of this disorder.47 Individuals with a deficiency in the mutase enzyme require medical nutrition therapy, described below. Despite treatment, those with severe mutase deficiency often have impaired developmental and medical outcomes.48,49 For patients with MMA caused by a mild, late-onset mutase deficiency or a defect in cofactor production, supplementation with high doses of vitamin B12 may improve metabolic control and allow for more normal development. This is particularly true for those with a cbl A defect.43 Other cofactor deficiencies, such as cbl B and cbl C defect, can have a more complicated clinical course and require both medical nutrition therapy and vitamin B12 supplementation.43,50 Liver transplantation is now an option for treatment of this disorder, particularly for those with severe enzyme deficiency. 5153
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Figure 22-4 Methylmalonic acidemia is caused by a defect in methylmalonyl CoA mutase. Two of 6 known cobalamin cofactor synthesis defects are shown, which also cause methylmalonic acidemia.
Adapted from Nyhan WL, Barshop BA, Ozand PT. Atlas of Metabolic Diseases. 2nd ed. New York, NY: Oxford University Press Inc; 2005. Reproduced by permission of Edward Arnold (Publishers) Ltd.
Acute Management
Initial Presentation Infants with MMA presenting in an acute episode require immediate medical attention to control acidosis, hyperammonemia, and hypoglycemia.43,54,55 Nutrition management during the acute phase of illness concentrates on delivery of nonprotein calories to help slow catabolism. Typically, intravenous (IV) dextrose at the maximum glucose infusion rate with additional lipid is provided to achieve maximal caloric intake. 55 IV carnitine may also be indicated.6 Medical foods for the treatment of MMA are available which contain all amino acids except ile, met, thr, and val.56 If enteral feedings are poorly tolerated, specialized parenteral solutions are available that lack the offending amino acids. As metabolic control improves, a standard infant formula or standard total parenteral nutrition solution is added to provide a complete source of protein and meet the individuals met, val, ile, and thr needs.3,5 Monitoring of ammonia, prealbumin, bicarbonate, and plasma amino acids is necessary to adjust the dietary prescription to achieve optimal metabolic control. Illness During illness and injury, an increase in the metabolic rate leads to catabolism of protein. In MMA, the offending amino acids cannot be utilized and a metabolic episode, with symptoms similar to those observed during the initial episode in infancy, can develop. Metabolic crisis associated with illness or injury can occur at any age and can be life threatening if not managed aggressively.48,55
For management of illness at home, a sick-day diet is prescribed to reduce intact protein and increase caloric intake. If tolerated, medical food is continued to provide adequate amino acids and kilocalories to promote protein anabolism. For individuals with less severe febrile illness, the sick-day diet may prevent the need for further medical intervention. For severe illness, aggressive medical intervention is required.6,55 Caretakers need to be educated about the signs of metabolic decompensation and provided with an emergency protocol that includes contact information for the metabolic team.
Chronic Management
The long-term medical nutrition therapy for individuals with mutase deficiency includes restriction of the amino acids ile, met, thr, and val with adequate caloric intake to prevent catabolism. 3,5,56 Often, a medical food restricted in these 4 amino acids provides the primary source of calories, other amino acids, and micronutrients. Intact protein from infant formula or expressed breast milk is added to provide adequate intake of ile, val, thr, and met. This allows for adequate growth and protein maintenance, but prevents excessive intake of these amino acids, which can lead to excessive production of methylmalonic acid and its metabolites. 57 The amount of intact protein allowed in the diet depends on the individuals tolerance for the offending amino acids. Supplementation with individual amino acids, particularly ile and/or val, may be required to meet needs of these offending amino acids without increasing the concentration of other offending amino acids. 3,56 Depending on the childs clinical status, foods such as fruits, vegetables, and
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grains can replace the amino acids provided by the standard infant formula or breast milk. For those responding to vitamin B12 supplementation, typical oral doses include 1000 to 2000 mcg/d or similar doses given 1 to 2 times per week via intramuscular (IM) injection. 58 Hydroxycobalamin may be better metabolized than cyanocobalamin in these disorders. 50 L-carnitine is often deficient in individuals with MMA. 59 Carnitine binds to the metabolites produced in this disorder; thus, individuals with MMA can have a higher requirement for this nutrient. Supplementation with prescription-strength L-carnitine (Carnitor) is common practice, especially if plasma carnitine deficiency is observed. Doses for carnitine supplementation range from 60 to 200 mg/kg.6 Side effects from excessive carnitine intake include diarrhea and a fishy odor. Laboratory monitoring is required to assess metabolic status and determine dietary prescription changes. Labs typically include plasma or serum concentrations of amino acids, carnitine, acyl carnitine profile, methylmalonic acid, ammonia, and/or urine organic acid analysis.54,56 In addition to these indicators, labs to assess general nutrition status such as iron indices, calcium, vitamin D, EFAs, and albumin/ prealbumin concentrations should be routinely assessed. 3
Figure 22-5 Nitrogen metabolism in the urea cycle. Ornithine transcarbamylase (OTC) deficiency results in hyperammonemia, elevated L-glutamine concentrations, and deficiency of L-arginine. Other enzymes in the urea cycle include angininosuccinate synthetase (AS), argininosuccinate lyase (AL), and arginase.
Ornithine Transcarbamylase Deficiency

Natural History
The most common inborn error of metabolism of the urea cycle is deficiency of the enzyme ornithine transcarbamylase (OTC) (Figure 22-5). OTC deficiency impairs urea cycle function, resulting in hyperammonemia as conversion of ammonia to nontoxic urea is impaired. Production of arginine is decreased, and arginine becomes an essential amino acid in this disorder.6,7 OTC deficiency is an X-linked disorder; therefore, males are often more severely affected than females. However, there is a wide range of clinical presentations, including adult-onset OTC deficiency in affected women.60 The severe form of the disease is characterized by overwhelming hyperammonemia (> 400 mol/L) in the newborn period causing recurrent vomiting, lethargy, irritability, and seizures, which can quickly cause coma and death if not treated aggressively. Mental retardation is common in those surviving the initial episode.60 Milder forms of the disorder may not present until later in life after a severe illness and can include neurological complications, such as psychosis.61 Long-term outcome with treatment varies greatly and often depends on the ability to prevent further episodes of hyperammonemia.
Acute Management
Acute management may be necessary at the time of initial presentation or with any intercurrent illness or injury. The goal of acute management of OTC deficiency is to slow protein catabolism and, thus, reduce ammonia production by providing a nonprotein, high-calorie nutrition source via enteral or parenteral nutrition. 55,62,63 As clinical status improves, essential amino acids are provided to prevent further protein breakdown. Essential amino acids can be provided with specialty total parenteral nutrition solutions or enteral medical foods designed for treatment of urea cycle disorders. Providing essential amino acids promotes protein anabolism, yet restricts intake of the nonessential amino acids that can contribute to the nitrogen load.62,63 Since arginine is an essential amino acid in OTC deficiency, supplementation with oral or IV L-arginine is often indicated during illness. Arginine bypasses the enzymatic block to allow for conversion of urea rather than further ammonia production. Acute medical management often includes use of nitrogen-scavenger drugs, which are available in both oral (Buphenyl) and IV forms (Ammunol). These medications bind to accumulated precursors to reduce toxicity.64,65 Liver transplantation is now an option for treatment of this disorder.66,67
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Chronic Management
There is a wide range of clinical phenotypes in OTC deficiency and, thus, dietary management needs to be individualized. Chronic management of OTC deficiency includes dietary restriction of total protein; approximately 50% of total protein from intact sources and 50% from a medical food containing essential amino acids as the protein source is typically recommended. 5,62,63,68 Often, the protein prescription for OTC deficiency is lower than the protein requirements outlined in the DRIs. In infancy, the intact protein source can include infant formula or expressed breast milk with transition to lower protein foods in childhood. The use of specialty low-protein food products is necessary to meet caloric needs, increase satiety, and provide variety in the diet. In addition, citrulline is routinely supplemented up to 170 mg/kg as it is the precursor for arginine and utilizes additional nitrogen via aspartate in the urea cycle.62 To assess metabolic control, frequent monitoring of ammonia and plasma amino acids is necessary. Of particular interest are citrulline and arginine to evaluate citrulline supplementation and glutamine which increases with excessive protein intake (Figure 22-5).69 Additionally, assessment of leucine, valine, and isoleucine is required as chronic use of a nitrogen-scavenging medication may reduce concentrations of the branched-chain amino acids. 64 Additional indices of nutrition status such as albumin/prealbumin and iron status should be routinely monitored. 3
Figure 22-6. Fatty Acid Oxidation and VLCAD Deficiency. Fatty acid oxidation requires entry of long-chain fatty acids (LCFAs) into the mitochondria. This process requires L-carnitine. Carnitine cycle enzymes include acyl-CoA synthetase (AS), carnitine palmitoyltransferase I and II (CPT I and CPT II), and acylcarnitine/carnitine translocase (CT). Once in the mitochondria, the -oxidation spiral sequentially oxidizes the fatty acyl-CoA to the 2-carbon unit acetyl-CoA. Oxidation of LCFA requires very long-chain acyl-CoA dehydrogenase (VLCAD) and a trifunction protein which includes 3 enzyme activities. In treatment of LCFA, supplementation with medium chain triglycerides (MCTs) bypasses the long-chain fatty acid enzymes and utilizes enzymes that oxidize medium and short-chain fatty acids including medium-chain acyl-CoA dehydrogenase (MCAD) and short-chain acyl-CoA dehydrogenase (SCAD) enzymes.
Very Long Chain Acyl-CoA Dehydrogenase Deficiency

Natural History
Very long chain acyl-CoA dehydrogenase deficiency (VLCADD) is an inborn error in the first step of mitochondrial -oxidation of long-chain fatty acids (LCFAs) (14 to 20 carbons in length) resulting in disturbed energy production with hypoglycemia, reduced ketone production, and production of abnormal long-chain fat metabolites (Figure 22-6).6,7 Severe forms of this disorder can cause cardiomyopathy and myopathy and can be fatal in infancy without medical intervention. Milder forms of this disorder may not present until later in life with episodes of muscle pain and rhabdomyolysis, especially after intense and/or prolonged exercise or during illness.70,71 Newborn screening can now detect infants with VLCADD. This disorder appears to be more common than earlier estimates since screening is identifying those with milder forms of this disorder.72 Longterm development and outcome of those diagnosed and treated early can be favorable.73,74
Adapted from Nyhan WL, Barshop BA, Ozand PT. Atlas of Metabolic Diseases. 2nd ed. New York, NY: Oxford University Press Inc; 2005. Reproduced by permission of Edward Arnold (Publishers) Ltd.
Acute Management
The primary goal of acute management of VLCADD is to provide sufficient kilocalories to prevent or reduce catabolism of fat stores.6,7 A dextrose infusion at the upper threshold of the glucose infusion rate is typically provided to reverse catabolism.55,75 As enteral feeding becomes possible, sources of glucose and medium-chain triglycerides (MCTs) can be given to meet calorie demands. Intralipid is contraindicated in VLCADD because it is a source of LCFAs.
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Chronic Management
Long-term management of VLCADD includes prevention of fasting, restriction of long-chain fat intake, and supplementation with MCTs. 5,74,76,77 Prevention of fasting, especially in the newborn period when energy stores are limited, is imperative to prevent breakdown of fat stores. Fasting guidelines need to be individualized, but typically fasting is limited to 4 hours for infants up to 4 months of age.74,78 Longer periods of fasting can be allowed as the infant ages, but often a feeding during the night is recommended during the first year.76 Nutrition therapy for VLCADD includes modification of fat sources to restrict intake of long-chain fat and supplement with MCTs. Depending on the severity of the disorder, long-chain fat intake may need to be reduced below 20% of total kilocalories during infancy. 5,74,76,77 The remaining fat kilocalories are supplied by MCTs, which include fatty acids of 8 to 12 carbons in length and thus can bypass the enzymatic block in LCFA oxidation. There are several medical foods available for treatment of VLCADD which contain limited amounts of long-chain fats and are supplemented with MCTs. In mild forms of this disorder, limited breastfeeding may be allowed.74,76,77 With the restriction in long-chain fat, it is important to assess the intake of the EFAs linoleic acid (LA) and alpha-linolenic acid (ALA). Supplementation with walnut, flax, or safflower oil may be necessary to meet LA and ALA needs.79 Some medical foods are supplemented with ARA and DHA. In older children with severe LCFA disorders, restriction of long-chain fat to approximately 10% of total calories may be necessary to maintain metabolic control.77,80 All fat from food should be considered long-chain fat since medium- and short-chain fats are limited in natural foodsources. Supplementation of low- or nonfat foods and beverages with a commercial MCT source (available in oil and powder) provides the remaining calories from fat. With intense exercise, consuming MCT prior to activity may be beneficial as an energy source during activity. 81 Addition of raw cornstarch to the nighttime feed may be indicated in some children with VLCADD. Cornstarch is a slowly digested source of glucose and is employed in the treatment of glycogen storage disease to prevent hypoglycemia. 82 Cornstarch supplementation may be helpful in fatty acid oxidation disorders to prevent low glucose concentrations and reduce production of abnormal fat metabolites during fasting.75 Because of poor digestion, cornstarch is contraindicated before 9 months of age. 82 Routine monitoring to assess metabolic control
typically includes measurement of fasting serum glucose, creatine phosphokinase (CK), plasma carnitine and acylcarnitine profiles, and erythrocyte essential fatty acids. 5,83
Galactosemia
Natural History
Classic galactosemia is an autosomal recessive disorder caused by the enzymatic deficiency of galactose-1-phosphate uridyl transferase (GALT) resulting in elevations of galactose-1-phosphate (Gal-1-P), galactitol, and galactonate (Figure 22-7).6,7 The incidence of classic galactosemia is approximately 1 in 60,000 births. Various mutations have been identified in the GALT gene. In the Caucasian population, a common mutation is Q188R; homozygosity of this mutation results in a severe phenotype, often with 0% enzyme.84 Another common mutation is S135L, which results in a milder clinical course and is prevalent in the African American population. Another form of galactosemia is the Duarte variant, which results in a mild phenotype that may not require dietary intervention. 85
Figure 22-7 Classic galactosemia is a caused by a deficiency of galactose-1-phosphate uridyl transferase (GALT). Elevations in galactose1-phosphate, galactose, galactitol and galactonate are present in this disorder.
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Galactosemia is detected by newborn screening; however, infants with severe galactosemia can present with symptoms before newborn screening results are available. Acute symptoms include cataracts, jaundice, failure to thrive, vomiting, sepsis, hepatomegaly, and liver failure. These symptoms resolve quickly with medical intervention and a diet restricted in galactose. 5,6,7 Treatment of classic forms of galactosemia requires a life-long galactose-restricted diet. Despite nutrition management, long-term complications of classic galactosemia can include mental retardation, neurological abnormalities, speech delay, and ovarian failure in females.86,87,88 Abnormal bone metabolism has also been described in this population.89 The specific cause of these complications remains unknown, although endogenous production of galactose has been implicated.90
amounts of both free and bound galactose.9496 It remains unclear if the minimal intake of galactose from some fruits and vegetables contributes excessive dietary galactose and need to be eliminated from the diet.97 Calcium and vitamin D intake needs to be assessed in those on a galactoserestricted diet. Supplementation is typically required for children who do not consume a soy-based formula or fortified soy milk. 3,5
Table 22-4 Foods and Ingredients That Contain Lactose or Galactose* Milk Casein Milk solids Calcium caseinate Nonfat dry milk Sodium caseinate Nonfat dry milk solids Lactose Dry milk Hydrolyzed whey protein Butter Whey and whey solids Buttermilk and buttermilk solids Lactalbumin Cream Lactoglobulin Garbanzo beans Dry peas/beans Organ meats Milk chocolate Ice cream Sour cream Sherbet Yogurt Cheese * These foods and ingredients are eliminated in the dietary management of classic galactosemia.
Acute Management
Infants identified with classic galactosemia should be immediately placed on a soy-based infant formula. Soy formulas, which contain soy protein isolate as the protein source, have a very low galactose content compared to cows milk-based formulas or breast milk. If an infant does not tolerate enteral feeds, standard total parenteral nutrition may be used. Efforts should be made to choose medications that are free of lactose extenders. Unlike some disorders of amino acid and fat metabolism, those with galactosemia do not develop metabolic episodes associated with illness.
Chronic Management
Long-term management of classic galactosemia requires restriction of galactose in the diet. Galactose is primarily derived from lactose.91 During infancy, powdered soy formula is provided and breastfeeding is not allowed. Powdered soy formula is recommended over ready-to-feed or concentrated liquid soy formulas. Liquid soy formulas contain a higher galactose content from the addition of carageenan, although the digestive availability of galactose from carageenan is unclear.92 Use of lactose-free elemental formulas, which contain no galactose, have been used to treat some infants with classic galactosemia with Gal-1-P concentrations that have not decreased into the treatment range by 4 to 6 months of age.93 When starting solids, all dairy products are contraindicated. Caregivers are instructed to check food labels for lactose- and galactose-containing foods and ingredients (Table 22-4). Galactose is also found in organ meats and some legumes. Fruits and vegetables contain varying
Erythrocyte Gal-1-P is the primary metabolite monitored in galactosemia and maintenance of Gal-1-P concentrations below 4 mg/dL is considered optimal.91 When evaluating Gal-1-P concentrations, patient-specific comparisons should be made; some individuals maintain Gal-1-P concentrations above 4 mg/dL even with strict dietary management. Gal-1-P is not a sensitive measure of treatment compliance; however, a significant increase above a patients typical Gal-1-P concentrations should be investigated for possible dietary indiscretions.98
1. PKU is often referred to as the model for newborn screening because: A. Screening is economically feasible and results are reliable. B. Early medical nutrition therapy is available. C. Nutrition therapy prevents mental retardation associated with untreated PKU. D. All of the above. 2. When is total parenteral nutrition indicated for an individual with methylmalonic acidemia (MMA)? A. Standard total parenteral nutrition solutions should never be given to patients with this disorder.
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B. Only specialty total parenteral nutrition solutions containing no isoleucine, methionine, threonine, and valine should be provided. C. Depending on a patients clinical status, a combination of specialty total parenteral nutrition and standard total parenteral nutrition can be provided. D. Total parenteral nutrition is always contraindicated in this disorder. 3. In very long chain acyl CoA dehydrogenase deficiency (VLCADD), is/are contraindicated because : A. Medium chain triglycerides; they cannot be metabolized B. Intralipid; of its long chain fat content C. Carbohydrates; they interfere with oxidation of fatty acids D. Cornstarch; it helps prevent hypoglycemia and rhabdomyolysis See p. 487 for answers.
References
1. Garg U, Dasouki M. Expanded newborn screening of inherited metabolic disorders by tandem mass spectrometry: clinical and laboratory aspects. Clin Biochem . 2006;39:315332. 2. Watson AS, Mann MY, Lloyd-Puryear MA, Rinaldo P, Howell RR. Newborn screening: toward a uniform panel and system. Executive summary. Genet Med. 2006;8:111S. 3. Acosta PB, Yannicelli S. The Ross Metabolic Formula System Nutrition Support Protocols. 4th ed. Columbus, OH: Ross Products Division/Abbott Laboratories; 2001. 4. Elsas LJ, Acosta PB. Inherited metabolic disease: amino acids, organic acids, and galactose. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern Nutrition in Health and Disease, 10th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2006:909959. 5. Acosta PB, ed. Nutrition Management of Patients with Inherited Metabolic Disorders. Sudbury, MA: Jones & Bartlett; 2009. 6. Nyhan WL, Barshop BA, Ozand PT. Atlas of Metabolic Diseases. 2nd ed. New York, NY: Oxford University Press Inc; 2005. 7. Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Online Metabolic & Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill, 2007. Available from http://www.ommbid.com. 8. Guldberg P, Romano V, Ceratto N, et al. Mutational spectrum of phenylalanine hydroxlyase deficiency in Sicily: implications for diagnosis of hyperphenylalaninemia in southern Europe. Hum Mol Genet. 1993;2:17031707. 9. Koch R, Azen C, Friedman EG, Williamson ML and Writing Committee for the PKU Collaborative Study. Paired comparisons between early treated PKU children and their matched sibling controls on intelligence and school achievement test results at eight years of age. J Inherit Metab Dis. 1984;7:8690.
10. Bickel H, Gerrard J, Hickmans EM. The influence of phenylalanine intake on phenylketonuria. Lancet. 1953; 265:812813. 11. Berry HK, Wright S. Conference on treatment of phenylketonuria. J Pediatr. 1967;70:142147. 12. Koch R, Burton B, Hoganson G, et al. Phenylketonuria in adulthood: a collaborative study. J Inherit Metab Dis. 2002;25:333346. 13. Azen CG, Koch R, Friedman EG, et al. Intellectual development in 12-year-old children treated for phenylketonuria. Am J Dis Child. 1991;145:3539. 14. National Institutes of Health. Phenylketonuria (PKU): Screening and Management. NIH Consensus Statement. Washington DC; 2000. 15. Waisbren SE, Noel K, Fahrbach K, et al. Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol Genet Metab. 2007;92:6370. 16. Levy H, Ghavami M. Maternal phenylketonuria: A metabolic teratogen. Teratology. 1996;53:176184. 17. Waisbern SF, Hanley W, Levy HL, et al. Outcomes at age 4 years in offspring of women with maternal phenylketonuria: the Maternal PKU Collaborative Study. JAMA. 2000;283:756762. 18. Waisbren SE, Azen C. Cognitive and behavioral development in maternal phenylketonuria offspring. Pediatrics. 2003;112:15441547. 19. Yagasaki M, Hashimoto S. Synthesis and application of dipeptides; current status and perspectives. Appl Microbiol Biotechnol. Epub. 2008;81:1322. 20. van Rijn M, Bekhof J, Dijkstra T, Smit PG, Moddermam P, van Spronsen FJ. A different approach to breast-feeding of the infant with phenylketonuria. Eur J Pediatr. 2003;162:323326. 21. Greve LC, Wheeler MD, Green-Burgeson DK, Zorn EM. Breast-feeding in the management of the newborn with phenylketonuria: a practical approach to dietary therapy. J Am Diet Assoc. 1994;94:305309. 22. Lawrence RL. Breastfeeding: A Guide for the Medical Profession. 5th ed. St. Louis, MO: C.V. Mosby Co; 2005. 23. Leamons JA, Reyman D, Moye L. Amino acid composition of preterm and term breast milk during early lactation. Early Hum Dev. 1983;8:323329. 24. Gropper SS, Acosta PB. Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid and urea nitrogen concentrations in humans. J Parenteral Enteral Nutr. 1991;15:4853. 25. Otten JJ, Helwig JP, Meyers LD. Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. Washington, DC: The National Academies Press; 2006. 26. Singh R, Lesperance E, Crawford K. PKU Food List. 2nd ed. Atlanta, GA: Emory University, Department of Human Genetics, Division of Medical Genetics; 2006. 27. Schuett V. Low Protein Food List for PKU. 2nd ed. Seattle, WA: National PKU News; 2002. 28. Schuett V. Low Protein Cookery for PKU. 4th ed. Madison, WI: The University of Wisconsin Press; 1996. 29. Schuett V, Corry D. Apples to Zucchini: A Collection of Favorite Low Protein Recipes. Seattle, WA: National PKU News; 2005.
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30. Acosta PB, Yannicelli S, Singh RH, Elsas LJ, Mofidi S, Steiner RD. Iron status of children with phenylketonuria undergoing nutrition therapy assessed by transferrin receptors. Genet Med. 2004;6:96101. 31. Robinson M, White FJ, Cleary MA, et al. Increased risk of vitamin B12 deficiency in patients with phenylketonuria on an unrestricted or relaxed diet. J Pediatr. 2000;136:545547. 32. Acosta PB, Yannicelli S. Plasma micronutrient concentrations in infants undergoing therapy for phenylketonuria. Biol Trace Elem Res. 1999;67:7584. 33. Hvas AM, Nexo E, Nielsen JB. Vitamin B12 and vitamin B6 supplementation is needed among adults with phenylketonuria (PKU). J Inherit Metab Dis. 2006;29:4753. 34. Moseley K, Koch R, Moser AB. Lipid status and long-chain polyunsaturated fatty acid concentrations in adults and adolescents with phenylketonuria on phenylalanine-restricted diet. J Inherit Metab Dis. 2002;25:5664. 35. Koletzko B, Beblo S, Demmelmair H, Hanebutt FL. Omega-3 LC-PUFA supply and neurological outcomes in children with phenylketonuria (PKU). J Pediatr Gastroenterol Nutr. 2009;48(suppl):S27. 36. Beblo S, Reinhardt H, Demmelmair H, Muntau AC, Koletzko B. Effect of fish oil supplementation on fatty acid status, coordination, and fine motor skills in children with phenylketonuria. J Pediatr. 2007;150:479484. 37. Puglisi-Allegra S, Cabib S, Pascucci T, et al. Dramatic brain aminergic deficit in a genetic mouse model of phenylketonuria. Neuroreport. 2000;11:13611364. 38. Matalon R, Michals-Matalon K, Bhatia G, et al. Double blind placebo controlled trial of large neutral amino acids in treatment of PKU: effect on blood phenylalanine. J Inherit Metab Dis. 2007;30:153158. 39. Schindeler S, Ghosh-Jerath S, Thompson S, et al. The effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study. Mol Genet Metab. 2007;91:4854. 40. Levy HL, Milanowski A, Chakrapani A, et al. Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentrations in patients with phenylketonuria: a phase III randomized placebo-controlled study. Lancet. 2007;370:504510. 41. Burton BK, Grange DK, Milanowski A, et al. The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study. J Inherit Metab Dis. 2007;30:700707. 42. Singh R, Jurecki E, Rohr F. Recommendations for personalized dietary adjustments based on patient response to tetrahydrobiopterin (BH4) in phenylketonuria. Top Clin Nutr. 2008;23:149157. 43. Merinero B, Perez C, Perez-Cerda A, et al. Methylmalonic acidemia: examination of genotype and biochemical data in 32 patients belonging to mut, cbIA or cbIB complementation group. J Inherit Metab Dis. 2008;31:5566. 44. Shevell M, Matiaszuk N, Ledley F, Rosenblatt D. Varying neurological phenotypes among mut0 and mut patients with methylmalonyl CoA mutase. Am J Med Genet. 1993;45:619624.
45. Sniderman LC, Lambert M, Giguere R, et al. Outcome of individuals with low-moderate methylmalonic aciduria detected through a neonatal screening program. J Pediatr. 1999;134:675680. 46. Chace D, DiPerna J, Kalas T, Johnson R, Naylor E. Rapid diagnosis of methylmalonic and propionic acidemias: quantitative tandem mass spectrometric analysis of propionylcarnitine in filter-paper blood specimens obtained from newborns. Clin Chem. 2001;47:20402044. 47. Dionisi-Vici C, Deodato F, Rschinger W, Rhead W, Wilcken B. Classical organic acidurias, propionic aciduria, methylmalonic aciduria and isovaleric aciduria: Long-term outcome and effects of expanded newborn screening using tandem mass spectrometry. J Inherit Metab Dis. 2006;29:383389. 48. Van der Meer SB, Poggi F, Spada M, et al. Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia. J Pediatr. 1994;125:903908. 49. de Baulny HO, Benoist JF, Rigal O, Touati G, Rabier D, Saudubray JM. Methylmalonic and propionic acidaemias: management and outcome. J Inherit Metab Dis. 2005;28:415423. 50. Andersson HC, Shapira E. Biochemical and clinical response to hydroxocobalamin versus cyanocobalamin treatment in patients with methylmalonic acidemia and homocystinuria (cblC). J Pediatr. 1998;132:121124. 51. Nyhan WL, Gargus JJ, Boyle K, Selby R, Koch R. Progressive neurologic disability in methylmalonic acidemia despite transplantation of the liver. Eur J Pediatr. 2002;161:377379. 52. Morioka D, Kasahara M, Horikawa R, Yokoyama S, Fukuda A, Nakagawa A. Efficacy of living donor transplantation for patients with methylmalonic acidemia. Am J Transplant. 2007;7:27822787. 53. McGuire PJ, Lim-Melia E, Diaz GA, et al. Combined liverkidney transplant for the management of methylmalonic aciduria: A case report and review of the literature. Mol Genet Metab. 2008;93:2229. 54. Lee NC, Chien YH, Peng SF, et al. Brain damage by mild metabolic derangements in methylmalonic acidemia. Pediatr Neurol. 2008;39:325329. 55. Prietsch V, Lindner M, Zschocke J, Nyhan WL, Hoffmann GF. Emergency management of inherited metabolic diseases. J Inherit Metab Dis. 2002;25:531546. 56. Yannicelli S. Nutrition therapy of organic acidaemias with amino acid-based formulas: emphasis on methylmalonic and propionic acidaemia. J Inherit Metab Dis. 2006;29:281287. 57. Ney DM, Bay C, Saudubray JM, et al. An evaluation of protein requirements in methylmalonic acidaemia. J Inherit Metab Dis. 1985;8:132142. 58. Wedel U, deBaulny HO. Branched-chain organic acidurias/ acidemias. In: Fernandes J, Saudubray JM, van den Berghe G, Walter JH, eds. Inborn Metabolic Diseases: Diagnosis and Treatment, 4th ed., rev. Heidelberg Germany: Springer Medizen Verlag, 2006:245260. 59. Chalmers RA, Roe CR, Stacey TE, Hoppel CL. Urinary excretion of L-carnitine and acylcarnitines by patients with disorders of organic acid metabolism: evidence for secondary insufficiency of L-carnitine. Pediatr Res. 1984;18:13251328.
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60. Maestri N, Clissold D, Brusilow S. Neonatal onset ornithine transcarbamylase deficiency: a retrospective analysis. J Peds. 1999;134:268-272. 61. Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr. 2003;162:410416. 62. Leonard JV. The nutritional management of urea cycle disorders. J Pediatr. 2001;138:S4045. 63. Singh RH. Nutritional management of patients with urea cycle disorders. J Inherit Metab Dis. 2007;30:880887. 64. Scaglia F, Carter S, OBrien W, Lee B. Effect of alternative pathway therapy on branched chain amino acid metabolism in urea cycle disorder patients. Mol Genet Metab. 2004;81:7985. 65. Batshaw ML, MacArthur RB, Tuchman M. Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr. 2001;138:S4654. 66. Puppi J, Tan N, Mitry RR, et al. Hepatocyte transplantation followed by auxiliary liver transplantationa novel treatment for ornithine transcarbamylase deficiency. Am J Transplant. 2008;8:452457. 67. McBride K, Miller G, Carter S, et al. Developmental outcomes with early orthotopic liver transplantation for infants with neonatal-onset urea cycle defects and a female patient with late-onset ornithine transcarbamoylase deficiency. Pediatrics. 2004;114:523526. 68. Acosta PB, Yannicelli S, Ryan AS, et al. Nutritional therapy improves growth and protein status of children with a urea cycle enzyme defect. Mol Genet Metab. 2005;86:448455. 69. Wilson CJ, Lee PJ, Leonard JV. Plasma glutamine and ammonia concentrations in ornithine carbamoyltransferase deficiency and citrullinaemia. J Inherit Metab Dis. 2001;24:691695. 70. Pons R, Cavadini P, Baratt S, et al. Clinical and molecular heterogeneity in very-long chain acyl-coenzyme A dehydrogenase deficiency. Pediatr Neurol. 2000;22:98105. 71. Smelt A, Poorthuis B, Onkenhout W, et al. Very long chain acyl-coenzyme A dehydrogenase deficiency with adult onset. Ann Neurol. 1998;43:540544. 72. Liebig M, Schymik I, Mueller M, et al. Neonatal screening for very long-chain acyl-CoA dehydrogenase deficiency: enzymatic and molecular evaluation of neonates with elevated C14:1-carnitine levels. Pediatrics. 2006;118:10651069. 73. Vianey-Saban C, Divry P, Brivet M, et al. Mitochondrial very-long-chain acyl-coenzyme A dehydrogenase deficiency: clinical characteristics and diagnostic considerations in 30 patients. Clin Chim Acta. 1998;269:4362. 74. Spiekerkoetter U, Lindner M, Santer R, et al. Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop. J Inherit Metab Dis. 2009;32:498505. 75. Vockley J, Singh RH, Whiteman DA. Diagnosis and management of defects of mitochondrial beta-oxidation. Curr Opin Clin Nutr Metab Care. 2002;5:601609. 76. Rohr F, van Calcar S. Very long chain acyl CoA dehydrogenase deficiency (VLCADD). Genetic Metabolic Dietitians International, 2008. Available at: http://www.gmdi.org/ guidelines. Accessed September 4, 2008.
77. Arnold GL, Van Hove J, Freedenberg D, et al. A Delphi clinical practice protocol for the management of very long chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2009;96:8590. 78. Walter J. Tolerance to fast: rational and practical evaluation in children with hypoketonaemia. J Inherit Metab Dis. 2009;32:214217. 79. Roe CR, Roe DS, Wallace M, Garritson B. Choice of oils for essential fat supplements can enhance production of abnormal metabolites in fat oxidation disorders. Mol Genet Metab. 2007;92:346350. 80. Gillingham M, Connor W, Matern D, et al. Optimal dietary therapy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Mol Gen Metab. 2003;79:114123. 81. Gillingham MB, Scott B, Elliott D, Harding CO. Metabolic control during exercise with and without medium chain triglycerides (MCT) in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency. Mol Genet Metab. 2006;89:5863. 82. Goldberg T, Slonim AE. Nutrition therapy for hepatic glycogen storage diseases. J Am Diet Assoc. 1993;93:14231430. 83. Spiekerkotter U, Schwahn B, Korall H, Trefz FK, Andresen BS, Wendel U. Very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency: monitoring of treatment by carnitine/acylcarnitine analysis in blood spots. Acta Paediatr. 2000;89:492495. 84. Elsas LJ, Langley S, Paulk EM, Hjelm LN, Dembure PP. A molecular approach to galactosemia. Eur J Pediatr. 1995;154:S217. 85. Ficicioglu C, Thomas N, Yager C, et al. Duarte (DG) galactosemia: A pilot study of biochemical and neurodevelopmental assessment in children detected by newborn screening. Mol Genet Metab. 2008;95:206212. 86. Waggoner DD, Buist NMR, Donnell GN. Long-term prognosis in galactosemia: results of a survey of 350 cases. J Inherit Metab Dis. 1990;13:802818. 87. Ridel KR, Leslie ND, Gilbert DL. An updated review of the long-term neurological effects of galactosemia. Pediatr Neurol. 2005;33:153161. 88. Bosch A. Classical galactosaemia revisited. J Inherit Metab Dis. 2006;29:516525. 89. Panis B, Forget P, van Kroonenburgh MJPG, et al. Bone metabolism in galactosemia. Bone. 2004;35:982987. 90. Berry GT, Moate PJ, Reynolds RA, et al. The rate of de novo galactose synthesis in patients with galactose-1phosphate uridyltransferase deficiency. Mol Genet Metab. 2004;81:2230. 91. van Calcar S, Wolff J. Galactosemia. In: Ekval S, Ekval VK, eds. Pediatric Nutrition in Chronic Disease and Developmental Disorders. 2nd ed. New York, NY: Oxford University Press. 2005:335339. 92. Acosta PB, Gross K. Hidden sources of galactose in the environment. Eur J Pediatr. 1995;154:16. 93. Ficicioglu C, Hussa C, Yager C, Segal S. Effect of galactose free formula on galactose-1-phosphate in two infants with classical galactosemia. Eur J Pediatr. 2008;167:595596.
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94. Gross K, Acosta PB. Fruits and vegetables are a source of galactose: implications in planning the diets of patients with galactosaemia. J Inherit Metab Dis.1991;14:253258. 95. Scaman C, Jin Wai Jim V, Hartnett C. Free galactose concentrations in fresh and stored apples (malus domestica) and processed apple products. J Agric Food Chem. 2004;52:511517. 96. Gropper S, Weese S, West P, Gross K. Free galactose content of fresh fruits and strained fruit and vegetable baby foods: more foods to consider for the galactose-restricted diet. J Am Diet Assoc. 2000;100:573575.
97. Kim H, Hartnett C, Scaman CH. Free galactose content in selected fresh fruits and vegetables and soy beverages. J Agric Food Chem. 2007;55:81338137. 98. Hutchesson AC, Murduck-Davis C, Green A, et al. Biochemical monitoring of treatment for galactosemia: biological variation in metabolic concentrations. J Inherit Metab Dis. 1999;22:139148.
Cardiac Disease
Anupama Chawla, MD, CNSP, DCH (UK) Janice Antino, RD, MS, CNSD, CSP, and Mindy Freudenberg, RD, MS, CNSD
23
Learning Objectives
1. Identify factors contributing to growth failure in children with congenital heart disease. 2. Summarize the components of nutrition assessment and optimal methods of nutrient delivery in children with congenital heart disease. 3. Recognize and manage postoperative complications and prescribe appropriate nutrition therapy.
CONTENTS
Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . 247
Malnutrition and Growth Nutrition Assessment Nutrition Management Complications After Congenital Heart Disease Surgery
Cardiovascular Disease in the PediatricPatient. . . . . . . 252 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
Congenital Heart Disease
Congenital heart diseases are abnormalities in the heart structure that are present at birth. Approximately 8 out of every 1,000 infants are born with congenital heart disease. Congenital heart disease can be classified into 2 major categories, cyanotic and acyanotic1 (Table 23-1). Pediatric heart disease can be a congenital or an acquired condition. This population is presented with unique challenges in meeting their energy requirements for optimal
Table 23-1 Two Major Categories of Congenital Heart Disease
Acyanotic Cyanotic
Atrial septal defect (ASD) Interrupted aortic arch Ventricular septal defect (VSD) Pulmonary atresia Patent ductus arteriosus (PDA) Ebsteins anomaly Common A-V canal (CAVC) Pulmonary stenosis* Coarctation of aorta* Aortic stenosis Tetralogy of Fallot* Transposition of the great vessels* Total anomalous pulmonary venous return* Truncus arteriosus* Tricuspid atresia* Hypoplastic left heart syndrome* * These conditions may transition to cyanotic state. 247
248
growth and development. Depending on the congenital heart disease lesion and its severity, a child with cogenital heart disease may face feeding difficulties and malnutrition during a critical developmental period.
Malnutrition and Growth

Failure to thrive and malnutrition is well documented in infants and children with congenital heart disease. 24 Malnutrition has been identified in both acyanotic and cyanotic congenital heart disease however the degree of growth delay is often related to the severity of the anatomical lesion and tends to be most severe in lesions associated with congestive heart failure (CHF). Cyanotic heart disease patients usually tend to be more undernourished due to their chronic hypoxic state and relatively prolonged course until final correction, as these infants require surgery in several stages. At birth, the weight of infants with congenital heart disease is usually appropriate for gestational age. Despite normal or near-normal birth weights, infants with congenital heart disease commonly experience a rapid decline in weight for age percentiles reflecting acute malnutrition. If malnutrition persists, height velocity will be affected within a few months, resulting in stunting. Weight gain can be considerably less than expected to maintain normal growth patterns. 5 Cameron et al reported the prevalence of acute and chronic malnutrition to be as high as 33% and 64%, respectively.6 Surgical correction has emerged as the most efficient method to improve the nutrition status of these infants. Surgical correction eliminates the cardiac factors contributing to malnutrition. Mitchell et al evaluated the nutrition status of 48 children with congenital heart disease before corrective surgery.7 Significant undernutrition was evident in all children irrespective of the cardiac lesion or the presence or absence of cyanosis. Fifty-two percent of the children had a weight under the third percentile for age, 83% had abnormal biochemical and hematological measurements reflecting compromised nutrition status, and 33% had abnormally high 3-methyhistidine suggesting a degree of active muscle wasting. Corrective surgery is usually not performed until a patient achieves an ideal weight and appropriate age or when growth failure or defect requires early correction. Eskedal et al also emphasized the role of nutrition in this population during the postoperative period. 8 They evaluated the growth of 2 groups of infants with congenital heart disease who underwent cardiac corrective surgery. Children who survived past the thirtieth postoperative day but subsequently died were compared to children who were long-term
survivors. Children who died had impaired weight gain postoperatively compared to the long-term survivors who showed a mean increase in weight age z scores. Depending on the type of cardiac lesion, an infant with congenital heart disease may undergo complete corrective surgery or a staged palliative intervention leading to complete repair. The type of surgical treatment and the remaining cardiac defect can have a profound impact on the nutrition rehabilitation process. The age and timing of corrective surgery may affect the potential for growth and nutrition recovery in infants with congenital heart disease.8 Infants with congenital heart disease will experience fewer deficits in weight and height if corrective surgery is performed in the first 10 days of life compared to infants undergoing surgery after the newborn period.9 Vaidyanathan et al evaluated the nutrition status of infants with congenital heart disease who underwent corrective surgery. Significant catch-up growth was evident after 3 months, suggesting that correction of the cardiac anomaly favorably influences the nutrition status of infants with congenital heart disease.4 Corrective and timely surgical intervention has been proposed as critical to avoid the long- and short-term consequences of malnutrition.4,9 Although somatic growth is often impaired before surgical intervention, growth usually dramatically improves to normal or near-normal values after corrective surgery. In most infants catch-up growth is largely complete within 6 to 12 months of surgery.4 Etiology of Growth Impairment The exact etiology for growth impairment in children with congenital heart disease remains unclear. Many factors have been identified as contributing to growth failure in this population (Table 23-2).
Table 23-2 Factors Contributing to Growth Failure in Congenital Heart Disease
Etiology
Increased energy requirements Decreased energy intake Increased nutrient losses Insufficient utilization of nutrients Malabsorption
Tachypnea and tachycardia can increase metabolic demands Anorexia, dysphagia, reflux, fatigue during feeding Protein-losing enteropathy, renal electrolyte losses Acidosis, hypoxia Gut edema
Decreased Nutrient Intake and Utilization Inadequate caloric intake, increased metabolic demands, or a combination of both may be responsible for significant growth impairment.9 Energy imbalance is a major factor contributing to malnutrition in these patients, and it
CARDIAC DISEASE
249
influences outcomes after corrective cardiac surgery. Feeding difficulties and intolerances are common during the first year of life in infants with congenital heart disease. Vomiting occurs frequently in this population and has been identified as the most common feeding intolerance.10,11 The energy intake of infants with congenital heart disease is often insufficient and loss of nutrients as a result of vomiting can further decrease the amount of energy available for growth. It has been estimated that vomiting after feeding can result in a loss of 12% of the infants energy intake.11 Utilization of nutrients is compromised in the setting of chronic hypoxia and acidosis is often seen in infants with congenital heart disease. Schwarz et al assessed the growth and energy intake of 19 infants with congenital heart disease who were not candidates for early corrective surgery.12 Anthropometric measurements began to improve only when energy intakes reached 150 kcal/ kg. Considering the diversity of the population and varying degrees of anomalies, an infant with congenital heart disease may require energy intakes of 140 to 200 kcal/kg body weight to induce growth.4 Energy Expenditure Infants with congenital heart disease have increased requirements of energy and protein needed to promote growth and development. Studies examining an energy deficit whether due to a decreased intake or increased energy expenditure can be difficult to interpret due to the heterogenicity of the congenital anomaly, severity of illness, and age.2 Several studies have been performed to evaluate the methods traditionally used to determine the energy requirements in this patient population. Leitch et al used respiratory calorimetry to measure resting energy expenditure (REE) and total energy expenditure (TEE) in 12 infants with uncorrected cyanotic congenital heart disease and compared them to a group of age-matched controls at 2 weeks and again at 3 months of age. No significant differences in REE were identified at either time, however a significant increase in TEE was identified at 3 months of age.2,3 Therefore an increased TEE but not an increased REE may be a primary factor in the reduced growth of infants with cyanotic congenital heart disease. This suggests that the use of REE should not be extrapolated to determine TEE, and that caloric recommendations determined by indirect calorimetry may significantly underestimate the actual energy needs of these patients. Nydegger et al used indirect calorimetry to assess the energy expenditure of 108 infants with various forms of congenital heart disease.9 When compared to healthy controls an increased REE was observed in infants with congenital
heart disease and normalized within 1 week after corrective surgery. It was also observed that standard equations fail to accurately predict REE in this population. When utilizing the gold standard of measuring energy expenditure, using the doubly labeled water technique, TEE was considerably and consistently elevated compared to healthy controls.5,11 Although this method is considered the gold standard to measure energy expenditure it is costly, requires specialized equipment, and is rarely used. Therefore, indirect calorimetry and predictive equations should be used cautiously as both may underestimate the energy needs of children with congenital heart disease.
A thorough and accurate nutrition assessment is the primary step for early recognition of feeding difficulties and growth delay in children with congenital heart disease. This will result in early intervention to help prevent nutrition deficiencies and optimize growth. A complete nutrition assessment includes a combination of methods that should include an accurate feeding history, visual clinical assessment, anthropometric evaluation, and biochemical indices (Table 23-3). Anthropometric data such as weight, length/height, weight-for-length, and head circumference can be evaluated using published growth charts from the Centers for Disease Control and Prevention (CDC) or the World Health Organization (WHO) (see Chapter 33). Measurements should be plotted and monitored over time to determine growth velocity and degree of growth failure. Congenital heart disease may be present in conjunction with an underlying chromosomal abnormality. In these condi tions anthropometric data can be evaluated using specialized growthcharts as available for children with trisomy 21, trisomy 18, Turners syndrome, and for infants born preterm.
Table 23-3 Components of Nutrition Assessment in Congenital Heart Disease Medical history Type of lesion (cyanotic vs. acyanotic), current medications, other medical conditions Feeding history Type of formula, concentration of formula, preparation methods, and amount consumed; duration of feeds Physical exam Fluid status/edema, cyanosis, respiratory rate (tachypnea) Biochemical indices Serum electrolytes, albumin, prealbumin. Total lymphocyte count and stool for alpha1-antitrypsin if suspicious of protein-losing enteropathy Anthropometric data Weight, length/height, weight-for-length, triceps skinfolds, mid-arm circumference Evaluation of growth Monitor weight gain and linear growth overtime Gastrointestinal function Evaluation of bowel pattern (eg, frequency and consistency), GI reflux
250
Biochemical evaluation should include prealbumin, serum albumin, and serum electrolytes including calcium, magnesium, and phosphorus. Serum albumin results must be interpreted with caution as it is highly sensitive to the patients hydration status. Prealbumin is influenced by infection, sepsis, inflammation, and operative course and should be evaluated with consideration of non-nutrition factors. Fluid overload secondary to congestive heart failure, or dehydration secondary to diuretics, can alter fluid and electrolyte balance and may affect renal function. If the serum albumin is low then protein-losing enteropathy (PLE) is a consideration and stool for alpha-1-antitrypsin and total lymphocyte count should be obtained to assess for PLE (see Protein-Losing Enteropathy in this chapter).
longer than 8 weeks) then placing a gastrostomy tube should be considered. A gastrostomy tube is better accepted socially and also decreases the risks associated with prolonged nasogastric tube feeds. Dislodgement of the tube, stenting of the lower esophageal sphincter with increased reflux, sinusitis, and nasal skin and cartilage breakdown are associated with long-term use of nasogastric tubes.13
Table 23-4 Concentrating Term Infant Formula
When using most infant powder: Preparing smaller volumes
Desired Concentration (cal/oz) 24 27*
Water (fl oz) 5 4.25
Level Scoop from Can 3 3
Nutrition Management
Adequate nutrition intake is not always easily achieved in infants and children with congenital heart disease. These infants require increased energy intakes to achieve significant growth but are often unable to achieve their nutrition goal due to anorexia and increased fatigue during feeding. Nutrient Delivery The primary goal is to maximize energy intake orally. When oral intake alone fails to support growth and development, alternative methods of nutrition delivery are indicated and should be initiated relatively early. Tube feedings should be considered to supplement inadequate oral intake. In an effort to maintain the infants hunger and satiety cycle, intermittent bolus tube feeds may be used to supplement oral nutrition intake. In order to preserve the infants oral motor function and desire to eat, supplemental feeds should be delivered after allowing the infant to feed orally for 10 to 15 minutes duration at each feed time. Infants and children with CHF often need to be fluid restricted. Concentrating formula helps provide adequate calories while limiting fluid intake. Increasing the formula concentration from 20 cal/oz to 24 or 27 cal/oz can be achieved by the addition of modular components or by reducing the water-to-powder ratio (Table 23-4). If intermittent bolus feeds are not tolerated because of compromised motility, reflux, or concomitant respiratory distress, then continuous feeds should be considered. Continuous feeds allow delivery of daily requirements with smaller hourly volumes with decreased energy expenditure.12 Continuous, 24-hour nasogastric feedings are a safe and effective method of achieving increased nutrient intake resulting in improved overall nutrition status. If it is anticipated that the infant will require supplemental feeds for a prolonged duration (eg, for
For specialized infant formulas check manufacturers guidelines.

Concentrating liquid formula with term infant powder
Starting Concentration 20 cal/oz (breast milk, ready-to-feed formula) 24 cal/oz
Volume
Desired Concentration 24 cal/oz 27* cal/oz
Term Infant Formula Powder 1 teaspoon 1 teaspoon
3 oz 4 oz
Using modulars to concentrate formulas

To prepare 24 to 28 cal/oz from 20 cal/oz formula
Modular
Volume of Formula 20 cal/oz 3 oz
To Prepare 2425 cal/oz Formula (amount of modular) 1 teaspoon
To Prepare 2728* cal/oz Formula (amount of modular) 1 teaspoons
Duocal (14 kcal/ tsp) (Nutricia) Vegetable Oil (9 kcal/5 mL) Triglyceride Oil (MCT Oil) (7.7 kcal/mL) (Nestle) Polycose (8 kcal/ tsp) (Abbott)
3 oz
1.5 mL
2.5 mL
3 oz
2 teaspoons
3 teaspoons
*2728 cal/oz may not supply enough water for some infants. Hydration status and renal solute load should be carefully monitored.
Infants and children who are unable to meet their nutrition needs via the enteral route should be considered for parental nutrition (PN). PN can be initiated pre- or postoperatively with a therapeutic goal of restoring or maintaining nutrition status and inducing somatic growth. The optimal timing for initiating PN is dependent on the childs baseline nutrition status and disease acuity. In view of the relatively
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high prevalence of malnutrition in infants and children with congenital heart disease, aggressive nutrition support via PN is an appropriate approach to prevent a further decline in their nutrition status. PN formulation in children with congenital heart disease requires close electrolyte monitoring, especially in patients on diuretics and digoxin therapy. Growth impairment is frequently documented in children with congenital heart disease. It has been well documented that growth in children with congenital heart disease can be significantly improved with adequate caloric intake.14 Significant caloric intake not only considerably impacts the surgical outcomes but also the ultimate growth and development in children with congenital heart disease.
infants weighing less than 3 kg transesophageal echocardiography should be used cautiously.17 Protein-Losing Enteropathy Protein-losing enteropathy (PLE) is an abnormal loss of protein from the digestive tract or the inability of the digestive tract to absorb proteins. The prevalence of PLE in infants and children with congenital heart disease seems most prominent after the Fontan procedure (anastomosis of the inferior vena cava to the pulmonary artery, preferred surgical correction for tricuspid atresia, hypoplastic left heart, and single ventricle physiology). PLE can be a life-threatening complication with onset of the disease occurring from 2 months to 10 years postoperatively.18 Within 10 years of Fontan procedure surgery, approximately 13% of patients will develop PLE. Forty-six percent of PLE patients develop significant morbidity and mortality within 5 years.18 Children with PLE lose protein molecules from the blood into the intestinal tract resulting in changes in bowel habits, abdominal discomfort, and diarrhea. Over time the concentrations of serum protein can become severely depleted, resulting in hypoproteinemia and especially hypoalbuminemia. Hypocalcemia and lymphocytopenia are often seen in this condition as well. The loss of serum proteins decreases the vascular oncotic pressure and promotes the development of edema, ascites, and pleural as well as pericardial effusion. Edema of the intestinal wall secondary to chronic hypoalbuminemia may result in poor absorption of nutrients and promote worsening of the diarrhea.19 Nutrition Management Nutrition management of infants and children with PLE should be tailored to the severity of bowel dysfunction, diarrhea, and malabsorption. Dietary changes should include increasing protein intake and transition from longchain triglycerides (LCTs) to a medium-chain triglyceride (MCT) based diet. The use of a MCT-enriched diet is based on the understanding that enterocytes directly absorb MCTs into circulation, allowing delivery of adequate calories while reducing lymphatic flow to allow for healing. MCTs are rapidly absorbed and reduce the amount of highprotein lymph fluid moving through the vessels within the intestines, thereby reducing the quantity of protein loss. 20 Specialized nutrition support with the use of very high MCT (80% to 90% of the total fat content) containing formulas (Table 23-5) should be provided to infants and children with intractable diarrhea who are unable to maintain their nutrition status with standard formula.20 When using these formulas for long-term use, essential fatty acid
Complications After Congenital Heart Disease Surgery

Feeding Difficulties Infants and children often experience feeding difficulties following cardiac surgery. Increased risk adjusted congenital heart surgery (RACHS) score, prolonged intubation, and intraoperative transesophageal echocardiography have been identified as risk factors associated with feeding difficulties among infants and children with congenital heart disease after surgery.15 Problems encountered may include a prolonged time to reach feeding goals, prolonged transition to oral feeds requiring tube feeding at discharge, and aspiration or reflux.15 Postoperative vocal cord dysfunction is also a clinically important complication following cardiac surgery and may increase the risk of aspiration due to an impaired airway protection. In a study by Sachdeva et al patients whose surgery involved manipulation of the laryngeal nerves were at greater risk for vocal cord injury with the presumed cause being injury to the vagus nerve. An infant or child with vocal cord dysfunction may benefit from a swallowing evaluation to identify the presence of aspiration.16 Although in this particular study only 1.7% were identified as having vocal cord dysfunction, of these patients 100% had abnormal swallowing study results. Most of these patients need modified oral feeds and or nutrition support. Patients who undergo cardiac surgery with the use of transesophageal echocardiography have been associated with a high risk of dysphagia as well. Transesophageal echocardiography has been identified to cause airway obstruction, common pulmonary vein compression, vascular compression, tracheal extubation, esophageal perforation, gastric perforation, and dental injury. Transesophageal echocardiography probe size in relation to the patients weight was identified as a risk factor for dysphagia. In
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(EFA) deficiency should be monitored. In severe cases the use of total parenteral nutrition may be implemented to allow complete enteric rest to minimize lymphatic flow and promote healing.
Table 23-5 Medium Chain Triglyceride Formulas for Infants and Children > 1 Year of Age
MCT FORMULAS FOR INFANTS
Formula Pregestemil (Mead Johnson) Alimentum (Abbott) Portagen (Mead Johnson) Monogen (Nutricia) EleCare (Abbott) Enfaport (Enfamil) Formula Vivonex Pediatric (Nestle Nutrition) Peptamin Junior (Nestle Nutrition) Vital jr (Abbott) Neocate One + (Nutricia) Neocate Junior (Nutricia) Pepdite Junior (Nutricia)
MCT:LCT ratio 55:45 33:67 87:13 90:10 33:67 84:16 MCT:LCT ratio 69:31 60:40 50:50 35:65 35:65 35:65
MCT FORMULA FOR CHILDREN > 1 YEAR OF AGE
Chylothorax Chylothorax, a known complication of pediatric cardiac surgery, requires special nutrition support considerations. Chylothorax is the accumulation of chyle within the pleural space. The chyle leak can be the result of injury to the thoracic duct, disruption of accessory lymphatics, or from an increased systemic venous pressure exceeding that in the thoracic duct.2124 Studies have suggested that the increase in postoperative chylothorax complications from 1% or less in the 1970s and 1980s to 2.5% to 4.7% currently may be due to the increased complexity of the surgeries performed and possibly to the earlier initiation of enteral feeds. 21 Chan reported an incidence of 3.8% from 2000 to 2002 with a higher percentage occurring after heart transplant and the Fontan procedure. The challenge in managing chylothorax is in maintaining fluids and electrolytes while minimizing the lymphatic leak. Chylothorax can be corrected surgically but the results are not always favorable and not always feasible for children who are possibly already compromised after having had congenital heart surgery. Adverse affects of chylothorax include immunosuppression, need for longterm chest tubes and intravenous access, and prolonged hospitalization. 22 Postoperative length of stay is reported to be significantly longer with a median of 22 days versus
8 days if a chylous leak develops. 23 Conservative management is usually attempted prior to surgery for the resolution of the leak. Conservative management includes pleural space evacuation, the use of low-fat diets with MCTs, or total parenteral nutrition for complete enteric rest. The use of a MCT-enriched diet is based on the understanding that MCTs are readily absorbed by the enterocytes into circulation, providing adequate calories and minimizing lymphatic flow to allow for healing. 23 For formula feedings, a high-MCT low-LCT formula may be used (Table 23-5). To prevent EFA deficiency, 2% to 4% of total calories should be in the form of linoleic acid with 0.25% to 0.5% from linolenic acid. 24 If patients are on oral feedings and adequate calories can be consumed, a low-fat diet may be sufficient. In the study by EH Chan 34 of 48 patients (71%) had resolution with changes to their enteral diet. 23 Octreotide, a long-acting synthetic analogue of somatostatin, has been used as a treatment for chylothorax drainage that did not respond to dietary manipulations alone. In a study conducted between 19812004, 83% of patients receiving octreotide responded with complete resolution of their chylothorax after approximately 15 days of treatment and no side effects from the octreotide therapy were noted after 2 weeks of treatment. 20 In a study by EH Chan et al the patients had variable results. There was no decrease in drainage over the treatment period in 4 of 5 patients and it was thought that octreotide has a better outcome with a low-flow leak versus higher drainage patterns noted in patients in this study. The early diagnosis and treatment of chylothorax can reduce the length of the chylous leak. At present, dietary management is the mainstay of treatment when managing these patients conservatively.
Obesity is a rising epidemic in children. As obesity rises there is a potential for the increase of early onset coronary artery disease. Childhood obesity significantly increases morbidity and mortality from cardiovascular disease (CVD). 24 Freedman et al studied obese children using the Bogalusa Heart Study database, and found a relationship between obesity and blood pressure, low-density lipoprotein (LDL) cholesterol, triglycerides, insulin concentration, and low levels of high-density lipoprotein (HDL) cholesterol, all of which are risk factors for CVD. There is evidence that atherosclerosis, the progressive narrowing and hardening of the arteries, begins in childhood. 25
Cardiovascular Disease in the PediatricPatient
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Preventive measures must be taken in children who have been identified at risk for CVD. Table 23-6 helps identify these children.
Table 23-6 Classification of Total and LDL Cholesterol Levels in Children and Adolescents From Families With Hypercholesterolemia or Premature Cardiovascular Disease
Category Total Cholesterol (mg/dL) LDL Cholesterol (mg/dL)
Acceptable Borderline High
< 170 170199 > 200
< 110 110129 > 200
Adapted from American Academy of Pediatrics Policy Statement. Cholesterol in Childhood (RE9805). Pediatrics. 1998;101(1):141147.
The National Cholesterol Education Program (NCEP) discusses the effects of early elevated lipid levels on adult atherosclerosis and coronary heart disease risk. The program focuses on prevention and lowering of lipids in children and adolescents. Eating behavior and genetics affect cholesterol levels. Behavioral changes require intervention at several levels. Individual approach by itself is less effective. The key to success requires both a population and also an individualized approach. One of the goals of lowering cholesterol levels in children and adolescents is through changing the eating behaviors on a population-wide basis. The panel concurs with the recommendations issued by the National Cholesterol Education Program Expert Panel on Population Strategies for Blood Cholesterol Reduction, as well as the guidelines of the American Heart Association.27 It is recommended to include a variety of food and consume calories adequate to support growth and maintain an ideal body weight while keeping fat intakes at the recommended levels (Table 23-7).
Table 23-7* Recommendations for Fat and Cholesterol Intake in Children > 2 Years of Age Saturated fat Total fat intake Cholesterol *Step I Diet < 10% of total calories < or equal to 30% of total calories < 300 mg/d
Infants require additional calories and fat to support growth and development and therefore restricting fat intake is not recommended for children less than 2 years of age. To support their efforts for population-wide changes, the NCEP also provides recommendations for organizations that influence the eating behaviors of children such as schools, health professionals, government agencies, and the food industry.
The individualized approach aims to identify and treat children and adolescents who are at the greatest risk of CVD. This approach aims at screening children who are from families with a history of premature CVD or at least one parent with high cholesterol. Universal screening is not cost effective and may impose an unnecessary stigma on a child.27 Children identified with an elevated cholesterol level at an early age should be treated. Initial therapy should always be diet modification accompanied by life-style changes, minimizing sedentary life style and promoting physical activity. Once identified through the screening protocol as having elevated LDL levels, diet therapy should be initiated. The Step I Diet mimics the recommendations of the population approach (Table 23-7). If LDL levels remain elevated after 3 months of adhering to the Step I Diet, the Step II Diet should be initiated. The Step II Diet reduces saturated fat to less than 7% of calories and cholesterol to less than 200 mg/d. Drug therapy is suggested in children 10 years or older if diet fails after 6 to 12 months for those with LDL levels greater than 190 mg/dL or > 160 mg/dL if other risk factors are also present. In 2006 the American Academy of Pediatrics came out with a policy statement on cardiovascular risk reduction in high-risk pediatric populations. This policy outlines CVD risk stratification based on existing comorbidities and assesses cardiovascular risk factors to stratify patients into At Risk, Moderate Risk, and High Risk categories. Life-style changes to include diet, exercise, and cessation of smoking as well as disease-specific management are the basis of its recommendations in all 3 groups. Pharmacologic intervention is recommended only if goals are not met. 28 Reis et al looked at risk factors in children and investigated whether families at risk for CVD can be identified.29 The authors looked at children to see if identification of risk factors in them would help predict risk factors in their parents. This population was targeted as children are more likely to receive regular primary care than adults. The participants underwent assessment of cardiovascular risk factors: obesity, hypertension, dyslipidemia, and metabolic syndrome. Parent-child association was strong for BMI, waist circumference, systolic blood pressure, triglyceride, and total cholesterol. Risk factors in children were found to be significant predictors for the same risk factors for their parents. This study suggests that CVD risk factors in children can predict elevated CVD risk factors in parents. Obesity, hypertension, insulin resistance, and dyslipidemia, also known as the metabolic syndrome or syndrome X (Chapter 14), are risk factors for childhood CVD. Studies suggest that obese children with risk factors for CVD
254
become obese adults with increased risk of morbidity from CVD. Prevention and early intervention should be a primary goal of health professionals and government agencies. The NCEP has reported on these issues and implemented recommendations for dietary changes, screening, and treatment of children and adolescents who are identified as at risk for CVD and for developing into an adult withCVD. 30
Summary
Children with congenital heart disease often have difficulty achieving adequate caloric intake to support their growth and development. A child should be provided with nutrition support to maximize growth and development prior to corrective surgery. Enteral or parenteral nutrition support may be needed postoperatively until the childs condition allows for adequate oral intake. Surgical outcomes and catch-up growth rates have significantly improved with adequate calories being delivered to this population.4,9 Postsurgical complications may occur depending on the complexity of the defect and surgical intervention. Complications that may arise postoperatively include protein-losing enteropathy and chylothorax, which require specialized nutrition modifications. Pediatric cardiac disease over the past two decades has extended to include CVD. Preventing, recognizing, and treating these children holds promise of impacting CVD and its complications in the adult population. CVD risk factors have been well identified in children. The NCEP has put forth recommendations and guidelines for early identification and intervention in children at risk for CVD.
3. Failure to thrive in infants with congenital heart disease is secondary to: A. Poor caloric intake B. Increased energy expenditure C. Hypoxia D. All of the above 4. When selecting a formula for treatment of infants with a chylous leak the following characteristics should be considered: A. Only long-chain triglycerides (LCTs) B. Only medium-chain triglycerides (MCTs) C. Fat blend (high MCT and low LCT) D. Fat blend (high LCT and low MCT) See p. 487 for answers.
References
1. The potential for growth and nutrition recovery in children with congenital heart disease seems to be most affected by: A. Degree of growth impairment B. Feeding difficulties C. Energy intake/expenditure D. Age and timing of corrective surgery 2. Infants with congenital heart disease may require caloric intake of to thrive. A. 100 kcal/kg/d B. 120 kcal/kg/d C. 90 kcal/kg/d D. 140200 kcal/kg/d
1. Prsa M, Saroli T et al. Birth prevalence of congenital heart disease. Epidemiology. 2009;20:466468. 2. Leitch C, Karn C, Peppard R, et al. Increased energy expenditure in infants with cyanotic congenital heart disease. J Pediatr. 1998;133(6):755760. 3. Leitch C. Growth, nutrition and energy expenditure in pediatric heart failure. Prog Pediatr Cardiol. 2000;11:195202. 4. Vaidyanathan B, Nair S, Sundarum KR, et al. Malnutrition in children with congenital heart disease (CHD): determinants and short-term impact of corrective intervention. Indian Pediatr. 2008;45:541546. 5. Barton JS, Hindmarsh PC, Scrimgeour CM, Rennie MJ, Preece MA. Energy expenditure in congenital heart disease. Arch Dis Child. 1994;70:59. 6. Cameron JW, Rosenthal A, Olsen AD. Malnutrition in hospitalized children with congenital heart disease. Arch Pediatr Adolesc Med. 1995;149(10):10981102. 7. Mitchell IM, Logen RW, Pollock JCS, Jamieson MPG. Nutritional status of children with congenital heart disease. Br Heart J. 1995;73:277283. 8. Eskedal LT, Hagemo PS, Seem E, et al. Impaired weight gain predicts risk of late death after surgery for congenital heart disease. Arch Dis Child. 2008;93:495501. 9. Nydegger A, Bines JE. Energy metabolism in infants with congenital heart disease. Nutrition. 2006;(22):697704. 10. da Silva VM, de Oliveira Lopes MV, de Araujo TL. Growth and nutritional status of children with congenital heart disease. J Cardiovasc Nurs. 2007;22(5):390396. 11. van der Kuip M, Hoos MB, Forget PP, Westerterp KR, Gemke RJ, de Meer K. Energy expenditure in infants with congenital heart disease, including a meta-analysis. Acta Paediatr. 2003;92:921927. 12. Schwartz MS, Gewitz HM, See CC, et al. Enteral nutrition in infants with congenital heart disease and growth failure. Pediatrics. 1990;86(3):368373.
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13. Durai R, Venkatraman R, Ng P. Nasogastric tubes 2: risks and guidance on avoiding and dealing with complications. Nurs Times. 2009;105(17):1416. 14. Sy K, Dipchand A, Atenafu E, et al. Safety and effectiveness of radiologic percutaneous gastrostomy and gastrojejunostomy in children with cardiac disease. Am J Roentgenol. 2008;191(4):11691174. 15. Kogon BE, Ramaswamy V, Todd K, et al. Feeding difficulty in newborns following congenital heart surgery. Congenit Heart Dis. 2007 Sep; 2(5):332337. 16. Sachdeva R, Hussain E, Moss M, et al. Vocal cord dysfunction and feeding difficulties after pediatric cardiovascular surgery. J Pediatr. 2007;151:312315. 17. Kohr LM, Dargan M, Hague A, et al. The incidence of dysphagia in pediatric patients after open heart procedures with transesophageal echocardiography. Ann Thorac Surg. 2003;76:14501456. 18. Feldt RH, Driscoll DJ, Offord KP, et al. Protein-losing enteropathy after the Fontan procedure. J Thorac Cardiovasc Surg. 1996;112:672680. 19. Ostrow MA, Hudsen F, Rychik J. Protein-losing enteropathy after Fontan operation: investigations into possible pathophysiologic mechanisms. Ann Thorac Surg. 2006;83(2):695700. 20. Parrish RC, Krenitky J, Willcutts K, Radigan A. Gastrointestinal disease. In: Gottschlich MM, DeLegge MH, Mattox T, Mueller C, Worthington P, eds. The A.S.P.E.N. Nutrition Support Core Curriculum: A Case-based Approach The Adult Patient. Silver Spring, MD: American Society for Parenteral and Enteral Nutrition; 2007:524525. 21. Chan S, Lau W, Wong W, et al. Chylothorax in children after congenital heart surgery. Ann Thorac Surg. 2006;82:16501656.
22. Pelletier GJ. Invited commentary. Ann Thorac Surg. 2005;80:18701871. 23. Chan EH, Russell JL, Williams WG, et al. Postoperative chylothorax after cardiothoracic surgery in children. Ann Thorac Surg. 2005;80(5):18641879. 24. Hise M, Brown C. Lipids. In: Gottschlich MM, DeLegge MH, Mattox T, Mueller C, Worthington P, eds. The A.S.P.E.N. Nutrition Support Core Curriculum: A Case-based Approach The Adult Patient. Silver Spring, MD: American Society for Parenteral and Enteral Nutrition; 2007:4870. 25. Zalesin KC, Franklin BA, Miller WM, et al. Impact of obesity on cardiovascular disease. Endocrinol Metab Clin N Am. 2008;37:663684. 26. Freedman DS, Khan LK, Dietz WH, et al. Relationship of childhood obesity to coronary heart disease risk factors in adulthood: The Bogalusa Heart Study. Pediatrics. 2001;108(3):712718. 27. American Academy of Pediatrics Policy Statement. Cholesterol in Childhood. (R E9805). Pediatrics . 1998;101(1):141147. 28. American Academy of Pediatrics Policy Statement. Cardiovascular risk reduction in high-risk pediatric populations. Pediatrics. 2007;119(3):618621. 29. Reis EC, Kip KE, Marroquin OC, et al. Screening children to identify families at increased risk for cardiovascular disease. Pediatrics. 2006;118:17891797. 30. National Cholesterol Education Program (NCEP): highlights of the report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. NCEP Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 1992;89:496501.
Renal Disease
Christina L. Nelms, MS, RD, CSP, CNSC, LD, Marisa Juarez, MPH, RD, LD, and Bradley A. Warady, MD
24
Learning Objectives
1. Describe normal kidney physiology and causes of pediatric renal failure. 2. Discuss nutrition care for chronic kidney disease and acute kidney injury in pediatric patients. 3. Review nutrition needs and specifications for infants, children, and adolescents receiving supplemental enteral and parenteral nutrition. 4. Discuss specific nutrition needs for other kidney disorders in pediatrics, including nephrotic syndrome, nephrolithiasis, and renal tubular disorders. Kidney disease in children is rare, with an incidence of about 75 per million of the age-related population for all stages of chronic kidney disease (CKD).1 Children may have acute kidney injury (AKI) from infections such as Escherichia coli or from other comorbid conditions, such as sepsis or multisystem organ failure. CKD is often progressive in nature and may develop as a result of congenital or autoimmunetype conditions. Pediatric patients with CKD are more commonly male because congenital posterior urethral valves, which only occurs in males, is a leading cause of CKD.2 However, CKD may present acutely at an advanced stage. Many children only exhibit mild symptoms such as fatigue or flu-type illness until there has been a substantial progression of the kidney damage. Irrespective of the cause of kidney injury, these patients typically have a variety of nutrition issues that should be addressed for optimal patient management. This chapter is intended to review those issues for the clinician.
CONTENTS
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256 Kidney Development and Function . . . . . . . . . . . . . . . . . . 257 Chronic Kidney Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . 258
Hemodialysis Peritoneal Dialysis Growth and Development Nutrition Assessment Nutrition Requirements Fluid and Electrolyte Balance Cardiovascular Disease and Lipid Management
Renal Transplant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268 Acute Kidney Injury (AKI) . . . . . . . . . . . . . . . . . . . . . . . . . 269

Continuous Renal Replacement Therapy Neonatal Issues
Background
Enteral Nutrition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272

Infant and Toddler Feeding Tube Feeding for Older Children
Parenteral Nutrition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274

Intradialytic Parenteral Nutrition
Nephrotic Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 Nephrolithiasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274

Hypercalciuria and Calcium-Based Stones Other Kidney Stones
Renal Tubular Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . 276

Renal Tubular Acidosis Bartters Syndrome Nephrogenic Diabetes Insipidus
Other Renal Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . 278

Oxalosis Other
256
RENAL DISEASE
257
Human kidney development, or nephrogenesis, begins during week 5 of gestation. The first functioning nephrons are formed by week 9 and the entire process is completed by 32 to 34 weeks gestation. Once nephrogenesis has been completed, the kidney is unable to respond to injury by de novo generation of nephrons. Key components of nephrogenesis include formation of the pelvicalyceal system, renal tubular development, and glomerulogenesis. Urine production begins at about 10 weeks gestation and by 20 weeks gestation, it accounts for approximately 90% of amniotic fluid. 3 The fraction of cardiac output received by the kidneys is only 2.5% during late gestation. It increases to nearly 20% during the initial 6 weeks of life.4 Kidney function, as measured by creatinine clearance, doubles during the first 2 weeks of life in term infants and reaches adult values by 2 years of age. 5 Normal serum creatinine values also increase with age.6 Most important from the clinical perspective is the fact that the kidney is key to a variety of functions that, if impaired, may significantly alter body homeostasis. These functions influence solute removal, fluid/electrolyte/water status, calcium, phosphorus and vitamin D metabolism, erythropoietin production, acid-base balance, and blood pressure, all of which must be addressed medically if kidney function is decreased on an acute or chronic basis. Acute renal failure, more accurately called AKI, is commonly characterized as an abrupt (hours to weeks) and prolonged loss of kidney function that is reversible in most cases.7 It is typically accompanied by a change in creatinine clearance and possibly in urine output. The causes of AKI are divided into 3 categories: prerenal, renal, and postrenal. The categories localize the predominant site of injury and help describe the mechanism of injury. For example, prerenal AKI primarily includes the state of reduced renal blood flow that might result from diarrhea and vomiting, burns, bleeding, or congestive heart failure. Insults to the renal glomeruli or tubules can give rise to renal or intrinsic AKI. Sources of injury include glomerulonephritis (eg, postinfection,
Table 24-1 NKF KDOQI Classification of the Stages of Chronic Kidney Disease8
Stage GFR (mL/min/1.73 m2)
Kidney Development and Function
systemic lupus erythematosus, membranoproliferative diseases, and Henoch-Schnlein purpura); nephrotoxins (eg, aminoglycosides, amphotericin B, and heavy metals); interstitial nephritis; hemolytic-uremic syndrome; or acute tubular necrosis (ATN). Finally, postrenal or obstructive AKI can be the sequela of disorders such as nephrolithiasis, neurogenic bladder, hemorrhage, renal tumors, or posterior urethral severe valves in newborns. Strict attention to the etiology of AKI and prompt therapeutic intervention often result in a return to baseline kidney function. In contrast to the reversible nature of AKI, CKD is a manifestation of irreversible renal injury. It often progresses to end-stage renal disease (ESRD), also known as CKD5, and the need for dialysis (CKD5D) and/or transplantation. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines classify CKD in children greater than 2 years of age, adolescents, and adults by the presence of kidney damage and the level of estimated glomerular filtration rate (GFR) (Table 24-1).8 A variety of disorders are associated with the development of CKD in pediatrics, as reflected by data from more than 7,000 patients enrolled in the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry (Table 24-2).2 The 2 most common diagnoses are obstructive uropathy and a/hypo/dysplastic kidneys and only 4 diagnoses individually represent greater than 4% of the patients enrolled in the registry. There is clear evidence from clinical studies that both hypertension and protein uria play a key role in the progression of CKD to ESRD.9,10 The developmental abnormalities of the urinary tract that account for the largest percentage of patients with CKD stages I-IV logically account for the largest (eg, 30%50%) number of children with ESRD (stage V CKD), resulting in the affected children having a life-long experience with their respective kidney disorders and the requirement for long-term medical and nutrition intervention. 2
Description
1 2 3 4 5
> 90 6089 3059 1529 < 15 (or dialysis)
Kidney damage with normal or increased GFR Kidney damage with mild reduction of GFR Moderate reduction of GFR Severe reduction of GFR Kidney failure
GFR = Glomerular Filtration Rate
258
Table 24-2 CKD Primary Diagnosis2

All Patients N Total Primary Diagnosis 7037 % 100.0
Obstructive uropathy A/hypo/dysplastic kidney Focal segmental glomerulosclerosis Reflux nephropathy Polycystic disease Prune Belly Renal infarct Hemolytic uremic syndrome SLE nephritis Familial nephritis Cystinosis Pyelo/interstitial nephritis Medullary cystic disease Chronic glomerulonephritis Congenital nephrotic syndrome Membranoproliferative glomerulonephritis Type I Bergers (IgA) nephritis Idiopathic crescentic glomerulonephritis Henoch-Schnlein nephritis Membranous nephropathy Wilms tumor Membranoproliferative glomerulonephritis Type II Other systemic immunologic disease Wegeners granulomatosis Sickle cell nephropathy Diabetic glomerulonephritis Oxalosis Drash syndrome Other Unknown
1454 1220 613 594 278 193 158 141 114 111 104 99 90 82 75 75 66 47 43 37 32 30 26 25 14 11 7 6 1110 182
20.7 17.3 8.7 8.4 4.0 2.7 2.2 2.0 1.6 1.6 1.5 1.4 1.3 1.2 1.1 1.1 0.9 0.7 0.6 0.5 0.5 0.4 0.4 0.4 0.2 0.2 0.1 0.1 15.8 2.6
According to the 2009 NKF KDOQI Clinical Practice Guideline for Nutrition in Children with CKD, the energy requirements for CKD stages 3 to 5 should be the estimated energy requirements (EER), with an adjustment for physical activity and body size.12 There is no evidence suggesting patients with CKD stages 3 to 5 have higher energy needs compared to healthy controls. However, these patients need regular assessments to adjust for inappropriate weight gain or loss. If energy needs cannot be met with regular solid food intake, consider oral supplementation with a product that meets any electrolyte, mineral, and/or fluid restrictions. Supplementation can include modulars of glucose polymers, protein, or fat if necessary to meet nutritional needs. Many of the metabolic complications of CKD are similar to those of AKI and ESRD, which will be discussed later.
Hemodialysis
Hemodialysis (HD) is the use of a machine to dialyze soluble substances and water from the blood by diffusion through a semipermeable membrane, using a catheter placed centrally or a fistula. It is often done for 3 to 5 hours, 3 or more times per week for patients in CKD5 who cannot live without regular dialysis. Malnutrition is a significant complication of CKD and a strong predictor for morbidity and mortality for adults receiving maintenance HD.1315 Protein-energy malnutrition (PEM) produces profound effects on growth and development and may be associated with increased risk of hospitalization and mortality in children on HD.13,16,17 In addition to dry weight, length/height, weight-forlength, body mass index (BMI)-for-age, head circumference, dietary intake, and serum albumin, the 2009 NKF KDOQI nutrition guidelines now include recommendations on monitoring normalized protein catabolic rate (nPCR) for children on HD. The primary biochemical marker of nutrition status has been albumin. However, recent studies indicate nPCR is superior to albumin as a marker of nutrition status in children on maintenance HD.16,18,19 These studies show serum albumin to be a poor indicator of nutrition status. Research also demonstrates that intradialytic parenteral nutrition (IDPN) significantly improves weight gain and nPCR in malnourished patients on HD.16,18 A nPCR of < 1 g/kg/d is a strong predictor of weight loss in adolescent patients.19 The protein catabolic rate (PCR) is a measure of protein intake. The nPCR is the PCR normalized to a function of body weight, measured in grams of protein per kilogram per day. nPCR is determined by first calculating the urea generation rate (G):
CKD is a permanent condition that involves a progressive loss of kidney function. The National Kidney Foundation describes 5 stages of CKD partially defined according to GFR that apply to children > 2 years of age11 (Table 24-1). A GFR of 90 or greater is considered normal. Stage 1 is a GFR of > 90 mL/min/1.73 m 2 with evidence of kidney damage, such as protein in the urine. There are added clinical signs of impaired kidney function as GFR decreases. At stage 5, the final stage defined by a GFR of < 15 mL/min/1.73 m 2 , the child requires dialysis or transplantation.
Chronic Kidney Disease
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G (mg/min) = {(C2 V2) (C1 V1)}/t where C2 = predialysis blood urea nitrogen (BUN) (mg/dL) C1 = postdialysis BUN V2 = predialysis total body water (dL; V2 = 5.8 dL/kg predialysis weight in kg) V1 = postdialysis total body water (dL; V1 = 5.8 dL postdialysis weight in kg) t = time (minutes) from end of the dialysis treatment to the beginning of next treatment. Then, using a modified Borah equation, nPCR is calculated: nPCR (g/kg/d) = 5.43 est G/V1 + 0.17 where V1 = postdialysis total body water (L; V1 = 0.58 postdialysis weight in kg)
Peritoneal Dialysis
Peritoneal dialysis (PD) is typically recommended for infants, toddlers, and approximately 50% of adolescents needing dialysis treatment. It is usually a nightly process. PD involves infusion of a glucose-based solution through a catheter surgically inserted into the peritoneal cavity. Diffusion allows for waste products to cross the peritoneal membrane. Fluid is then drained from the peritoneal cavity and fresh fluid is infused. In most children, this process occurs over 10 to 12 hours while they sleep. A daytime dwell is often left in the cavity during the day and drained before nightly dialysis is resumed. The peritoneal membrane transport capacity can be determined by conducting the Peritoneal Equilibration Test (PET). Patients may be classified as high, high-average, low-average, or low transporters depending on how rapid solute (eg, creatinine, glucose) moves across the peritoneal membrane during a 4-hour test exchange. High transporters tend to have more porous peritoneal membranes and thus rapidly remove waste products such as creatinine, but also tend to lose significant amounts of potassium and protein across the peritoneum. The rapid absorption of glucose from the dialysate decreases the osmotic gradient and results in less fluid removal from these same patients. In contrast, low transporters tend to remove less kidney waste, but also lose less protein and potassium and remove fluid well. The nutrition prescription for the peritoneal dialysis patient is, in turn, often influenced by what kind of transporter the PD patient is.
Children receiving PD typically have a poor energy intake, often taking in less than 75% of needs.20 Even after accounting for glucose calories derived from the dialysis fluid, energy intake is still often insufficient. On the other hand, protein intake is generally sufficient. Reduced height, weight, and muscle mass are common findings, although the reduced weight and muscle mass for age may be consistent with overall short stature and size as these patients are often proportional. Many plasma proteins, including albumin, total protein, transferrin, and individual amino acids, are found to be decreased in patients undergoing PD. Although these patients do lose about 7% to 10% of protein intake (depending on body surface area) into the dialysis effluent, inadequate caloric intake or uremia can affect amino acid and protein profiles.20,21 Infants on PD have twice the protein losses per square meter of body surface area than adult-sized adolescents22 and thus may need greater protein supplementation per kilogram. However, it is important not to provide excessive protein intake. Excess protein has been shown to increase body acidity, creating poor bone mineralization. Sometimes patients may have extreme protein losses in urine or through the peritoneum. Increasing protein far above the dietary reference intake (DRI) may just exacerbate further protein loss in these patients and create a high acid load. Use clinical judgment when assessing protein-related laboratory values to determine if added protein will benefit hypoalbuminemic patients. Adequate, but not excessive, amounts of protein are important in this population.23 Serum triglycerides and cholesterol are often elevated, likely due to dextrose infusion of PD. Younger children (<10 years of age) often have more lipid abnormalities than older children.20 Similar to nPCR in HD, protein equivalent of nitrogen appearance (PNA) has been recommended to assess dietary protein intake in adults receiving PD. In adults PNA is calculated by measuring urea nitrogen content of both urine and dialysate, and then multiplying the result by 6.25 with a modification for pediatrics. However, it is only valid when the patient is not anabolic or catabolic and can have great variability.12 Protein metabolism is age dependent, with younger children having greater differences. Due to these factors and limited pediatric data, PNA is not routinely performed in pediatric patients.24
Growth and Development

Poor growth is a common manifestation of CKD in children. Growth velocity suffers as GFR declines. Many factors contribute to growth failure, including decreased
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appetite with poor energy intake, acidosis, excessive urinary sodium losses, renal osteodystrophy, and abnormalities of the growth hormone-insulin-like growth factor (GH-IGF) axis.25 Steroid therapy may also contribute to poor growth. One of the goals of nutrition intervention in the pediatric CKD patient is to promote growth. Linear Growth and Growth Hormone There are many factors that may affect growth, such as age at onset of kidney disease, the primary renal disease, and the quantity of residual kidney function. However, adequacy of
Figure 24-1 Short Stature Assessment and Treatment Algorithm26
nutrition and treatment of growth hormone resistance are treatable components and will be discussed in this context. Linear growth in children with CKD is often impacted by the nutrition status of the patient. Adequacy of nutrition should be assessed prior to consideration of growth hormone (GH) therapy (Figure 24-1).12,26 Evidence suggests that improved dialysis, as indicated by better solute clearance, along with caloric and protein intake at or above the recommended intake for age, helps prevent growth failure.27 Supplementation by gavage feedings may be needed to meet nutrition needs.
Reprinted with permission from: Mahan JD, Warady BA. Assessment and treatment of short stature in pediatric patients with chronic kidney disease: a consensus statement. Pediatr Nephrol. 2006;21:917930.
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In young children, growth failure is primarily mediated by inadequate nutrition. Adequate caloric intake, adjusting calories based on height and weight gains, is essential for adequate growth in infants and toddlers. Common causes of CKD in infants and toddlers are congenital disorders, such as obstructive uropathy and renal dysplasia, with associated sodium wasting and polyuria. In children with these disorders, supplementation of water and 2 to 4 mEq of sodium (as chloride, bicarbonate, or both) per 100 mL of formula is recommended.28 KDOQI pediatric nutrition guidelines recommend correcting the serum bicarbonate level to at least 22 mmol/L.12,26 Adequate sodium supplementation and correction of acidosis is essential for growth. GH insensitivity/resistance and alterations in the somatotropic hormone axis are other significant factors influencing the growth of children with CKD. Typically, growth occurs as a result of the action of insulin-like growth factor 1 (IGF-1), a product released from the liver following stimulation by endogenous GH. In children with CKD, serum levels of IGF-1 binding proteins may be increased seven- to tenfold, due to a reduction in renal filtration. The increase in IGF-1 binding proteins decreases the free or bioactive levels of IGF-1 and, as a result, limits growth despite normal or elevated levels of circulating GH. Additionally, inadequate protein or caloric intake may impair GHs ability to stimulate IGF-1. In this situation, therapeutic doses of recombinant human growth hormone (rhGH) may be given to patients with CKD, resulting in improved height velocity.29 The KDOQI Clinical Practice Guideline for Nutrition in Children with CKD indicates that children with CKD (including transplant patients) and a height or height velocity standard deviation score (SDS) < 1.88 or height-for-age < 3rd percentile qualify for treatment with rhGH.12 A Cochrane review of studies assessing GH in children with CKD, including predialysis, dialysis, and transplant patients, indicates that treated children had a significant increase in height SDS and height velocity at 1 year after starting therapy. The reported side effects are similar to control patients. 30 Despite the safety and efficacy of the therapy, rhGH is currently used in only a minority of growth-retarded children with CKD, which is especially concerning for those who could benefit the mostyoung children and those in the early stages of CKD. Some of the reasons for the underutilization of rhGH include family refusal, secondary hyperparathyroidism, and noncompliance, as recently reported by Greenbaum et al. 31 However, in this study 51% of patients with short stature did not receive GH and 25% of those patients did not have an apparent
explanation. According to the authors, many of the factors leading to nonuse may have been resolved with intervention. Although kidney transplantation may improve the growth of younger children, many older children do not achieve adequate catch-up growth with transplantation alone. This situation may change with the introduction of steroid-free immunosuppressive regimens. Most important is that poor final adult height affects quality of life, and there may be other psychosocial implications for short children and adolescents. Although likely not a direct relationship, poor height has been associated with increased mortality and hospitalizations. Figure 24-1 reviews the process of growth evaluation and rhGH initiation and monitoring, including the essential assessment of nutrition parameters prior to its initiation.26 A dose of 0.35 mg/kg/wk is suggested for children with renal disease. Adequacy of Weight Gain Weight gain should be monitored often, with the most frequent assessments occurring with infants and toddlers with CKD. Dry weight should be used when assessing weight parameters (see Dry Weight, below). If poor weight gain occurs, contributing factors should be identified and corrected. Many patients with CKD have a compromised and/or restricted dietary intake, and nutritional supplements are required to meet age-appropriate nutrition goals. Oral supplements should be provided first, followed by tube feeding (nasogastric or gastrostomy) if deemed necessary. Infants with significant CKD typically demonstrate delays in feeding and often require enteral tube-feeding support for an extended period of time.16 In fact, tube feeding may provide relief to parents and caretakers concerned about their childs poor intake. Some children may require more aggressive nutrition therapy (eg, IDPN) to help reverse a catabolic state (see Intradialytic Parenteral Nutrition, below). It is important to recognize that all infants receiving a substantial portion of their daily nutrition needs by a non-oral route need continued oral stimulation to promote normal oral motor development. Finally, there is some preliminary evidence suggesting intensified and daily HD may be associated with improved growth and nutrition status. 32,33 More research on this subject is needed.
Malnutrition is a serious complication of CKD, especially in CKD5D. There is no single measurement to adequately define nutrition status in CKD.25,16 It is challenging to assess this population due to the metabolic and growth complexities that are present. Early nutritional intervention may be
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critical in optimizing growth and development. KDOQI recommends routine monitoring of the following parameters in children with CKD.12 The recommended frequency of assessment can be found in the KDOQI guidelines. Dry Weight: Dry weight is the patients weight at a euvolemic state. Dry weight should be assessed regularly and used when assessing growth, including weight-for-age and BMI-for-age. In oliguric or anuric patients requiring dialysis, fluid overload will influence weight as well as will other anthropometric measures such as head circumference and mid-arm circumference. Fluid overload is the most common source of error in measuring anthropometric data in this population. 34 In other renal diseases in which urine-concentrating capacity is impaired and volume depletion is common, dry weight is equally important in assessing growth. Length/Height: Length or height should be measured as in other pediatric populations. Length- and heightfor-age trends are an indication of the chronic nutrition status. Height velocity can be assessed using reference data from the Fels Longitudinal Study. 34 This can be assessed in 6-month intervals. Weight-for-Length: This calculation is used for children < 2 years to assess weight-to-length proportion. BMI-for-age: BMI should be used in patients with kidney disease as with assessment of other pediatric populations. Dry weight should be used when calculating BMI-for-age. Because there is a predisposition for stunted growth and developmental delays in CKD, BMI-for-height age (the age at which height is at the 50th percentile) may be more appropriate in assessing BMI and ideal body weight. Using chronological age to assess BMI and ideal body weight may actually overestimate ideal body weight. 35 Studies have shown a U-shaped curve in BMI-for-age versus mortality risk, meaning that both a very high and a very low BMI is associated with an increased risk of mortality in kidney disease. 36 Head Circumference: As described in the nutrition assessment chapter (Chapter 33), regular measurements should be taken through 3 years of age and plotted on the 2006 World Health Organization head circumference-for-age curve.12 Note any variance not associated with a comorbidity. Dietary Intake: Dietary intake should be assessed regularly. A 3-day food diary or 3 24-hour diet recalls with at least 1 weekend day are acceptable methods to measure intake. Both have limitations, but they can be useful in
gaining a better understanding of actual intake patterns and eating behaviors.12 Serum Albumin: The 2000 KDOQI pediatric nutrition guidelines include serum albumin as a marker of nutrition status. However, recent studies highlight the limitations of using albumin in this manner, including its long half-life and the dilutional effect of excess fluid. Also, lower levels are often a manifestation of inflammation, increasing the association of increased risk of mortality with hypoalbuminemia. 37 Therefore, serum albumin may be used as a nutrition status marker, but with caution if hypoalbuminemic factors such as acute physiological stress or fluid overload are present. 35 Specifics on nutrition assessment (Table 24-3) are included in the chapter on nutrition assessment (Chapter 33). Unless specifically described, the calculation and assessment of these measurements apply to patients with renal disease as well as other populations.
Table 24-3 Nutrition Assessment12,34-37 Anthropometrics Dry (Target) Weight & Weight-for-age percentile Length or Height-for-age percentile Length or height velocity-for-age percentile Weight/Length percentile (for < 2 years) BMI-for-age percentile (for > 2 years)* Body Weight* Ideal Head circumference-for-age percentile (for < 3 years) * BMI-for-height age percentile and ideal wt based on BMI-for-height age may be more appropriate Medical History Assess for conditions relevant to nutrition status and care Intake Assessment Tools Food diary Diet recall: 24-hour recall x 3 Labs Electrolytes: Na, K, Cl, bicarbonate Minerals: Ca, Phos, Mg Glucose Lipids: Triglycerides, cholesterol Renal Function: BUN, Cr Malnutrition signs nPCR (HD) Fluid Status Blood pressure Urine output I/O HD: non-invasive monitoring, intradialytic weight gain Medications Assess for medications that may influence nutrition parameters
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Macronutrients
Energy
The estimated energy requirement (EER) for energy is the recommended starting point for pediatric patients with CKD stages 3 to 5.12 A balance of calories from all 3 macronutrientscarbohydrate, protein, and fatis desirable. The recommended range of 45% to 65% of energy from carbohydrate and 30% to 40% from fat as set by the Institute of Medicine (IOM) is acceptable for children with CKD. Because cardiovascular disease (CVD) is a significant and frequent complication of CKD in children, carbohydrate and fat sources should be closely monitored and altered in the setting of dyslipidemia. Diet management of dyslipidemia should include heart-healthy fats such as monounsaturated and polyunsaturated fat rather than saturated or trans fats. 38,39 Complex carbohydrates should replace simple sugars. If carbohydrate and fat modules are needed to increase calories to promote growth while conforming to fluid restrictions, add them proportionally to keep the macronutrient content consistent with the base/ standard formula. (See Cardiovascular Disease and Lipid Management section, below, for further discussion.)
Protein
Micronutrients Children with CKD are at risk for micronutrient deficiencies due to poor intake, poor absorption, abnormal renal metabolism, medication interactions, and potential dialysis losses. Adequate intake of fat-soluble and water-soluble vitamins, zinc, and copper should be encouraged. There is risk to growth and overall health if these micronutrients are deficient. Supplementation of these vitamins and minerals is necessary if dietary intake is low or if there is clinical evidence of a deficiency and/or low blood levels. Because excess losses of water-soluble vitamins are possible in all dialysis patients, all children with stage 5D CKD should take a water-soluble vitamin supplement.12
Fat-Soluble Vitamins
Children with CKD may demonstrate lower dietary protein intakes compared to healthy children. If children are unable to consume adequate amounts of protein to meet their needs, protein modulars or concentrated formula may be used. However, if there is evidence of a high protein intake, it may be beneficial to restrict protein intake to 100% to 140% of the DRI in children with CKD stage 3 and up to 100% to 120% of the DRI in CKD stages 4 and 5.12 By restricting protein, phosphorus is also restricted which may prove beneficial in terms of preventing CVD and helping to control renal osteodystrophy, the so-called chronic kidney diseasemetabolic bone disorder (CKD-MBD). Because CVD increases mortality and an abnormal calcium and phosphorus balance is a nontraditional risk factor for CVD (see section on Cardiovascular Disease), regularly evaluate protein intake as a source of excessive phosphorus intake. Patients on HD may only require 0.1 g/kg/d more than the DRI to account for dialytic losses. PD patients may only require 0.2 g/kg/d to 0.3 g/kg/d more than the DRI.12 However, other factors, such as inflammation or recent infection, which may contribute to protein catabolism should be considered when making recommendations on protein needs.
Both dialysis and predialysis patients with significant renal impairment have high retinol levels, despite having a normal intake of vitamin A. This may be because of increased retinol-binding protein found in renal failure. Although elevated retinol levels are not found to be toxic to these patients, supplemental vitamin A to patients with renal impairment is not recommended.4042 There has been some concern that excess vitamin A levels may be associated with altered calcium homeostasis and hyperparathyroid bone disease in adults with CKD. More evidence indicates the association is not a concern and oral intake from food should not be limited.43 Vitamin D has a significant and unique role when discussed in the context of CKD. It is well known that vitamin D synthesis from the inactive to active form takes place in the kidney, and patients with CKD typically need supplementation with the active form of vitamin D, calcitriol. As GFR declines, plasma concentrations of 1,25-dihydroxyvitamin D (1,25-(OH)2D) decline concurrently. There usually is a concurrent increased parathyroid hormone (PTH) level, inducing secondary hyperparathyroidism.44 Limitation of dietary phosphorus can improve 1,25-(OH)2D levels, which will be discussed later.45 Recent research indicates that dietary or inactive vitamin D (25-hydroxyvitamin D) may also have an important role in bone metabolism. Low plasma 25-hydroxyvitamin D is an independent and major risk factor for hyperparathyroidism, infection, and autoimmune diseases, even in healthy children.46,47 Recent evidence also indicates that 25-hydroxyvitamin D may be necessary for bone metabolism and is often deficient in children with CKD. The KDOQI Clinical Practice Guideline for Nutrition in Children with CKD suggests measuring serum 25-hydroxyvitamin D levels at least once per year and
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supplementing with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) if levels are < 30 ng/mL. Once levels are replete, a maintenance supplement of up to 800 International Units and yearly serum levels are appropriate.12 Serum vitamin E levels are often elevated in CKD and vitamin E is not cleared well by dialysis.42 However, recent evidence suggests that vitamin E may be beneficial in the treatment of anemia. In one centers study of 10 children on HD, patients given 15 mg/kg/d of vitamin E had improved hemoglobin and hematocrit when compared to control patients on epogen alone. Vitamin E therapy was also found to reduce oxidative stress and insult. Some vitamin E supplementation may be beneficial for patients who are anemic.48 However, excessive vitamin E intake is not recommended due to poor renal clearance. Vitamin K is synthesized by the intestine and there is no evidence of dialysis losses. Unless a patient is receiving long-term antibiotic therapy, there is no need for supplementation in CKD.12
Water-Soluble Vitamins
A water-soluble vitamin supplement may be appropriate for children with CKD stages 3 to 5 if dietary intake and/ or laboratory values are low. Supplementation is recommended for CKD stage 5D due to potential dialysis losses. Low intakes of many water-soluble vitamins are common in patients with CKD, often because of dietary phosphorus restrictions and poor intake due to uremia. Additionally, many water-soluble vitamins are lost during dialysis treatments. Adult patients who receive continuous ambulatory peritoneal dialysis (CAPD) have been documented to have low levels of vitamin B1 (thiamin), vitamin B6 (pyridoxine), folic acid, and vitamin C.42 Vitamin B12 (cyanocobalamin) and B2 (riboflavin) were normal. Low intakes of vitamins B1, B6, and B12 were also noted. Supplementation of watersoluble vitamins produced increased levels of B6, folic acid, and vitamin C. Similar vitamin losses have been noted in HD patients. Biotin, riboflavin, and vitamin B12 have been found to be normal in these same HD patients. Vitamin C and folic acid levels, while low, have been easily corrected with low-dose supplementation. Vitamin B6 and vitamin B1 are typically low, requiring supplementation.49 Hyperhomocysteinemia is common in children with CKD. However, only a small percentage of these have low folate levels, and a smaller percentage have low vitamin B12 levels. 50 Treatment with 1 mg of folic acid has been shown to improve homocysteine levels significantly and to increase serum folic acid levels in pediatric patients. 51 Whether there is improved morbidity and morbidity outcomes is unknown.
A large study of adult patients treated with high-dose folic acid, vitamin B6, and vitamin B12 did have lower serum homocysteine levels, but no evidence was found of improved cardiovascular morbidity or mortality. This study was consistent with studies in the general population regarding cardiovascular risk with homocysteine. High doses of folic acid can potentially mask a vitamin B12 deficiency. 52 Another consideration for folic acid supplementation is to improve erythropoietin-resistant anemia. Five milligrams of folic acid has been found to improve hemoglobin and reduce epogen requirements in pediatric and adolescent HD patients. 53 In light of this evidence, folic acid supplementation is likely beneficial to pediatric patients in moderate doses as part of a standard renal multivitamin supplement. It may not be as critical as earlier research indicated. Although vitamin B6 losses are minimal in children on PD, intake is typically limited due to poor appetite and dietary restrictions, resulting in low serum levels. Supplementation of 2 mg/d is considered appropriate. 54 Intake of vitamin C, like the B vitamins noted above, is often poor in CKD. Vitamin C is also lost through dialysis treatment. Supplementation of vitamin C, as part of a water-soluble vitamin supplement, is recommended for CKD patients stages 3 to 5 who are at risk for deficiency and for all CKD stage 5D patients. However, excess amounts of vitamin C may be detrimental. Ascorbic acid and amino acids are precursors to oxalate. High doses of vitamin C may contribute to higher blood oxalate levels which, along with the reduced oxalate clearance common in renal damage, can contribute to secondary oxalosis. Therefore, it is key to assess predialysis patients for adequate vitamin C intake to determine need for supplementation, remembering vitamin C excretion is not impaired with declining renal function. For dialysis patients supplement only to approximately the DRI or slightly higher, enough to replace dialysis losses.12,55 There are currently no pediatric renal vitamins available on the market in the United States. However, many adult-formulated vitamins are appropriate for older children and adolescent patients. The goal is to find a vitamin with a content that is close to or slightly above the DRI for age for the patient in question. Adult preparations of liquid renal vitamins are also available and smaller doses can be titrated to more closely meet the DRI requirements for younger children and infants.12 Many adult renal vitamins provide much more than the DRI for younger children and, consequently, supplemented children may have normal or above-normal serum concentrations of vitamins, including thiamin, riboflavin, vitamin B6, and folic acid. Because these vitamins are water soluble, it is not likely to cause harm.41
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Infants may receive more vitamins and minerals than older children due to the use of infant formula. 56 However, a small dose of a renal-appropriate vitamin may still be necessary to replenish dialysis losses.
Minerals
disease, and serum levels. Fluid control is important to minimize interdialytic weight change in dialysis patients. An intradialytic change of < 5% is optimal.12 Fluid control is also necessary to control blood pressure.
Sodium
An inadequate intake of zinc and copper is frequently found in patients with CKD due to diet restrictions, dialysis losses, and poor oral intake. Zinc metabolism has been noted in chronic renal disease and nephrotic syndrome with low serum levels, especially in the face of proteinuria and uremia. 57 Zinc levels typically improve within one year of renal transplant. Zinc deficiency can cause impaired wound healing, skin changes, anemia, taste changes, and growth retardation, among other problems. Children on PD have been found to have losses of zinc across the peritoneum with resultant low serum levels. These levels improve with supplementation of zinc. 58 A small, single-center study indicates that copper levels may be low in CKD stage 5D patients due to medication interaction. 59 Thus, assess both zinc and copper levels on a regular basis in dialysis patients; semi-annually is suggested. Supplementation to the DRI if low, or to therapeutic levels if critically low, may improve serum values. Nondialysis patients may need to have zinc levels checked if they present with poor intake or show clinical symptoms of zinc deficiency. Abnormalities of selenium metabolism have also been noted in patients with CKD. In a study of adult HD patients, plasma selenium levels were found to be significantly lower than controls, but corrected with supplementation. 60 Selenium is noted to be involved with the regulation of thyroid function, and low thyroid-stimulating hormone (TSH) levels and increased T3 levels were found in these patients. However, there have been no studies of selenium in children with CKD and supplementation is not recommended at this time.12 Iron deficiency, manifesting as anemia, is typical in CKD. The primary cause is insufficient production of erythropoietin (EPO) by the impaired kidneys. Iron deficiency, blood loss from medical procedures, hyperparathyroidism, and acute or chronic inflammation may all contribute. Anemia is typically managed with therapeutic doses of EPO and iron supplementation, as needed. 61 However, the intricacies of anemia require medical management and thus are outside the scope of this chapter.
Sodium is often restricted to help control volume overload and blood pressure. According to the 2005 Dietary Guidelines for Americans older than 2 years, all individuals with hypertension should limit sodium intake to <1500 mg/d.62 This is complicated by the environmental cues and peer pressures that promote high sodium intake, especially where fast food is concerned. Stringent sodium restrictions are challenging. A more reasonable sodium restriction of 2000 to 3000 mg/d may be better accepted and hence adhered to in older children or adolescents. The amount of sodium restriction needed should be based on individual patient parameters such as blood pressure, fluid gains, and nutrition intake. Most sodium in the diet comes from processed foods. Therefore, an increased intake of fresh foods versus processed or canned foods will decrease dietary sodium intake. Using natural herbs and spices to season foods versus table salt is extremely helpful in reducing sodium content in foods. It is not only important to educate patients on low-sodium foods, but also on how to read nutrition facts labels. According to the U.S. Department of Agriculture (USDA), foods with < 5 mg sodium per serving are considered sodium- or salt-free. Foods with < 35 mg sodium per serving are considered very low sodium; and foods with <140 mg sodium per serving are low sodium.62 The use of salt substitutes is often contraindicated in CKD patients because potassium chloride is typically substituted for sodium chloride. Potassium chloride can cause hyperkalemia in those at risk for the condition. Some PD patients may lose large amounts of potassium across their peritoneal membrane and may actually benefit from additional potassium. Infants and children with CKD often have primary disorders such as posterior urethral valves that cause polyuria and salt wasting. These children must have supplemental sodium and free water to maintain proper balances.
Potassium
Fluid and Electrolyte Balance

Fluid and electrolyte restrictions will vary among individuals according to urine output, stage of CKD, primary
Dietary potassium is often restricted to prevent hyperkalemia because as kidney failure progresses, the ability to excrete potassium is decreased. Hyperkalemia can, in turn, lead to impaired muscle function, including the heart, resulting in cardiac death. When dietary management is not sufficient to keep serum potassium levels acceptable, medication may be
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necessary to prevent or treat hyperkalemia. It is important to remember that certain medications, such as steroids and ace-inhibitors, have a drug-nutrient interaction that causes hyperkalemia. Hypokalemia can occur in certain diseases such as Fanconis syndrome in which a renal tubular defect is present. CKD5D patients on PD may filter out large amounts of potassium, often requiring a high-potassium diet to maintain normal serum levels.12,63 Adult patients are typically advised to limit potassium to 2000 to 3000 mg/d. There is no direct evidence for appropriate amounts for children. However, an extrapolation of the 2000- to 3000-mg recommendation is < 30 to 40 mg/kg/d or 0.8 to 1 mmol/ kg/d. However, for infants and young children, 1 to 3 mmol/ kg/d may be an appropriate place to start.12 Restriction can be adjusted based on individual tolerance and serum lab values.
Phosphorus
It is well known that elevated phosphorus levels increase PTH levels in patients with CKD, even as early as stage 3 CKD. Elevated PTH levels lead to high bone turnover, increasing risk for bone calcium loss and consequent calcium deposition in organs and small vessels (CKDMBD). A low oral intake of phosphorous in the diet can help prevent elevated serum phosphorus and PTH levels. Even when phosphorus levels are normal in the earlier stages of CKD, limiting oral phosphorus intake can improve PTH values and increase 25-hydroxyvitamin D levels.45 Low levels of active Vitamin D (calcitriol) exacerbate phosphate retention, which increases calcium bone loss. Supplementation of vitamin D is necessary to increase calcium uptake by the gut and suppress the parathyroid to prevent calcium bone loss. The downside of vitamin D therapy is that it also increases phosphorus absorption, possibly increasing serum phosphorus levels.64 Consequences of excess phosphorus intake in patients with advanced stages of CKD are increased cardiovascular morbidity and mortality. An elevated calcium X phosphorus product can result in calcification of soft tissues and small vessels. In adult patients, a phosphorus level above 6.5 mg/dL is correlated with an increased risk of death, and those with the highest calcium X phosphorus product have the greatest risk.65 The KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Children With Chronic Kidney Disease indicate that the calcium X phosphorus product in pediatric patients should be < 65 mg2/dL2 in children 12 years of age and younger and < 55 mg2/dL2 in adolescents > 12 years of age.65 These guidelines also recommend that serum phosphorus
levels should be maintained within age-appropriate reference ranges for CKD stages 1 to 4; and between 4 to 6 mg/ dL for ages 1 to 2 years and 3.5 to 5.5 mg/dL for adolescents for CKD stage 5 and 5D. Hypophosphatemia that arises due to phosphate wasting disorders, overcorrection, or other causes should be corrected by liberalization of diet or medication changes. Hypophosphatemia is associated with increased morbidity or mortality and poor growth. The KDOQI pediatric bone guidelines also suggest that when PTH levels are elevated for the given stage of CKD, dietary phosphorus should be limited to the DRI for age. When phosphorus values and PTH values exceed reference ranges for age and stage of CKD, phosphorus should be limited to 80% of the DRI.12,66 However, this guideline can equate to low intake in children younger than age 8. It should be noted that less than 500 mg of phosphorus, even in young children, may not allow for adequate caloric intake. An exception are children who get a controlled amount of phosphorus via a set amount of enteral formula by mouth or feeding tube. Limiting phosphorus in the pediatric diet may be a challenge, especially as fast food and convenience food increases in the usual diet of children and adolescents. About 60% of dietary phosphorus is absorbed from the typical naturalfood mixed diet. Assuming natural foods are consumed, the average adult man consumes an average of 1550 mg of phosphorus per day, with over half consuming more than 1600 mg daily. The average woman consumes about 1000 mg daily. Foods high in protein typically contribute the most phosphorus in a natural diet with dairy and meats, including fish, providing 20% to 30% each of the usual daily intake. These numbers are increasing as more instant and restructured foods as well as colas, which have phosphate additives, are on the market. Foods made with phosphate additives, including many instant and restructured foods, have almost 100% absorption of phosphate content. Estimates are that these foods could contribute to dietary phosphorus intake by about 1 gm daily, even with unchanged protein and calcium intakes.67 Additionally, Sullivan et al looked at chicken products with phosphate-containing additives and found that the phosphorus content of these products was higher in every instance than the phosphorus content expected from a nutrient database, averaging 84 mg/100 g of product or greater. This study concludes that standard nutrition databases do not currently account for the recent influx of phosphate additives in foods. This, coupled with the great variation of phosphorus content between products, makes it difficult to estimate phosphorus content of foods and to advise patients who need to limit dietary phosphorus. The
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increase in processed foods with phosphate additives on the market makes controlling phosphorus and having a healthful diet difficult for CKD patients as well as practitioners who advise them.68 A common treatment for elevated serum phosphate levels is phosphorus binders. These medications induce excretion of phosphorus through fecal elimination when taken with meals. Phosphorus binders that are available include calcium-based binders, notably calcium carbonate and calcium acetate (Phoslo), sevelamer carbonate (Renvela), and lanthanum carbonate (Fosrenol). Lanthanum carbonate is not recommended for pediatric patients at this time as long-term bone effect is not known. Sevelamer has been shown to be as effective in lowering serum phosphorus levels as calcium-based binders and, because it does not contribute to calcium intake, it is much less likely to increase serum calcium levels.69 The KDOQI guidelines indicate that phosphorus binders should be used when the serum phosphorus level is elevated and does not normalize with dietary restriction alone. The guidelines also indicate calcium-based binders should be the initial therapy in infants and young children, but noncalcium-based binders may be used if further correction of hyperphosphatemia is needed.66 Either type may be used in adolescents. Calciumbased binders are discussed below. Factors such as residual kidney function and dialysis also play a large role in determining serum phosphorus levels. Creatinine clearance provides a good estimate of phosphorus clearance. If creatinine levels are higher, patients typically have less phosphorus losses through urine and dialysis. High transporters receiving PD also enjoy greater phosphorus clearance than patients who are low or average transporters.70 Increased dialysis time also improves phosphorus clearance. Patients receiving nocturnal HD, which is typically 6 to 10 hours nightly while the patient is sleeping, typically have twice the phosphorus clearance of patients who receive standard 3 times per week HD.71
Calcium
Insufficient dietary calcium intake may result in poor bone mineralization. However, excess intake may contribute to an increased risk for CVD. Consequently, a balance of an adequate, but not excessive, intake of calcium is important for children with CKD. Although at least 100% of the DRI for age is recommended for children with CKD, there are many sources that may contribute to calcium intake. The total elemental calcium intake derived from dietary intake, enteral supplementation, and calcium-based phosphorus binders should not provide more than 200% of the DRI for
calcium, or 2500 mg for adolescents in which twice the DRI would exceed 2500 mg.66 If intake is inadequate, a calcium supplement is useful. It should be offered away from mealtime and iron supplements to allow maximum calcium absorption. Calcium gluconate, lactate, acetate, or carbonate are all alternatives and should be given in doses < 500 mg at a time for best absorption. Calcium citrate should not be given as it can increase aluminum absorption. Calcium chloride should also be avoided as it can contribute to metabolic acidosis.12 If patients are hypocalcemic (< 8.8 mg/dL), calcium and vitamin D therapy should be considered.66 The KDOQI pediatric bone guidelines indicate that serum calcium levels should not exceed norms for age in CKD, and should be on the lower end of normal in ESRD. As noted above, calcium carbonate (TUMS or others) and calcium acetate (Phoslo) are often used as phosphorus binders in children with CKD. Research indicates that use of calcium-based binders may contribute to hypercalcemia, and as mentioned previously, may contribute to the development of soft tissue calcification with organ and small vessel damage. Calcium acetate has a higher binding capacity than calcium carbonate. Forty-five milligrams of phosphorus is bound by 667 mg of calcium acetate as opposed to 39 mg of phosphorus per 1250 mg of calcium carbonate. Twenty-five percent of calcium is absorbed from calcium acetate versus 40% from calcium carbonate, resulting in a lower calcium load from calcium acetate.72 Intestinal calcium absorption is suboptimal in patients with CKD, especially as renal failure advances, due to low levels of 1,25-(OH)2D. Low dietary intake due to poor appetite and dietary restrictions is also common.73 Consequently, higher doses of active vitamin D can decrease the patients need for calcium supplements.12 Elevated serum calcium levels are also a concern. If PTH is low, bone is not turning over at a rate necessary for proper growth and bone maintenance, a state known as adynamic bone disease. In this case, or if serum calcium levels exceed 10.2 mg/dL on 2 consecutive measurements, excess calcium is not appropriate as the bone cannot incorporate calcium appropriately. In these cases excess vitamin D therapy or calcium supplementation should be lowered or ceased. If discontinuation of binders and vitamin D therapy is not enough to lower serum calcium levels, low-calcium dialysate should be considered but is not the preferred option.66,74
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Other Electrolytes of Concern
Magnesium metabolism is often altered in patients with CKD resulting in low ionized levels and high total circulating levels.75 Typically, serum magnesium levels will be elevated or high-normal in dialysis patients; however, at this time, dietary alterations are not generally recommended. Other minerals of concern are those that may be impacted by ongoing dialysis treatments. Minerals such as lead, mercury, and cadmium have been noted to be elevated in long-term dialysis patients. Contamination of dialysis fluids may contribute to these mineral abnormalities.76 Aluminum has been found very harmful to patients with renal impairment, and toxicity historically has caused severe bone disease and encephalopathy in patients with kidney disease. Prevention of excess aluminum intake by choosing non-aluminum-based medications and avoiding aluminum contamination in dialysate or parenteral solutions is critical.
Cardiovascular Disease and Lipid Management

CVD is the major cause of mortality in patients with CKD, accounting for about 25% of deaths.77 Children with ESRD have a 1000-fold higher risk of cardiac death compared to non-ESRD children.77 Additionally, children with CKD are among the American Heart Associations (AHAs) list of high-risk pediatric populations. 39 Traditional risk factors including hypertension (HTN), left ventricular hypertrophy (LVH), and dyslipidemia are highly prevalent in adult CKD patients. However, recent data show that nontraditional markers or uremic factors are also contributing to CVD in adult patients. These factors include dyslipidemia, abnormal calcium and phosphorus levels, vascular injury due to vascular calcifications and arteriosclerosis, inflammation, anemia, fluid overload, and proteinuria.78 Uncontrolled HTN is the most significant risk factor for CVD and develops early in CKD. As CKD progresses, HTN becomes more profound. Therefore, HTN control should be a major goal in decreasing not only CVD risk, but the risk of CKD progression as HTN exacerbates the rate of kidney failure. Volume and pressure overload contribute to the HTN and LVH present in many children with CKD. 38 If uncontrolled, LVH may lead to cardiomyopathy and cardiac failure. Therefore, blood pressure and volume control are needed to help reduce manifestations of CVD. Dyslipidemia also typically occurs as CKD progresses. It is characterized by hypertriglyceridemia, and elevated levels of very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and total cholesterol. Low levels of highdensity lipoprotein (HDL) are present as well. According
to the AHA, treatment starts with lifestyle changes of diet and exercise. Drug therapy is added when diet and exercise are not sufficient to keep lipids at acceptable levels. 38 The KDOQI guidelines do not recommend dietary intervention for dyslipidemia in malnourished children with CKD. However, in non-malnourished children, a change to a heart-healthy fat, increased fiber, and a limitation in sugar intake are recommended.12,39 Obesity, especially in the posttransplant population, contributes to CVD risk and the development of other risk factors for CVD including dyslipidemia, HTN, and diabetes mellitus. Therefore, weight management should be included in the nutrition intervention (see Renal Transplant section). A non-traditional risk factor for CVD is abnormal calcium and phosphorus levels. Calcifications form in the vessels and soft tissues, including the heart. As many as 60% of pediatric patients on dialysis have soft-tissue calcifications at time of death (see Phosphorus and Calcium sections).79 Inflammation is another non-traditional risk factor that appears to contribute to CVD risk. Systemic inflammation is often characterized by elevated serum c-reactive protein (CRP) levels. Evidence suggests an elevated CRP level is associated with cardiac morbidity and mortality in CKD patients.80 Causes of inflammation include the presence of uremic toxins increasing oxidative stress, chronic infections, increased presence of proinflammatory cytokines, and abnormal calcium and phosphorus metabolism.81 There is also evidence of reverse epidemiology for low serum cholesterol levels, low serum homocysteine levels, and low BMI.78,82 Just as hypercholesterolemia, possibly high serum homocysteine levels, and a high BMI can be risk factors for CVD, low cholesterol, low homocysteine, and a low BMI can be risk factors, suggesting that malnutrition is a risk factor for CVD. A syndrome known as MIA (malnutrition, inflammation, and atherosclerosis syndrome) is thought to be the main cause of mortality in adults. This syndrome is based on evidence of a strong link between these 3 factors and an increased risk of mortality in CKD patients. 80 There are not significant data in the pediatric literature to suggest the same parameters increase the risk of mortality in pediatric patients. More studies in this area are needed.
Renal Transplant
The ultimate medical goal for children with ESRD is renal transplantation, either from a living donor or a deceased organ donor. However, transplantation is considered a treatment modality and not a cure for CKD. Children who have received a renal transplant should be considered to have
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CKD. Unfortunately, until advances in medicine provide improved medication treatment or alternatives to human organs, slow deterioration of a renal transplant is probable. Close attention to the nutrition and overall health care of the transplant recipient is often paramount to the longevity of the transplanted kidney. CVD is not only a significant risk for mortality in pediatric and young adult ESRD patients, but is also much more common in kidney transplant patients of this age group than in the general population. The reduction of risks for CVD, infection, and psychosocial issues compared to patients on dialysis typically makes transplant the more desirable alternative for renal replacement therapy. However, hyperlipidemia, hyperhomocysteinemia, inflammation, malnutrition, anemia, and hyperglycemia or insulin resistance can all occur in the transplant patient and are factors that may contribute to the development of CVD. Several medications used for immunosuppression and prevention of graft loss may have side effects that are damaging to the kidney and to the overall health of the recipient. Although many centers have developed protocols that minimize corticosteroid usage, these medications are still frequently used in transplant recipients. Adverse effects of transplant medications include HTN, hyperlipidemia, hyperglycemia, increased appetite leading to weight gain, peptic ulcer disease, osteoporosis, muscle wasting, and an increased risk of infection. Calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus can cause hyperglycemia, hypomagnesemia, hyperkalemia, HTN, and nephrotoxicity. T-cell receptor (mTOR) inhibitors such as sirolimus have potential side effects of hypertrigly ceridemia, hypercholesterolemia, diarrhea, delayed wound healing, and mouth ulcers. The use of antiproliferative agents such as mycophenolate mofetil and azathioprine may result in gastrointestinal side effects such as nausea and diarrhea, sore throat, or altered taste acuity.83 A clinician must be aware of these potential side effects and work with the patient to optimize nutrition intake while minimizing side effects. Transplant patients should be advised to limit concentrated sweets, especially when medication doses are highest, such as soon after transplant or when treating rejection. Unless patients are underweight, water and other fluids low in simple sugars are recommended to control weight gain, limit hyperglycemia, and promote good dental health. After transplant, patients often need to continue to limit their sodium intake to prevent or control HTN. Correction of abnormal mineral or electrolyte concentrations is recommended if needed.12,84
Adequate intake of calcium is important for bone health, not only given the potential for transplant medicationrelated side effects such as osteoporosis, but also because of bone damage that may have already occurred related to CKD. Calcium and vitamin D intakes of at least 100% of the DRI are usually suggested. However, if transplant function has deteriorated such that serum phosphorus and PTH levels are elevated, total elemental calcium intake should not exceed 200% of the DRI, as indicated for other CKD patients at a similar stage.12,84 Dietary inclusion of highmagnesium foods and limitation of high-potassium foods may be warranted if laboratory values dictate. However, pharmacological management may be necessary with treatment of hypomagnesemia with magnesium oxide, or less frequently gluconate-based magnesium preparations. Persistent or severe hyperkalemia can be treated with medications such as fludrocortisone or with Kayexalate-treated formula. Hyperlipidemia can be treated with diet modification (eg, increase in polyunsaturated fats and decrease in saturated fat) and medication. The use of 3 to 4 grams of omega-3 fatty acids daily may also lower serum lipids.84 Fluid intake is key for the transplant recipient to assure adequate perfusion and renal artery flow to the transplanted kidney. In pediatric patients, this is typically 1.5 to 4 L/d depending on the size and activity of the child. 84 Intake of 2 to 3 L is typical for adult-sized adolescents. In young children, including infants and toddlers, adequate fluid intake may be especially important to prevent ATN, graft thrombosis, and graft nonfunction. Transplant success in this age population is best when adult-sized kidneys are used. However, due to a childs small heart, blood volume, and blood vessels, the need for a large blood flow may be difficult to meet, resulting in loss of kidney function. One centers experience indicates that total fluid intake (enteral formula and water orally and via tube feeding) of 2500 mL per body surface area (2500 mL/cm2/d) and sodium intake of 8 to 10 mEq/kg/d prevented these complications. Salvatierra et al describe an increased sodium and fluid protocol that reversed a high creatinine in one infant who had a low sodium and fluid intake. Lower GFRs were noted in the non-protocol patients.85,86 This type of protocol may be necessary for 6 months to a year after transplant.85
Acute Kidney Injury (AKI)
AKI, formerly referred to as acute renal failure (ARF), is a temporary condition of kidney dysfunction typically characterized by electrolyte imbalances, an increase in blood urea nitrogen (BUN) and serum creatinine, and a decrease in urine output.87 (For further discussion of physiology,
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refer to the section on Kidney Development and Function.) Although kidney function is usually restored once the etiology of AKI is eliminated or corrected, supportive therapy is required in the interim. Therapy may or may not include temporary dialysis. If dialysis is required, there is no standard treatment modality. PD, HD, and continuous renal replacement therapy (CRRT) are all used. CRRT is chosen by an increasing number of pediatric centers because of the safety and efficacy of the technique, even in those patients who are experiencing hemodynamic instability.87,88 Nutrition assessment and planning for the patient with AKI typically follow the same guidelines for CKD5D and critical illness. There are no set standards for estimating caloric and protein needs in the setting of AKI, either with or without the use of dialysis. Needs are based on the age-related needs of the patients, in addition to modifications based on comorbid medical conditions such as sepsis. Hypercatabolism and alterations in metabolism are common in AKI. Some of the alterations of metabolism include decreased protein synthesis and inefficient use of proteins by the cells, altered amino acid pools, hyper glycemia secondary to insulin resistance, lipid alterations caused by impaired lipolysis, acidosis, and electrolyte imbalances. The primary goal of nutrition therapy in patients with AKI is to prevent catabolism as much as possible. The patient with AKI and not on dialysis may need more rigid electrolyte and fluid restrictions. If a nutritional supplement is required, use a renal supplement, such as Suplena or Nepro, that is nutrient dense and has a low renal solute load. For infants, Similac PM 60/40 is usually the most appropriate choice. Once renal function is restored, a regular diet and/or supplement is appropriate. However, when dialysis is performed, depending on the modality, restrictions may vary (see sections on Continuous Renal Replacement Therapy, Hemodialysis, and Peritoneal Dialysis). Nutrition guidelines in AKI when patients are provided HD or PD are similar to those for CKD and HD and PD. However, fluid and electrolyte concerns as well as prevention of catabolism take priority to more long-term concerns associated with CKD, such as CVD, growth, and renal osteodystrophy.
Continuous Renal Replacement Therapy

CRRT is an umbrella term that can include continuous arteriovenous hemofiltration (CAVH), continuous venovenous hemofiltration (CVVH), slow continuous ultrafiltration (SCUF), continuous arteriovenous hemodiafiltration (CAVHDF), continuous venovenous hemodiafiltration (CVVHDF), continuous arteriovenous
hemodialysis (CAVHD), and continuous venovenous hemodialysis (CVVHD). CRRT replaces kidney function on a continuous or nearly continuous basis in terms of solute and fluid removal and has been found to increase survival in critically ill children, even infants less than 10 kg.89 Because CRRT is a relatively new technology, there is little literature regarding nutrition needs associated with it, especially in children. Consistent with adult studies, enteral nutrition is the first choice for the route of nutrition support in children receiving CRRT. Because CRRT efficiently improves clearance of solutes, phosphorus, potassium, sodium, and other electrolytes or minerals typically do not need to be limited. They may actually need to be supplemented. A renal formula may increase gastrointestinal complications, such as diarrhea or emesis, due to high osmolality, and use of a standard formula is appropriate. Gastric emptying can be problematic in this population with slow gut motility. It may be alleviated by using transpyloric feeding. A standard tube-feeding formula started at a slow, continuous rate and monitored for tolerance is optimal, even in children on vasoactive and sedative drugs.90 Caloric needs of the primary condition should determine caloric needs during CRRT. Acute renal failure, itself, is typically not thought to increase calorie needs. Oftentimes CRRT is used to support patients with AKI secondary to conditions such as burns or sepsis in which caloric requirements may be markedly increased. Although dialysis may cause some inaccuracies in measurement of caloric needs due to carbon dioxide removal by the dialysis membrane, indirect calorimetry (IC) is still considered the gold standard and has been used in studies to determine caloric needs of pediatric patients receiving CRRT.91 Protein losses may be very high in patients receiving CRRT. Maxvold et al91 attempted to assess nitrogen balance and amino acid loss in pediatric patients. In this study, children receiving 120% to 130% of IC-predicted resting energy expenditure (REE) and 1.5 g/kg protein were in negative nitrogen balance. That amount of protein seemed inadequate for this population. A recent study with adult patients indicated that at least 2.5 g/kg protein may be necessary to achieve a positive nitrogen balance.92 Thus, protein needs for children receiving CRRT are likely to be at least as high, if not higher because the baseline protein per kilogram needs are greater in children than adults. Studies in both adults and pediatrics demonstrate a 10% to 25% loss of amino acids in CRRT via the dialysis filter.93 There are no published studies assessing the micronutrient needs for children receiving CRRT. However, adult
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studies indicate micronutrient loss is high in this patient population. High losses of trace elements and vitamins, such as selenium, copper, and thiamin, are common. It is speculated that other water-soluble vitamins are lost in a similar fashion.94,95 Experts recommend doubling the standard trace element preparations for adult patients receiving CRRT plus an additional 100 mg of thiamin and 100 mcg of selenium supplementation.96 It is likely that additional micronutrient supplementation, proportional to the DRI for age, would also be appropriate for children.
Neonatal Issues
AKI is common in the neonatal intensive care unit and may be of primary origin, such as congenital renal disease, or secondary to conditions such as sepsis, drug toxicity, obstruction, hypoxia, or respiratory distress. Twenty percent of new dialysis cases are reported to be newborns.97 Mortality is high (46%) in neonates and low-birth-weight infants with AKI.98 Dialysis, including PD, CRRT, or less commonly HD, may be used to maintain fluid, acid-base, and electrolyte balance as well as remove toxins in the short or long term. It is important to remember that serum laboratory values, such as phosphorus and potassium, may have higher normal limits for neonates than for older infants and children. Fluid balance is important because patients may have high urine output due to sodium and fluid-wasting renal disorders, stomas, emesis, or suction. This may necessitate a high fluid intake, replacing losses and providing maintenance needs. Poor urine output or additional sources of fluids, such as medication drips, may lead to fluid restrictions, and the need to concentrate formula with additives or to use parenteral nutrition (PN).99 Oliguric and anuric infants typically should receive 25 to 30 mL/kg/d, with infants < 26 weeks gestational age possibly needing more.100 Controlling HTN and edema are often critical in this population. Maintenance fluid needs are a good starting point, with adjustment based on clinical conditions.101 Often children with high fluid and sodium losses require sodium supplementation of 1 to 3 mEq/kg/d.100 Correct acidosis with supplementation of sodium bicarbonate.97 Sodium bicarbonate supplementation of 1 to 2 mEq/kg/d may be needed to prevent hyperkalemia. If serum potassium levels are high, limit potassium to 1 to 2 mEq/kg/d.100 It is important to be aware of medications that may affect nutrition. Pressors or narcotics may decrease gastric motility and may affect tolerance to enteral feeding. Continuous jejunal or transpyloric feedings may be better tolerated than nasogastric feedings. Anti-hypertensives can increase
serum potassium levels. Diuretics may cause potassium and chloride losses that need to be replaced. Antibiotic therapy may result in the need for vitamin K supplementation, especially as gut flora and vitamin K production may not be established in the neonate.99 The energy and protein needs for a neonate with AKI are estimated to be 120 kcal/kg/d and 2.5 g/kg/d, respectively.99 Another proposed guideline has been 8 to 12 kcal/ cm/d.99 Patients on PD may receive some carbohydrate calories from dialysate solution.100 A patient on dialysis may need greater amounts of protein because of urine and dialysate protein losses. Whereas the above recommendations are a good starting place, the quantity of protein administered may need to be adjusted based on laboratory values and individual needs. For example, a child with poor urine output not receiving renal replacement therapy will need reduced amounts of protein in contrast to the child receiving continuous dialysis.99 Often, nutrition needs are not able to be met by oral intake alone and tube feeding is a commonly used alternative. It should be emphasized that neonates who are tube fed should still be encouraged to take at least a portion of their feedings by mouth. Breast milk is the optimal choice and partial breastfeeding or bottle-fed breast milk should be considered. If oral intake is not well tolerated, regular oral stimulation is necessary. If breast milk is not an option, a whey-based formula, especially a low-electrolyte, lowaluminum, and vitamin A formula, discussed later, is the next best option. Caloric density of breast milk or formula can be gradually increased from 20 kcal/oz to more than 30 kcal/oz as needed if there is volume intolerance or restriction. Typically it is done with glucose polymer or fat modulars as opposed to volume concentration to reduce renal solute load.99 Some concentration of formula may be acceptable in premature infants with increased needs for calcium and phosphorus for bone accretion, especially if serum phosphate levels are appropriate. However, phosphate retention related to renal failure should be kept in mind. Calcium needs should especially be assessed and supplementation may be needed.100 However, calciumbased medications and vitamin D that patients with kidney disease may be receiving may increase calcium uptake and lessen the need for calcium supplementation to the level that other premature infants need. Increasing formula concentration may not be appropriate even if higher phosphate and calcium load is needed as aluminum and other solute concentration also increases. Feeding tolerance should be closely monitored. Reflux and delayed gastric emptying are common in renal
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impairment and should be treated if needed. Treatment options include decreasing concentration of the formula with a slow increase back to desired concentration, slowing the rate of delivery, using continuous feeds, and possibly adding medications to enhance gastric motility.99 Bolus feeds, if tolerated, are most physiologic. Some infants may do best with a combination of bolus feeds during the day and continuous feeds overnight. In some cases, oral and/or tube feeding cannot meet the nutrition needs of the neonate, mandating the use of parenteral nutritional (PN) support. Glucose monitoring with PN is mandatory, with consideration for the use of an insulin drip if needed to provide adequate carbohydrate calories while keeping serum glucose levels normal. Use of a neonatal amino acid solution, such as Trophamine, is appropriate as is the use of 20% intralipids to provide energy and essential fatty acids. Lipids are started at 1 g/kg and then increased to increase calorie intake, but typically not greater than 3 g/kg. Triglycerides should be monitored and lipids should be advanced only if triglyceride values are < 250 mg/dL. If triglyceride values are > 300 mg/dL, lipids should be reduced or stopped.99 Parenteral solution additives, particularly micronutrients cleared renally, should be based on an individual patients response. Small amounts of potassium in the parenteral solution, especially if the patient is on dialysis, are often still appropriate. Start with half or less of standard amounts for neonates without renal impairment. Likewise, the reduction of magnesium and phosphorus in PN to one-third or one-half the normal amount may be beneficial and prevent low serum levels. Selenium, chromium, and molybdenum may need to be intermittently given or avoided due to impaired renal clearance and liver impact. Zinc and copper intakes should remain standard, unless liver impairment is present, in which case copper may need to be limited. In high-output renal failure, additional zinc may be needed and assessing serum values may be beneficial.97,100 A multivitamin is needed to provide water-soluble vitamins while limiting the quantity of fat-soluble vitamins99 (see discussion on micronutrients in Chronic Kidney Disease section). Close follow-up of a neonate with previous or ongoing renal impairment is important, and growth and feeding tolerance should be monitored postdischarge. Easy-to-read formula mixing instructions in household measurements as well as demonstration of mixing is important.99 Preterm or low-birth-weight infants who suffered AKI may be at particular risk for medical complications later in life, likely due to the loss of renal mass from the early insult or as a result of failure to complete glomerulogenesis.98 Problems that may
occur include high blood pressure and proteinuria associated with a low GFR. Height and weight gains tend to be impaired in these patients and mandate close monitoring/ supervision of their nutrition status. Growth goals are the same as other neonates. Further discussion of the neonate is found in the chapter on nutrition, growth, and development (Chapter 13).
Enteral Nutrition
Inadequate intake is common in children with CKD. Gastroesophageal reflux, medication taste, uremia, as well as thirst for water instead of formula may contribute to this problem. The KDOQI Clinical Practice Guidelines for Nutrition for Children indicate that supplemental nutrition support should be considered in CKD stages 3 to 5 or 5D to meet energy needs if the child is not growing or gaining weight well. Additionally, oral intake of an energy-dense diet and/or supplements is the preferred source of nutrition support, followed by tube feeding, if energy needs are not met orally.12 The majority of infants and young children who receive PD as treatment for ESRD require supplemental enteral feedings for adequate growth. There is some concern that the use of a gastrostomy may be a risk for peritonitis. Peritonitis is the most significant risk of PD and can permanently damage or alter a patients peritoneal cavity and limit the use of this dialysis modality in the future. Consequently, most experts recommend placement of a percutaneous gastrostomy (PEG) or an open gastrostomy if an anti-reflux procedure is needed, prior to the initiation of PD. If a gastrostomy is needed after initiating dialysis, an open gastrostomy has a lower risk of peritonitis than a PEG placement.101 When supplemental feedings are given via tube feeding, intake needs can typically be met in young children. In one study, both caloric and protein needs were met or exceeded in infants and young children receiving gastrostomy feeding with 61% of needs coming from supplemental feeding.100 However, whether intake from supplemental feedings, even if meeting estimated nutrition needs, improves height and weight standard deviation scores remains controversial.102,103
Infant and Toddler Feeding

Frequent nutrition assessment and revision of plan of care is essential for optimal management of the infant and young child with CKD or on dialysis. One dialysis centers experience reports that dietetic contacts, including direct, phone, and patient-related activities such as school contacts, averaged about 6 per month for children < 5
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years of age, as opposed to about 3 per month for children > 5 years of age.104 Breast milk, which is low in phosphorus, calcium, and other minerals, is an optimal food source for infants with CKD. As a second choice, a whey-based formula is most appropriate for this population. Of note, the potential for aluminum toxicity is an important concern for patients with kidney impairment. Breast milk has the lowest content of aluminum and infants fed breast milk have the lowest serum aluminum levels.105 Whey-based formulas have the nextlowest aluminum concentration, followed by whey-based formula fortified with carbohydrate and lipid modulars. Preterm formulas are higher yet in aluminum followed by casein hydrolysate formulas. Consequently, soy and casein hydrolysate formulas are not recommended for children with renal impairment. As noted in the discussion of neonates, concentrating formula with a reduction of the water-to-formula ratio is not an ideal approach for patients with CKD due to the electrolyte and renal solute load. Adding fat and carbohydrate modulars, as well as protein modulars as needed based upon the protein needs of the infant, is the most appropriate way to increase caloric intake or to concentrate the formula density in this population. Infants often require supplemental tube feeding to meet nutrition needs, as discussed above. Infants may benefit from continuous overnight feeding and bolus feedings during the day.12,106 Renal wasting disorders such as renal dysplasia are a common cause of renal impairment in this age group, and sodium supplementation using sodium bicarbonate or sodium chloride is often needed.107 Sometimes phosphate additives are also needed to correct serum phosphate levels in patients who use a low-phosphorus formula. Introducing solids at age-appropriate times is important, limiting but not avoiding foods high in electrolytes or protein based on the childs underlying renal condition.12 Children with CKD may have oral hypersensitivity and food-aversive behavior. It is important to offer a wide array of foods, increasing texture gradually and allowing infants to experience food exploration and other good feeding habits such as family mealtimes. Many of these children exhibit aversive tendencies. Speech, occupational, or child psychology therapists as part of a multidisciplinary team may aid normal feeding skill advancement. Need for intervention should be identified in a timely manner to prevent more lengthy feeding delays. Even for children who are tube fed, oral stimulation, including non-threatening contact with food or pacifier use, is beneficial to encourage oral development. It is recommended to positively reinforce
oral feeding acceptance and ignore feeding refusal. Gradual introduction of oral feeding in children with food aversion is preferred to rapidly stopping tube feeding to promote growth and adequate intake as well as appropriate advancement to a regular diet. Many children advance to an oral diet after transplantation, when factors such as uremia, excess thirst, or gastrointestinal reflux may be reduced.12,106 The latter problem may occur in as many as 70% or more of infants with chronic renal disease and may result in impaired intake, increased feeding refusal, and excess emesis. The potential need for standard reflux precautions, medication, or even surgical intervention (fundoplication) should be assessed in this situation.108 Infants and toddlers often suffer from high potassium levels. One method to reduce potassium content of the formula is to treat it with sodium polystyrene sulfonate (Kayexalate). Work by Bunchman et al indicates that adding Kayexalate to formula and allowing it to precipitate for 30 minutes in a refrigerator, and then pouring off the formula from the residue that has settled to the bottom of the container, is an effective way to reduce potassium content of liquid beverages including breast milk and formula.109 Although potassium content reduces significantly (and calcium and magnesium to lesser degrees), sodium content greatly increases. In these experiments, sodium content of the treated liquids increased an average of 234%. The greatest removal of potassium coupled with the lowest addition of sodium was found to be at the 30-minute time point. This sodium exchange may be of benefit in the infant with wasting disorders, and should be taken into account. The Bunchman group used Kayexalate in the amount of 1 g/mEq of potassium in the formula; however, this approach may overcorrect potassium levels if potassium is only moderately elevated, and the dose should be adjusted on an individualized basis per patient tolerance and requirement.
Tube Feeding for Older Children

Older children and adolescents may benefit from tube feeding to meet their nutrition needs, but social and cosmetic reasons often prevent initiation of tube feedings in this age group. However, some children who were infants or toddlers with CKD or on dialysis remain on tube feeding past toddler years because of both parent and patient desires or where inadequate intake is an issue. In this situation, it may be best to only provide tube feeding overnight to allow for hunger during daytime hours to help advance feeding skills and transition to a completely oral feeding regimen.12
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Malnutrition is caused by multiple factors including anorexia, poor food intake, the catabolic effects of dialysis, and the demands of growth.15,16 Because of these issues, meeting the needs of catch-up growth can be challenging with oral and enteral supplementation alone. Network 14 data suggest that 4.5% to 7.5% of the dialysis population has malnutrition to a degree that requires a greater nutrition intervention than nutrition counseling, diet liberation, and oral or enteral supplementation can provide. 33 In the case of mild to severe intolerance of oral or enteral supplements due to gastrointestinal dysfunction, PN may be necessary to ensure adequate nutrition. Patients with CKD5 often have a fluid restriction. Hence, this approach to therapy requires central venous access to accommodate the concentrated high osmolar parenteral solution. These guidelines provide general recommendations for CKD and AKI patients. For specific recommendations for PN for neonates or in CRRT, see sections on Neonatal Issues and Continuous Renal Replacement Therapy.
IDPN is shown to be an effective and safe treatment for adults on chronic hemodialysis with PEM.93,111113 The updated KDOQI nutrition guidelines now provide recommendations for its use in children.12
Nephrotic Syndrome
Intradialytic Parenteral Nutrition

Intradialytic parenteral nutrition (IDPN) is a non-invasive method of providing carbohydrate, protein, and lipids to undernourished patients during HD via venous access. It is supplemental to other forms of nutrition, including PN. The main goals of this therapy are to replace nutrients lost during HD, increase dry body weight, prevent further muscle wasting, improve the patients appetite and strength, increase albumin and nPCR, and decrease hospital admissions. IDPN is typically composed of a concentrated dextrose and amino acid solution and a separate lipid solution.110 The solution must be formulated based on the patients needs and tolerance. Concentrate dextrose is used to minimize the amount of free water given but keep glucose infusion rate to 5 to 9 mg/kg/min. While the energy provided may seem minimal, its purpose is to maximize protein utilization. Serum glucose levels must be monitored because of the potential for hyperglycemia. Serum glucose levels should be maintained at < 200 mg/mL, using insulin if needed. Because of increased insulin levels, there is a potential for hypokalemia and hypophosphatemia; therefore, serum potassium and phosphorus levels should be monitored as well. Amino acids typically provide about 1.3 g protein per kilogram per treatment. Lipids are given as a 20% intralipid solution. Triglycerides must be monitored before and after the initial lipid infusion to assure tolerance. If there is a 50% rise above baseline levels, there may be inadequate clearance of fat and lipids should be discontinued.
Nephrotic syndrome (NS) is a combination of symptoms occurring in association with various renal and systemic diseases; it is not a single disease. NS is characterized by proteinuria, hypoalbuminemia, hyperlipidemia, anasarca, and oliguria. Weakness, anorexia, and headaches are common. Most children with NS have what is known as minimal change disease. The cause of minimal change disease is unknown. Most patients will have more than one episode of severe proteinuria, but most will outgrow the disease and not develop permanent kidney damage.114 The main treatment goals are to increase urine output and decrease/correct proteinuria. The major rationale for making diet changes in the patient with NS is to diminish manifestations of the syndrome, replace nutrients lost in urine, and reduce the risk of causing further renal damage. The dietary reference intake (DRI) for age based on ideal body weight (IBW) is the appropriate standard to be used for energy and protein needs. Although proteinuria and hypoalbuminemia may be present, a high-protein diet is not recommended because it can contribute to further kidney damage. Edema and diuretic therapy make the patients weight parameters unreliable. Patients are usually sodium and fluid restricted to control edema. As a guide to sodium restriction, a sodium content of 1 to 2 mEq/kg is used in most circumstances (Table 24-4). Fluids are restricted if a patient is fluid overloaded.114
Nephrolithiasis
Nephrolithiasis refers to kidney stones or calculi within the urinary tract. Calcium and oxalate, sometimes with phosphate, are the primary components of the most common kind of stone in all age groups (50% to 75%), followed by uric acid stones (10% to 20%), struvite (ammonium-magnesium phosphate) stones (5% to 10%), and cystine stones (1% to 2%). Nephrolithiasis is most common in Caucasians and males. Being overweight, having HTN, and living in a warm climate are additional risk factors for stone formation. Although the majority of stones are primary and idiopathic in nature, a variety of kidney or urinary tract disorders can be associated with the development of stones; they include medullary sponge kidney, distal tubular acidosis, secondary hyperuricemia, and obstructive uropathy. Other disorders such as sarcoidosis, Crohns disease, thyroid or parathyroid
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disease, disorders of calcium or vitamin D metabolism, and drug ingestion may contribute as well. Nephrolithiasis may lead to CKD with some conditions, such as infection stones and primary hyperoxaluria, being particularly troublesome, potentially causing scarring.1,115 Renal stone disease appears to be increasing in pediatric patients. In one center, the overall incidence of kidney stones increased more than fourfold from the 1990s to the 2000s, with the most significant increase present in children younger than 10. There was distinct familial tendency for stone formation, and obese children comprised 31% of the patients with stones.113 Hypercalciuria and hypocitraturia are found in pediatric stone formers116,117 and are common metabolic abnormalities in these patients. Changing societal and environmental dietary habits in children, such as increased sodium and animal protein intake, as well as a decreased fruit and vegetable intake, may play a role. Such habits reduce potassium and citrate and increase sodium and acid load in the typical childhood diet. Children who form kidney stones are likely to have repeat kidney stones. However, proper nutrition care is paramount in treatment and may significantly reduce or eliminate recurrence of stone formation.1,116
Hypercalciuria and Calcium-Based Stones

Hypercalciuria, or an excessive loss of calcium in the urine, predisposes a patient to calcium-based kidney stones. Hypercalciuria is thought to be both familial and related to environmental factors.115 In this type of stones, calcium typically combines with oxalate or phosphate. Preventing the loss of calcium is key to reducing the incidence of kidney stone formation. Acid may contribute to this kind of stone formation. Diets high in animal protein can reduce urine citrate and increase acid load, predisposing bones to calcium loss. Some patients who form calcium-based stones and have hypocitraturia have a higher risk of stones because
Table 24-4 Nutrition for Kidney Stone Management1,115121
Increase Fluid (at least 1 oz/kg) Increase Fruit and Vegetable Intake
citrate increases the solubility of urine calcium.118,119 Fruit and vegetable intake has an integral role in decreasing some of these risk factors. Research indicates that increasing fruit and vegetable intake not only increases potassium intake, an important protective factor, but also increases citrate intake. Additionally, fruits and vegetables confer an alkali load, reducing the risk of calcium loss and stone formation. A high sodium intake is another important risk factor for stone formation. Sodium increases urinary calcium losses and may lower urinary citrate. It may also interfere with the actions of some medications used to treat hypercalciuria.119 Of interest, although excessive calcium intake is not advised, restriction of calcium is detrimental to stoneformers. Patients with hypercalciuria have bone calcium loss, and limiting calcium intake can put patients at further risk for poor bone status. Additionally, many calcium-rich foods are high in potassium. Finally, limiting calcium may increase the stone-forming factor oxalate in the urine, due to decreased availability of calcium to bind with oxalate.119,120 Potassium citrate may be recommended as a medication if compliance with diet is poor. A high magnesium intake may also be a protective factor as well as limiting cola-containing beverages, however both interventions mechanisms of action are unknown.1 Fluid intake is an important preventive measure for all types of kidney stones. Adequate fluid intake has been shown to almost eliminate super-saturation of stoneforming agents.119 Urine output, and thus fluid intake, appears to be inadequate in more than half of pediatric patients, in one centers experience. It has been suggested that a urine output of 1 mL/kg/h is adequate to avoid saturation of stone components in the urine, thus limiting stone formation.117 Other recommendations are that the urine output should be as high as 35 mL/kg/d. The 1 mL/kg/h rule can be equated, for practical purposes and to account for insensible losses, to a recommendation of 1 oz/kg of
Limit Acid-Based Foods
Limit Meats and Protein
Limit Oxalate
Limit Sodium
DRI Calcium Intake*
Calcium-based stones Oxalosis or hyperoxaluria with calcium-based stones Uric acid stones Cystine stones Struvite stones Other kidney stones
X X X X X X
X X X X ?
X X X X ?
X X DRI, especially limit purines X X
X X
X X
X ?
*Although DRI calcium intake is appropriate general medical management for general pediatric health, including patients with a variety of kidney stone disorders, avoidance of excessive or inadequate intakes of calcium are especially important in the types of kidney stones notated.
276
body weight or more per day.117 Another guideline for fluid intake is 2 L or more for adults or adult-sized adolescents.119 A more general qualitative guideline is that a child or teen should be encouraged to consume enough fluid so that their urine is near colorless.1,117 Reducing protein intake may also be helpful to prevent kidney stones but does not seem to be as critical as high fluid and potassium intake and limited sodium. Although limiting meat intake may be difficult for some, certainly discouraging particularly high-protein intake is a goal at minimum.1 In turn, practical dietary recommendations would indicate the need to limit sodium to 2000 to 2400 mg daily; provide 100% of the DRI for potassium with at least 5 fruits and vegetables, particularly those high in potassium; 100% of the DRI for calcium; and adequate fluid intake for size and age. Oxalate Primary hyperoxaluria is rare, and will be discussed further below. However, secondary hyperoxaluria may result from fat malabsorption or idiopathic increased absorption of oxalate. Oxalate intake may need to be restricted in hyperoxaluric stone formers.119 Because hyperoxaluria is rare, reported at only 6% of stone formers in one pediatric study, it may be unnecessary to restrict oxalate to prevent stones in hypercalciuria alone or in other types of kidney stones.117 In fact, limiting oxalate in hypercalcuric patients is not shown to reduce stone formation in a study of adult patients.120 Cystinuria Cystinuria is an autosomal-recessive disorder and is the cause of about 10% of kidney stones in children. The disorder is related to impaired transport of the amino acids cystine, ornithine, lysine, and arginine. Of these, cystine is insoluble in the urine and thus it can cause stone formation. Recurrent stone formation is common without medical management, but even with medical management adherence may be poor due to side effects and lack of treatment efficacy. Cystinuria often leads to renal insufficiency, including ESRD, due to recurrent stone formation and frequent intervention. Male patients tend to be more severely affected. Medications are often used in treatment; however, dietary interventions may be beneficial as well. As in other types of stones, high fluid intake, low-sodium diet, and foods high in alkali, such as fruits and vegetables, are recommended. Limiting acid load by limiting excess protein intake is appropriate. A 2g sodium diet has been shown to reduce urinary cystine concentration. A fluid intake of 3 L/d is recommended in
children to reduce cystine concentration. A patient ideally should drink prior to bedtime, upon waking, and also at night. Neutral or alkali beverages are recommended. Additionally, limiting methionine intake, which is metabolized to cystine, is helpful. Limiting protein-rich foods including meat, fish, eggs, soy, and wheat can reduce methionine intake and thus urinary cystine excretion. However, strict protein restriction is not advised in children. Protein to the DRI in children is appropriate for growth and may limit excess cystine production. Unfortunately, adherence to a lowsodium and lower-protein diet may be poor. High vitamin C intake is often recommended for treatment of cystinuria, but it is controversial. Cystinuric patients often produce other types of kidney stones and excess ascorbic acid may increase oxalate production. In the absence of other types of stones, 3 g of vitamin C has been recommended for adolescents with cystinuria.121
Other Kidney Stones

Uric acid stones, found in 2% to 4% of pediatric stone formers, are often a consequence of a high purine load. Limitation of animal protein and other high-purine foods should be considered. Meat, including fish, should be reduced to the DRI for protein. Other foods that should be limited include meat extracts such as bullion, meat gravies, cocoa, mushrooms, high-yeast products, peas, and beans. Organ meat should be avoided.1, 119 Struvite calculi consist of magnesium ammonium phosphate or a calcium phosphorus mix and are often called infection stones as they frequently result from urinary tract infections. Unlike other stone disease, these stones form in an alkali environment and increasing urine acidity may help. Ascorbic acid is suggested as a treatment.1 Other stones include 2,8-dihydroxyadenine calculi, which should be treated with purine restriction, and xanthine stones, which should be treated with increased fluid intake.1
Renal Tubular Disorders

Renal Tubular Acidosis
Renal tubular acidosis in characterized by an inability to acidify urine and, left untreated, growth impairment is common as are nephrolithiasis and nephrocalcinosis, or calcium deposits in the kidney. Typical treatment of this condition is alkali therapy.122 In clinical practice, monitoring for failure to thrive and for renal stone disease is imperative. Metabolic bone disease and bone calcium loss may require nutrition monitoring as well.1
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Bartters Syndrome
Bartters syndrome is an autosomal-recessive disorder with symptoms of poor growth, hypokalemia, and metabolic alkalosis. Some mixed forms of Gitelman syndrome and Bartters syndrome may include hypomagnesemia. Gitelman syndrome resembles Bartters but is a milder disorder. Lack of sodium, chloride, and water reabsorption cause urine losses in the 4 to 8 L/m 2/d range. Chloride loss causes alkalosis, increasing potassium wasting. Sometimes calcium absorption is impaired, creating hypercalciuria. Treatment includes replacement of sodium, chloride, potassium, and often magnesium. Monitoring for growth failure is important.1
Nephrogenic Diabetes Insipidus

Nephrogenic diabetes insipidus (NDI) is typically an X-linked autosomal recessive disorder and impairs water reabsorption in the kidney. It manifests as vomiting, anorexia, failure to thrive, and constipation in young infants. Hypernatremia is common. Aggressive water supplementation is needed, and infants will often need overnight tube feedings to meet fluid needs. The amount of fluid needed may inhibit adequacy of caloric intake, and growth and intake should be carefully monitored in this population.1 The NDI Foundation recommends a sodium intake of 500 mg daily and potential benefit from a low-protein diet. The low-sodium diet, however, is the cornerstone of treatment. The goal of this diet is to reduce solute load on the kidneys and thus the amount of urine the kidneys must excrete.123
Table 24-5 General Nutrition Management of Renal Dysfunction

Nephrotic Syndrome ARF No dialysis ARF PD or HD ARF CRRT CKD (Stage 3-5) CKD5 HD CKD5 PD
Energy* Protein
DRI DRIdo not supplement to replace urinary losses
EER for age or original disease state DRI or less per BUN monitoring
EER for age or original disease state DRI with 0.2 g/kg increases for hemo, 0.4 g/ kg increases for PD Will vary. Consult with renal/primary team to determine. Limit
EER for age or original disease state At least 2.5 g/ kg or greater
EER for age Stage 3: 100%140% x DRI/kg IBW Stage 4-5: 100%120% x DRI/kg IBW 13 mEq/ kg will vary according to edema or HTN unless sodium wasting Most will tolerate > 3 mEq/kg/d
EER for age DRI + 0.1** g/kg IBW
EER for age DRI + 0.150.3** g/ kg IBW (dependent on age)
Sodium
13 mEq/kg will vary according to edema or HTN Restriction not needed
Will vary. Consult with renal/primary team to determine. Tightly limit
Typically no restriction; may need electrolyte supplementation
Potassium
Phosphorus Fluids
Micronutrients *DRI typically appropriate unless specific notation.
Restriction not needed Will vary according to UOP . Consult with renal team to determine. DRI
Tightly limit Will vary according to UOP . Consult with renal team to determine. Tightly limit fat-soluble vitamins
Limit Will vary according to UOP. Consult with renal team to determine. Limit fatsoluble vitamins May need additional replacement fluids. May need supplementation especially selenium and thiamin.
13 mEq/ kg will vary according to edema or HTN unless sodium wasting Generally unrestricted unless low transporter. Will need to be monitored. Limit to 80%100% x DRI to keep serum levels WNL. 13 mEq/ kg will vary according to edema or HTN unless sodium wasting 13 mEq/kg but will vary according to serum levels and age Generally unrestricted Replace UOP , insensible losses, + UF Replace UOP, insensible losses, + ~1 L/d
100% DRI. Supplement water soluble if needed.
100% DRI. Water-soluble vitamin supplement is recommended.
*Energy requirements may need to be adjusted for physical activity level and/or based on rate of weight gain or loss. **Protein requirements may need to be adjusted according to dialytic protein and amino acid losses.
278
In clinical practice, growth may be impaired with limited caloric intake from such a strict diet. Sodium allowance should be adjusted according to the patients tolerance, growth, and clinical picture, but should be limited as much as possible.
children. Close attention to electrolytes and growth are often the primary role of nutrition care in these diseases.
Other Renal Dysfunction

Oxalosis
Primary hyperoxaluria (type 1) is an autosomal-recessive disorder characterized by a deficiency in glyoxalate aminotransferase. Oxalosis is the final stage of primary hyperoxaluria in which calcium oxalate accumulates in the blood and tissues due to an abundance of oxalate production and deposition of crystals in the kidneys. This accumulation in the kidneys is known as nephrocalcinosis and causes progressive renal failure. As renal failure progresses, oxalate accumulates because of the continued excessive production and the impaired renal excretion. While frequent HD can help clear oxalate and attempt to control oxalate deposition, success is often limited and further buildup in the tissues can occur. Oxalate can deposit in the bones, eyes, heart, vessels, and nerves. The optimal treatment is a combined liver-kidney transplantation. A kidney transplant alone is not recommended because the liver continues to produce oxalate and can cause renal failure in the transplanted kidney. Typically, the treatment protocol during the immediate posttransplantation period will include hyperdilution or hyperdiuresis through superhydration methods to keep the concentration of urine crystals at low levels. A lowoxalate diet is recommended. Excessive vitamin C intake may increase risk of oxalate stone formation and should be avoided. Secondary hyperoxaluria can occur in the context of fat malabsorption because unabsorbed fat binds with calcium making it unavailable to bind oxalate. A low-fat diet with increased calcium intake is recommended. A high fluid intake is important for urine oxalate removal. Potassium citrate, pyridoxine, magnesium citrate, and other medications may be helpful.1
1. What is the optimal feeding route for children in acute renal failure receiving CRRT that need supplemental nutrition? A. Parenteral nutrition B. Nasogastric feeding of a renal formula C. Transpyloric feeding of a standard tube feeding formula D. Nasogastric feeding of a standard tube feeding formula 2. Which of the following vitamins or minerals may be beneficial to supplement to pediatric patients receiving dialysis treatments? A. Vitamin B6 B. 25-hydroxyvitamin D C. Folic acid D. All of these 3. Which of the following comorbid diseases is responsible for 25% of deaths in CKD patients? A. ESRD B. Respiratory arrest C. Cardiovascular disease D. Diabetes mellitus 4. Which of the following statements regarding nPCR is false? A. Recent studies show that serum albumin is a better nutrition marker than nPCR. B. KDOQI does not recommend monitoring nPCR in chronic hemodialysis patients. C. It is a measure of protein intake in g/kg/d. D. nPCR is an algebraic equation. See p. 487 for answers.
References
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74. Kurz, P, Monier-Faugere MC, Bognar B, et al. Evidence for abnormal calcium homeostasis in patients with adynamic bone disease. Kidney Int. 1994;46:855561. 75. Pedrozzi NE, Truttman, AC, Faraone R, et al. Circulating ionized and total magnesium in end-stage kidney disease. Nephron. 2002;92(3):616621. 76. Skarupskiene, I, Kuzminskis V, Bumblyte IA, et al. Changes of trace elements in blood of patients with chronic renal failure. Dial Transplantation. 2005;34(12):870880. 77. Parekh RS, Carroll CE, Wolfe RA, Port FK. Cardiovascular mortality in children and young adults with end-stage renal disease. J Pediatr. 2002;141:191197. 78. Mitnefes MM. Cardiovascular complications of pediatric chronic kidney disease. Pediatr Nephrol. 2008;23:2739. 79. Milliner DS, Morgenstern BZ, Murphy M, Gonyea J, Sterioff S. Lipid levels following renal transplantation in pediatric recipients. Transplant Proc. 1994;26:112114. 80. Stenvinkel P, Heimburger O, Paultre F, et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int. 1999;55:18991911. 81. Sylvestre LC, Fonseca KP, Stinghen AE, Pereira AM, Meneses RP, Pecoits-Filho R. The malnutrition and inflammation axis in pediatric patients with chronic kidney disease. Pediatr Nephrol. 2007;22:864873. 82. Wong CS, Gipson DS, Gillen DL, et al. Anthropometric measures and risk of death in children with end-stage renal disease. Am J Kidney Dis. 2000;36:811819. 83. McPartland KJ, Pomposelli JJ. Update on immunosuppressive drugs useds in solid-organ transplantation and their nutrition implications. Nutr Clin Pract. 2007;22:467473. 84. Fine RN, Webber SA, Olthoff KM, Kelly DA, Harmon WE, eds. Pediatric Solid Organ Transplantation. 2nd ed. Oxford UK: Blackwell Publishing; 2007. 85. Salvatierra O Jr, Singh T, Shifrin R, et al. Successful transplantation of adult-sized kidneys into infants requires maintenance of high aortic blood flow. Transplantation. 1998;66:819823. 86. Salvatierra O Jr, Millan M, Concepcion, W. Pediatric renal transplantation with considerations for successful outcomes. Semin Pediatr Surg. 2006;15:208217. 87. Andreoli SP. Acute renal failute. Pediatrics. 2002;14:183188. 88. Star RA. Treatment of acute renal failure. Kidney Int. 1998;54:18171831. 89. Symons JM, Brophy PD, et al. Continuous renal replacement therapy in children up to 10kg. Am J Kidney Dis. 2003;41(5):984989. 90. Lopez-Herce J, Sanchez C. Transpyloric enteral nutrition in the critically ill child with renal failure. Intensive Care Med. 2006;32:15991605. 91. Maxvold NJ, Smoyer WE, Custer JR, Bunchman TE. Amino acid loss and nitrogen balance in critically ill children with acute renal failure: A prospective comparison between classic hemofiltration and hemofiltration with dialysis. Crit Care Med. 2000;28(4):11611165. 92. Scheinkestel F, Adams F, et al. Impact of increasing parenteral protein loads on amino acid levels and balance in critically ill anuric patients on continuous renal replacement therapy. Nutrition. 2003;19:733740.
93. Zappitelli M, Goldstein SL, Symons JM, Somers MJ, et al. Protein and calorie prescription for children and young adults receiving continuous renal replacement therapy: A report from the Prospective Pediatric Continuous Renal Replacement Therapy Registry Group. Pediatr Crit Care Med. 2008;36:32393245. 94. Nakamura AT, Btaiche IF, Pasko DA, Jain JC, Mueller BA. In vitro clearance of trace elements via continuous renal replacement therapy. J Ren Nutr. 2004;14(4):214219. 95. Berger, MM, Shenkin, A, et al. Copper, selenium, zinc, and thiamine balances during continuous venovenous hemodiafiltration in critically ill patients. Am J Clin Nutr. 2004;80:410. 96. Chiolero, R. Berger M. Nutritional support during renal replacement therapy. Acute Kidney Inj. 2007;156:267274. 97. Moghal NE, Embleton ND. Management of acute renal failure in the newborn. Semin Fetal Neonatal Med. 2006;11:207213. 98. Abitbol CL, Bauer CR, Montane B, Chandar J, Duara S, Zilleruelo G. Long-term follow-up of extremely low birth weight infants with neonatal renal failure. Pediatr Nephrol. 2003;18:887893. 99. Spinozzi NS, Nelson P. Nutrition support in the newborn intensive care unit. J Ren Nutr. 1996;6(4):188197. 100. Groh-Wargo S, Thompson M, Hovasi Cox J, eds. ADA Pocket Guide to Neonatal Nutrition. Chicago, IL: American Dietetic Association; 2009. 101. Ledermann SE, Spitz L, Moloney J, Rees L, Trompeter RS. Gastrostomy feeding in infants and children on peritoneal dialysis. Pediatr Nephrol. 2002;17:246250. 102. Coleman JE, Watson AR, Rance CH, Moore E. Gastrostomy buttons for nutritional support on chronic dialysis. Nephrol Dial Transplant. 1998;13:20412046. 103. Ellis EN, Yiu V, Harley F, et al. The impact of supplemental feeding in young children on dialysis: A report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol. 2001;16:404408. 104. Coleman JE, Norman LJ, Watson AR. Provision of dietetic care in children on chronic peritoneal dialysis. J Ren Nutr. 1999;9(3):145148. 105. Hawkins NM, Coffey S, Lawson MS, Delves HT. Potential aluminum toxicity in infants fed special infant formula. J Pediatr Gastroenterol Nutr. 1994;19:377381. 106. Warady BA, Kriley M, Belden B, Hellerstein S, Alon U. Nutritional and behavioural aspects of nasogastric tube feeding in infants receiving chronic peritoneal dialysis. Adv Perit Dial. 1990;6:265268. 107. Rodriguez-Soriano J, Arant BS, Brodehl J, Norman ME. Fluid and electrolyte imbalances in children with chronic renal failure. Am J Kidney Dis. 1986;7(4):268274. 108. Ruley EJ, Bock GH, Kerzner B, Abbott AW, Majd M, Chatoor I. Feeding disorders and gastroesophageal reflux in infants with chronic renal failure. Pediatr Nephrol. 1989;3:424429. 109. Bunchman TE, Wood EG, Schenck MH, Weaver KA, Klein BL, Lynch RE. Pretreatment of formula with sodium polystyrene sulfonate to reduce dietary potassium intake. Pediatr Nephrol. 1991;5:2932. 110. Council on Renal Nutrition of New England. Intradialytic parenteral nutrition. In: Renal Nutrition Handbook for Renal Dietitians. Massachusetts National Kidney Foundation; 1993:8698.
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111. Cherry N, Shalansky K. Efficacy of intradialytic parenteral nutrition in malnourished hemodialysis patients. Am J Health Syst Pharm. 2002;15:17361741. 112. Chertow GM, Ling J, Lew NL, Lazaras JM, Lowrie EG. The association of intradialytic parenteral nutrition administration with survival in hemodialysis patients. Am J Kidney Dis. 1994;24:912920. 113. Kopple JD, Foulks CJ, Piraino B, Beto JA, Goldstein J. Proposed Health Care Financing Administration Guidelines for Reimbursement of Enteral and Parenteral Nutrition. Am J Kidney Dis. 1995;26:995997. 114. National Kidney Foundation. Childhood Nephrotic Syn drome. http://www.kidney.org/atoz/atozItem.cfm. Accessed November 6, 2008. 115. Ramello A, Vitale C, Marangella M. Epidemiology of nephrolithiasis. J Nephrol. 2000;13(3):S45S50. 116. VanDervoort K, Wiesen J, Frank R, et al. Urolithiasis in pediatric patients: a single center study of incidence, clinical presentation and outcome. J Urol. 2007;177:23002305. 117. Lande MB, Varade W, Erkan E, Niederbracht Y, Schwartz GJ. Role of urinary supersaturation in the evaluation of children with urolithiasis. Pediatr Nephrol. 2005;20:491494.
118. Meschi T, Maggiore U, Fiaccadori E, et al. The effect of fruits and vegetables on urinary stone risk factors. Kidney Int. 2004;66:24022410. 119. Pak CYC. Medical management of urinary stone disease. Nephron Clin Pract. 2004;98:4953. 120. Bataille P, Pruna A, Gregoire I, et al. Critical role of oxalate restriction in association with calcium restriction to decrease the probability of being a stone former: insufficient effect in idiopathic hypercalciuria. Nephron. 1985;39:321324. 121. Knoll T, Zollner A, Wendt-Nordahl G, Michel MS, Alken P. Cystinuria in childhood and adolescence: recommendations for diagnosis, treatment and follow-up. Pediatr Nephrol. 2005;20:1924. 122. Caldas A, Broyer M, Dechaux M, Kleinknecht C. Primary distal tubular acidosis in childhood: clinical study and longterm follow-up of 28 patients. J Pediatr. 1992;121:233241. 123. NDI Foundation. Diagnosis and Treatment of NDI. http://w w w.ndif.org/pages/6-Diagnosis_Treatment. Accessed December 9, 2008.
Gastrointestinal Disease
Donald George, MD and Elizabeth Bobo, MS, RD, LDN, CNSD
25
CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
Mechanisms of Nutrition Deficiency Nutrition Assessment
Learning Objectives
Gastroesophageal Reflux. . . . . . . . . . . . . . . . . . . . . . . . . . Celiac Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inflammatory Bowel Disease. . . . . . . . . . . . . . . . . . . . . . . Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pancreatic Insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disorders of Chyle Loss. . . . . . . . . . . . . . . . . . . . . . . . . . . Functional Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Gastroparesis Constipation Cyclic Vomiting Syndrome Irritable Bowel Syndrome
286 287 289 291 292 293 294 295
1. Enumerate the mechanisms leading to nutrition deficiency in gastrointestinal diseases. 2. List several common gastrointestinal diseases in children and review the pathophysiology as it applies to nutrition. 3. Describe the role of nutrition support as primary treatment of inflammatory bowel disease, celiac disease, and functional gastrointestinal disorders.
Introduction
Eosinophilic Conditions of the Gut. . . . . . . . . . . . . . . . . . 296 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
The tasks of ingesting, processing, digesting, and absorbing nutrients are coordinated through a complex network of neural and hormonal factors that help direct the function of specialized gastrointestinal (GI) cells. GI diseases may cause malnutrition by affecting nutrient intake, nutrient absorption, or nutrient requirements. When dealing with a patient who has a GI disease, the clinician must determine if the patient is malnourished, whether nutrition deficiencies are likely to occur, and whether the patient would benefit from nutrition therapy.
Mechanisms of Nutrition Deficiency

Mechanisms responsible for nutrition deficiency are summarized in Table 25-1. They include the following: Disordered Ingestion Disordered ingestion may result from refusal to feed, an inadequate diet, or from difficulty swallowing. Difficulty swallowing can be related to oral, neurological, or esophageal diseases. Inability to chew or produce saliva also interferes with the ability to swallow. In addition, a number of behavioral problems (eg, food aversion, depression, and
283
284
eating disorders) influence the ability to ingest nutrients. Gastric inflammation or vomiting of any cause will limit the ability to eat. Failure of Digestion Failure of digestion occurs in diseases that affect the production of digestive enzymes from the stomach (pepsin), pancreas (pancreatic insufficiency), or the surface of the GI tract (lactase deficiency or sucrase-isomaltase deficiency). Bile acids are important in the solubilization of fat, and patients with cholestasis of any cause will have impaired digestion. Failure of Absorption Failure of absorption occurs if there is an inadequate surface area available either due to mucosal injury or to surgical foreshortening of the GI tract. There may be failure of systems involved in particular nutrient absorption (eg, pernicious anemia, glucose-galactose malabsorption). Lack of luminal factors such as biliary secretions will impair absorption, especially of lipids. Deficiency of luminal bile salts occurs in liver disease, gallbladder disease, or disease of the biliary ducts. In rare instances, absorption may not occur despite an adequate surface area. Congenital anomalies such as microvillus inclusion disease preclude normal absorption while motility problems such as pseudoobstruction may interfere with absorption by inhibiting movement of the food bolus. Increased Needs A hypermetabolic state resulting in increased energy needs can occur in diseases with fever, increased work of breathing, or because of medications needed. Nutrition deficiency usually involves multiple mechanisms. For example, a patient with Crohns disease may have a poor appetite or be unable to eat because of pain or oral ulcers. In addition, there may be small bowel involvement or intestinal resection that affects absorption (eg, vitamin B12 in the terminal ileum). Some patients with Crohns disease will have lactase deficiency. Further, the presence of fever or underlying inflammation may increase needs for energy and protein.
Table 25-1 Mechanisms of Nutrition Deficiency

Mechanism Examples
Disordered Ingestion
Failure of Digestion
Failure of Absorption
Increased Needs
Anorexia Dental disease Dysphagia of any cause Esophagitis Foreign body Inadequate access to food Pancreatic enzyme deficiency Sucrase-isomaltase deficiency Cholestasis with failure of bile salt secretion Short bowel syndrome due to surgery Celiac disease Liver disease Movement disorders Fever
Nutrition assessment is an essential component of the evaluation of all children. Monitoring of growth should be part of the routine well-child examination. Assessment of both linear and ponderal growth of the child or adolescent is central to evaluation of nutrition status. Alterations in patterns of linear growth and weight gain (both inadequate as well as excessive weight gain) may be the earliest manifestation of disease. Malnutrition is commonly diagnosed in hospitalized patients and is also a common comorbidity in patients with GI disease.13 Malnutrition during illness may complicate the response to therapies or impair recovery (Table 25-2). Thus, nutrition assessment is an integral part of both the initial and ongoing evaluation of all children with acute and/or chronic disease and is of crucial importance in the evaluation of the child with GI disease. The initial nutrition evaluation includes both subjective and objective assessment of the patients current nutrition status and projected nutrition requirements. The subjective assessment includes the presence and duration of GI symptoms, fever, frequent infections, fatigue, food aversion, allergies to particular foods, or feeding intolerance. Specific attention is paid to previous growth, detailed diet history, changes in body weight and dietary intake, GI symptoms (eg, abdominal pain, diarrhea, and vomiting), and anorexia. The objective assessment should include data from clinical, anthropometric, and laboratory evaluations (Table 25-3). Clinical data include the diagnosis, current medical or surgical problems, allergies, and medications that may affect nutrition support options. Objective measures of nutrition status include growth indices (both previous and current), current weight, and Tanner stage.
GASTROINTESTINAL DISEASE
285
The determination of body mass index (BMI) for children > 3 years of age provides important information regarding the nutrition status. In children < 2 years of age, weight-forlength is used. In children between the ages of 2 and 3, BMI is used when a standing height is obtained while weight-forlength is used when a recumbent length is obtained. Specific normative data are available.
Table 25-2 GI Nutrient Deficiencies4,44,57
Nutrient Signs/Symptoms of Deficiency Laboratory Markers
Iron
Fatigue Microcytic anemia
Folate
Vitamin B12
Calcium Vitamin D
Vitamin A
Vitamin K Vitamin E
Megaloblastic anemia Glossitis Diarrhea Forgetfulness Megaloblastic anemia Ataxia Diarrhea Mental status changes Paresthesias Glossitis Osteopenia Osteoporosis Tetany Bone pain Muscle weakness Tetany Osteomalacia Rickets Night blindness Decreased appetite Decreased immune function Hyperkeratosis Bleeding Bruising Hemolytic anemia Truncal ataxia Hypo or areflexia Diarrhea Dry skin Skin sloughing on palms Mental status changes Hair loss Growth stunting Anorexia Muscle cramps Bone pain Nausea Seizures
hgb hct MCV RDW % TIBC ferritin serum iron serum folate red blood cell folate MCV MCV hgb serum vitamin B12
Table 25-3 Nutrition Assessment History Gastrointestinal Symptoms (diarrhea, vomiting) Feeding tolerance Allergies/Aversion Developmental feeding skills Recent changes in growth or intake Clinical Data Diagnosis Medications Anthropometry (height, weight, Tanner stage) Laboratory Blood: Electrolytes, CRP , albumin, prealbumin, CBC, vitamin levels, minerals (eg, iron and zinc) Stool: pH and reducing substances (carbohydrate malabsorption) Quantitative fat Body composition: DEXA, bioelectric impedance
serum total calcium serum ionized calcium serum alk phos 25-hydroxyvitamin D
plasma vitamin A
PTT serum creatinine creatinuria serum vitamin E:total serum lipid ratio serum alk phos serum zinc* urinary zinc**
Zinc
Magnesium
serum magnesium
* Zinc binds to serum proteins, which can make levels appear low if protein levels are depleted. ** Associated with disease status.
Careful examination of the child is the initial step in evaluation.4 Obesity and wasting are obvious. Edema, dehydration, excess fat, or decreased muscle mass can be appreciable. Anthropometric measurements, including midarm circumference and skinfold thickness determinations, are useful. It is standard practice to measure these parameters in patients at risk for chronic malnutrition such as those with pancreatic insufficiency, inflammatory bowel disease, celiac disease, or short bowel syndrome in which maldigestion or malabsorption may be prominent. It is rare to find many stigmata of severe malnutrition in children. Most often wasting, sometimes accompanied by edema, is seen. The clinician, however, should have special concern for micronutrient deficiencies, especially in children with inflammatory disorders or disorders of absorption. Specific attention is paid to examination of the abdomen. Abdominal tenderness, abdominal distention, and the presence of bowel sounds not only provide helpful clues to the nature of the disease process but also influence treatment decisions. There may be other findings that suggest nutrient deficiency. Angular stomatitis and dermatitis may suggest riboflavin deficiency. Dry cracked skin in areas exposed to sunlight suggests niacin deficiency. Dystrophic nails, spooning of the nails, or pallor of the conjunctiva or skin may suggest iron deficiency. Peripheral neuropathy can be seen with a number of vitamin deficiencies including thiamin, B6, B12 , and niacin. Zinc deficiency is often manifested by alopecia and perioral or perianal rash. Bowing of the legs, tetany, or rickets suggest vitamin D deficiency. Petechiae, bruising of the skin, or bleeding gums may indicate vitamin K deficiency as may be seen in liver disease.
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Gastroesophageal reflux (GER) is the passage of gastric contents into the esophagus with or without regurgitation. It can occur several times a day in healthy infants, children, and adults. 57 Regurgitation occurs daily in 40% of healthy infants and usually resolves spontaneously by 12 to 24 months of age.810 However, regurgitation occurs at least weekly in 12% to 15% of children ages 3 to 17 years 6 (Table 25-4). Gastroesophageal reflux disease (GERD) refers to reflux-associated tissue damage (eg, esophagitis) or symptoms severe enough to impair quality of life.11
Table 25-4 Incidence of Regurgitation Infancy (Daily GERD) 3 mo 6 mo 12 mo Children (Weekly) 39 y 1017 y 40% 30% 15% 12% 15%
Gastroesophageal Reflux
intake.15 In these cases specialized nutrition support may be needed. This may be accomplished orally with the use of specialized formulas or supplements. In some patients with complicated GER or GERD, alternate enteral access may be needed. Factors that influence this decision include aspiration risk, degree of malnutrition, the age of the child, and associated anatomical or neurological problems.
Table 25-5 Common Presentation of GERD
Age Examples
Infant
Child
The genesis of reflux-related injury and reflux symptoms is not the same. Each relates to a combination of factors that lead to an excessive number of reflux events, impaired clearance of material from the esophagus, increased acidity, or decreased buffering of the refluxed material or impaired protection of the esophageal or supraesophageal mucosa.12 The most important mechanism causing GER is transient lower esophageal sphincter (LES) relaxations.13 Delayed gastric emptying, increased intra-abdominal pressure, and chronically reduced LES resting pressure have also been implicated.14 Studies of gastric emptying have shown it is related to both the composition and caloric density of the feedings. Higher fat diets or diets of higher caloric density will slow the emptying and thereby promote reflux. GER and GERD have a variety of presentations that vary with age. Regurgitation associated with poor growth, irritability, or airway compromise are common reasons for evaluation in infancy. Heartburn and epigastric abdominal pain are more common complaints in older children and adolescents. Abnormal posturing (Sandifers syndrome) and acute life-threatening events (ALTEs) are typical manifestations in the infant with GERD but are rarely seen in older children or adults (Table 25-5). Regurgitation in infancy most often is nothing serious. Most instances of infantile GER resolve spontaneously. However, a minority of infants may have severe or prolonged problems that lead to caloric insufficiency and malnutrition. Some severe cases result in failure to thrive (FTT). FTT may be due to persistent vomiting, difficulty feeding (coughing or gagging), and feeding aversion with subsequent lack of
Adolescent
Regurgitation Vomiting Feeding difficulties (acute) Unexplained crying Failure to thrive Posturing Vomiting Cough Abdominal pain Sore throat Respiratory difficulties Hoarseness Regurgitation Chest pain Heartburn Epigastric pain Dysphagia
Disordered ingestion or nutrient losses due to vomiting or regurgitation dominate the clinical picture. In children who have poor weight gain, or weight loss, attention is paid to modalities to increase calories. Insufficient oral intake can be related to pain associated with eating, food aversion due to vomiting, or dysphagia associated with esophagitis. Treatments to reduce emesis in infants with regurgitation include smaller feedings, thickening the formula with cereal or a pre-thickened formula, and positioning. Smaller, more frequent feeds are often suggested but are sometimes impractical and poorly tolerated by babies and parents. Thickening of feedings has been shown to reduce symptomatic GER. Agents commonly used to thicken formula include rice cereal, guar gum, carob bean gum, locust bean gum, pectin, pre-gelatinized waxy rice starch, and soy polysaccharides.15,16 Thickened formulas lessen the frequency of emesis, but may contribute to some undesirable side effects. Despite a significantly reduced number of episodes of obvious reflux and emesis, pH probe studies do not indicate a reduction in exposure to acid in the esophagus.17,18 Further, studies found increased postprandial coughing
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in infants fed thickened formula, suggesting continued reflux despite improvement in emesis.19 Thickening infant formulas is relatively free of major side effects; however, complications such as increased cough and increased acid exposure are documented.20,21 Also of concern is the effect of thickened formulas on the macronutrient content of formula as well as micronutrient absorption. Thickening of formulas with rice cereal alters the macronutrient composition of the formula by providing additional calories and protein. Importantly, indigestible carbohydrate thickening agents, such as locust bean gum, have been linked with decreased bioavailability of calcium, zinc, and iron. Conversely, digestible carbohydrate thickening agents, such as pre-gelatinized waxy rice starch, have not been linked with decreased nutrient absorption. 22 Due to lack of definite data regarding the efficacy of thickened formulas it is recommended that they only be used under medical supervision.16,20,23 In older children with GER, the nutrition therapy is dependent on individual tolerance to various foods. There is sparse evidence to support avoidance of caffeine, coffee in particular, peppermint, chocolate, and spicy foods.2326 Obesity and exposure to alcohol and tobacco smoke may worsen GER.23 Spearmint does not have an effect on esophageal reflux nor does the fat content of a meal except in the absence of delayed gastric emptying.2628 Data suggest that GER may be reduced in malnourished, neurologically hindered children when they have been nutritionally repleted.29 Medications commonly used in the treatment of GER include proton pump inhibitors (PPIs) and H2 histamine receptor antagonists. These medications are associated with various nutrition-related side effects (Table 25-6). Also worthy of mention is the decreased absorption of supplemental iron associated with PPI usage. 30 There are concerns as well about possible infection risk from long-term use of PPIs. 31,32
Table 25-6 Potential Effects of Medications Used for GERD30
Side effect Proton pump inhibitor H2 Histamine receptor antagonist
Prokinetic medications are often suggested to improve gastric emptying. Metoclopramide is often prescribed although evidence supporting its effectiveness is scant. It reduces symptoms, however it is associated with many side effects that limit its use. 33 Erythromycin has prokinetic activity and improves gastric emptying although it has not been shown to improve GER symptoms. These medications are most commonly used in patients with weight loss or failure to gain related to GER. Clinical outcome in GER can be measured in a variety of ways. Symptom reduction can be monitored by recall or the use of diaries with symptom severity and frequency estimates. For GER causing poor weight gain, improvement in weight gain over time is the accepted measure. Lower esophageal pH recording is accepted as a valid measure of GER, however serial recordings are rarely used in clinical practice.
Celiac Disease
Diarrhea Constipation Abdominal pain Nausea/vomiting Anorexia Anemia Weight gain/loss Hepatotoxicity
X X X X X X X
X X X X
Celiac disease is a T-cell mediated autoimmune, chronic inflammatory disorder. It is characterized by damage to the small intestinal mucosa in genetically susceptible individuals and is due to abnormal reactions to the gliadin fraction of wheat gluten and similar peptides present in barley and rye. There is a specific peptide fragment of gliadin, made up of 33 amino acids, that is resistant to degradation by pancreatic, gastric, or small intestinal conditions or enzymes, that passes through the epithelial barrier and interacts with immune cells of the intestine. Immune responses affecting both the adaptive and innate immunity promote an inflammatory reaction in the lamina propria of the intestinal wall leading to villus atrophy. The genetic factors are linked to the human leukocyte antigen (HLA) system, which regulates the immune response. The availability of serologic testing for celiac disease has changed our understanding of both the prevalence and presentation of the disease. Previously celiac disease was diagnosed mainly in patients who had typical symptoms (Table 25-7). Screening studies now suggest that celiac disease occurs in roughly 1% of the population. There is little difference in the rates in Europe compared to North America, North Africa, or the Middle East. 34 The typical presentation of celiac disease usually occurs in the first few years of life and manifests as diarrhea with growth failure and anemia. It is now recognized that celiac disease can present at any age following inclusion of gluten in the diet and has a variety of manifestations, many of which are extraintestinal in nature. Indeed, with the development and implementation of screening of patients at
288
risk (Table 25-8) it is clear that some patients with celiac disease are asymptomatic despite significant intestinal mucosal injury. Further, patients may have symptoms that do not immediately call to mind intestinal disease. Older children and adolescents may present with constitutional symptoms such as fatigue or lassitude. GI symptoms may be mild or even absent. Patients with celiac disease often have derangements of bone and mineral metabolism and idiopathic osteopenia may be the sole clinical feature. 35,36
Table 25-7 Presentation of Celiac Disease Typical (Usually Young) Weight loss Failure to grow Vomiting Diarrhea Bloating Anorexia Abdominal pain Atypical (Adolescent Constipation Young Adult) Short stature Dermatitis Herpetiformis Osteopenia Elevated liver enzymes Arthritis Iron deficiency Anemia Dental enamel defects Silent (Any age) No obvious signs or symptoms; patient identified when tested because of risk factors and on biopsy has typical enteropathy Latent (Any age) Mild or non-specific symptoms identified by screening; positive serology but normal biopsy. May develop typical disease at a later time.
Table 25-8 Groups at Risk for Celiac Disease Relative of Patient with Celiac Disease Diabetes Mellitus (Type 1) Down Syndrome Thyroiditis Turner Syndrome William Syndrome Other Autoimmune Diseases
The mainstay of diagnosis of celiac disease remains the small intestinal biopsy with demonstration of the typical features of enteropathy. Serologic tests are a valuable adjunct in the diagnosis and are often the initial diagnostic tool in
patients with unexplained GI symptoms, anemia, or poor growth. Further, they are used to screen high-risk groups, and to aid in monitoring compliance with diet. Serologic tests available include the tissue transglutaminase (tTG) IgG and IgA and anti-endomysial (AEM) antibodies. Antireticulin antibodies are rarely used as the more sensitive and specific tests are commonly available. Recently serology using antibodies to deamidated gliadin have become available. These appear to have sensitivity and specificity similar to those of the tTG antibodies. The effects of celiac disease on nutrition status are profound. A patient may have linear and/or ponderal growth failure. Diarrhea and weight loss may also be present. In addition vitamin and mineral deficiencies may be present at the time of diagnosis. A thorough physical assessment of the patient and assessment of laboratory values when indicated are necessary to identify such deficiencies. Attention is paid to growth, bony abnormalities, and pigmentary changes. Laboratory investigation, including serology, is often revealing. In particular microcytic or macrocytic anemia may be present due to impaired absorption of iron or folic acid in the proximal intestine37,38or B12 in the distal small bowel. Other nutrients of concern include, but are not limited to, fat-soluble vitamins (A, D, E, and K), zinc, and calcium. Special attention is paid to vitamin D. Calcium supplementation may also be needed. Inadequate calcium may be due to malabsorption or poor dietary intake. Lactose intolerance is common in untreated patients due to damage to the villi. Most often this improves with treatment; however, adult-type lactase deficiency, not associated with intestinal injury, may complicate the clinical picture. The primary nutrition management of celiac disease includes complete avoidance of all gluten and correction of any vitamin/mineral deficiencies. The fundamental basis of the gluten-free (GF) diet includes avoidance of wheat, barley, and rye. Oats that are specifically labeled gluten free may be consumed in the diet; however, general commercial oats may not be consumed secondary to crosscontamination with wheat in processing. 39 Refer to Table 25-9 for a list of gluten-containing and gluten-free grains. The diet is more cumbersome than simply avoiding the grains listed as containing gluten as there may be secondary hidden sources of gluten in processed foods in the form of additives. Detailed patient instruction on label reading and avoiding cross-contamination is crucial for proper adherence to the GF diet. When replenishing vitamin/mineral stores with dietary supplements it is important to read the label for the presence of gluten as many dietary supplements are notGF.
289
Table 25-9 Grains and Gluten

Gluten Containing Gluten Free
Barley Bulgur Couscous Dinkle (spelt) Durum Einkorn Emmer Farina Fu Graham flour Kamut Seitan Semolina Rye Wheat Triticale Note: This is not an all-inclusive list.
Amaranth Arrowroot Buckwheat Corn Flaxseed Rice Millet Milo Potato flour Quinoa Sorghum Soy Tapioca Tef Taro flour Urd
Removal of gluten from the diet usually results in clinical and histological recovery. Specialized oral feedings or enteral feedings are rarely necessary in a patient with celiac disease. Parenteral feedings are not used unless there is some other indication for that therapy. When the diagnosis of celiac disease is confirmed, routine nutrition follow-up of the child is necessary to monitor growth parameters, promote adherence to the diet, and to assure proper nutrition, particularly because many of the gluten-free products are not fortified. Ongoing monitoring of vitamins (especially A, D, B12 , and folate), as well as assessment of anemia and markers of bone health, is suggested.40 Fortunately, with proper nutrition and adherence to the GF diet, bone density in children returns to normal 1 year post-initiation of the diet.41 Clinical outcome is measured by resumption of normal growth and weight gain and by monitoring of serologic markers, especially tTG and IgA. Failure of tTG IgG and IgA levels to return to normal values after adherence to a gluten-free diet for 6 to 12 months warrants further inspection of the childs diet for inadvertent gluten consumption.
Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) refers to chronic inflammation anywhere along the GI tract. The term includes Crohns disease, ulcerative colitis, and indeterminate colitis (ie, IBD with features that do not allow clear distinction between Crohns disease and ulcerative colitis). These are chronic conditions that affect children of any age although they most commonly manifest in the second decade of life.
The most important risk factor for developing IBD is a positive family history. The incidence of Crohns disease seems to be increasing in childhood while the rates of ulcerative colitis are steady. IBD may present at any age. Ulcerative colitis is more common in younger children. Peak age of incidence of Crohns disease is in the second decade of life. Inflammation of the bowel leads to a number of derangements that culminate in diarrhea, GI bleeding, and abdominal pain. Other symptoms depend on the location of inflammation within the GI tract. For example, vomiting is more prominent in patients with gastric or small bowel disease. The most common presentation is a patient with abdominal pain and diarrhea. Stools may be bloody. Weight loss is common, especially in patients with Crohns disease. However, non-specific manifestations of the disease may be the initial manifestations and failure to recognize their importance may lead to delay in the diagnosis. Joint pain and swelling, skin rashes, muscle pain, elevated liver enzymes, or eye changes (uveitis, iritis, or episcleritis) may be present prior to any specific GI manifestation. Oral ulcerations can range from painless to severe pain with bleeding. It is well recognized that deterioration of linear and ponderal growth may precede the development of more specific symptoms by months or in some cases even years. The effect of IBD on nutrition status is multifaceted. Growth, bone health, and macronutrient and micronutrient stores are commonly affected and malnutrition is common.42 Weight loss is a common presenting symptom in all forms of IBD. Linear growth failure can occur as well but is more frequently associated with Crohns disease. Nutrition assessment of children with IBD includes measurements of weight, height, and calculation of body mass index (BMI). These values should be plotted and followed serially on appropriate Centers for Disease Control and Prevention (CDC) growth charts.43 The importance of tracking these measurements is emphasized by the fact that upon diagnosis the majority of children with ulcerative colitis and especially Crohns disease will have growth failure.44 In fact, reduced linear growth velocity may precede GI manifestations of IBD by months or even years.4547 Criteria for defining growth failure include a height velocity < 3rd percentile, a height < 3rd percentile, or a bone age less than chronological age by 2 or more standard deviations.48 Males may be more susceptible to growth failure, but all children with IBD are at risk.43,49 Factors affecting risk include malnutrition, treatment modality, and intestinal inflammation. Malnutrition in IBD patients is multifactorial and
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includes energy losses, increased requirements, malabsorption, and decreased energy intake due to diarrhea, abdominal pain, and other disease-related side effects. 50 Further contributing to malnutrition is poor appetite related cytokine activity in the inflammatory process. 51,52 Inflammatory cytokines have also been shown to reduce insulin-like growth factor 1 (IGF-1). 5355 Children with active Crohns disease often have lower levels of serum IGF-1 levels than controls. In addition, chronic usage of corticosteroids as treatment can suppress IGF-1 and also decrease osteoblast activity.43,56 Limited data suggest that nutrition therapy in comparison to corticosteroid usage may be beneficial in the treatment of Crohns disease and spare linear growth.48 More research is needed to substantiate these findings.48 Assessment of nutrition status includes sufficiency of vitamin and mineral stores. Analyses of dietary records and/or 24-hour food recall as well as laboratory values are helpful in assessing micronutrient status. Commonly deficient nutrients include iron, folate, vitamin B12 , vitamin D, calcium, zinc, and magnesium.43,57 Refer to Table 25-2 for information regarding deficiency signs/symptoms and laboratory markers. Reduced iron stores are associated with decreased intake, reduced absorption, and increased losses (ie, blood loss). Often, iron supplementation is required along with a diet rich in iron and vitamin C to correct the deficiency. 57 Laboratory values to monitor iron status include hemoglobin, reticulocyte count, mean corpuscular volume red blood cell (RBC) distribution width, ferritin, transferrin saturation, and iron. 50 Folate stores may be affected by insufficient intake, because many good sources of folate (eg, leafy green vegetables) are often not tolerated by the child with active inflammation. In addition, medications used in disease treatment such as methotrexate and sulphasalazine have direct and deleterious effects on folate metabolism. Children on these medications need folate supplementation.43,57 Vitamin B12 deficiency may occur in children with involvement of the stomach and terminal ileum and in cases of bacterial overgrowth.44,57 Notably, deficiency may be masked by supplementation of folate. Deficiency is corrected by intramuscular injection, oral supplementation, or nasalgel. 57 Maintenance of adequate calcium and vitamin D stores is imperative in children with IBD, particularly in those receiving steroid therapy due to the relationship of steroid usage and decreased bone mineral density. Lactose intolerance often limits consumption of milk and dairy products, rich in these nutrients. 57 Supplementation may be required
to obtain values within normal limits. Research suggests that supplementation of vitamin D above the standard recommendation may be necessary to achieve an appropriate 25-hydroxyvitamin D level. 58 Children with Crohns disease of the upper intestine and children with darker complexions may have an increased need for vitamin D supplementation. 58,59 The winter season may also dictate increased need. 58 Zinc and magnesium deficiencies are associated with increased stool output and may require supplementation. Treatment is usually given empirically as interpretation of serum zinc levels is sometimes difficult. Oral magnesium supplementation is important, but can worsen diarrhea if administered at increased doses over a short timeframe.43,57 Energy and protein needs of the child with IBD are based on collected anthropometric data as well as disease status. In the adequately nourished child with IBD, resting energy expenditure (REE) is no different than in healthy children.43 However, in children with insufficient energy stores and increased inflammation, energy needs may be elevated 5% to 35% above estimated needs.43 There are no guidelines for protein supplementation at this time.43 However, it may be prudent to increase protein delivery in a child with inflammation, infection, or postoperatively. 57 Enteral nutrition (EN) is the recommended route of nutrition support in IBD when needs cannot be met through oral intake alone. Parenteral nutrition (PN) may be indicated if the enteral route is not feasible or insufficient to solely meet nutrient needs.43 Furthermore, PN may be indicated preand/or postoperatively. Refer to the chapter on pediatric surgery (Chapter 32) for more information regarding PN and surgery. There is evidence that nutrition therapy may be as effective in inducing disease remission as corticosteroid usage in children with active Crohns disease. 6063 This method of treatment may be particularly beneficial in children with ileal or ileocolonic IBD. With EN as primary therapy the child follows a supplement-only diet, either orally or with tube feedings, for approximately 8 weeks. 53,62 There is no significant difference in outcomes of patients receiving a polymeric or elemental diet.64,65 After 8 weeks solids are gradually reintroduced as the nutrition supplement is concurrently reduced. 53,62 There may also be a role for nutrition therapy in maintaining disease remission. 6668 However, in North America the primary mode of treatment for pediatric IBD patients is corticosteroids, in part secondary to compliance issues with nutrition-based treatment regimens.43,69 Conversely, nutrition therapy is more
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commonly employed in Western European countries.69 Decreased bone mineral density, as determined by dual energy x-ray absorptiometry (DEXA) scan, is an unfortunate side effect of IBD. Osteopenia may result from malnutrition, inadequate calcium intake or malabsorption, vitamin D deficiency, physical inactivity, or corticosteroid use or may be related to cytokines released as part of the inflammatory disease. Children receiving 7.5 mg/d of steroids, a lifetime dose of 5 g, or 12 months of exposure are particularly at increased risk and should be monitored closely. 50
Diarrhea
Worldwide, diarrheal disease is a major cause of morbidity and mortality in children. Despite improvements in sanitation, aggressive use of oral rehydration therapy and early refeeding, diarrhea remains a significant cause of undernutrition and malnutrition in both developed and developing countries. Diarrhea is defined as the excessive loss of fluid and electrolyte in the stool. This may also be associated with nutrient loss. Acute diarrhea (ie, diarrhea of sudden onset) is most often related to infection or specific food intolerance. Chronic diarrhea (diarrhea that lasts more than 2 weeks without obvious cause) has a number of possible etiologies. It is beyond the scope of this chapter to discuss in detail the many different causes of diarrhea. Emphasis here is on the general principles guiding nutrition therapy in patents with the symptoms. The basis for diarrhea is impaired transport of intestinal content including nutrients, electrolytes, and other solutes. Water movement across the intestinal mucosa depends on the active and passive fluxes of solute. Diarrhea encompasses 4 mechanisms that often overlap. Each mechanism may present a unique nutrition challenge (Table 25-10). In addition, patients with diarrhea often do not ingest adequate amounts of nutrients.
Table 25-10 Pathophysiology of Diarrhea Osmotic Increased osmotic load due to failure to absorb Secretory Net intestinal secretion of fluid and electrolytes Motility Rapid transit with failure to dry Inflammatory Combination of the above with added exudative loss of protein Medication Opioids Calcium Channel Blockers Anti-cholinergic
Osmotic diarrhea happens when a non-absorbed material, often carbohydrate, creates an osmotic load in the distal
bowel and produces increased fluid losses. This can be due to either congenital or acquired disease. A common example is diarrhea associated with lactose intolerance. Excessive sugar intake by children, either juices or sodas, may contribute to osmotic diarrhea. Ingestion of non-absorbable materials such as sorbitol or xylitol, used in some candies, will cause diarrhea as well. This type of diarrhea will stop with fasting or the removal of the offending solute. Secretory diarrhea occurs when the intestinal surface cells secrete fluid into the lumen of the bowel. This may be due to congenital disorders, such as congenital chloridorrhea, or acquired. Toxins may induce fluid and electrolyte secretion. This is seen with cholera and some other infections. Also some tumors may produce hormones that induce secretion. Secretory diarrhea does not stop with fasting. Children with motility-type diarrhea often have normal absorption and digestion; however, they have rapid transit with resultant looseness and fluidity of stools. This mechanism predominates in toddlers diarrhea or irritable bowel syndrome. Intestinal inflammation is associated with diarrhea. It often involves elements of the other 3 mechanisms. In addition there may be increased loss of blood and protein. Infectious enteritis, celiac disease, IBD, eosinophilic disease of the GI tract, and certain medications can cause intestinal inflammation. Diarrhea can affect nutrition status in numerous ways. Reduced and/or altered dietary intake, fecal loses of macronutrients and micronutrients, fluid losses, and malabsorption of ingested nutrients are all factors that can compromise the child with diarrhea. Prolonged diarrhea coupled with insufficient dietary intake may result in growth failure.70,71 Interestingly, malnutrition is an independent risk factor for development of diarrhea.70 Thus, correction of diarrhea-associated malnutrition is not only crucial for assuring proper growth of the child but also for prevention of future diarrheal episodes. Impaired absorption and/or increased losses of carbohydrates, particularly lactose, protein, fat, and fluids, are associated with acute and chronic diarrhea episodes.70,7274 In cases of acute diarrhea the degree of malabsorption and/ or loss is dependent upon the type and severity of infection.73 A common occurrence during infectious diarrhea is the development of dehydration. Subsequently, acidosis secondary to high output of bicarbonate may occur. To correct severe dehydration (> 10% loss in body weight) 100 mL/kg of sodium-containing fluid should be administered intravenously. The amount of sodium depends on the type of dehydration. Within the first hour, half of the
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dosage may be administered while the remaining fluids may be given over a 3- to 6-hour period. Plasma expanders may also be indicated. Following correction of dehydration, maintenance fluids may be given. If dehydration is mild, oral fluids may be given using an oral rehydrate solution (ORS) containing sodium, chloride, bicarbonate, and potassium at a dosage of 50 to 120 mL/kg over 4 to 6 hours, then followed by maintenance fluids. Fluids with a high osmotic load, such as sodas, should not be given as they may worsen the diarrhea.70 In the absence of vomiting, feeding of a regular diet (ie, breast milk, infant formula, and/or solids) should begin after rehydration commences to reduce or prevent malnutrition and subsequent growth stunting.70,71,74 Caloric intake enhances recovery.74 The approach to management of chronic diarrhea is dependent on the etiology of the condition. For example, in cases of sucrase-isomaltase deficiency the management strategy is avoidance of dietary sucrose due to the absence of the sucrase-isomaltase enzyme on the intestinal surface. This condition usually presents when juices, formula, or solids containing sucrose are introduced to the infants diet.75 Absence of the sucrase-isomaltase enzyme prevents breakdown and absorption of the sucrose disaccharide, which in turn results in osmotic diarrhea.76 Other symptoms include, but are not limited to, failure to thrive, colic, abdominal distention, and gassiness.75,77 Similarly, individuals with chronic lactose intolerance also may present with abdominal distention, gassiness, and diarrhea. Lactose intolerance is a result of absence of the lactase enzyme to break down the dairy carbohydrate lactose. Management of this condition involves avoidance of lactose-containing foods/beverages or supplementing with lactase pills prior to ingestion of lactose-containing foods. Fructose is found in the diet as the free sugar, as a component of the disaccharide sucrose, and in a polymeric form (fructans). Free fructose has limited absorption in the small intestine. Fructans are neither digested nor absorbed. Fructose malabsorption contributes to osmotic load. In addition, it provides substrate for bacterial fermentation and may affect GI motility, all leading to diarrhea. This malabsorption may contribute to abdominal pain. Treatment is dietary restriction of fructose and fructan intake. In both acute and chronic diarrhea various micronutrients may be compromised either due to failure of absorption or increased losses in the stool. Losses commonly associated with diarrhea include zinc, copper, folate, magnesium, vitamin A, vitamin B12 , and trace elements, particularly selenium.70,72,78,79 The clinician should be mindful of signs of deficiency of these nutrients and conduct laboratory
screening as appropriate. Supplementation of probiotics, particularly of Lactobacillus GG and Saccharomyces boulardii, may be beneficial in the management of diarrhea.80,81 However, there are currently no standard guidelines for using probiotics in the management of pediatric diarrhea.
Pancreatic Insufficiency
The pancreas is a small but metabolically active organ that has both manufacturing (exocrine) and control (endocrine) functions. Islet cells within the pancreas make insulin and glucagon, central to glucose homeostasis. The exocrine pancreas consists of cells organized into acini and the duct system providing a pathway to the small intestine. The pancreatic juice secreted by these cells contains bicarbonate as well as digestive enzymes. Some of these enzymes (amylase, lipase, and phosphor lipase) are secreted in an active form. Others (eg, trypsin, chymotrypsin) are secreted in inactive forms (zymogens). Activation of the zymogens occurs when pancreatic juice mixes with enterokinase in the duodenum. Secretion of pancreatic juice in response to a meal is controlled by many factors including the nervous system and hormones such as pancreozymin and secretin among others. This secretion of the digestive enzymes is a tightly regulated feedback loop. If the amount of digestive enzyme delivered to the intestine is inadequate for the digestion of the fat, carbohydrate, and protein in the meal, pancreatic insufficiency exists. Cystic fibrosis (Chapter 28) is the most common cause of pancreatic insufficiency in childhood. Other causes of pancreatic insufficiency in childhood are rarer (Table 25-11).
Table 25-11 Pancreatic Insufficiency Not CF Congenital Shwachman-Diamond syndrome Pearson syndrome Johanson-Blizzard syndrome Specific enzyme defects Acquired Chronic pancreatitis Common duct obstructions
Shwachman-Diamond syndrome is the second most common cause of pancreatic insufficiency in children. It is estimated to occur in 1 in 20,000 live births. It results from the failure of normal development of pancreatic exocrine tissue in utero. The normal tissue is replaced with fat. 82,83 The ductal tissue remains intact and over time there is improvement in pancreatic function. 84 A specific gene defect has been described.85 The presenting features include pancreatic insufficiency, hematologic abnormalities (especially variable neutropenia), bone abnormalities (especially
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metaphyseal dysostosis), and short stature. Steatorrhea is most prominent early in life. Because of the neutropenia, there is concern for infectious complications. Johanson-Blizzard syndrome is a rare disorder and the incidence and natural history are unknown. Patients have pancreatic insufficiency with midline ectodermal defects and hypoplasia of the alae nasae.86 Even more rare is Pearson syndrome, which is exocrine pancreatic insufficiency associated with sideroblastic anemia.87 It results from defects in mitochondrial DNA.88 Because it is a mitochondrial disease, there can be multiorgan involvement. In addition, isolated congenital deficiencies in lipase and trypsinogen are described but are exceedingly rare. These are treated with enzyme replacement therapy. Amylase deficiency with associated starch intolerance is described in infants but is typically developmental in nature and no cases are described in adults. It can cause diarrhea but is rarely a cause of poor growth and rarely requires treatment. Failure to thrive, as indicated by growth failure and malnutrition, is commonly associated with pancreatic insufficiency. It is a result of maldigestion, malabsorption, insufficient caloric intake, and increased caloric requirements. As a product of malabsorption, fat-soluble vitamin deficiency may develop.89 Malabsorption, calorie loss, and failure to thrive are treated with dietary intervention, pancreatic enzyme replacement therapy, and supplementation of fat-soluble vitamins. Nutrition management of diseases of pancreatic insufficiency dictates a diet liberal in fats and calories and supplemented with pancreatic enzyme replacement therapy.89 Research indicates that pancreatic insufficient individuals have a higher resting energy requirement than pancreatic sufficient individuals.90 Thus, calories will likely need to be provided in greater than 100% of estimated needs.89 Pancreatic enzyme replacement should be conducted using proprietary preparations due to the lack of data with the usage of generic enzyme preparations.91 Enzymes should be ingested prior to meals, snacks, and consumption of milk products to aid in digestion of fat. Enzyme dosage should not exceed 2500 lipase units/kg per meal or 4000 lipase units/g fat per day to avoid fibrosing colonopathy.92 For more detailed information pertaining to pancreatic enzyme replacement therapy refer to the chapter on pulmonary diseases (Chapter 28). Also in need of supplementation may be the fat-soluble vitamins A, D, E, and K. These vitamins should be supplemented with a water miscible form. Refer to the chapter on pulmonary diseases (Chapter 28) for a more detailed discussion of these vitamins.
Pancreatitis
Pancreatitis is an inflammatory process of the pancreas with variable involvement of other organs and tissues. Exposure to a causal factor initiates a cascade of events in which trypsinogen is converted to trypsin in quantities that overwhelm the innate protective mechanisms. Causes of pancreatitis include trauma, infection, drugs or toxins, multisystem disease, and congenital abnormalities of the pancreatic or biliary ductal system. Many cases do not have a clear trigger identified. In children most cases are either acute and isolated or recurrent acute attacks. Chronic pancreatitis is seen more commonly in adults. In children it is most often related to structural malformation or a specific gene defect as seen in hereditary pancreatitis. The incidence of acute pancreatitis in childhood is uncertain. Though not rare, it accounts for a small proportion of pediatric admissions.93,94 Likewise, the incidence of chronic pancreatitis is not clear. Most of the pancreas is composed of acinar cells. Ductules and ducts connect the acini to the duodenum. The islet cells (which secrete insulin and glucagon) function independently of the acinar cells. The acinar cells synthesize and store digestive enzymes. All enzymes except amylase and lipase are stored as inactive proenzymes that require activation by the action of trypsin. Trypsinogen (the inactive form of trypsin) is activated in the lumen of the bowel by the mucosal enzyme enterokinase. In some instances, trypsinogen may auto-activate. This premature activation of trypsin with subsequent activation of other proteases leads to digestion of the pancreas itself. There are a number of mechanisms for protection of acinar cells from this auto-activation including presence of trypsin inhibitors that block the action of trypsin; also, trypsin can inactivate itself through autolysis. This inactivation reaction is a calcium-dependent process and aberrations of calcium concentration may trigger an episode of acute pancreatitis. If any of these mechanisms are disturbed, pancreatic injury will result. Pancreatitis is diagnosed by the combination of abdominal pain with elevation of the levels of amylase and lipase in the serum. The levels of the enzymes do not predict the severity of pancreatitis. There are no scoring systems applicable to children as there are for adults. Clinical features suggestive of more severe disease include hypotension, renal failure, altered sensorium, and hemorrhage. Initial management of children with acute pancreatitis is analgesia and intravenous fluids. If vomiting is present, a nasogastric tube is used to decompress the stomach. In patients with mild disease, enteral feedings are withheld for
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a short period. Re-initiation of feedings is based on resolution of abdominal pain and ileus and vomiting. Most patients with mild disease recover quickly without complications. Patients with severe pancreatitis often show signs of hemodynamic instability and are at risk for multiple complications including severe nutrition depletion. Nutrition support is important in these patients and is considered an active therapeutic intervention.95 Patients can be fed enterally by nasogastric (NG) or nasojejunal (NJ) tube or by the intravenous route. Although there are a number of studies in adults, data concerning nutrition support in pediatric patients with pancreatitis are scarce. Adult studies suggest a trend to fewer adverse outcomes in patients who receive enteral as opposed to parenteral feedings, however the effect on outcome is not clear.96 There does not seem to be a difference in feedings of polymeric versus semi-elemental or immune-enhancing formulas.97 A study in children with severe acute pancreatitis found little difference between EN and PN in length of stay, infection, mortality, or need for surgery.98 Chronic pancreatitis is a condition where continued inflammation of the pancreas produces irreversible changes in the gland. In some cases it is related to continued recurrent injury from acute attacks. Often the etiology is not clear even when risk factors are present. In adults, repeated exposure to toxins (eg, alcohol) is often implicated. In children, hereditary factors such as mutation of the trypsinogen molecule, or mutations of the cystic fibrosis transmembrane regulator (CFTR) gene or trypsin inhibitor genes are often sought. Autoimmune disorders, both isolated autoimmune pancreatitis as well as systemic autoimmune diseases, are seen. Patients with recurrent acute pancreatitis are at risk for developing chronic pancreatitis.99 Treatment of chronic pancreatitis revolves around several concerns: chronic pain, development of diabetes due to islet cell destruction, and pancreatic insufficiency due to acinar cell destruction. Pain impacts ability to ingest nutrients, and the treatment of chronic pain is beyond the scope of this chapter. In addition the treatment of diabetes mellitus is discussed elsewhere (Chapter 21). Digestive enzyme insufficiency is a late complication of chronic pancreatitis. The treatment for pancreatic digestive enzyme insufficiency is enzyme replacement. The goal is to provide enzyme supplements enough to restore digestive function. The dose of pancreatic enzyme is calculated according to the lipase content. A usual dose of enzyme is 1000 to 2500 units of lipase per kilogram of body weight per meal. This is often altered based on the estimated fat content of the meal. This is discussed in more detail in the chapter on cystic
fibrosis (Chapter 28). Both polymeric as well as elemental dietary supplements have been used for nutrition support, and there are scant data evaluating the effectiveness in children. It deserves to be restated that a major goal of nutrition support in these patients is maintenance of normal growth. Chyle is a creamy fluid consisting of fat, protein, electrolytes, and lymphocytes and is an important aspect of the metabolism of fat. Triglycerides are broken down in the intestinal lumen to fatty acids and mono-acyl glycerols. They are absorbed into the intestinal epithelial cells. This process is aided by the action of bile salts mixing with the fatty acids forming micelles that enhance the transport of the molecules. Within the enterocytes, the absorbed fatty acids are re-esterified to glycerol and the resultant lipid is complexed with proteins (forming chylomicrons) and transported through the lymphatic system of the GI tract and abdomen ultimately into the thoracic duct and then into the blood stream. Disorders of chyle loss are rare with the most common disorders being chylothorax or chylous ascites. Chylothorax is defined by pooling of lymphatic fluid, chyle, in mediastinal or pleural cavities. Chylous ascites occurs when there is lymphatic disruption in the abdominal cavity with resultant pooling of chyle in the abdomen. This condition is usually seen as a complication of surgery100 although congenital defects of lymph flow are also described. For more detailed information refer to the chapter on cardiac disease (Chapter 23). A less common disorder of chyle is that of intestinal lymphangiectasia. This condition results from failure of lymph flow often related to inflammation, causing enlargement of intestinal lymph vessels, which causes breakage of the lacteals and spillage of chyle into the intestinal lumen.101 As a result protein losing enteropathy, hypoalbuminemia, and edema may result. Hypogammaglobulinemia is often present. Edema of the intestinal mucosa causes malabsorption. Steatorrhea is typically seen.102 Even more rare are the disorders of chylomicron formation such as abetalipoproteinemia in which there is a defect in the ability to complex the lipids with carrier proteins and therefore the lipid is not carried into the lymphatic system. Regardless of the specific disorder of chyle processing, the nutrition approach is similar. The initial treatment is restriction of dietary fat. A low-fat, high-protein diet is recommended because there is usually associated protein loss in the GI tract. Because medium-chain length fatty acids and triglycerides can be metabolized without entry into the lymphatic system, dietary fats should be primarily
Disorders of Chyle Loss
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from medium-chain triglycerides (MCTs), often by using a specialized high MCT, low long-chain triglyceride (LCT) formula.101 The rationale of this diet is twofold. One, the decreased amount of fat lowers the amount of circulating chyle. This reduction lowers the risk of lacteal cells becoming dilated and releasing chyle. Two, MCTs are directly transported via the portal system, which reduces lymphatic circulation.101,102 Most often, this diet is needed for 4 to 8 weeks.100 One should be cautious to supply sufficient amounts of essential fatty acids, linoleic and linolenic acids, to prevent deficiency. The American Academy of Pediatrics recommends that a minimum of 3% of calories should come from these essential fatty acids.100 PN may be initiated in instances when EN is not adequate to meet nutrient needs or not indicated for other reasons. Lipids in PN are not absorbed via the lymphatic system and have no affect on the condition.
considered. Poor absorption of ingested carbohydrate may trigger symptoms in susceptible individuals. Therefore, restrictions of lactose (milk), fructose (carbonated beverages and certain fruits), or dietary starches (corn, wheat, oat, and potato) are sometimes tried. Restriction of non-absorbable sugar alcohols, often used as artificial sweeteners (eg, sorbitol, xylitol), is advised. It is important to avoid multiply restrictive diets as they may lead to nutrition insufficiency.
Gastroparesis
Gastroparesis is the delay of emptying of the stomach in the absence of a mechanical obstruction. There are multiple causes (Table 25-12). Disorders of the intestinal musculature (myopathic) and the intestinal nervous system (neuropathic), both congenital and acquired, are described. Common causes are immaturity (especially in premature infants), viral infections, systemic diseases, and drugs. Gastroparesis often complicates the management of type 1 diabetes mellitus. Evaluation should include assessment of gastric anatomy and function (eg, upper GI series x-ray or gastric emptying study) but also the search for and treatment of any underlying condition and bacterial overgrowth. Importantly, malnutrition may be both a cause as well as a result of gastroparesis.
Table 25-12 Conditions Associated with Gastroparesis Infection Postviral illness (eg, rotovirus) Neurological Disease Mitochondrial disorders Familial dysautonomia Systemic Disease Diabetes Malnutrition Connective tissue disorders
Functional Disorders
The functional disorders are a diverse group of conditions in which symptoms persist for a prolonged period and there is no specific tissue change associated with the symptom. These include recurrent and/or chronic abdominal pain, chronic non-specific diarrhea, gastroparesis, cyclic vomiting syndrome, and constipation. Because the underlying pathophysiology is unclear, both the evaluation and treatment is related to the predominant symptom. Malnutrition is rare in this group of patients and, if present, suggests an alternative diagnosis. Frequently, dietary interventions are suggested for symptom control. These include increasing fiber, reducing fermentable carbohydrate, and altering the fat content of the diet. These interventions are often recommended and frequently reported to be helpful though data documenting effectiveness are lacking. Chronic abdominal pain is a common symptom in children and adolescents and it is estimated to affect 10% to 15% of the population at some time.103 The etiology and pathogenesis are unknown and there are no specific diagnostic markers to help in diagnosis. The clinical presentation and careful history and physical examination will often suggest that the diagnosis is functional abdominal pain. A few laboratory or x-ray studies may assist in the evaluation and are remarkable for their normality. The role of dietary modifications in the management of the functional abdominal pain disorders is not established. If symptoms are mainly post-prandial or include the sensation of bloating, a low-fat diet is sometimes recommended. If diarrhea or constipation is prominently associated with the pain, an increase in the amount of fiber in the diet is
There are many symptoms of gastroparesis including nausea, vomiting, bloating, upper abdominal discomfort, early satiety, heartburn, esophageal reflux, and decreased appetite.104106 These symptoms may lead to malnutrition and the need for nutrition support. Initial treatment of gastroparesis should include maximizing the therapy of treatable systemic illness (eg, optimizing glycemic control in the diabetic patient) and eliminating causes such as medications. The nutrition assessment of a child with gastroparesis should include a dietary recall and/or dietary record, evaluation of changes in weight over time, laboratory studies, description of symptoms, and listing of medications as well as nutrition supplements.107 The dietary recall and or/record provides important information regarding both symptoms and feeding. Factors to consider are meal volume
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tolerance, preference of liquids over solids, and fiber and fat tolerance.107 Because early satiety is commonly seen in gastroparesis, small frequent meals may be better tolerated than 3 large meals.104,107 Liquids are often better tolerated than solids. Thus, a diet of liquids and/or purees may be more effective in delivering ample nutrition than a conventional solid-based diet.104,106,107 Avoidance of a high-fiber and high-fat diet, with the exception of fat in liquid nutrition, is also often beneficial in delivering nutrition as both of these nutrients delay gastric emptying.107 Dietary osmolality is less an issue in managing gastroparesis.107 Laboratory markers include ferritin, glucose, and hemoglobin A1C. Iron deficiency anemia is common in this cohort of patients, in part due to symptom management. Usage of acid-reducing medications to manage reflux and heartburn decreases gastric acid, needed to convert dietary iron to its more absorbable form. Further, usage of jejunal tube feeds to control vomiting and promote weight gain can increase the risk of iron deficiency anemia as the duodenum is the main area of iron absorption.107 Ferritin is a more appropriate marker to screen for iron deficiency anemia than hemoglobin and hematocrit. However, it is important to remember that ferritin is an acute phase respondent and will not be accurate during acute inflammation.107,108
in some children it may be beneficial to undergo a trial of a high-fiber (0.75 g soluble fiber per year of age), lactose-free, and low-fructose diet for symptom management.115
Cyclic Vomiting Syndrome

Although increasingly recognized in children, the pathogenesis of cyclic vomiting syndrome remains unknown. The clinical features overlap with those of abdominal migraine. The distinguishing characteristic is a repeated pattern of stereotypical episodes of severe vomiting often associated with pallor, lethargy, and abdominal pain. The episodes are similar in onset and usually duration. There is often a prodrome of variable duration. An important feature is that the children return to baseline health in between episodes. In cyclic vomiting syndrome the primary nutrition concern is management of any fluid and electrolyte disturbances that may arise as there is no known dietary intervention to prevent onset or reduce duration of the condition.103
Irritable Bowel Syndrome

In irritable bowel syndrome (IBS) there is no significant evidence to support that diet causes or can treat the condition. It may be prudent to undergo an elimination trial of lactose-, fructose-, and/or sorbitol-containing foods as intolerance to these foods manifests as abdominal pain.116118 The role of dietary fiber, particularly that of soluble fiber, in symptom management, especially of constipation, is debatable. Soluble fiber is found in fruits, vegetables, and whole grains. When ingested, fiber helps to give the stool a gel-like consistency and serves as a fuel source for colonic bacteria. The end result is a reduction in gut transit time and, subsequently, a reduction in constipation and intracolonic pressure.119,120 To date, there are no definitive conclusions as to the benefit of fiber in IBS symptom management.121 Nutrition counseling should be individualized based on the patients reported foodsymptom correlations secondary to limited pediatric data on the topic.122 The suspected offending food should be removed from the diet for 2 to 3 weeks. If no relief in symptoms is observed, the food may be added back to the diet.
Constipation
Constipation is a common symptom among humans of all ages and is often especially troubling in infants and young children. It is most often both self-limited and short lived. However, a substantial number of patients have symptoms that persist for 6 months or more. Constipation may be related to inadequate intake of fluid or fiber, side effects of medication, inactivity, or disordered bowel motility. Most cases are idiopathic and fulfill the definitions of functional constipation. Although most recognize a role for diet in both the etiology and the treatment of constipation, there are little data to allow identification of specific foods as either causal or beneficial. The role of cows milk in constipation has been recognized for some time, although the mechanism is unclear.109 There is increasing evidence to suggest a role of cows milk protein sensitivity in constipation.110,111 In addition, it is known that the fat content of milk may also be associated with harder or more difficult-to-pass stools. Historically, a high-fiber diet has been recommended for children with constipation. However, few studies document benefit.112,113 There is also no conclusive evidence that fiber supplements or a lactose-free diet is beneficial in alleviating recurrent abdominal pain in children.114 However,
Eosinophilic Conditions of the Gut
Eosinophilic gastroenteritis is a condition characterized by either patchy or diffuse infiltration of eosinophils anywhere in the GI tract. Damage to the GI tract is due to both the infiltration and degranulation of eosinophils. The triggering process is not clear. Both IgE and non-IgE mediated sensitivities are described. Many patients (especially older
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patients) have conditions such as a high eosinophil count, asthma, allergic rhinitis, or eczema suggesting underlying atopy. Allergies to food or inhalants are sometimes implicated. In addition there is often a family history of atopy. It may affect children of any age. The signs and symptoms are non-specific and the presentation varies by location, depth and extent of the eosinophilic infiltration (Table 25-13). There may be involvement of the mucosal, muscular, or serosal layers. Mucosal disease presents as nausea and vomiting, diarrhea (often bloody), malabsorption, and weight loss. When the muscular layers are involved, there are signs and symptoms of obstruction. If there is serosal involvement there may be ascites. The most common symptom is colicky abdominal pain.
Table 25-13 Presentation Characteristics of Eosinophilic Gastroenteritis by Tissue
TISSUE PRESENTATION CHARACTERISTICS
abdominal pain, diarrhea, hematochezia, poor growth/ weight gain, and iron deficiency anemia.124 The recommended dietary treatment is avoidance of the offending allergens. Particular attention should be paid to the quality of the diet as malnutrition may develop if numerous foods are eliminated.123 For some children usage of an amino acid based formula may be appropriate.124
Summary
Mucosal
Diarrhea GI bleeding Vomiting Abdominal pain Vomiting Colicky Abdominal pain Ascites Abdominal pain
Because of the central role of the digestive system in maintaining normal nutrition, disease of the GI tract, liver, or pancreas has a profound influence on growth and development of children. Provision of adequate nutrition support can not only improve nutrition parameters and growth but also in many cases can treat the underlying disease. Careful evaluation of the child with assessment of nutrition needs is the initial step in effective management. The clinical examination and judiciously applied laboratory investigation will identify nutrition deficiencies. With understanding of the underlying disease process, appropriate nutrition management can improve growth, quality of life, and outcomes of these patients.
Muscular
Serosal
The most frequently seen form of eosinophilic gastroenteritis is proctitis in infants. The disorder is characterized by the bloody diarrhea in an infant less than 2 months of age. Cases of food-induced eosinophilic proctocolitis are reported regardless of being breastfed or formula fed. Infants presenting with this condition usually have normal linear and ponderal growth. The infants will have diarrhea, usually accompanied by mucous and/or blood, and often with pain or straining at the time of bowel motion. Biopsy of the rectal mucosa will show eosinophilic infiltration of the mucosa. Frequently the diagnosis is made on clinical presentation alone. The dietary management of this condition involves elimination of the offending protein until approximately 9 to 12 months of age. If an infant is breastfed then the offending protein should be removed from the mothers diet. Earlier introduction of the protein will usually result in bleeding.123 In older children with eosinophilic conditions of the gut symptoms include, but are not limited to, vomiting,
A 15 year old boy is admitted to the hospital because of diarrhea and abdominal pain. He has had unintentional weight loss of 15 pounds in the last 3 months. Laboratory evaluation reveals: Albumin 3.1 Total Protein 6.2 Hemoglobin/hematocrit 9.3/27 MCV 71 (nl >79) WBC 11,500 Radiology studies demonstrated inflammation of the ileum and cecum. 1. Diet therapy should include: A. A polymeric defined formula diet B. A semi-elemental defined formula diet C. An elemental defined formula diet D. Any of A, B, or C E. A clear liquid diet 2. His medical therapy includes methotrexate and sulphasalazine. Supplementation should include: A. Folate, B12, and iron B. Pyridoxine, thiamin, and magnesium C. B12, vitamin C, and manganese D. Folate, vitamin C, and copper
298
3. In a patient with celiac disease, a gluten-free diet should be maintained: A. Until diarrhea subsides B. Until normal linear growth is established C. Until new and as yet undiscovered treatments are available D. Until bone mineral density has returned to normal E. A gluten-free diet is not necessary 4. Enterokinase is synthesized by: A. Pancreatic acinar cells B. Intestinal mucosal cells C. Liver cells D. Neutrophils 5. Enterokinase is an enzyme that: A. Digests fat B. Activates eosinophil degranulation C. Transports glucose into the cell D. Activates trypsinogen to trypsin See p. 487 for answers.
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Hepatic Disease
Samuel A. Kocoshis, MD and Renee A. Wieman, RD, CSP, LD, CNSD
26
Learning Objectives
1. Recognize the energy and protein requirements of children with chronic liver disease. 2. Describe nutrition support modalities for children with chronic liver disease. 3. Understand the diagnosis and management of metabolic liver diseases such as glycogenoses and Wilsons disease. 4. Comprehend the factors causing malabsorption in pediatric liver disease. Children with liver disease face an important nutrition impediment because the liver is so crucial for maintaining homeostasis. The liver is responsible for synthesis, storage, and metabolism of carbohydrate, protein, and fat. Additionally, major growth factors such as insulin-like growth factor-1 (IGF-1) and its binding proteins are directly synthesized by the liver. Under conditions of severe liver dysfunction, pediatric patients become growth-hormone resistant.1 In addition to growth hormone resistance, the pediatric patient suffering from chronic liver disease is prone to hypoglycemia because the liver is the major storage organ for glycogen, and a malfunctioning liver has reduced glycogen stores. Protein synthesis may be directly impaired and amino acid utilization for energy may also be accelerated in the face of reduced glycogen stores. 2 Furthermore, detoxification of ammonia and synthesis of clotting proteins may also be impaired. Finally, the synthesis of cholesterol and high-density lipoproteins may be impaired as can uptake, hydrolysis, and transport of triglycerides. 3 These changes can result in hypertriglyceridemia and concomitant hypocholesterolemia under conditions of severe hepatic dysfunction.
CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 Malnutrition in Liver Diseases . . . . . . . . . . . . . . . . . . . . . 303
Inadequate Intake Iatrogenic Factors Malabsorption Hypermetabolism
Specific Pediatric Liver Disorders. . . . . . . . . . . . . . . . . . . 305

Neonatal Cholestasis Non-Cholestatic Liver Disease
Nutrition as Primary Therapy for SelectLiverDisorders. 306

Glycogen Storage Disease Wilsons Disease Nonalcoholic Fatty Liver Disease (NAFLD)
Introduction
Assessment of Nutrition State . . . . . . . . . . . . . . . . . . . . . 307 Specific Nutrient Requirements . . . . . . . . . . . . . . . . . . . . 307

Energy Protein Lipids and Fat-Soluble Vitamins Fluids Other Vitamins and Minerals
Enteral Nutrition Support . . . . . . . . . . . . . . . . . . . . . . . . . 308 Parenteral Nutrition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308
302
HEPATIC DISEASE
303
Nutrition management of infants and children with liver disease is a critical component of the overall care required for optimal interventions and metabolic control of these patients. It is best accomplished via a team approach with the team being composed of multiple medical disciplines including hepatologists, nurses, dietitians, pharmacists, social workers, speech therapists, occupational therapists, and physical therapists. Nutrition requirements are dependent on the disease being treated, the anticipated disease course, and the likelihood that liver transplantation will be necessary. Acute diseases such as viral or toxin-induced hepatitis typically require no supportive therapy alone, whereas nutrition therapy is the definitive therapy for some metabolic disorders.
Malnutrition in Liver Diseases
Malnutrition is common in pediatric liver disease and adversely affects survival prior to and following liver transplantation. Beyond the impaired intermediate metabol ism of carbohydrate, protein, and fat, a variety of factors ac counts for malnutrition in the context of primary hepatic disease. Most studies exploring mechanisms of malnutrition in liver disease have been performed in adults, but it is known that malnutrition can occur both prior to and after liver transplantation in children. Even though those mechanisms may not have been fully investigated in pediatric patients, it is quite likely that they contribute to pediatric as well as adult malnutrition among patients with liverdisease.
anorexia is hepatic encephalopathy. Anorexia has long been recognized as a major symptom of encephalopathy, and it is remarkably difficult to treat without successfully treating the underlying cause of liver disease. Among children with inflammatory hepatitides, pro-inflammatory cytokines are released. The relationship between these cytokines and anorexia is very well established. While the phenomenon of hyperinsulinemia and insulin resistance has not been established in children with chronic liver disease, it has been established in adults, and may also contribute to their anorexia. 5 Yet another factor potentially contributing to anorexia is zinc deficiency, which is known to be quite common among patients with chronic liver disease. 6 Finally, the gastric capacity of children with either massive hepatosplenomegaly or ascites may be so restricted due to gastric compression by viscera or ascitic fluid that adequate oral intake becomes impossible.
Iatrogenic Factors
The effect of iatrogenic factors upon the nutrition state of pediatric liver patients should not be minimized. Excessive restriction of sodium in the absence of fluid overload will result in a salt depletion syndrome, and may actually induce a secondary hyperaldosteronism that would not have been present otherwise. This factor can lead to both malnutrition and growth failure. Unwarranted protein restriction can also result in deficiencies of both somatic and visceral proteins with subsequent malnutrition. Therefore, clinicians caring for children with liver dysfunction should refrain from restricting either salt or protein in the absence of ascites or encephalopathy refractory to pharmacotherapy. Known to be relatively safe, large-volume paracentesis has been a popular therapy for adults with ascites, but it has been relatively unpopular in the pediatric setting because of concerns about the large, rapid fluid shifts that might be induced.6 This potential complication notwithstanding, the practice now has advocates within the pediatric hepatology community. If large-volume paracentesis is used in pediatric patients, the loss of plasma proteins can be prodigious, rendering the patient deficient in both visceral and somatic proteins. Hence, for patients undergoing paracentesis, adequate protein intake should be maintained in the absence of overt encephalopathy. Many of the medications administered to children with hepatic disease may negatively impact upon their nutrition state. Diuretics, if administered overzealously, may salt-deplete them. Broadspectrum systemic or enteral antibiotics may eliminate vitamin K-synthesizing enteric flora, resulting in vitamin K deficiency among cholestatic patients. Additionally,
Inadequate Intake
A foremost concern among adult and pediatric liver patients is inadequate dietary intake. A simple reason that intake might be inadequate is that these patients are frequently offered low-protein, low-sodium diets that are unappetizing and unappealing. This practice may not only result in suboptimal oral intake but also provide a diet of poor caloric quality. Secondly, many forms of liver disease result in anorexia. One potential mechanism is elevation of serum and tissue leptin levels.4 Leptin, an appetite-suppressing hormone, is probably cleared via the liver, and serum levels are elevated in patients with hepatic fibrosis as well as other forms of liver disease. The role of leptin in producing anorexia among patients with liver disease remains controversial, specifically because leptin levels are consistently normal in some forms of liver disease such as primary biliary cirrhosis and consistently elevated in other forms such as Laennecs cirrhosis.4 A third factor accounting for
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neomycin, commonly administered for hepatic encephalopathy, is believed to produce villous atrophy, to reduce intestinal surface area, and to result in malabsorption of multiple nutrients. Administration of lactulose for encephalopathy may speed intestinal transit enough to result in malabsorption as well. Finally, cholestyramine, an anion exchange resin used to treat the pruritis of cholestasis by binding bile acids, may be so efficient that the intraluminal bile acid concentration may fall below the critical micellar concentration, resulting in fat and fat-soluble vitamin malabsorption.7 Because cholestyramine exchanges organic anions for chloride, hyperchloremic metabolic acidosis with resultant growth failure and malnutrition may occur in children on this medication.
Malabsorption
Pediatric patients with liver disease are more likely to have cholestatic disease than their adult counterparts. In cholestatic patients, bile acids are retained within the liver, and excreted very poorly into bile. Therefore, intraduodenal primary bile acid concentrations customarily fall below the critical micellar concentration necessary for efficient solubilization and transport of fat and fat-soluble vitamins across the unstirred water layer into the enterocyte. Thus malabsorption is very common and requires enteral administration of large quantities of fat-soluble vitamins as well as an enteral cocktail of medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs) in food or formula. Patients must receive enough long-chain fat to prevent essential fatty acid deficiency (EFAD) and they must receive enough medium-chain fat to optimize their enteric fat balance. Linoleic and linolenic acids, which are essential fatty acids (EFAs), are long-chain fats that can only be derived via dietary LCTs. MCT formulas that were designed during the late 1960s for cholestatic patients were deficient in LCTs, commonly resulting in EFAD among this population.8 Malabsorption may occur in select cases of pediatric cholestasis from not only intraluminal bile acid deficiency but also from exocrine pancreatic insufficiency. Both cystic fibrosis and Shwachman-Diamond syndrome, systemic disorders characterized by exocrine pancreatic insufficiency, may present during the neonatal period with cholestasis. Exocrine pancreatic insufficiency is a less-recognized feature of two childhood disorders characterized by severe cholestasis: progressive familial intrahepatic cholestasis, type 1 (PFIC1) and Alagille syndrome. PFIC1, previously known as Byler disease, is due to a mutation in the ATP8B1 gene, previously known as the FIC1 gene. ATP8B1 mutations
result in reduced activity of the FXR nuclear receptor, which maintains intra-hepatocyte bile acid homeostasis along with moduating the activity of the cystic fibrosis transporter (CFTR). As a result, patients with PFIC1 frequently experience diarrhea, malabsorption, recurrent pancreatitis, and pancreatic fibrosis which results in exocrine pancreatic insufficiency.9 Patients with Alagille syndrome also experience exocrine pancreatic insufficiency. Alagille syndrome arises due to mutations in the Jagged 1 gene that participates in the notch signaling pathway.10 These mutations result in bile duct malformations leading to intrahepatic bile duct paucity. Children with Alagille syndrome frequently have steatorrhea disproportionate in magnitude to their degree of cholestasis. Studies have documented pancreatic insufficiency in Alagille syndrome patients which is due to pancreatic ductal and acinar malformations. Similar pancreatic histology is seen in Jagged 1 knock-out animals whose pancreatic ductules and acini are malformed in a fashion similar to bile ductules.11 It is notable that any form of chronic liver disease, whether cholestatic or noncholestatic, may be associated with exocrine pancreatic insufficiency. Longstanding cirrhosis and portal hypertension occasionally result in exocrine pancreatic insufficiency due to either pancreatic fibrosis on the basis of venous congestion or due to the absence of hepatic regulatory mechanisms for satisfactory pancreatic enzyme secretion in response to a dietary stimulus.12 Intestinal function itself may become impaired among children with chronic liver disease. Portal hypertension with or without cholestasis may be so severe as to result in protein-losing enteropathy. In addition, the elevated serum bile acid concentrations observed in cholestasis may have a deleterious effect upon small intestinal function. In studies performed among dogs with surgically created Thirry-Vella loops, exposure of the mesenteric artery to bile acids at concentrations of 8 to 22 mol results in impaired transport of water and electrolytes.13
Hypermetabolism
The prevalence of hypermetabolism is unknown in children with liver disease, but at least 30% of cirrhotic adults are hypermetabolic.2 Even though some cirrhotic adults are normometabolic and a few are hypometabolic, those who are hypermetabolic display measured resting energy expenditure (REE) 20% or more above predicted energy expenditure. Hypermetabolism in cirrhotic adults is closely associated with suboptimal total body mass and total body protein. One documented mechanism for this phenomenon is increased adrenal tone presumably because of reduced
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hepatic catecholamine metabolism. Those patients with documented hypermetabolism express a starvation pattern when their respiratory quotient is measured. They have respiratory quotients approaching 0.6, documenting that they begin utilizing fat for energy quite early after a fast suggesting reduction in glycogen stores. Under these conditions, gluconeogenesis is increased and protein catabolism is accelerated. Thus hypermetabolic patients with cirrhosis are best served by taking 4 or 5 meals per day and receiving adequate dietary protein even in the face of encephalopathy. For this reason, pharmacologic management of encephalopathy should be attempted prior to reduction of protein in cirrhotic patients.
Specific Pediatric Liver Disorders

Neonatal Cholestasis
Infantile liver disease is quite commonly cholestatic in nature.14 Extrahepatic biliary atresia is responsible for approximately 50% of cases among infants with cholestasis. Others suffer from a wide variety of infectious and metabolic disorders. As molecular medicine has advanced, disorders previously lumped within the wastebasket diagnosis of neonatal hepatitis are now being recognized as discrete entities. Infantile cholestatic disorders such as Alagille syndrome, neonatal iron storage disease, PFIC1, PFIC2, PFIC3, citrin deficiency, Niemann-Pick type C, type I tyrosinemia, galactosemia, hereditary fructose intolerance, and type IV glycogenosis are but a few of the myriad infantile disorders characterized by cholestasis at the time of presentation. Cholestasis, while not universally present, may also be the dominant symptom for selected patients with -1-antitrypsin deficiency or cystic fibrosis. Nutrition strategies may be the definitive therapy for some of these disorders. For example, elimination of dietary galactose for galactosemia and fructose for hereditary fructose intolerance are curative. For other disorders, such as tyrosinemia, reduction of dietary tyrosine is helpful, but not curative. Because the block in tyrosine metabolism results in the overabundance of toxic intermediates such as succinylacetone, succinylacetoacetate, fumarylacetoacetate, and maleylacetoacetate, upstream inhibition of tyrosine metabolism with 2-(2-nitro-4-trifluoromethylbenzoyl)1,3-cyclohexanedione (NTBC) has been life saving insofar as metabolism is shunted to nontoxic intermediates such as parahydroxy-phenylpyruvate.15 The etiology for neonatal iron storage disease is uncertain, but evidence is accumulating that it is an alloimmune disorder with maternal antibodies affecting the fetal liver.16 Iron storage may thus
be secondary rather than primary. Unlike the therapy of adult-onset hemochromatosis associated with mutations in the HFE gene, therapy of neonatal iron storage probably should not include chelation, which can theoretically render infants susceptible to bloodstream infections with siderophagic bacteria. Whatever the cause of neonatal cholestasis, the basic nutrition strategy should be to provide ample quantities of fat-soluble vitamins (A, D, K, and E) and to monitor vitamin levels and/or coagulation studies frequently to prevent fat-soluble vitamin deficiency. Because some element of fat malabsorption nearly always occurs during cholestatic periods a substantial percentage of fat calories should be given in the form of MCTs, which do not require micellar solubilization prior to absorption into the portal circulation. However, infants should not be overloaded with MCTs insofar as they cannot be stored and must be immediately oxidized, rendering infants at risk for metabolic acidosis from the short-chain fatty acid oxidation products.17 Furthermore, MCTs are less calorically dense than LCTs because of the reduced number of carbon atoms in their skeleton. Finally, in the 1980s, overenthusiastic efforts to provide MCTs to cholestatic infants resulted in providing diets inadequate in EFAs thereby producing EFAD. At worst, with complete biliary diversion, about 50% of long-chain fats can be absorbed without full solubilization. Therefore, infants with cholestasis should receive a mixture of MCTs and LCTs. 8 Formulas with a 1:1 mix of the two types of fat tend to result in optimal fat balance for cholestatic infants.
Non-Cholestatic Liver Disease

Some pediatric liver disorders result in cholestasis only intermittently. Among these disorders are the viral hepatitides, autoimmune hepatitis, -1-antitrypsin deficiency, the glycogenoses, mitochondrial hepatopathies, Wilsons disease, and nonalcoholic steatohepatitis. When the patient is not cholestatic, absorption is customarily normal and specialized formulas may be unnecessary, but it is imperative to provide adequate caloric and protein intake. It is also important to recognize the underlying metabolic abnormalities that impede adequate assimilation of calories and to design nutrition regimens that maximize energy availability. The provision of 150% of the estimated caloric and protein requirement to cirrhotic patients is quite reasonable based upon adult data suggesting hypermetabolism. 2 Additionally, patients with primary mitochondrial disorders or glycogenoses should be advised to avoid prolonged fasting. The incomplete beta oxidation in mitochondrial disease
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and absent glycogenolysis will result in hypoglycemia and/ or the production of other toxins.
Nutrition as Primary Therapy for SelectLiverDisorders

Glycogen Storage Disease
The glycogen storage diseases (GSDs), also known as glycogenoses, are a group of disorders whereby enzyme defects adversely affect glycogen degradation or glycogen synthesis. There are at least 10 of these disorders of which some affect liver, some affect muscle, and some affect both. Dietary therapy is variably effective for these disorders18 (eg, the only effective therapy for type IV GSD is liver transplantation). Among those for which dietary therapy is beneficial, types II and VI have shown only modest responses to high-protein diets with the only definitive therapy for type II being enzyme replacement. The greatest dietary advances have been made for type I. This disorder, caused by impaired movement of glucose-6-phosphatase into or out of the endoplasmic reticulum, is characterized by fasting hypoglycemia, hyperuricemia, lactic acidosis, and hyperlipidemia. Type IB is also characterized by neutrophil dysfunction and frequently inflammatory bowel disease. Late complications include hepatic adenomas, pulmonary hypertension, and renal hyperfiltration. Initial trials of continuous enteral glucose or polycose infusions instituted during the 1980s in order to prevent hypoglycemia had the unexpected benefit of totally or partially reversing lactic acidosis, hyperuricemia, and hyperlipidemia. Glucose infusion rates of 8 mg/kg/min for infants, 6 mg/kg/min for children, and 4 mg/kg/min for adults were empirically noted to be beneficial. More recently, raw cornstarch has been utilized in preference to glucose polymers because of its longer duration of action obviating the need for a nasogastric tube or gastrostomy tube feedings. It is important that the cornstarch be uncooked, because cooking partially hydrolyzes it and produces a glucose tolerance curve similar to that of glucose. A dose of 1.75 to 2.75 g/kg will deliver about 5 to 7mg/kg/min of glucose for approximately 6 hours.18
for central nervous system and renal manifestations. Wilsons disease, if diagnosed early, can be treated with copper chelators. The hepatic manifestations vary from mild transaminase elevation to fulminant hepatic failure. Customarily when the total body copper level is elevated, there is a reciprocal deficiency in zinc which is a cofactor for alkaline phosphatase synthesis. Therefore, in Wilsons disease, the alkaline phosphatase level is disproportionally low in the presence of severe liver dysfunction. Chelation is employed to increase copper excretion or to decrease copper absorption. D-penicillamine has been used for years, but trientene is just as effective with a lower risk of complications. Zinc can be used to prevent copper absorption by competitive inhibition of intestinal transporters. A newer agent, tetrahydromolybdenate, shows great promise insofar as it complexes with copper in the intestinal lumen rendering copper unabsorbable, and it is absorbed itself, complexing with serum copper and albumin, thereby preventing cellular uptake of copper. Beyond chelation, dietary therapy is important, especially in the early phases of treatment. High-copper foods such as shellfish, nuts, gelatin, mushrooms, liver, and soy products should be avoided. In addition, the copper content of the patients major water supply should be analyzed if well water is consumed.
Nonalcoholic Fatty Liver Disease (NAFLD)

It is ironic that overnutrition should be the etiology of a liver disease that is seen in pandemic proportions throughout the world. Approximately 20% of the population of the United States is obese, and 75% of obese individuals have some degree of fatty liver. NAFLD may range in severity from simple fatty infiltrate on one end of the spectrum to nonalcoholic steatohepatitis (NASH) on the other end. 20 By definition, NASH is characterized by both fat and inflammation, and its prognosis is far worse than that of fatty liver alone. Natural progression or a second hepatic insult of any sort may result in fibrosis and eventually cirrhosis. The factors governing the progression of NAFLD to NASH are not fully understood, but oxidative stress seems to play a role in the process. Therapy should target comorbid conditions such as type 2 diabetes mellitus and hypertri glyceridemia as well as emphasizing weight reduction. In addition, treatment with betaine, n-acetylcysteine, vitamin E, or ursodeoxycholic acid may lower liver enzyme levels. Oral hypoglycemics such as gemfibril or metformin may decrease hepatic steatosis and improve liver enzyme levels whereas clofibrate seems to be ineffective. Ultimately, the most reliable therapy is a sensible weight loss regimen. The optimal rate of loss should be < 0.9 kg/wk because too rapid
Wilsons Disease
Wilsons disease is due to a mutation in a p-type ATPase responsible for transporting copper across membranes to permit formation of metallothionein and to permit biliary excretion of copper.19 Defective copper excretion results in excessive hepatic copper stores leading to hepatic dysfunction. Excessive brain and renal copper stores are responsible
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a rate may result in excessive lipid peroxidation and more rapid progression to fibrosis.20
Specific Nutrient Requirements

Energy
Increased energy needs have been shown in some pediatric clients with liver disease with elevated REEs up to 127% to 140% of the predicted REE values. 25 Energy requirements vary as well, based on age, activity level, degree of malnutrition, and malabsorption. These infants and children can require up to 130% to 150% of the recommended daily allowance (RDA) for energy based on ideal weight for length. Infants with cholestatic liver disease generally require 120 to 150 kcal/kg/d based on estimated dry weight rather than measured weight in the presence of ascites. 25
Assessment of Nutrition State
A subjective global assessment is one of the most reliable and acceptable standards of assessment when compared with other objective measures. Based on this assessment, patients can be evaluated and grouped into those who require immediate and aggressive nutrition interventions, those at risk of developing malnutrition, and those who will do well without nutrition interventions. 21,22 A comprehensive nutrition assessment is imperative in infants and children with liver disease. Reassessments should be done periodically (~monthly) to evaluate lean body mass changes and the complicating side effects that lead to changes in intake (ie, anorexia, early satiety, nausea), in addition to diarrhea and the use of diuretics which leads to increased losses. Continual nutrition evaluations are imperative to determine the degree of malnutrition and execute individualized nutrition care plans adapted to preserve somatic and adipose body reserves while curtailing the metabolic instability universal with progressive disease. The assessment should begin with a complete and meticulous review of medical, laboratory, and physical information focusing on nutrition-related problems. A detailed diet history of usual dietary intake of calories, protein, and fat sources; weight changes; and medication intake should also be evaluated. This information will assist in tailoring an attainable and realistic plan for maximal nutrition preservation. The usual anthropometric markers of nutrition status are not reliable in patients with advanced liver disease. Body weight can be dramatically elevated from ascites, edema, and hepatosplenomegaly, masking weight loss. 23 Malnutrition is best appraised through serial upper extremity measurement of mid-arm muscle circumferences (MAMCs) and triceps skinfolds (TSFs). The upper extremities are less subject to fluid accumulation and provide insight into body mass stores.23 These anthropometric measures are easily performed, inexpensive, non-invasive, and can provide key information for detecting nutrition decline, mandating urgent restoration of these stores with aggressive nutrition interventions. Plasma protein levels of albumin, prealbumin, and retinol-binding protein, which are synthesized in the liver, are more a marker of the severity of the liver disease than the visceral protein status.24
Protein
Goals for age are generally provided unless encephalopathy with fulminant hepatic failure and an elevated ammonia level are observed. Enough protein must be provided to preserve lean body mass and prevent catabolism with the breakdown of endogenous protein stores, but not contribute to hyperammonemia and encephalopathy. Infants generally require 3 to 4 g/kg/d.24 The use of branched-chain amino acid (BCAA) formulas or supplements in infants and children, though improving nitrogen balance, 26 has fallen out of favor because the cost/benefit ratio remains low.
Lipids and Fat-Soluble Vitamins

There is no rationale for restricting lipids and fats in children with liver disease insofar as they are the main source of calories during infancy and early childhood. Increased dietary fat intake may augment the amount of steatorrhea observed, but potentially increases the overall amount of calories absorbed. Formulas that contain ~50% of the fat as MCT oil are recommended for infants and children with cholestatic liver disease, but the clinician should make certain that proper intake of long-chain fatty acids (~10% of calories) is maintained to prevent EFAD. MCT oil can affect the palatability and acceptance of oral formula so choosing a formula with a lower concentration of MCT oil may be required to achieve sufficient intake.24 Fat-soluble vitamin (A, D, E, and K) supplementation is standard in infants and children with cholestatic liver disease and customary doses are listed in Table 26-1. Vitamin K deficiency has dire consequences because of the risk of fatal hemorrhagic disease, and prophylactic supplementation is indicated. Vitamin D deficiency may take longer to develop, but becomes evident in children during periods of rapid bone growth. Children with liver disease can easily develop rickets and osteoporosis, and pathologic
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fractures may result. Vitamin E deficiency can lead to neuromuscular abnormalities, which are reversible when adequate vitamin E supplementation is initiated. Vitamin A deficiency is rarely seen in these children because it is the least sensitive to malabsorption. These vitamin levels should be evaluated at least every 3 months and aggressive supplementation initiated to normalize plasma level. 27
TABLE 26-1 Fat-Soluble Vitamin Recommendations
Vitamin Amount Given
Vitamin A (aqueous) 25-OH vitamin D Vitamin E Vitamin K
1000 IU/kg/d up to 25000 IU 35 mcg/kg/d 2025 IU/kg/d as TPGS 2.55 mg/d 3 times per week
Fluids
Management of fluid homeostasis, ascites, and sodium balance mandate maintaining a delicate balance for pediatric patients with liver disease. The decision to diurese a patient with hyponatremia generally depends upon a global assessment of fluid status. A patient with signs of dehydration should be given salt when hyponatremic whereas a patient appearing overhydrated may actually be suffering from dilutional hyponatremia and require diuresis with fluid and salt restriction. Only non-nutritive fluids should be limited when fluid restriction is initiated. 28 Salt restriction should not be excessive, because salt elimination is much more benignly accomplished via loop diuretics.
Other Vitamins and Minerals

The incidence of water-soluble vitamin deficiency in children with liver disease has not been comprehensively studied, and clinical manifestations are rare given that infant and pediatric formulas that are supplemented with these vitamins are required in large volumes in order to increase caloric intake. Iron supplementation may be required if recurrent mucosal hemorrhage from varices or gastropathy takes place. Urinary excretion of zinc is increased in chronic cholestatic liver disease, but the cause and associated consequences are unknown based on the current literature.29
polymers and medium-chain fats. By not concentrating the formula base alone, protein concentrations can be maintained within appropriate ranges for age and weight. Free water should be sufficiently provided to keep osmolality of the formula low. A 30 cal/oz MCT-containing formula is ideal for infants. Formula selections should contain at least 50% of the fat as MCT oil for maximized enteral absorption of fat calories. Several palatable infant and pediatric enteral formulas containing at least 50% of the fat as MCT oil are currently marketed. Patients with arm muscle circumferences below the 5th percentile should receive supplemental nutrition prior to transplantation. 30 When infants and children are unable to consume adequate calories to maintain their lean body mass, supplemental enteral tube feeding should be initiated. Nasogastric tubes are preferred if patients can tolerate adequate formula volume to achieve goals because they are easily placed and replaced if removed. However, in many instances nasojejunal feeding tubes must be utilized because of emesis and volume intolerance secondary to poor gastric emptying. Gastrostomy tubes are generally not placed in the face of ascites, and organomegaly may preclude their placement percutaneously. Nocturnal drip feedings are frequently used so that normal oral feeding during the day can be maintained. This feeding schedule may also be beneficial for patients with progressive liver disease or infants with small body mass who are unable to maintain normal glucose levels overnight. Progression to 24-hour continuous tube feeding infusions may be required to provide the increased calories required for proper nutrition.
Enteral Nutrition Support
Caloric intake can be improved via the use of supplemental nasoenteric tube feedings with high-calorie formulas when oral intake is inadequate to achieve goals. Increased caloric intake can first be achieved through increasing formula concentration and adding modular additives such as glucose
Parenteral nutrition (PN) should be considered only when enteral supplementation fails or cannot be utilized (ie, during periods of gastrointestinal hemorrhage). In some cases it may be required in addition to enteral support when lean body mass cannot be maintained. If possible, some enteral alimentation should be given if only to maintain gut integrity. When long-term PN is required, careful monitoring of copper levels is mandatory to prevent either toxicity or deficiency. Most centers employ standard amino acids, dextrose, lipids, electrolytes, and minerals in quantities meeting nutrition needs while minimizing metabolic complications. Even though enrichment in BCAAs may improve nitrogen balance marginally, adequate protein nutriture may be attained by providing standard amino acids. 30
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Conclusion
The goals of nutrition for pediatric patients with liver disease are to optimize their potential for normal growth and development, prevent further liver injury, prevent worsening of the patients nutrition status, minimize the risk of infection, avoid vitamin and mineral deficiency, and improve the patients quality of life. This requires detailed attention to all of the components of nutrition support by caregivers, by the patient, and by the patients family working as a team to provide optimal care.
1. What is the best serial marker of nutrition status in pediatric patients with liver disease? A. Fat-soluble vitamin levels B. Upper extremity anthropometric measurements C. Prealbumin D. Weight/length or BMI E. A & D 2. Which of the following liver disorders is most likely to be associated with exocrine pancreatic insufficiency? A. Hepatitis C B. Alagille syndrome C. Autoimmune hepatitis D. Extrahepatic biliary atresia 3. In the nutrition therapy of Wilsons disease which should be avoided? A. Grapefruit B. Red meat C. Endive D. Lobster 4. Which of the following have been utilized for the nutrition therapy of glycogen storage disease, type I? A. Subcutaneous octreotide B. Glucagon infusions C. Cooked cornstarch D. Metformin E. Raw cornstarch See p. 487 for answers.
References
1. Bucuvalas JC, Horn JA, Chernausek SD. Resistance to growth hormone in children with chronic liver disease. Pediatric Transplantation. 1997;1:7379. 2. Merli O, Riggio M, Leonetti F, et al. Impaired nonoxidative glucose metabolism in patients with liver cirrhosis: effects of two insulin doses. Metabolism. 1997;46:840843. 3. Muller P, Felin R, Lambrecht J, et al. Hypertriglyceridaemia secondary to liver disease. Eur J Clin Invest. 1974;4:419428.
4. Ben-Ari Z, Schafer Z, Sulkes J, et al. Alterations in serum leptin in chronic liver disease. Dig Dis Sci. 2002;47:183189. 5. Selberg O, Burchert W, Van Der Hoff J. Insulin resistance in liver cirrhosis. Positron-emission tomography scan analysis of skeletal muscle glucose metabolism. J Clin Invest. 1993;91:18971903. 6. Gines P, Arroyo V. Is there still a need for albumin infusions to treat patients with liver disease? Gut. 2000;46:588590. 7. West RJ, Lloyd JK. The effect of cholestyramine on intestinal absorption. Gut. 1975;16:9398. 8. Pettei MJ, Daftary S, Levine JJ. Essential fatty acid deficiency associated with the use of a medium-chain-triglyceride infant formula in pediatric hepatobiliary disease. Am J Clin Nutr. 1991;53(5):12171221. 9. Knisely AS. Progressive familial intrahepatic cholestasis: a personal perspective. Pediatr Dev Pathol. 2000;3:113125. 10. Piccoli DA, Spinner NB. Alagille syndrome and the Jagged1 gene. Semin Liver Dis. 2001;21:525534. 11. Golson ML, Loomes KM, Oakey R, et al. Ductal malformation and pancreatitis in mice caused by conditional Jag1 deletion. Gastroenterology. 2009;136:17611771.e1. 12. Lee SP, Lai KS. Exocrine pancreatic function in hepatic cirrhosis. Am J Gastroenterol. 1976;65(3):244248. 13. Berant M, Diamond E, Alon U, et al. Effect of infusion of bile salts into the mesenteric artery in situ on jejunal mucosal transport function in dogs. J Pediatr Gastroenterol Nutr. 1988;7:588593. 14. Bezerra JA, Balistreri WF. Cholestatic syndromes of infancy and childhood. Semin Gastrointest Dis. 2001;12:5465. 15. Masurel-Paulet A, Poggi-Bach J, Rolland MO, et al. NTBC treatment in long-term tyrosinaemia type I outcome in French patients. J Inherit Metab Dis. 2008;31:8187. 16. Rand EB, Karpen SJ, Kelly S, et al. Treatment of neonatal hemochromatosis with exchange transfusion and intravenous immunoglobulin. J Pediatr. 2009;155:566571. 17. Wanten GJ, Naber AH. Cellular and physiological effects of medium-chain triglycerides. Mini Rev Med Chem. 2004;4:847857. 18. Heller S, Worona L, Consuelo A. Nutritional therapy for glycogen storage diseases. J Pediatr Gastroenterol Nutr. 2008;47(Suppl 1):S15S21. 19. Pfeil S, Lynn DJ. Wilsons disease: copper unfettered. J Clin Gastroenterol. 1999;29:2231. 20. McCullough AJ. Update on nonalcoholic fatty liver disease. J Clin Gastroenterol. 2002;34:255262. 21. Merli M, Romiti A, Riggio O, et al. Optimal nutritional indexes in chronic liver disease. J Parenter Enteral Nutr. 1987;11(Suppl 5):S130S134. 22. Hasse J, Strong S, Gorman MA, Liepa G. Subjective global assessment: alternative nutrition assessment technique for liver transplant candidates. Nutrition. 1993;339343. 23. Sokol RJ, Stall C. Anthropometric evaluation of children with chronic liver disease. Am J Clin Nutr. 1990;52:203208. 24. Protheroe SM. Feeding the child with chronic liver disease. Nutrition. 1998;14:796800. 25. Pierro A, Koletzko B, Carnelli V, et al. Resting energy expenditure is increased in infants with extra hepatic biliary atresia and cirrhosis. J Pediatric Surg. 1989;24:534538.
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26. Sokal E, Baudoux MC, Collette E, et al. Branched chain amino acids improve body composition and nitrogen balance in a rat model of extra hepatic biliary atresia. Pediatr Res. 1996;40:6671. 27. Sokol RJ, Butler-Simon N, Conner C, et al. Multicenter trial of d-alpha-tocopheryl polyethylene glycol 1000 succinate for the treatment of vitamin E deficiency in children with chronic cholestasis. Gastroenterology. 1993;104:17271735. 28. Gines P, Guevara M. Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management. Hepatology. 2008;48:10021010.
29. Saner G, Solu D, Yiitba M, Skc S, Elkabes B. Zinc nutrition in children with chronic liver disease. J Trace Elements in Exp Med. 2000;13:271276. 30. Goulet OJ, de Ville de Goyet, Otte JB, Ricour C. Preoperative nutritional evaluation and support of liver transplantation in children. Transplant Proc. 1987;19:32493255.
Intestinal Failure
Robert H. Squires, Jr., MD
27
Learning Objectives
1. Understand that while intestinal length is important, it is not the only factor that determines a childs ability to reach enteral autonomy. 2. Understand that the intestinal adaptive process takes months and even years before enteral autonomy can, if ever, be achieved. 3. Describe why enteral nutrition is necessary for intestinal adaptation to occur. 4. Explain how lipid-lowering strategies for soy-based lipid preparations or substitution with a fish-oil based lipid can improve serum aminotransferase levels and reduce serum bilirubin. Intestinal failure (IF) in infants and children is a devastating condition that can be broadly defined as the inability of the intestinal tract to sustain life without supplemental parenteral nutrition (PN).1,2 Prior to PN, many infants died as a consequence of insufficient bowel length or function. Infants found to have an abdominal catastrophe at laparotomy for conditions such as necrotizing enterocolitis (NEC), volvulus, or gastroschisis were simply closed and made comfortable to await the natural course of their tragic circumstance. However, with the development of safe PN, central line placement and care, improved medical and surgical management, including intestinal transplantation, these infants now have an opportunity to survive with a satisfactory or even excellent quality of life. The clinical course for the child can be challenging and frustrating to the family as well as those who provide medical care and support. Intestinal adaptation, if it occurs at all, can require months or years before the intestine can adequately
311
CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 Definition of Intestinal Failure . . . . . . . . . . . . . . . . . . . . . 312
Scope of the Problem
Etiology of Intestinal Failure. . . . . . . . . . . . . . . . . . . . . . . 313 Intestinal Adaptation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 Management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313

Enteral Nutrition Parenteral Nutrition Fluid Management Medications Non-Transplant Surgery General Principles
Complications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
Nutrition Deficiencies Functional and Metabolic Complications Liver Disease Central Line Complications
Introduction
Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
Growth and Development Quality of Life Intestinal Transplant
312
accommodate the growing child independent from PN. Along the way, the child is at risk for episodes of dehydration, electrolyte imbalance, and macro- and micronutrient deficiencies. More importantly, life-threatening complications such as sepsis, end-stage liver disease, and vascular thrombosis may occur. Management of children with IF is best provided by an experienced multidisciplinary team that includes experts in pediatric gastroenterology, surgery, nutrition, nursing, social work, and feeding techniques. Most management strategies have not been rigorously investigated, leaving much to experience, tradition, trial and error, or art as most would prefer. The great majority of studies of children with IF are single-site experiences, with small numbers of patients collected over many decades. 36 The goals of this brief chapter are to review the topic of intestinal failure and outline some strategies that might be useful in the care and management of infants and children with intestinal failure. The small intestine almost doubles in length during the last trimester with the normal full-term infant having 210 to 350 cm at birth.7 This fact makes defining residual bowel length problematic when the resection and residual length measurements occur early in the third trimester. While the literature attempts to define short bowel syndrome (SBS) as the remnant intestine measuring less than 75 cm, a better approach was put forward by Teitelbaum and colleagues. 6 They propose incorporating gestational age into the assessment and suggest that infants with less than 10% of their estimated bowel length are at increased risk of death than those with a longer residual bowel length. Intestinal failure is a functional description independent of bowel length and better reflects the nature of the clinical condition encountered in practice. It identifies a child whose loss of intestinal length or competence is below the minimal amount necessary to maintain normal digestion and absorption of nutrients and fluids for weight gain and growth in children independent of PN. Such a definition acknowledges children with conditions such as immune-mediated enteropathy, enteric myopathy, mitochondrial disorders, intestinal pseudoobstruction, tufting enteropathy, and microvillus inclusion disease who have a normal length of intestine but inadequate function to sustain life without PN.
estimated the incidence of extreme SBS to be between 3 to 5 per 100,000 births per year.9 However, improvements in neonatal intensive care, anesthesia, and surgical techniques have improved survival of children who would have previously died, thus it is likely that the incidence and prevalence has increased in recent years.10 Other estimates suggest that at least 16,000 children are on home PN (HPN) in the United States, but the precise number on PN for management of IF/SBS is unknown.11 More importantly, we have no estimate of the number of children with SBS who have been weaned from PN but remain at risk for various nutritional and growth abnormalities as a consequence of their altered intestinal anatomy. The annual costs for managing a PN-dependent patient with IF/SBS are estimated to range between $100,000 and $150,000 with a mortality rate of approximately 30% at 5 years for those who cannot be weaned from PN.10
Table 27-1 Causes of Intestinal Failure in Children Prenatal Gastroschisis/Omphalocele Intestinal atresia Total intestinal or very long-segment Hirschsprungs disease Constitutive enterocyte disorders Tufting enteropathy Microvillus inclusion disease Megacystis microcolon hypoperistalsis syndrome Malrotation/Volvulus Bladder extrophy Neonatal Necrotizing enterocolitis Vascular thrombosis Desquamative enteropathy (Intracellular 4 integrinmutation) Malrotation/Volvulus Postnatal Complicated intussusception Trauma Seat belt injury Suction evisceration (eg, swimming pool drain) Riding lawn mower injury Extensive vascular anomaly Autoimmune/immune mediated enteropathy Tumor Fibroma Desmoid Sclerosing encapsulating peritonitis (abdominal cocoon) Munchausen Syndrome by Proxy Protracted diarrhea of infancy Intestinal motility disorders Mitochondrial defects/mutations Intestinal pseudoobstruction
Definition of Intestinal Failure
Scope of the Problem

Surprisingly, neither the incidence nor prevalence of IF/SBS in the United States is well known.8 In 1992, Wallander et al
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Conditions associated with IF in infants and children are generally due to surgical short bowel syndrome (SBS), motility disorders, or enterocyte abnormalities (Table 27-1).1 SBS is the underlying cause in the majority of these patients, the etiology of which may be congenital abnormalities such as gastroschisis, intestinal atresia, malrotation with volvulus, or acquired causes such as necrotizing enterocolitis (NEC), vascular thrombosis, or trauma. Less commonly seen are motility disorders such as total aganglionosis and chronic intestinal pseudoobstruction or enterocyte abnormalities such as microvillus inclusion disease and tufting enteropathy. Intestinal adaptation is a complex and incompletely understood process that ensues following significant bowel resection to compensate for the loss of intestinal surface area. It is characterized by both functional and morphologic changes in the remnant bowel.12,13 Enteral nutrition (EN) is necessary for adaptation. Clinical features associated with patients who are eventually weaned from PN include the absence of jaundice or cholestasis, a shorter duration of PN, the presence of the ileal-cecal valve, an intact colon, small bowel length greater than 15 cm, and placement of the small intestine in continuity with the colon. 5 The underlying physiologic mechanisms by which these clinical factors might directly impact the adaptive process in the human is incompletely understood. For instance, it is not clear whether the ileal-cecal valve must be physically present or whether its presence merely serves as a marker for a long colon segment. Over time, the residual bowel lengthens and dilates and is thought to be a positive sign of adaptation. However, this anatomical change may be associated with complications such as altered intestinal motility that can result in stasis of luminal contents and bacterial overgrowth which can negatively impact adaptation. Surgical techniques aimed to improve intestinal function by increasing bowel length and reducing bowel diameter include the Bianchi procedure and Serial Transverse Enteroplasty (STEP).14,15 The adaptive process occurs over many months or years. 5,16 Increased enteral intake, or hyperphagia, is associated with intestinal adaptation in adults.17 The impact of luminal nutrients upon intestinal adaptation is complex, but likely involves a direct trophic effect on intestinal epithelium, as well as stimulation of trophic hormones and pancreaticobiliary secretions.18 In animal models, it appears that a more complex nutrient enhances adaptation better than one that is simple or more processed.
Etiology of Intestinal Failure
Intestinal Adaptation
For example, disaccharides enhance adaptation more effectively than monosaccharides,19 and whole proteins are more adaptogenic than protein hydrolysates. 20 Testing these findings in the human have not been undertaken in a rigorous fashion. Hormones and growth factors such as growth hormone, glucagon-like peptide 2, glutamine, cholecystokinin, gastrin, insulin, peptide YY, and entero glucagon, as well as dietary fiber and short-chain fatty acids have been shown to be involved in the adaptive process, but their clinical significance in humans remains unclear.18 The functional capabilities of the remnant intestine also impacts adaptation. For instance, complete absence of the ileum precludes absorption of bile acids and vitamin B12 . The absence of the ileal-cecal valve appears to have a negative impact on intestinal adaptation for some, but not all patients. 35,21,22 However, it is possible that the presence of a sufficient length of colon may be just as, if not more, important than the presence or absence of the ileal-cecal valve.23,24 A biomarker for intestinal adaptation, such as citrulline,25 would ideally reflect the quality and quantity of intestinal function, but its clinical usefulness is uncertain. Markers of hepatic function in patients with IF have not been evaluated. Valid biomarkers are urgently needed so that successful rehabilitation regimens can be objectively identified, and adaptation failure can be recognized earlier. Translational studies to identify potential genetic susceptibilities that would favor or impede intestinal adaptation have not been performed.26
Management
Enteral Nutrition
Enteral feeding is essential if intestinal adaptation is to occur. The 2 initial considerations are the type of formula used and the manner in which it is provided. Breast milk is preferred and its use has been associated with decreased duration of PN. 3 The beneficial effects of breast milk are attributable to its immunoprotective properties, effect on postnatal development of intestinal flora, and its nutrient composition that includes long-chain triglycerides (LCTs), free amino acids, nucleotides, and growth factors as well as complex protein and fat. 27 When breast milk is unavailable, however, formula choice is complicated by a variety of options that reflect differences in the desired complexity of protein, fat, and carbohydrate. Complex nutrients, such as polysaccharides and whole protein, increase the functional workload of the intestine, and as result, may stimulate adaptation.28 Unfortunately, studies to identify the ideal enteral protein 2931 and lipid32 have been plagued by insufficient
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numbers of patients or have been extrapolated from animal models. A variety of methods are used to deliver enteral feedings to the intestinal lumen and include oral, gastric as bolus or continuous, or jejunal which can only be given as a continuous feeding. Advantages of early oral feeding include stimulation of oral digestive enzymes and maintenance of oral feeding skills to prevent oral aversion. 33 If the patient is capable of oral feeding, but is incapable of taking sufficient calories, supplemental direct enteral feeding is possible via a nasogastric tube, gastrostomy, or direct jejunal feeding. Continuous enteral infusion was found to be more beneficial in very low birth weight infants, 34 but studies in piglets suggest that bolus feedings are more advantageous. 35 Continuous versus bolus feedings have not been thoroughly studied in older infants and children. Clinical decisions to adjust the enteral feeding regimen are determined by a number of factors, primarily stool or ostomy output, evidence of malabsorption, and other less objective symptoms such as abdominal fullness, irritability, and regurgitation. Currently, decisions related to advancing enteral feeding, weaning PN, and long-term monitoring of patients at risk for growth failure are based almost completely upon experience, tradition, and art rather than evidence-based algorithms. However, the understanding of the relative importance of these factors, how they are incorporated into the daily management, and how they impact adaptation in patients with IF/SBS is critical if management of infants with IF/SBS is to move beyond art and tradition and into an evidence-based practice of medicine.
based. It is administered to prevent essential fatty acid deficiency and to provide an efficient, high-density caloric source. An estimated 0.5 g/kg/d of intravenous lipid is the minimal requirement to prevent deficiency.45 An intravenous lipid preparation containing omega-3 fatty acids was recently reported to reduce the incidence of PN-related cholestasis,46 but it has not been rigorously studied in children. Similar reductions in serum bilirubin have been achieved by limiting soy-derived lipid to 1 g/kg/d or less. Serum electrolytes are monitored on a regular basis and adjustments in electrolyte concentration are based on individual needs of the patient. Guidelines for pediatric vitamin, mineral, and trace element supplementation are available, but they are supported by a paucity of data. 37 While PN is life saving in children with IF/SBS, long-term use of PN is often complicated by sepsis and liver disease which can become life threatening. Given the host of potential complications associated with PN and IF/SBS, careful longitudinal monitoring should be implemented to reduce complications and improve outcome. The frequency of monitoring will depend upon patient age, duration of PN, and acute changes in the clinical condition. Growth parameters (eg, height or length, weight, head circumference) should be checked at each clinical visit. For infants and young children, monthly visits are typical. For older children, on stable PN, visit frequency can be extended to every 3 to 4 months. Please see chapter on evaluation and monitoring (Chapter 36).
Fluid Management
In addition to PN, children may also require supplemental fluid management. This is particularly important for children with an ileostomy or those who are in continuity, but with a short length of colon. These children are at increased risk of developing salt and water depletion and should be monitored carefully.47 Unless the childs fluid and electrolyte requirements are very consistent day to day and week to week, supplemental fluids should be calculated and administered separate from PN as this allows for more rapid, and less expensive, adjustments in fluid and electrolyte administration.
Parenteral nutrition (PN), first introduced in the late 1960s, is now an established life-saving treatment for children with IF/SBS. 3638 Components of PN include glucose, amino acids, lipids, electrolytes, vitamins, minerals, trace elements, and water. Glucose is the primary source of energy in PN, but glucose oxidation varies depending upon age and diagnosis. 39,40 Glucose infusion rates that are in excess of the patients oxidative capacity will promote fat deposition.41 While glucose infusion rates vary, an intake greater than 10 mg/kg/min may result in the conversion of glucose to fat.42 An amino acid solution, ranging from > 2.5 g/kg/d for preterm infants to 0.75 g/kg/d for adolescents, is administered to support protein metabolism.43 Amino acids are best utilized when balanced with a proper proportion of nonnitrogen calories. The ideal ratio of nitrogen:non-nitrogen calories is estimated to be between 1:150 to 1:400.44 The lipid source currently available in the United States is soy
Medications
A variety of medications are used to manage symptoms and complications associated with IF/SBS. It is important to know that not one of them has been studied in a randomized fashion in an adequately powered study. Intestinal dysmotility is common in children with IF/ SBS. Anti-motility agents (eg, loperamide) are used in an
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attempt to delay intestinal transit in hopes to provide a longer duration of contact between the intestinal mucosa and luminal nutrients. Children with gastroschisis are more likely to have problems with delayed gastric emptying and non-propulsive intestinal motility. In this setting, pro-motility agents (eg, metoclopramide, erythromycin, or amoxicillin-clavulanic acid) have been used to improve intestinal motility. Cisapride was removed from the market in the United States due to its association with cardiac arrhythmias. Anti-secretory agents are used to reduce fluid secretion and stool output. Histamine-2 blockers and proton pump inhibitors might be useful during the early months following massive intestinal resection. However, continued use, in the absence of clear benefit, may place the child at increased risk for bacterial overgrowth or Candida esophagitis as gastric acid serves a useful function in limiting fungal and bacterial growth. Bile acid binding resins (eg, cholestyramine) have been tried in patients with little or no ileum when increased stool output is thought to be related to bile acid malabsorption. These agents are not easily administered, have little or no palatability, and their efficacy in this clinical setting has not been tested.
become an accepted technique at many intestinal failure centers. 52 While there is a growing literature describing individual experiences with non-transplant surgery for children with IF/SBS, the relatively small numbers of patients, retrospective nature of data collection spanning many years, and heterogeneous definitions and patient characteristics have limited the ability to promulgate data-driven indications and timing for these techniques.
General Principles
With the understanding that management of IF is highly individualized and that evidence-based practice supported by randomized, controlled trials is lacking, the following outline might serve as a principled guide to the management of intestinal failure in children:
Non-Transplant Surgery
Half of children with SBS will have more than one abdominal operation.48 Following the initial surgical intervention, subsequent surgeries often address complications such as stricture, intestinal dilation, and placement of invasive feeding devices which are all considered standard of care.49 Longitudinal intestinal lengthening and tailoring (LILT) and STEP represent advanced techniques that both taper dilated segments of bowel and increase intestinal length. Digestive function may improve not only because aboral flow is facilitated by a normalized luminal caliber, but also because subsequent adaptation may lead to increased intestinal surface area. LILT was first described in 1980 by Bianchi,15 and has since been used at many centers.1 Criteria for using LILT vary, but generally require greater than 20 cm of symmetrically dilated intestine in the context of residual intestine > 40 cm.1 Standardized indications, contraindications, and surgical guidelines have not been developed, which may explain inconsistent results reported in literature. 50 STEP involves the application of a stapling device incompletely across a dilated loop of intestine in serial fashion to create a zig-zag pattern that results in a lumen both narrower and longer. Since its description by Kim et al 51 in 2003, it has
1. TPN a. Glucose infusion rate: < 15 mg/kg/min for the duration of infusion. b. Protein: < 3 g/kg/d, closer to 3 for infants, lower for older children. c. Fat: In the first month, may need 12 g/kg/d; but after that, with an eye on the degree of cholestasis and total caloric needs, would consider different strategies. i. 1 g/kg/d given every other day; or MWF or M/Th. ii. Lipid reduction presumes that some enteral feeding is possible. iii. Follow essential fatty acids every 3 months. d. Fluid: Based on needs, it is hard to provide sufficient calories with less than 125 cc/kg/d; may need additional salt and water to support losses. 2. Enteral feeds a. Use oral feeds if at all possible to maintain oral skills and stimulate EGF, even if the child has a G-tube. 35 cc/feed and then gradually increase as one can. b. Breast milk is preferred and a casein hydrolysate/MCTcontaining formula is the authors fallback, assuming that intestinal adaptation is favored by a more complex enteral diet; use of an amino acid-containing formula can be reserved for protein allergy. c. J-tubes should be used rarely, as they further shorten the length of useable bowel length. 3. Advancing feeds/reducing PN a. The patient will tell you. i. More concerned about the volume of stools than the number (which can be confused with squirts); so, for example, 10 stools per day may be okay if only 34 or so are big enough to leave the diaper; if the bottom is not excoriated; if the family is comfortable; if hydration is maintained.
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ii. Aim for a rate of weight gain that follows the isopleth in a box that surrounds the 5th percentile; adjust for SGA. Not trying to achieve weight gain at the 50th percentile, although if one can with minimal PN support, that is fine. The goal is to find the minimal amount of PN to support reasonable weight gain and growth. b. Once on < 25% total calories from PN, and reasonable stool output and satisfactory weight gain and growth is established, one may consider a change from PN to D10 LR observe for 23 months; then hold the fluids for 2months or so before pulling the line; unless the line is so much trouble that keeping it in is too problematic. 4. Non-transplant surgery a. When to consider in a child with short bowel syndrome i. A sufficient length of small bowel is dilated and 1. Enteral feedings are not able to be advanced 2. The child is experiencing poor weight gain and/ or growth b. What type of surgery? i. May be surgeon specific; a learning curve is needed for both the STEP and Bianchi, but more so for the Bianchi ii. You can STEP a STEP, and STEP a Bianchi, but you cannot Bianchi a STEP
Functional and Metabolic Complications

Following massive bowel resection that alters normal intestinal physiology, a number of acute and chronic medical complications develop that prompt an effort for medical interventions. Unfortunately, many interventions and treatments have not been adequately studied with sufficient numbers of patients. Hypergastinemia develops shortly after small bowel resection and can reduce nutrient absorption by inactivating pancreatic enzymes, and precipitating bile salts, thus leading to diarrhea as well as nausea and vomiting. 5860 Small case series have reported mixed benefits of acid reduction to improve absorption. 6164 However, there are no large trials demonstrating a benefit to the use of these medications in children with IF/SBS. Indiscriminate use of these medications may predispose patients to small bowel bacterial overgrowth, calcium and iron malabsorption, or a heightened risk of Candida esophagitis or sepsis.65 Bile acid malabsorption as a consequence of ileal resection can result in a secretory diarrhea that complicates fat and fat-soluble vitamin absorption.66 Rapid intestinal transit occurs following small bowel resection67,68 and is often managed with the use of anti-motility agents such as loperamide which have mixed effects on water and salt balance.69,70 Nephrolithiasis, when it occurs in the setting of IF/SBS, is typically due to either uric acid or calcium oxalate stones.71 Alterations in gastrointestinal motility, along with the use of acid blocking agents, may increase the bacterial content in the small intestine resulting in bacterial overgrowth (BO). BO can deconjugate luminal bile acids making them ineffective in micellar formation and can be associated with mucosal inflammation, nutrient deficiencies (notably vitamin B12), D-lactic acidosis as well as cramps, diarrhea, GI bleeding, and arthritis. The relationship between small bowel BO and systemic sepsis is not well understood.7275 BO is most often treated empirically with intermittent oral doses of broad-spectrum antibiotics, and in some cases probiotics, but there are many varying practices for the frequency and duration of administration with no data available to evaluate relative efficacies. D-lactic acidosis is a unique feature of patients with IF/SBS and was first described in children in 1983.76 The combination of a high anion gap acidosis and altered mental status that develops after a high carbohydrate enteral feeding should prompt the clinical suspicion of D-lactic acidosis. Treatment involves discontinuation of enteral feeding, selective bowel decontamination, and, if needed, a surgical procedure aimed at decreasing intestinal diameter and reducing bacterial overgrowth.77,78 Frequent
Complications
Nutrition Deficiencies
Deficiencies in vitamins, minerals, and trace elements are associated with IF/SBS. Malabsorption of fat-soluble vitamins A, D, E, and K may result from an insufficient intraluminal concentration of bile acids secondary to excess fecal loss. 53 Surgical resections of the duodenum or ileum, which have unique absorptive functions, add to the risk of developing nutrition deficiencies. The duodenum is a primary site for iron and folate absorption and its resection can result in these micronutrient deficiencies. Absence of the ileum, with its unique ability to absorb vitamin B12 and bile acids, places the patient at risk for fat-soluble vitamin and vitamin B12 deficiency. Calcium and magnesium deficiencies can result from binding to intraluminal long-chain fatty acid. 54,55 Deficiencies of other minerals and trace elements such as zinc, riboflavin, thiamin, biotin, and also selenium can occur. 56 In addition, nutrient deficiencies hinder intestinal adaptation further compounding the clinical impact. 57
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antibiotic therapy may, paradoxically, place the patient at risk for D-lactic acidosis by creating a selective advantage for D-lactate producing bacteria.79
Liver Disease
Liver disease is the most frequent complication of long-term PN with consequences that include cirrhosis, end-stage liver disease, and even death.80 The incidence of IF/SBS-associated liver disease (IFALD) is as high as 50% in infants who receive PN for 2 months with end-stage liver disease developing in 90% of premature infants on PN for more than 3 months.81 Elevated serum transaminase and bilirubin levels are commonly observed in infants on PN, but these levels can normalize and jaundice resolve with intestinal adaptation and PN withdrawal. The long-term outcome of IFALD in patients who adapt is unknown. The population currently thought to be at greatest risk for IFALD are premature infants with a birth weight < 1 kg and those with IF/SBS resulting from surgical resection.8284 The etiology of IFALD remains unknown but is likely multi-factorial with prematurity, multiple abdominal surgeries, lack of enterally stimulated bile flow, bacterial sepsis, and components or deficiencies of PN infusates all potential contributors. Treatment of PN-associated liver disease is empiric and imperfect. Current strategies to avert liver disease associated with long-term PN include employing a choleretic such as ursodeoxycholic acid, 85 bowel decontamination to treat bacterial overgrowth, 83,85 vigilant daily catheter care,86 and modifying PN formulations. Infusing PN calories over less than 24 hours, casually referred to as cycling PN, is thought to improve cholestasis.87 The underlying mechanism for this action and effect is not clearly understood, but may involve providing a metabolic rest from the continuous infusion of calories, protein, and/or carbohydrate. Administration of pediatric formulations of PN that include specific targeted amino acids including taurine88 and limiting the infusion of dextrose so as to potentially decrease steatosis have also been utilized.89 Decreasing the aluminum and manganese content in PN may decrease hepatotoxicity.90,91 Decreasing the amount or altering the type of lipids administered may improve serum transaminase levels, reverse PN-associated liver disease, or reduce lipid peroxidation.46,92,93 Recently, use of a fish oil-based intravenous lipid source was found to be associated with improvement of serum bilirubin in two children,46 although its long-term use in an animal model was associated with increased fibrosis.94 Unfortunately, most of these interventions to reduce or prevent IFALD are employed empirically and lack significant clinical confirmation in large pediatric trials. Once end-stage liver
disease develops, portal hypertension, variceal and stomal bleeding, infection, hypoglycemia, and hyperammonemia occur, making a combined liver-intestinal transplant the only remaining life-saving measure.
Central Line Complications

Maintaining central venous catheter (CVC) access is critical in the long-term management of IF/SBS. Loss of vascular access can be fatal in this population and is an indication for intestinal transplantation. As a result, salvage of the CVC line is a strategy employed to preserve vascular access. In addition, the advancement of newer approaches such as recanalization of a thrombosed vessel has been employed in selected patients when vascular sites are limited.95,96 The threshold for removing CVC lines and referral to centers that perform recanalization is likely variable from both an institutional and physician standpoint. A greater understanding of the source of this variability will allow standardization to a best practice model and allow centers participating in this collaborative to preserve access sites and better equip patients for long-term survival. Sepsis is an important cause of death in children with IF/SBS. Accordingly, multiple factors contribute to the management of suspected sepsis in the patient with IF/SBS including age and presence of a CVC. Catheter-associated bloodstream infections (CABSIs) are responsible for a majority of the infectious morbidity. While the true incidence of CABSIs is unknown, IF/SBS patients constitute a high-risk group within the CVC population. Potential risk factors include the proximity of fecal material to line entry sites and connections, frequent line access for laboratory tests, and intestinal bacterial translocation. While translocation occurs in animal models, its proof in human populations is elusive.97 At the same time, several lines of evidence suggest a role for bacterial translocation in IF/ SBS. There is a greater incidence of enteric organisms isolated in cultures from these patients compared to other populations with CVC lines.98 Furthermore, a comparison of CVC isolates with fecal flora and mesenteric lymph node cultures were highly concordant.99 Finally, the incidence of infection has been demonstrated to be increased while advancing enteral feeds.100 While CABSIs are of the greatest concern, patients with IF/SBS are also subject to numerous other central line-related complications. Of these, thrombosis and line breakage are the 2 most frequent. Fortunately, there is a high salvage rate and treatment with thrombolytics or CVC repair has been shown to result in a high CVC salvage rate.101 The development of consensus guidelines based upon the
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accrual of data across the population of IF/SBS is predicted to reduce CVC-associated complications as well as lengthen the life-span of each individual catheter and preserve access sites critical to survival and potential transplantation.
Outcomes
Growth and Development
Infants and children must digest and absorb sufficient calories, vitamins, minerals, and trace elements to gain weight, grow, and develop. Children with IF/SBS are incapable of sustaining adequate growth and development without supplemental PN. Successful intestinal adaptation implies complete independence from PN while continuing to demonstrate satisfactory growth and development. However, there are no prospective studies available to address long-term growth and development in children with IF/SBS following PN withdrawal. A recent retrospective study of 87 children identified over a period of 16 years provides some insight into the long-term problems that children with IF/SBS may face.16 The authors found that in those children who achieved enteral autonomy, maximum weight gain and growth was achieved during the first 4 years after weaning PN. However, between 4 and 8 years post-PN, weight gain and growth, expressed as a z score, appeared to decline with the weight z score 8 years post-PN almost identical to the weight at the time of weaning and height z score slightly lower than the score at the time of weaning. Interestingly, 21 children were noted to enter puberty at an age similar to their peers.
posttransplant care and immunosuppression protocols, these outcomes have drastically improved. 2 More than 900 intestinal transplants have now been performed in all age groups worldwide, with more than 500 in the pediatric population.2,3 Five-year patient survival rates exceed 50% worldwide.4 Unfortunately, the indications for intestinal transplant are broad and subject to a significant degree of interpretation. There is a need for evidence-based parameters that would improve the selection of patients for intestinal transplant and determine optimal timing for transplant to maximize outcomes and minimize the need for combined organ transplantation. A subset of patients with IF/SBS and associated liver disease may benefit from an isolated liver transplant.105107 It has been postulated that IFALD may hinder bowel adaptation and delay progression toward enteral feeding tolerance.8 In fact, various authors have reported remarkable bowel adaptation and feeding tolerance after isolated liver transplant for severe IFALD.4,5,105
Quality of Life
Studies in adult patients have identified reduced quality of life (QOL) scores in patients with SBS, which were further reduced if the patient was on HPN. Interestingly, the presence of a stoma did not appear to influence their quality of life.102 Similarly detailed studies that address QOL and school performance have not been performed in children, however, children on HPN appear to fare better than those hospitalized for PN.103,104
Intestinal Transplant
Intestinal transplant is reserved as the final life-saving procedure for patients with irreversible IF/SBS and lifethreatening complications of PN administration. In 1994, very few intestinal transplants were performed in the pediatric population worldwide (approximately 25 according to the Intestinal Transplant Registry), with unsatisfactory outcomes in these early years.1 With advances in
1. A 30-week infant with 35 cm of small bowel, an ilealcecal valve, and an intact colon has an advantage over a full-term infant with the same anatomy because: A. Etiologies for short bowel syndrome are different between the two groups. B. Premature infants who survive are constitutionally stronger than full-term infants. C. The small intestinal length doubles in the last trimester. D. Complications associated with PN are less frequent in the premature infant. 2. A clinical feature associated with enteral autonomy is: A. Being a female B. Small intestine in continuity with the colon C. Absent ileal-cecal valve D. Having fewer than 10 stools per day 3. PN associated liver disease is caused by: A. Intravenous lipid B. Lack of enteral feeding C. Recurrent infections D. Multiple factors, including all of the above 4. The best method to provide enteral feeding for children with intestinal failure is via: A. Gastrostomy B. Nasogastric tube C. Jejunal feeding D. Oral feeding See p. 487 for answers.
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1. Goulet O, Ruemmele F, Lacaille F, Colomb V. Irreversible intestinal failure. J Pediatr Gastroenterol Nutr. 2004;38(3):250269. 2. Kocoshis SA, Beath SV, Booth IW, et al. Intestinal failure and small bowel transplantation, including clinical nutrition: Working Group Report of the Second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition . J Pediatr Gastroenterol Nutr. 2004;39(Suppl 2):S655S661. 3. Andorsky DJ, Lund DP, Lillehei CW, et al. Nutritional and other postoperative management of neonates with short bowel syndrome correlates with clinical outcomes. J Pediatr. 2001;139(1):2733. 4. Goulet OJ, Revillon Y, Jan D, et al. Neonatal short bowel syndrome. J Pediatr. 1991;119(1 ( Pt 1)):1823. 5. Quios-Teijeira RE, Ament ME, Reyen L, et al. Long-term parenteral nutritional support and intestinal adaptation in children with short bowel syndrome: a 25-year experience. J Pediatr. 2004;145(2):157163. 6. Spencer AU, Neaga A, West B, et al. Pediatric short bowel syndrome: redefining predictors of success. Ann Surg. 2005;242(3):403409; discussion 409412. 7. Touloukian RJ, Smith GJ. Normal intestinal length in preterm infants. J Pediatr Surg. 1983;18(6):720723. 8. DeLegge M, Alsolaiman MM, Barbour E, et al. Short bowel syndrome: parenteral nutrition versus intestinal transplantation. Where are we today? Dig Dis Sci. 2007;52(4):876892. 9. Wallander J, Ewald U, Lackgren G, et al. Extreme short bowel syndrome in neonates: an indication for small bowel transplantation? Transplant Proc. 1992;24(3):12301235. 10. Schalamon J, Mayr JM, Hollwarth ME. Mortality and economics in short bowel syndrome. Best Pract Res Clin Gastroenterol. 2003;17(6):931942. 11. Colomb V. Economic aspects of paediatric home parenteral nutrition. Curr Opin Clin Nutr Metab Care. 2000;3(3):237239. 12. Tavakkolizadeh A, Whang EE. Understanding and augmenting human intestinal adaptation: a call for more clinical research . J Parenter Enteral Nutr. 2002;26(4):251255. 13. Drozdowski L, Thomson AB. Intestinal mucosal adaptation . World J Gastroenterol. 2006; 2(29):46144627. 14. Javid P, Kim H, Duggan C, Jaksic T. Serial transverse enteroplasty is associated with successful short-term outcomes in infants with short bowel syndrome. J Pediatr Surg. 2005;40(6):10191023; discussion 10231024. 15. Bianchi A. Intestinal loop lengthening--a technique for increasing small intestinal length. J Pediatr Surg. 1980;15(2):145151. 16. Goulet O, Gobet B, Talbotec C, et al. Outcome and longterm growth after extensive small bowel resection in the neonatal period: a survey of 87 children. Eur J Pediatr Surg. 2005;15(2):95101. 17. Crenn P, Morin MC, Joly F, Penven S, Thuillier F, Messing B. Net digestive absorption and adaptive hyperphagia in adult short bowel patients. Gut. 2004;53(9):12791286. 18. DiBaise JK, Young RJ, Vanderhoof JA. Intestinal rehabilitation and the short bowel syndrome: part 1. Am J Gastroenterol. 2004;99(7):13861395.
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54. Ament ME. Bone mineral content in patients with short bowel syndrome: the impact of parenteral nutrition. J Pediatr. 1998;132(3 Pt 1):386388. 55. Fleming CR, George L, Stoner GL, et al. The importance of urinary magnesium values in patients with gut failure. Mayo Clin Proc. 1996;71(1):2124. 56. Buchman AL. Etiology and initial management of short bowel syndrome. Gastroenterology. 2006;130(2 Suppl 1):S5S15. 57. Ziegler TR, Evans ME, Fernndez-Estvariz C, Jones DP. Trophic and cytoprotective nutrition for intestinal adaptation, mucosal repair, and barrier function. Annu Rev Nutr. 2003;23:229261. 58. Buxton B. Small bowel resection and gastric acid hypersecretion. Gut. 1974;15(3):229238. 59. Go VL, Poley JR, Hofmann AF, Summerskill WH. Disturbances in fat digestion induced by acidic jejunal pH due to gastric hypersecretion in man. Gastroenterology. 1970;58(5):638646. 60. Williams NS, Evans P, King RF. Gastric acid secretion and gastrin production in the short bowel syndrome. Gut. 1985;26(9):914919. 61. Cortot A, Fleming CR, Malagelada JR. Improved nutrient absorption after cimetidine in short-bowel syndrome with gastric hypersecretion. N Engl J Med. 1979;300(2):7980. 62. Nightingale JM, Walker ER, Farthing MJ, Lennard-Jones JE. Effect of omeprazole on intestinal output in the short bowel syndrome. Aliment Pharmacol Ther. 1991;5(4):405412. 63. Tang SJ, Nieto J, Jenson DM, Ohning GV, Pisegna JR. The novel use of an intravenous proton pump inhibitor in a patient with short bowel syndrome. J Clin Gastroenterol. 2002;34(1):6263. 64. Malagelada JR. Pathophysiological responses to meals in the Zollinger-Ellison syndrome: 2. Gastric emptying and its effect on duodenal function. Gut. 1980;21(2):98104. 65. Chocarro MA, Galindo TF, Ruiz-Irastorza G, et al. Risk factors for esophageal candidiasis. Eur J Clin Microbiol Infect Dis. 2000;19(2):96100. 66. Westergaard H. Bile acid malabsorption . Curr Treat Options Gastroenterol. 2007;10(1): 2833. 67. Nightingale JM, Kamm MA, van der Sijp JR, et al. Disturbed gastric emptying in the short bowel syndrome. Evidence for a colonic brake. Gut. 1993;34(9):11711176. 68. Reynell PC, Spray GH. Small intestinal function in the rat after massive resections. Gastroenterology. 1956;31(4):361368. 69. Nightingale JM, Lennard-Jones JE, Walker ER. A patient with jejunostomy liberated from home intravenous therapy after 14 years; contribution of balance studies. Clin Nutr. 1992;11(2):101105. 70. Rodrigues CA, Lennard-Jones JE, Thompson DG, et al. The effects of octreotide, soy polysaccharide, codeine and loperamide on nutrient, fluid and electrolyte absorption in the short-bowel syndrome. Aliment Pharmacol Ther. 1989;3(2):159169. 71. Nightingale JM. Hepatobiliary, renal and bone complications of intestinal failure. Best Pract Res Clin Gastroenterol. 2003;17(6):907929.
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72. Dibaise JK, Young RJ, Vanderhoof JA. Enteric microbial flora, bacterial overgrowth, and short-bowel syndrome. Clin Gastroenterol Hepatol. 2006;4(1):1120. 73. OKeefe SJ. Bacterial overgrowth and liver complications in short bowel intestinal failure patients. Gastroenterology. 2006;130(2 Suppl 1):S67S69. 74. Puwanant ML, Mo-Suwan, Patrapinyokul S. Recurrent D-lactic acidosis in a child with short bowel syndrome. Asia Pac J Clin Nutr. 2005;14(2):195198. 75. Quigley EM, Quera R. Small intestinal bacterial overgrowth: roles of antibiotics, prebiotics, and probiotics. Gastroenterology. 2006;130(2 Suppl 1):S78S90. 76. Perlmutter DH, Boyle JT, Campos JM, Egler JM, Watkins JM. D-Lactic acidosis in children: an unusual metabolic complication of small bowel resection. J Pediatr. 1983; 102(2):234238. 77. Mayne AJ, Handy DJ, Pierce MA, George RH, Booth IW. Dietary management of D-lactic acidosis in short bowel syndrome. Arch Dis Child. 1990;65(2):229231. 78. Hosie S, Loff S, Wirth H, Rapp HJ, von Buch C, Waag KL. Experience of 49 longitudinal intestinal lengthening procedures for short bowel syndrome. Eur J Pediatr Surg. 2006;16(3):171175. 79. Coronado BE, Opal SM, Yoburn DC. Antibiotic-induced D-lactic acidosis. Ann Intern Med. 1995;122(11):839842. 80. Goulet O, Ruemmele F. Causes and management of intestinal failure in children. Gastroenterology. 2006;130(2 Suppl 1):S16S28. 81. Kelly DA. Liver complications of pediatric parenteral nutritionepidemiology. Nutrition. 1998;14(1):153157. 82. Teitelbaum DH. Parenteral nutrition-associated cholestasis. Curr Opin Pediatr. 1997;9(3):270275. 83. Kelly DA. Intestinal failure-associated liver disease: what do we know today? Gastroenterology. 2006;130(2 Suppl 1):S70S77. 84. Beale EF, Nelson RM, Bucciarelli RL, Donnelly WH, Eitzman DV. Intrahepatic cholestasis associated with parenteral nutrition in premature infants. Pediatrics. 1979;64(3):342347. 85. Gnsar C, Melek M, Karaca I, et al. The biochemical and histopathological effects of ursodeoxycholic acid and metronidazole on total parenteral nutrition-associated hepatic dysfunction: an experimental study. Hepatogastroenterology. 2002;49(44):497500. 86. Colomb V, Fabeiro M, Dabbas M, Goulet O, Merckx J, Ricour C. Central venous catheter-related infections in children on long-term home parenteral nutrition: incidence and risk factors. Clin Nutr. 2000;19(5):355359. 87. Burstyne M, Jensen GL. Abnormal liver functions as a result of total parenteral nutrition in a patient with short-bowel syndrome. Nutrition. 2000;16(1112):10901092. 88. Cooke RJ, Whitington PF, Kelts D. Effect of taurine supplementation on hepatic function during short-term parenteral nutrition in the premature infant . J Pediatr Gastroenterol Nutr. 1984;3(2):234238. 89. Bresson JL, Narcy P, Putet G, Ricour C, Sachs C, Rey J. Energy substrate utilization in infants receiving total parenteral nutrition with different glucose to fat ratios. Pediatr Res. 1989;25(6):645648.
90. Advenier E, Landry C, Colomb V, et al. Aluminum contamination of parenteral nutrition and aluminum loading in children on long-term parenteral nutrition. J Pediatr Gastroenterol Nutr. 2003;36(4):448453. 91. Kafritsa Y, Fell J, Long S, Bynevelt M, Taylor W, Milla P. Long-term outcome of brain manganese deposition in patients on home parenteral nutrition. Arch Dis Child. 1998;79(3):263265. 92. Goulet O, de Potter S, Antbi H, et al. Long-term efficacy and safety of a new olive oil-based intravenous fat emulsion in pediatric patients: a double-blind randomized study. Am J Clin Nutr. 1999;70(3):338345. 93. Cavicchi M, Crenn P, Beau P, Degott C, Boutron MC, Messing B. Severe liver complications associated with longterm parenteral nutrition are dependent on lipid parenteral input. Transplant Proc. 1998;30(6):2547. 94. Kohl M, Wedel T, Entenmann A, et al. Influence of different intravenous lipid emulsions on hepatobiliary dysfunction in a rabbit model. J Pediatr Gastroenterol Nutr. 2007;44(2):237244. 95. Rodrigues AF, Van Mourik IDM, Sharif K, et al. Management of end-stage central venous access in children referred for possible small bowel transplantation. J Pediatr Gastroenterol Nutr. 2006;42(4):427433. 96. Lang EV, Reyes J, Faintuch S, Smith A, Abu-Elmagd K. Central venous recanalization in patients with short gut syndrome: restoration of candidacy for intestinal and multivisceral transplantation. J Vasc Interv Radiol. 2005;16(9):12031213. 97. Lichtman SN. Translocation of bacteria from gut lumen to mesenteric lymph nodes--and beyond? J Pediatr Gastroenterol Nutr. 1991;13(4):433434. 98. Piedra PA, Dryja DM, LaScolea LJ Jr. Incidence of catheterassociated gram-negative bacteremia in children with short bowel syndrome. J Clin Microbiol. 1989;27(6):13171319. 99. Kurkchubasche AG, Smith SD, Rowe MI. Catheter sepsis in short-bowel syndrome. Arch Surg. 1992;127(1):2124; discussion 2425. 100. Weber TR. Enteral feeding increases sepsis in infants with short bowel syndrome. J Pediatr Surg. 1995;30(7):10861088; discussion 10881089. 101. Moukarzel AA, Haddad I, Ament M, et al. 230 patient years of experience with home long-term parenteral nutrition in childhood: natural history and life of central venous catheters. J Pediatr Surg. 1994;29(10):13231327. 102. Carlsson E, Bosaeus I, Nordgren S. Quality of life and concerns in patients with short bowel syndrome. Clin Nutr. 2003;22(5):445452. 103. Candusso M, Faraguna D, Sperli D, Dodaro N, et al. Outcome and quality of life in paediatric home parenteral nutrition. Curr Opin Clin Nutr Metab Care. 2002;5(3):309314. 104. Heine RG, Bines, JE. New approaches to parenteral nutrition in infants and children. J Paediatr Child Health. 2002;38(5):433437. 105. Botha JF, Grant WJ, Torres C, et al. Isolated liver transplantation in infants with end-stage liver disease due to short bowel syndrome. Liver Transpl. 2006;12(7):10621066.
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106. Diamond IR, Wales PW, Grant DR, Fecteau A. Isolated liver transplantation in pediatric short bowel syndrome: is there a role? J Pediatr Surg. 2006;41(5):955959. 107. Horslen SP, Sudan DL, Iyer KR et al. Isolated liver transplantation in infants with end-stage liver disease associated with short bowel syndrome. Ann Surg. 2002;235(3):435439.
Pulmonary Disorders
Allison Mallowe, RD, LDN, Suzanne Michel, MPH, RD, LDN, and Maria Mascarenhas, MBBS
28
Learning Objectives
1. Understand the role of nutrition in lung disease. 2. Discuss nutrition as related to complications of cystic fibrosis (CF). 3. List components of nutrition assessment for persons with pulmonary disease. 4. Understand micronutrient abnormalities that can occur in CF.
CONTENTS
Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
Pathophysiology
Nutrition Assessment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 Nutrition Recommendations . . . . . . . . . . . . . . . . . . . . . . . 325

Macronutrients Micronutrients Minerals
Nutrition Support. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pancreatic Enzymes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eating Behaviors and CF. . . . . . . . . . . . . . . . . . . . . . . . . . Nutrition-Related Cystic Fibrosis Complications. . . . . . .
Osteoporosis or Bone Disease CF-Related Diabetes Lung Transplantation Gastrointestinal
329 330 330 331
Cystic Fibrosis
Pathophysiology
Cystic fibrosis (CF) is a common autosomal recessive genetic disorder that is most frequently seen in people of northern European descent. In the United States CF occurs in approximately 1 in 2,500 live births and affects approximately 30,000 Americans. The CF gene was isolated in 19891 and since then more than 1,500 mutations have been identified. The gene, which is localized on the short arm of chromosome 7, is called the cystic fibrosis transmembrane regulator (CFTR) and controls the flow of sodium and chloride ions across the cell membrane. Mutations in the gene result in abnormal epithelial ion transport in multiple organs in the body. Clinical outcomes have been related to the type of mutation. With the advent of almost universal newborn screening programs in the United States, it is estimated that the average life expectancy will increase from the current median predicted life expectancy of 37.4 years. 2 Diagnosis during the newborn period by newborn screening results in early nutrition intervention and improved nutrition status, which may lead to better quality of life and prolonged survival. (See Table 28-1 for clinical features and diagnosis of CF.) Historically an abnormal
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Other Chronic Lung Diseases . . . . . . . . . . . . . . . . . . . . . . 332

Overview and Pathophysiology Bronchopulmonary Dysplasia Asthma Technology Dependent Nutrition Assessment Nutrition Recommendations Bone Health in Chronic Lung Disease
Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
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sweat test (chloride values > 60 mEq/L) was considered diagnostic, but it is now recognized that this gold standard may not always be abnormal. Based on the severity of the mutation, the clinical picture is variable and gene analysis, nasal potential differences, and sputum cultures may be required for the diagnosis of CF. 3
Table 28-1 Clinical Features and Diagnosis of Cystic Fibrosis
Clinical Features Manifested in Infants Clinical Features Manifested in the General CF Population
Meconium ileus Meconium peritonitis Intestinal atresia Recurrent obstructive respiratory disease/infections Rectal prolapse Failure to thrive Obstructive jaundice Hyponatremic dehydration Malabsorption Salty taste in sweat (when kissed) Zinc deficiency Fat-soluble vitamin deficiency
Recurrent cough or wheeze Clubbing of fingers and toes Hyperinflation of chest Cystic fibrosis-related diabetes Chest wall deformities Nasal polyps Cirrhosis and portal hypertension Recurrent pancreatitis Gallbladder disease Focal biliary cirrhosis Zinc deficiency & EFAD dermatitis Fat-soluble vitamin deficiencies Hyponatremic deficiency without renal disease
EFAD: essential fatty acid deficiency. Adapted from Gottschlich MM. Pulmonary disease. In: Gottschlich MM. The Science and Practice of Nutrition Support: A Core-Based Curriculum. Dubuque, IA: Kendall/Hunt Publishing Co; 2001:501516.
Because the expression of the CF gene is limited to epithelial cells, the organs affected are primarily mucusproducing organs such as lungs, gastrointestinal (GI) tract, liver, pancreas, and sweat glands.4 The transport of sodium and chloride across cell membranes is regulated by cyclic adenosine monophosphate and calcium, both of which are controlled by CFTR. 5 The respiratory epithelial cells are impermeable to chloride ions which results in an increase in airway sodium absorption. The movement of sodium into the cells results in the movement of water into the cell, leading to dehydration of the airway mucus and decreased ciliary function. This results in viscous secretions in the lung, liver, pancreas, and GI tract and in duct obstruction in sweat glands and elevated sweat chloride levels. Pulmonary involvement is initially associated with infection with Staphylococcus aureus and later Pseudomonas aeruginosa. Chronic pulmonary damage, bronchiectasis, fibrosis, and decreasing lung function occur over time. Impaired gas exchange occurs secondary to airflow resistance, hyperinflation, and uneven distribution of ventilation. Bacterial adherence and colonization both result
in a sustained host inflammatory response. Stimulated neutrophils release large amounts of oxidants and proteases including elastase which leads to increased mucus production, bacterial trapping, and further lung damage.6 Clinical symptoms include cough, production of mucus, air trapping, and ultimately end-stage lung disease requiring lung transplantation. In the pancreas there is accumulation of thick mucus in the acinar glands leading to an obstruction of the ducts. Damage occurs in the glands due to the release of lytic enzymes resulting in chronic inflammation, fibrosis, fatty infiltration of the pancreas, and pancreatic insufficiency (PI). These changes can occur in utero in patients with severe mutations. PI is seen in about 70% to 80% of patients at diagnosis.7 Patients with adequate pancreatic function at diagnosis who are pancreatic sufficient (PS) may go on to develop PI over time, hence need to be monitored carefully. Clinical symptoms of PI include malabsorption, diarrhea, weight loss, poor growth, vitamin deficiencies, increased gas, and abdominal pain. Some patients may have a voracious appetite in an effort to ingest sufficient calories to compensate for energy loss in their bowel movement from maldigestion and malabsorption. Approximately 5% to 15% of persons with CF will develop cystic fibrosis-related diabetes (CFRD) and it is expected that this number will increase as life expectancy increases. 8 Similar fluid and electrolyte disturbances occur in the GI tract causing sticky mucus and stool accumulation which can result in meconium ileus in the newborn and distal intestinal obstruction syndrome (DIOS) in older children and adults. Meconium ileus, or the build-up of meconium in utero, is the earliest manifestation of CF. Infants can be born with meconium plugs, intestinal obstruction, atresias, volvulus, perforations, and meconium pseudocyst. DIOS is the accumulation of sticky stool in the GI tract, primarily in the terminal ileum and cecal area. It may occur in all persons who have CF (PI and PS). Predisposing factors are decreased fluid intake, decreased salt intake, malabsorption, and decreased motility. Other changes in the GI tract include abnormal gastric and intestinal motility. In the liver CFTR is expressed in the biliary epithelium, and similar abnormalities of ion transport occur. This results in the decreased flow of bile with secondary hepatocyte damage, inflammation, fibrosis, and cirrhosis. In males, obstruction of the vas deferens results in infertility and in patients with mild mutations may be the presenting feature that leads to the diagnosis of CF.
PULMONARY DISORDERS
325
There is a strong correlation between pulmonary function and nutritional status. In children, a body mass index (BMI) at or above the 50th percentile has been associated with improved survival and optimal lung function. Associations between deteriorating lung function and worsening nutrition status have been noted.4,9 Malnutrition results from: increased needs (increased metabolic rate,10 infections, work of breathing, cough); increased losses (malabsorption due to pancreatic, liver, and intestinal disease; intestinal resection; vomiting; and CFRD); and decreased nutrient intake (anorexia, gastroesophageal reflux disease (GERD), eating disorders, abdominal pain, constipation, malaise, and medications). Aggressive nutrition intervention is often required to improve nutrition status. Nutrition assessment is an important component in the care of persons who have CF. Factors that affect nutrition status include maldigestion and malabsorption of fat, protein, carbohydrates, and fat-soluble vitamins; decreasing pulmonary function; chronic pulmonary infections and increased oxidative stress; decreased energy intake; increased energy requirements; and CFRD. A comprehensive nutrition assessment must be performed at diagnosis and yearly. This consists of an assessment of (1) growth including pattern of weight and height based on the growth curve, head circumference (as appropriate), and BMI percentile; (2) biochemical indicators such as vitamin and mineral levels; (3) nutrient intake; (4) eating behavior and family eating patterns; (5) pancreatic enzyme replacement therapy (PERT) management; (6) physical activity; (7) severity of lung disease; (8) presence of any comorbidity such as CFRD, chronic infections, cirrhosis, or bacterial overgrowth; and (9) factors which may impact the patients ability to meet nutrition goals. Assessment of bone health should be performed yearly and, as indicated, growth parameters (height, weight, head circumference, weight for length, or BMI percentile) should be assessed and monitored at every visit. Arm anthropometrics can be measured as well. Based on the above information caloric requirements are calculated, vitamin and mineral prescription adjusted, and anthropometric goals calculated. A nutrition screen must be performed at every visit so as to identify inadequate weight gain, weight loss, and faltering of linear growth. When these occur, a nutrition assessment must be performed, causes identified, and appropriate interventions implemented (Table 28-2).
Table 28-2 Nutrition Assessment Parameters for Cystic Fibrosis

Parameter Frequency of Assessment andReassessment
Anthropometrics Occipital-frontal head circumference Body weight, height, length, head circumference MAMC, TSF Nutritional Intake 24-hour recall 3-day dietary fat balance coefficient of fat absorption < 93% or 85% in infants fecal elastase used to define steatorhhea Biochemical CBC with differential Iron studies Fat-soluble vitamins Alpha-tocopherol Serum plasma retinol 25-OH vitamin D PIVKA II Essential Fatty Acid Deficiency Ratio of triene to tetraene 25-OH vitamin D
Measured only up to age 2 years Every 3 months Annually Routine care and diagnostic Evaluate weight loss, growth, diagnosis
Routine care and diagnosis Diagnose iron deficiency anemia Routine care and diagnosis
Diagnostic Yearly
MAMC: mid-arm muscle circumference; TSF: triceps skinfold; CBC: complete blood count. Adapted from Gottschlich MM. Pulmonary disease. In: Gottschlich MM. The Science and Practice of Nutrition Support: A Core-Based Curriculum. Dubuque, IA: Kendall/Hunt Publishing Co; 2001:501516.
Nutrition Recommendations
Macronutrients
Energy As previously described, individuals who have CF have increased energy needs. Exact caloric prescriptions and formulas to calculate caloric need are difficult to provide due to individual patient variation11 but improved weight status has been found at intakes ranging from 110% to 200% of energy needs for the healthy population.12 Energy needs of each patient should be assessed on an individual basis and reflect the pattern of weight gain and fat stores.13 An estimation of individual caloric need is based upon nutrition status, growth pattern, fat stores, current dietary intake, degree of fat malabsorption, clinical status (including pulmonary
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function), level of activity, and incorporation of additional requirements for nutrition repletion, weight gain, and/or catch-up growth.14 Fat The energy goal can be best achieved by consuming a diet that contains 35% to 40% of calories as fat.13 Ongoing research suggests that a diet containing sources of linolenic acid (LA), such as flax seed, canola, and soy oils and cold-water marine fish, may be beneficial for persons who have CF.15 Historically the amount but not type of fat has been emphasized. Clinicians are encouraged to be aware of the symptoms of essential fatty acid deficiency (EFAD). Most common symptoms of LA deficiency are poor growth and scaly skin lesions, confirmed by an increase in triene-tetraene ratio of plasma lipids.8 EFAD can occur not only in patients with severe lung disease, significant malabsorption, and/or cirrhosis but also in patients with normal nutrition status. It is not known whether the deficiency is due to a primary metabolic disorder or due to malabsorption and increased oxidative stress.15 Protein Specific recommendations for protein intake in CF are not available, although there is some evidence that protein needs are met if a higher calorie diet is consumed14 and 15% to 20% of total calories are from protein.16 Carbohydrate The diet should contain sufficient carbohydrate to meet energy needs. As with persons who do not have CF, it is best if the source is from foods which contribute to the overall nutrient intake, including fiber. Infants Infants require a diet that will promote optimal weight gain, and, when indicated, catch-up growth. Human milk or standard infant formula is recommended. When necessary, fortified human milk or calorically dense formula may be used to promote and/or maintain weight gain.17 Infants with CF have specific sodium requirements (see section on Sodium Chloride). Infants may require 120 to 150 kcal/kg/d to achieve catch-up growth.13 Hydrolyzed protein formulas containing medium-chain triglycerides (MCTs) are not indicated in the absence of a medical reason, such as bowel surgery with significant bowel resection due to meconium ileus or liver abnormalities. Solids are added to the diet of infants who have CF on the same schedule used for nonaffected infants.8 Care must be taken when adding solids to avoid replacing nutrient- and energy-rich infant milks with
low-calorie, low-nutrient foods. Adding oil to commercial jarred infant foods will increase calories; up to 1 teaspoon of oil to every 4 oz of baby food is suggested. Revised guidelines for infant feeding emphasize the safety and benefits of earlier introduction of meat for the energy, protein, zinc, and iron content for all infants.8 Parents who wish to prepare homemade solids may require instruction. Positive feeding behaviors should be encouraged throughout the feeding experience.17
Micronutrients
All persons with CF, both PI and using PERT and PS,18 require supplementation with micronutrients. Deficiencies of fat-soluble vitamins19 and zinc20 have been demonstrated in infants diagnosed through newborn screening and do not correct without appropriate supplementation and, if indicated, PERT. Children and adolescents are at risk for micronutrient deficiencies due to:14 Inadequate intake Malabsorption possibly due to suboptimal PERT Malabsorption due to residual or incomplete bile salt absorption Poor clinical status and poor lung function Increased utilization and reduced bioavailability Liver disease Bowel resection Late diagnosis of CF Poor adherence to or inappropriate supplementation. Fat-Soluble Vitamins Multivitamins designed to meet the fat-soluble vitamin needs of persons who have CF (CF-specific multivitamins) are available in North America (Table 28-3). These vitamins contain fat- and water-soluble vitamins and zinc. The content reflects the recommendations provided in the U.S. Pediatric Nutrition Consensus Report,13 the European Nutrition Consensus Report,21 the U.S. Bone Consensus Report,22 and/or current research. Dosage and form of the CF-specific multivitamin supplementation is dependent on results of laboratory evaluation of vitamin levels and the patients age. Patients may require additional single-nutrient supplements (ie, vitamins A, E, D, K), if blood levels cannot be maintained on the CF-specific multivitamins. If the CF-specific multivitamin is unavailable, single-vitamin supplements are necessary to make up the difference in content of traditional multivitamins compared to recommendations. For additional information specific to vitamins and CF the reader is referred to www.SourceCF.com for newsletters.
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Table 28-3 Fat-Soluble Vitamins and Zinc Content of Multivitamins1

Age CFF Consensus Report 2 SourceCF Drops, Chewables, Softgels ADEK Chewables AquADEKs Drops, Softgels Vitamax Drops, Chewables Poly-Vi-Sol Drops Centrum Chewable, Tablet
012 months 13 years 48 years 918 years > 18 years
1,500 5,000 5,00010,000 10,000 8000
012 months 13 48 918 years > 18 years 012 months 13 48 years 918 years > 18 years 012 months 13 48 years 918 years > 18 years 012 months 13 years 48 years 9 yearsAdult
4050 80150 100200 200400 400 4004 8004 800 800 800 300500 300500 300500 300500 1,000
Vitamin A (IU) Retinol and Beta-Carotene (BC) 4627 (1 mL) 75% BC 5,751 (1 mL) 87% BC 11,502 (2 mL) 87% BC 9254 (2 mL) 75% BC 16,000 / chewable 9,000 / chewable Ages 410 yrs 18,167 88% BC 60% BC / 1 softgel, 92% BC 18,000 / 2 Ages 10 and up 32,000 / 2 softgels chewables 36,334 / 2 softgels, 88% BC 60% BC 92% BC 18,000 / 2 36,334 / 2 softgels 32,000 / 2 softgels chewables 92% BC 88% BC 60% BC Vitamin E (IU) 50 (1 mL) 50 (1 mL)3 100 (2 mL) 100 (2 mL)3 Ages 410 yrs: 150 / 200 / chewable 150 / chewable 1 softgel Ages 10 and up: 300 400 / 2 softgels 300 / 2 chewables / 2 softgels 400 / 2 softgels 300 / 2 chewables 300 / 2 softgels Vitamin D (IU) 500 (1 mL) 400 (1 mL) 1000 (2 mL) 800 (2 mL) Ages 410 yrs: 800 / 1000 / chewable 400 / chewable 1 softgel Ages 10 and up: 2000 / 2 softgels 800 / 2 chewables 1600 / 2 softgels 2000 / 2 softgels 800 / 2 chewables 1600 / 2 softgels Vitamin K (mcg) 400 (1 mL) 400 (1 mL) 800 (2 mL) 800 (2 mL) Ages 410 yrs: 700 / 800 / chewable 150 / chewable 1 softgel Ages 10 and up: 1600 / 2 softgels 300 / 2 chewables 1400 / 2 softgels 1600 / 2 softgels 300 / 2 chewables 1400 / 2 softgels Zinc (mg) 5 (1 mL) 5 (1 mL) 10 (2 mL) 10 (2 mL) For 410 yrs: 7.5 / chewable 15 / chewable 10 / softgel For Ages 10+: 30/ 2 softgels 15 / 2 chewables 20 / 2 softgels
3,170 (1 mL) 0%BC 1,500 (1 mL) 0% BC 6,340 (2 mL) 0% BC 3,000 (2 mL) 0% BC 5,000 / chewable 3,500 / chewable 50% BC 29% BC 10,000 / 2 7,000 / 2 tablets chewables 29% BC 50% BC 10,000 / 2 7,000 / 2 tablets chewables 29% BC 50% BC 50 (1 mL) 100 (2 mL) 200 / chewable 400 / 2 chewables 400 / 2 chewables 400 (1 mL) 800 (2 mL) 400 / chewable 800 / 2 chewables 800 / 2 chewables 300 (1 mL) 600 (2 mL) 200 / chewable 400 / 2 chewables 400 / 2 chewables 7.5 (1 mL) 15 (2 mL) 7.5 / chewable 15 / 2 chewables 5 (1 mL) 10 (2 mL) 30 / chewable 60 / 2 tablets 60 / 2 tablets 400 (1 mL) 800 (2 mL) 400 / chewable 800 / 2 tablets 800 / 2 tablets 0 0 10 / chewable 50 / 2 tablets 50 / 2 tablets 0 0 15 / chewable 22 / 2 tablets
1. The content of this table is as of December 2008. Products also contain a full range of water-soluble vitamins. Information not included in this table. Fora copy of the full table, go to: www.SourceCF.com. 2. Cystic Fibrosis Foundation. Pediatric Nutrition for Patients with Cystic Fibrosis Consensus Conference Report March 2001 (Table 7). 3. Also contains mixed tocopherols. 4. Based on Guidelines to Bone Health and Disease in Cystic Fibrosis Consensus Conference Report June 2002 (Figure 2). 5. ADEK is registered trademark of Axcan Pharma Inc., AquADEKs is a registered trademark of Yasoo Health Inc., Vitamax is a registered trademark of Shear/Kershman Labs. Inc., Poly-Vi-Sol Drops is a registered trademark of Mead Johnson and Company, Centrum is a registered trademark of Wyeth Consumer Care. Table reproduced with permission of SourceCF Inc., a subsidiary of Eurand Pharmaceuticals, Inc.
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Vitamin A
Vitamin A plays an important role in vision, immunity, lung health, and overall health, yet excessive intake of retinol can cause liver and/or bone complications. Retinol is an acute phase reactant and best measured when the patient is not ill. Liver disease or zinc deficiency can cause low serum retinol levels. The total vitamin A content of CF-specific multivitamins is based on both retinol and beta-carotene. The risk of toxicity is avoided with a higher concentration of betacarotene.
Vitamin E
Water-Soluble Vitamins Deficiency of water-soluble vitamins in CF is rare, but has been reported in patients not receiving multivitamins and/or receiving medications interfering with B vitamins. 30 Over time, patients who have had a resection of the terminal ileum will develop vitamin B12 deficiency requiring supplementation.14
Minerals
Sodium Chloride Persons who have CF lose excessive sodium in their sweat and require supplementation throughout the year, especially in the summer months. Inadequate salt intake can be life threatening and/or result in poor appetite with subsequent poor growth. All infants who have CF and an elevated sweat test are to be supplemented with 12.6 mEq (1/8 teaspoon) of salt daily from birth to 6 months of age at which time the dose is increased to 25.2 mEq (1/4 teaspoon) daily.17 The salt is added in small, frequent amounts to baby formula or applesauce used to dose PERT until the daily dose is met. Salt supplementation is continued until the child is eating a diet rich in salt and added salt. Children and adolescents are to be counseled to consume salt, over and above their usual intake, when participating in physical activity. It may be necessary to add salt to sports drinks to meet sodium chloride needs (1/8 teaspoon to 12 oz). 31 Zinc Pancreatic insufficient infants, prior to treatment with PERT, lose excessive zinc in their stool. Acrodermatitis enteropathica like rash, which resembles a severe rash in the diaper area and the perioral area, is a clinical symptom of zinc deficiency and is treated with PERT and zinc supplementation. More subtle symptoms of zinc deficiency which can be seen at any age include lack of appetite, dysgeusia, poor growth, and compromised immunity. Laboratory studies to determine zinc status are generally uninformative. When zinc deficiency is suspected the usual supplemental dose is 1mg elemental zinc per kilogram daily for 6 months in addition to that contained in the patients daily multivitamin. Over-the-counter infant vitamin drops do not contain zinc. Over-the-counter childrens chewable vitamins and adult formulations contain zinc as do all of the CF-specific multivitamins. When choosing a zinc preparation, it is important to note which zinc salt is in the chosen product so that the correct dose can be determined. For example, zinc sulfate is 23% elemental zinc but zinc gluconate is only 14% elemental zinc.
Optimizing serum vitamin E will prevent the neurological complications once seen in people who have CF. More recently the role of vitamin E as an antioxidant in preserving overall health in CF has been investigated.23 Vitamin E is transported in the body with lipid, including cholesterol. People who have CF often have low cholesterol levels, therefore serum levels should be assessed as a ratio of vitamin E24 to total lipid 25 or to total cholesterol.25 Liver disease can cause low vitamin E levels.
Vitamin D
Persons who have CF are at risk for low serum vitamin D. Current repletion recommendations22 do not correct serum levels in the majority of patients.26 Patients with liver disease may have low vitamin D levels. Serum 25-hydroxyvitamin D [25(OH)D] should be assessed annually, preferably in the late fall and, if necessary, treated daily with D3-cholecalciferol. The exact dose necessary for all patients is unknown at this time; therefore dosage is based on individual need.
Vitamin K
Vitamin K is essential for normal blood clotting and bone health. Persons who have CF are at risk for vitamin K deficiency due to fat malabsorption and routine use of antibiotics. Additionally, any patient who has CF and liver disease is at greater risk for vitamin K deficiency. Clotting time, or PT (prothrombin time), has been the standard test for assessing overall vitamin K nutrition, but a number of studies using PIVKA II provided evidence that in CF, vitamin K deficiency exists in patients with normal PT.2729 Over-the-counter multivitamins contain insufficient vitamin K to meet the needs of persons who have CF. The vitamin K content of CF-specific multivitamins is sufficient for the majority of patients, although some people may require additional supplementation based on laboratory results.
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Iron Iron status in the general population is affected by a number of factors, including dietary intake, blood loss, and medications. For persons with CF, all of these factors, plus malabsorption, hemoptysis, short bowel syndrome, bacterial overgrowth, liver and renal diseases, and chronic inflammation contribute to altered iron status. Patients can have iron deficiency anemia, anemia of chronic disease or a combination of both. Prior to prescribing iron supplementation the form of anemia must be defined. 32 Assessing iron status in CF is complicated by chronic inflammation. Serum ferritin, an acute-phase reactant, may be falsely elevated in CF, thus masking iron deficiency anemia. Measurement of soluble transferring receptor levels may be helpful in diagnosis. Calcium It is important to optimize the calcium intake of persons who have CF. In lieu of specific calcium recommendations for person who have CF, the RD should refer to those in the DRI. The CFF Bone Consensus Report may be referred to for more detail regarding bone health and CF. 22 At a minimum, the adequate intake levels should be achieved in all patients. Magnesium Patients receiving aminoglycosides may require supplemental magnesium. Blood levels should be monitored. 33 Fluoride CF-specific vitamins do not contain fluoride; therefore the patients primary care physician may need to prescribe a supplement if local water is not fluoridated. Assessment Blood levels of fat-soluble vitamins should be measured at diagnosis for patients diagnosed greater than 1 year of age and annually thereafter.13 For newly diagnosed infants, it is recommended that levels of vitamins E, A, and D be assessed 1 to 3 months after starting supplementation and annually thereafter.17 Prothrombin time is insensitive to vitamin K deficiency in CF.27 PIVKA II provides a better indicator of vitamin K nutrition, but laboratory reference standards for full-term infants are not available, and therefore checking PIVKA II levels is not recommended in the newborn period. Serum electrolytes and complete blood count is measured at 2 to 3 months of age and annually or as indicated.17 For children and adolescents assessment of fat-soluble vitamins, including PIVKA II and CBC with differential, is done at diagnosis and annually, unless otherwise indicated.
Laboratory studies for individual micronutrients may be necessary when modifying the treatment care plan, such as starting tube feeding. There is a positive correlation between pulmonary function and weight.12 The CF Foundation recommends the following nutrition goals: Infants: weight for length at the 50th percentile by 2 years of age Children 2 to 20 years of age: BMI percentile at or above the 50th percentile Adults: BMI of 22 for women and 23 for men12 Additionally, children are expected to meet their genetic potential for growth. Therefore, nutrition interventions to reach and maintain weight and growth goals are often necessary. Behavioral interventions for parents, caregivers, and patients may also help improve caloric intake, thus weight gain. 34 Weight percentiles are believed to be at their lowest during the first 2 years of life and early adolescence therefore making aggressive nutrition intervention important during these time periods. 35 For toddlers and older children, initially using high-calorie oral supplements or additives may be indicated. Infant formula can be concentrated or high-calorie modulars added to provide adequate calories. However in some children this may not be sufficient to sustain a desired weight and growth status and enteral feeding may be indicated. There are no specific guidelines regarding when to initiate enteral feeding in the pediatric CF population. The CF Foundation Clinical Practice Guidelines Subcommittee on Growth and Nutrition has determined that for children with growth deficits, oral or enteral supplements should be used to improve the rate of weight gain.12 Enteral tube feeding can be via nasogastric tube, gastrostomy tube, or jejunostomy tube. The nasogastric tube can be inserted and removed daily for short-term use. Adherence to this intervention may prove difficult. A gastrostomy tube may be more appropriate and allow for flexibility of feeding. Feeding via the gastrostomy tube can be intermittent, bolus, or continuous feeds. Continuous feeds generally occur nocturnally. Nighttime feedings allow for regular meal and snack pattern during the day. Enteral tube feeding may be complicated by early morning fullness and vomiting, loss of appetite, and poor body image and self-esteem concerns. The reader is directed to papers related to these concerns. 3537 It is important to strike a balance between initiation of enteral feeding and severity of lung disease to optimize the benefit of the intervention. Feeding via a jejunostomy tube is infrequent in patients
Nutrition Support
330
with CF and usually occurs in patients with significant upper gastrointestinal dysmotility, failure of anti-reflux procedures, intubated patients, and in some postoperative patients. Parenteral nutrition (PN) is considered a more aggressive intervention and not routinely used in the daily management of CF. Persons who are pancreatic insufficient require PERT. Pancreatic damage and destruction occurs in utero or after birth, resulting in the absence of bicarbonate rich and enzyme-containing pancreatic juice in the duodenum to help digest food. PERT has played a pivotal role in improving the care and outcome of persons with CF. 38 There are a variety of enzymes available with subtle differences among brands and forms. As of this writing the most commonly used enteric-coated enzymes in the United States are: Creon by Solvay; Pancrecarb by Digestive Care; Zenpep by Eurand; and Ultrase by Axcan, Inc. Due to changes in PERT content mandated by the Food and Drug Administration and to be put in place by April 2010 the reader is referred to the manufacturers Web site for details regarding enzyme content. A non-enteric-coated form of enzyme, such as Viokase by Axcan, is subject to destruction by the acidic gastric environment.8 Microspheres and microtablets are enteric-coated to protect the enzyme from the acidic gastric milieu. The enteric coating allows for activation to occur in the alkaline pH of the duodenum, past the acidic gastric contents. If the pancreas is unable to deliver bicarbonate pancreatic juice to the duodenum, gastric acid from the stomach is not neutralized resulting in an acidic duodenal pH. Acidity in the gastrointestinal tract may prevent or retard dissolution of enteric-coated pancreatic enzymes. 39 If activation does not take place in the small intestine, absorption of macro- and micronutrients cannot occur. Additional medications which reduce or block acid production and raise the duodenal pH may be needed to enhance PERT effectiveness. Even so, all nutrients may not be fully absorbed. If fat malabsorption persists, consider lack of bile acids an etiology. The pancreatic enzyme replacement products contain lipase, protease, and amylase for digestion of fat, protein, and carbohydrates, respectively. Enzyme activity or potency is based on the amount of lipase per capsule or gel cap. For example, for Creon 5 the 5 refers to 5,000 lipase units per capsule. Creon 5 also contains 3,600 amylase units and 200 protease units. PERT starting dose for infants of 2,000 to 4,000 units of lipase per 120 mL of formula or breast milk is recommended. 39 Though dosing is best calculated using units of
Pancreatic Enzymes
lipase per gram of fat ingested, it is perhaps more practical to use a dosing schedule with weight-adjusted guidelines. 39 For children less than 4 years of age the recommendation is to began at 1,000 lipase units per kilogram per meal and over 4 years of age 500 lipase units per kilogram per meal. Dosing for snacks is routinely half of usual meal dose. The recommendations are not to exceed a dose of 2,500 units of lipase per kilogram body weight per meal or 10,000 lipase units per kilogram per day and are based on a usual intake of 3 meals plus 2 snacks per day. 39 Persons with CF should be viewed individually in regards to dosing and response to PERT. Careful monitoring of growth, stool pattern, and the absence or presence of gastrointestinal symptoms is necessary to determine the adequacy of therapy. For infants and children unable to swallow enzyme capsules, the enzyme beads are removed from the capsule(s) and mixed with a small amount (1/8 to 1/2 teaspoon for infants, more for children) of applesauce and given at the time of each feeding.8 PERT is given at the beginning of the feeding or meal. If mealtime is more than 30 minutes, then it is recommended that the dose be split and given at the beginning and halfway during the meal. For infants, to avoid mucosal erosion, the mouth should be checked for beads following each feeding. The infants perianal area may require protection against enzyme excreted in the stool. Patients can be instructed to apply a thick layer of barrier cream to protect the skin around the anus. Persons with CF who receive nasogastric tube, gastrostomy tube, or jejunostomy tube feedings need PERT supplementation. The amount and type of enzyme given depends on the type of formula and the ability of the patient to take enzymes orally. In general a meal dose of PERT is given before and after night tube feeds when using an intact formula.13 Some patients may benefit from an additional dose midway during the feedings at night. During the day PERT is best given before each bolus and this dose is dependent on the amount and type of fat in the bolus. Enzymes can be administered via the gastrostomy tube if the size of the bead is small enough to go through the tube and not cause clogging. PancrecarbFour by Digestive Care contains microspheres/microtabs that fit through a gastrostomy tube. The reader is referred to the manufacturers Web site for more information.
Eating Behaviors and CF
The importance of nutrition in CF is recognized by the CF Care Team and by parents of children who have CF. Pressure surrounding the importance of nutrition includes: improving and maintaining weight and adherence to PERT
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and supplemental vitamins and/or minerals. As a result, mealtimes can become challenging. Parents of children with CF commonly report mealtime behavior problems including: poor appetite, avoidance of eating by talking, and spitting out food. 34 A negative correlation between the childrens caloric intake and the number of problematic mealtime behaviors has been identified.40 Young children appear to be particularly at risk for behavioral difficulties at mealtime if their parents feel unusually concerned about their childrens health and caloric/food intake.40 For parents of infants with CF, the transition from formula to solids may present a challenge and parents may need guidance surrounding positive eating behaviors and high-calorie solids. The toddler stage is typically characterized by changing food interests and neophobia (fear of new foods), which for children with CF may complicate the selection of high-fat foods and food additives. 34 Parents may benefit from guidance to prevent and/or manage food refusal behaviors. Anticipatory guidance might include education centered on avoidance of parental behaviors that may inadvertently reinforce noneating behaviors and advice directed toward reinforcement of desired behaviors through praise and limit setting.40 As children become adolescents, a struggle for control and independence may ensue. In this period, the challenge may be providing education and direction so that the child/ adolescent makes appropriate choices that improve or maintain optimal nutrition status. Birch has stated that the foundation for teen and adult eating styles is laid in childhood as the parent and child work through issues of control regarding feeding andeating.41
levels, prolonged corticosteroid usage, delayed puberty, low calcium intake, history of fractures, family history of osteoporosis, significant lung disease, or liver disease. 22 Normative data are available for DEXA scans for children above 3 years of age. Treatment includes optimizing nutrition (calcium, vitamins D and K, and nutrition status), increasing physical activity, controlling underlying inflammation, decreasing use of corticosteroids as indicated, and addressing any hormone deficiencies. In adults bisphosphonates have been used in patients with osteoporosis and stress fractures, but in children there are limited data on their safety.
CF-Related Diabetes
CF-related diabetes (CFRD) shares features of both type 1 and type 2 diabetes, but it is a distinct clinical entity.43 Diabetes occurs when people either are insulin deficient or insulin resistant. Individuals with CFRD are insulin deficient as a result of destruction by fibrosis or scarring of beta cells in the pancreas that produce insulin.44 Glucose metabolism is strongly influenced by factors unique to CF, including undernutrition, chronic and acute infection, elevated energy expenditure, glucagon deficiency, malabsorption, abnormal intestinal transit time, and liver dysfunction. These factors are not static and may fluctuate over time in CF.43 Retrospective studies have shown that pulmonary decline and weight loss begin 2 to 4 years before diagnosis of CFRD.43 Symptoms of CFRD include polydipsia, polyuria, weight loss or inability to gain weight despite aggressive nutrition intervention, poor growth, and poor progression of puberty or unexplained chronic decline in pulmonary function.43 Any patient with these symptoms should be screened for CFRD using the CF Foundation recommendation.43 In the routine management of CF, casual glucose levels are measured annually. If the person has a random blood glucose level of 126 mg/dL, further workup for CFRD should be conducted. Tests include fasting blood glucose or 2-hour oral glucose tolerance test (OGTT). The CF Foundation assembled a consensus conference on CFRD and issued recommendations for monitoring glucose intolerance; refer to these recommendations for further screening of CFRD.43 When discrepancies exist between the nutrition recommendations of the 2 diseases, the CFRD recommendations supersede those for type 1 and type 2 diabetes. The CF Foundation Consensus Statement on Diagnosis, Screening, and Management of Cystic Fibrosis Related Diabetes Mellitus43 currently promotes these 2 principles
Nutrition-Related Cystic Fibrosis Complications

Osteoporosis or Bone Disease
Bone disease is increasingly recognized in persons who have CF. Decreased bone density, fractures, and kyphosis occur earlier in persons with CF than in healthy controls.42 The incidence of osteoporosis and fracture increases with increasing age and are prevalent in adult patients and in those with end-stage lung disease. Predisposing factors include inflammatory cytokines, vitamin D deficiency, inadequate calcium intake, use of corticosteroids, delayed puberty, short bowel syndrome, and liver disease. It is recommended that patients 8 years of age or older with the following risk factors get a baseline dual energy X-ray absorptiometry (DEXA) scan: small body size, low weight for height, decreased physical activity, low vitamin D
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for nutrition management of CFRD: Achievement of optimal nutrition status through intake of sufficient calories is critical for survival in persons with CF. Near-normalization of blood glucose levels is necessary to ensure optimal nutritional and metabolic status Diet guidelines for type 1 and type 2 diabetes are not recommended for people who have CFRD.43 Ideally the person with CFRD is to maintain/achieve a healthy body weight and is encouraged to continue a high-calorie, highfat and high-sodium diet. Carbohydrate counting, meal timing, and insulin therapy are significant interventions for management of CFRD.16
Lung Transplantation
Lung transplantation remains the most aggressive therapy for end-stage lung disease.45 Persons with CF are candidates for lung transplantation when they exhibit severely reduced lung function and progressive deterioration in their health and quality of life.16 For children and adults, the largest obstacle to long-term survival remains chronic allograft rejection secondary to the development of bronchiolitis obliterans. Common weight criteria for adults are 80% to 130% IBW or BMI of 18.5 to 30 kg/m. There is no pediatric weight criterion. Further research in the area of weight and nutrition status is needed in the pediatric lung transplant population.
in the ileocecal junction resulting in abdominal pain and vomiting. Treatment/prophylaxis consists of optimizing fluid and electrolyte intake, correction of any malabsorption and the use of laxatives/stool softeners, such as polyethyleneglycol. Prevention is vital, and an attempt to find the precipitating factor for every episode should be made. Celiac disease, inflammatory bowel disease, eosinophilic esophagitis, and GI malignancies may also occur in CF. Patients with pancreatic sufficiency are at risk for recurrent bouts of pancreatitis. Over time some of these patients may become PI. The most common liver lesion in patients with CF is fatty liver. Also seen are hepatitis, fibrosis, and cirrhosis with portal hypertension. Gallbladder dysfunction is frequent and a non-functioning gallbladder or gallstones can be seen on ultrasound examination. Biliary dyskinesia can result in right upper quadrant abdominal pain. Some patients with liver disease will progress to end-stage liver disease and develop complications from cirrhosis (portal encephalopathy and uncontrolled variceal bleeds) and require liver transplantation.
Other Chronic Lung Diseases

Overview and Pathophysiology
Chronic lung disease (CLD) is seen in premature infants who have significant respiratory disease, in infants and children with congenital heart disease who need ventilator support in the neonatal period, in patients with difficult-tomanage asthma or reactive airways disease (RAD), and in patients with chronic respiratory insufficiency requiring ventilator support.
Gastrointestinal
Gastrointestinal (GI) manifestations are frequently seen in persons with CF and involve all parts of the GI tract.46 Gastroesophageal reflux (GER) occurs at all ages and the incidence varies between 25% and 100% depending on the study. Complications of GER include feeding disorders, decreased caloric intake, failure to thrive, apnea in infants, vomiting, esophagitis, worsening of lung disease, esophageal strictures, and Barretts esophagus. Reflux can be a significant problem in lung transplant recipients and is associated with rejection in the posttransplant period. Often a fundoplication is recommended in the pretransplant period. Gastroparesis and constipation can be seen in CF and the latter may be 3 times more frequent than DIOS. Bacterial overgrowth occurs in up to 60% of patients.47 Predisposing factors include frequent antibiotic use, intestinal dysmotility, history of previous GI surgery, and sticky intestinal secretions that trap bacteria. DIOS is seen in all persons with CF, not just in those with PI. Dehydration of the intestinal secretions, coupled with electrolyte imbalances and sticky mucus, and poor motility lead to the accumulation of stool
Bronchopulmonary Dysplasia
Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that develops in preterm infants given positive pressure ventilation and oxygen. The pathophysiology is complex and due to small airway damage, abnormal alveolar development, and decreased surface area for gas exchange.48 Additionally there is damage to small blood vessels in the lungs and secondary damage to the heart and brain. BPD is most commonly seen in preterm infants with a birth weight of more than 1250 g and 30 weeks gestational age. Males tend to be more affected. Surfactant therapy is used soon after birth to prevent lung damage. Energy requirements are increased and are in the range of 125 to 150 kcal/kg/d.49 Vitamin A supplementation is important and often used in the neonatal intensive care unit to prevent BPD. Vitamin E supplementation is not helpful. These patients also have large insensible water losses and need extra fluid which results in
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opening of the patent ductus arteriosus and further stress on the lungs. Fluid restriction often results in inadequate nutrition intake. Calcium status is poor due to decreased intake and increased losses from diuretics. Adequate intakes of calcium and phosphorus, protein (33.5 g/kg/d), and antioxidants (copper, zinc, and manganese) are required and it is important to avoid excessive carbohydrate intake because it can impact on pulmonary function by altering the respiratory quotient. These patients often receive corticosteroids and diuretics for treatment of the lung disease often with significant consequences: increased sodium, potassium and magnesium losses, kidney stones, gallstones, and bone disease. Infants with severe BPD are at high risk for the following problems during the first 2 years of life: pulmonary infections, frequent hospitalizations, RAD, and more frequent visits to the doctor. These patients also may have developmental delay, poor muscular development, poor feeding skills, poor growth, and chronic lung disease. Infants with BPD often have impaired weight for length and problems with oxygen diffusion resulting in a chronic oxygen requirement. Caloric needs are high because catch-up growth is often a goal. The co-existence of reflux and BPD can exacerbate poor oral motor function and can worsen feeding problems in patients with developmental delay. Reflux can also worsen lung disease. Supplemental feeds are often required.
and omega-3 fatty acids has been associated with a reduction in symptoms and reduced development of asthma in those with atopy. 52 In children a linear association between obesity (increased BMI) and asthma has been noted with a 6% increase in prevalence per unit increase of BMI. 53
Technology Dependent
Children with chronic respiratory failure may require chronic ventilatory support. At-risk children include those with: neuromuscular dystrophy, spinal muscular atrophy, Duschennes muscular dystrophy, spinal cord injuries, BPD, congenital diaphragmatic hernia, severe lung malformations, congenital hypoventilation syndrome, and myelomeningiocoele. From the above diagnoses, of patients who require ventilator support, patients with BPD and neuromuscular dystrophy are the most frequent. Respiratory support can be non-invasive (BIPAP) or invasive (tracheostomy and ventilator). The pathophysiology includes respiratory insufficiency (seen in BPD and pulmonary hypoplasia), secondary damage to the lungs from severe cardiac disease resulting in decreased surface area, decreased oxygen absorption, increased carbon dioxide retention, poor lung development, small-volume lungs, and insufficient vascular bed. There may also be decreased central drive for respiration as seen in persons with congenital central hypoventilation syndrome. Since these patients have decreased work of breathing, their energy requirements are subsequently decreased. If careful attention is not paid to their nutrition regimens, they can have excessive weight gain which can further impact their respiration status negatively. Often, in an attempt to decrease calories, overall nutrient intake, especially protein and mineral intake, suffers. These patients may also be at risk for bone disease due to decreased weight bearing and micronutrient deficiency (vitamin D and calcium).
Asthma
Asthma or RAD is the most common cause of hospital admissions in children. It is a chronic pediatric lung disease where there is chronic inflammation of the airways involving eosinophils, mast cells, T lymphocytes, macrophages, neutrophils, and epithelial cells. Additionally there is variable air flow obstruction and increased bronchial responsiveness to a variety of environmental stimuli. The presence of airway edema and mucus contributes to the obstruction and bronchial reactivity that is seen. 50 Environmental triggers affect the normal development of the respiratory and immune systems in genetically predisposed individuals. 51 Patients often require chronic inhaled or pulses of systemic corticosteroids. Excessive oral cortico steroid use over time can result in growth failure, fluid and sodium retention, a voracious appetite, excessive weight gain, hypertension, glucose intolerance, and obesity. There appears to be considerable variation in the side effects of inhaled corticosteroids. Growth, puberty and bone health can be affected depending on the duration and dose. 52 Early data suggest the use of antioxidants, Lactobacillus,
For children with BPD and asthma it is best to monitor growth on a regular basis. Anthropometrics provide critical information regarding the growth of the infant or child. In the infant with BPD, factors that may increase caloric requirements include increased basal metabolic rate, increased work of breathing, chronic illness or infections, and respiratory distress or metabolic complications.54 The infant may struggle with fluid sensitivity, which may limit the intake of calories and nutrients. Infants may have interrupted feeding skill development, therefore may be poor oral feeders.54
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Nutrition Recommendations
In critically ill infants with BPD, efforts are made to prolong life. Caloric provision is often relegated to secondary importance, compared to pulmonary edema, reduced cardiac output, and electrolyte imbalance. 54 Please refer to the section on nutrition in the neonatal intensive care unit for more detailed information on caring for the critically ill infant. As the infants condition improves, concerns regarding fluid overload and thermal losses remain. Continued monitoring of intake, growth, and development is essential. Individualizing macronutrient needs based on the patients growth in relation to the goal is best. Specific to the infant with BPD, calcium and phosphorous may be further compromised by diuretic therapy, steroid therapy, long-term use of parenteral nutrition, and feeding delays. 54 For further information on micronutrients, please refer to the vitamin and mineral chapters (Chapters 6, 7, and 8). A diet providing appropriate amounts of macro- and micronutrients based on the U.S. Department of Agriculture dietary guidelines for age is recommended. Increased appetite, abdominal fat accumulation, sodium and fluid retention, and steroid-induced glucose intolerance are common side effects of oral corticosteroid therapy. Monitoring weight and linear growth on a regular basis is important. Nutrition support is discussed in Chapter 34.
Bone Health in Chronic Lung Disease

Pharmacologic therapy is an element in treating asthma. The use of oral and high-dosed inhaled steroids has an effect on nutrition status. Chronic corticosteroid use does induce osteoporosis. 54 Therefore, adequate amounts of calcium and vitamin D supplementation are vital. To assess adequacy of calcium and vitamin D include diet assessment, vitamin D level, and DEXA scan. Normative data are available for DEXA scans for children above 3 years of age.
Summary
Nutrition is an important part of the management of the child who has chronic lung disease. In general the goal is normal growth and development and correction of nutrition abnormalities that result from the underlying medical condition and the therapies used to treat the disease. Good nutrition status has been associated with improved lung function and outcomes in patients with cystic fibrosis.
1. Pancreatic enzymes are available in non-enteric-coated and enteric-coated form. How does the enteric coating help with nutrient absorption? A. Enteric coating is subject to destruction by the harsh acid-peptic gastric environment B. Allows the enzymes to get through the build-up of thick mucus in the pancreatic ducts C. Allows for the activation to occur in the alkaline pH of the duodenum, past the gastric contents of the stomach 2. Which fat-soluble vitamin blood levels should be checked in persons with CF and why? A. Vitamins A, D, K, and E and zinc. These are insensitive markers in CF. B. Vitamins A, D, E, and PIVKA II, to assure adequacy. C. Vitamins A, D, E, and PIVKA II. These are insensitive markers in laboratory tests. 3. A baseline DEXA scan is recommended at the age of 8 years, especially if risk factors are present. Which of the following set of risk factors are necessary to be aware of? A. Small body size, low weight for height, decreased physical activity, low vitamin D levels, cortico steroid usage, delayed puberty, low calcium intake, history of fractures, family history of osteoporosis, significant lung disease or liver disease B. Increasing physical activity, large body frame, asthma, low calcium intake C. Increasing physical activity, large body frame, low weight for height, history of fractures, cortico steroid use, delayed puberty, liver disease 4. In BPD, energy requirements are elevated. What other nutrition treatments might be beneficial? A. Optimize vitamin E in nutrition intake B. Supplement vitamin A; provide appropriate fluid intake and adequate amounts of calcium, phosphorous, protein, and antioxidants; and avoid excessive intake of carbohydrates C. Provide high levels of carbohydrates and fluids See p. 487 for answers.
References
1. Riordan J, Rommens J, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245(4922):10661073. 2. Cystic Fibrosis Foundation Patient Registry. 2007 Annual data report to the center directors, Bethesda, MD.
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3. Farrell PM, Rosenstein BJ, White TB, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation Consensus Report. J Pediatr. 2008;153(2):S4S14. 4. Amin R, Ratjen F. Cystic fibrosis: a review of pulmonary and nutritional therapies. Adv Pediatr. 2008;55:99121. 5. Walker WA, Watkins JB, Duggan, C. Nutrition in Pediatrics: Basic Science and Clinical Applications. 3rd ed. Hamilton, London: BC Decker Inc; 2003:672. 6. Tiddens H, Rosenfeld M. Respiratory manifestations of cystic fibrosis. In: Taussig LM, Landau LI, eds. Pediatric Respiratory Medicine. 2nd ed. Mosby Elsevier; 2008;871887. 7. Gaskin K, Allen J. Exocrine pancreatic disease including cystic fibrosis. In: Walker WA, Watkins JB, Duggan C, eds. Nutrition in Pediatrics. Hamilton, London: BC Decker Inc; 2003:671685. 8. American Academy of Pediatrics, Committee on Nutrition. Kleinman RE, ed. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: The American Academy of Pediatrics; 2009. 9. Konstan MW, Butler SM, Wohl MEB, et al. Growth and nutritional indexes in early life predict pulmonary function in cystic fibrosis. J Pediatr. 2003;142:624630. 10. Stallings VA, Tomezsko JL, Schall JI, et al. Adolescent development and energy expenditure in females with CF. Clin Nutr. 2005;24:737745. 11. Trabulsi J, Ittenbach RF, Schall JI, et al. Evaluation of formulas for calculating total energy requirements of preadolescent children with cystic fibrosis. Am J Clin Nutr. 2007;85:144151. 12. Stallings VA, Stark LJ, Robinson KA, Feranchk AP, Quinton H; Clinical Practice Guidelines in Growth and Nutrition Subcommittee (Ad Hoc Working Group). Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc. 2008;108:832839. 13. Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2002;35:246259. 14. Australasian Clinical Practice Guidelines for Nutrition and Cystic Fibrosis, 2005. www.cysticfibrosis.org.au/pdf/CF_ Nutrition_Guidelines.pdf. Accessed December 2008. 15. Maqbool A, Schall JI, Garcia-Espana JF, et al. Serum linoleic acid status as a clinical indicator of essential fatty acid status in children with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2008;47(5):635644. 16. Gottschlich MM. Pulmonary disease. In: Gottschlich MM. The Science and Practice of Nutrition Support: A Core-Based Curriculum. Dubuque, IA: Kendall/Hunt Publishing Co: 2001:501516. 17. Borowitz D, Robinson KA, Rosenfeld M, et al. Management of infants diagnosed with cystic fibrosis: A Cystic Fibrosis Foundation workshop report. J Pediatr. Accepted for publication. 18. Lancellotti L, DOrazio C, Mastella G, Lippi U. Deficiency of vitamins E and A in cystic fibrosis is independent of pancreatic function and current enzyme and vitamin supplementation. Eur J Pediatr. 1996;155:281285.
19. Feranchak AP, Sontag MK, Wagerner JS, Hammond KB, Accurso FJ, Sokol RJ. Prospective, long-term study of fatsoluble vitamin status in children with cystic fibrosis identified by newborn screen. J Pediatr. 1999;135(5):601610. 20. Krebs NF, Sontag M, Accurso FJ, Hambidge KM. Low plasma zinc concentrations in young infants with cystic fibrosis. J Pediatr. 1998;133(6):761764. 21. Sinaasappel M, Stern M, Littlewood J, Wolfe S, Steinkamp G, Heijerman HGM. Nutrition in patients with cystic fibrosis: a European consensus. J Cyst Fibros. 2002;1:5175. 22. Aris RM, Merkel PA, Bachrach LK, et al. Consensus Statement: Guide to bone health and disease in cystic fibrosis. J Clin Endocrinol Metab. 2005;90:18881896. 23. Wood LG, Fitzgerald DA, Lee AK, et al. Improved antioxidant and fatty acid status of patients with cystic fibrosis after antioxidant supplementation is linked to improved lung function. Am J Clin Nutr. 2003;77:150159. 24. Horwitt MK, Harvey CC, Dahm CH Jr, Searcy MT. Relationship between tocopherol and serum lipid levels for determination of nutritional adequacy. Ann NY Acd Sci. 1972;203:223236. 25. Huang SH, Schall JI, Zemel BS, Stallings VA. Vitamin E status in children with cystic fibrosis and pancreatic insufficiency. J Pediatr. 2006;148:556559. 26. Green D, Carson K, Leonard A, et al. Current treatment recommendations for correcting vitamin D deficiency in pediatric patients with cystic fibrosis are inadequate. J Pediatr. 2008;153:554559. 27. Beker LT, Ahrens RA, Fink RD, et al. Effect of vitamin K1 supplementation on vitamin K status in cystic fibrosis patients. J Pediatr Gastroenterol Nutr. 1997;24:512517. 28. Wilson DC, Rashid M, Durie PR, et al. Treatment of vitamin K deficiency in cystic fibrosis: effectiveness of a daily fat-soluble vitamin combination. J Pediatr. 2001;138:851. 29. Conway SP, Wolfe SP, Brownlee KG, et al. Vitamin K status among children with cystic fibrosis and its relationship to bone mineral density and bone turnover. Pediatrics. 2005;115:13251331. 30. McCabe H. Riboflavin deficiency in cystic fibrosis: three case reports. J Hum Nutr Dietet. 2001;14:365370. 31. Kriemler S, Wilk B, Schurer W, Wilson W, Bar-Or O. Preventing dehydration in children with cystic fibrosis who exercise in the heat. Med Sci Sports Exerc. 1993;31:774779. 32. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005; 352:10111023. 33. vonVigier RO, Truttmann AC, Zindler-Schmocker K, et al. Aminoglycosides and renal magnesium homeostasis in humans. Nephrol Dial Transplan. 2000;15:822826. 34. Powers SW, Byars KC, Mitchell MJ, Patton SR, Schindler T, Zeller MH. A randomized pilot study of behavioral treatment to increase caloric intake in toddlers with cystic fibrosis. Childrens Health Care. 2003;32(4):297311. 35. Erksine JM, Lingard C, Sontag M. Update on enteral nutrition support for cystic fibrosis. Nutr Clin Pract. 2007;22:223232. 36. Abbott J, Conway S, Etherington C, et al. Perceived body image and eating behavior in young adults with cystic fibrosis and their healthy peers. J Behav Med. 2000;23:501517.
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37. Gilchrist FJ, Lenney W. Distorted body image and anorexia complicating cystic fibrosis in an adolescent. J Cystic Fibros. 2008;7(5):437439. 38. Littlewood JM. The historical development of nutritional and dietetic management of cystic fibrosis. Based on a paper delivered at the XIIIth International Cystic Fibrosis Congress. Stockholm, Sweden; June 2000. Available from http://www. cysticfibrosismedicine.com. 39. Borowitz DS, Grand RJ, Drurie PR, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. J Pediatr. 1995;127(68):14. 40. Crist W, McDonnell P, Beck M, Gillespie CT, Barrett P, Mathews J. Behavior at mealtimes and the young child with cystic fibrosis. J Dev Behav Pediatr. 1994;15(3):157161. 41. Birch LL, Fischer JA. Appetite and eating behavior in children. Pediatr Clin North Am. 1995;42(4):931953. 42. Henderson RC, Spector BB. Kyphosis and fractures in children and young adults in cystic fibrosis. J Pediatr. 1994;25(2):208212. 43. Moran A, Hardin D, Rodman D, et al. Diagnosis, screening and management of cystic fibrosis related diabetes mellitus: a consensus conference report. Diabetes Res Clinical Practice. 1999;45:6173. 44. ORiordan S, Robinson P, Donaghue KC, Moran A. Management of cystic fibrosis-related diabetes. Pediatr Diabetes. 2008;9(part I):338344. 45. Thiou TG, Cahill BC. Pediatric lung transplantation for cystic fibrosis. Transplantation. 2008;86(5):636637.
46. Mascarenhas MR. Treatment of gastrointestinal problems in cystic fibrosis. Curr Trea Options Gastroenterol. 2003;6(5):427441. 47. Fridge JL, Conrad C, Gerson L, Cox K. Risk factors for small bowel bacterial overgrowth in cystic fibrosis. J Pediatr Gastroenterol Nutr. 2007;44(2):212218. 48. Rajiah P. Bronchopulmonary dysplasia [emedicine website]. June 9, 2006. Available at http://emedicine.medscape.com/ article/406564. Accessed December 2008. 49. Cox JH. Bronchopulmonary dysplasia. In: Groh-Wargo S, Thompson M, Cox JH, eds. Nutritional Care for High-Risk Newborns. Chicago, IL: Precept Press Inc; 2000. 50. Morris MJ. Asthma [emedicine website]. July 10, 2008. Available at http://emedicine.medscape.com/article/29630. Accessed December 2008. 51. Sly PD. Asthma: Disease mechanisms and cell biology. In: Taussig LM, Landau LI, eds. Pediatric Respiratory Medicine. 2nd ed. Mosby Elsevier; 2008;791804. 52. Landau LI, Martinez FD. Asthma: Treatment. In Pediatric Respiratory Medicine. 2nd ed. Mosby Elsevier; 2008:829844. 53. Sithole F, Douwes J, Burstyn I, et al. Body mass index in childhood: a linear association. Asthma. 2008;45(6):473477. 54. Queen Samour P, King K. Pulmonary diseases. In: Queen Samour P, King K. Handbook of Pediatric Nutrition. 3rd ed. Sudbury, MA: Jones and Bartlett Publication;2005:307349.
Organ Transplantation
Anita Nucci, PhD, RD, LD, Sharon Strohm, MBA, RD, LDN, Neelam Katyal, MS, RD, LDN, and Beth Lytle, RD, LDN
29
CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337 Indications for Organ Transplantation . . . . . . . . . . . . . . . 338 Nutrition Assessment Before Transplant . . . . . . . . . . . . . 339
Anthropometric Assessment Physical Examination Biochemical Tests Macro- and Micronutrient Requirements Feeding History
Learning Objectives
Nutrition Management After Transplantation . . . . . . . . . 340

Intestine Liver Kidney Heart Lung
1. Describe the indications for pediatric intestine, liver, kidney, heart, and lung transplantation. 2. Describe the key nutrition factors that should be examined prior to solid organ transplantation in children. 3. Explain the posttransplant nutrition management issues related to each of the following solid organs: intestine, liver, kidney, heart, and lung. 4. State the current outcomes, including morbidity and mortality, of childhood organ transplantation. Transplantation of organs such as the liver, kidney, and heart has been performed successfully in children for several decades and comprises 30%, 45%, and 16% of all pediatric transplants, respectively.1 The number of intestinal transplants performed annually has increased considerably over the last 20 years and reductions in both morbidity and mortality have been observed. However, neither the number of children receiving a lung transplant (~2% of all transplants in children) nor the survival rate after lung transplantation has changed in the last decade.1 Despite differences between children and adults in the causes of organ failure that result in organ transplantation, and response to and complications associated with immunosuppression, graft survival rates are similar.1 Advances in surgical techniques and the emergence of tacrolimus as the primary therapeutic immunosuppressive agent in organ transplantation has improved survival.13 Even with these improvements, postoperative nutrition management remains challenging for some organ transplant recipients as complications may result in the need for modifications in nutrition therapy. Coordinated interdisciplinary team
337
Introduction
Food Safety. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345 Current Status of Organ Transplantation inChildren . . . 346
338
management of the pediatric transplant patient is necessary to address the many issues that may arise, including compliance with medication and nutrition regimens. Long-term outcomes such as adequate growth and development and improved quality of life are still being examined. The diagnoses that lead to the majority of intestine, liver, kidney, heart, and lung transplants in children are shown in Table 29-1.1 Children with irreversible intestinal failure may be considered as candidates for intestinal transplantation. Patients are considered to have intestinal failure when fluid, electrolyte, and nutrition status cannot be maintained without parenteral nutrition (PN) and this dependence on PN has led to complications that include catheter infections, sepsis, loss of venous access, cholestatic liver disease, and in some instances, liver failure.4,5 The initial evaluation of potential transplant candidates includes determination of venous access, functional status of the intestine (including motility studies), length of the intestine, degree of liver damage from PN, and the involvement of other organs in the disease. This information helps the medical team to identify which type of allograft the patient will need. Allograft options include an isolated small intestine, liver/ small intestine, or a multivisceral graft (liver, stomach, duodenum-pancreas, and small bowel).
Table 29-1 Diagnoses That Lead to the Majority of Intestine, Liver, Kidney, Heart, and Lung Transplants in Children
Organ Diagnoses
Indications for Organ Transplantation
Intestine
Liver
Kidney
Heart Lung
Gastroschisis Midgut volvulus Necrotizing enterocolitis Intestinal pseudoobstruction Biliary atresia Acute hepatic necrosis Metabolic disease Aplasia/hypoplasia/dysplasia Obstructive uropathy Focal segmental glomerular sclerosis Congenital disease Cardiomyopathies Cystic fibrosis Congenital heart disease (primarily those < 1 year of age) Primary pulmonary hypertension
Liver transplantation is the only therapy available for children with end-stage liver disease. Complications while awaiting liver transplantation may include gastrointestinal bleeding and encephalopathy, jaundice, pruritus, and
ascites. Growth failure is also common.1 Approximately half of pediatric liver transplant recipients receive a standard orthotopic liver transplant with a whole organ. Younger children more often receive a split-liver transplant from a deceased donor or a reduced size graft from a deceased or living donor. Kidney transplant is the most common of solid organ transplants. It is a reasonably safe and cost-effective treatment for end-stage renal disease (ESRD). Optimal nutrition status prior to transplant correlates favorably with posttransplant outcomes. ESRD in infants and young children is most commonly due to congenital anomalies. Forty-five percent is related to renal hypoplasia or dysplasia, obstructive or reflux uropathy due to posterior urethral valves, agenesis or abdominal muscular defects (prune belly syndrome), or pyelonephritis. Renal failure in older children is generally caused by acquired renal disease, known as glomerulonephritis. In infants with ESRD, early transplantation should be considered to avoid risks that can develop from chronic uremia and dialysis.6 In patients who are awaiting a renal transplant, there is a higher mortality rate for those who are on chronic dialysis than those who are not. Children with renal disease may receive a kidney transplant prior to the time when the disease becomes end-stage. Complications from chronic renal insufficiency include failure to thrive, delayed psychomotor development, hypervolemia, hyperkalemia, and metabolic bone disease. Children who have received a kidney transplant have improved survival as well as improved rehabilitation compared to children on chronic dialysis.7 The majority of children undergoing orthotopic heart transplantation have congenital heart disease. While end-stage cardiomyopathy and congenital heart disease with ventricular failure are the primary reasons for transplantation,1 a subset of children are transplanted due to protein-losing enteropathy (PLE) after a Fontan procedure. PLE eventually results in low serum blood protein with subsequent ascites and edema as a result of the inability to maintain fluid within the vascular space of the abdomen and peripheral tissues, respectively. Other symptoms such as diarrhea and malnutrition may also be present. The primary reason for lung transplantation, particularly in children over the age of 1 year, is cystic fibrosis (CF) followed by idiopathic pulmonary arterial hypertension. Heart-lung transplantation has become less common in recent years due in part to the decreased availability of both organs with the increased use of isolated heart transplants. Additional reasons include improved surgical technique for isolated lung transplantation and the recognition that
ORGAN TRANSPLANTATION
339
heart-lung transplants are not necessary for children with these disorders. It is, however, indicated in situations where end-stage lung disease is coupled with severe dysfunction of the left ventricle.8
Physical Examination
Along with anthropometric measurement, a child should also be given a physical examination. This preliminary look may then lead to more detailed evaluation, if necessary. Hair that is sparse or easily breakable may indicate malnutrition. Dry skin may be a sign of vitamin A or folic acid deficiency and skeletal changes may point to problems with vitamin D or calcium metabolism.
Nutrition Assessment Before Transplant

Anthropometric Assessment
A thorough nutrition assessment pretransplant is critical to help maximize a childs nutrition status and increase the chance of a successful outcome after transplant. Anthropometric measurement in children is a valuable tool because it is easily obtained and age-specific standards are available. Growth measures should be plotted and followed over time for all transplant candidates. These include weight, length or height, weight for length or height, and occipital head circumference (if < 3 years of age). If the patient is > 2 years of age, body mass index (BMI) should also be calculated and monitored. Adjustments in energy intake should be made to maintain growth velocity, unless contraindicated due to the childs condition. Measurement of triceps skinfold thickness and mid-arm circumference may also be followed. However, it is important to use appropriate instruments, the same observer, and serial measurements to interpret these results.
Biochemical Tests
Monitoring of laboratory tests helps the clinician to adjust the provision of nutrients and electrolytes in the diet, enteral feedings, intravenous replacement fluids, and/or PN both pre- and posttransplant. Table 29-2 shows the basic biochemical tests that are often monitored before transplant by type of solid organ.913
Macro- and Micronutrient Requirements

Calorie requirements for children on oral or enteral nutrition (EN) are usually assessed based on the dietary reference intakes (DRIs) for age with modifications made to maintain or accelerate growth and development.14 Indirect calorimetry remains the best and most accurate way to assess basal metabolic requirements. However, this option is often not practical to perform, or it may produce unreliable results
Table 29-2 Biochemical Tests Monitored Before Transplant by Type of Solid Organ913
Biochemical Tests Intestine Liver Kidney Heart Lung
CBC with platelets PT/PTT Electrolytes CO2 BUN and creatinine Calcium, phosphorous, magnesium Glucose Liver function tests Alkaline phosphatase Amylase, lipase Albumin Triglyceride Vitamins
X X X X X X X X X X X X A E D (25 and 1,25 OH) B12 RBC folate Zn Cu Se Mn Carnitine
X X X X X X X
X X X X X
X X X X X
X X X X X X X X X X A E D (25-OH)
X X X A E D (25-OH) if no renal impairment D (1,25 OH) if renal impairment X X
Minerals
Other
PTH
Glycosylated hemoglobin
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if a child is mechanically ventilated and there are multiple air leaks. For children on both EN and PN, calorie requirements are usually estimated at 5% to 10% less than the estimate for oral/enteral intake alone. Calorie requirements in those dependent on PN may be even lower. Overfeeding, particularly for those receiving PN, may enhance the onset of cholestatic liver disease in children with intestinal failure.15 Malnutrition, if present, should be corrected if possible prior to transplant as it places the recipient at an increased risk of infection, impaired wound healing, and extended rehabilitation after transplant. Assessment of macro- and micronutrient intake is needed to determine need for supplementation or need to obtain nutrition lab values. Stool or ostomy output should be assessed to determine if stool studies are warranted or further nutrition lab studies are needed or if medications should be considered. Protein requirements are generally estimated based on the DRI for age.16 Adjustments are made based on the childs liver and renal function.
weight, and growth status as well as pretransplant nutrition state, ventilation status, wound healing, and the presence or absence of sepsis and rejection. Caloric requirements may range from 70% to 120% of estimated requirements. Protein is generally provided at 150% of the estimated nutrition need and may be adjusted if renal or liver dysfunction occurs.18 Additional zinc may be required in addition to any other micronutrient that was previously deficient.18 Initial Enteral/Parenteral Nutrition Support A continuous PN solution should be initiated in the early postoperative period. The length of time that the initial nutrition support will need to be provided, or subsequently resumed after discontinuation, depends upon the childs ability to tolerate enteral feedings as well as the development of complications (eg, rejection, sepsis, and pancreatitis). The volume and nutrient content of the solution should be determined by the childs renal and cardiopulmonary function and biochemical indices. Measures such as serum electrolytes, glucose, blood urea nitrogen (BUN), creatinine, triglyceride, albumin, prothrombin time (PT) and partial thromboplastin time (PTT), platelets, and liver function tests should be monitored regularly to assess organ function and the need to modify the PN or intravenous (IV) fluid solutions. An IV fluid solution of normal saline or Lactated Ringers is provided immediately posttransplant to maintain fluid and electrolyte balance as well as replace ileostomy and gastric fluid losses. Upon the presence of ileostomy output or other evidence of bowel function, enteral feedings should be started (generally on postoperative day 3 or 4). Feedings should be initiated continuously at a small volume and advanced by small increments depending upon stoma output and abdominal status. The choice of a starting feeding formula as well as the route of administration (gastrostomy versus jejunostomy) varies from center to center. If stoma output increases, formula advancement should be paused and fiber supplements and/or antidiarrheal agents may be provided. In addition, formula volume may also need to be reduced and fluid replacement increased. If a surgical jejunostomy is placed during surgery then feedings should be transitioned from a jejunostomy to gastrostomy tube once the goal volume is reached.18 An oral diet of clear liquids may be initiated once the child has been extubated and enteral tube feedings have been initiated and tolerated. The oral diet should be advanced as tolerated but exclude foods high in simple carbohydrates to control osmotic diarrhea. Some children may also be sensitive to lactose-containing or high-fat
Feeding History
A complete nutrition assessment should also include a history of enteral feeding tolerance and current eating habits. Children with chronic diseases have often tried many different types of infant and enteral formulas before choosing the most tolerated option. It is important to note the type of formula and route and the percentage of calories that are contributing to the childs total calorie intake when providing both EN and PN. Infants and children who receive long-term enteral feedings are also at risk for oral aversion due to the absence of oral feeding.9 Normal feeding and swallowing development may have been missed. For children who can swallow, oral feeding of small amounts of varied food tastes and textures is encouraged. Maintenance of oral stimulation may help in the posttransplant period when the patient is transitioning from enteral to oral feedings. Children with oral aversion or other feeding issues should be referred to a feeding clinic as soon as possible.17 A Video Feeding Study may be needed to evaluate the safety of the child to take oral fluids and solids.
Nutrition Management After Transplantation

Intestine
Nutrition Requirements Protein and calorie requirements of the post-intestinal pediatric transplant patient will vary based on the childs age,
341
foods. As oral intake and absorption improves, continuous enteral feedings should be cycled to overnight feedings in an attempt to improve daytime oral intake. Children who are orally aversive from years of dependency on PN may require outpatient feeding therapy or an inpatient feeding program. Advancement of Enteral/Oral Feeding and WeaningofParenteral Nutrition PN weaning should begin when the child is medically stable. PN should be gradually reduced by 2- to 4-hour increments with a goal of a 12-hour infusion. Glucose levels should be monitored regularly during the weaning process. Nutrition Management of Complications Immunosuppressive therapy posttransplant may result in complications including hyperglycemia, hyperkalemia, hypertension, hypomagnesemia, and hyperlipidemia, all of which may require changes in nutrition therapy. Tacrolimus has been shown to cause hyperkalemia and hypomagnesemia.19 Potassium intake must be carefully monitored, and many patients require magnesium supplementation. Corticosteroids are now reserved primarily for rejection episodes but when used can cause hyperglycemia. Insulin therapy may be necessary in the short term to control blood glucose levels. Corticosteroids and other immunosuppressive drugs may also place patients at risk for hyperlipidemia. Chylous ascites can be a complication post-intestinal transplant due to lymphatic ducts being severed. Giving formula containing medium-chain triglyceride (MCT) oil, which is water soluble and does not rely on this source of transportation, will assist in the prevention of chylous ascites. Should it occur, PN may be the primary or single source of nutrition until resolved. EN and an oral diet containing long-chain triglycerides (LCTs) can be slowly reintroduced as tolerated. Food allergies are not uncommon in children post-intestinal transplant. Symptoms include increased stool output, abdominal distention or pain, abdominal cramping, weight loss, and failure to thrive.18 Milk-protein, wheat, peanuts, and egg allergies are the most commonly reported.20 Diagnosis may be made by tissue eosinophilia on gastrointestinal biopsy, a serum radioallergosorbent test (RAST), or serum IgE. Generally, foods reported as a Class 3 or 4 allergen after a RAST should be restricted from the childs diet.18 Some intestinal transplant patients also experience fat malabsorption. Symptoms include an increased stool output, oily stool, weight loss, or abdominal cramping. Diagnosis may
be made with a fecal fat test. Pancreatic enzyme therapy may be of benefit in patients with a quantitative fecal fat >20%.21 Growth and development should be monitored closely after transplant. Studies have shown improved growth velocity in recent years.22,23 Caloric requirements should be based on growth as well as activity and absorption levels. Factors that may affect growth include episodes of rejection that necessitate corticosteroid usage and sepsis events that result in reduction or discontinuation of enteral/oral feedings.
Liver
Nutrition Requirements Postoperative nutrition requirements for liver transplant recipients should be designed to provide sufficient calories to minimize catabolism and prevent complications from pretransplant nutrition issues. Biochemical parameters should be monitored and nutrition therapy adjusted as needed.24 A postoperative liver transplant patient may require PN if he or she is malnourished, has had complications, or if a lengthy recuperation is expected. During the immediate postoperative period, PN should be infused continuously.14 Guidelines for initiating postoperative PN are shown in Table 29-3.18,24,25 A tube feeding may provide total enteral nutrition or be used in conjunction with the oral route if intake is suboptimal. Breast milk is always preferred, if available. An intact protein, age-appropriate formula should be used to start, with a change to a hydrolyzed protein or a free amino-acid hypoallergenic formula if an intolerance should occur. The caloric density of formulas may need to be manipulated depending upon fluid restrictions and caloric requirements. Initially the tube feeding should run continuously until the oral diet is advanced. As the oral diet is advancing, nocturnal enteral feedings or daytime bolus feedings may need to be considered to support nutrition requirements. In addition, a daily multivitamin supplement for age should be provided.24 The posttransplant oral diet may be described as a healthy diet for age with careful consideration of the current Food Pyramid as well as the 2005 Dietary Guidelines for Americans.26,27 The protein, fat, and carbohydrate content of the diet should follow these guidelines with additional consideration given for complications such as renal impairment, hypertension, hyperkalemia, and diabetes mellitus. Calcium should be supplemented if intake is insufficient.
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Table 29-3 Guidelines for Initiating Parenteral Nutrition after Liver Transplant18,24,25
Nutrient Guidelines
Calories
Protein
Fat Carbohydrate
Multivitamins Trace Minerals
Fluid
Avoid overfeeding Initially provide 120%130% of resting energy expenditure to meet postoperative transplant needs Pre-existing nutrition needs, surgical complications, wound healing, sepsis, and rejection may further necessitate additional calories Provide 15%20% of total calories as protein Infants: 33.5 g/kg dry body weight 12 years: 2.53 g/kg dry body weight 313 years: 1.52.5 g/kg dry body weight Adolescents: 11.5 g/kg dry body weight Additional consideration should be given to renal function and wound healing Trophamine (B. Braun, Irvine, CA) is the preferred amino acid source due to its branched chain amino acid content and lower pH for maximum solubility of calcium and phosphorus (cysteine is added only for children < 1 year of age) Provide 30% of total calories as fat 20% intravenous fat is preferred for its caloric density Provide 50%55% of total calories as carbohydrate Begin at same concentration as the initial intravenous fluid and advance glucose as tolerated to a maximum of: Term Infants: 14 mg/kg/min 110 years: 11 mg/kg/min 1118 years: 8.5 mg/kg/min Provide standard intravenous multivitamin for age Provide parenteral trace mineral solution based on weight Provide full amount of trace minerals in patients without liver dysfunction Provide dose trace minerals + full amount of zinc with liver dysfunction secondary to cholestasis Zinc should be supplemented at 1 times the DRI for age if wound healing is an issue Based on weight, renal and cardiopulmonary function Maintenance fluids: 110 kg dry body weight: 100 mL/kg/d 1020 kg dry body weight: 1000 mL + 50 mL/kg for each kg over 10 2030 kg dry body weight: 1500 mL + 20 mL for each kg over 20
Feeding Disorders Advancement of the oral diet may be challenging in some patients postoperatively. Oral aversion may occur in those who required long-term PN, EN, and mechanical ventilation. These patients may require consultation from an occupational and/or speech therapist. Patients who required special diet restrictions before transplant (eg, protein restriction) may continue to prefer the taste of their restricted diet. Temporarily, these patients may continue their pretransplant medical nutrition enteral formulas until they readily incorporate a variety of foods in their diet. Growth and Development Long-term goals for patients after liver transplant include nutrition and life-style factors. Optimization of linear growth and physical development as well as socialization and participation in daily activities are desired. Calorie requirements will vary with age, activity, and growth rate. Children who exhibit linear growth impairment will need
calorie goals based on the DRI for height age.9 Those without growth delay may initially consume calories based on the DRI for age. Growth delay is common after liver transplant due to the nutrition impact of the original disease and use of corticosteroids. Catch-up growth for weight occurs more rapidly than height.1,28,29 Linear growth and weight should be monitored at primary care physician visits, and transplant centers alerted for any change in growth velocity. 30
Kidney
Nutrition Requirements The nutrition recommendations for kidney transplant patients immediately and later after transplant are shown in Table 29-4. An age-appropriate oral diet can be started once bowel function has resumed. An enteral tube feeding is rarely needed after kidney transplant. However, for patients who were fed via gastrostomy tube prior to transplant, it may be necessary to continue tube feedings and gradually
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Table 29-4 Nutrition Recommendations for Pediatric Kidney Transplant Recipients

Nutrient Immediately Posttransplant Later After Transplant
Calories Protein Carbohydrates Fat Phosphorus Calcium Potassium Sodium Iron Fluids Vitamins
DRI for height-age. May need additional calories if patient is underweight prior to transplant 125%150% DRI for age Avoid simple sugars 30%40% of total calories May need higher intakes, provide supplements as necessary Unrestricted Unrestricted unless necessary Mildly restricted Supplement as indicated by serum values Unrestricted DRI. Supplementation usually not necessary unless severely malnourished prior to transplant, Vitamin D if indicated
DRI for height-age DRI for age Unrestricted unless obesity is present 30%40% of total calories May need higher intakes, provide supplements as necessary Unrestricted Unrestricted Unrestricted unless hypertension or edema is present Supplement as indicated by serum values Unrestricted DRI. Supplementation usually not necessary unless severely malnourished prior to transplant, Vitamin D if indicated
to transition over to oral feeds. Gastrostomy tubes should only be removed after fluid and caloric needs are met orally. 31 PN is also rarely needed after kidney transplant unless the patient has acute tubular necrosis, intractable diarrhea, non-functional gastrointestinal tract, or small bowel obstruction. Volume and nutrients are adjusted based on urinary output and graft function. Long-term nutrition goals after kidney transplant include promoting wound healing, promoting anabolism, preventing infection, promoting adequate growth, minimizing side effects of medications, maintaining serum mineral and electrolyte levels within normal limits, and maintaining blood pressure within appropriate limits for age. Nutrition Management of Complications Hypertension can be caused by fluid overload, immunosuppressive agents, obesity, and/or a pre-existing condition of hypertension. Therapy may include a sodium-restricted diet, diuretics, or hypertensive drugs. Hyperglycemia may be caused by corticosteroid use. Simple sugars should be eliminated from the diet until glucose levels return to normal. The development of new onset insulin-dependent diabetes has been reported in a small percentage of recipients. 32 Hyperlipidemia resulting from the use of medications (eg, corticosteroids, calcineurin inhibitors, and sirolimus) as well as malnutrition and obesity should be evaluated and treated as it can hasten the progression of renal disease. 33 Lipid profiles should be monitored and patients placed on a moderate-fat diet with emphasis on healthy fats such as olive oil, fish, and nuts. Anemia is a complication of renal failure but does not always resolve after transplantation. The presence of iron deficiency and dosage of immunosuppressant have been identified as causative factors associated
with anemia after transplant. 34 Excessive weight gain may result from an increased calorie intake secondary to steroid therapy, fewer dietary restrictions, and improved feeling of well being as well as a lack of exercise. Presence of bone disease may limit physical activity and decrease energy expenditure. Early counseling with a dietitian and repeated nutrition interventions are needed to promote a healthy lifestyle and initiate a regular exercise regimen. Steroid dosage should be decreased to the lowest amount possible without loss of graft function. Decreased bone mass, fragility, and fractures are a known complication after transplant in adults. Alterations in bone mass have been found in children and adolescents as well with the greatest decrease in bone mineral density observed during the first 6 months after transplant. 35 Bone mineral density studies should be performed on a regular basis for all children after transplant. Calcium, phosphorous, and vitamin D supplements are prescribed based on the patients intake and serum levels. Adequate growth rate is directly related to age of onset of disease and duration of disease and is assessed by standard deviation scores or height deficit score (z score). Height potential is greatly reduced in children with chronic kidney disease before age 2 because one-third of growth occurs during the first 2 years of life. Additional factors include metabolic acidosis, renal osteodystrophy, and catabolic states associated with infection, corticosteroid dosage, and renal function after transplant. 36 Newer induction protocols may allow steroid-free immunosuppressive regimens that in turn may prevent obesity, hypertension, stunted growth, and non-compliance. 37 Use of recombinant growth hormones during puberty has been found to be effective in increasing height. 38 Physical adverse effects
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such as cushingoid appearance, short stature, scars, obesity, hirsutism, and gum hyperplasia can cause lower self-esteem and increased stress in adolescents. This may lead to noncompliance with medication therapy and an increased risk of graft rejection. A social worker and child life specialist can provide valuable insight and support in such situations.
Lung
Nutrition Requirements The post-lung transplant nutrition goals are to provide energy to prevent weight loss, promote healing, and prevent infection while minimizing gastrointestinal complications and avoiding drug-nutrient interactions. Calorie needs are increased due to the bodys effort to fight infection and promote wound healing. In contrast, the body uses less energy due to the decreased work of breathing and limited activity level immediately posttransplant. Considering this combined effect, calorie requirements are typically 100% to 120% of the DRI for age.14 Protein needs are elevated due to the healing process after surgery and are two times the DRI.16 Enteral/Oral Supplementation After transplant, the patient should be advanced to a regular diet as soon as tolerated. Oral nutrition supplements may be encouraged to maximize energy intake. Initially the patient may not be able to meet calorie needs from oral intake because of side effects (ie, nausea and vomiting) from immunosuppressive medications. If the patient loses 10% of his or her admission weight and is not able to meet caloric needs orally then supplemental tube feeds should be recommended. Tube feedings have been shown to be more effective than oral intake for weight gain after transplant.46 The patient often eats orally throughout the day and receives nocturnal tube feeds. For patients with CF and pancreatic insufficiency, semi-elemental formula may be necessary. If calorie and protein needs are not met by oral diet and/or EN then PN should be initiated. Pancreatic Enzyme Supplements/Vitamin-Mineral Supplementation Patients with CF and pancreatic insufficiency will continue to have pancreatic disease posttransplant. Pancreatic enzyme therapy should resume with all meals and snacks. Previous vitamin and mineral supplementation should continue. Patients with CF are at risk of developing high vitamin A and vitamin E serum levels after transplant. These levels should be monitored because adjustments are frequently required.47 Magnesium levels tend to be low after transplant and supplementation may be necessary. Nutrition Management of Complications Common complications after lung transplant that require nutrition intervention include infection and rejection, diabetes, osteoporosis, renal complications, and
Heart
Nutrition Requirements The nutrition goals for posttransplant pediatric heart transplant recipients include achieving and maintaining ideal body weight, limiting sweets and foods high in concentrated sugar, reducing foods high in fat and cholesterol, and limiting salt.12 Most pediatric heart transplant recipients progress to a full oral diet within 4 days of transplant. 3942 The exception are those orally aversive infants and children who were dependent on EN and/or total parenteral nutrition pretransplant. These patients may require additional nutrition support while receiving intensive oral rehabilitation therapy. Dietary Modification Alterations in diet may be necessary due to side effects of medications and immunosuppression therapy. Hypertension, hyperglycemia, and weight gain are common in posttransplant pediatric heart recipients.12 Lipid abnormalities have been reported at 1 year posttransplant.43 Calcineurin inhibitors may create these elevated serum lipid levels, and a heart-healthy, low-cholesterol, low-saturated fat diet is recommended. 39 Osteoporosis is universal among pediatric posttransplant recipients. 39 The combined effects of nutrition status before transplant along with calcineurin inhibitors and steroids result in decreased calcium absorption and bone formation. Supplemental vitamin D (400800 International Units) and calcium (12001500 mg) are recommended. 39 In addition, an annual dual-energy x-ray absorptiometry (DEXA) scan may be warranted in some cases. There are little data on the use of biphosphates, calcitonin, and hormone replacement therapy in the pediatric posttransplant population. Pretransplant growth parameters will impact the amount of catch-up growth needed posttransplant.4445 Infants and children have demonstrated appropriate growth velocity and weight gain posttransplant. Weight gain with lack of linear catch-up growth is characteristic of the adolescent heart transplant population. 39
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gastrointestinal complications. Infection and rejection are significant obstacles that occur after lung transplantation. Both problems are related to the immune system. Infection can be a complication from oversuppression while rejection is a result of too little suppression. Immunosuppressant drugs are medications given to prevent rejection of the transplanted organ and it is a difficult balancing act to determine the correct amount of immunosuppression required for each patient.48 Common immunosuppressive medications include tacrolimus, cyclosporin, prednisone, mycophenolate, rapamycin, and azathioprine. Medication doses are measured in the blood and adjustments are determined from these levels. Food can alter the absorption of these drugs so it is important that patients take these medications either fasting or with meals on a consistent basis. It is important to note any vomiting or diarrhea because this can also influence the drug level. Other medications including antacids, antibiotics, and antifungals can interfere with immunosuppressant levels. Grapefruit, grapefruit juice, or juice that contains grapefruit juice is discouraged because it has also been shown to alter levels. Impaired glucose tolerance and diabetes is relatively common after lung transplantation, especially in patients with CF. Hyperglycemia is due to the use of high-dose prednisone posttransplant and has also been associated with the use of tacrolimus and cyclosporine. It is important to monitor metered blood glucose levels several times per day and periodically check glycosylated hemoglobin levels. The recommended treatment consists of diet modification and insulin therapy.49 Bone disease or osteoporosis is a problem generally seen in patients with various types of respiratory diseases both before and after transplant. 50 Exposure to medications used after surgery, which includes long-term use of prednisone, cyclosporine, and tacrolimus, have all been associated with bone loss. DEXA scans should be monitored annually posttransplant to examine changes in bone density over time. Recommendations for management of bone health include maintaining a normal weight, calcium and vitamin D supplementation, and routine exercise. 51 Renal function should be monitored closely after transplant because immunosuppressant drugs used to prevent rejection can cause renal impairment. Patients with CF are at greater risk for renal insufficiency as compared to patients with other respiratory diseases. 52 Adequate amounts of fluids should be encouraged with alterations in electrolyte imbalances. It is especially important to increase oral fluids when gastrostomy feeds are being decreased to make up the difference of fluid loss from the tube feeds. Alterations in
diet may be necessary based on abnormalities indicated in blood work. Distal intestinal obstruction syndrome (DIOS) is a common complication in CF transplant patients, with an estimate of 20% incidence in the early posttransplant period. 53 The combination of narcotics for pain management, inadequate intake food and fluid intake, and bed rest put these patients at extremely high risk of developing problems. Symptoms are characterized by abdominal pain, abdominal distention, and vomiting. Some transplant centers give polyethylene glycol lavage solution as routine care to prevent DIOS after surgery. 53 Recommendations for prevention of DIOS are to monitor bowel movements, resume previous pancreatic enzyme regimen, encourage adequate fluid intake, and use stool softeners as needed. Lung transplantation is an accepted treatment option for patients with various types of end-stage lung diseases. There is currently a lack of research in the area of post-lung transplant nutrition. Close monitoring of nutrition status is essential to improve patient survival. As the success rates improve, so will our understanding of both medical and nutrition aspects of lung transplantation. Because most transplant recipients are receiving immunosuppressive medications, they are particularly susceptible to developing a foodborne illness caused by bacteria and other pathogens that can contaminate food. The major pathogens that can cause foodborne illness and the most common sources of contamination associated with these pathogens are shown in Table 29-5. 54 The United States Department of Agriculture, Food Safety and Inspection Service recommends the following 4 basic steps to food safety: (1) clean hands and surfaces often as bacteria can be spread from surfaces to food; (2) separate meat, poultry, seafood, and eggs from ready-to-eat foods to avoid cross-contamination; (3) cook foods to proper temperatures; and (4) chill foods promptly. In addition, it is important to adhere to the manufacturer Sell-by and Use-by dates when purchasing and consuming perishable foods. When eating out, transplant recipients should avoid any food that contains uncooked ingredients and speak to the food preparer to ensure that foods have been cooked to a proper minimum internal temperature. In general, buffets should be avoided. When traveling, gel packs should be used to keep food cold (40oF or below) as well as insulated containers to keep cooked food hot (140oF or above). 54
Food Safety
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Table 29-5 Major Foodborne Pathogens and Common Sources

Pathogen Sources
Bacteria Campylobacter Escherichia coli Listeria monocytogenes Salmonella Vibrio vulnificus Viruses Norovirus Protozoa Cryptosporidium Toxoplasma gondii
Raw and uncooked meat, poultry, milk, and untreated water Undercooked or raw beef, contaminated produce, raw milk, unpasteurized juices and ciders Unpasteurized dairy products, sliced deli meats, deli-style prepared egg, ham, seafood, and chicken salads Raw and undercooked eggs, undercooked poultry and meat, unpasteurized dairy products or juice, contaminated produce Raw or undercooked fish or shellfish Any food or water contaminated by someone who is infected with the virus Uncooked or contaminated food or water Raw or undercooked meat or foods; objects contaminated with cat feces
Survival rates have continued to improve for both patients and organ grafts.1 The 1- and 5-year survival rates for liver and heart transplant recipients are approximately 90% and 85%, respectively.1,55 The 5-year survival rate for children who have received a kidney transplant has been reported at 95%.1,56 A recent report on the current status of pediatric intestinal transplantation noted that the 1- and 5-year patient survival rate at centers of excellence has reached 95% and 77%, respectively. 57 Patient survival for children who have received a lung transplant has remained relatively constant over the past decade with 5-year survival at 50%. 58 Non-compliance with immunosuppressive treatment regimens remains a problem, particularly in the adolescent transplant population, and is one factor related to graft failure.1 Improvements with immunosuppressant treatment therapies and increases in survival rates have enlarged the population of pediatric transplant recipients. Interdisciplinary team management of the pediatric transplant recipient is essential to assist with the complex medical and psychological issues that can result from chronic disease and the complications that can result from immunosuppressant therapy after transplant. In addition to medical issues, patients and families also need to adjust to the new life that transplantation has provided. In recent years, reported outcomes after transplant have included not only survival
Current Status of Organ Transplantation inChildren
statistics but also discussions related to the achievement of or return to physical, emotional, and social quality of life. 59 Growth and development are important determinants of quality of life. Impaired growth and development is a complication often experienced by pediatric transplant patients. The presence or absence of impaired growth is affected by the length of illness and graft function, the use of corticosteroids, and development of infectious complications. 59 Quality of life after transplant often depends upon the type of organ or organs received. Differences may also exist in perceived quality of life between the transplant recipient and his or her caregivers. Perceived physical and social function after pediatric intestinal transplant was reported by recipients to be similar to other school children. However, their parents felt that their health and physical abilities were less than normal.60 Children and adolescents who have had a kidney transplant have reported improved quality of life in terms of physical and social well-being compared to children on dialysis.61 An early study on the effect of heart or heart-lung transplantation on quality of life in children showed improvement of quality of life within the early post-operative period.62 In another quality of life study completed with heart transplant recipients, adolescents perceived their quality of life and well-being as excellent compared to healthy controls.63 Finally, while greater quality of life has been reported after pediatric lung transplantation, the development of complications such as infection is more common in children than adults and results in reduced perception of quality of life.64 While it is difficult to measure quality of life in the pediatric population, interest in the data is rising as life expectancy is increasing. 59
1. Which of the following biochemical complications may occur shortly after intestinal transplantation and require changes in nutrition therapy? A. Hyperkalemia, hypermagnesemia, hyperglycemia, and hyperlipidemia B. Hyperkalemia, hypomagnesemia, hypoglycemia, and hyperlipidemia C. Hyperkalemia, hypomagnesemia, hyperglycemia, and hyperlipidemia D. Hyperkalemia and hypermagnesemia 2. Common nutrition-related complications after kidney transplant include: A. Hyperlipidemia B. Obesity C. Hyperglycemia D. All of the above
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3. Which of the following supplements are not recommended for children with cystic fibrosis and pancreatic insufficiency after lung transplantation? A. Pancreatic enzymes B. Standard enteral formula C. Parenteral nutrition D. Vitamins and minerals See p. 487 for answers.
References
1. Sudan D, Bacha EA, John E, Bartholomew A. Childhood organ transplantation. Pediatr Rev. 2007;28(12):439452. 2. Todo S, Tzakis A, Abu-Elmagd K, et al. Cadaveric small bowel and small bowel-liver transplantation in humans. Transplantation. 1992;53(2):369376. 3. Grant D, Abu-Elmagd K, Reyes J, et al. 2003 report of the Intestine Transplant Registry: a new era has dawned. Ann Surg. 2005;241:607613. 4. Nucci A, Barksdale E, Beserock N, et al. Long-term nutritional outcome after pediatric intestinal transplantation. J Pediatr Surg. 2002;37(3):460463. 5. Kowalski L, Nucci A, Reyes J. Intestinal transplantation. In: Rolandelli RH, Bankhead R, Boullata JI, Compher CW, eds. Clinical Nutrition Enteral and Tube Feeding. 4th ed. Philadelphia, PA: Elsevier Saunders; 2005:523529. 6. Khwaja K, Humar A, Najarian J. Kidney transplants for children under one year of age A single center experience. Pediatr Transplant. 2003;7(3):163167. 7. Bartosh SM. Recipient characteristics: ESRD, chronic renal failure, glomerulonephritis. In: Fine RN, Webber S, Kelly D, Harmon W, Olthoff K, eds. Pediatric Solid Organ Transplantation. 2nd ed. Malden, MA: Blackwell Publishing; 2007:146152. 8. MacLaughlin EF. Recipient characteristics: Lung transplantation, heart-lung transplantation, cystic fibrosis. In: Fine RN, Webber S, Kelly D, Harmon W, Olthoff K, eds. Pediatric Solid Organ Transplantation. 2nd ed. Malden, MA: Blackwell Publishing; 2007:314335. 9. Strohm S, Reyes J, Koehler A. Pediatric small bowel transplantation. In: Hasse JM, Blue LS, eds. Comprehensive Guide to Transplant Nutrition. Chicago, IL: American Dietetic Association; 2002:216225. 10. Sutton MM. Pediatric liver transplantation. In: Hasse JM, Blue LS, eds. Comprehensive Guide to Transplant Nutrition. Chicago, IL: American Dietetic Association; 2002:182215. 11. Miller D, MacDonald D. Management of pediatric patients with chronic kidney disease. Nephrol Nurs J. 2006;33(4):415429. 12. Heart Transplant Team, Childrens Hospital of Boston. Pediatric heart transplantation: a practical parent guide. http:// www.experiencejournal.com/cardiac/clinic/htbook.shtml. Accessed December 7, 2008. 13. Fulton JA, McKenna A. Pediatric lung transplantation. In: Hasse JM, Blue LS, eds. Comprehensive Guide to Transplant Nutrition. Chicago, IL: American Dietetic Association; 2002:153171.
14. Food and Nutrition Board, Institute of Medicine. Energy. In: Otten JJ, Pitzi Hellwig J, Meyers LD, eds. Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. Washington, DC: National Academy Press; 2006:625651. 15. Jeejeebhoy KN. Management of PN-induced cholestasis. Pract Gastroenterol. 2005;24:6268. 16. Food and Nutrition Board, Institute of Medicine. Protein and amino acids. In: Otten JJ, Pitzi Hellwig J, Meyers LD, eds. Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. Washington, DC: National Academy Press; 2006:740772. 17. Byars KC, Burklow KA, Ferguson K, et al. A multicomponent behavioral program for oral aversion in children dependent on gastrostomy feedings. J Pediatr Gastroenterol Nutr. 2003;37(4):473480. 18. Phillips SK, McGhee B, Reyes J. Pediatric Liver, Intestine, and Multivisceral Transplantation: A Manual of Management and Patient Care. Hudson, OH: Lexi-Comp, Inc; 2003. 19. Fung J, Allessiani M, Abu-Elmagd K, et al. Adverse effects associated with the use of FK506. Transplant Proc. 1991;23:31053108. 20. Koehler A, Yaworski J, Gardner M, et al. Coordinated interdisciplinary management of pediatric intestinal failure: a 2-year review. J Pediatr Surg. 2000;35(2):380385. 21. Strohm S, Koehler A, Mazariegos G. Nutrition management in pediatric small bowel transplant. Nutr Clin Prac. 1999;14:5863. 22. Kowalski L, Nucci A, Perez G, Mazariegos G, Sindhi R. Nutritional outcomes after elimination of routine steroid therapy in pediatric intestinal transplantation [abstract]. World Transplant Congress; 2006. 23. Lacaille F, Vass N, Sauvat F. Long-term outcome, growth and digestive function in children 2 to 18 years after intestinal transplantation. Gut. 2008;57:455461. 24. Sutton MM. Pediatric liver transplantation. In: Hasse JM, Blue LS, eds. Comprehensive Guide to Transplant Nutrition. Chicago, IL: American Dietetic Association; 2002:182215. 25. The Nutrition Support Committee. In: Barksdale EM, Nucci A, Yaworski JA. Parenteral Nutrition Manual. 5th ed. Pittsburgh, PA: Childrens Hospital of Pittsburgh; 2003. 26. Department of Health and Human Services. My Pyramid Food Guidance System. Washington, DC: United States Department of Agriculture; 2005. 27. Department of Health and Human Services. Dietary Guidelines for Americans 2005. Washington, DC: United States Department of Agriculture; 2005. 28. Alonso E. Growth and developmental considerations in pediatric liver transplantation. Liver Transplant. 2008;14:585591. 29. Burra P, De Bona M. Quality of life following organ transplantation. Transpl Int. 2007;20:397409. 30. Balistreri W, Welch T, Daniels S. Care of children with solidorgan transplants. In: McMillan J, Geigin RD, DeAngelis C, Jones D. Oskis Pediatrics. 4th ed. New York, NY: Lippincott Williams & Wilkins; 2006:26062608. 31. Wong H, Mylrea K, Manion CA, Bass MI, Feber J, Filler G. Caregivers attitudes towards gastrostomy removal after renal transplantation. Pediatr Transpl. 2005:9;574578.
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32. Furth S, Neu A, Colombian P, Plotwick L, Turner ME, Flvush B. Diabetes as a complication of Tacrolimus (FK506) in pediatric renal transplant patients. Pediatr Nephrol. 1996;10:6466. 33. Saland JM, Ginsberg H, Fisher EA. Dyslipidemia in pediatric renal disease: epidemiology, pathophysiology and management. Curr Opin Pediatr. 2002:14(2);197204. 34. Kausman JY, Powell HR, Jones CL. Anemia in pediatric renal transplant recipients. Pediatr Nephrol. 2004:19;526530. 35. Feber J, Cochat P, Braillon P. Bone mineral density in children after renal transplantation. Pediatr Nephrol. 2000;14:654657. 36. Fine RN. Management of growth retardation in pediatric recipients of renal allografts. Nat Clin Pract Nephrol. 2007;3:318324. 37. Ellis D, Shapiro R, Moritz M, et al. Renal transplantation children managed with lymphocyte depleting agents and lowdose maintenance tacrolimus monotherapy. Transplantation. 2007:83(12);15631570. 38. Hokken-Koelega AC, Stijnen T, de Ridder MA, et al. Growth hormone treatment in growth-retarded adolescents after renal transplantation. Lancet. 1994;343:13131317. 39. Blume E. Current status of heart transplantation in children: Update 2003. Pediatr Clin North Am. 2003;50:1384. 40. Wagner K, Webber SA, Kurland G, et al. New onset diabetes mellitus in pediatric thoracic organ recipients under tacrolimus based immunosuppression. J Heart Lung Transplant. 1997;16:275282. 41. Chin D, Rosenthal D, Bernstein D. Lipoprotein abnormalities are highly prevalent in pediatric heart transplant recipients. Pediatr Transpl. 2000;4:193199. 42. Penson MG, Winter WE, Fricker FJ, et al. Tacrolimus-based triple drug immunosuppression minimizes serum lipid elevations in pediatric cardiac transplant recipients. J Heart Lung Transplant. 1999;18:707713. 43. Pahl E. Heart transplantation: Literature review 2005-2006. Pediatr Transpl. 2007;11:709715. 44. Canter C, Shaddy R, Bernstein D, et al. Indications for heart transplantation in pediatric heart disease. Circulation. 2007;115:666667. 45. Cohen A, Addonizio LF, Softness B, et al. Growth and skeletal maturation after pediatric heart transplantation. Pediatr Transpl. 2004;8:126135. 46. Fulton JA, Orenstein DM, Koehler AN, Kurland G. Nutrition in pediatric double lung transplant patient with cystic fibrosis. NCP. 1995;10:6772. 47. Robert R, Durie P, Verjee Z, Chaparro C, Corey M, Tullis E. Increased vitamin A and E levels in adult cystic fibrosis patients after lung transplantation. Transplantation. 2005;79(5):613615. 48. Visner GA, Goldfarb SB. Posttransplant monitoring of pediatric lung transplant recipients. Curr Opin Pediatr. 2007;19:321326.
49. Moran A, Hardin D, Rodman D; and the Consensus Committee. Consensus Document Diagnosis, Screening, and Management of Cystic Fibrosis Related Diabetes Mellitus. Bethesda, MD: Cystic Fibrosis Foundation. 1999. 50. Shane E, Papadopoulos A, Staron RB, et al. Bone loss and fracture after lung transplantation. Transplantation. 1999;68(2):220227. 51. Dosanijh A. A review of nutritional problems and the cystic fibrosis lung transplant patient. Pediatr Transpl. 2002;6:388391. 52. Schindler R, Radke C, Paul K, Frei U. Renal problems after transplantation in renal patients. Nephrol Dial Transplant. 2001;16(7):13241328. 53. Gilljam M, Tullis E, Keshavjee S, Hutcheon M. GI complications after lung transplantation in patients with cystic fibrosis. Chest. 2003;123:3741. 54. Food Safety and Inspection Service. Food Safety for Transplant Recipients: A Need-to-Know Guide for Bone Marrow and Solid Organ Transplant Recipients. Washington, DC: United States Department of Agriculture. 2006. 55. North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) 2006 Annual Report. Rockville, MD; 2006. 56. Fricker FJ, Addonizio L, Bernstein D, et al. Heart transplantation in children: indications. Report of the Ad Hoc Sub-committee of the Pediatric Committee of the American Society of Transplantation (AST). Pediatr Transplant. 1999;3:333342. 57. Mazariegos GV, Squires RH, Sindhi RK. Current perspectives on pediatric intestinal transplantation. Curr Gastroenterol Rep. 2009;11:226233. 58. Marshall HI, Aurora P, Christie JD, et al. Registry of the International Society of Heart and Lung Transplantation . J Heart Lung Transplant. 2008;27(9):937983. 59. Burra P, De Bona M. Quality of life following organ transplantation. Transpl Int. 2007;20:397409. 60. Sudan D, Horslen S, Botha J, et al. Quality of life after pediatric intestinal transplantation: the perception of pediatric recipients and their parents. Am J Transplant. 2004;4:407. 61. Rubik J, Grenda R, Jakubowska-Winecka A, Dabrowska A. Quality of life in children and adolescents with end-stage renal disease treated with dialysis and kidney transplantation. Pol Merkuriusz Lek. 2000;8:280. 62. Wray J, Radley-Smith R, Yacoub M. Effect of cardiac or heartlung transplantation on the quality of life of the paediatric patient. Qual Life Res. 1992;1:4146. 63. Pollock-BarZiv SM, Anthony SJ, Niedra R, Dipchand AI, West LJ. Quality of life and function following cardiac transplantation in adolescents. Transplant Proc. 2003;35:2468. 64. Mallory GB, Spray TL. Pediatric lung transplantation. Eur Respir J. 2004;24:839.
Oncology, Hematopoietic Transplant, andSurvivorship

CONTENTS
General Oncology Overview. . . . . . . . . . . . . . . . . . . . . . . . Hematopoietic Transplant. . . . . . . . . . . . . . . . . . . . . . . . . Late Effects of Treatment for Survivors of Childhood Cancer . . . . . . . . . . . . . . . . . . . . . Appendix 30-1: Algorithm For Nutritional Intervention In The Pediatric Oncology Patient. . . . . . . . Appendix 30-2: Algorithm for Nutritional Intervention and Categories of Nutritional Status in the Pediatric Oncology Patient References and Resources . . . . . . . Appendix 30-3: Categories of Nutritional Status for the Pediatric Oncology Patient. . . . . . . . . . . . . . . . . . Appendix 30-4: Gastrointestinal Supportive Care Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
349 354 362 365
30
Nancy Sacks, MS, RD, LDN, Elizabeth Wallace, RD, CNSC, LDN, Seema Desai, MS, RD, LDN, CNSD, Vinod K. Prasad, MD, MRCP (London), David Henry, MS, BCOP, Virginia Guzikowski, MSN, CRNP, Liesje Nieman Carney, RD, CNSD, LDN, Beth Bogucki Wright, MS, RD, CSP, LDN, and Susan Rheingold, MD
Learning Objectives
366 367 368
1. Evaluate the nutrition status of the pediatric oncology patient and determine the caloric, macronutrient, and micronutrient needs of the patient. 2. Identify the common nutrition issues for children undergoing hematopoietic stem cell transplantation. 3. Choose the most effective mode of nutrition support and monitor its tolerance in the pediatric oncology population. 4. Identify the nutrition and activity goals for survivors of childhood cancer. 5. Become more knowledgeable regarding types of medication used to alleviate gastrointestinal problems.
General Oncology Overview
Pediatric cancer is the leading cause of death by disease in children under the age of 15 years. It is estimated that 1 in 475 children will develop cancer by age 15 years, accounting for more than 13,000 new cases of pediatric cancer a year in the United States (ages 019 years). As a result of multimodal therapy, the 5-year survival has improved from less than 50% in the 1970s to almost 80% today. Although the cure rate varies, it is estimated that by the year 2010 that 1 out of 250 young adults will be a survivor of childhood cancer.1 The type of cancer and treatments utilized adversely impact nutrition status of the child with cancer during and following therapy; therefore, it is essential to maximize nutrition status at diagnosis, throughout therapy, and after.
Nutrition Aspects: Diagnoses and Malnutrition

The risk of malnutrition is a significant concern during pediatric cancer treatment. Due to the increased nutrition needs for growth and development during childhood, and
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the metabolic stress of cancer, malnutrition is a frequent treatment complication. Between 6% and 50% of children will present with acute malnutrition at diagnosis.25 Higher incidence of malnutrition may be related to delay in diagnosis, extent of disease, and location of the tumor. During the course of therapy, malnutrition is observed in 8% to 32% of children.6 Higher incidences of malnutrition have a direct correlation with more intensive courses of treatment, often including transplant. Younger children may be at particularly higher risk of acute malnutrition due to limited nutrient stores and increased demand for growth. Nutrient needs may not be met due to increased metabolic demands, depleted stores, or inadequate intake.7,8 Inadequate nutritional intake is common during therapy, which can result in acute and long-term malnutrition. Nutrition status should not be assessed by weight or appearance alone as large tumor burdens may disguise the loss of adipose and lean muscle mass, thereby making it difficult to assess nutrition status at diagnosis. Certain diagnoses are more likely to result in nutrition problems due to altered metabolism, physiological changes, and effects of antineoplastic therapy.9 Children with sarcomas, neuroblastoma, and brain tumors typically present at diagnosis with protein depletion and weight loss.10,11 Other diagnoses that are at high risk for nutrition complications include advanced stage Wilms tumor and acute myelogenous leukemia (AML).
Radiation Therapy Radiation therapy is a treatment used independently or in conjunction with surgery and chemotherapy. Radiation destroys the genetic material within the cell, thereby killing the malignant cell.14 Complications arise from radiation therapy because healthy cells in the radiation field are inevitably damaged during treatment. The area most susceptible to nutrition effects of radiation is the GI tract.15 Mucosa from the mouth to the anus can be damaged causing malabsorption of nutrients, diarrhea, and severe pain both with and without oral intake. In adults, the effect on appetite is dependent on the involved radiation field, total dose of radiation, and number of fractions received.16 Acute side effects of radiation may begin as early as 1 week from the initiation of radiotherapy, and last several weeks after the final fraction. Patients receiving cranial radiation can develop postradiation somnolence syndrome 6 to 8 weeks after completion of radiation, causing severe lethargy and flu-like symptoms. Expected side effects based upon the location of the radiation field are found in Table 30-1.
Table 30-1 Nutrition-Related Side Effects of Radiation Therapy
Location Adverse Reaction
Central Nervous System Brain and Spinal Cord
Multimodal Treatment and the Effects on Nutrition

Surgery Surgical intervention is necessary for most solid tumors. Nausea, vomiting, fatigue, altered bowel motility, and decreased appetite pre- and postoperative are complications that can impact the ability to meet nutrient requirements. Solid tumors involving the gastrointestinal (GI) tract can cause changes in absorption and nutrient delivery, and affect digestion and absorption prior to surgical resection.12 Postoperative complications from GI tract or intraperitoneal organ surgery can include impaired swallow function, decreased gastric capacity or emptying, ileus of the small bowel, and altered bowel length and integrity. Children malnourished at the time of surgery have been found to have compromised wound healing and an increased risk of morbidity and mortality, whereas well-nourished patients have fewer surgical complications.13
Head and Neck Tongue, Larynx, Pharynx Oropharynx, Tonsils, Salivary Glands
Abdomen and Pelvis GI Tract, Reproductive Organs, Rectum, Colon, Testicles
Nausea/Vomiting Fatigue Loss of Appetite Alterations in Pituitary Functions Growth Failure Xerostomia Sore Mouth/Throat Dysphagia Mucositis Altered Taste and Smell Fatigue Loss of Appetite Nausea/Vomiting Diarrhea Abdominal Cramping Bloating Gas Enteritis and Colitis Lactose Intolerance Fatigue Loss of Appetite
Chemotherapy Classic cytotoxic chemotherapy works by inhibiting the division of rapidly dividing cells.17 Although cancer cells are the main target, rapidly dividing normal cells including those of the GI tract, taste buds, hair, and bone marrow are equally affected. The effect of chemotherapy on the patients nutrition status is associated with the exact medication used, dose, route of administration, and length of treatment.
ONCOLOGY, HEMATOPOIETIC TRANSPLANT, ANDSURVIVORSHIP
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The most common nutrition-related side effect of cytotoxic drugs is nausea and vomiting, but with modern anti-emetics the degree of emesis is much less severe. Loss of taste buds can make familiar foods unpalatable and cause decreased appetite. All of these, along with anticipatory effects, lead to anorexia. Some chemotherapy agents have the side effects of diarrhea, others constipation, and many lead to mild-to-severe mucositis due to slow replacement growth of the mucosa. These all can significantly alter the digestion and absorption of nutrients.17,18 Narcotic pain medication and anti-emetics can cause drowsiness and increase sleep time, leading to a secondary anorexia.
Table 30-2 Role of Cytokines and Hormones in Cancer Cachexia

Cytokine Effect on nutrition
Tumor Necrosis Factor (TNF)
Interleukin-1 (IL-1) Interleukin-6 (IL-6) Interferon (INF)-g Peptide YY (PYY) Ghrelin
Nutrition Aspects of Cancer

Metabolic Cancer cachexia is defined as a state of malnutrition characterized by anorexia, weight loss, muscle wasting, asthenia, depression, chronic nausea, and anemia and results in physiological distress, changes in body composition and alterations in carbohydrate, lipid, and protein metabolism.19,20 These metabolic alterations result in weight loss from muscle and adipose tissue, which compounds the effects of inadequate intake and anorexia. Cytokines are substances made by the cells of the immune system that mediate cell and tissue function and assist in regulating satiety signals and gastric emptying.21,22 Elevated cytokine levels are found in patients with cancer, likely contributing to the complex metabolic response of cancer cachexia. 23,24 Table 30-2 outlines the role of selected cytokines in nutrition and cachexia. Research has demonstrated that changes in glucose, protein, and lipid metabolism in cancer patients cause weight loss even before the patient experiences decreased appetite and oral intake.2426 Energy utilization in the body can range from hypo- to hypermetabolism.29 Tumor cells use glucose as their main energy source, as well as anaerobic metabolism and amino acids for tumor cell growth.26,30 Inefficient energy utilization by the tumor causes increased activity of the Cori cycle to produce lactic acid to be converted to glucose. Gluconeogenesis, the production of glucose from the breakdown of fat and protein stores, aids in glucose homeostasis. 31 Despite the increased demand for glucose, patients frequently exhibit relative glucose intolerance and insulin resistance. 32 An increase in lipolysis and decrease in lipogenesis allows for large losses in fat mass in oncology patients. Muscle protein synthesis is reduced, and acute phase protein production in the liver is increased, leading to the risk of muscle catabolism.
Suppresses lipoprotein lipase20 Increases cortocotropin-releasing hormone which suppresses food intake27 Blocks neuropeptide Y induced feeding; increases corticotropinreleasing hormone27 Induces cachexia and acute phase proteins in animal models20,28 Induces cachexia; INF-g antibodies reversed wasting27 Levels increased with greater disease burden; inverse correlation with BMI24 Low values associated with greater disease burden24
Physiological The toxicity of chemotherapy can cause changes in organ function resulting in altered nutrient metabolism and excretion. Cisplatin and cyclophosphamide can cause electrolyte wasting by the kidneys that can last for weeks after the agent is given. Mild to moderate transaminitis and hyperbilirubinemia are common side effects of chemotherapy, demonstrating direct effects on hepatic function. Tumors of the nasopharynx, neck, mediastinum, and GI tract and organs can cause direct obstruction and lead to decreased oral intake. Other side effects of therapy leading to suboptimal intake are described in detail above. Psychological Emotional well-being is essential to achieving and maintaining physical health, including an optimal nutrition status. Depression and anxiety affects up to 20% of all patients diagnosed with cancer and one study in children with cancer found that 59% had mild psychological problems. 33 While anxiety appears to affect younger children, and depression older, both can lead to inactivity, loss of appetite, self-criticism, and hopelessness. Self-image and self-esteem, including perception of weight status and physical appearance, are important to monitor in the pre-teen and teenage population. Learned food aversions due to fear from eating and vomiting seem to affect toddlers and young children. A specialized feeding program may be necessary to help overcome food aversions and resume normal oral intake and eating patterns during or after completion of treatment.
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Evaluation of Nutrition Status and Determination ofNutrient Requirements

Energy and Protein Determining nutrition status at diagnosis and potential for malnutrition is necessary for good supportive care.19 Although no specific nutrition protocols exist for pediatric oncology, it is recommended that a patients nutrition status be categorized using guidelines developed by The Childrens Oncology Group (COG), Cancer Control Nutrition Sub-Committee (Appendix 30-1). The American Dietetic Association (ADA) has developed adult nutrition protocols for medical, surgical, and radiation oncology patients that may serve as a resource for the pediatric population, and for the adolescents and young adults frequently treated in pediatric oncology centers. 34,35 Table 30-3 contains accepted subjective and objective measures commonly used to evaluate pediatric nutrition status. Caloric and protein needs are difficult to assess in the pediatric oncology population, and are affected by current nutrition status, disease state, and therapy protocols. Appendix 30-2 contains formulas to assist in estimation of caloric and protein needs. An activity/stress factor may need to be utilized with these formulas; however, recent literature reports that weight loss may be better correlated to decreased oral intake and not increased energy expenditure. 36 Serum albumin and prealbumin values may indicate depleted protein stores, although these values can be influenced by hydration status, stress, and liver function and should be interpreted based on clinical status. 37 Growth and Development The goal of nutrition intervention for the child with cancer is to provide adequate nutrients for growth and development, and reverse protein-calorie malnutrition. Optimal growth and weight gain in pediatric patients is essential for maximizing physical tolerance to treatment and decreasing the amount of treatment delays. 8,38,39 Strategies for nutrition intervention for specific symptoms should be implemented in all patients. Table 30-4 provides general recommendations for nutrition intervention during therapy.40 Nutrition support should be individualized for each child, with the development of a nutrition plan based upon the patients nutrition assessment, disease type and stage, treatment, and quality of life considerations. Studies show that pediatric patients who receive intervention from a registered dietitian during active treatment have improved weight status through therapy.40 Guidelines for nutrition intervention for pediatric cancer patients have been devel 2010 A.S.P.E.N. www.nutritioncare.org
oped by the American Academy of Pediatrics (AAP) and modified by Andrassy and Chwals4,41 as well as the Cancer Control Nutrition Sub-Committee of The Childrens Oncology Group (Appendix 30-2).
Outcomes Measures
Biochemical Evaluation Laboratory tests should be closely monitored from initial nutrition assessment through repletion. One should assess basic electrolytes (sodium, potassium, chloride, bicarbonate), glucose, renal function (creatinine, blood urea nitrogen), minerals (calcium, phosphorus, magnesium), liver function tests (alkaline phosphatase, serum aminotransferases, gamma glutamyl transferase (GGT), total bilirubin), triglycerides, and cholesterol. Serum albumin and prealbumin values may reflect protein stores.
Table 30-3 Components of Nutrition Assessment Medical History Diagnosis stage and date Past medical history Medication history Anticipated therapy protocol Anthropometics* Weight history BMI/Weight-for-age Height-for-age Recent growth trends % Ideal body weight % Usual body weight % Diagnosis weight Mid-arm circumference Triceps skinfold Dietary Intake Current intake (amounts, stage, feeding times) Evaluation Usual intake Feeding behavior Modified oral intake Tube feeds Parenteral nutrition Vitamin/Mineral supplementation Gastrointestinal Nausea Symptoms/Side Vomiting Effects Constipation Diarrhea Dry mouth Taste changes Mouth sores Difficulty swallowing Early satiety Laboratory Electrolytes Assessment Blood glucose Serum proteins Absolute neutrophil count Complete blood count Liver function tests Quality of Life Activity level Family support system Depression/Anxiety Pain Treatment plan Resources * Refer to Appendix 30-1, Algorithm for Nutritional Intervention and Appendix 30-2, Categories of Nutritional Status in the Pediatric Oncology Patient.
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Table 30-4 Nutrition Strategies for Symptom Management

Symptom Dietary Intervention Strategies
Nausea/Vomiting
Anorexia
Diarrhea Dysgeusia
Mucositis Xerostomia
Small frequent meals, high carbohydrate content, non-acidic beverages, cold clear foods and beverages, avoid extreme temperatures and highly seasoned items, avoid high-fat content items Small frequent meals, nutrient-dense foods and supplements, carbohydrate and protein modulars, create a pleasant atmosphere, dine with the child, vary colors/flavors/textures of foods Low fat, cold, or room temperature foods, avoid caffeine, encourage adequate fluid intake Herbs, spices, and marinades, cold non-odorous foods, fruit-flavored beverages, good oral hygiene, mint mouthwashes, lemon-flavored beverages and sour candies Soft diet, smooth bland moist foods, frozen slushes/ices/ice cream, high-calorie liquid beverages Moist foods, encourage liquids with meals, add sauces/gravy/butter/broth, add vinegar and lemons to stimulate saliva, good oral hygiene
adolescents with leukemia. Suboptimal nutrition prior to or while receiving therapy for acute lymphoblastic leukemia (ALL) resulted in longer duration of treatment, prolonged hospitalization, higher infection rate, increased mortality during the first 2 phases of treatment, and lower rate of 5-year survival.4648 Tolerance to Treatment Tolerance to treatment and delays in treatment are associated with nutrition status and disease. Patients treated for stage IV neuroblastoma who were malnourished at diagnosis or who had weight loss early in treatment had increased delays in therapy. 38,44 Malnourished patients with ALL or Wilms tumor were more likely to require a reduction in drug therapy relative to their better-nourished peers. 8,39,49 Patients who developed anthracycline-associated cardiomyopathy were more likely to be malnourished at initiation of therapy. 50
Selection of Nutrition Support Route

Anthropometric Physical examination is an important piece of the nutrition evaluation. Promoting consistent growth along chart curve percentiles is essential for long-term assessment. Growth should be plotted and monitored for each patient monthly on weight-for-age, length/height-for-age, body mass index (BMI)-for-age (> 2 years), weight-for-length (< 2 years), and head circumference (< 3 years of age). Measurement of triceps skinfold thickness and mid-arm circumference for assessment of fat and muscle stores may be beneficial when unable to obtain accurate weights (eg, critically ill patients, fluid retention).42 Disease Outcome Though it cannot be used as an independent marker of mortality, more severe malnutrition is frequently related to a worse prognosis. 39,43,44 Several studies in pediatric solid tumors have shown a correlation between outcome and nutrition status. 39,43,44 There is a direct correlation between outcome and nutrition status in localized solid tumors, but not in patients with metastatic disease. 2 Decreased relapse rates have been correlated with improved nutrition status in children with localized solid tumors and lymphomas, but not with advanced disease at diagnosis.2 Children with stage IV neuroblastoma who were malnourished at diagnosis had a significantly higher incidence of disease recurrence and death 1 year into treatment.45 Similar results have been published associating poor survival outcomes in malnourished and obese children and Oral Nutrition Oral nutrition is important to continue to promote normalized and developmentally appropriate feeding for children and should be encouraged as much as is medically reasonable. Patients and families should be educated on the appropriate strategies to alter nutrient intake using modulars and supplements. Unfortunately many pediatric patients on oral diet alone have significant weight loss and muscle wasting51,52 and need to be supported by other means. Enteral Tube Feeding Enteral tube feeding (TF) may significantly enhance a childs nutrition status during cancer therapy. 5254 Selection of the correct formula must be determined in order to maximize nutrient intake. Though no large clinical trials have been conducted, research suggests that a calorie concentrated formula may be more beneficial to malnourished patients receiving TF. 53 Preliminary evidence regarding the use of TF as supplementation or full calories, prior to developing weight loss, shows an overall improvement in the patients nutrition status at the end of therapy. 55 Tube feedings can be provided enterally via nasogastric (NG), nasojejunal (NJ), or a percutaneous endoscopy gastrotomy (PEG) tube. Benefits of a PEG tube include a one-time placement in a location that is not apparent, especially in an appearance-conscious adolescent. It also bypasses the issue of tube displacement with emesis and traumatic tube replacement during periods of mucositis. The placement of
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a prophylactic PEG tube prior to the initiation of radiation for head and neck cancers in adults has resulted in decreased incidence of morbidity related to weight loss. 5 This practice should be considered for pediatric patients as many radiation side effects that affect adults also affect children. The disadvantage of a PEG tube is the requirement for surgical placement and a risk of cellulitis at the incision site. Parenteral Nutrition Parenteral nutrition (PN) support has been documented to increase a patients overall nutrition status, weight, and anthropometric measurements, but has not improved clinical outcomes.45,56 Though PN can provide shortterm improvement, the effects often subside when the PN is discontinued. 57 Appendix 30-1 outlines intervention considerations for oral, enteral, and parenteral nutrition.
Complementary and Alternative Medicine

Patients and families with chronic diseases often look to resources outside of conventional medicine for treatment. Complementary medicine is used in conjunction with conventional medicine, while alternative medicine replaces the westernized approach. An increasing number of patients are using complementary and alternative medicine (CAM). The use of CAM in pediatrics has been reported in up to 84% of patients in recent years. 58 The AAP has developed a task force to review issues and develop resources for patients and health care practitioners. 59 Limited clinical trials exist on the use of CAM in the pediatric oncology population. Children should not be placed on adult dosages of nutrition-related supplements due to differences in metabolism and concerns of drug interactions and toxicity. Further evaluation and clinical trials need to be conducted before CAM can be routinely recommended to patients.
Complications of Cancer Treatment

Anorexia or loss of appetite is a common side effect of cytotoxic therapy. Though typically seen as an independent symptom, there are many variables that can cause anorexia. Weight loss, cachexia, dehydration, persistent vomiting, and early satiety can all cause anorexia in children. Anorexia may be perpetuated by continuous cycles of chemotherapy and other treatments. Children receiving chemotherapy are at an increased risk of developing infections. Per data in adults, it is understood that malnutrition can increase that risk by 15% to 20%, and it likely translates to pediatrics.22 Energy requirements may increase by 30% in patients fighting viral or bacterial
infections.23,60 Infections also induce a release of cytokines IL-1, IL-6, and TNF, further compounding the cancer cachexia phenomenon.61 Nutrient metabolism and absorption can also be altered during an infection due to increased production of catecholamines, cortisol, glucagons, and growth hormone. Mucositis, the inflammation of mucosal membranes lining the digestive tract, is a side effect of many chemotherapy agents and radiation. Mucositis can range in severity from mild erythema to extensive mucosal sloughing at any location in the GI tract. Oral mucositis can severely impact oral intake and limit the placement of NG tubes secondary to pain. Some research suggests that supplementing the patient with oral glutamine may help to prevent and decrease the severity of mucositis.62 Diarrhea causes a loss of fluids and electrolytes, as well as nutrient malabsorption, and can be linked directly to specific chemotherapies, radiation to the abdominal and pelvic areas, and abdominal surgery. Other potential causes for diarrhea during therapy include primary and secondary infections, antibiotics, adverse drug effects, and stress. Malabsorption complicates the use of some nutrition interventions such as oral and TF. When combined with limited nutrient intake, malabsorption can contribute to severe weight loss in a short period of time. Surgery may cause altered nutrient transit time, limiting the ability for intestinal absorption. Chemotherapy induces vomiting, diarrhea, mucositis, and enteritis, and radiation can cause malabsorption throughout the entire GI tract. A decreased production in saliva during and postradiation to the head and neck causes a decrease in oral enzymes, while abdominal and pelvic radiation can cause enteritis and diarrhea. Late effects of radiation may include mucosal inflammation and intestinal fibrosis after an extended period posttherapy which may not be reversible.15 Additional complications including dysgeusia, anosmia, and xerostomia can significantly alter oral intake because of decreased palatability or decreased tolerance of certain textures. Though these complications generally subside, they can create long-standing food aversions.
Hematopoietic Transplant
Hematopoietic stem cell transplantation (HSCT) is performed to replace diseased and defective bone marrow and restore hematopoietic and immunologic function. It is a broad category and encompasses bone marrow transplantation (BMT), peripheral blood stem cell transplantation (PBSCT), and umbilical cord blood transplantation (UCBT) depending on the source of hematopoietic stem
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cells. HSCT is a treatment option for children with a variety of potentially fatal diseases including malignancies, immunodeficiency syndromes, severe aplastic anemia, Fanconis anemia, and inherited metabolic disorders like Krabbes disease and Hurler syndrome. Pediatric malignancies treated with HSCT include acute myeloid and lymphoblastic leukemia, Hodgkins disease and non-Hodgkins lymphoma, myelodysplastic syndrome, and some solid tumors (eg, high-risk neuroblastoma). HSCT offers the only curative option for many of these children. HSCT can be autologous (the patient receives his or her own stem cells); allogeneic (the patient receives cells from another person who may be a sibling, or parent (haplo) or an unrelated donor); or syngeneic (when an identical twin is the cell donor). Donors are selected on the basis of many factors including the level of human leukocyte antigen (HLA) matching. HLAs are genetically defined proteins or antigens that are highly polymorphic and are encoded by the major histocompatibility complex (MHC). Class I HLA (-A, -B, and -C) antigens are expressed on almost all nucleated cells of the body. Class II proteins (-DR, -DQ , and -DP) are mainly expressed on hematopoietic cells (B cells, dendritic cells, and monocytes). Currently HLA typing is performed by DNA-based methods. While full HLA matching is preferred, mismatched donors are appropriate in certain situations, especially if the graft source is a cord blood unit. Donor availability and clinical requirements determine the source of the stem cells. The donors may be related or unrelated to the patient.
2.
3.
4.
Transplantation Process
1. Conditioning. The purpose of the conditioning regimen is to destroy the defective or diseased marrow, kill cancerous cells, create space for donor cells, and prevent rejection of donor cells by neutralizing the patients immune system. Conditioning therapy (also known as cytoreduction or preparative regimen) consists of a combination of chemotherapy drugs with or without radiation and is given over a number of days prior to transplant. There are 2 types of conditioning regimen: (1) myeloablative and (2) non-myeloablative. Myeloablative, also known as conventional conditioning regimen, uses high-dose chemotherapy and/or total body irradiation that destroys or myeloablates the bone marrow. The high-dose chemotherapy and radiation causes acute and long-term toxicities including severe mucositis, myelosuppression, nausea, vomiting, liver function abnormalities, and cardiotoxicity. The non-myeloablative conditioning uses a milder form of 5.
6.
chemotherapy and/or radiation and therefore causes less toxicity and can be used in patients with comorbidities. These transplants are also called mini or reduced intensity transplants. However, risk of relapse is higher following non-myeloablative transplants. Infusion. After the completion of conditioning and usually a day or 2 of rest, the stem cells are infused via an intravenous catheter. It can take 30 minutes to 4 hours to infuse the cells depending on the type of donor source and whether the product required any manipulation (eg, volume depletion, red blood cell (RBC) depletion, or T-cell depletion). Pancytopenia. The conditioning regimen leads to suppression or ablation of the bone marrow causing a decrease in white blood cells (WBCs), platelets, and RBCs. This period usually lasts for 2 to 4 weeks depending on the donor source, cell dose, and many other factors. During this period of pancytopenia, patients have no white cell count and are at increased risk of infections. Antimicrobial prophylaxis is commonly used in this period. The patients also require blood and platelet transfusions. Engraftment. Engraftment is confirmed when absolute neutrophil count (ANC) is > 500 per cubic mm for 3 consecutive days. Sometimes, it may take many weeks for cells to engraft. During this process, some patients may develop hyperacute graft versus host disease (GVHD) which is also called engraftment syndrome and is characterized by fever, rash, weight gain, and in some cases severe capillary leak and pulmonary edema. Post-engraftment. In this period of continuing recovery patients are vulnerable to many complications like acute GVHD, graft failure, organ toxicity, drug-related adverse reactions, and infections. Long term. While most patients recover very well without major complications, they are at risk for a number of long-term problems including delayed and slow growth and development, organ dysfunction, neurocognitive issues, endocrine problems, chronic GVHD, avascular necrosis, secondary malignancy, and others.
Nutrition Evaluation and Nutrient Requirements

Children undergoing HSCT are at increased risk of malnutrition and it is critical to assess their needs, anticipate problems, and institute appropriate preventive nutrition support in a timely manner. The toxicity of conditioning regimen affects the integrity of the GI tract causing
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mucositis, nausea, vomiting, and diarrhea. These symptoms may be further exacerbated by posttransplant complications like GVHD, infections, use of multiple antibiotics, and immunosuppressive medications. These and other complexities of HSCT are important to understand. The nutrition status in some patients may be suboptimal due to previous treatments, prolonged hospitalizations, and other problems that have affected their ability to eat or drink well. Certain diagnoses are more likely to be associated with malnutrition at the time of diagnosis and during therapy (eg, acute myelogenous leukemia and high-risk neuroblastoma) which require much more intense initial chemotherapy before they are even referred for HSCT. Fifty-four percent of pediatric patients undergoing HSCT were reported to have suboptimal nutrition status pretransplant.42 Impaired pretransplant nutrition status was found to be a negative prognostic factor leading to delayed engraftment.42 Prevention of malnutrition and preservation of nutrition status is vital for better transplant outcomes. A complete nutrition assessment should be performed at the time of hospital admission. Nutrition status and nutrient needs continue to change throughout the transplant process, therefore continued assessment and evaluation is important during the transplant process (refer to Table 30-3 for components of nutrition assessment). Physiological and psychological complications affecting nutrition status during therapy are discussed in depth in the General Oncology section of this chapter and thus will not be addressed here. Anthropometric Assessment Height, weight, and BMI are good indicators of nutrition status. These should be measured at the time of admission and throughout the recovery process. Serial anthropometric measurements over a period of time are a good measure of long-term nutrition status. Growth charts should be maintained to help assess the growth velocity. However, during early posttransplant stage, one should be careful about using weight and BMI as the sole criteria to assess changes in nutrition status. Body weight and BMI are affected by hydration. Cheney et al observed fluid shifts during the first 4 weeks after transplant and concluded that the change in body weight did not correlate with the body cell mass or fluid volume changes.63 Importantly, calculated arm muscle area correlated well (p < 0.05) with changes in body cell mass and is a better reflection of nutrition status. BMI has been reported to be a poor predictor of nutrition status when compared with body cell mass.42 Despite these limitations, serial height, weight, and BMI measurements combined with assessment of caloric and protein
intake and fluid balance are critically important and useful. Weekly measurement of mid-arm circumference should be considered. Energy and Protein Needs Patients undergoing HSCT show changes in energy requirements throughout the process.6466 During this period, patients are in a hypermetabolic state with increased catabolism due to mucositis, fever, tissue repair, and marrow regeneration. Increase in the metabolic rate can also be caused by the conditioning regimen, fevers, and posttransplant complications.64 As a result, the caloric needs of the HSCT patient have been reported to be as high as 150% of the basal metabolic rate (BMR) of non-stressed well-nourished patients and 180% to 200% of BMR of malnourished patients.6769 On the other hand, Duro et al observed significant decreases in resting energy expenditure (REE) following allogeneic stem cell transplant in patients with leukemias and aplastic anemia, with return of energy expenditure to pretransplant levels after engraftment. REE decreased by 4% to 7% per week posttransplant as measured by indirect calorimeter.66 Duggan et al also reported significant decline in REE after HSCT in pediatric patients. Some of the decrease in REE is being attributed to decrease in lean body mass.65 Studies assessing energy requirements in HSCT are limited and equivocal. Further studies are needed to better determine the caloric needs of pediatric patients during transplant and posttransplant. Based on current literature, indirect calorimetry for assessing caloric requirement is the gold standard. In absence of indirect calorimetry one should use clinical judgment while using the calorie calculation formula and continue to assess for potential overfeeding/underfeeding. Protein requirements are increased to minimize loss of lean body mass and promote tissue repair. Table 30-5 provides caloric and protein requirements of HSCT pediatric patients.
Table 30-5 Caloric and Protein Requirements of Pediatric HSCT Patients67,69,71
Age Calories Protein (g/kg/d)
012 mo BMR* x 1.61.8 3 BMR x 1.61.8 2.53 16 y 710 y BMR x 1.41.6 2.4 1114 y BMR x 1.41.6 2 BMR x 1.51.6 1.8 1518 y > 19 y BEE**x 1.5 1.5 *For BMR equation, refer to Appendix 30-2. **BEE equations: Male: 66 + (13.7 x wt in kg) + (5 x ht) (6.8 x age) Female: 665 + (9.6 x wt in kg) + (1.7 x ht) (4.7 x age)
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Fluid Needs In general, daily fluid needs can be assessed using the Holliday-Segar method.70 However, one must take into consideration the various factors that impact daily fluid balance. For example, fluid need is increased with fever, GI losses (eg, vomiting, diarrhea), mucositis, open skin wounds, and other factors.67 Liver and kidney dysfunction may lead to fluid retention and may require fluid restriction. In addition to the total parenteral nutrition, and oral or enteral intake, patients receive additional fluid with medications and blood products and these must be taken into account. Therefore, close monitoring of fluid status is important. Vitamin and Mineral Needs Vitamin and mineral requirements for patients undergoing HSCT have not been determined. The nutrition support regimen should meet 100% of the dietary reference intake (DRI) of vitamins and minerals. If oral intake or enteral nutrition support does not meet the vitamin and mineral needs, then an iron-free multivitamin and mineral supplement should be provided. Generally, iron supplementation is not required in HSCT patients because they receive frequent blood transfusions and supplemental iron can result in iron overload. The risk of vitamin and mineral deficiency is particularly higher if the patient has diarrhea, vomiting, and malabsorption. Thiamin, vitamin K, vitamin D, calcium, or zinc deficiencies have been seen in some patients. Vitamin K deficiency as determined by PIVKAII level was seen in 31% of pediatric patients undergoing HCST and was attributed to use of phenytoin, inadequate intake, or malabsorption. 54 The investigators did not find a direct correlation between prothrombin time and vitamin K status. However, in clinical practice prothrombin time is a good indicator of significant vitamin K deficiency and can guide vitamin K therapy. Antibiotic use has been shown to decrease the production of vitamin K in the body. HSCT patients receive multiple antibiotic treatments posttransplant; therefore, vitamin K supplementation of 1 mg/ kg should be provided weekly.67,71 In patients with severe chronic diarrhea, zinc losses may be significant and supplementation may be necessary. Patients undergoing HSCT often receive multiple agents that alter bone metabolism as part of their treatment. These include methotrexate, steroids, cyclosporine, and total body irradiation. For many patients, physical activity and exposure to sun is limited and can lead to additional nutrition problems like osteopenia, vitamin D deficiency, and eventually poor bone health. Therefore, serum vitamin D and calcium should be routinely monitored and
supplemented. For further information on bone health, see Late Effects of Treatment in Survivorship in this chapter.
Provision of Nutrition Support

Oral Route High-dose chemotherapy and posttransplant complications lead to anorexia, mucositis, nausea, vomiting, and diarrhea, causing poor oral intake and malabsorption. Chemotherapy drugs like busulfan, melphalan, cyclophosphamide, methotrexate, carboplatin, and most others can cause taste changes. The etiology of taste changes in HSCT may be multifactorial including mucositis, hyposalivation, and side effects of medications like antibiotics, antihypertensives, and antidepressants.72 About a third of patients receiving chemotherapy and/or radiation demonstrate food aversion. Patients learn to avoid foods that remind them of uncomfortable feelings of nausea and vomiting.73 Oral intake and appetite in HSCT patients does not return to a normal state until they are 4 to 6 weeks posttransplant.74 Severity of oral mucositis and GVHD are the most significant factors affecting return of oral intake.68 Appetite stimulants may be useful to help stimulate appetite in patients who have engrafted and do not have GVHD. Sometimes, even after return of oral intake and absence of GVHD, oral feeding may be difficult due to malabsorption. At this time a complete GI workup to rule out fat and carbohydrate malabsorption, pancreatic insufficiency, and bacterial overgrowth may be warranted. In infants and toddlers with food aversion, feeding therapy with the help of speech and occupational therapy should be considered. Refeeding a child after HSCT is a slow process and needs careful monitoring of symptoms and frequent assessment. Diet Restrictions Most institutions prescribe a neutropenic or low bacteria diet in the posttransplant period. In addition, a low-lactose diet may also be recommended. The goal of a neutropenic diet is to restrict foods that are believed to contain large amounts of potentially pathogenic bacteria, which can cause infections in the immuno-compromised patient. Such food items include non-pasteurized dairy products; aged cheeses; fresh fruits and vegetables; deli meats and cheeses; deli-type salads (eg, potato salad, egg salad, tuna salad, and pasta salads); undercooked meat, poultry, egg, fish, and seafood; food with visible mold; salad dressings made with egg and moldy cheeses; and bakery food products.69 Listeria monocytogenes, Escherichia coli, Salmonella, Cryptosporidium parvum, and Campylobacter are the most
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common pathogens that cause food-borne illness. Signs and symptoms of a food-borne illness include stomach ache, abdominal pain, diarrhea, nausea, vomiting, headache, fever, and chills.75 Studies have shown inconsistent results regarding the effect of dietary modification on the incidence of food-borne illness.76,77 Current A.S.P.E.N. guidelines for HSCT adult patients state that until further research is available it seems prudent to restrict high-risk foods, as described above, during neutropenia.78 It is important to encourage patients and caretakers to practice safe food handling. Enteral Nutrition Benefits of enteral nutrition (EN) in protecting the gut integrity, preventing bacterial translocation, and being cost-effective are well known. However, enteral feeding has not been the norm for most pediatric HSCT patients mainly because of risk of bleeding with tube placement in the presence of pancytopenia and mucositis and due to concerns about delayed gastric emptying and malabsorption of nutrients.68,79 In 2 small studies involving a total of 49 patients, enteral feeding was found not only to be feasible and cost-effective but also to be as successful as PN in preserving the nutrition status of children undergoing allogeneic HSCT.80,81 In an earlier study, Papadopoulo et al reported that EN, when tolerated, is beneficial and prevents the deterioration of nutrition status of pediatric patients undergoing HSCT.82 EN may be attempted if there is no active pathology in the GI tract and continued if the patient is able to tolerate it. In case of intolerance, it may be possible to modify the formula and tube placement. For example, nasoduodenal (ND) or nasojejunal (NJ) tubes may have a lower risk of causing vomiting and aspiration. 83 Refer to the Algorithm (Appendix 30-1) in making decisions regarding type of tube, delivery system, and formula selection. Parenteral Nutrition In the setting of severe regimen-related GI toxicities leading to poor oral intake and intolerance to EN, PN has been historically used to support patients after HSCT. There are mixed studies regarding the benefits and indications of PN use in HSCT patients. In 1987, Weisdorf and colleagues84 demonstrated that prophylactic use of PN in previously well-nourished HSCT patients was associated with positive outcomes. In 1997, Charuhas et al71 reported that patients who were randomized to PN resumed PO intake 6 days later than an intravenous (IV) hydration group, and even though the IV hydration group experienced 1.14% weight loss there was no difference seen in re-admission, relapse,
or survival rates. However Roberts et al74 in 2005 reported no difference in length of stay, engraftment time, days to resume oral intake, and rate of infection in patients who received PN versus patients on oral diet. They concluded that prophylactic use of PN results in improved nutrition status and does not affect the time to resume oral intake. Reported benefits of PN include reversal of protein energy malnutrition, restoration of immune-competence, and enhanced tolerance to anti-neoplastic therapy. 69 However, use of PN is associated with increased risk for several complications including line infections, hyper glycemia, hypertriglyceridemia, and cholestasis.67 Patients who present with compromised nutrition status prior to transplant are at risk of refeeding syndrome (Chapter 19). If a patient is at high risk for refeeding syndrome, nutrition support should be slowly advanced to meet goal energy requirements.85,86 As with any patient receiving PN, the patient should be monitored closely and the nutrition support regimen adjusted accordingly. Since most studies are done on heterogeneous patient populations with regards to type of transplant, diagnosis, kind of conditioning, age, and pretransplant nutrition status and the small sample size, there are no established criteria as to when PN should be initiated. Based on our clinical experience PN should be initiated after transplant for pediatric patients who receive myeloablative conditioning regimen, who are expected to have severe mucositis, or patients with poor nutrition status prior to transplant. However patients with non-myeloablative conditioning regimen, with minimal or no mucositis, and adequate nutrition status prior to transplant may be placed on oral or enteral nutrition. Clinical judgment about the type of nutrition support should not only include the specifics of patient population but also the risk and benefits of PN.
Nutrition Monitoring During HSCT

Monitoring and evaluating the efficacy of nutrition support in patients undergoing HSCT is very important and a complex process. However, there is a paucity of data to support the use of a single specific test or a battery of tests that could be used broadly in most clinical situations. This section will examine the published data on various measures of nutrition assessment. Fluid and Electrolyte Multiple factors, including the type and quantity of feeding, impact fluid and electrolyte status. Decisions about the volume and composition of total parenteral nutrition as well as of the type and amount of enteral formula must be
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Table 30-6 Side Effects of Some of the Drugs Commonly Used During HSCT
Drug Usage Side effect
Steroids Methotrexate Cyclosporine Tacrolimus
Immunosuppressive Immunosuppressive Immunosuppressive Immunosuppressive
Hyperglycemia, weight gain, osteoporosis, fluid and sodium retention, cardiomyopathy, hypercholesterolemia, hypertriglyceridemia, gut infection Mucositis, nausea, vomiting, diarrhea, hepatic and renal toxicities Hypertension, nephrotoxicity, significant hyperkalemia, hypomagnesemia, hepatotoxicity, hyperglycemia, hyperlipidemia, hypercholesterolemia, nausea, vomiting Hypertension, nephrotoxicity, hyperkalemia, hypomagnesemia, hyperbilirubinemia, hypercalcemia, hypercholesterolemia, hyperglycemia, hyperlipidemia, hyperphosphatemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, elevated hepatic enzymes, nausea/vomiting, anorexia, diarrhea Edema, hyperlipidemia, hypercholesterolemia Nausea, vomiting, diarrhea, anorexia, renal impairment, neutropenia Infusion reactions, increased infection risk, hypotension, nausea, vomiting Nephrotoxicity, anorexia, nausea, vomiting, diarrhea, elevated hepatic enzymes, hyperbilirubinemia Nausea, vomiting, diarrhea Nephrotoxicity Nephrotoxicity Hepatotoxic, skin rash, visual problems Nephrotoxicity Hepatotoxic
Sirolimus Cellcept Antithymoocyte globulin (ATG) Acyclovir Cefepime Amikacin Gentamicin Voriconazole Amphotericin Micafungin
Immunosuppressive Immunosuppressive Immunosuppressive Antiviral Antibiotic Antibiotic Antibiotic Antifungal Antifungal Antifungal
Source: Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2009. http://www.clinicalpharmacology.com. Accessed December 2009.
based on the state of fluid and electrolyte balance which must be monitored daily and carefully. Mucositis, diarrhea, vomiting, excessive salivation, fever, and other factors increase fluid losses. However, fluid retention is commonly seen at the time of engraftment. Other problems including sinusoidal obstruction syndrome (SOS) (formerly known as veno-occlusive disease (VOD)) and renal insufficiency may also cause fluid retention. In addition, they lead to electrolyte problems. Severe inflammatory reaction in the posttransplant period may lead to capillary leak and thirdspacing of fluids. In such a situation the weight may be high but the intravascular compartment is depleted. Many drugs like tacrolimus, cyclosporine, amphotericin, vancomycin, and ifosfamide can cause increased urinary losses of electrolytes requiring increased supplementation. Table 30-6 shows side effects of some of the drugs commonly used in HSCT. In general one should monitor basic biochemical indices like sodium, potassium, chloride, blood urea nitrogen, creatinine, glucose, calcium, phosphorus, and magnesium. See Table 30-7 for a suggested schedule for monitoring of biochemical indices.
Table 30-7 Suggested Schedule for Monitoring Blood Biochemical and Other Indices During Early Stages of HSCT
Lab Frequency
Sodium, potassium, chloride, carbonate, BUN, creatinine, calcium, magnesium Phosphorus Ionized calcium LFTs, albumin, total bilirubin Prothrombin time Vitamin D (25 OH D2+D3) Zinc Manganese, copper, selenium Triglycerides Weights Input/output
Every day until stable on total parenteral nutrition (TPN), then 3 times per week while on longterm TPN 3 times per week until stable on TPN, then weekly With consistent low-serum calcium 3 times per week until Day +30, then weekly while on TPN Weekly while on multiple antibiotics Pretransplant; then every 3 months until 1 year When increased losses suspected Monthly when on long-term TPN (46 weeks) Weekly while on intravenous lipid emulsion Daily while inpatient, then with every outpatient visit Daily while inpatient
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Triglycerides and Liver Function Tests Fasting triglyceride levels should be obtained prior to administration of intravenous fat emulsion (IVFE), and then weekly for the duration of the IVFE therapy. Cyclosporine, corticosteroids, tacrolimus, and sirolimus can all result in elevated triglyceride levels. Serum triglyceride levels should be monitored weekly if a patient is receiving any of the medications listed.67,71,79 During the first 4 weeks posttransplant, patients are at risk for SOS. Liver function tests (LFTs) should be monitored at least 3 times a week. If increasing levels are noted, more frequent LFTs may be necessary. Micronutrients Copper, selenium, and manganese levels should be monitored monthly if a patient has been receiving PN for more than 1 month, or in the presence of hyperbilirubinemia.67,71,87 If zinc supplementation is implemented, zinc levels (ie, serum or plasma zinc) should be monitored. However, zinc levels in blood are adversely affected by inflammation or infection so this should be taken into account when interpreting results. Clinical discretion should be used when evaluating zinc levels, keeping in mind that zinc levels in blood do not reflect tissue stores. Other Biochemical Indices Low serum albumin is predictive of an increase in mortality, poor outcome, complication rate, and length of stay and may be low in severe and chronic malnutrition, but it is not a good marker of acute nutrition status. 37 Nitrogen balance may be useful to assess protein status but the accuracy of the calculation is compromised in patients with vomiting, diarrhea, and renal insufficiency. Also, a 24-hour urine collection in pediatric patients may be difficult. Serum transferrin, prealbumin, and retinol binding protein are also not good indicators of nutrition status. 37 During inflammatory states, their hepatic synthesis is decreased by as much as 25% and their intravascular concentration is reduced due to capillary leak.88 Other factors like hydration, infection, and liver and renal insufficiency also affect their levels. Growth Weight trends should be monitored daily, as well as intake and output, throughout the entire transplant period.67 Length should be monitored monthly but one should be mindful that critically ill transplant patients will likely not attain age-expected linear velocity, despite provision of optimal nutrition support. Although weight fluctuates with fluid shifts, one study revealed that weight decreased overall and height increased slowly (1.7 cm/mo) 4 months
posttransplant.89 The same study showed that triceps skinfold (TSF) measurements and midarm circumference also decreased. Therefore, TSF measurements should be obtained and monitored. Fluid shifts will not affect skinfold measurement.89 Bone growth can be monitored by obtaining a dual-energy x-ray absorptiometry (DEXA) scan bi-annually.90
HSCT Complications Impacting Nutrition

Pediatric patients undergoing HSCT are at significant risk for developing many complications that may have direct and indirect impact on the nutrition status. The most important are described below. Mucositis Mucositis, or inflammation and breakdown of the mucosal lining of the mouth and gut, may occur in up to 100% of patients undergoing HSCT with high-dose chemotherapy.91 Severity depends on many factors including the dose intensity of chemotherapy and use of concomitant radiation. Moderate to severe mucositis often requires IV narcotics. In the presence of moderate and severe mucositis oral intake is nearly impossible and PN is the only option. Severe mucositis also predisposes to infections.92
Graft versus Host Disease

GVHD is caused by an immunologic reaction in which donor-derived T-cells recognize the host cells as foreign and attack them. Generally, acute GVHD occurs before 100 days posttransplant and chronic GVHD develops after more than 100 days from transplant. This definition/classification is being replaced with the new classification by the National Institutes of Health that includes late-onset acute GVHD (after day 100) and an overlap syndrome with features of both acute and chronic GVHD.93,94 Immunosuppressive drug combinations are used to prevent GVHD. Calcineurin inhibitors, cyclosporine, and tacrolimus are generally used with methotrexate, mycophenolate, steroids, or sirolimus. High-dose steroids are used to treat acute GVHD.95 For treating chronic GVHD, steroids with or without calcineurin inhibitors are used.96 Acute GVHD The organs most commonly affected in acute GVHD are the skin (81%), gut (54%), and liver (50%).97 Skin is usually the first organ to be involved. Symptoms of acute gut GVHD include nausea, vomiting, loss of appetite, abdominal pain, and diarrhea, which is secretory in nature and is voluminous (> 2 L/d in severe cases).98 Gut GVHD most commonly
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Table 30-8 Staging and Grading of Acute GVHD Stage Skin* Liver bilirubin Gut^# + Maculopapular rash < 25% body surface 23 mg/dL Diarrhea, 5001000 mL/d or persistent nausea ++ Maculopapular rash 2550% body surface 36 mg/dL Diarrhea, 10001500 mL/d +++ Generalized erythroderma 615 mg/dL Diarrhea, > 1500mL/d ++++ Desquamation and bullae > 15 mg/dL Abdominal pain with or without ileus *Use rule of nines or burn chart to determine extent of rash. ^ Diarrhea volumes apply to adults. # Persistent nausea requires endoscopic biopsy evidence of GVHD histology in the stomach or duodenum. Overall Grade 0 (none) I (mild) II (moderate) III (severe) IV (Life threatening) Skin 0 + to ++ + to +++ ++ to +++ + to ++++ Liver 0 0 + ++ to +++ ++ to ++++ Gut 0 0 + ++ to +++ ++ to ++++ Functional Impairment 0 0 + ++ +++
Reprinted with permission from Sullivan KM. Graft-vs-host disease. In: Blume KG, Forman SJ, Appelbaum F, eds. Thomas Hematopoietic Cell Transplantation. 3rd ed. Oxford: Blackwell Publishing; 2004:635664.
affects the lower GI tract causing severe, high-output diarrhea associated with bleeding and cramping abdominal pain.99 GVHD of the upper GI tract causes decreased appetite, nausea, and vomiting.79 Active GVHD leads to mucosal degeneration, malabsorption, and protein loss. Liver GVHD is characterized by cholestatic hyperbilirubinemia, however it can be difficult to differentiate other causes of liver function impairment; the differential diagnosis includes SOS, infection, sepsis, drug effects, iron overload, or PN-induced cholestasis.98 Acute GVHD is graded based on the extent of skin, liver, and gut involvement (see Table 30-8 for staging and grading). Long-term survival (5 years) for grade III is 25% and grade IV is 5%.100 Prevalence of acute GVHD varies from 35% to 45% in full matched sibling donors to 60% to 80% in patients with 1 antigen HLA mismatched transplant.101 With the same degree of HLA mismatch, patients receiving umbilical cord blood transplant have lower frequency of acute GVHD (35% to 65% compared to 60% to 80% in patients receiving unrelated donor graft).102 Chronic GVHD Chronic GVHD involves skin, gut, liver, lungs, eyes, mouth, and bone marrow. Risk factors for development of chronic GVHD include the age of the patient and history of acute GVHD. About 22% to 29% of pediatric patients undergoing HSCT will develop chronic GVHD.103 In adult patients, chronic GVHD ranges from 30% to 50% in HLA-matched sibling transplant.104 A low-fiber, low-lactose, low-fat, bland diet may be necessary during periods of acute GVHD, but use of this dietary modification is not the norm.69 PN is warranted when
diarrheal output worsens with ingestion of food and EN. Pancreatic Insufficiency If diarrhea continues in absence of GVHD, patients should be evaluated for pancreatic insufficiency.105 Of pediatric patients undergoing HSCT, 4.9% were found to have acute pancreatitis.102 Bacterial Overgrowth Bacterial overgrowth has not been well studied and defined in this group of patients. However, based on clinical reports, if diarrhea continues after GVHD and infection and pancreatic insufficiency is ruled out, patients should be worked up for bacterial overgrowth. Long-term use of antibiotics and patients inability to take oral diets for prolonged periods after HSCT can alter the type and quantity of bacterial flora similar to short gut. Infection The immuno-suppressed patient is highly susceptible to bacterial, viral, and fungal infections. C. difficile infection is one of the common infections identified in the transplant population.106 Some of the viral infections known to cause diarrhea in HSCT patients are adenovirus, cytomegalovirus, astrovirus, and rotavirus.107 Infections affecting the GI tract can lead to intolerance of oral intake and EN. Antiviral, antifungal, and antibiotic medications can cause loss of appetite, nausea, vomiting, diarrhea, and malabsorption. Antibiotic medications may also decrease the amount of lactase enzyme in the intestine; if symptomatic, these patients may benefit from a low-lactose diet.108,109
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Hemorrhagic Cystitis High-dose cyclophosphamide can lead to hemorrhagic cystitis, a complication characterized by bloody urine. Fluid intake may need to be twice the maintenance needs in order to irrigate the blood clots in the bladder. Viral infections unique to the immuno-compromised patient, which include adenovirus and BK virus, can also lead to hemorrhagic cystitis.67,87,108 Sinusoidal Obstruction Syndrome SOS is usually seen between 1 to 4 weeks posttransplant and reflects regimen-related toxicity.110 Injury to the endothelial cells of the sinusoids, thickening of the hepatic venules due to edema, and deposition of fibrin, factor VII, and blood cell fragments leads to narrowing and increased resistance to the blood flow through the venules. This causes hepatic congestion and portal hypertension.111 Weight gain, hyperbilirubinemia, ascites, right upper-quadrant pain, and hepatomegaly are the clinical symptoms associated with SOS. Severe SOS can lead to liver failure, hepatorenal syndrome, portal hypertension, and multiorgan failure. Pre-existing liver dysfunction, previous transplantation, abdominal irradiation, conditioning regimen, adrenoleukodystrophy, and neuroblastoma are some of the risk factors for SOS.112 The incidence of SOS in children after HSCT ranges from 5% to 40%,112 and the mortality rate in severe SOS has been reported to be as high as 47%.113
Risk factors for late effects can be due to tumor, from direct tissue effects, tumor-induced organ dysfunction, and mechanical effects. The multimodal treatment used during treatment can also be responsible for many late effects. The Childrens Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers (COG-LTFU Guidelines)115 extensively review late effects of treatment used. Genetic predisposition, capacity for normal tissue repair, organ function not affected by treatment, developmental status, and pre-morbid state can influence development of late effects.114,116
Long-Term Follow-Up Guidelines

The COG-LTFU Guidelines115 are clinical practice guidelines used in screening and management of late effects that can result from therapy used during treatment for pediatric malignancies. The guidelines are evidence-based (utilizing established associations between therapeutic exposures and late effects to identify high-risk categories) and grounded in the collective clinical experience of experts (matching the magnitude of the risk with the intensity of the screening recommendations). These guidelines are appropriate for survivors of childhood, adolescent, or young adult cancers 2 or more years following the completion of cancer therapy. Given the wide age range, some guidelines may not be applicable (ie, limiting alcohol intake in a 10-year-old); therefore, clinicians must be guided by the age of the patient and the relevance of the guidelines. References related to each late effect and patient education materials on a variety of topics are also included in the guidelines.115 When determining guidelines for cancer survivors it is important to use traditional assessment/recommendations taking into account the age of the survivor and his or her pertinent clinical history. Suggestions are geared toward leading a healthy lifestyle and include nutrition and activity guidelines. The recommendations for cancer survivors is that they adopt the prevention guidelines.
Conclusion
Nutrition assessment, support, and monitoring during the transplant process are critical parts of patient management. These measures are even more important in pediatric patients because of small size, need for continuing growth and development, and the potential for rapid deterioration. Comprehensive assessment may include information about anthropometrics, food intake, appetite, presence of infection, organ dysfunction, wounds, nausea, vomiting, diarrhea, and mucositis amongst others. Good clinical judgment is critical and decision making should be individualized in an effort to provide optimal nutrition management.
Gastrointestinal (GI) Problems in Survivors117

Treatment for childhood cancer can result in chronic problems of the intestine or other parts of the GI system including bowel obstruction, gallstones, esophageal stricture, hepatic fibrosis, colorectal cancer, and chronic enterocolitis. Treatments that increase risk for having GI problems include: Radiation doses of 30 Gy (3000 cGy/rads) or higher to the chest, neck, pelvis, or abdomen Surgery in the pelvis or abdomen
Late Effects of Treatment for Survivors of Childhood Cancer
The 5-year survival rate for pediatric cancer has improved and is about 80% for some diagnoses, although many patients experience late effects or long-term health-related outcomes that can result in organ dysfunction, second malignant neoplasms, and adverse psychological sequelae.114
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Other risk factors include a family history of gallstones, colorectal or esophageal cancer, patient history of bowel adhesions (scarring) or bowel obstruction (blockage), use of tobacco, or chronic GVHD Possible symptoms of GI problems can include chronic nausea, vomiting, acid reflux, constipation or diarrhea, pain (with swallowing or abdominal), change in appetite, weight loss, black tarry stools or blood in stool, abdominal distention, and jaundice. Suggestions for managing GI problems include118: 1. Eat 5 or more servings of fruits and vegetables daily. 2. Choose a variety of foods from all food groups. 3. Include high-fiber foods in diet (eg, whole grain breads, cereal). 4. Avoid foods high in sugar (eg, candy, soda). 5. Choose low-fat milk and dairy products. 6. When eating meats, choose leaner cuts and broil or boil when preparing. 7. Decrease high-fat foods (potato chips, french fries). 8. Limit the use of alcohol. 9. Do not smoke or use tobacco and avoid second-hand smoke.
Bone Health115
Bone is a living growing tissue (206 bones in the body) made up of calcium, phosphorus, magnesium, vitamin D, and fluoride. All of these nutrients are important in the development and maintenance of bone and other calcified tissues. A consequence of childhood cancer treatment is a decrease in peak bone mass from normal levels and an increased loss of calcium from the bones. Survivors are at increased risk for osteoporosis, a result of poor bone formation or too much bone loss; therefore fractures may occur as bones become weaker. Osteoporosis is diagnosed by an X-ray technique, known as DEXA, which measures bone density or bone mass and takes less than 20 minutes to complete. Risk factors for osteoporosis are as follows: 1. General risk factors include female, family history of osteoporosis, Caucasian or Asian, older age, small/thin frame, smoking, diet low in calcium, increased amounts of alcohol, caffeine or soda, lack of weight-bearing exercise and diet that is high in salt. 2. Risk factors in survivors of childhood cancer include anti-cancer treatment utilizing methotrexate or corticosteroids as well as radiation to weight-bearing bones. Other medical treatments such as anticonvulsants and medication used to treat early puberty and endometriosis (Lupron) can affect bones. Drugs including aluminum-containing antacids (Maalox), cholesterol-
lowering medication (cholestyramine) and high-dose heparin for prolonged periods are risk factors. 3. Suggestions for decreasing risk of osteoporosis include activity with weight-bearing (walking, dancing) and resistance (light weight lifting) exercises. General guidelines for calcium requirements are 1000 to 1500 mg/d (elemental calcium), but may vary based on age, clinical history, and results of DEXA scan. Food sources include dairy products (milk, cheese, yogurt) and non-dairy sources (ie, salmon, collards, broccoli, white beans, fortified foods such as orange juice and some cereals). Calcium is found in supplements as a salt and is bound to carbonate, gluconate, citrate, or lactate. The recommendations are based on elemental calcium. Calcium carbonate is the most prevalent form of calcium supplement on the market and should be taken after meals as it requires stomach acid for better absorption. It provides more elemental calcium (40% elemental) than calcium citrate; therefore, not as many tablets are required. Calcium citrate is the best absorbed supplemental form of calcium. It does not require extra stomach acid for absorption; therefore, it may be taken any time during the day, even on an empty stomach. Some brands list total weight of calcium salt, not the amount of elemental calcium. Generic brands are less expensive, but they may not meet United States Pharmacopeia (USP) standards for quality and purity. It is best to avoid oyster shell, bone meal, or dolomite as they may contain lead, mercury, or arsenic. The Nutrition Facts Label should state the Percent Daily Value (%DV) based on 1000 mg of elemental calcium. It is necessary to individualize calcium requirements based on age and clinical history. Vitamin D is needed to absorb calcium and is generally found in dairy products that are fortified. It is recommended that supplementation not exceed 800 International Units per day, but should be based on age and clinical history. Although we are able to make Vitamin D through sun exposure, it is felt that most people do not make enough due to the use of sunscreens and limited sun exposure.
Heart Health after Treatment for Childhood Cancer119

Cancer treatments that can cause heart problems include chemotherapy (anthracyclines) and radiation to the heart or surrounding tissues. Types of heart problems that can occur after treatment include left ventricular dysfunction, cardiomyopathy, arrhythmias, valvular stenosis or insufficiency, pericardial fibrosis, and coronary artery disease. Risk factors for developing heart problems can be due to other medical conditions (obesity, high blood pressure,
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diabetes, elevated cholesterol or triglycerides). Aerobic exercise is generally safe and healthy for the heart, but some forms of exercise can be stressful to the heart (eg, wrestling and heavy weight lifting). Survivors who might be at risk for having heart problems should check with their health care provider before starting an exercise program. Tests that are done to monitor heart function include electrocardiogram (ECG), echocardiogram, or MUGA scan and should be recommended by a health care provider if appropriate. In order to prevent problems with the heart it is best to stay at a healthy body weight, limit fat intake to no more than 30% of calories, exercise moderately for at least 30 minutes on most days, and avoid smoking.
Diet and Physical Activity for Survivors119

American Institute for Cancer Research Recommendations for Cancer Prevention118 include the following: 1. Be as lean as possible (not underweight). 2. Be physically active (30 minutes on most days). 3. Avoid sugary drinks. Limit intake of processed foods high in fat and/or added sugar, or low in fiber. 4. Eat a variety of vegetables, fruits, whole grains, and legumes (beans). 5. Limit consumption of red meat (beef, pork, lamb). Avoid processed meats. 6. If consumed, limit alcoholic drinks to 2 for men and 1 for women per day. 7. Limit consumption of salty foods and foods processed with salt (sodium). 8. Do not use supplements to protect against cancer.
9. Do not smoke or chew tobacco. 10. Handle food safely (immune system may be affected in survivors risk for food-borne illness). 11. Rethink the pattern of eating with two-thirds of a meal comprising vegetables, fruits, whole grains, and beans and one-third coming from cheese or animal foods. Maximize the variety of vegetables and fruits eaten as they contain phytochemicals (plant compounds that have been shown to act as antioxidants, boost the immune system, have anti-inflammatory, antiviral, and antibacterial effects, and aid in cellular repair). Nutrients should be provided in the diet from a variety of sources. Protein is needed for growth, repair of body tissue, and assistance with maintaining immune function. Carbohydrates and fats are the bodys major energy (calorie) sources. Vitamins and minerals are essential for proper growth and development and are needed to utilize the energy in food. Water is important to prevent dehydration, which may cause a person to feel listless or dizzy. Benefits of regular exercise and good nutrition for childhood cancer survivors include promoting healing of tissues/organs damaged by cancer and treatment, building strength and endurance, reducing risk of certain types of adult cancers and diseases (eg, diabetes, heart disease), decreasing stress, and providing a feeling of well-being. Although late effects can occur in survivors of pediatric cancer, a healthy lifestyle including proper diet and physical activity are important to maximize quality of life and prevent the incidence of certain chronic diseases.
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Appendix 30-1: Algorithm For Nutritional Intervention In The Pediatric Oncology Patient
Identify appropriate category: Age > 2 years choose either BMI (Body Mass Index) or IBW (Ideal Body Weight) Age < 2 years choose WT/LT (Weight for Length) or IBW (Ideal Body Weight)
Categories for Nutritional Status

Underweight BMI WT/LT IBW < 5th % ile < 10th % ile < 70% Severe > 70-80% Moderate > 80-90% Mild Normal 5-85th % ile 10-90th % ile > 90-110 % > 110-120% Risk of Overweight / Overweight* > 85-95th % ile > 95th % ile > 90th % ile > 120%
*Evaluate for weight gain or loss
> 5 % wt loss from Usual Body Weight (UBW) or during therapy or Crossing > 2 percentile channels NO Meeting > 80 % estimated nutritional needs through oral intake (food and supplements) YES NO Encourage oral intake/supplements and monitor weight/adequacy of diet once a month. NO Will impending treatment adversely affect nutritional status and ability to meet needs orally? YES NO Oncologic prognosis warrants TPN (Total Parenteral Nutrition) or TF (Tube Feeding) YES Can patient safely tolerate/absorb nutrients via GI tract? NO Is expected need for nutritional support > 5 days? YES NO TPN until GI tract can be safely used YES Is patient a candidate for tube feeding? NO Can intolerance be alleviated by changing formula or using antiemetics/motility agents NO Monitor and intervene as needed TPN YES High risk of pulmonary aspiration or excessive emesis NO NO Gastric feeds YES Post-pyloric feeds YES YES
Can tolerance be alleviated by changing formula, method of administration or adding medication? YES Implement necessary changes
Tube feedng required for > 3 months NO Nasoenteric tube feeding Nasogastric (NG) Nasoduodenal (ND) Nasojejunal (NJ) YES Enterostomy tube feeding (PEG vs.G-Tube) Gastrostomy (GT) Jejunostomy (JT) Gastro-Jejunostomy (G-JT)
NO
Provide tube feedings as tolerated and wean when oral consumption is > 50% estimated needs
YES
Can patient tolerate feedings in strength and amounts necessary to meet estimated needs?
Childrens Oncology Group, Cancer Control Nutrition Sub-Committee 10/04. Reprinted with permission.
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Appendix 30-2: Algorithm for Nutritional Intervention and Categories of Nutritional Status in the Pediatric Oncology Patient References and Resources
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Appendix 30-2, continued
Appendix 30-3: Categories of Nutritional Status for the Pediatric Oncology Patient
Identify appropriate category: Age > 2 years choose either BMI1 (Body Mass Index) or IBW2 (Ideal Body Weight) Age < 2 years choose WT/LT3 (Weight for Length) or IBW2 (Ideal Body Weight) Weight loss/gain may or may not be present
Underweight BMI WT/LT IBW < 5th % ile < 10th % ile < 70% Severe70-80% Moderate > 80-90% Mild Normal 5-85th % ile 10-90th % ile > 90-110 % > 110-120% Risk of Overweight / Overweight* > 85-95th % ile > 95th % ile > 90th % ile > 120%
BMI - Body Mass Index (percentile) Hammer LD, Kraemer HC, Wilson DM, Ritter PL, Dornbusch SM. Standardized percentile curves of body-mass index for children and adolescents. American Journal of Disease of Child. 145:259263, 1991. Pietrobelli A, Faith MS, Allison DB, Gallagher D, Chiumello G, Heymsfield, SB. Body mass index as a measure of adiposity among children and adolescents: A validation study. Journal of Pediatrics. 132:204210, 1998. 2 IBW - Ideal Body Weight for height or length (percentage) Waterlow JC. Classification and definition of protein-calorie malnutrition. British Medical Journal 3: 566-569, 1972. 3 WT/LT - Weight for Length (percentile) Motil KJ. Sensititve measures of nutritional status in children in hospital and in the field. International Journal ofCancer: Suppl. 11: 2-9, 1998.
1
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Appendix 30-4: Gastrointestinal Supportive Care Medications
Nutrition support efforts in pediatric and adult cancer patients are often complicated by problems with gut motility, hyperacidity, nausea and vomiting, loss of appetite, and treatment-induced mucositis. This appendix discusses some of the medications available to help treat these conditions.
is on metoclopramide. Other drugs such as tacrolimus and cyclosporine may have increased absorption when a patient is on metoclopramide.123 Doses of metoclopramide should be reduced in patients with renal dysfunction.
Erythromycin
This drug is a macrolide antibiotic, but it also is a motilin receptor agonist that increases proximal gut motility.120,124 Prokinetic effects are evident at doses as low as 4 to 12 mg/kg/d as compared to the 30 to 50 mg/kg/d used for antimicrobial effects. Numerous studies suggest activity of erythromycin for improving feeding tolerance in children.120,124 Typical problems with antimicrobial doses of erythromycin include gastrointestinal upset, diarrhea, and inhibition of P450 1A2 and 3A4 enzymes causing drug interactions. These effects are less likely at the lower doses used for motility. Although rare, there are some concerns about adverse effects such as hepatotoxicity, ototoxicity, cardiac arrhythmias, and pyloric stenosis.124 The latter has been reported mostly in infants less than 2 weeks old. A theoretical concern is the potential for low-dose antibiotics to stimulate resistance among bacteria. This has not been documented with the use of erythromycin for motility and thus is an unknown. Caution should be used in patients with hepatic impairment, largely due to the potential of erythromycin to cause hepatotoxicity.
Motility Agents (Metoclopramide, Erythromycin)
These agents have numerous uses, including to aid nasogastric intubations, and for gastroparesis, gastroesophageal reflux, and intolerance to feedings.
Metoclopramide/Reglan
This drug blocks dopamine and at higher doses, 5 HT3 (serotonin) receptors. Its effects on motility may involve increased release of acetylcholine in the gut. The effect on the gut is increased forward peristalsis in the stomach and duodenum. Metoclopramide has been used for the indications listed above as well as for chemotherapy-induced nausea and vomiting. The latter use typically requires higher doses. Data confirming the clinical utility vary with the indication. For chemotherapy-induced nausea and vomiting, combinations of high-dose metoclopramide with dexamethasone and either diphenhydramine or lorazepam were demonstrated to be effective in the 1980s, but serotonin receptor antagonists such as ondansetron have been shown to be superior. Metoclopramide is typically effective in aiding intubations for patients with slow gastric motility and for gastroparesis. Data proving utility in pediatric patients with gastroesophageal reflux or feeding intolerance are harder to find.120 Children are more sensitive to extrapyramidal side effects of dopamine blockers. Diphenhydramine (Benadryl) is effective at preventing or treating dystonias, while lorazepam is often more effective at reducing akathisias.121 While akathisias and dystonias are generally easily reversed, there are a few reports of tardive dyskinesias causing long-term movement disorders.120 In February 2009, the Food and Drug Administration (FDA) announced it was requiring a boxed warning in the labeling regarding the risk of tardive dyskinesia with higher doses or longer-term use of metoclopramide. Manufacturers must implement a risk evaluation and mitigation strategy to ensure patients receive a medication guide discussing the risk.122 The major drug interactions involving metoclopramide relate to its ability to speed transit through the gut. Drugs that are designed for sustained release or that have slow dissolution and absorption may have reduced absorption while a patient
Acid-Blocker Medications
H2 receptor antagonists and proton pump inhibitors have been used mostly for ulcers or gastroesophageal reflux disease in adults. They may be useful in children in situations where blocking acid secretion is helpful. Although antacids or sucralfate may be reasonable for short-term use in pediatrics, the aluminum that can be absorbed from sucralfate and some antacids contraindicates any longer term use.
H2 Receptor Antagonists (Famotidine/Pepcid, Ranitidine/Zantac, Nizatidine/Axid, Cimetidine/ Tagamet)

These drugs block histamine-induced acid secretion. Higher doses of H2 receptor antagonists block acid secretion better than lower doses, although proton pump inhibitors block acid secretion better than high doses of H2 receptor antagonists.125127 Some data support the use of H2 receptor antagonists for gastroesophageal reflux disease in infants and young children, although a potential limitation to chronic use is the development of tolerance to the acid neutralization.128 Adverse effects are uncommon but include headaches, sedation, and gastrointestinal side
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effects. Cimetidine may inhibit the metabolism of some drugs, but other H2 receptor antagonists are not likely to affect drug metabolism. Any of these drugs may alter the absorption of other drugs that are sensitive to higher gastric pH (eg, ketoconazole, itraconazole, ampicillin, iron). All 4 of these drugs require reduced doses in patients with renal impairment. H2 receptor antagonists are available in nonprescription formulations.
Proton Pump Inhibitors (Omeprazole/Prilosec, Lansoprazole/Prevacid, Pantoprazole/Protonix, Esomeprazole/Nexium, Rabeprazole/Aciphex)

These drugs block hydrogen/potassium ATPase (the proton pump), effectively blocking acid secretion induced by virtually all stimuli. Proton pump inhibitors have shown good activity in adults with GERD and hypersecretory syndromes, and there is some evidence for efficacy in children with gastroesophageal reflux disease.128 As with H-2 receptor antagonists, adverse effects are rare but include headaches and gastrointestinal effects such as abdominal pain, constipation, or diarrhea. Altered absorption of other drugs can occur due to elevated gastric pH, and omeprazole may inhibit some hepatic P450 enzymes, reducing metabolism of some drugs such as warfarin.128 Proton pump inhibitors work best when administered 15 to 30 minutes before a meal.129 Administration of lansoprazole or omeprazole through an NG tube is best accomplished by either using the lansoprazole Oral Disintegrating Tablet, or mixing the enteric coated granules from the lansoprazole or omeprazole capsule or packet for suspension in 8.4% sodium bicarbonate solution (1 mEq/mL parenteral solutions are generally used for this).130,131 These formulations are less viscous and appear to go through tubes better. An alternative is mixing the contents with an acidic fruit juice, which preserves the enteric coating until the granules reach the alkaline contents of the small intestine. Another alternative may be the intravenous formulations available for pantoprazole and lansoprazole. Mixing enteric-coated granules in water for administration results in a more viscous solution that does not go through enteric tubes as well. Dosaging guidelines are not available, but doses may need to be reduced in patients with significant hepatic impairment. Omeprazole is available as a nonprescription drug.
antagonists and dopamine blockers are generally useful for all 3 causes. Other drugs discussed here are mostly used for chemotherapy-induced nausea and vomiting. The most recent American Society of Clinical Oncology antiemetic guidelines include suggestions regarding radiation-induced emesis.121 The National Comprehensive Cancer Network publishes emesis guidelines (updated annually) on its Web site, and the Multinational Association of Supportive Care in Cancer also has published guidelines on the Internet. All of these guidelines currently divide chemotherapy drugs into classes that are high, moderate, low, or minimal likelihood of causing emesis. Combinations of a serotonin receptor antagonist with a steroid and aprepitant (Emend) are recommended for highly emetogenic chemotherapy regimens by all guidelines. Combinations of a serotonin receptor antagonist and a steroid are generally recommended for moderately emetic regimens, a single agent (often steroids) for low emetogenicity, and antiemetics only as needed for minimally emetic regimens.
Serotonin Receptor (5HT3 or 5-hydroxytryptamine-3) Antagonists (Ondansetron/Zofran, Granisetron/ Kytril, Dolasetron/Anzemet, Palonosetron/Aloxi)
These drugs block the effects of serotonin at the 5HT3 receptors in the gut and the chemotherapy receptor trigger zone. They are generally better at reducing vomiting than at reducing nausea.132 Used in equivalent doses, there are few differences between these agents, although palonosetron has a longer duration of activity, apparently due to its tighter binding to receptors and longer half-life. Palonosetron may be better at preventing delayed nausea and vomiting due to this activity, although most studies have compared it to a single dose of the shorter acting agents, which are more likely to be used daily. In this class of drugs, the oral route of administration is equally effective as intravenous, as long as the patient is not actively vomiting. Recently, all antiemetic guidelines have dropped serotonin receptor antagonists from their recommended drugs to treat delayed nausea and vomiting (more than 24 hours after chemotherapy) due to the minimal evidence for their efficacy.133 The most likely adverse effects with serotonin receptor antagonists are headaches, and constipation with multiple-day use.132 Prolongation of the QTc interval has been reported with this class of drugs, although it is generally not thought to be clinically significant. However, the dolasetron package insert does contain a warning regarding use in patients at increased risk of arrhythmias, and dolasetron is not approved for use in children in Canada due to reports of cardiovascular adverse effects (arrhythmias, cardiovascular arrest).134 Patients who have
Antiemetics
Antiemetics in pediatric hematology/oncology patients are used primarily for nausea and vomiting due to chemotherapy, radiation, and surgery. Serotonin receptor
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received therapy with anthracyclines (doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone, cisplatin, or ifosfamide) are at the greatest risk for cardiovascular side effects. The latter 2 can cause electrolyte abnormalities due to renal tubular losses of calcium, magnesium, potassium, phosphate, and bicarbonate. These losses may require supplementation, and oral supplementation generally tastes bad and is poorly absorbed. Anthracyclines and mitoxantrone cause damage to cardiac myofibrils that may result in heart failure for some patients. This is most common when young children receive the drug, and at lifetime doses above 300 mg/m2 for younger children and 450 to 550 mg/m2 for older children and adults. Ondansetron has a prolonged half-life in patients with severe liver impairment and doses should be reduced. Palonosetron, dolasetron, and granisetron do not need dose adjustments in renal or hepatic dysfunction.134
or metoclopramide, but can be used as single agents for mildly emetic regimens. Glucocorticoids have a long list of adverse effects, but the ones most commonly seen with short-term use are hyperglycemia, gastrointestinal upset, hypertension, and mental or behavioral changes. Doses should be reduced when used with aprepitant, as mentioned above.
Phenothiazines (Prochlorperazine/Compazine, Promethazine/ Phenergan, Chlorpromazine/ Thorazine) and Butyrophenones (Haloperidol/ Haldol, Droperidol/Inapsine)
These drugs block dopamine receptors in the vomiting center and chemotherapy-receptor trigger-zone. These agents are currently recommended mostly for acute nausea and vomiting from mildly to moderately emetic chemotherapy regimens, or for breakthrough nausea and vomiting. Prochlorperazine and promethazine have been used for delayed nausea and vomiting with some success. Potential side effects include sedation, anticholinergic effects such as urinary retention or constipation, and alpha-adrenergic blockade effects such as hypotension. However the major adverse effects are extrapyramidal effects: akathisias (restlessness) and dystonias (muscle contraction) such as trismus and torticollis. These effects occur more frequently in children and many pediatric practitioners limit the use of dopamine blockers due to these side effects. Diphenhydramine (Benadryl) will generally reverse extrapyramidal effects within 30 to 60 minutes, and has often been used prophylactically to reduce the risk of extrapyramidal reactions. Also of note are specific issues with 2 of these drugs. First, droperidol is either not used or dose-limited in many institutions due to its ability to lengthen the QTc interval and cause arrhythmias. Second, IV promethazine can be very irritating on injection, and if injected into an artery can cause significant tissue damage. Many institutions are limiting its use to low doses or oral administration. Risk may be minimal if central lines are available for administration, which is commonly the situation in children with cancer. Additionally, promethazine has a boxed warning in the package insert against using it in patients less than 2 years old, due to reports of fatal respiratory depression.
Aprepitant (Emend and Fosaprepitant, theIntravenous Emend)

This drug is a neurokinin-1 receptor antagonist (its ligand is Substance P) that has been found to produce a small reduction in acute nausea and vomiting, but a larger reduction in delayed nausea and vomiting. The FDA-approved dosing is for the first 3 days of the chemotherapy regimen, combined with a serotonin receptor antagonist and a steroid, but not as a single agent. Until 2008, only the oral formulation was available and therefore there was not an easy way to administer this drug to most children. Although adolescents are often large enough to be dosed as adults, children have generally not been treated with aprepitant. A potential problem with aprepitant is its ability to inhibit P450 microsomal enzymes and reduce metabolism of other drugs. Dexa methasone doses of approximately 12 mg with aprepitant are equivalent to 20 mg without aprepitant. Warfarin doses will generally require reduction also. There is concern that some chemotherapy drugs may have reduced clearance when patients take aprepitant, but currently there are little data suggesting clinical problems with this potential interaction. Regardless, it is important to only use aprepitant for highly emetic regimens as indicated in current practice guidelines, and to use caution when concomitant chemotherapy agents are known to be metabolized by hepatic P450 enzymes.
Glucocorticoids (Dexamethasone/Decadron, Methylprednisolone Sodium Succinate/Medrol)

These drugs have been used as antiemetics since the early 1980s, but it is still not clear how they work. They are used mostly in combinations with a serotonin receptor antagonist
Cannabinoids (Dronabinol/Marinol, Nabilone/ Cesamet)

These drugs have been used mostly for patients who have not responded well to more typical antiemetics. These drugs are synthetic versions of THC (tetrahydrocannabinol), the psychoactive component of marijuana. Early studies suggested these agents were most effective in younger adult
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patients, patients who had smoked marijuana, and patients who developed euphoria while taking them. While many pediatric institutions have some experience using these agents in children, there are little data published on use in children, and most of those data are with nabilone. Recommended doses of dronabinol are very high; some patients tolerate the drug better when lower doses are used and started prior to the chemotherapy. Adverse effects are the same as for marijuana, including euphoria or dysphoria, hypotension, tachycardia, increased appetite, dry mouth, and occasionally hallucinations.
Atypical Antipsychotics (Olanzapine/Zyprexa)

These drugs are similar to the dopamine blockers discussed above, but are less likely to cause extrapyramidal side effects. Very few studies have been published, but there are several case reports and small studies showing efficacy of olanzapine in adult patients who have not responded well to more standard antiemetics.132 Adult recommended doses are 5 to 10 mg per day, with 2.5 to 5 mg per day being used in case reports in children. Other than sedation, few side effects have been reported with short-term use.
the drugs tried, only progestins and glucocorticoids showed a benefit in cancer-induced anorexia and weight loss. There are doubts about even these drugs, as the weight gain from progestins such as megestrol may consist more of fat and water than lean body mass136 and glucocorticoids have negative anabolic effects that result in muscle weakness over time. Studies have shown at least some increased appetite and weight gain benefit from methylprednisolone (Medrol), dexamethasone (Decadron), and prednisone. In addition to the short-term side effects discussed above in the antiemetic section, glucocorticoids have numerous long-term side effects that include osteoporosis, aseptic necrosis, cataracts, easy tearing of the skin, and loss of muscle strength. Perhaps the best use of these agents for increasing appetite is in hospice patients where the longer term adverse effects are of less consequence.
Megestrol/Megace and Medroxyprogesterone/ Provera

These drugs are progestins that have an effect of increasing appetite and causing weight gain. Most studies of megestrol have involved only adults, but one pediatric study used megestrol in a few patients for whom cyproheptadine (see below) did not work. Five of 7 children responded with weight gain.137 As noted above, there is some doubt about the nature of the weight gained (fluid retention or fat versus lean body weight), but there are numerous studies documenting the weight gain.135 Potential adverse effects of significance include thrombophlebitis, photosensitivity, impotence in men, and Cushings syndrome with adrenocortical suppression and the potential for Addisonian crisis.134,138
Antihistamines (Diphenhydramine/Benadryl) and Benzodiazepines (Lorazepam/Ativan)

These drugs have been used as adjunctive agents for chemotherapy-induced nausea and vomiting. Neither has good activity on its own as an antiemetic for chemotherapy, although the sedation they cause may help the patient sleep and have less nausea and vomiting. Diphenhydramine has good anticholinergic activity in the brain, and is therefore able to reduce and/or treat extrapyramidal reactions from dopamine blockers. Likewise, lorazepam is beneficial in reducing or treating akathisias caused by dopamine blockers. Lorazepams activity as an antianxiety medication and its ability to cause anterograde amnesia in some patients may help reduce anticipatory nausea and vomiting. Some pediatric patients develop paradoxical reactions to these agents, becoming agitated instead of sedated. This appears to be more common in younger patients and with higher doses. Additionally, some pediatric patients become weepy or have hallucinations, limiting the usefulness oflorazepam.
Dronabinol/Marinol (But Not Nabilone)

This drug has been studied for weight gain in adults, and is FDA approved for treating anorexia in AIDS patients. Little data are available on use in cancer patients with anorexia or in pediatrics. While it does stimulate appetite for periods of at least 5 months, there is minimal evidence for efficacy in causing weight gain or reducing weight loss in cancer patients.134,135,138,139 As noted above in the antiemetic section, there are many potential adverse effects associated with dronabinol, however the doses used for appetite stimulation are lower (2.5 mg twice daily) than those used for antiemesis, so there may be fewer adverse effects.
Appetite Stimulants
Weight loss in cancer patients may be due to numerous factors, as described in detail in the prior sections. Appetite stimulants have been used in attempts to counter weight loss in cancer patients, but studies have had mixed results. A review of adult studies by Yavuzsen135 suggests that of all
Cyproheptadine/Periactin
This drug is a serotonin antagonist and antihistamine that has been studied as an appetite stimulant in cancer patients.
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An earlier study in adults showed increased appetite but no less weight loss than with a placebo in adults with advanced malignancies.140 A recent study in children with cancer found that many did respond with weight gain, with drowsiness as the only common side effect.137 Studies with this agent are ongoing in children. Doses may need to be reduced in patients with hepatic impairment.
to maintain oral intake. Opioids can be very helpful, but frequently subject the patient to constipation and sometimes to nausea and vomiting, itching, or when dosed excessively, respiratory depression. A number of drugs have been used in attempts to reduce the frequency and severity of mucositis (prevention).
Medications for Mucositis
Chlorhexidine/Peridex
Chlorhexidine/Peridex has antiseptic-type effects, and since mucositis can result from fungal or viral mouth infections, this product might help. However there is minimal evidence for benefits in preventing or treating mucositis with chlorhexidine. Recent guidelines from the Multinational Association of Supportive Care in Cancer (MASCC) do not recommend its use for either prophylaxis or treatment.141 Since most chlorhexidine-containing products also contain alcohol, they may elicit pain in patients who already have mucositis.
Mucositis consists of inflammatory ulcerations in the mouth and gut that usually result from chemotherapy, radiation, or the conditioning regimens for HSCT. Mucositis occurs inconsistently after chemotherapy regimens outside of the transplant setting, and the time course after chemotherapy generally parallels that of neutropenia. These features make it difficult to study since it occurs erratically and resolves with or without therapy. Medications used for mucositis fit into two categories: prevention or treatment. Treatments treat symptoms, having little if any effect on the healing rate of the mucositis. When mucositis is seen in the mouth, presumably it is occurring throughout the gut, including the stomach. Administration of acid-blocking drugs is commonly thought to help, although data on the value of this treatment are scarce. Medications used to treat symptoms of mucositis include drugs such as Magic Mouthwash combinations, Gelclair, and opioids.
Glutamine
Glutamine is an amino acid that is thought to be especially important to cells of the gut. Studies in the past have suggested that it might help maintain the integrity of the gut in patients receiving long-term total parenteral nutrition, or may help prevent chemotherapy-induced mucositis. Studies have suggested reductions in mucositis for autologous stem cell transplant patients, but there also has been a suggestion of increased relapses.141143 The most recent MASCC guidelines do not recommend the use of glutamine, but there is enough interest that studies of specialized formulations of glutamine are in clinical trials.
Magic Mouthwash
This usually contains viscous lidocaine, diphenhydramine, and an antacid or nystatin. Lidocaine is a strong local anesthetic, diphenhydramine is a weak local anesthetic, and the antacid may help neutralize acid in the stomach, although the dose is probably too low to effectively raise gastric pH. Nystatin is in combinations at some institutions because mucositis may cause or be caused by Candida infections (thrush). There are little if any published data on the efficacy of these combinations, but they relieve symptoms in some patients. Combinations containing viscous lidocaine have been reported to cause systemic lidocaine toxicity if used in relatively high or frequent doses, especially in small children or infants. Doses should be limited if the medication is to be swallowed. This is not a problem if it is swished and spit out. Gelclair is a polymer-type combination of polyvinylpyrrolidone, hyaluronic acid, and glycyrrhetinic acid. It coats the mucosa of the mouth, protecting it from air and irritants that elicit pain. It is suggested not to eat or drink for an hour or more after using the Gelclair. Some patients seem to benefit from this product. Opioids are used when less potent treatments fail, and may allow the patient
Palifermin/Kepivance
Palifermin/Kepivance is a recombinant human keratinocyte growth factor. It is approved and used for reducing mucositis in patients with hematologic malignancies receiving hematopoietic stem cell transplants. Use in solid tumors is considered contraindicated by many practitioners due to the potential for stimulating epithelial cells (and perhaps the cancers); however, studies in solid tumors in patients receiving standard chemotherapy are in progress. Palifermin is expensive and does cause some side effects such as thick tongue, altered taste, and rashes. Palifermin has been demonstrated to reduce the duration and severity of oral mucositis as well as the use of opioids in patients receiving autologous HSCT for hematologic malignancies. There are less data for allogeneic transplants. The MASCC guidelines mention numerous other products (favorably or unfavorably), most of which are
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not currently used in pediatrics. Slurries or suspensions of sucralfate (Carafate) have been used in children with oral mucositis, but there is a lack of efficacy data in general, plus several negative studies in adults with radiation-induced oral mucositis.141 Another product that is being studied currently in children is Traumeel S. It is a homeopathic mixture of approximately a dozen herbals or supplements that is not thought to have side effects, although allergies to ingredients would be a possibility. One study in children and young adults receiving stem cell transplants showed favorable results and further studies are ongoing.144
5. Survivors of childhood cancer can be at greater risk for osteoporosis due to: A. History of corticosteroid use B. Methotrexate containing regimen C. Use of anticonvulsants D. All of the above See p. 487 for answers.
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References
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99. Przepiorka D, Weisdorf D, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15(6):825828. 100. Cahn JY, Klein JP, et al. Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: a joint Societe Francaise de Greffe de Moelle et Therapie Cellulaire (SFGMTC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study. Blood. 2005;106(4):14951500. 101. Petersdorf EW, Longton GM, et al. The significance of HLA-DRB1 matching on clinical outcome after HLA-A, B, DR identical unrelated donor marrow transplantation. Blood. 1995;86(4):16061613. 102. Barker JN, Wagner JE. Umbilical-cord blood transplantation for the treatment of cancer. Nat Rev Cancer. 2003;3(7):526532. 103. Zecca M, Prete A, et al. Chronic graft-versus-host disease in children: incidence, risk factors, and impact on outcome. Blood. 2002;100(4):11921200. 104. Atkinson K. Chronic graft-versus-host disease. Bone Marrow Transplant. 1990;5(2):6982. 105. Akpek G, Valladares JL, et al. Pancreatic insufficiency in patients with chronic graft-versus-host disease. Bone Marrow Transplant. 2001;27(2):163166. 106. Barker CC, Anderson RA, et al. GI complications in pediatric patients post-BMT. Bone Marrow Transplant. 2005;36(1):5158. 107. Chakrabarti S, Collingham KE, et al. Isolation of viruses from stools in stem cell transplant recipients: a prospective surveillance study. Bone Marrow Transplant. 2000;25(3):277282. 108. Wingard JR. Opportunistic infections after blood and marrow transplantation. Transpl Infect Dis. 1999;1(1):320. 109. Burgunder MR, Dickson BJ. Hematopoietic stem cell transplantation. In: Kogut VJ, Luthringer SL. Nutritional Issues in Cancer Care. Pittsburgh, PA: Oncology Nursing Society; 2005:253263. 110. Richardson PG, Elias AD, et al. Treatment of severe venoocclusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. Blood. 1998;92(3):737744. 111. Kumar S, DeLeve L, Kamath P, Tefferi A. Hepatic venoocclusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation. Mayo Clin Proc. 2003;78:589598. 112. Cesaro S, Pillon M, et al. A prospective survey on incidence, risk factors and therapy of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Haematologica. 2005;90(10):13961404. 113. Song JS, Seo JJ, et al. Prophylactic low-dose heparin or prostaglandin E1 may prevent severe veno-occlusive disease of the liver after allogeneic hematopoietic stem cell transplantation in Korean children. J Korean Med Sci. 2006;21(5):897903. 114. National Cancer Institute. Nutrition in Cancer Care (PDQ ). http://www.cancer.gov/cancerinfo/pdq/supportivecare/ nutrition/healthprofessional. Accessed November 1, 2008.
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Trauma and Burns

Arlet G. Kurkchubasche, MD
31
Learning Objectives
1. Understand the components of the stress response and how these contribute to hypermetabolism in trauma and burn patients. 2. Identify childhood conditions that place patients at risk for trauma and child abuse as well as nutrition impairment. 3. Understand the injury pattern seen in blunt trauma and how it impacts the ability to use enteral nutrition. 4. Understand limitations of methods for predicting energy needs in pediatric patients with significant burn injury.
CONTENTS
Nutrition Considerations in the PediatricTrauma Patient . . . . . . . . . . . . . . . . . . . . . . . . . 378
General Background on Trauma in Childhood Closed Head Injuries/Traumatic Brain Injury Spinal Cord Trauma Blunt Abdominal Trauma/Solid Visceral Injuries Blunt Abdominal Trauma/Hollow Visceral Injuries Thoracic Injuries Summary on Pediatric Trauma
Pediatric Burns. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383

Features Specific to the Pediatric Patient Energy Estimates in Burn Injury
Clinical Example 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384

Answer/Considerations

Nutrition Considerations in the PediatricTrauma Patient

Trauma, burn injury, and surgery are known stressors resulting in hormonal, metabolic, and immune derangements. The initial physiological response to these events is well studied and is generally described in terms of the hormonal and cytokine responses. These responses include the centrally mediated release of adrenocorticotropic hormone (ACTH), which stimulates cortisol release from the adrenal glands. This augments the action of epinephrine and norepinephrine, which are released from the adrenal medulla via sympathetic stimulation and impact the cardiovascular response. Glucagon is responsible for mobilizing glucose availability via glycogenolysis and gluconeogenesis. During the initial resuscitation, tissue perfusion is reduced and there is an overall (transient) reduction in metabolic rate. This is promptly followed by the hypermetabolic/catabolic phase of injury, which is mediated by the hypothalamicpituitary axis and the proinflammatory cytokines (ie, tumor necrosis factor, interleukin-6). This phase is characterized
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TRAUMA AND BURNS
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by changes in glucose homeostasis, with insulin promoting lipolysis and proteolysis to generate glucose, while relative insulin resistance contributes to elevated serum glucose levels during this acute phase. Trauma and burn injury have provided good clinical models for studying these responses because they are quantifiable injuries in terms of trauma scores and extent of burn injury. The physiological responses in the pediatric patient are fundamentally no different than in the adult. The focus of nutrition management is aligned with the fundamentals of critical care, which attempt to optimize all organ function by optimizing perfusion and tissue oxygenation. Support of this hypermetabolic state, with an aim to control the resultant hyperglycemia and to limit the extent of proteolysis, becomes the focus of nutrition interventions. The specific nutrient requirements and whether certain micronutrients either become conditionally essential or can impact the elaboration of pro- and anti-inflammatory cytokines and other agents such as nitric oxide have been the subject of intense research. The premise of this chapter on trauma and burns is that the nutrition support of the child in the critical care unit follows clinical guidelines that parallel those of the child presenting with shock and sepsis or respiratory failure. Distinguishing this surgical scenario is that appropriate consideration must be given to the actual physical and physiological insult. These patients generally require a much higher consideration of pain-related issues because of the associated tissue damage than in the non-physically injured child. While the use of narcotic and non-narcotic medications contributes to an amelioration of metabolic demands, it also promotes intestinal dysmotility and ileus and thereby impacts enteral feeding tolerance. The use of agents such as propofol, which are solubilized in a lipid solution, requires reconsideration of the nutrient allocation by parenteral nutrition. Because of the nature of organ and skin injury, there are more frequent interruptions of nutrient delivery as a consequence of surgical interventions. As a result, many patients remain undernourished in this acute phase of injury when reliance is placed on enteral feedings alone and frequent periods of non-feeding are necessary for procedures under conscious sedation and general anesthesia. In this set of patients, the goals of energy provision are estimated to be 130% to 160% of resting energy expenditure (REE) with an expectation to initiate this by day 3 and consistently deliver this by 7 days postinjury. The route of administration is dependent on patient-specific factors. For instance, the patient with extensive burn wounds is best served by
elimination of multiple vascular access sites and provision of nutrients via the intact intestinal system. The patient with blunt abdominal trauma and an extensive pancreatic injury may not be able to tolerate gastric feedings and should be considered for jejunal feeding if such access is possible. In the interim, provision of energy needs should occur by the parenteral route.
General Background on Trauma in Childhood

Trauma accounts for significant morbidity, mortality, and long-term disability in children. The patterns of pediatric trauma are both age and gender related. Mechanisms for injury in children in the first 3 years of life include falls, poisoning (including caustic ingestions), transportationrelated injuries, foreign body aspiration or ingestion, burn injuries, assault/neglect, and submersion/drowning mechanisms. With the older child, falls and bicycle/pedestrian and transportation-related injuries assume a greater frequency. These primarily blunt mechanisms are accompanied later in adolescence by an increasing number of penetrating injuries. The specific organ injuries are broadly classified as neurotrauma (closed head injury/traumatic brain injury and spinal cord injury), thoracic trauma (chest wall, pulmonary, and cardiac), abdominal-pelvic trauma (solid and hollow visceral, genitourinary), and musculoskeletal injuries (long bone and pelvic fractures, craniofacial injuries). An anatomical classification system allows for injury severity scoring, which has a strong relationship with outcomes including morbidity, mortality, and length of stay. While most children are generally healthy prior to their acute injury, others have underlying diagnoses such as neuro-developmental delay, disorders on the autism spectrum, or attention deficit disorder. These conditions not only modify their risk-taking behaviors and place them at risk for injury but also potentially contribute factors that may result in nutrition depletion over a shorter period of time than expected. On the opposite end of the spectrum, children injured as passive bystanders/occupants of a vehicle may also present with significant issues related to overweight/ obesity.1 These issues may complicate their acute management and impact their nutrition support in the acute phase. The sections below provide brief descriptions of the most common forms of pediatric trauma and serve to provide a perspective on when, in the course of injury, enteral nutrition is feasible and when there should be an anticipation of prolonged non-enteral nutrition.
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Closed Head Injuries/Traumatic Brain Injury

The brain has an inordinately high metabolic demand and under normal circumstances brain metabolism and cerebral blood flow are generally tightly regulated. When there is a traumatic brain injury there is frequently a change in cerebral perfusion as a consequence of intracranial pressure changes.2 Despite this, the brain remains critically dependent on the uninterrupted delivery of both oxygen and glucose. Failure to support the brain adequately during this period likely impacts long-term outcomes. Hypothermia protocols in pediatric traumatic brain injury aim to reduce the metabolic needs during periods of relative hypoperfusion. Clearly the nutrition support of such a severely injured patient will require assurance of glucose provision, however the concomitant use of medications such as glucocorticoids and development of diabetes insipidus (DI) place this patient at risk for hyperglycemia. Furthermore, sodium and water balance are affected by the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and DI, as well as by administration of resuscitative fluids which may include hypertonic saline. These electrolyte and fluid balance issues may impact the ability to provide proteins, which along with lipids remain essential during the catabolic phase. Once neuro recovery is underway, maintenance of muscular tone for adequate respiratory function and physical rehabilitation is critical. The use of immune-enhancing diets containing omega-3 fatty acids, branched-chain amino acids, and nucleotides has been evaluated in head injury patients and has not shown benefit over the use of standard nutritional formulations. 3 With a transition into rehabilitation facilities, nutrition management is still tightly regulated, because these patients often have impaired swallowing and airway protection. Estimating caloric needs is difficult and there are many studies documenting a difference between the calculated needs of the predictive equations and actual needs based on nitrogen balance studies.4,5 The concern is that overfeeding will lead to hyperglycemia for the reasons mentioned above and an excessive respiratory quotient (RQ ) which will impact the patients ventilatory management.
includes the acute use of steroids in those with incomplete injury as well as hypothermia protocols. The nutrition assessment of these patients becomes a very individualized task due to variability in neuromuscular deficit and metabolic demand despite ongoing perfusion.6,7
Blunt Abdominal Trauma/Solid Visceral Injuries

Solid organ injuries are some of the most frequent injuries encountered in the pediatric patient. In contrast to the adult population, these injuries are frequently isolated and can be managed non-operatively. Despite their prevalence, there has been no universally accepted algorithm for their management. While radiographic parameters permit grading of injuries to indicate severity of injury, it is the hemodynamic response to injury that determines the immediate course of action. Operative intervention is reserved for those with profound or persistent hemodynamic instability. Simple immobilization with bed rest may be sufficient in most patients to permit intrinsic mechanisms for hemostasis to result in formation of a stable hematoma. Since the stomach is intricately associated with the spleen via the short gastric vessels, it is usually decompressed or enteral feedings are at least withheld for 24 hours to avoid gastric distention and retching. If there has been a significant amount of blood in the abdomen, this not only creates abdominal pain but also is responsible for a transient ileus. The period of observation with bed rest is variable and is generally related to the degree of injury. Hemodynamic instability despite transfusion is the predominant factor in determining whether non-operative management will be successful. With hemodynamically unstable splenic injuries, splenic salvage can be attempted operatively or splenectomy may become necessary. Given the role of the spleen in the immunocompetency of the child, every effort is made to avoid splenectomy. Hepatic injuries rarely require operative intervention. In the most severe instances an avulsion of the liver off the retrohepatic vena cava occurs, and these injuries are generally immediately fatal. Parenchymal injuries are best managed non-operatively especially if Glissons capsule is intact. The abdominal wall provides some compression and containment, which is lost with laparotomy. When hemodynamic instability mandates exploration, the liver is packed with laparotomy sponges to compress the injured tissues, arterial inflow can be reduced by occluding the hepatic artery manually, and either injured segments can be compressed with large sutures or resected. Control of hemorrhage is as much a surgical as medical event in that hypothermia and coagulopathy can rapidly obviate any
Spinal Cord Trauma

This constellation of injuries more often affects the adolescent in the context of sports injuries, diving, and motor vehicle crashes. Depending on the level of spinal cord injury, the patient may become dependent on mechanical ventilation and lose the use of all truncal and extremity musculature. The peri-injury protection of the spinal cord remains a topic of active research and controversy and
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surgical advances. In the patient who is or becomes stable, postoperative management will assess bilirubin levels which may become elevated for a number of reasons (shed blood, biloma formation, biliary ascites). Intestinal bleeding may be from hemobilia in which a fistula forms from the vascular system into the biliary ductal system. Depending on the degree of shock, the liver parenchyma may exhibit some degree of hepatic dysfunction which should be taken into account when selecting medications. With restoration of adequate perfusion, this is usually only a transient phenomenon. These solid organ injuries are rarely associated with significant gastrointestinal dysfunction and oral diets are resumed within several days of injury. Depending on the severity of injury and on whether there are additional injuries, these patients may benefit from caloric supplementation. This is because these children may not demonstrate a normal appetite and may develop constipation due to the lack of physical activity. Pancreatic Trauma The pancreas is typically injured as a consequence of a compression force to the mid-abdomen. This may be a bicycle handlebar or another object striking the epigastrium or it can be the consequence of a deceleration injury associated with the use of a seatbelt. Child abuse must always be considered when the mechanism is otherwise not obvious. Complete fractures of the pancreas occur over the neck of the organ where it crossed the spinal column. Initial laboratory assessment in the trauma room has been found to be inadequate for detection of this injury. Amylase and lipase levels rise typically 8 hours after injury. Computed tomography (CT) scan of the abdomen is the typical study that raises concern, but it may not be sufficiently sensitive. While adult trauma protocols would mandate operative exploration, there are series in pediatric patients in which the injury is managed non-operatively with the use of endoscopic retrograde cholangiopancreatography (ERCP) for stenting of the ampulla and even across a major ductal injury. These cases are controversial and the most conservative approach may indeed be exploration with resection of the tail of the pancreas, thereby eliminating the ongoing leak of pancreatic enzymes. Resections at this level of the pancreas are not expected to affect glucose homeostasis, although there are some reports of late pancreatic exocrine insufficiency, which present with malabsorption as evidenced by diarrheal stools. The patient who develops a pancreatic pseudocyst as a consequence of the trauma can be managed with laparoscopic, open, or endoscopic cyst gastrostomy. This is usually
delayed for 4 to 6 weeks to allow the cyst wall to mature. This allows the cyst content of pancreatic secretions to drain into the intestinal tract with ultimate expectation that the ductal defect will heal and that the pseudocyst involutes. The extent of nutrition support depends on the physiological impact of this traumatic pancreatitis. When jejunal access can be safely established, it is reasonable to use this route once there is evidence of return of intestinal motility. In the most severely injured, with ongoing pancreatitis and perhaps complications such as tissue necrosis and infection, parenteral nutrition (PN) is likely essential in the early postinjury period. Renal Trauma Injuries to the kidneys are typically unilateral, and assessment must include evaluation of the ureter and bladder. Typically, delayed phase images on CT scan will identify urinary extravasation. In the absence of urine extravasation, renal injuries are primarily managed non-operatively. Patients remain at bed rest until the hematuria subsides. If urinary extravasation occurs it is classified as contained or free. The former may permit ongoing non-operative management although placement of a ureteral stent or percutaneous drainage would be advised in the latter. In rare cases a primary nephrectomy is performed. Late consequences of renal injury include the development of renovascular hypertension. These patients generally experience a transient ileus and then are able to resume an enteral diet. There are rarely concerns of renal insufficiency that would lead to consideration of special diets. Adrenal Hemorrhage The adrenal glands have an exuberant blood supply from multiple sources. While generally protected in the retroperitoneum, they are at risk for direct injury, but rarely as an isolated organ. Injury is generally evident as adrenal hemorrhage but does not necessarily portend adrenal insufficiency, even when bilateral. When isolated, these injuries have minimal impact on the overall nutrition management of the patient.
Blunt Abdominal Trauma/Hollow Visceral Injuries

Duodenal Injuries Duodenal hematoma and perforation are not infrequently encountered in pediatric trauma. They occur with blunt force trauma to the epigastrium (ie, bicycle handlebar injury, non-accidental trauma). While most duodenal hematomas are dealt with non-operatively, duodenal perforation
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is a significant injury that demands prompt operative intervention to avoid morbidity and even mortality. Duodenal hematomas become symptomatic when extraluminal blood impacts on the luminal caliber, resulting in gastric outlet obstruction. Passage of a transduodenal feeding tube is almost always possible, either by radiographic guidance or endoscopically. This allows the patient to receive enteral nutrition despite the proximal obstruction, which may require decompression with a concomitant nasogastric tube. Operative intervention is rarely indicated in this injury. Pancreatic injury may be concomitant so it is wise to check for chemical pancreatitis before initiating feeds. Resolution of the obstruction can occur within 10 to 14 days of injury as evidenced by improved gastric emptying. Duodenal perforation is a much more significant injury which, depending on its extent, will require either primary repair with drain placement or sometimes more complicated surgical solutions to protect the duodenal repair from leakage (ie, pyloric exclusion with gastrojejunostomy). Typically the pyloric channel will open 4 to 6 weeks later, which prompts the gastrojejunostomy to close spontaneously. These patients will often require parenteral nutrition support in the early postoperative phase until the gastrojejunal anastomosis becomes functional. Small Intestine and Colon Injuries Jejunoileal perforations or mesenteric injuries resulting in devascularized segments of small intestine are frequently associated with seatbelt injuries and other mechanisms resulting in deceleration forces on the abdomen. These are most commonly identified in the first 24 hours, however, later strictures from ischemic injury without perforation can cause late (> 4 weeks) symptoms of enteral intolerance. Unless there is an extensive delay in diagnosis, most of these injuries can be treated with resection and anastomosis. When peritoneal contamination is extensive, the patients hemodynamic status is not optimal, and the perfusion of the involved segment is questionable, it is often prudent to proceed with stomal diversion. These same principles apply to colon perforation, which is rare and more commonly encountered in penetrating mechanisms of injury. These injuries require a brief period of non-enteral feeding, but then permit rapid reinstitution of normal dietary habits.
parenchyma, resulting in pulmonary injury which most often consists of contusion rather than overt tissue disruption. Similarly the pliability of the intrathoracic vessels results in fewer great vessel injuries than seen in the adult population. Blunt cardiac trauma is also well-compensated for with the capacity to offset contractility compromise with an increased heart rate response. When intrathoracic injuries occur that require operative intervention, recovery is supported by the generally healthy state of these organs. Often these injuries occur in the setting of multiple traumas and then require mechanical pulmonary support. When in isolation, they are usually of minimal consequence to nutrition management. Pelvis and Extremity Trauma When long bone fractures and pelvic fractures occur in multiply injured trauma patients these injuries contribute to the injury severity score and consequently to the nutrition and metabolic demands of the patient. When these bony injuries are associated with overlying open soft tissue wounds the risk for infection is increased. Operative management for limiting the extent of contamination and fixation of the fracture are routine measures. Even simple immobilization, whether of a long bone fracture or the pelvis, has metabolic consequences to the patient. The importance of providing adequate vitamin D and calcium is emphasized in the current literature. The focus of the American Academy of Pediatrics consortium on calcium was to limit the fracture risk for young children and adolescents.8,9 In the skeletally immature pediatric patient, the consequences of growth plate fractures, non-union of fractures, and subsequent growth impairment are critical to address. In the absence of multiple organ injury involving the abdomen, these patients rapidly resume enteral intake. Targets for caloric intake should include consideration of level of activity. Facial trauma constitutes a specific subset of musculoskeletal trauma but has the added concerns for impacting enteral alimentation when the mandible and maxilla are involved.
Summary on Pediatric Trauma

While much pediatric trauma is of a minor and ambulatory nature, those children with major single-system injuries or multiply injured pediatric trauma patients require early and intense evaluation for nutrition support. After restoration of vital organ perfusion, consistent nutrition support is a critical intervention to assure meeting the high metabolic demands imposed by injury.10
Thoracic Injuries
Thoracic injuries in children may be remarkably unassociated with chest wall signs of trauma. The bony thoracic case is sufficiently pliable in the young child to permit complete transduction of the impact energy to the lung
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Pediatric Burns
Burn trauma encompasses injuries that occur as a result of flame, thermal and chemical exposure, inhalation of smoke, and electrical contact. These continue to inflict significant morbidity and mortality on patients at the extremes of age. Young children are particularly vulnerable to both accidental and non-accidental burn injuries. The management of burns has evolved dramatically in the past 30 years with a centralization of care for the more severely injured patients. This has allowed for more concentrated experiences as well as focused clinical trials. The result of these data has been significantly improved outcomes, with decreased mortality attributable to shock and wound sepsis. These patients, however, require extensive and chronic support from a multidisciplinary team to return to optimal functional status. With a better understanding of the metabolic consequences of burn injury on both the animal research as well as on the clinical research front, the consistent emphasis on the importance of nutrition support has persisted as one of the hallmarks of burn care.11
Features Specific to the Pediatric Patient

Children, as compared to adults, will have deeper burn injuries for a given injury mechanism as a consequence of the thinner dermal structure and architecture. In contrast to the older patient, their thermal injury occurs as a consequence of contact with hot liquids in 70% of cases, rather than flame burn. The percent total body surface area (TBSA) involvement by second- and third-degree burns remains a critical determinant of mortality. An understanding of individualized burn resuscitation, guided by %TBSA involvement, has led to virtual elimination of burn shock as a cause of immediate death. With injuries involving > 20% of TBSA there is an associated stress response which leads to the hypermetabolic state that has been well described with burn injury. It is less clear how TBSA impacts the severity of the stress response invoked when greater areas are involved,12 although TBSA > 30% to 40% results in tenfold elevations of urinary catecholamines.13 Attempts to modulate the severity of this response have been diverse and have included wound management strategies, enteral feeding strategies, and the use of pharmacologic agents. Current therapies that employ early burn wound excision and grafting have had a significant impact in reducing wound infections, reducing transdermal losses of fluid and protein, and achieving earlier healing and rehabilitation. The improved technologies for coverage of burn wounds with reduced frequency of painful dressing changes also will reduce metabolic demands.14,15
Use of the intestinal tract for alimentation has been promoted for burn injuries in particular. Concerns about mucosal atrophy and impairment of the gut-associated immune defenses as a consequence of non-use have been key motivators. While enteral feeding may frequently require administration via nasoenteric tubes, often oral supplementation is well received by young children. At times, simple nighttime supplementation to reach target caloric goals is sufficient. Choice of formula is typically based on calculated caloric needs with special emphasis on protein content. Early enteral feeding has not shown the benefit demonstrated with delayed enteral feeding and risks using an underperfused intestinal tract, thereby subjecting the patient to additional morbidity.16,17 The use of pharmacologic agents such as growth hormone, oxandrolone (a testosterone analog), and insulin-like growth factor results in decreased catabolism, but it is unclear how this ultimately will affect clinical course and outcomes. The use of low-dose insulin has been described as a useful intervention, which may be a consequence of control of hyperglycemia in a state of relative insulin resistance.18 Inhalation injury also has a greater potential for complications in the young child as a consequence of the decreased luminal diameter of the trachea and bronchi with a propensity for formation of obstructive casts and secretion plugs. Early intubation and respiratory toilet are important especially in those with associated facial burn injury, given the rapid and dramatic swelling associated with thirdspace extravasation of resuscitative fluids. These patients remain at risk for prolonged respiratory support and ventilator-associated pneumonias which further impact their hypermetabolic state.19 Recent studies document that the highest mortality is encountered in children under 4 years of age with TBSA > 30% and inhalation injury.20
Energy Estimates in Burn Injury

Children start off with greater metabolic and specific nutrient demands (greater caloric demand per kilogram) as compared to their adolescent and young adult counterparts, a demand that is amplified by the injury. They generally have lower energy stores, which are more rapidly depleted. Their propensity toward fevers, despite the absence of infection, further compounds their energy demands. Despite the ubiquitous use of the Harris Benedict equation and other variants to estimate caloric needs for these patients, these remain very rudimentary tools and there are data that they do not accurately reflect actual needs as measured by indirect calorimetry.21 Providing excess calories will not obviate the proteolysis accompanying the hypermetabolic
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response, but likely contributes to hyperglycemia. How hyperglycemia specifically impacts the incidence of wound infection in burn patients is not known; however, there is enough suggestive evidence from other models of critical illness to avoid blatant overnutrition. On the opposite end, we know that undernutrition negatively impacts wound healing and maintenance of lean body mass. Muscle catabolism, particularly involving the muscles of respiration, leads to functional debilitation which can be measured in terms of prolonged respiratory support; however, physical rehabilitation of the core muscles and extremities is similarly impacted in the later stages of therapy. Despite the consistent recommendation to assess these patients with indirect calorimetry, in general, a target of 120% to 130% of REE is believed to be appropriate.22 The composition of the energy sources is primarily carbohydrate (up to 60% of calories) but with maximum glucose load limited to 7 mg/kg/min to not only avoid hyperglycemia, but also to limit lipogenesis which results in increased oxygen consumption and carbon dioxide elaboration which raises the RQ. Lipids should initially deliver between 12% to 15% of total non-protein calories. This lower proportion has been associated with improved clinical outcomes as compared to the higher lipid-containing diets (35% calories from fat) in a randomized clinical trial.23 The use of omega-3 containing fatty acids is theoretically beneficial from the standpoint of reducing the precursors for prostaglandin E2 and leukotrienes, thereby limiting further immunosuppression. The protein needs are exacerbated in burn patients because of the additional losses via the open wounds in addition to the standard urine losses and the gluconeogenesis as seen in other instances of hypermetabolism. Daily intake of 2.5 g/ kg/d and up to 4 g/kg/d may be necessary and is limited by the patients state of hydration and renal function. Specific immune-enhancing diets which contain high protein loads, omega-3 fatty acids, and branched-chain amino acids and nucleotides have not been shown to be superior to standard high-protein diets.24,25 The preferred route of nutrition support remains enteral feedings and these should be instituted as soon as it is deemed safe to use the intestinal tract. In some institutions the early use of postpyloric feedings is encouraged, and techniques have been developed to safely place these devices at the bedside.26 Although initial studies suggested that early feeding would be beneficial, no clear benefit has been demonstrated in terms of decreased length of stay, morbidity, or mortality.17 As with any other invasive procedure, the risks and benefits must be considered when initiating enteral feeds. There are case reports of early
aggressive enteral feeding leading to luminal obstruction and perforation.27 PN support retains a critical role in those patients with a prolonged ileus or persistent systemic and visceral hypoperfusion. Laboratory evaluation using the standard visceral proteins is limited in the immediate/acute injury period and may be more useful as a predictor of outcomes, rather than as a measure of visceral protein status. The degree of hypoalbuminemia observed in early burn injury is attributable to the losses via the burn wound. Further complicating their interpretation is that albumin therapy is prevalent in burn resuscitation and does not reflect intrinsic production. Weight and other anthropometrics are also invalidated in the early resuscitative phase given the rapid expansion of the extravascular space. Trends in prealbumin and other visceral proteins as well as weight changes once the acute resuscitative phase is complete are reasonable to monitor.
Clinical Example 1
A morbidly obese 14-year-old is transported to the trauma center after being involved in a multi-vehicle collision as a restrained passenger. Although alert and oriented she is dyspneic and is found to have a pneumothorax. She has a significant air leak, suggesting a bronchial injury. She is intubated and undergoes bronchoscopy with subsequent thoracotomy for repair of a proximal airway injury. Her initial abdominal exam was unremarkable but limited by obesity. Focused Assessment with Sonography for Trauma (FAST) exam was not possible and the urgent intervention for her airway delayed further evaluation. She develops abdominal tenderness which prompts CT evaluation and subsequent laparotomy for a left hepatic duct avulsion with ischemia to the left lobe of the liver. What are her requirements for energy support in this phase of her acute illness? How are they best met?
The energy assessment of the overweight and morbidly obese teenager who requires critical care support is extraordinarily difficult. In this time of metabolic stress, the goal should not be weight management, but preservation of protein status. Estimates for caloric intake are best derived from assessment of metabolically active tissues and these are more closely related to ideal body weight than actual. Not only will this patient need to heal her traumatic injuries but she now has two additional wounds (thoracotomy and laparotomy) to heal. Indirect calorimetry will likely provide the best guidance in this scenario. Given the intra-abdominal injuries one would expect a period of ileus to follow
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and thus provision of nutrients should not be delayed and initially can occur by parenteral route.
Clinical Example 2
A 12-year-old equestrian sustained a kick to her stomach while grooming her horse. Her initial abdominal CT shows a hematoma over the neck of the pancreas. There is no free fluid in the abdomen. She is nauseated and a nasogastric tube evacuates bilious fluid. Over the next 24 hours she continues to complain of abdominal pain and her amylase rises to 950. Do you advise nutritional supplementation at this point? It is now 5 days later, an ERCP has been done, and there is no major ductal injury. Her abdominal pain is improved and amylase is 200. What do you expect her ability to eat will be within the next 48 hours?
and protein can be started early via this route. At the time of operation it would be ideal to have a nasoenteral tube placed for subsequent enteral feeding access. Energy requirements are notoriously difficult to predict and indirect calorimetry remains the most accurate tool.
Pancreatic injuries, despite non-operative management, can lead to significant metabolic stress as a consequence of the inflammatory nature of the retroperitoneal injury (hematoma) which is further exacerbated by release of pancreatic enzymes. While we can expect this patient to have been active and healthy from a nutrition standpoint, we would anticipate a return to GI function within perhaps 5 days. The information related to the ERCP would suggest that cautious introduction of enteral feeds would be acceptable and that her response to enteral stimulation of pancreatic secretions must be monitored. Should she develop recurrent pain and pancreatitis with oral intake, institution of PN until such time as a jejunal feeding tube can be placed would be appropriate.
1. Blunt abdominal trauma with injury to the liver: A. Requires prolonged support on parenteral nutrition B. Requires specialized formulas to account for hepatic insufficiency C. Rarely requires operative intervention D. Is rare in the pediatric patient 2. Pancreatic trauma may result in all except: A. Chemical pancreatitis B. Prolonged intestinal ileus C. Clinical features of pancreatic insufficiency D. Diabetes mellitus 3. Closed head injury patients unequivocally benefit from provision of immuno-nutrients. A. True B. False 4. Total burn surface area (TBSA) is most predictive of: A. Mortality B. Metabolic stress C. Energy needs D. None of the above See p. 487 for answers.
References
Clinical Example 3
A 2-year-old is brought to the trauma/burn unit with 35% TBSA injury from a hot oil burn to his face, trunk, and lower extremities. Within 24 hours, he has developed anasarca, but is hemodynamically stable and making urine at 1 mL/ kg/h. He is scheduled to undergo burn wound excision on the following day. When do you consider starting nutrition support? How do you best determine his caloric needs? How do you initiate caloric intake?
This child has sustained a significant injury and is expected to exhibit a stress response leading to catabolism. Nutrition support will become essential to re-establishing a positive nitrogen balance. Given the extent of injury this child will likely have central venous access and provision of glucose
1. Rana AR, Michalsky MP, Teich S, Groner JI, Caniano DA, Schuster DP. Childhood obesity: A risk factor for injuries observed at a level-1 trauma center. J Pediatr Surg. 2009;44(8):16011605. 2. Philip S, Udomphorn Y, Kirkham F, Vavilala M. Cerebrovascular pathophysiology in pediatric traumatic brain injury. J Trauma. 2009;67(2 Suppl):S128. 3. Briassoulis G, Filippou O, Kanariou M, Papassotiriou I, Hatzis T. Temporal nutritional and inflammatory changes in children with severe head injury fed a regular or an immuneenhancing diet: a randomized, controlled trial. Pediatr Crit Care Med. 2006;7(1):56. 4. Havalad S, Quaid M, Sapiega V. Energy expenditure in children with severe head injury: Lack of agreement between measured and estimated energy expenditure. Nutr Clin Pract. 2006;21(2):175. 5. Joffe A, Anton N, Lequier L, et al. Nutritional support for critically ill children. Cochrane Database Syst Rev. 2009(2):CD005144.
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6. Patt P, Agena S, Vogel L, Foley S, Anderson C. Estimation of resting energy expenditure in children with spinal cord injuries. J Spinal Cord Med. 2007;30(Suppl 1):S83. 7. Brown RL, Brunn MA, Garcia VF. Cervical spine injuries in children: a review of 103 patients treated consecutively at a level 1 pediatric trauma center. J Pediatr Surg. 2001;36(8):1107. 8. Baker SS, Cochran WJ, Flores CA, et al. American Academy of Pediatrics. Committee on Nutrition. Calcium requirements of infants, children, and adolescents. Pediatrics. 1999;104(5):1152. 9. Goulding A. Risk factors for fractures in normally active children and adolescents. Med Sport Sci. 2007;51:102. 10. Hasenboehler E, Williams A, Leinhase I, et al. Metabolic changes after polytrauma: an imperative for early nutritional support. World J Emerg Surg. 2006;1:29. 11. Purdue G. American Burn Association presidential address 2006 on nutrition: yesterday, today, and tomorrow. J Burn Care Res. 2007;28(1):1. 12. Atiyeh B, Gunn SWA, Dibo S. Metabolic implications of severe burn injuries and their management: a systematic review of the literature. World J Surg. 2008;32(8):1857. 13. Chan M, Chan G. Nutritional therapy for burns in children and adults. Nutrition. 2009;25(3):261. 14. Saba S, Tsai R, Glat P. Clinical evaluation comparing the efficacy of aquacel ag hydrofiber dressing versus petrolatum gauze with antibiotic ointment in partial-thickness burns in a pediatric burn center. J Burn Care Res. 2009;30(3):380. 15. Saffle JR. Closure of the excised burn wound: temporary skin substitutes. Clin Plast Surg. 2009;10;36(4):627641. 16. Venter M, Rode H, Sive A, Visser M. Enteral resuscitation and early enteral feeding in children with major burnseffect on McFarlane response to stress. Burns. 2007 6;33(4):464471. 17. Peck M, Kessler M, Cairns B, Chang Y, Ivanova A, Schooler W. Early enteral nutrition does not decrease hypermetabolism associated with burn injury. J Trauma. 2004;57(6):1143.
18. Schulman C, Ivascu F. Nutritional and metabolic consequences in the pediatric burn patient. J Craniofac Surg. 2008;19(4):891. 19. Palmieri T, Warner P, Mlcak R, et al. Inhalation injury in children: a 10 year experience at Shriners Hospitals for children. J Burn Care Res. 2009;30(1):206. 20. Sheridan RL, Schnitzer JJ. Management of the high-risk pediatric burn patient. J Pediatr Surg. 2001 8;36(8):13081312. 21. Suman OE, Mlcak RP, Chinkes DL, Herndon DN. Resting energy expenditure in severely burned children: analysis of agreement between indirect calorimetry and prediction equations using the Bland-Altman method. Burns. 2006 5;32(3):335342. 22. Chan MM, Chan GM. Nutritional therapy for burns in children and adults. Nutrition. 2009 3;25(3):261269. 23. Garrel DR, Razi M, Larivire F, et al. Improved clinical status and length of care with low-fat nutrition support in burn patients. J Parenter Enteral Nutr. 1995;19(6):482. 24. Saffle JR, Wiebke G, Jennings K, Morris SE, Barton RG. Randomized trial of immune-enhancing enteral nutrition in burn patients. J Trauma. 1997;42(5):793800. 25. Marin V, Rodriguez-Osiac L, Schlessinger L, Villegas J, Lopez M, Castillo-Duran C. Controlled study of enteral arginine supplementation in burned children: impact on immunologic and metabolic status. Nutrition. 2006;22(7-8):705. 26. Cone L, Gilligan M, Kagan R, Mayes T, Gottschlich M. Enhancing patient safety: the effect of process improvement on bedside fluoroscopy time related to nasoduodenal feeding tube placement in pediatric burn patients. J Burn Care Res. 2009;30(4):606. 27. Scaife CL, Saffle JR, Morris SE. Intestinal obstruction secondary to enteral feedings in burn trauma patients. J Trauma. 1999;47(5):859.
Surgery
Arlet G. Kurkchubasche, MD
32
Learning Objectives
1. Identify factors that impact the nutrition requirements associated with the acute metabolic changes in the pediatric and neonatal surgical patient. 2. Identify methods for optimizing nutrition support along the entire perioperative period by utilizing clinical assessment, laboratory analysis, and bedside calorimetry. 3. Provide a basis for determining when to initiate and progress enteral feeding in a core group of neonatal surgical conditions. 4. Delineate the strategies to limit the progression of cholestatic jaundice in the postoperative infant with intestinal dysfunction.
CONTENTS
General Nutrition Considerations in Pediatric Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
General Nutrition Considerations in Neonatal Surgery
Surgical Considerations in Infants with Congenital Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

Proximal Intestinal Obstruction Distal Intestinal Obstruction Abdominal Wall and Diaphragm Hepatobiliary Disorders
Other (Non-GI) Malformations . . . . . . . . . . . . . . . . . . . . . 400 Nutrition Support in Infants with Acute GI-Related Disorders. . . . . . . . . . . . . . . . . . . . . . . . 401
Necrotizing Enterocolitis Isolated Intestinal Perforation Intestinal Malrotation and Midgut Volvulus Pyloric Stenosis
Nutrition Support in Children and Adolescents Requiring Operation. . . . . . . . . . . . . . . . . . . 403

General Principles Feeding Access in Pediatrics Insertion of Gastrostomy
General Nutrition Considerations in Pediatric Surgery
The metabolic consequences of surgical stress have been extensively studied and show a characteristic/stereotypic response in terms of hormone and cytokine elaboration. The resultant hypermetabolic state during the phase of injury and recovery has been the focus of nutrition support. In pediatrics, the challenge is not only to provide those nutrients to support the immediate metabolic needs but also to avert catabolism of limited stores of protein and fat, while providing substrate for growth and development. In the surgical patient, wound failure, infection, and mortality are primary outcome measures that have been related to the perioperative nutrition condition. The discipline of surgical nutrition arose at a time when nutrition support was often unavailable to those in the immediate postoperative period because of a lack of enteral tolerance. The institution of parenteral nutrition (PN) changed the face
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of postoperative care for this subset of patients. Malnutrition and consequent complications were the cause of demise for many neonatal patients with disorders which nowadays one is hard-pressed to consider lethal. As the ability to provide PN support has improved, an awareness of its potential for adverse effects has become apparent, specifically the unique problem of cholestasis in the pediatric population. With further advances in the science of intestinal physiology, our appreciation for the complexity of the intestinal tract in terms of its role in water, electrolyte, and nutrient assimilation as well as immune sampling functions became evident. Provision of appropriate nutrition held the promise of enhanced immune function, fewer complications related to catabolism, and overall improved outcomes. Studies on immunomodulatory agents provided either parenterally or enterally in clinical sepsis have been conducted on adults and pediatrics alike. In the pediatric literature the focus came to rest on the components of breast milk, which appeared beneficial in averting gut-derived sepsis.1 The limitations of clinical research in pediatrics are evident when it comes to studies requiring repeated blood sampling and invasive procedures; however, there is reason to believe that the findings from adult clinical trials can be applied to the pediatric patient. There is a wealth of knowledge from observational studies in pediatrics about the growth needs for all age groups and many congenital/heritable conditions, but these studies are generally careful to exclude the more complex surgical patient. The best quantitative neonatal and pediatric data related to the effects of the metabolic response to stress are derived from studies of a relatively homogenous group of infants who undergo cardiopulmonary bypass for repair of congenital cardiac disease or who require extracorporeal membrane oxygenation (ECMO) for pulmonary support.2,3 These infants, however, cannot represent the entire spectrum of pediatric surgical conditions and much work remains to be done. Nutrition assessment and support of the pediatric surgical patient requires consideration of the acute impact of surgical intervention as well as the more chronic consequences of operation. Potential postoperative complications, as well as the underlying congenital disorder, may further contribute to persistent impairment of intestinal function. Associated conditions, such as cholestatic jaundice, which may be related to the primary problem or occur as a consequence of sepsis or prolonged total parenteral nutrition exposure, further compromise the recovery of the patient.4 The first section of this chapter will focus on perioperative nutrition support and the general concept of adjustments in the nutrition considerations of the neonatal
and pediatric patient in response to altered metabolic demands as a consequence of operation. Patients who experience similar stresses as a consequence of trauma or burn injury are discussed elsewhere (Chapter 31). The second section focuses on nutrition support strategies specific to the various congenital, typically anatomic, gastrointestinal (GI) disorders encountered in the neonatal pediatric surgery patient. Surgical care of the newborn infant and extending to the skeletally mature adolescent requires a fundamental knowledge of the physiological changes that occur with growth and maturation. Based on the underlying condition, these patients will have variable impairments of GI function that may be related to intestinal motility, surface absorptive capacity, and immune function. The perioperative state is a dynamic phenomenon and as the patients clinical status evolves, constant reassessment and redirection of nutrition care must occur. Because these patients also represent a spectrum of acute and chronic disease and/or disability, one uniform set of standards for nutrition care can be difficult to generate. The principles upon which guidelines are established should focus on and correspond to the general American Society for Parenteral and Enteral Nutrition guidelines for nutrition assessment in pediatrics. These include: 1. Individualized assessment of nutrition status to determine urgency and extent of patient support needs. 2. Consideration of the timing of onset of postoperative nutrition support and the appropriate use of total parenteral nutrition when the alimentary tract is compromised, with consideration for provision of either enteral or parenteral nutrition support within 3 days of hospitalization. 3. Provision of nutrition in a manner (enteral or parenteral) most consistent with safe clinical practice. 4. Avoidance of potential complications by continuous reassessment of individual risk/benefit ratios including determining optimal timing for alimentary tract challenge. 5. Employing methods for determining the adequacy of nutrition support.
General Nutrition Considerations in Neonatal Surgery

Neonatal Assessment, Nutrient Composition, and Targets for Nutrition Support in the Early Postoperative Period Infants with congenital disorders of the abdomen and especially the intestinal tract have fluid and nutrition requirements that require frequent reassessment in the
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immediate perioperative period. The excess fluid demands to restore or maintain vital organ perfusion in the perioperative period are not necessarily accompanied by a greater demand for caloric provision. 57 It is important to consider these requirements separately and avoid the potential for overfeeding and hyperglycemia. There are many factors in the postoperative patient that impact the energy estimates; these include the use of mechanical ventilation, the provision of external heat support, the use of sedating agents, and neuromuscular blockers. Pain control has a tremendous impact on the perioperative hormonal stress response. Preemptive analgesia, local block, and caudal blocks all contribute to reducing the stress response and are part of current surgical practice. For instance, in infants undergoing patent ductus arteriosus (PDA) ligation it was demonstrated that a fentanyl anesthetic resulted in improved protein metabolism. 8,9 While the assessment of volume status can be quantified using weight, fluid balance records, and occasionally invasive monitoring with central venous pressures, this process is not as straightforward when assessing metabolic demands. Unless nitrogen balance studies are readily accessible, the best estimates for caloric provision are made on the basis of the infants gestational age and formulas for the resting energy expenditure (REE) of the infant in the acute phases as well as in the recovery phase, which is best modified with estimated stress factors. Unfortunately the impact of nutrition interventions is measured in intervals approaching weeks rather than days and is generally based on the infants ability to demonstrate anticipated rates of growth and other anthropometric measures. Ideally, one would be able to assess parameters consistently, such as the infants glucose homeostasis, and verify adequate glycogen stores and a positive nitrogen balance along with the anticipated weight gain. However, these are impractical goals in the immediate postoperative period; therefore one must focus on maintaining euglycemia and avoiding hyperlipidemia and azotemia/uremia, while providing an escalating amount of balanced macronutrients in the form of carbohydrate, lipid, and protein. Laboratory parameters are used to assess nutrition status; however, these must be used as trends rather than as absolute measures in the infant, for whom there are often no gestationally appropriate controls.10 In the acute hypermetabolic phase there is whole-body proteolysis to provide not only substrate for gluconeogenesis but also for protein synthesis of necessary enzymes and other acute phase reactants. Principal laboratory markers include total protein, albumin, prealbumin (evaluated in the context of a normal
C-reactive protein (CRP)), and retinol-binding protein. These function as the measures of protein anabolism after the acute phase of injury and are difficult to interpret earlier. Whereas one strives for meeting the metabolic needs and accomplishing weight gain and growth in the healthier infant, the short-term goals in the postoperative patient are targeted to provide for sufficient substrate to prevent catabolism and allow for anabolism in the context of wound healing. Often, non-protein in an amount of 60 to 80 kcal/ kg/d, perhaps even less, will be sufficient to meet these initial goals in the neonate.11 It has been documented that preterm neonates often require a generous protein supply, perhaps as high as 4 g/ kg/d, which primarily serves to provide substrate for tissue repair and does not independently prevent catabolism of the existing muscle mass. By counting this protein delivery as energy-yielding caloric intake, this may result in inadequate caloric provision. This is the basis for calculating and targeting non-protein calories in the acute perioperative setting. In order to provide an optimal substrate for nutrient assimilation, a non-protein calorie-to-nitrogen ratio of 130:1 to 210:1 is generally recommended as the target total parenteral nutrition solution. Whereas the calculation of caloric targets in terms of non-protein calories may be important in the early perioperative phase, this should again convert to total caloric intake once the acute wound-healing demands return toward baseline. The time for this transition is perhaps best estimated by normalization of the CRP and should correspond to clinical indicators such as wound status, return of intestinal function, and lack of infectious complications. Cholestasis: PN-Associated and of Other Origins In contrast to the adult experience with overfeeding resulting in steatosis, cholestasis is a significant problem in pediatric surgical patients, who frequently require prolonged PN support and are at further risk for hepatic injury by virtue of their non-enteral feeding status and susceptibility to sepsis. The generally accepted measure of significant cholestasis is the direct bilirubin exceeding 2mg/dL. For those patients anticipated to have a prolonged dependence on total parenteral nutrition ( > 1 month) this authors institution initiates cycling of PN when the clinical condition permits, usually after the first month of life (term gestation infant) when it is predicted that glycogen stores are adequate and the infant perhaps is receiving some enteral feedings. Cycling off glucose infusion requires that the patient can maintain euglycemia to prevent the
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development of hypoglycemia. Seizures as a consequence of hypoglycemia carry the most profound risk for neurological devastation. The procedure for cycling involves reducing the rate of total parenteral nutrition infusion to 50% for 1 hour prior to discontinuing infusion and reinitiating the next bag of PN at a 50% rate for 1 hour before achieving the goal rate (see Figure 32-1) The targets for cycling on neonates are 4 to 6 hours off infusion; however, this must include consideration of glucose infusion rates, which may be significantly higher with consolidation of total parenteral nutrition. The authors institution provides lipid infusions as 24-hour infusions, which helps maintain patency of the catheters without the need for additional fluid infusions when heparin locking might not be desirable because of multiple entries into the catheter hub. Both components are cycled when the patient is discharged to home on total parenteral nutrition and the catheter can be heparin locked for an extended period. Other considerations to limit PN-associated cholestasis for those infants on complete parenteral nutrition involve maintaining relative ratios between macronutrients. Examples of this include targeting a non-protein calorieto-nitrogen ratio of approximately 180:1, and the provision of lipid calories not exceeding 30% of total non-protein calories. The role of lipids with a more anti-inflammatory profile (eg, omega-3 fatty acids) is not yet clear and, in the absence of a diverse assortment of lipid sources, it may be wise to use Intralipid (a soy-based and omega-6 fatty acid based solution) judiciously.12,13 Limitation of lipid calories may, however, necessitate pushing the glucose infusion rate (GIR) as high as 15 mg/kg/min to achieve caloric goals. Clearly the initiation of enteral feeds is one of the most critical steps14 in this process, and cycling nonabsorbable enteral antibiotics may additionally be instituted to limit the potential for bacterial overgrowth and enteral-derived sepsis which would further compound the cholestatic injury to the liver. The use of ursodeoxycholic acid is beneficial when the terminal ileum is in continuity or proximal to a stoma. As the infant enters the phase of recovery, absent any infectious or wound-healing complications, the focus changes toward the more typical pediatric goals of nutrition support covering the acute needs as well as those demanded for growth and development. Here the documentation of weight gain, resolution of the acute phase reactants (eg,CRP), and establishment of a trend of increasing prealbumin values become the primary outcome measures for the efficacy of nutrition support. As mentioned above, the focus on providing protein purely for wound-related anabolism is reduced at this point.
Initiation and Choice of Enteral Alimentation Enteral nutrition is incrementally introduced when there is evidence of GI tract motility and assurance that anastomoses, if performed, have achieved satisfactory healing. General principles in managing postoperative patients include a conceptual understanding of normal postoperative events including paralytic ileus, delayed gastric emptying, the effect of narcotic analgesics, and the perianastomotic edema that may impede transit during the first 48 hours postoperation. General guidelines for determining the ability to initiate feeding include an assessment of (1) gastric output both in terms of quality (bilious vs. gastric or even salivary content) and volume; (2) physical examination for evaluation of abdominal distention and the presence of bowel sounds; and (3) assessment of output whether by stoma or per rectum, remembering that motility recovers first in the distal intestine and therefore that occasional stool output is not an assurance of actual GI transit. The recognition of potential intestinal complications such as anastomotic leak, intraabdominal sepsis, wound failure at the level of the abdominal wall closure, and even stomarelated problems (eg, stomal stenosis or prolapse) is critical to those managing these patients. The timing of initiation of feeds therefore depends on an assessment of the risks and benefits of providing enteral nutrients. Choice and mode of feeding are often predicated by the infants gestational maturity, the history of mucosal injury/disruption, effectiveness of motility, urgency to transition off PN, and the presence of gastroesophageal reflux (GER). In general, breast milk should remain the first choice for all of its innate qualities in optimizing gut mucosal function and immunity. Although donor breast milk will lack some of the immune benefits, it remains a desirable nutrient source. When commercial formulas are necessary, infants who have no history of a compromised intestinal wall (mucosal damage, transmural edema/fibrosis) can be started on standard hydrolyzed whey-based formulas for gestational age, whereas those infants who have a positive history should be started on a more elemental substrate to optimize absorption in the presence of a compromised mucosal barrier. Casein hydrolysates (Pregestimil, Alimentum) are common choices for the surgical infant and the specific formula is often based on the fat composition and osmotic load. However, these specialized formulas only provide a fraction of the calcium and phosphorus needs for a preterm infant, and this must be taken into consideration with supplementation, when possible. More elemental, extensively hydrolyzed formulas (Neocate, EleCare), which consist of amino acids and peptides and were designed to obviate
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Figure 32-1
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protein allergies, may in some instances be better tolerated in those with compromised motility as well. Theoretically they reduce the luminal content of nutrients reaching the distal intestine and perhaps limit bacterial overgrowth and carbohydrate fermentation, which result in excess reducing substances being excreted along with luminal fluids in the form of diarrhea or frequent loose stools. As the patients intestinal tract recovers, transition to a more complex and age-appropriate formula can be accomplished in a gradual manner. In contrast, infants with congenital disorders that do not affect the intestine itself, such as infants with omphalocele, congenital diaphragmatic hernia, malrotation without volvulus, pyloric stenosis, and thoracic conditions, should be able to tolerate standard formulas. Guidelines for caloric estimates in critically ill surgical infants requiring respiratory support are difficult to establish, but are best assessed using a metabolic cart.6 Whereas the acutely, short-term ventilated patient probably does not require a major revision in energy provision, this is countered by those infants who are chemically relaxed and actively ventilated and not participating in their work of breathing. Most of the recent publications have focused on the subset of neonatal cardiac surgery patients2,3 who can be analyzed as a reasonably cohesive group. In between this spectrum are the infants with congenital diaphragmatic hernia who, while intubated, are variably assisted in ventilation and require attention to avoid an inappropriate respiratory quotient (RQ ) which might adversely impact their ability to eliminate CO2 . Clearly, each of these patients is unique and generic formulas cannot be applied. These issues are more extensively discussed in chapters on critical care and specific consideration must additionally be placed given the surgical patients underlying condition. The goal is to have a patient who is in optimal nutrition shape. To the surgeon this is a multifactorial evaluation, which hopefully indicates that the infant has an appropriate weight gain of 1% to 2% of body weight per day and is demonstrating appropriate somatic growth in length, head circumference, and triceps skinfold measurement. Furthermore, based on laboratory parameters, the child will either have achieved a serum albumin within normal limits or at least show a trend of progressively escalating prealbumin values. A multifactorial assessment is particularly important when contemplating a secondary surgical intervention, such as a stoma closure. To achieve these goals one can ideally provide a balanced enteral and parenteral regimen. Sufficient enteral nutrition (EN) (trophic or greater) should be provided to stimulate the mucosa and maintain its health, promote motility, and avoid recurrent luminal obstruction.
The limits of tolerance are probably best defined by evaluating the volume and nature of the output. Because stool output is not measured in terms of frequency of stools with a stoma, the guideline to be used is that output should not exceed one-third of total enteral intake. Other formulas include the assessment of normal stoma output on the basis of weight, with expected output estimated at 1 mL/kg/h and tolerable amount to allow progression of enteral feeds set at either 30 mL/kg/d or 2 mL/kg/h.15 Excess outputs serve as indicators of inadequate absorptive capacity and osmotic fluid losses and should be further evaluated with the content of reducing substances and stool pH. Reducing substances will shed light on carbohydrate malabsorption with contents of 1% or greater in the presence of loose stools constituting an indication for intervention, depending on the type of enteral intake. Stool pH will reflect whether there are organic acids generated by unabsorbed sugars, and this can happen independent of the presence of reducing substances. Ideally a target caloric goal is established for each patient and EN is pushed to the limit of tolerance with PN providing the balance of calories necessary to achieve weight gain and laboratory goals. While consistently pushing the limits of the intestinal tract, it is important not to have frequent setbacks which ultimately delay operation to restore continuity and thereby compromise the best case scenario for complete adaptation. The use of distal refeeding provides a valuable adjunct in these situations, at least contributing to restoring a complete enterohepatic pathway for bile if the distal ileum has been retained.16 The benefits are, however, counterbalanced by the often arduous contraptions that have to be created to collect and reinfuse the stoma output and the risk of perforating the distal intestine with repeated catheterization. The decisions involved in these complicated cases require that all care providers reach consensus on the short- and long-term plans for the patient. Only then can the ideal nutrition support plan be instituted. All surgical patients must be monitored carefully for the onset of jaundice. Often the default reason for the onset of direct hyperbilirubinemia is the use of PN; however, surgical patients can develop intestinal obstruction whether it be at the level of an anastomosis, at the level of a proximal stoma, or at a random site due to peritoneal adhesions. These conditions must remain in the foreground as correctable causes of obstructive jaundice. Others conditions include drug-related cholestasis (seen with cephalosporins), lowgrade sepsis, and even secondary disorders such as biliary tract disease (gallstones and sludge) or pyloric stenosis.
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Surgical Considerations in Infants with Congenital Disorders

Proximal Intestinal Obstruction
A congenital proximal intestinal obstruction is usually recognized antenatally or immediately postnatally and typically prompts urgent operative intervention. While these conditions can be temporized with effective nasogastric suction, delay of operation is reserved for those infants with suspected congenital heart disease who will require further evaluation (ie, patients with esophageal atresia and duodenal atresia) or would benefit from a stabilization of their transitional circulation changes before undergoing anesthesia and operative stress. Although unusual, the concern for the presence of an underlying non-survivable metabolic disorder or lethal chromosomal disorder constitutes a second justification for delaying surgical intervention. Esophageal Atresia The most complex decision making involves infants who have esophageal atresia, and are significantly preterm and/or low birth weight. Operation may safely be delayed 1 to 2 days while postnatal circulation stabilizes and the child undergoes screening evaluations for disorders in the VACTERL association (vertebral, anorectal, cardiac, tracheo-esophageal, renal, and limb). During this time most neonates will be started on at least peripheral total parenteral nutrition with a plan to escalate to central total parenteral nutrition once appropriate venous access has been established, either via a temporary umbilical venous catheter, peripherally inserted central catheter (PICC) line, or surgically placed central venous line inserted at the time of operative repair. The expectation is that the infant will not be able to utilize the intestinal tract until approximately 7 days postoperatively when the esophageal anastomosis is evaluated for patency and absence of leak. Many surgeons will not place a trans-anastomotic feeding tube at the time of operation, because gastric feedings will likely be associated with a significant incidence of GER (on the basis of probable anatomic distortion of the angle of His) and this should be avoided until the esophageal anastomosis is shown to be without leak. The association of trans-anastomotic tubes with anastomotic complications remains speculative, but unsubstantiated in the literature.17 When there is a leak, the period of non-enteral alimentation may extend for another 5 to 7 days, since there is no safe esophageal access to the stomach or beyond. The use of gastrostomy tubes generally has been limited to those infants with long-gap atresia who will undergo esophageal
reconstruction/repair at a later date, or to those infants who are expected to have poor oral-motor skills or other feeding dysfunction based on concomitant disorders (trisomy, retrognathia, etc). Given the reliance on total parenteral nutrition for a period of 7 days or more, most neonatal centers will either place central venous access preoperatively (PICC line) or surgically place access at the time of reconstruction. Because these considerations for alimentation are not based on technique, there is no difference in the postoperative management in thoracoscopic or open repair of esophageal atresia. After the esophageal anastomosis is verified to be free of leak with a contrast esophagram, the contrast is followed through the duodenum primarily to establish the absence of malrotation. Duodenal stenosis due to annular pancreas and an even duodenal atresia can co-exist with esophageal atresia. This will not be apparent at operation because the abdominal cavity is not entered. Enteral feeds can be commenced, preferably by mouth, to avoid repeated instrumentation of the esophagus. It must be kept in mind that there will be esophageal dysmotility based on the lack of a progressive peristaltic wave down the esophagus and based on the perhaps more capacious proximal pouch that empties as much by gravity as by propulsive esophageal wall activity. Delayed emptying through the anastomosis will result in prompt oral regurgitation but also will result in tracheal compression which becomes evident as desaturation with feeds. These events are expected even in the absence of a stricture, and are only further accentuated by any luminal compromise. Infants must be maintained with the head of the bed elevated and should be fed as upright as possible. The goal of oral feeding should be to allow the infant to practice frequently with low-volume amounts (510 mL every 3 hours). Once these are tolerated, the progression of feeds should be gradual, but should remain on a frequent basis (every 3 hours) as the next barrier to reaching full feeds will be GER. When breastfeeding is initiated it should similarly be limited in time, and this interval for feeding is progressed as the infant tolerates. Although it is difficult to measure intake, reports of weighing the infant pre- and postfeed suggest that this may be a method to quantitate intake. The stomach capacity will increase with time; however, any acid reflux is detrimental to the anastomosis and can result in stricture formation. These infants therefore should be placed on acid reduction therapy immediately postoperatively, and this therapy is usually maintained for 6 to 12 months. The addition of metoclopramide may be helpful when feeds are first initiated, so as to promote
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gastric emptying. Optimally the infant will progress to full feeds over a period of 5 to 7 days, although it is not unusual for those infants who are more symptomatic with tracheomalacia to take longer. These infants may require repeated intubation for mechanical ventilatory support or they may require support with high-flow nasal cannula oxygen which compromises their ability to tolerate gastric feeds. In these instances it may be advisable to place a transpyloric feeding tube to enable the infant to take EN and be weaned off PN, while his or her airway disability is being addressed. In severe cases, this may constitute an indication for placement of a gastrostomy tube. The current reluctance to place a gastrostomy is that the physical distortion of the stomach as a result of a gastrostomy may further negatively impact GER, which in turn may adversely affect healing of the anastomosis. Surgical therapy of GER, while necessary in a subset of infants, is avoided due to (1) the inherent dysmotility of the esophagus which may not be able to overcome any level of obstruction distally and (2) anatomically by the shortened length of the esophagus. While these concerns can be taken into account surgically with a less tight fundoplication and esophageal lengthening procedures such as the Collis gastroplasty, these are best avoided, unless a recalcitrant esophageal stricture forms.18 During infancy, the choice of infant formula should be based on gestational age. There are no specific intestinal absorptive defects to prompt the use of more elemental formulas. Caloric concentration of infant formulas is often necessary and advisable to accomplish achieving nutrition goals, given the propensity for reflux. Long-term nutrition problems in esophageal atresia relate to ongoing problems with GER and proximal strictures. Surveillance esophagrams are sometimes indicated and mechanical or hydrostatic fluoroscopic dilatation is usually effective in treating strictures. With progression to solid foods, these children must be coached to chew well and to consume liquids with their meals to overcome any potential residual esophageal dysmotility. It is not unusual for overly large pieces of food to become lodged at the level of anastomosis and result in esophageal obstruction. This problem tends to resolve with age, the increasing caliber of the esophagus, and maturity of the child. Duodenal Atresia Infants with duodenal atresia are most often identified antenatally and parents can be advised about their anticipated perinatal course in a prenatal consultation. The focus of these discussions from a pediatric surgical standpoint is the operative management of the anatomic defect and the
anticipated need for PN in the pre- and perioperative period while awaiting healing of the anastomosis, resolution of any peri-anastomotic swelling, and onset of effective peristalsis in the dilated proximal duodenal segment. While most infants can undergo this reconstructive operation within 48 hours of birth, there are some in whom the management of prematurity and congenital heart disease will dictate the timing of operation and the provision of total parenteral nutrition will be prolonged in duration. Based on the specific functional cardiac defect, a decision can be made with the cardiologists to proceed early with abdominal operation before the pulmonary pressures rise significantly and impact the perioperative fluid and cardiac management. This would reduce the cholestatic consequences of the combination of anatomic obstruction with prolonged PN, a combination which may become detrimental with time. For anatomic reasons, the repair of duodenal atresia involves no resection, but creates an anastomosis joining the dilated proximal segment to a segment of the tiny, previously unused duodenum. At operation an assessment is made of the distal bowel to assure that there are no further sites of atresia, the duodenum is assessed in terms of its caliber and contractility for possible tapering duodenoplasty, and the overall situation is assessed for the potential need for prolonged gastric decompression via gastrostomy. In a child who requires a duodeno-duodenostomy, has a reasonable caliber anastomosis, and a not overly dilated proximal pouch, enteral feeds can generally be started after the fifth postoperative day. Duodenal leak can be a catastrophic complication due to the leakage of activated pancreato-biliary secretions. Often a contrast study for anatomic and functional evaluation is requested in these infants prior to commencing feeds. In contrast to most postoperative patients, the assessment for when to start feeds has less to do with the bilious aspirate from the nasogastric (NG) tube or drainage from the gastrostomy feeding tube (G-tube) than to do with volume. Because of the congenital obstruction, the pylorus is often incompetent and bile will flow retrograde into the stomach. The progressive decrease in output, however, indicates forward peristalsis through the anastomosis and is the best indication that it is safe to start enteral feeds. When breast milk is not available, the choice of infant formula is based on gestational age. There are no predictable associated absorption disorders to require specialized formulas. The mode of feeding again is dependent on the childs anatomic and functional considerations. While intermittent oral feeds may be a successful strategy, often a more rapid transition from PN to EN is achieved with continuous gastric feeds which are then transitioned to bolus and oral feeds. Certainly oral
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feeds can be added on top of continuous feeds to allow the infant to acquire oral motor skills. The more complicated infants have greater duodenal dysmotility and may have required a tapering enteroplasty. These infants often have a G-tube inserted to facilitate gastric decompression, thereby protecting the anastomosis and allowing the infant greater success in extubating from mechanical ventilation without a nasogastric tube in place. Given the potentially complex and prolonged postoperative course in this disorder, PN is started routinely and converted to central formulation once central venous access has been established. Jejunoileal Atresia As the anatomic site of obstruction extends further distally, the immediate postoperative problems related to provision of EN generally are less frequent and less severe. These proximal obstructions can occur in isolation as well as in various constellations of increasing complexity, culminating with the type IV apple peel deformity. In the simple mucosal web or single transmural atresias, operative considerations are relatively simple if the infant has normal overall intestinal length. A resection of the abnormally dilated jejunal segment and primary anastomosis to the distal unused bowel results in the least size discrepancy between adjacent limbs of intestine and predictably has the least common incidence of peri-anastomotic obstruction and dysmotility. These infants would be anticipated to tolerate the onset of enteral feedings once bilious NG output has resolved and volumes have decreased in concert with the passage of bile-pigmented stool output. This can occur 5 to 10 days after operation and therefore mandates use of PN in the interim. Infants with multiple intestinal atresia are likely to have compromise of the overall bowel length, and operative methods to salvage length must be considered in relation to the infants gestational age and how this relates to ongoing longitudinal growth of the intestine during the third trimester. Infants delivered at term and diagnosed with multiple intestinal atresia have less opportunity to compensate for lost intestinal length. The most proximal segment of intestine will be the only segment dilated, and length can be preserved by performing a standard longitudinal tapering enteroplasty. Only in the event of severe congenital short bowel should more novel techniques such as the serial transverse enteroplasty procedure (STEP) or Bianchi be considered to optimize salvage of mucosal surface area while promoting intestinal contractility.19 As many as possible of the subsequent atretic portions of intestine should be salvaged using a shish-kebab technique in which continuity is created over a device such as a broviac catheter.20 The calculated risk, however, is the non-union of segments with
either leak or obstruction as a consequence. Surgical clinical judgment will dictate what is reasonable to salvage.21,22 In the most complex variant of jejunoileal atresia, the apple peel deformity, there is a complex malformation of the proximal intestine along with preservation of the distal ileum on a vascular pedicle that provides retrograde perfusion for a variable length of intestine. The particular anatomic appearance of the twisted intestine, may-poled around the single vascular trunk originating from the distal ileal arcade, is important to recognize such that inadvertent further vascular compromise is avoided by torque from a poorly aligned enteric anastomosis. Furthermore, careful perioperative fluid management is essential to preserve adequate perfusion to the distal most intestine. Hypotension will result in splanchnic vasoconstriction compromising mucosal flow to particularly this section of bowel. Nutrition considerations in these infants focus on the provision of adequate PN calories via central access, with early consideration of techniques to limit cholestatic disorders since the process to complete conversion to enteral feeds may be prolonged by dysmotility and complications such as necrotizing enterocolitis (NEC). With the intent to gradually stimulate the bowel for adaptation, continuous feeds are most often initiated and the infants who often have G-tubes to facilitate this are allowed to sham-feed by mouth and eventually are later converted to full bolus feeds by mouth or G-tube.23
Distal Intestinal Obstruction

Distal intestinal obstruction usually involves the terminal ileum and beyond. These infants will present with abdominal distention which is not relieved with nasogastric decompression. Distal ileal atresia or obstruction from inspissated meconium can result in volvulus of the distended, fluid-filled segment and cause ischemic necrosis of more extensive regions of the intestine. In the absence of significant intestinal loss, these conditions are unlikely to require more than conventional perioperative nutrition support. Resection of the right colon including the ileocecal valve is usually well tolerated. The need for replacement of vitamin B12 must be considered at a later time (age 2 years) if a significant portion of terminal ileum accompanies the resection. More extensive colon resections, as might be encountered in Hirschsprungs disease, have more significant effects on resorption of water and electrolytes. Patients with Hirschsprungs disease and anorectal malformations require long-term dietary management with the focus on achieving optimal evacuation of stool.
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Colon Atresia Colon atresia is a rare condition, accounting for only 10% of all intestinal atresia. Most common is a vascular defect at the level of the middle colic artery resulting in an interruption of continuity at the mid-transverse colon. The right colon becomes massively distended since a competent ileocecal valve may not allow for distribution of the enteric contents into the terminal ileum. Operatively there are several solutions for this condition. An extended right hemicolectomy with anastomosis of the ileum to the transverse colon results in permanent loss of a significant surface area for nutrient and water absorption. Fortunately the left colon can compensate for the water absorption with adaptation and the patient should not have persistent watery stools. More complicated solutions focus on preserving the right colon with a proximal diverting stoma in the hopes that it will decompress and regain its normal caliber and motility. The nutrition considerations in these patients are generally simple and are impacted by whether a second reconstructive operation is necessary. Meconium Ileus and Variants This is a condition usually associated with cystic fibrosis (CF), resulting in distal ileal obstruction as a consequence of the abnormal luminal contents which become inspissated. Meconium ileus may be complicated further by either (1) perforation of the obstructed bowel resulting in meconium peritonitis or (2) volvulus of the distended bowel resulting in ischemia and stricture formation which may appear identical to an atresia. While simple meconium ileus, in which there is only luminal inspissation, can be decompressed with sequential gastrograffin enemas, operation is sometimes necessary. In the process of attempting to decompress the obstructed segment with saline or N-acetylcysteine irrigation, it is possible to perforate or excessively traumatize the intestine. Often the safest choice is placement of a T-tube that provides access for continued postoperative irrigation and gradual resolution of the obstruction. In the event of complicated meconium ileus due to luminal discontinuity, a resection and primary anastomosis may be possible, but because of the risk of recurrent distal obstruction, creating a vented anastomosis (Bishop Koop or Santulli stoma) provides the greatest assurance of success. This allows the enteric contents to evacuate per stoma should distal obstruction re-occur and provides direct access to the distal bowel to treat with 3% N-acetylcysteine solution. The most difficult variant to deal with operatively is meconium peritonitis, in which the site of perforation may be unable to be identified or mobilized to create a stoma. A proximal
diverting stoma becomes necessary with staged exploration and restoration of continuity at a later date. If the distal end of the bowel can be identified this is helpful in trying to prepare it for the subsequent operation and for consideration of distal refeeding of proximal stoma output (see later section in this chapter). Nutrition management of these infants requires consideration of the likely underlying diagnosis of CF, which must be verified by testing. While in the past it was taught that EN with a protein hydrolysate formula or breast milk did not require provision of pancreatic enzymes, common practice now is to provide these enzymes nevertheless, to optimize whatever enteral intake is available for absorption. This has to be balanced with the past concerns for mucosal damage from specific formulations of enzyme dosing. This infant with a diverting stoma is a classic example of the nutrition decision-making involved with a child who will require a second, complicated operation, 6 weeks or more in the future (see section on management of stoma output). Cholestatic jaundice is based not only on total PN exposure, but also on potentially underlying liver disease associated with CF. Once intestinal continuity to a stoma or the rectum is established postoperatively the goal is to wean total PN support expeditiously while recognizing that these infants tend to have a higher than usual caloric requirement. Hirschsprungs Disease Hirschsprungs disease is a consequence of the absence of the ganglion cells from the rectum and distal-most colon, typically involving the rectosigmoid. The enteric ganglion cells are essential to receptive relaxation of the intestine and their absence results in a functional obstruction of the colon with remarkable dilation of the normal colon proximal to the transition zone beyond which these neural crest cells failed to migrate during the embryonic period. The consequence is a functional obstruction at the level of the absence of ganglion cells (aganglionosis). Hirschsprungs disease most often affects term or near-term infants and is unusual in preterm infants. The newborn who is diagnosed and promptly undergoes reconstructive operationwhether it be an open operation, laparoscopic assisted, or transanal is likely to be able to start normal EN within 5 days of operation. Therefore the provision of even peripheral total PN, during the first few days of life, once the child has been diagnosed, is probably sufficient. This scenario, however, changes with a late diagnosis of Hirschsprungs disease, which is often associated with significant failure to thrive, enterocolitis, and long-segment disease. These situations are independent predictors of a difficult postoperative course
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and therefore surgeons will often choose not to operate immediately and instead to manage these patients medically (with irrigations if the transition zone is distal) or perform a stoma at the point where ganglion cells are present. Failure of the initial reconstruction potentially leads to a lifetime of anorectal disability. Once diverted, or established on an effective irrigation program, the alimentary tract can again be challenged with nutrients and should be able to function appropriately, allowing the infant to thrive. The infant with total colon aganglionosis is essentially diverted at the level of the terminal ileum. He or she may require total PN support transiently until such time when adaptation has occurred. The rare infant with aganglionosis extending into the small intestine often will suffer from severe short bowel syndrome (SBS) and must be managed accordingly. Anorectal Malformations Children with isolated anorectal malformations generally have no specific nutrition requirements. Their anorectal defect will either respond to progressive dilation allowing for a delayed operative intervention or will require a diverting colostomy. These children grow and develop normally in the absence of associated disorders. After reconstruction, children with Hirschsprungs disease and low variants of imperforate anus will have issues related to stooling, with some developing severe functional constipation which may progress to overflow incontinence. Children with high imperforate anus tend to have problems with fecal incontinence either due to absence of the sphincter complex or deficient innervation. Appropriate dietary management along with a supervised bowel management program are essential to the well being of children with this spectrum of disease. Dietary considerations include provision of sufficient non-absorbable fiber intake along with sufficient liquid intake to assure daily evacuation.
Beckwith-Wiedemann syndrome is diagnosed when omphalocele is associated with macroglossia, hypoglycemia, and hemihypertrophy. This is a transient metabolic condition with no long-term implications for glycemic control, but places the patient at risk for solid organ tumors. Associated congenital heart disease may involve various intracardiac defects or a constellation of defects involving the heart, pericardium diaphragm, and sternum which are referred to as the Pentalogy of Cantrell. Depending on the size of the abdominal wall defect, the liver and intestine are typically extra-abdominal, and reconstruction can be accomplished in one vs. several stages. A small omphalocele can be closed within days after birth once associated anomalies have been excluded. The child is typically kept NPO preoperatively, although this may not strictly be necessary, but convenient for the preoperative evaluations. Once a small omphalocele is closed, enteral alimentation can be commenced as soon as there is evidence of GI motility/function. While there are no predictable GI problems, extrinsic gastric compression from the oversized liver and GER are not uncommon and may require transient postpyloric feeding. In the more complicated giant omphaloceles, PN is commonly started to bridge the childs nutrition needs while multiple operative procedures interfere with consistent EN. Ethical considerations arise when an infant with omphalocele is diagnosed with a lethal chromosomal disorder such as trisomy 18. Often the surgical condition can be managed in a non-operative manner and EN can be delivered in a relatively non-invasive manner via a nasogastric feeding tube if the child will not feed by mouth. The outcomes of omphalocele should be excellent but for the most complex disorders. Gastroschisis Gastroschisis is frequently the more complex defect from the standpoint of operative interventions and providing optimal nutrition support. This abdominal wall defect is typically a relatively small full-thickness aperture to the right of the umbilical cord insertion. Much of the GI tract is extruded through this defect and is bathed in amniotic fluid through pregnancy. The exposed intestine is at risk for torsion, vascular impairment from a tight fascial defect which remains fixed as the intestine and its mesentery enlarge, and is subject to serosal irritation and trauma by virtue of its extraperitoneal location. Immediate postnatal coverage of the intestine is accomplished by either primary abdominal closure or more commonly by placement of a temporary silo. This sterile silastic tube accommodates
Abdominal Wall and Diaphragm

Omphalocele Omphalocele and gastroschisis are two very distinct congenital disorders with completely different considerations in terms of their postnatal GI function. While both conditions involve the presence of an abdominal wall defect, the intestine is protected within a membrane in patients with omphalocele and is not subject to the fascial constriction and amniotic exposure encountered in gastroschisis. Omphalocele can be associated with genetic disorders as well as renal and cardiac defects and it is typically these conditions that determine the outcome of these patients.
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the intestine and is secured via a flexible but reinforced ring at its open end, which slides under the abdominal wall fascia, thereby creating a covered extension of the peritoneal cavity. Gradual compression of the silo from the top down forces the intestine into the gradually expanding abdominal space and allows for the ultimate abdominal wall closure. Although there are multiple variations in the technique to achieve reduction and closure, there do not appear to be any remarkable differences in outcome in terms of time to full feeds and hospital discharge.24 Non-operative, bedside closure with simple coverage using the umbilical remnant has also been described and is being evaluated for its longterm outcomes. The most important predictor of outcomes appears to be the original condition of the intestine. The intestinal surface in gastroschisis has a variable appearance and ranges from non-edematous, pliable, and virtually normal intestine without surface adhesions to stiff, edematous bowel whose contour and continuity cannot be assessed visually or even by palpation. Further complicating the presenting features is the tendency for these children to have a shorter than normal length of intestine. Fortunately some of these changes will resolve with time; however, the period of time to normal intestinal peristalsis can be quite variable. After an extended period of observation of 4 to 6 weeks, without evidence of bowel continuity, contrast studies are indicated to evaluate whether there is an intestinal atresia present. Evaluation much earlier is without benefit, as the abdomen will be quite hostile to exploration. An interesting situation arises when an atretic segment is recognized at birth. Although the intuitive response would be to divert at that level to allow for some enteral stimulation, this is not generally advisable. There is limited abdominal wall surface area for a stoma and the edema of the intestine rarely allows it to reach the abdominal wall in an orientation that is feasible for creation of a stoma. It is currently considered best practice to close the abdomen and correct the atresia at a second operation.25,26 Given the primary dysfunction of the intestine on multiple levels, these infants may require an extended period of PN support. During the initial few weeks, the infant remains decompressed with a nasogastric tube. Again, in contrast to other children who may require prolonged decompression, there is a reluctance to perform any visceral procedure, even a gastrostomy, due to abdominal wall constraints and the altered surface characteristics of the GI tract. Unless these children are extremely preterm, they usually have an uneventful perioperative course with a short duration of mechanical ventilation. There are no
known interventions that lead to a more rapid resolution of wall edema. In general these infants require a generous amount of intravenous fluid support in the first few days as they are projected to be relatively volume depleted on presentation and continue to require good vascular perfusion of the intestine. The peripheral edema which may appear occurs on a different basis than that of the intestine, which likely happens as a consequence of vascular and lymphatic congestion at the level of the fascial ring defect. In contrast to the peripheral edema, it is unlikely that diuresis affects this visceral edema in the early phases. The onset of intestinal feeding must coincide with evidence of effective full intestinal peristaltic activity as evidenced by decreasing NG outputs and onset of stooling. Early feeding into a dysmotile and transmurally altered intestine likely accounts for the higher incidence of NEC in gastroschisis than any other gestational age-matched infant population. While bolus feedings have benefit in stimulating hormonally regulated secretions from the pancreatobiliary tract, they are limited by virtue of the initially small capacity of the stomach. Because cholestasis is common in these infants, there is a desire to wean them off PN expeditiously; however, this is best achieved not by starting feeds prematurely, but by providing continuous enteral stimulation via continuous drip feeds, once motility is evident. These can certainly be augmented by interval bolus feeds which allow the child to develop the necessary oral feeding skills and may stimulate the GI hormones. Vigilance is essential as the enteral component is advanced. Guidelines for advancement of feeds should take into account the frequency of stools as well as the pH and reducing substances as these may indicate poor absorption and/or an excessive osmotic load. Because of the perceived fragility of the intestine, this authors practice is generally to use a more elemental formula and limit the osmolality of the formula, trying not to increase the caloric density of feeds until the child is nearly fully established on EN. Setbacks relate to septic events concerning the central line, which are usually gram negative in etiology and reflect the ongoing reduced mucosal barrier defense in the intestine. Given the combination of cholestasis and poor motility, these patients are great candidates for cycled enteral antibiotics to obviate bacterial overgrowth and its complications. Gastroschisis is one of the more common causes of neonatal SBS. The etiologies involve congenital torsion or ischemic necrosis of entire segments of intestine, simple atresias, and postnatal loss of intestine due to poor perfusion, NEC, or surgical catastrophes. Caloric estimates for the needs of these infants depend on their phase of recovery. In the initial
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postnatal period there appears to be an intense inflammatory state as evidenced by elevated CRP which resolves as the bowel recovers. The incidence of cholestatic jaundice is likely multifactorial in this population.26 Congenital Diaphragmatic Hernia Congenital diaphragmatic hernia (CDH) involves a heterotopic location for the viscera within either chest cavity as well as associated developmental defects in lung and pulmonary vascular development and maturation. While the former is a surgically correctable defect, the second component determines the childs clinical course and ultimate prognosis. Infants with CDH therefore fall into several categories. There are those with a diaphragmatic defect, usually first detected postnatally, in whom there is little hemodynamic and pulmonary compromise; they tolerate the operation well and can relatively quickly be transitioned to enteral feedings. Infants in whom the defect was identified early in gestation tend to have a greater degree of pulmonary hypoplasia and more difficulty with pulmonary hypertension. These infants may require cardiac and pulmonary support via ECMO. Nutrition support in this disorder therefore spans the whole spectrum and must be individualized. The GI tract, although displaced initially, is fundamentally normal in terms of its motility and absorption capacity. As such there are no specific recommendations for the type of enteral alimentation. Consideration will need to be given to the fact that total fluid provision will likely be restricted in the postoperative patient as he or she is weaned off ventilatory support. While it is enticing to provide highly concentrated formulations, this has to be balanced with the potential for mucosal damage leading to enteric-derived sepsis in vulnerable infants who likely have multiple vascular access points. Provision of adequate calories will likely be best accomplished by this means once the infant has tolerated enteral feedings and becomes limited in the amount of volume that can be delivered for reasons of gastric capacity and emptying. All children with CDH have some degree of foregut dysmotility, which renders them at risk for GER.27,28 The risk of reflux with aspiration is particularly pronounced in these patients who already have a compromised pulmonary system, given the nature of the congenital defect. This forms the basis for providing continuous feeds initially to full enteral needs and then transitioning them to bolus feeds. Again, the provision of continuous enteral feedings should not be a disincentive to allow for oral feeds. This can be structured to be the volume of feeds targeted to be delivered over 1 hour or even more as the child tolerates.
Infants with CDH and severe cardiopulmonary compromise requiring inotropic support and other medications such as nitric oxide for stabilization of the pulmonary hypertension present challenges to the provision of even a fraction of the targeted caloric requirements. The assessment of caloric needs is especially difficult because there are so many confounding factors such as level of sedation, possible chemical muscular relaxation, degree of mechanical respiratory support, and level of temperature support provided. During this phase the goal of nutrition support is to provide those essential components to allow for basic metabolic needs and repair of tissues. Calories earmarked for growth and development become priorities as the infants clinical condition improves. When these patients require cardiopulmonary support on ECMO , the assumption was that just as the lungs were being rested, the metabolic demand would decrease. This has been shown to be an incorrect assumption; these patients continue to exhibit the hypermetabolic response, and this even persists after decannulation.29,30 In the past there has been debate as to the safety of administering lipids to an infant on ECMO. The consensus now is that they can safely be administered via a central line separate from the ECMO circuit, whereas the dextrose and amino acid solution is typically administered via the cannulae and in this situation only, can safely exceed dextrose concentrations greater than 20% since there are sufficiently high flow rates directly into the atrium. Provision of high glucose loads along with insulin therapy has been shown to be beneficial in this population in terms of limiting protein catabolism. 31,32
Hepatobiliary Disorders
Biliary Atresia Infants presenting with direct hyperbilirubinemia are promptly evaluated for surgically correctable biliary tract disorders such as biliary atresia and choledochal cyst. While other conditions such as neonatal hepatitis also lead to similar laboratory presentations, they, as well as a host of infectious disorders and enzymatic defects, require medical support only. Biliary atresia most often becomes evident at 1 month of life and the infant may have experienced failure to thrive of unknown etiology. Hallmarks of clinical diagnosis include jaundice, acholic stools, and dark urine. Ultrasound, HIDA scan, and percutaneous liver biopsy should confirm the diagnosis. Once established, preoperative administration of vitamin K is one of the standard recommendations to optimize coagulation parameters. The diagnosis is further confirmed intraoperatively by demonstrating lack of the
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extrahepatic ductular system. Reconstruction involves creation of a jejunal limb that is anastomosed to the portal plate, the region of the liver where the hepatic ducts would be presumed to originate from the liver parenchyma. In fortunate situations, there is early evidence of bile flow with resolution of the hyperbilirubinemia. Postoperative steroids are frequently used as a choleretic and to reduce the parenchymal inflammation within the liver. This postoperative course is typically a period of 5 days of non-enteral alimentation to allow for healing of the intestinal anastomosis with subsequent initiation of enteral feedings. With the frequent delay in diagnosis to 2 months of age, some infants will be in very poor nutrition condition. On preoperative assessment, some surgeons will opt to place central venous access at the time of operation, to provide the debilitated child with some nutrition in the interim so as to optimize healing and prevent further weight loss. There is no indication for preoperative nutrition repletion because decompression of the obstructed biliary tract is the most important goal. Postoperative feedings are generally breast milk if available, or a protein hydrolysate formula with approximately 50% medium-chain triglyceride (MCT) oil to provide MCTs which are more easily absorbed by the infant with liver disease. These children have impaired ability to digest fats and require supplementation of the fat-soluble vitamins A, D, E, and K. There are reports of these infants requiring a disproportionately larger caloric intake than for others their size. More on the nutrition support of the child with surgically non-correctable liver disease is discussed elsewhere. 33,34 Choledochal Cyst Infants with this congenital disorder may present during the neonatal period or later, but generally before age 5 years. The acute presentation may include pancreatitis in addition to hyperbilirubinemia. These children rarely have chronic malnutrition despite complaints of abdominal pain. Subsequent to resection of the choledochal cyst, which involves variable portions of the extrahepatic ductal system, and reconstruction of biliary outflow with a standard roux-en-Y hepaticojejunostomy, these patients will be able to consume a normal diet and in the absence of significant underlying liver disease do not need special nutritional formulations.
by routine postoperative guidelines and have no special nutritional considerations, other than those imposed by virtue of prolonged ventilatory support and concern for reflux with aspiration. Many of these operations can now safely be achieved with minimally invasive techniques further reducing the surgical stress, postoperative pain response, and minimizing wounds to heal. Infants born with chylothorax, or those who develop it as a consequence of perioperative complications, are managed depending on the amount of daily chylous output with gut rest with PN support and the subsequent introduction of enteral feeds with high MCT oil concentration. Urologic, Neurosurgical, and Orthopedic Infants born with complex urological defects such as bladder exstrophy and cloacal exstrophy will certainly require a number of staged surgical interventions by various specialists. The intestinal tract is intact and generally normal in bladder exstrophy whereas there is imperforate anus with exteriorization of the hindgut between two bladder halves in cloacal exstrophy. This portion of the hindgut will need to be tubularized to create a distal stoma or require proximal diversion. Hydronephrosis, prune belly syndrome, and other congenital renal anomalies may have evidence of renal insufficiency or failure that will require adjustments to the infants nutrient intake as discussed in other chapters. Congenital neurosurgical and orthopedic interventions generally do not involve the peritoneal cavity or even the retroperitoneum and therefore do not impact enteral feeding status. Depending on the extent of operation and metabolic stress, adjustments primarily affect caloric goals and will need to be individualized. A thoughtful consideration of the impact of general anesthesia, which is virtually uniform in neonatal patients undergoing surgery, will suggest that resumption of enteral intake occur in a slightly delayed manner. Neonatal Airway Disorders Infants who require interventions on their airway frequently have associated aerodigestive disorders that may extend to foregut dysmotility syndromes. Reconstructive interventions for laryngomalacia, subglottic stenosis, and tracheomalacia require protection of the airway from GER. Often tracheostomy can be averted by appropriate management of enteral feedings along with pharmacologic interventions to limit exposure of the glottic structures to acid gastric contents. This may require insertion of a postpyloric feeding tube to assure continued nutrition support without the risk of reflux. If chronic in nature, then early consideration for a
Other (Non-GI) Malformations

Thoracic Disorders Children who require thoracic operations for congenital lung lesions or even foregut duplications can be treated
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Nissen fundoplication is appropriate. Infants with airway compromise have an increased work of breathing and may exhibit failure to thrive even despite mechanical feeding. Once supported with a tracheostomy, the infant will often show rapid catch-up growth and can sustain a reduction in what is normally considered caloric goals. It is important to remember that despite the presence of a tracheostomy, the airway is not completely protected from either GER or aspiration salivary secretions because the pediatric airway often does not require a cuffed tracheostomy, and every conscious effort is made to preserve some airflow past the cords to prevent progressive subglottic stenosis.
Nutrition Support in Infants with Acute GI-Related Disorders

Necrotizing Enterocolitis
NEC remains one of the most frequent indications for emergency operation on preterm neonates. Although the mortality has decreased over time and management of intestinal dysfunction has improved, this remains a diagnosis with a significant morbidity and mortality. Although this is not to be an exhaustive summary on the pathophysiology of NEC, it is important to understand some of the mechanisms thought to be responsible for its development as these influence the way surgeons treat infants who have experienced and may be at further risk for mucosal injury. NEC is best considered a consequence of exposure of an immature and nave intestinal tract with potentially compromised perfusion to pathogenic organisms, which traverse the intestinal barrier to initiate the gut-derived sepsis syndrome. The gut mucosal barrier is compromised on several levels in the premature infant. 35 The normally acid environment of the stomach serves as an initial barrier to microbes, yet acid production is often immature and is often altered iatrogenically by providing acid-suppressing medications, in the hopes of avoiding gastritis and ulceration. Other factors include the limited supply of luminal protective factors such as the lectins and IgA provided by maternal milk. Structurally the mucosal surface provides opportunities for attachment of bacteria via a decreased mucus barrier, tight junctions which may not be as tight as in older, term infants, and active translocation mechanisms which optimally are suited for sampling a safer environment than that provided in a neonatal intensive care unit (NICU). The mucosal integrity may become further compromised with decreased visceral perfusion. The mucosa is at greatest risk with hypoperfusion, and mucosal sloughing as evidenced by bloody stools is an early indication of potential NEC (Bell
stage 1 NEC). Altered perfusion may be the consequence of primary cardiac events (congenital heart disease, PDA), pulmonary compromise with consequent hypoxia and resultant shunting away from the viscera, and other events such as hemorrhage (pulmonary, intraventricular). Beyond the mucosal border the immaturity of the host immune system is overcome due to limited phagocytic and bactericidal activity of neutrophils and other components of the gut-associated lymphoid tissue (GALT). These speculated factors would all contribute to facilitating an enteric source of sepsis. Needless to say the etiology of NEC is manifold and complex. The radiographic hallmarks are pneumatosis intestinalis and portal venous gas, both of which portend that there has been transgression of the mucosa by gasproducing organisms. If the sepsis can be controlled and the intestine is able to maintain its integrity, no operative intervention is necessary (Bell stage 2 NEC). However, if evidence of perforation becomes evident or the abdominal sepsis fails to come under control, operative intervention becomes mandatory (Bell stage 3 NEC). The options are often dictated by the infants size and degree of clinical instability. In the smallest and most unstable infant, placement of a peritoneal drain may be all that can be safely offered while in larger or more stable infants a limited laparotomy at the bedside or in the operating room may allow for more definitive therapy. At operation the extent of intestinal involvement becomes apparent. In the least severe circumstances, a limited segment of intestine has transmural gangrene or has perforated. Resection and diversion with stoma versus primary anastomosis are decided upon based on the patients overall condition and specifically the condition of the intestine. In infants with more extensive and even skip involvement, proximal diversion and only excision of those areas of definite gangrene become the guiding principles so as to preserve as much intestinal length as possible. Despite optimal management, these affected areas may progress to full-thickness gangrene or heal as fibrotic strictures, further compromising residual length and potentially resulting in SBS. Survival is only possible if the sepsis is controlled. 36 The acute management focuses on providing adequate perfusion to the residual intestine in order to allow it to recover from the initial insult. This results in the generous provision of intravenous fluids early on and the restriction of fluids upon resolution of the sepsis in order to optimize pulmonary function. This compromises the ability to provide optimal nutrition in a consistent manner. Enteral feeding would be considered no earlier than 7 days of therapy. As in other complex GI disorders a coherent plan has to
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be generated by the managing teams so as to best utilize a combination of EN and PN. Recurrent sepsis and progressive cholestatic jaundice are the predictors of mortality. All techniques available to limit these complications should be utilized in these patients. Reconstitution of the full GI tract is accomplished after 6 weeks to limit operative complications and to have given sufficient time for strictures to form and to be identified such that they can be treated at the same operation. 37 Even in those infants managed without operative intervention, the clinicians must maintain suspicion for developing strictures, particularly if the colon was involved, which can be difficult to tell non-operatively. Aggressive feeding of an infant with a distal bowel obstruction will only lead to recurrence of NEC. 38 While the specific amino acid composition of neonatal total parenteral nutrition is addressed in other sections, much attention had been focused on the utility of providing glutamine to this population with a compromised gut mucosal barrier; however, this does not appear to be an effective strategy. 39,40 Infants who survive the early postoperative course associated with NEC are among the highest risk infants for intestinal dysfunction, SBS, and cholestasis. All nutrition techniques described earlier in relation to initiation of trophic feedings, enteral antibiotics, and cycling of modulation of total parenteral nutrition should be applied in this context. The optimal timing of refeeding and stoma closure remain topics of controversy and are often individually determined or institutional preferences rather than evidence-based protocol-driven events.
of antibiotic therapy apply as they do in NEC infants. From a nutrition standpoint one assumption to be made is that the remainder of the GI tract will not have experienced the same generalized mucosal insult as encountered in NEC and that enteral feedings and rehabilitation should be achievable with greater success rates.
Intestinal Malrotation and Midgut Volvulus

Midgut volvulus as a consequence of intestinal malrotation can occur at any age, having been described both prenatally and in adult patients. The first month of life is, however, the most common time of presentation. The infant who is born with intestinal malrotation and experiences a midgut volvulus can be severely compromised. With timely diagnosis and intervention, the midgut (proximal jejunum to mid-transverse colon) should be salvageable. At operation the abdomen may be filled with chylous ascites as a consequence of obstruction and rupture of the mesenteric lymphatics. Untwisting of the mesenteric pedicle will restore venous drainage and allow for improved arterial inflow. Resection is only considered if there are regions of complete necrosis. Any intestinal segment with borderline perfusion is retained and reassessed at 24 hours with a second-look laparotomy to avoid unnecessary resection leading to SBS. Depending on the extent of the intestinal injury, these infants must initially be fed cautiously to avoid a second hit to a compromised bowel. The perioperative nutrition support team again must target metabolic needs as well as protein substrate for tissue repair. In the absence of any significant intestinal resection, there should be no ongoing considerations. The management of the child who suffers massive intestinal loss is covered in the chapter on intestinal failure (Chapter 27). As with NEC these infants are the most likely to have lost the terminal ileum and will likely require vitamin B12 supplementation in the future.
Isolated Intestinal Perforation

This is a condition that closely mimics NEC in that it presents with evidence of visceral perforation, usually pneumoperitoneum in the absence of pneumatosis, or portal venous gas and thus requires some surgical intervention. The infants affected with this disorder are usually extremely low-birth-weight infants (< 750 g), in their first week of life, and may never have been fed. Often the diagnosis remains speculative since many are treated with peritoneal drainage only and isolated involvement of only a small intestinal segment cannot be verified other than by operation. These infants are generally thought to have a better prognosis because of limited colonization of the GI tract during the first week of life, better source control of sepsis once the abdomen has been drained, a self-sealing perforation site, and consequently a less profound sepsis syndrome. The initiating events remain elusive, but may be related to focal perfusion defects or focal luminal injury by medications such as indomethacin. The same concerns for indications for laparotomy, length of NPO status, and length
Pyloric Stenosis
Infants with pyloric stenosis primarily require rehydration and correction of electrolytes preoperatively but then can be relied upon to resume a normal infant diet. How this is initiated varies by institution. In general, no postoperative feeding tubes are placed as these put the exposed pyloric channel mucosa to the risk of perforation. The infants are typically hungry and have good feeding skills. In this authors institution, our feeding protocol was developed to provide a consistent algorithm that allows the vast majority of infants to be discharged to home within 24 hours of operation. We hold oral feeds for 6 hours, and then test the stomach with 2 small-volume (15 mL) Pedialyte feeds 2 hours apart. If the
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child experiences no vomiting, then formula or breast milk is offered at 30-mL volumes every 3 hours and advanced by 15 mL every second feed to a maximum of 60 mL, which provides the necessary volumes for the average 3 to 3.5 kg infant with pyloric stenosis. At this point the infant can be discharged home and feedings are advanced as tolerated by the parents with the proviso that individual volumes should not be excessive so as to minimize reflux. Recurrent vomiting will always raise the spectre of recurrent stenosis or of an incomplete operation, both of which are rare events in experienced hands. The infants stomach is capacious given the preoperative obstruction, but more frequent limited volume feeds will assure retention of feeds and optimal absorption. All parents are amazed by the infants persistent need to feed within the first month postoperation. This resolves spontaneously as the child achieves catch-up growth. Persistent vomiting should prompt consideration of gastroesophageal reflux, which can be ameliorated with antacid therapy including even a dose of sodium bicarbonate, which may also act to help disintegrate a mucus plug in the pyloric channel. More serious considerations should include the potential for an intraoperative bowel injury or wound/fascial dehiscence. Typically these infants will have other symptoms in addition to persistent vomiting. If ranitidine was provided perioperatively it can usually be discontinued at the follow-up visit 3 to 4 weeks later. Most of these infants have undergone multiple formula changes prior to their diagnosis; we reassure parents that the formula is now less important and that they should use what they have at home and what is most accessible.41 At other institutions the interval of time to feeding may differ as will the protocol, even to the point of providing the infant with improvised feeds. The technique (laparoscopic or open) of pyloromyotomy does not have an impact on tolerance of feeds or time to discharge.
Nutrition Support in Children and Adolescents Requiring Operation

General Principles
In the older child and adolescent, many of the surgical interventions for GI problems are of an acute nature (ie, appendicitis, Meckels diverticulum, duplications of the GI tract, and intestinal obstruction due to hernia) where there are typically no premorbid nutrition impairment concerns. Those children presenting with more chronic disorders, such as inflammatory bowel disease, polyposis syndromes, and chronic GER require a closer evaluation of their nutrition status before elective surgery is contemplated. Some
of these chronic conditions can be the consequence of neonatal interventions with adapted SBS, late stenosis, and dysmotility in the atresia (duodenal and jejunoileal) patients. Malignancies affecting the GI tract are generally rare and most frequently involve lymphomas, although carcinoid tumors, desmoid tumors, and other solid visceral tumors will impact the GI tract. Abdominal visceral transplantation is yet another surgical intervention in which specialized focus on nutrition management must occur. These more complex topics of irritable bowel syndrome, malignancy, and transplantation are addressed in individual chapters elsewhere. The nutrition management of the acutely ill surgical patient is generally focused on resumption of enteral intake and, when this becomes delayed beyond 5 to 7 days, consideration is given to PN support. There is evidence from the critical care literature to indicate that many of these acutely ill patients are significantly undernourished while in the ICU. There is also evidence that simple calculation of REE without accounting for physical activity underestimates caloric requirements.42,43 While there is a consistent attempt to provide medical patients and traumatized patients in the ICU setting with early enteral feedings, these principles cannot be applied to the surgical patient who likely is at higher risk for anastomotic breakdown, abdominal sepsis, and the development of complications such as surgical site infections, fascial dehiscence, and enterocutaneous fistulae which then further complicate clinical and nutrition management. Despite these surgical concerns, the initiation of enteral feedings should be a clinical goal to allow transition off PN support at the earliest feasible time. The ability to handle complex wound failure has been markedly improved with advances in enterostomal care and with the use of negative pressure wound devices that contribute to more rapid closure of open wounds and even enterocutaneous fistulae. The earlier control of fluid and protein losses from these wounds should impact overall protein balance in a favorable manner. The subset of children who present the highest risk for emergency operation are those with chronic malnutrition. Examples include children with failure to thrive on the basis of congenital heart disease or developmental delay resulting in inadequate oral intake, and children with spine deformities (severe kyphosis and scoliosis) who are at risk for the superior mesenteric artery (SMA) syndrome in which there is duodenal obstruction as a consequence of extrinsic compression of the third portion of the duodenum between the SMA and the vertebral column. Children with spastic quadriplegia and seizure disorders may have a limited
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gastric capacity and poor gastric emptying with a tendency to reflux, which thereby has limited their enteral intake. Children with malignancies often are nutritionally depleted as a consequence not only of the disease process but also the therapies applied. At childrens hospitals we have become much more attuned to the preoperative nutrition evaluation of these patients in an effort to optimize surgical outcomes from often extensive surgical interventions. Much of the focus therefore becomes provision of feeding access for nutrition support.
Feeding Access in Pediatrics

Many children are referred for placement of enteral feeding devices. If access is required for more than a temporary situation, the options include the various techniques of gastrostomy placement (percutaneous endoscopic gastrostomy (PEG), laparoscopic G-tube, open G-tube), insertion of a gastrojejunal device, and direct jejunal feeding tubes. Despite their seemingly simple and innocuous nature, these interventions have the potential for complications and morbidity.44,45 When placing a gastrostomy, consideration should be given to the potential for promoting increased reflux on the basis of anatomic alterations. Children who have typically only consumed small amounts of food may not have evidence of reflux until larger volumes are directly administered into the gastric lumen. A preoperative evaluation should be conducted to assess the risks, particularly when these children are developmentally delayed and at risk for aspiration. The concomitant construction of a fundoplication may become necessary. Anatomic evaluation will also determine whether there are impediments to proper gastric emptying that may be amenable to correction at the same operation. The principal diagnosis to be considered is malrotation with partial duodenal obstruction on the basis of Ladds bands. Typically a pH study or impedance study is conducted to address the former question and an upper GI study is performed to exclude all forms of distal obstruction. If consideration is given to an antireflux operation, a nuclear medicine gastric emptying scan can be useful. These tests can also provide information regarding reflux although less quantifiable than those noted above. Gastric outlet procedures (eg, pyloromyotomy and pyloroplasty) are occasionally considered in those patients with increased concern for early failure of a fundoplication.
Insertion of Gastrostomy
When a gastrostomy tube is inserted for the sole purpose of providing enteral access, enteral feedings can be commenced
within 24 hours of operation. With open and laparoscopic techniques there may be some initial postoperative ileus; however, the main reason for decompressing the stomach or at least avoiding exogenous input is to allow a seal to form between the gastrostomy and the abdominal wall so that with retching and vomiting there is no extravasation between these structures into the peritoneal cavity. How the enteral feedings are provided depends on the childs underlying situation. If the enteral feedings are for supplementation of oral feeds, then oral intake can certainly be started and G-tube feeds given as small bolus volumes which are increased according to tolerance. In children with neurological deficits/developmental delay, initiation of G-tube feeds may be best assessed by open vented feeds. Rapid egress of formula from the feeding bag into the stomach with no regurgitation into the tube suggests a large-capacity stomach that will accommodate additional volumes, whereas slow evacuation into the stomach suggests a smaller stomach capacity or increased resistance because of abdominal wall contraction, possibly due to pain or spasticity. In this latter situation it may turn out to be more efficient to provide feeds initially as slow continuous drips rather than bolus volumes. Closed infusion of feeds certainly is the least cumbersome but risks GER with potential for aspiration, or requires communication from the patient that the stomach is full. This may be exhibited as retching, or visceral pain initiated by overdistention. In some children with significant reflux there may be various concerns about proceeding with a fundoplication. Perhaps the child is so nutritionally depleted that the risks are not in favor of proceeding with a major operation. In this situation a gastrostomy tract can become the conduit for a gastrojejunostomy tube which allows for gastric decompression and jejunal feedings. The disadvantage to the commercially available tubes is that they have a minimum size of 16 French and therefore are excessively large and stiff for infants, but become usable at a patient size of about 10 kg. In smaller patients other devices can be jury-rigged to achieve the same tasks. These tubes are meant as transient feeding support devices, and repeated insertion by required fluoroscopy is not ideal in the pediatric patient. The authors institution uses them as a bridge to help the patient achieve an improved nutrition state, thereby becoming a better candidate for fundoplication. Children with neurodevelopmental impairment, spasticity, and seizures often have a higher risk for disruption of their fundoplication and the option of avoiding this operation by the use of jejunal tubes is often enticing. Discussions with their family and caretakers should evaluate not only
SURGERY
405
the childs operative risk but also whether continuous feeding via a GJ tube or J tube will interfere with their daily activity schedule. These tubes do not allow for bolus feedings other than through the gastrostomy limb. Often the ability to provide intermittent bolus feeds is a significant improvement in quality of life for both the child and family.46 With the advent of the laparoscopic fundoplication, there is less surgical impact in terms of abdominal wall wound healing and pain, although early studies showed that surgical stress in terms of hormone release was not altered. With excellent short-term results this operation has gained favor; however, the long-term efficacy of this operation, especially in the higher risk populations, is still under evaluation.47 Primary jejunostomy tubes have been avoided in all but the most chronic and perhaps institutionalized patients since they represent a long-term commitment to continuous enteral feedings. Operatively a tract is developed through the abdominal wall and an imbricated jejunal limb before the tube enters the jejunal lumen. This establishes a relatively long tract for reliable replacement of the tube in the correct orientation and minimizes risk of leakage. These tubes certainly have their role in the management of complex surgical patients. When preoperative nutrition repletion is not feasible before an urgent surgical intervention, the focus must then be on providing early nutrition support, which may require the placement of central venous access or reliable enteral access for this purpose at the time of operation.
4. Which clinical diagnosis is expected to have impairment of intestinal motility and may require prolonged total PN support? A. Gastroschisis B. Omphalocele C. Hirschsprungs disease D. Malrotation without midgut volvulus See p. 487 for answers.
1. Barlow B, Santulli T, Heird W, Pitt J, Blanc W, Schullinger J. An experimental study of acute necrotizing enterocolitis - the importance of breast milk. J Pediatr Surg. 1974;9(5):587. 2. Nydegger A, Bines JE. Energy metabolism in infants with congenital heart disease. Nutrition. 2006 8;22(7-8):697704. 3. Owens J, Musa N. Nutrition support after neonatal cardiac surgery. Nutr Clin Pract. 2009;24(2):242. 4. Vaidyanathan B, Radhakrishnan R, Sarala D, Sundaram K, Kumar R. What determines nutritional recovery in malnourished children after correction of congenital heart defects? Pediatrics. 2009;124(2):e294. 5. Jaksic T, Shew SB, Keshen TH, Dzakovic A, Jahoor F. Do critically ill surgical neonates have increased energy expenditure? J Pediatr Surg. 2001 1;36(1):6367. 6. Garza JJ, Shew SB, Keshen TH, Dzakovic A, Jahoor F, Jaksic T. Energy expenditure in ill premature neonates. J Pediatr Surg. 2002 3;37(3):289293. 7. Pierro A, Eaton S. Metabolism and nutrition in the surgical neonate. Semin Pediatr Surg. 2008 11;17(4):276284. 8. Gruber EM, Laussen PC, Casta A, et al. Stress response in infants undergoing cardiac surgery: a randomized study of fentanyl bolus, fentanyl infusion, and fentanyl-midazolam infusion. Anesth Analg. 2001 April 1;92(4):882890. 9. Shew SB, Keshen TH, Glass NL, Jahoor F, Jaksic T. Ligation of a patent ductus arteriosus under fentanyl anesthesia improves protein metabolism in premature neonates. J Pediatr Surg. 2000 9;35(9):12771281. 10. Hulst JM, van Goudoever JB, Zimmermann LJI, Tibboel D, Joosten KFM. The role of initial monitoring of routine biochemical nutritional markers in critically ill children. J Nutr Biochem. 2006 1;17(1):5762. 11. Reynolds RM, Bass KD, Thureen PJ. Achieving positive protein balance in the immediate postoperative period in neonates undergoing abdominal surgery. J Pediatr. 2008 1;152(1):6367. 12. de Meijer VE, Gura KM, Le HD, Meisel JA, Puder M. Fish oil-based lipid emulsions prevent and reverse parenteral nutrition-associated liver disease: The Boston experience. J Parenter Enteral Nutr. 2009 Sept 1;33(5):541547. 13. Lee SI, Valim C, Johnston P, et al. The impact of fish oil-based lipid emulsion on serum triglyceride, bilirubin, and albumin levels in children with parenteral nutrition-associated liver disease. Pediatr Res. Aug 14 [Epub ahead of print] 2009.
References
1. Which of the following strategies are considered beneficial in reducing cholestasis? A. Provision of > 40% of calories as lipid emulsion B. Maintaining GIR > 15 mg/kg/min C. Continuous provision of PN D. Initiation of enteral feedings 2. Which is a contraindication to commencing enteral feedings? A. Bilious nasogastric output in jejunoileal atresia B. Contrast extravasation on postoperative day 7 after esophageal atresia repair C. Abdominal distention with lack of stoma output D. All of the above 3. On a 3-kg infant status post stoma closure after resection for NEC, when should enteral feedings be limited? A. Number of bowel movements exceeds 8 over 24-hour period B. Reducing substances < 1/2% C. Fecal pH > 7 D. Mucoid stools
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14. Javid PJ, Collier S, Richardson D, et al. The role of enteral nutrition in the reversal of parenteral nutrition-associated liver dysfunction in infants. J Pediatr Surg. 2005 6;40(6):10151018. 15. Boarini JH. Principles of stoma care for infants. J Enterostomal Therapy. 1989;16(1):2125. 16. Al-Harbi K, Walton JM, Gardner V, Chessell L, Fitzgerald PG. Mucous fistula refeeding in neonates with short bowel syndrome. J Pediatr Surg. 1999;34(7):1100. 17. Alabbad SI, Ryckman J, Puligandla PS, Shaw K, Nguyen LT, Laberge J. Use of transanastomotic feeding tubes during esophageal atresia repair. J Pediatr Surg. 2009 5;44(5):902905. 18. Goyal A, Jones MO, Couriel JM, Losty PD. Oesophageal atresia and tracheo-oesophageal fistula. Arch Dis Child Fetal Neonatal Ed. 2006;91(5):F381. 19. Ching YA, Fitzgibbons S, Valim C, Zhou J, Duggan C, Jaksic T, et al. Long-term nutritional and clinical outcomes after serial transverse enteroplasty at a single institution. J Pediatr Surg. 2009;44(5):939. 20. Yardley I, Khalil B, Minford J, Morabito A. Multiple jejunoileal atresia and colonic atresia managed by multiple primary anastomosis with a single gastroperineal transanastomotic tube without stomas. J Pediatr Surg. 2008 11;43(11):e45e46. 21. Piper HG, Alesbury J, Waterford SD, Zurakowski D, Jaksic T. Intestinal atresias: Factors affecting clinical outcomes. J Pediatr Surg. 2008 7;43(7):12441248. 22. Wales PW, Dutta S. Serial transverse enteroplasty as primary therapy for neonates with proximal jejunal atresia. J Pediatr Surg. 2005 3;40(3):E31E34. 23. Stollman TH, de Blaauw I, Wijnen MHWA, van der Staak FHJM, Rieu PNMA, Draaisma JMT, et al. Decreased mortality but increased morbidity in neonates with jejunoileal atresia; a study of 114 cases over a 34-year period. J Pediatr Surg. 2009 1;44(1):217221. 24. Pastor AC, Phillips JD, Fenton SJ, Meyers RL, Lamm AW, Raval MV, et al. Routine use of a SILASTIC spring-loaded silo for infants with gastroschisis: A multicenter randomized controlled trial. J Pediatr Surg. 2008 10;43(10):18071812. 25. Phillips JD, Raval MV, Redden C, Weiner TM. Gastroschisis, atresia, dysmotility: Surgical treatment strategies for a distinct clinical entity. J Pediatr Surg. 2008 12;43(12):22082212. 26. Walter-Nicolet E, Rousseau V, Kieffer F, Fusaro F, Bourdaud N, Oucherif S, et al. Neonatal outcome of gastroschisis is mainly influenced by nutritional management. J Pediatr Gastroenterol Nutr. 2009;48(5):612. 27. Diamond I, Sterescu A, Pencharz P, Kim J, Wales P. Changing the paradigm: Omegaven for the treatment of liver failure in pediatric short bowel syndrome. J Pediatr Gastroenterol Nutr. 2009;48(2):209. 28. Muratore CS, Utter S, Jaksic T, Lund DP, Wilson JM. Nutritional morbidity in survivors of congenital diaphragmatic hernia. J Pediatr Surg. 2001 8;36(8):11711176. 29. Keshen TH, Miller RG, Jahoor F, Jaksic T. Stable isotopic quantitation of protein metabolism and energy expenditure in neonates on- and post-extracorporeal life support. J Pediatr Surg. 1997;32(7):958. 30. Shew SB, Keshen TH, Jahoor F, Jaksic T. The determinants of protein catabolism in neonates on extracorporeal membrane oxygenation. J Pediatr Surg. 1999;34(7):1086.
31. Agus MSD, Javid PJ, Ryan DP, Jaksic T. Intravenous insulin decreases protein breakdown in infants on extracorporeal membrane oxygenation. J Pediatr Surg. 2004 6;39(6):839844. 32. Hulst JM, van Goudoever JB, Zimmermann LJ, Hop WC, Bller HA, Tibboel D, et al. Adequate feeding and the usefulness of the respiratory quotient in critically ill children. Nutrition. 2005 2;21(2):192198. 33. Willot S, Uhlen S, Michaud L, Briand G, Bonnevalle M, Sfeir R, et al. Effect of ursodeoxycholic acid on liver function in children after successful surgery for biliary atresia. Pediatrics. 2008;122(6):e1236. 34. DeRusso P, Ye W, Shepherd R, Haber B, Shneider B, Whitington P, et al. Growth failure and outcomes in infants with biliary atresia: A report from the biliary atresia research consortium. Hepatology. 2007;46(5):1632. 35. Petrosyan M, Guner Y, Williams M, Grishin A, Ford H. Current concepts regarding the pathogenesis of necrotizing enterocolitis. Pediatr Surg Int. 2009;25(4):309. 36. Hall NJ, Peters M, Eaton S, Pierro A. Hyperglycemia is associated with increased morbidity and mortality rates in neonates with necrotizing enterocolitis. J Pediatr Surg. 2004 6;39(6):898901. 37. Al-Hudhaif J, Phillips S, Gholum S, Puligandla PP, Flageole H. The timing of enterostomy reversal after necrotizing enterocolitis. J Pediatr Surg. 2009 5;44(5):924927. 38. Bohnhorst B, Mller S, Drdelmann M, Peter CS, Petersen C, Poets CF. Early feeding after necrotizing enterocolitis in preterm infants. J Pediatr. 2003 10;143(4):484487. 39. Albers MJIJ, Steyerberg E, Hazebroek FWJ, et al. Glutamine supplementation of parenteral nutrition does not improve intestinal permeability, nitrogen balance, or outcome in newborns and infants undergoing digestive-tract surgery: results from a double-blind, randomized, controlled trial. Ann Surg. 2005;241(4):599. 40. Calder P. Immunonutrition in surgical and critically ill patients. Br J Nutr. 2007;98 (Suppl 1):S133. 41. St. Peter SD, Tsao K, Sharp SW, Holcomb III GW, Ostlie DJ. Predictors of emesis and time to goal intake after pyloromyotomy: analysis from a prospective trial. J Pediatr Surg. 2008 11;43(11):20382041. 42. van der Kuip M, de Meer K, Westerterp KR, Gemke RJ. Physical activity as a determinant of total energy expenditure in critically ill children. Clin Nutr. 2007 12;26(6):744751. 43. Singer P, Berger MM, Van den Berghe G, Biolo G, Calder P, Forbes A, et al. ESPEN guidelines on parenteral nutrition: Intensive care. Clin Nutr. 2009 8;28(4):387400. 44. Vervloessem D, van Leersum F, Boer D, Hop WCJ, Escher JC, Madern GC, et al. Percutaneous endoscopic gastrostomy (PEG) in children is not a minor procedure: Risk factors for major complications. Semin Pediatr Surg. 2009 5;18(2):9397. 45. Beres A, Bratu I, Laberge J. Attention to small details: Big deal for gastrostomies. Semin Pediatr Surg. 2009 5;18(2):8792. 46. Veenker E. Enteral feeding in neurologically impaired children with gastroesophageal reflux: Nissen fundoplication and gastrostomy tube placement versus percutaneous gastrojejunostomy. J Pediatr Nurs. 2008 10;23(5):400404. 47. Kane TD. Laparoscopic Nissen fundoplication. Minerva Chir. 2009;64(2):147.
PART IV
NUTRITION CARE OF THE PEDIATRIC PATIENT
33. Assessment of Nutrition Status by Age and Determining Nutrient Needs . . . . . . . . . . . . . . 409 Liesje Nieman Carney, RD, CNSD, LDN Jennifer Blair, MA, RD, CSP, LDN 34. Parenteral and Enteral Nutrition Support: Determining the Best Way to Feed. . . . . . . . . . . . . 433 Liesje Nieman Carney, RD, CNSD, LDN Andrea Nepa, MS, RD, CSP, LDN Sherri Shubin Cohen, MD, MPH Amy Dean, MPH, RD, LDN Colleen Yanni, MS, RD, LDN Goldie Markowitz, MSN, CRNP 35. Implementation of the Plan. . . . . . . . . . . . . . . . . . 448 Beth Lyman, RN, MSN Jennifer M. Colombo, MD Jodi L. Gamis, OTR 36. Evaluation and Monitoring of Pediatric Patients Receiving Specialized Nutrition Support . . . . . . . . 460 Elaina Szeszycki, PharmD, BCNSP Wendy Cruse, MMSc, RD, CNSD Michelle Strup, PharmD 37. Ethical Issues in the Provision of Nutrition . . . . . . 477 Patrick M. Jones, MD, MA Brian Carter, MD
Assessment of Nutrition Status by Age and Determining Nutrient Needs

Liesje Nieman Carney, RD, CNSD, LDN and Jennifer Blair, MA, RD, CSP, LDN
33
Contents
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409 Nutrition Assessment of Premature Infants. . . . . . . . . . 409
Classification Parameters Special Considerations Energy Needs Growth
Learning Objectives
Nutrition Assessment of Full-Term Infants and Children.411 Nutrition Assessment of Adolescents . . . . . . . . . . . . . . 412
Vitamin and Mineral Needs
1. Identify the important components of a pediatric nutrition assessment. 2. Describe and differentiate the nutrition needs among premature infants, full-term infants, children, and adolescent pediatric populations. 3. Recognize potential nutrition deficiencies and excesses commonly found among the pediatric population.
Background
Diet History. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414 Anthropometric Measurements. . . . . . . . . . . . . . . . . . . 414

Weight Length/Height Head Circumference Body Mass Index-for-Age Mid-Arm Circumference and Triceps Skinfold Growth Charts Biochemical Indices Physical Exam
Nutrition assessment of infants, children, and adolescents enables practitioners to identify those at nutrition risk for weight loss, poor growth, obesity, and nutrient deficits and excesses. Components of a detailed nutrition assessment include anthropometric measurements with comparison to reference standards, a detailed diet history, biochemical indices monitoring, and physical examination.
Nutrition Assessment of Premature Infants

418 420 421 422 423
Appendix 33-1: Estimating Nutrient Needs . . . . . . . . . . Appendix 33-2: Percentiles of Upper Arm Circumference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix 33-3: Triceps Skinfold Percentiles. . . . . . . . . Appendix 33-4: Fetal-Infant Growth Chart. . . . . . . . . . . Appendix 33-5: NCHS/CDC Growth Charts . . . . . . . . . .
Nutrition assessment of premature infants is a critical component in the medical management of high-risk neonates. Routine assessment is vital to ensure adequate nutrition status of the critically ill neonate. Premature infants are classified according to their birth weight and gestational age at birth. The goal for the premature infant is to mimic intrauterine weight gain.1-3
Classification Parameters
Premature infants are classified by the infants gestational age, growth curve parameters, and maturational examination. The maturational examination, known as the Ballard score, is a postnatal, indirect method of assessing a neonates gestational age. It is based upon indicators of fetal
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neuromuscular and physical maturation.4 Premature infants are defined by their weight at birth. Table 33-1 depicts these classifications.
Table 33-1 Classification of Preterm Infants by Birth Weight Low birth weight (LBW) Very low birth weight (VLBW) Extremely low birth weight (ELBW) Micronate < 2500 g < 1500 g < 1000 g < 750 g
The Lubchenco growth chart is a classification of newborns based on maturity and intrauterine growth. 5 Along with intrauterine weight charts, these charts allow the identification of infants with unusual growth patterns. The Lubchenco growth curve classifies infants as: large for gestational age (LGA), appropriate for gestational age (AGA), or small for gestational age (SGA). AGA infants fall between the 10th and 90th percentile on the weight per gestational age curve, whereas LGA infants plot greater than the 90th percentile and SGA infants less than the 10th percentile. Reasons infants may present as LGA include genetic factors, infants of diabetic mothers, and those who have transposition of the aorta. 5 SGA infants may simply be genetically small or may have suffered from intrauterine growth restriction (IUGR). Symmetrical IUGR generally occurs when the unborn baby experiences a problem during early development; on the other hand, asymmetrical IUGR is often due to a problem later in pregnancy. Conditions causing IUGR in infants include exposure to intrauterine infection; poor intrauterine nutrient provision (eg, placental or umbilical cord defects); intrauterine exposure to tobacco, narcotics, or alcohol; chronic lack of oxygen (ie, hypoxia); birth defects (eg, severe cardiovascular defect), and congenital malformations such as Down syndrome, Turners syndrome, and trisomy 18. 5
feeds compared to the premature infant with a healthy gut. These conditions often require protein hydrolysate or free amino acid formulas while the gastrointestinal tract adapts. Protein hydrolysates and free amino acid formulas do not provide the higher nutrient components provided with premature formulas. This may require additional nutrient supplementation, such as calcium and phosphorus, to meet the needs of the premature infant. Long-term PN support in the premature infant places the infant at increased risk for osteopenia of prematurity. This is due to the inability to match intrauterine calcium and phosphorus accretion rates, without precipitation of the parenteral solution. The premature infants respiratory status may alter his or her energy requirements and the ability to feed orally. For instance, chronically ventilator-dependent infants may require decreased energy requirements since they are not working to breathe. Conversely, infants may have increased energy expenditure during times of weaning from respiratory support. Appropriate caloric provisions are often difficult to determine, and are best estimated by closely monitoring daily weight changes. Infants with chronic lung disease (CLD) and bronchopulmonary dysplasia (BPD) often require fluid restrictions, requiring formula concentration and the use of modular supplements to meet their increased energy and nutrient requirements within the constraints of fluid restrictions.
Energy Needs
The premature infants weight may decrease 10% to 15% in the first week of life due to decreased water content of the extracellular volume. Until the weight is regained, the infants birth weight should be used to estimate energy and nutrient needs.
Growth
The premature infant should be weighed nude, at the same time of day, on the same scale, on a daily basis to evaluate nutrition status. The infants average daily weight gain is compared (in grams per kilogram daily or grams per day) to expected intrauterine weight velocity charts. Please refer to Table 33-2.6 Extreme weight changes may be due to fluid shifts or medical conditions, and these factors should be considered before modifying an infants nutrition support regimen.
Special Considerations
Specific medical conditions will alter the neonates nutrition needs and ability to feed enterally and by mouth. For instance, gastrointestinal anomalies such as gastroschisis, omphalocele, and necrotizing enterocolitis (NEC) will mandate feeding the infant with parenteral nutrition (PN) support for longer time periods until after surgical intervention. Furthermore, infants with NEC may suffer from short bowel syndrome (SBS) postsurgery and may require long-term PN support. The transition to enteral feeds is often tenuous and requires slower advancement to full
ASSESSMENT OF NUTRITION STATUS BY AGE AND DETERMINING NUTRIENT NEEDS
411
Table 332 Average Daily Intrauterine Weight Gain7

Age Interval (weeks) Average Daily Weight Gain (g/d) Mean Weight (g) Average Daily Weight Gain (g/kg/d)
2425 2526 2627 2728 2829 2930 3031 3132 3233 3334 3435 3536 3637 3738 Mean
11.4 15.7 18.6 21.4 22.6 23.1 24.3 25.7 27.1 30 31.4 34.3 35.7 31.4 25.2
904961 9611001 10011065 10651236 12361300 13001484 14841590 15901732 17321957 19572278 22782483 24832753 27532866 28663025
12.2 16 18 18.6 17.8 16.6 15.8 15.5 14.7 14.2 13.3 13.1 12.7 10.7 14.9
Nutrition Assessment of Full-Term Infants and Children
a reference standard for other children the same age in the United States and can aid in the determination of conditions such as malnutrition and obesity. Evaluation of growth is best monitored over a period of time. Poor weight gain is an indicator of acute malnutrition (ie, wasting) while inadequate length or height velocity is indicative of chronic malnutrition (ie, stunting). Tables 33-4 and 33-5 provide wasting and stunting criteria.11 Waterlow developed these standards to classify children as either stunted (ie, low height-for-age) or wasted (ie, low weightfor-height). Frisancho12 argues that although the Waterlow criteria have the advantage of being based on easily obtainable information, measurements of height and weight, the criteria are ineffective for distinguishing the truly malnourished child from those who are simply underweight. For instance, a child suffering from protein malnutrition will present with a low weight-for-height, but so will a tall and normally lean child.12 Additionally, an obese child will present with a high weight-for-height, as might a muscular, large-frame child.12
Table 33-4 Waterlow Criteria for Degree of Wasting11 (wt/ht %std) > 120% Obese 110120% Overweight 90110% Normal variation 8089% Mild wasting 7079% Moderate wasting < 70% Severe wasting Table 33-5 Waterlow Criteria for Degree of Stunting11 (ht/age %std) > 95% Normal 9095% Mild 85-89% Moderate < 85% Severe
The purpose of the nutrition assessment of infants and children is to (1) evaluate growth, body size measurements, and composition as compared to national standards; (2) determine an estimation of nutrient needs; and (3) evaluate the adequacy of the nutrition regimen. Infants experience a more rapid growth velocity as compared to children. The need for medical care may impact the childs nutrition status by altering metabolic requirements and nutrient intake, and can result in weight loss and decreased height or length velocity.8 Refer to Table 33-3 for reference standards of growth velocity, both weight and length, in healthy children.9
Table 33-3 Recommendations for Weight and Length Gain for Healthy Children8,9
Age Weight (g/d) Length (cm/mo)
< 3 mo 36 mo 612 mo 13 y 46 y 710 y
2535 1521 1013 410 58 512
2.63.5 1.62.5 1.21.7 0.71.1 0.50.8 0.40.6
Infants and childrens weights, length or height, head circumference (measured for those less than 3 years of age), and weight-for-length or body mass index (BMI)-forage should be plotted on the National Center for Health Statistics (NCHS) and Centers for Disease Control and Prevention (CDC) standard growth charts.10 This provides
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Table 33-6 Recommended Dietary Allowances13,15

Age kcal/kg 1989 RDAs Protein g/kg 2002 DRIs
06 mo 712 mo 13 y 46 y 710 y Males 1114 y 1518 y Females 1114 y 1518 y
108 98 102 90 70 55 45 47 40
1.52 (AI) 1.2 1.05 0.95 (48 y) 0.95 (913 y) 0.85 (1418 y)
0.85 (1418 y)
Estimation of energy requirements can be determined using the 1989 Recommended Dietary Allowance (RDA) or the 2002 Dietary Reference Intake estimated energy requirements (EER). Both of these methods represent energy needs of the healthy child. Refer to Table 33-6 for the RDAs for energy.13 The resting energy expenditure (REE) can be estimated using the World Health Organization (WHO) equation (Table 33-7).14 Using the WHO equation to determine the REE with an activity factor (see Table 33-8) may be more helpful in estimating energy needs of the acutely ill child. Refer to Appendix 33-1 Estimating Nutrient Needs for a comprehensive description of the various methods to estimate energy needs.
Table 33-7 WHO Equation14
Age kcal/d
The DRI for protein, as outlined in Table 33-6, is used to estimate protein needs15 for both the healthy child as well as the hospitalized child. However, clinical conditions should be considered when estimating protein requirements. Some situations may require protein intakes greater than the DRI to achieve a positive nitrogen balance. Examples include major surgery, wound healing, infection, and catch-up growth. Conversely, the critically ill patient with acute renal failure may benefit from a moderate protein restriction (but not less than the DRI for age). Maintaining adequate hydration is crucial in both the healthy and hospitalized infant and child. Guidelines for determining maintenance fluid requirements are outlined in Table 33-9.16,17
Table 33-9 Fluid Requirements16,17 110 kg 1020 kg > 20 kg 100 mL/kg 1000 mL + 50 mL each kg over 10 kg 1500 mL + 20 mL for each kg over 20 kg
Males 03 310 1018 1830 Females 03 310 1018 1830
60.9W 54 22.7W + 495 17.5W + 651 15.3W + 679 61W 51 22.5W + 499 12.2W + 746 14.7W + 496
Table 33-8 Activity and Stress Factors14

Activity/Stress Adjustment Factors
REE x 1.3: For a well-nourished child at bedrest with mild to moderate stress REE x 1.5: For a normally active child with mild to moderate stress; an inactive child with severe stress (ie, trauma, stress, cancer), or a child with minimal activity and malnutrition requiring catch-up growth REE x 1.7: For an active child requiring catch-up growth or an active child with severe stress
Nutrition assessment of adolescents should include measurements of weight, height, and BMI-for-age with plotting on CDC growth curves, an estimation of nutrient needs, diet history, and analysis of biochemical indices. Refer to Tables 33-6 through 33-9 for the RDAs for kilocalories, the DRIs for protein, the WHO equation, activity factors, and maintenance fluid guidelines, respectively. Special conditions during adolescence that need to be considered include the increased energy and nutrient requirements that occur during puberty, as well as the behavioral, social, and emotional changes that occur during adolescence.18,19 Increases in lean body mass result in an increased demand for energy, protein, calcium, and iron intakes.18 Dietary habits during adolescence that pose a risk for nutrient deficiencies or overnutrition include the following: skipping meals, eating more meals outside the home (often high in fat with low-nutrient density), binge eating, following fad diets, and taking dietary supplements.18,19 Adolescents are at risk for inadequate calcium and vitamin D intake due to skipping meals, avoidance related to dieting behaviors, and replacing milk intake with sodas and sports drinks. Females are at increased risk of iron deficiency due to the onset of menses. A comprehensive diet history will aid in the identification of nutrition concerns such as nutrient deficiencies, unhealthy dietary practices, the use of dietary supplements,
Nutrition Assessment of Adolescents
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and potential eating disorders. Please refer to the Diet History section of this chapter for a more detailed explanation.18,19
Vitamin and Mineral Needs

Calcium According to the American Academy of Pediatrics (AAP), the primary need for dietary calcium in otherwise healthy infants, children, and adolescents is to enhance bone mineral absorption.20 Maintaining adequate calcium intake during childhood is necessary for maximizing peak bone mass and decreasing the risk of osteoporosis later in adulthood.20 Exercise, in addition to calcium intake, is important for achieving peak bone mass. Wyshak and Frisch21 reported a positive relationship between cola consumption and bone fractures. However, it is uncertain if this may be attributed to the potential excess phosphorus content found in colas, or due to the diminished calcium intake related to decreased consumption of dairy products (specifically milk). Currently, dual-energy radiograph absorptiometry (ie, DEXA scan) is the method used in many studies to measure bone mineral content and bone mineral density of specific areas or the entire skeleton, with notably negligible levels of radiation exposure.20 According to the AAP, the optimal primary nutritional source during the first year of life is human milk. No available evidence shows that exceeding the amount of calcium retained by the exclusively breastfed term infant during the first 6 months of life or the amount retained by the human milk-fed infant supplemented with solid foods during the second 6 months of life is beneficial to achieving long-term increases in bone mineralization. 20 The exception to this is premature infants, who benefit from fortified human milk and premature infant formulas that have additional mineral supplementation. Data demonstrate that the bioavailability of calcium in human milk is greater than that found in infant formulas and cows milk. Therefore, infant formulas contain increased concentrations of calcium content to be more comparable to that found in human milk. According to the AAP, calcium retention is relatively low in toddlers and increases as puberty approaches. 20 Most available data conclude that calcium intakes of 800 mg daily are adequate for bone mineral accretion in pre-pubescent children. The majority of bone formation and the efficiency of calcium absorption are highest during puberty. Data from balance studies suggest that maximal net calcium balance is achieved with intakes of 1200 to 1500 mg daily in most healthy adolescents.20 Calcium intakes on food labels are indicated as a
percentage of the Daily Value (DV) in each serving. The DV is currently set at 1000 mg daily. Calcium supplementation should be considered for children who are unable to achieve adequate dietary sources of calcium. Calcium supplements vary in their bioavailability, and may be comparable to or greater than that of dairy sources.20 Iron Iron deficiency is the most common nutrition deficiency in the world.22 The incidence of iron deficiency anemia peaks in children between the ages of 6 and 20 months, or earlier with premature infants, with a second peak around puberty. Iron deficiency may adversely affect the childs psychomotor development and cognitive function.22 Those at risk for developing iron deficiency include premature and low birth-weight infants, overweight children, children with caregivers of low socioeconomic status, adolescent females, and athletes.22 Additionally, toddlers are often at a risk for iron-deficiency anemia due to transitioning from iron-fortified formula to cows milk. More than 80% of the iron stores of the term infant are accreted during the third trimester of pregnancy. Therefore, infants born premature require more iron postnatally during the first year of life to catch up to infants born at term. 23 Iron intake requirements for premature infants range from 2 mg/kg/d for infants with birth weights between 1500 and 2500 g to 4 mg/kg/d for infants weighing less than 1500g at birth.24,25 Adequate iron stores are needed for optimal growth and development. According to the AAP Infants who are not breastfed or who are partially breastfed should receive an iron-fortified formula (containing between 4 to 12 mg of iron per liter) from birth to 12 months.23 The recommended treatment dose for iron deficiency anemia is 3 to 6 mg/kg/d in 3 divided doses, ideally with concomitant vitamin C intake to enhance iron absorption. Prophylactic iron supplementation is recommended for those identified at an increased risk of iron deficiency anemia.22 Vitamin D Cases of rickets continue to be reported in the United States and other Western countries. One of the causes of rickets is vitamin D deficiency. Vitamin D deficiency is attributed to exclusively breastfed infants due to breast milks low vitamin D content and those with decreased sun exposure due to an inadequate conversion within the body to the active form of vitamin D. As a result, the AAP recently issued updated guidelines for vitamin D intake for infants, children, and adolescents to prevent vitamin D deficiency which in turn will reduce the incidence of rickets. These new guidelines
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replaced the 2003 AAP recommendations for a daily intake of 200 International Units of vitamin D for infants in the first 2 months of life, children, and adolescents. The 2008 guidelines recommend a daily intake of 400 International Units of vitamin D for all infants, children, and adolescents starting from the first few days of life.26,27 Fluoride According to the CDC, dental caries may be the most prevalent of infectious diseases in our nations children. Primary tooth decay can affect childrens growth, lead to malocclusion, and result in pain and potentially life-threatening swelling.28,29 Recommendations to aid in the prevention of dental caries include the establishment and maintenance of good oral hygiene, optimizing systemic and topical fluoride exposure, and the elimination of prolonged exposure to simple sugars in the diet.28 The American Academy of Pediatric Dentistry (AAPD) reports that the adjustment of fluoride levels in community water to the optimal concentration is the most beneficial and inexpensive method of reducing the incidence of dental caries. However, when drinking water fluoridation is not possible, the AAPD supports the intake of daily fluoride supplements and the use of fluoride-containing preparations (eg, toothpastes, gels, and mouth rinses). Topical fluoride use in children is cautioned, due to the risk of excessive exposure to fluoride. 30 Table 33-10 details recommendations for fluoride supplementation based on levels found in community drinking water. 31
Table 33-10 Level of Fluoride in Community Drinking Water (ppm)* and Recommended Fluoride Supplementation
Measured Levels < 0.3 < 0.30.6 > 0.6
composition. This will enable the practitioner to gain insight into energy, protein, micronutrient deficiencies, and excesses. When interviewing the caregiver, the practitioner must be diligent in obtaining information regarding food and formula preparation, food availability, and behavioral eating patterns. This will aid in providing insight to potential barriers such as improper formula preparation, potential food insecurities related to poor socioeconomic status, and behavioral conditions affecting the childs diet.
Anthropometric Measurements
Anthropometric measurements are a crucial component of the nutrition assessment. A series of measurements obtained over a period of time provides a more accurate and comprehensive indication of a childs growth.
Weight
Weights of children under the age of 2 should be measured on a leveled scale that is frequently calibrated. The scale should be calibrated regularly with appropriate standards. The nude infant is placed on the scale, making sure the weight is evenly distributed on either side of the center of the scale. Weight is recorded to the nearest 10 g.12,32 For children older than 2 years of age, the weight should be measured using a standing scale. The calibration of the scale should also be done regularly with appropriate standards. Subjects are to stand still in the middle of the scale, with their body weight evenly distributed between both feet. Light indoor clothing should be worn. Weights should be recorded to the nearest 100 g.12,32
Length/Height
With children under 3 years of age, length should be obtained in the recumbent position using a length board. This is a device consisting of a flat board and a moveable footboard, which are perpendicular to the table surface. A fixed measuring tape is present with the 0 end at the edge of the headboard. The infants length should be recorded as the distance between the headboard and the footboard. An assistant should hold the infant/toddlers head with the child looking upward and the crown of the childs head against the headboard. The examiner holds the infants legs straight with the feet against the board and the toes facing up. The footboard is placed flat against the infant/ toddlers feet. The measurement is recorded to the nearest 0.1 cm.12,32 Children older than 3 years of age are to be measured, without shoes, using a standiometer. A standiometer is a metric tape affixed to a vertical surface and a moveable
Age 06 mo 6 mo3 y 36 y 616 y *1 ppm = 1 mg/L31 None 0.25 mg/d 0.5 mg/d 1 mg/d None None 0.25 mg/d 0.5 mg/d None None None None
Diet History
A detailed diet history is an important component of the nutrition assessment. Methods of obtaining diet histories include usual intake patterns, 24-hour recall, written diet records provided by the caregiver, and calorie counts for the hospitalized pediatric patient. Of these, the most accurate method of diet intake assessment is to obtain a 3- to 5-day diet record, which can then be analyzed for nutrient
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block that is attached to the vertical surface at a right angle, that can be brought down to the crown of the head. Stature can also be measured on a platform scale, but it is a less accurate measure than that obtained with a standiometer. The subject should stand with heels together and his or her back as straight as possible. The heels, buttocks, shoulders, and head should touch the wall or vertical surface of the measuring device. The subjects weight should be evenly distributed between both feet with the head positioned horizontally. The arms should hang freely at the sides, with palms facing the thighs. The moveable block is brought down until it puts sufficient pressure on the head to compress the hair. Measurements are recorded to the nearest 0.1 cm.12,32 When a subjects stature cannot be obtained standing, either due to the inability to stand or excessive spinal curvature, stature can be extrapolated from measuring knee height or tibial length. Knee height is obtained with a sliding broad-blade caliper. While lying in a supine position, the subjects knee and ankle are bent to form a 90-degree angle. The fixed blade of the caliper is placed under the heel of the foot, and the other blade is placed over the anterior surface of the thigh, over the condyle of the femur. The shaft of the caliber is held parallel to the tibia shaft, with pressure applied to compress the tissue. Measurements are recorded to the nearest 0.1 cm and then converted to stature12,32 by using the following equations: Males: 64.19 (0.04 age) + (0.02 knee height) Females: 84.88 (0.24 age) + (1.83 knee height) Tibial length is unique from knee heightit is a valid measurement in children with lower extremity contractions. Unfortunately, knee height is unable to be obtained when the feet are contracted because it is not possible for the fixed blade of the caliper to be placed under the heel of the foot. To obtain a tibial length, one measures from the superomedial edge of the tibia to the inferior edge of the medial malleolus using a flexible steel tape. The following is a formula33,34 for the estimation of stature in children with cerebral palsy using tibial length: (3.26 tibial length in cm) + 30.8 = estimated stature (cm) Genetic influences should be considered when evaluating any linear growth abnormality. Obtaining parental stature is essential to help differentiate when a growth pattern is normal for the childs genetic potential or not. Adjustments for parental stature are based on the average height of the
childs biological parents, called the mid-parental height, which is calculated as follows: Mothers height + fathers height 2 = mid-parental height The impact of mid-parental height on a childs growth can be evaluated by using one of two methods: Garn and Rohmann defined percentile ranges for corrected height of children35; and Himes et al36 formulated adjustment factors that are added to the childs measured stature.
Head Circumference
Occipital-frontal circumference (OFC) should be obtained in infants and children until 3 years of age. Head circumference is measured with a narrow, non-stretchable measuring tape. The tape should cross the forehead, just above the supraorbital ridges, passing around the head at the same level on both sides to the occiput. The tape should be moved up and down until maximum circumference is obtained. Sufficient tension should be placed on the tape to press the hair against the skull. 37
Body Mass Index-for-Age

Body mass index-for-age (BMI-for-age) is an indicator of potential nutrition-related health concerns. The BMI can be used to define patients as obese, overweight, adequately nourished, at risk for underweight, and underweight. The BMI (kg/m 2) is derived by taking the subjects weight in kilograms and dividing by height in meters squared. BMI is most useful when measurements are taken periodically and compared over time for trends. Table 33-11 outlines BMI criteria.10,12
Table 33-11: Interpretation of BMI for Ages 218 Years34
Percentile Interpretation
< 5th %ile 515th %ile 1585th %ile 8594th %ile 95th %ile
Underweight At risk for underweight Adequate Overweight Obese
Mid-Arm Circumference and Triceps Skinfold

Mid-arm circumference (MAC) and triceps skinfold measurements (TSF) are utilized to assess fat and muscle mass. These measurements should be monitored over a period of time to evaluate for changes. These measurements
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are useful for further evaluating fat and muscle mass of children whose weight-for-height or BMI-for-age fall less than the 5th percentile or above the 95th percentile, and for those suffering from malnutrition. Skinfold measurements may also be obtained on other sites of the body, such as subscapular and suprailiac.12,32,37 Refer to Table 33-12 for methods to calculate MAC and TSF.
Table 33-12 Anthropometric Equations12 Arm Muscle Area (AMA) = [(MAC in cm 10) - (3.14 TSF)] 12.56 Upper Arm Area = [(MAC in cm 10)] 0.785 [3.14] Arm Fat Area (AFA) = Upper Arm Area AMA
To measure mid-upper arm circumference, the subjects right arm is bent to a 90-degree angle at the elbow, with the upper arm held parallel to the body. The distance between the acromion, the bony protrusion on the posterior of the upper shoulder, and the olecranon (ie, the tip) of the elbow is measured. Mark the midpoint between these two landmarks with ink. The subjects arm should be relaxed and hanging loosely by the side of the body. The metric tape should be positioned around the upper arm at the marked midpoint. The tape should be snug, but not pinching the skin. Record the measure to the nearest 0.1 cm.12,32 Refer to Appendix 33-2 for the MAC measurement tables to interpret measurements obtained. 38 Triceps skinfold thickness is measured with a skinfold caliper. Skinfold thickness is measured at the midpoint upper arm circumference (refer to mid-upper arm circumference measure above). The subjects arm should hang loosely at the side and the examiner should grasp a vertical pinch of skin and subcutaneous fat between the thumb and forefinger, about 1 cm above the previously marked midpoint. The skinfold is pulled away from the muscle and the caliper is placed on the marked midsection. Three readings should be taken, and the average of the 3 is recorded in millimeters. The reading is measured as soon as the calipers come in contact with the skin and the dial reading stabilizes.12,32 See Appendix 33-3 for triceps skinfold percentiles.
(NICU). Limitations of this curve included the small sample size, the 26-week gestational age start, and the 500-g graph increments. In 2003, Tanis R. Fenton6 created an updated growth chart, which allows for a comparison of infants growth from 22 weeks gestation through 10 weeks postterm. Data compilation was also based on a larger sample size. Comparisons were made between the new chart and the Babson and Benda chart. Growth results from the National Institute of Child Health and Human Development Research Network (NICHD) were then superimposed on the new chart to validate growth results. Additionally, a large-scale grid was used for accuracy of plotting. The increments are 100 g of weight, as opposed to Babson and Bendas 500 g, 1 cm for both head circumference and length, and 1-week intervals for time. Refer to Appendix 33-4 for this growth chart. It can also be downloaded from http://www. biomedcentral.com/1471-2431/3/13. While in the NICU, infants weights should be plotted daily. Head circumference and length should be measured and plotted weekly. The optimal body composition of growing premature infants is unknown. However, the most comprehensive growth assessment uses the calculation of growth velocity and size in relation to correlating gestational ages on the growth chart.6 CDC Curves (Birth to 36 Months and 2 to 20 Years) The National Center for Health Statistics (NCHS) growth curves are references of height and weight used to evaluate growth and nutrition status of infants, children, and adolescents. The NCHS curves were compiled from a combined sample of data derived from the NCHSs Health Examination Survey, conducted during 1963-1965 and 1970-1974, and data from the Fels Research Institute.12 The 2000 CDC growth charts represent the revised version of the 1977 NCHS growth charts.10 Please refer to Appendix 33-5 for the CDC Growth Curves for Males (birth to 36 months), Females (birth to 36 months), Males (2 to 20 years), and Females (2 to 20 years).
Biochemical Indices
Biochemical parameters are also an essential component of a comprehensive nutrition assessment. Routine laboratory monitoring with the pediatric population includes complete blood counts and blood lead levels to rule out lead exposure. Abnormal hemoglobin (Hgb) and hematocrit (Hct) levels can aid in the detection of iron, vitamin B12, and folate deficiencies. A complete blood count can identify the degree and features of anemia. Red cells are microcytic and hypochromic
Growth Charts
Fenton for Premature Infants The Babson and Benda 1976 fetal-infant growth graph for premature infants was commonly used to assess growth of premature infants in the neonatal intensive care unit
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in iron deficiency anemia. In early phases of iron deficiency, decreased levels of mean corpuscular volume (MCV) and mean hemoglobin content (MCH) are seen. As the iron deficiency progresses, decreased levels of Hgb and Hct develop.22 If iron deficiency is suspected, a complete iron profile should be ordered. A low serum iron concentration with an elevated total iron-binding capacity (TIBC) and decreased levels of ferritin are a diagnostic indicator of iron deficiency.22 However, if Hgb and Hct are low with an elevated MCH, vitamin B12 and folate deficiencies should be considered. Serum vitamin B12 and folate levels should be drawn. Those consuming a vegetarian diet or having undergone ileocecal valve resection (from gastrointestinal surgery) are at a greater risk of developing vitamin B12 deficiency.
Table 33-13 Nutrition Concerns Based on Physical Examination1,27,33
Site Physical Examination
Serum albumin, transferrin, and prealbumin are indicators of visceral protein status. Depleted levels can be an indication of visceral protein depletion and malnutrition. However, other clinical conditions (eg, altered fluid status, inflammation, acute infection) may falsely decrease levels.
Physical Exam
Physical examination of the pediatric patient is also a vital component of the nutrition assessment. Physical examination can provide insight into conditions such as malnutrition, obesity, edema, dehydration, and vitamin deficiencies and excesses. Table 33-13 outlines some nutrition concerns based on physical examination.2,33,39
Potential Nutritional/Metabolic Status
Skin Integrity
Pallor Dry, scaly skin Dermatitis
Iron, folate, or vitamin B12 deficiency Vitamin A or essential fatty acid deficiency Essential fatty acid deficiency; zinc, niacin, riboflavin, or tryptophan deficiency Iron deficiency Protein deficiency Vitamin A or C deficiency Protein-calorie malnutrition Protein-calorie malnutrition Iodine deficiency Riboflavin, niacin, or vitamin B6 deficiency Vitamin C deficiency Vitamin B complex, iron or vitamin C deficiency Riboflavin deficiency Niacin, folate, riboflavin, iron, or vitamin B12 deficiency Vitamin A deficiency
Nails
Spoon shape Lackluster, dull Mottled, pale, poor blanching
Face Neck Mouth
Moon face Bilateral temporal wasting Enlarged thyroid Dry, cracked, red lips Bleeding gums Inflammed mucosa
Tongue Eyes
Magenta color Beefy red color and diminished taste Night blindness; dull, dry appearance to sclerae or inner lids; dull, milky appearance of the cornea Cracked, red corners Dull, lackluster, thin, sparse Easily pluckable Excessive dental caries Rounded, distended Increased temperature Increased respiratory rate
Riboflavin or niacin deficiency Protein, iron, zinc, or essential fatty acid deficiency Protein deficiency Excessive simple carbohydrate intake Gas, edema, ascites, obesity Increased energy and fluid requirements Altered calorie and protein requirements Energy needs may be increased if weaning from ventilator support or decreased if chronically ventilator dependent
Hair Dentition Abdomen Temperature Respiration
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Appendix 33-1 Estimating Nutrient Needs

Name of Equation or Formula ENERGY 1989 Recommended Daily Allowance (RDA) Description Based on the median energy intakes of children followed in longitudinal growth studies It can overestimate needs in non-active populations (eg, bedridden) and does not provide a range of energy needs. Though an outdated reference, still widely used. Calculations for the Equation or Formula Applicable to Which Patient Populations? Most often used for healthy infants and children Source Committee on Dietary Allowances, Food and Nutrition Board, National Research Council. Recommended Dietary Allowances. 10th ed. Washington, DC: National Academy Press; 1989.
Infants: 00.5 y: 108 x Wt (kg) 0.51 y: 98 x Wt Children: 13 y: 102 x Wt 46 y: 90 x Wt 710 y: 70 x Wt Males: 11-14 y: 55 x Wt 15-18 y: 45 x Wt Females: 11-14 y: 47 x Wt 15-18 y: 40 x Wt Estimated Energy Replaces the 1989 Recommended EER = TEE + energy deposition Requirements Dietary Allowances (RDA). Ages 0-36 mo: (EER) (new DRI/ 0-3 mo: (89 x wt [kg] - 100) + 175 Energy needs were determined from IOM equation) & 4-6 mo: (89 x wt [kg] - 100) + 56 children with normal growth, body Physical Activity (PA) composition, and activity, and who are 7-12 mo: (89 x wt [kg] - 100) + 22 Co-Efficients 13-36 mo: (89 x wt [kg] -100) + 20 also metabolically normal. Ages 3-8 yBoys: EER = 88.5 - (61.9 x age [y]) + PA x (26.7 x wt [kg] + 903 x ht[m]) + 20 kcal PA = 1 if PAL is estimated to be > 1 < 1.4 (sedentary) PA = 1.13 if PAL is estimated to be > 1.4 < 1.6 (low active) PA = 1.26 if PAL is estimated to be > 1.6 < 1.9 (active) PA = 1.42 if PAL is estimated to be > 1.9 < 2.5 (very active) Ages 3-8 yGirls: EER = 135.3 - (30.8 x age [y]) + PA x (10 x wt [kg] + 934 x ht [m]) + 20 kcal PA = 1 if PAL is estimated to be > 1 < 1.4 (sedentary) PA = 1.16 if PAL is estimated to be > 1.4 < 1.6 (low active) PA = 1.31 if PAL is estimated to be > 1.6 < 1.9 (active) PA = 1.56 if PAL is estimated to be > 1.9 < 2.5 (very active) Ages 9-18 yBoys: EER = 88.5 - (61.9 x age [y]) + PA x ( 26.7 x wt [kg] + 903 x ht [m]) + 25 kcal PA = 1 if PAL is estimated to be > 1 < 1.4 (sedentary) PA = 1.13 if PAL is estimated to be > 1.4 < 1.6 (low active) PA = 1.26 if PAL is estimated to be > 1.6 < 1.9 (active) PA = 1.42 if PAL is estimated to be > 1.9 < 2.5 (very active) Ages 9-18 yGirls: EER = 135.3 - (30.8 x age [y]) + PA x (10 x wt [kg] + 934 x ht [m]) + 25 kcal PA = 1 if PAL is estimated to be > 1 < 1.4 (sedentary) PA = 1.16 if PAL is estimated to be > 1.4 < 1.6 (low active) PA = 1.31 if PAL is estimated to be > 1.6 < 1.9 (active) PA = 1.56 if PAL is estimated to be > 1.9 < 2.5 (very active) EER (new DRI/IOM Weight Maintenance TEE in Overweight Boys Ages 3-18 y: equation) & obesity TEE = 114 - (50.9 x age [y]) + PA x (19.5 x weight [kg] + 1161.4 x height [m]) co-efficients/factors PA = 1 if PAL is estimated to be > 1 < 1.4 (sedentary) PA = 1.12 if PAL is estimated to be > 1.4 < 1.6 (low active) PA = 1.24 if PAL is estimated to be > 1.6 < 1.9 (active) PA = 1.45 if PAL is estimated to be > 1.9 < 2.5 (very active) Weight Maintenance TEE in Overweight Girls Ages 3-18 y: TEE = 389 - (41.2 x age [y]) + PA x (15 x weight [kg] + 701.6 x height [m]) PA = 1 if PAL is estimated to be > 1 < 1.4 (sedentary) PA = 1.18 if PAL is estimated to be > 1.4 < 1.6 (low active) PA = 1.35 if PAL is estimated to be > 1.6 < 1.9 (active) PA = 1.6 if PAL is estimated to be > 1.9 < 2.5 (very active) Schofield A predictive equation for calculating Males: basal metabolic rate (BMR) in healthy 0-3 y: (0.167 x wt [kg]) + (15.174 x ht [cm]) - 617.6 children that was developed by analysis 3-10 y: (19.59 x wt [kg]) + (1.303 x ht[cm]) + 414.9 of Fritz Talbot tables. 1018 y: (16.25 x wt [kg]) + (1.372 x ht[cm]) + 515.5 > 18 y: (15.057 x wt [kg]) + (1.0004 x ht[cm]) + 705.8 Females: 0-3 y: (16.252 x wt[kg]) + (10.232 x ht [cm]) - 413.5 3-10 y: (16.969 x wt [kg]) + (1.618 x ht [cm]) + 371.2 1018 y: (8.365 x wt [kg]) + (4.65 x ht [cm]) + 200 >18 y: (13.623 x wt [kg]) + (23.8 x ht [cm]) + 98.2) FAO/WHO The WHO equation was developed Males: for use in healthy children; however, it 03 y: (60.9 x wt [kg]) - 54 is commonly used to predict resting 310 y: (22.7 x wt [kg]) + 495 energy expenditure (REE) of acutely ill 1018 y: (17.5 xwt [kg]) + 651 patients in the hospital setting. Females: 03 y: (61 x wt [kg]) - 51 310 y: (22.5 x wt [kg]) + 499 1018 y: (12.2 x wt [kg]) + 746
Children with normal growth, body composition, and activity, and who are also metabolically normal.
National Academy of Sciences, Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients) (2005).
Overweight children who National Academy of Sciences, are metabolically normal Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients) (2005).
Healthy children, acutely Schofield WN. Predicting basal ill patients in the hospital metabolism rate, new standards and setting review of previous work. Hum Nutr: Clin Nutr. 1985;39C:591.
Healthy children who are World Health Organization. Energy acutely ill patients in the and Protein Requirements. Report hospital setting of a Joint FAO/WHO/UNU Expert Consultation. Technical Report Series 724. World Health Organization, Geneva, 1985.
Source: Ludlow V, Randall R, Burritt E, Rago D. Estimating Nutrient Needs, Pediatric Module. A.S.P .E.N. Enteral Nutrition Practitioner Tutorial Project, pending publication.
419

Name of Equation or Formula Estimating calorie needs for developmental disabilities Description Children with developmental disabilities (DD) may have a slower basal energy need due to a decreased muscle tone, growth rate, and motor activity. The recommendation to calculate energy needs in children with DD per cm of height is based on the fact that they tend to have a shorter height when compared to children with normal growth. Calculations for the Equation or Formula Applicable to Which Patient Populations? Children with developmental disabilities *This reference applies to the specific ages listed. Please refer to another equation for ages outside of the referenced ages, and apply an appropriate activity/stress factor. Source Rokusek C, Heindicles E. Nutrition and Feeding of the Developmentally Disabled. Brookings, SD: South Dakota University Affiliated Program, Interdisciplinary Center for Disabilities;1985.
Cerebral palsy (age 5-11 y*): Mild-moderate activity: 13.9 kcal/cm height Severe physical restrictions: 11.1 kcal/cm height Severe restricted activity: 10 kcal/cm height Athetoid Cerebral Palsy: Up to 6,000 kcal/day (adolescence) Down Syndrome (5-12 y*): Boys 16.1 kcal/cm height Girls 14.3 kcal/cm height Prader-Willi Syndrome (for all children and adolescents): 10-11 kcal/cm height for maintenance 8.5 kcal/cm height for weight loss Myelomeningocele (Spina bifida) (Over 8 years of age and minimally active): 9-11 kcal/cm height for maintenance 7 kcal/cm height for weight loss Approximately 50% RDA for age after infancy Petersons Failure to This calculates nutrients in excess of the [RDA for weight age (kcal/kg) x Ideal body weight for height] Actual weight Thrive (FTT) requirements of the RDA. Concerns with using this equation include refeeding syndrome. FAO/WHO/UNU Food and Agriculture Organization, World Boys 1018 y BMR = 16.6 weight (kg) + 77 height (m) + 572 (aka Dietz Health Organization, United Nations equation) University Girls 1018 y BMR = 7.4 weight (kg) + 482 height (m) + 217 White equation Developed for use in the pediatric critical care population by including temperature as a gauge of the bodys inflammatory response. It is not commonly used in clinical practice, and recent studies have shown decreased accuracy especially in smaller, younger patients. This equation should not be used in patients less than 2 months of age. STRESS FACTORS FOR ENERGY Stress Factors The use of stress factors along with predictive energy equations should be considered for use in hospitalized children whose energy requirements may be altered due to metabolic stress. PROTEIN A.S.P.E.N. Clinical Guidelines: Nutrition Support of the Critically Ill Child EE (kJ/day) = (17 age [mo]) + (48 weight [kg]) + (292 body temperature [C]) - 9677
Infants and children who Peterson K, et al. Team Management present underweight and of Failure-to-thrive. J Am Diet Assoc. need to achieve catch-up 1984;84:810. growth Overweight/obese adolescents in an outpatient setting Pediatric critical care population Dietz WH, Brandini LG, Schoeller DA. Estimates of metabolic rate in obese and non-obese adolecents. J Pediatr. 1991;118:146149. White MS, Shepherd RW, McEniery JA. Energy expenditure in 100 ventilated, critically ill children: improving the accuracy of predictive equations.Crit Care Med. 2000;28(7):23072312.
Starvation 0.700.85 Surgery 1.051.5 Sepsis 1.21.6 Closed head injury 1.3 Trauma 1.11.8 Growth failure 1.52 Burn 1.52.5 02 y: 23 g/kg/d 213 y: 1.52 g/kg/d 1318 y:1.5 g/kg/d
Pediatric hospitalized population
Leonberg B. ADA Pocket Guide to Pediatric Nutrition Assessment. Chicago, IL: American Dietetic Association; 2007. TABLE 8.10
Metabolic stress increases catabolism and breakdown of lean body mass. To meet the increased demands of metabolic stress and spare the use of endogenous protein stores, a greater amount of protein is needed in this population until the underlying stress has been overcome. Recommendations are based on limited data. For the injured child Metabolic stress increases catabolism and breakdown of lean body mass. To meet the increased demands of metabolic stress and spare the use of endogenous protein stores, a greater amount of protein is needed in this population until the underlying stress has been overcome. Dietary Reference Replaces the 1989 Recommended Intake (DRI) Dietary Allowances (RDA). Protein needs were determined from children with normal growth, body composition, and activity, and who are also metabolically normal.
Pediatric critical care population
Mehta NM, Compher C, A.S.P.E.N. Board of Directors. A.S.P.E.N. Clinical Guidelines: Nutrition Support of the Critically Ill Child. J Parenter Enteral Nutr. 2009;33(3):260276.
0-2 y: 2-3 g/kg/d 2-13 y: 1.5-2 g/kg/d Adolescents: 1.5 g/kg/d
Pediatric critical/surgical Jaksic T. Effective and efficient care population nutritional support for the injured child. Surg Clin North Am. 2002;82(2):379391, vii.
06 mo: 1.52 g/kg/d *This is an Adequate Intake recommendation, not enough research has been conducted to establish an RDA for this age group.
612 mo: 1.2 g/kg/d 1236 mo: 1.05 g/kg/d 413 y: 0.95 g/kg/d 1418 y: 0.85 g/kg/d >18 y: 0.8 g/kg/d 1989 Based on the median nutrient intakes 06 mo: 2.2 g/kg/d Recommended of children followed in longitudinal 612 mo: 1.6 g/kg/d Dietary Allowance growth studies 13 y: 1.2 g/kg/d (RDA) It can overestimate needs in non-active 46 y: 1.1 g/kg/d populations (eg, bedridden) and does 714 y: 1 g/kg/d 1518 y (males): 0.9 g/kg/d not provide a range of energy needs. 1518 y (females): 0.8 g/kg/d Though an outdated reference, still widely used. Petersons Failure to This calculates nutrients in excess of the [Protein Required for Weight Age (g/kg/d) x Ideal Weight for Age (kg)] Actual Thrive (FTT) requirements of the RDA. Weight (kg) Concerns with using this equation include refeeding syndrome. It can be calculated using a method similar to the one for calories above.
National Academy of Sciences, Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients) (2005). Committee on Dietary Allowances, Food and Nutrition Board, National Research Council. Recommended Dietary Allowances.10th ed. Washington, DC: National Academy Press; 1989.
Infants and children who Peterson K, et al. Team Management present underweight and of Failure-to-thrive. J Am Diet Assoc. need to achieve catch 1984;84:810. up growth
420
Appendix 33-2 Percentiles of Upper Arm Circumference
Reprinted with permission from Frisancho AR. New norms of upper limb fat and muscle areas for assessment of nutritional status. Am J Clin Nutr. 1981;34:25402545.
421
Appendix 33-3 Triceps Skinfold Percentiles
Reprinted with permission from Frisancho AR. New norms of upper limb fat and muscle areas for assessment of nutritional status. Am J Clin Nutr. 1981;34:25402545.
422
Appendix 33-4 Fetal-Infant Growth Chart A new fetal-infant growth chart for preterm infants developed through a meta-analysis of published reference studies.
Fenton TR. Fetal-infant growth chart for preterm infants. BMC Pediatrics. 2003 Dec 16;3(1):13. Reproduced with permission from BioMed Central.
423
Appendix 33-5
424
425
426
427
428
429
430
431
1. Important components of the nutrition assessment of the pediatric population include(s): A. Dietary history B. Anthropometric measurements C. Physical examination D. All of the above 2. The American Academy of Pediatrics recommends the following for vitamin D intake: A. 200 International Units daily for all age groups B. 400 International Units daily, starting at 2 months of age C. 400 International Units for all infants, children, and adolescents, starting at birth D. 200 to 400 International Units per day, based on deficiency symptoms and risk of rickets 3. Spoon-shaped nails and depleted Hgb and Hct levels may be an indication of: A. Folate deficiency B. Vitamin B12 deficiency C. Vitamin C deficiency D. Iron deficiency See p. 487 for answers.
References
1. American Academy of Pediatrics, Committee on Nutrition. Kleinman RA, ed. Pediatric Nutrition Handbook. 5th ed. Elk Grove, IL: American Academy of Pediatrics; 2004:149154. 2. Faulhaber D. Nutrition assessment of premature infants. In: Nevin-Folino N, ed. Pediatric Manual of Clinical Dietetics. 2nd ed. Chicago, IL: Pediatric Nutrition Practice Group; 2003:127144. 3. Ziegler EE, Thureen PJ, Carlson SJ. Aggressive nutrition of the very low birthweight infant. Clin Perinatol. 2002;29:225244. 4. Ballard JL, Khoury JC, Wedig K, et al. New Ballard Score, expanded to include extremely premature infants. J Pediatr. 1991;119:417423. http://www. Ballardscore.com. Accessed September 17, 2008. 5. Lubchenco LO, Hansman C, Boyd E. Classification of newborns based on maturity and intrauterine growth. Pediatrics. 1966;37:403. 6. Fenton TR. A new growth chart for premature babies: Babson and Bendas chart updated with recent data and a new format. BMC Pediatrics. 2003;(3)13. http://biomedcentral.com/14712431/3/13. Accessed September 17, 2008. 7. Katrine KF. Anthropometric assessment. In: Groh-Wargo S, Thompson M, Hovasi-Cox J, eds. Nutritional Care for HighRisk Newborns. 3rd ed. Chicago, IL: Precept Press; 1994:13. 8. Faulhaber D. Nutrition assessment of infants and children. In: Nevin-Folino N, ed. Pediatric Manual of Clinical Dietetics. 2nd ed. Chicago, IL: Pediatric Nutrition Practice Group; 2003:145162.
9. Fomon SJ, Haschke F, Ziegler EE, Nelson SE. Body composition of reference children from birth to age 10 years. Am J Clin Nutr. 1982;35:1169. 10. National Health and Nutrition Examination Survey. CDC Growth Charts: United States. http://www.cdc.gov/nchs/ about/major/nhanes/growthcharts/background.htm. Accessed October 18, 2008. 11. Waterlow JC, Buzina R, Keller W, Lane JM, Nichamon MZ. The presentation and use of height and weight data for comparing the nutritional status of children under the age of 10 years. Bull World Health Organization. 1977;55(4):489498. 12. Frisancho AR. Anthropometric Standards for the Assessment of Growth and Nutritional Status. Ann Arbor, MI: The University of Michigan Press; 2004. 13. Food and Nutrition Board, Committee on Dietary Allowances. Recommended Dietary Allowances. 10th ed. Washington DC: The National Academies Press; 1989. 14. World Health Organization. Energy and Protein Requirements. Report of a Joint FAO/WHO/UNU Expert Consultation. Technical Report Series 724. World Health Organization, Geneva; 1985. 15. Otten JJ, Pitzi Hellwig J, Meyers LD, eds. Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. 16. Holliday MA, Segar WE. The maintenance for water in parenteral fluid therapy. Pediatrics. 1957;19:823832. 17. Oh TH. Formulas for calculating fluid maintenance requirements. Anesthesiology. 1980; 53:351353. 18. American Academy of Pediatrics, Committee on Nutrition. Adolescent nutrition. In: Kleinman RA, ed. Pediatric Nutrition Handbook. 5th ed. Elk Grove, IL: American Academy of Pediatrics; 2004:149154. 19. Faulhaber D. Nutrition assessment of adolescents. In: Nevin-Folino N, ed. Pediatric Manual of Clinical Dietetics. 2nd ed. Chicago, IL: Pediatric Nutrition Practice Group; 2003:163172. 20. American Academy of Pediatrics, Committee on Nutrition. Calcium requirements of infants, children, and adolescents. Pediatrics. 1999;104:11521157. http://aappublications.org/ cgi/content/full/pediatrics;104/5/1152. Accessed October 11, 2008. 21. Wyshak G, Frisch RE. Carbonated beverages, dietary calcium, the dietary calcium/phosphorus ratio, and bone fractures in girls and boys. J Adolesc Health. 1994;15:210215. 22. Borgna-Pignatti C, Marsella M. Iron deficiency in infancy and childhood. Pediatric Annals. 2008;37(5):329337. 23. American Academy of Pediatrics, Committee on Nutrition. Iron fortification of infant formulas. Pediatrics. 1999;104:119123. http://aappublications.org/cgi/content/ full/pediatrics;104/1/119. Accessed October 12, 2008. 24. American Academy of Pediatrics, Committee on Nutrition. Iron supplementation for infants. Pediatrics. 1976;58:765768. 25. Siimes MA, Jarvenpa AL. Prevention of anemia and iron deficiency in very-low-birth-weight infants. J Pediatr. 1982;101:277280. 26. Pupillo J. Bone up on new vitamin D recommendations: all infants, children, adolescents should get at least 400 IU a day. AAP News. 2008;29:1.
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27. Wagner CL, Greer FR, and the Section on Breastfeeding and Committee on Nutrition. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 2008;122:11421152. http://aappublications.org/cgi/ content/full/pediatric;122/5/1142. Accessed November 13, 2008. 28. American Academy of Pediatrics, Section on Pediatric Dentistry. Policy statement: Oral health risk assessment timing and establishment of the dental home. Pediatrics. 2003;111:11131116. 29. US Department of Health and Human Services; National Institute of Dental and Craniofacial Research. Oral health in America: A report of the surgeon general. Rockville, MD: National Institutes of Health; 2000. 30. American Academy of Pediatric Dentistry, Council on Clinical Affairs. Policy statement on the use of fluoride. Adopted 5/2000; revised: 5/2001. http://www.aapd.org/members/ referencemanual/pdfs/Fluoride.pdf. Accessed October 11, 2008. 31. US Department of Health and Human Services. Recommendations for using fluoride to prevent and control dental caries in the United States. MMWR Recomm Rep. 2001;50(-14). http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5014a1. htm. Accessed November 13, 2008.
32. Lohman TG, Roche AF, Martorell R, eds. Anthropometric Standardization Reference Manual. Champaign, IL: Human Kinetics Books; 1998. 33. Splender Q , Cronk C, Charney E, et al. Assessment of linear growth of children with cerebral palsy: use of alternative measures of height or length. Dev Med Child Neurol. 1989;31:206214. 34. Stevenson RD. Use of segmental measures to estimate stature in children with cerebral palsy. Arch Pediatr Adolesc Med. 1995;149:658662. 35. Garn S, Rohmann C. Interaction of nutrition and genetics in the timing of growth and development. Pediatr Clin North Am. 1966;13:353379. 36. Himes J, Roche A, Thissen D, et al. Parent-specific adjustments for evaluation of recumbent length and stature of children. Pediatrics. 1985;75:304313. 37. Leonberg BL. ADA Pocket Guide to Pediatric Nutrition Assessment. Chicago, IL: American Dietetic Association; 2008. 38. Frisancho AR. New norms of upper limb fat and muscle areas for assessment of nutritional status. Am J Clin Nutr. 1981;34:25402545. 39. Hammond K. The nutritional dimension of physical assessment. Nutrition. 1999;15:412417.
Parenteral and Enteral Nutrition Support: Determining the Best Way to Feed
Liesje Nieman Carney, RD, CNSD, LDN, Andrea Nepa, MS, RD, CSP, LDN, Sherri Shubin Cohen, MD, MPH, Amy Dean, MPH, RD, LDN, Colleen Yanni, MS, RD, LDN, and Goldie Markowitz, MSN, CRNP
34
CONTENTS
When to Use Enteral versus ParenteralNutrition Support. . . . . . . . . . . . . . . . . . . . . . . 431 Determining the Best Enteral Approach. . . . . . . . . . . . . . 432
Functional Barriers to Oral Enteral Nutrition Structural Barriers to Enteral Nutrition Candidates for Enteral Nutrition Inadequate Oral Intake and Prematurity Inadequate Oral Intake and BronchopulmonaryDysplasia Inadequate Oral Intake and Cystic Fibrosis Inadequate Oral Intake and Congenital Heart Disease Inadequate Oral Intake and Renal Disease Inadequate Oral Intake in Burns, Sepsis/Critical Illness, and HIV Enteral Nutrition: Routes of Administration
Learning Objectives
Parenteral Nutrition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434

Gastrointestinal Conditions Prematurity Congenital Heart Disease Anorexia Nervosa Relative Indications for PN Access for Administering PN Macronutrients Electrolytes Vitamins, Minerals, and Trace Elements PN Additives: Heparin, Carnitine, and Cysteine Complications of PN Monitoring Aluminum in PN
1. Discuss indications for nutrition support in infants and children. 2. Identify when it is appropriate to utilize parenteral nutrition versus enteral nutrition. 3. Name examples of structural or functional barriers to safe oral intake in medically compromised children. 4. Explore the types of enteral nutrition formulas, access options, and administration modalities. 5. Distinguish between a feeding disorder and an eating disorder. 6. Explore why an interdisciplinary approach is necessary to treat feeding disorders.
Feeding Teams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440

Etiologies of Feeding Disorders Evaluation and Treatment of Feeding Disorders
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
The decision to utilize enteral versus parenteral nutrition primarily depends upon whether the gastrointestinal (GI) tract can be used safely or not. Peripheral parenteral nutrition (PPN) is generally reserved for patients for a short period of time who cannot use their GI tracts, whereas central parenteral nutrition (CPN) is appropriate for longterm needs.1 Whenever possible, oral feeding or enteral nutrition (EN) is preferred over parenteral nutrition (PN) to maintain GI mucosal integrity, absorptive ability, and immune function.2 Medical conditions that usually require PN support include the following: necrotizing enterocolitis (NEC), diaphragmatic hernia, omphalocele, meconium ileus, intestinal atresia, gastroschisis, and short bowel syndrome (SBS). 3,4 There are some clinical situations in which enteral feeding may be contraindicated, but this must be evaluated on a case-by-case basis. Examples of clinical situations
433
When to Use Enteral versus ParenteralNutrition Support
434
where PN may be warranted due to an increased risk for poor bowel perfusion include hemodynamic instability or use of high-dose vasopressors. Severe pulmonary disease, cystic fibrosis, congenital heart disease, chylothorax, renal disease on peritoneal dialysis, severe sepsis, and anorexia nervosa are additional conditions in which PN support has been utilized in special circumstances. 3,4
Determining the Best Enteral Approach
Infants and children with a variety of disorders may be unable to meet their nutrient needs via exclusive oral intake. Some medical conditions make it difficult or impossible to safely consume food and hydration by mouth, or to digest and/or absorb food effectively. Other diagnoses are associated with high energy needs, making it is difficult for the infant or child to consume adequate amounts orally. In general, children who require EN support are those who are unable to obtain more than 80% of caloric needs by mouth, or who require an extended period of time to eat (ie, more than 4 hours per day). Children who are malnourished or exhibit poor growth also benefit from EN support. Children under the age of 2 who have poor growth or weight gain for more than 1 month or children over the age of2 with weight loss or lack of weight gain for 3 months also require nutrition support. A child who has decreased 2 or more weight or height growth channels, or persistently has a triceps skinfold (TSF) of less than the 5th percentile, is likely malnourished enough to warrant nutrition support as well. 3
Patients with congenital anomalies such as tracheoesophageal fistula (TEF), esophageal atresia, cleft palate, and Pierre Robin syndrome require a source of nutrition that bypasses the oral route, at least until the condition is surgically repaired.4 EN support would also be indicated in cases of obstruction of the oral cavity and surrounding areas such as cancer of the head/neck, or mechanical ventilation. Injuries such as caustic ingestion, trauma, or burns to the head/ neck area may impede ability to consume oral intake as well.4 Other types of severe oral injury that may warrant EN support include mucositis and Stevens-Johnson syndrome cases that involve oral lesions.
Candidates for Enteral Nutrition

Candidates for EN vary in the degree to which they depend upon the tube. Children with the ability to eat yet are stunted in growth or malnourished may only need tube feedings as a supplement to oral intake, which may be administered nocturnally or as bolus feedings between meals. Tube feedings can also be administered on an as-needed basis, such as only when intake of a meal is poor or when the child goes through a period of feeling poorly (eg, during chemotherapy). Likewise, children with significant oral aversions who consume a limited variety and/or volume of food may need supplemental tube feedings to provide the remainder of their daily nutrient needs. On the other hand, children who are not capable of consuming food orally receive tube feedings as their sole source of nutrition. Children with neuromuscular disorders often fall into this category. Children who require highly specialized diets, such as the ketogenic diet or formulas indicated for metabolic disorders, may require EN. This is usually due to the unpalatable formulas or the absolute need for the child to receive 100% of the daily formula prescription. Children who have experienced delayed introduction of oral feeding (eg, when tube feedings are required for a long period of time in infancy) or unpleasant oral-tactile experiences (eg, frequent or prolonged oral intubation and suctioning) are especially at risk. 3,7 It appears that there is a window of opportunity in which the infant learns how to eat by mouth. 3 When infants are unable to take anything orally for a prolonged time (eg, prolonged oral intubation) they are at risk for long-term oral aversion due to tactile defensiveness.
Functional Barriers to Oral Enteral Nutrition

Functional barriers to safe oral intake may include neurological or neuromuscular diseases, genetic/metabolic syndromes, and prematurity.4 For example, bulbar dysfunction is common in patients with severe spinal muscular atrophy, which can lead to problems with eating and swallowing, as well as aspiration pneumonia. Reflux related to delayed gastric emptying can also occur. 5 Chewing and swallowing difficulties are common in children affected by neuromuscular disorders, and can lead to aspiration.6 In fact, most children with cerebral palsy benefit from tube feedings.6 Children with neurological impairments, such as severe seizure disorders or anoxic brain injury, usually require enteral feeding long-term. 3 Infants or children with neurological impairments may also develop oral aversions due to sensory integration disorders.
Structural Barriers to Enteral Nutrition

Structural barriers to oral intake include congenital anomalies, obstructions, injuries, and some types of surgery.
Inadequate Oral Intake and Prematurity

In premature infants, the inability to coordinate the suckswallow-breathe pattern may prevent safe oral feedings. 8
PARENTERAL AND ENTERAL NUTRITION SUPPORT: DETERMINING THE BEST WAY TO FEED
435
Although historically it was thought that the ability to coordinate sucking and swallowing with breathing did not develop until 32 to 34 weeks gestation, studies are presently investigating the theory that there is a positive association between attainment of successful oral feedings at less than 32 weeks gestation and the implementation of oral stimulation protocols. Multiple medical issues in the premature infant, such as long-term dependency on mechanical ventilation, make it difficult to achieve normal oral intake. One study demonstrated a significant correlation between prematurity and feeding disorders.9 Children with feeding disorders had significantly lower birth weights for gestational age, and infants born before 34 weeks gestation had more GI and oral sensory problems.9 It has been observed that a very small percentage of premature infants require long-term EN because they are unable to meet all their nutrient needs orally.10
Inadequate Oral Intake and Congenital Heart Disease

Children with congenital heart disease often show growth failure for a variety of reasons. Anorexia, hypermetabolism, frequent respiratory infections, decreased circulation, malabsorption, and pulmonary hypertension are all factors that contribute to poor nutrition status. 8 Increasing respiratory effort as a result of accumulation of pulmonary fluid can cause feeding difficulties as well. In this case EN may be required to prevent excessive energy expenditure from occurring during oral feedings. Infants and children may have delayed feeding skills as a result of chronic illness and prolonged hospitalization. Chronic malnutrition is especially common in children with cyanotic heart disease.15 Depending on the degree of malnutrition and the ability to tolerate oral feedings, infants and children with congenital heart disease may need supplemental EN to maintain adequate nutrient intake. Energy needs may be increased 20% to 33% due to congenital heart disease.7
Inadequate Oral Intake and BronchopulmonaryDysplasia

Bronchopulmonary dysplasia (BPD) occurs relatively frequently in infants who are born prematurely.11 Infants and young children with BPD are at increased risk for growth failure and nutrient deficits. This is thought to be a result of the excessive energy expenditure required for breathing and/or poor nutrition intake. Poor oral intake is common due to oral aversion, fatigue secondary to increased work of breathing, and anorexia secondary to chronic illness.12 Therefore, patients with BPD often require EN support to promote normal growth and maintain good weight gain.
Inadequate Oral Intake and Renal Disease

Infants and children with renal disease often exhibit poor appetite. In addition, the need for a restrictive diet (eg, low sodium, low potassium, and low phosphorus) may decrease the childs intake since preferred foods must be limited. The decision to provide nutrition support needs to be considered on an individual basis, depending upon many factors some of which include nutrition status and willingness to eat.7 It is generally accepted that most infants and young children on peritoneal dialysis need supplemental tube feedings to maximize their growth potential.16 At this time, there are limited data regarding the use of nutrition support in infants and children on hemodialysis. Therefore, general nutrition support recommendations for this population are not available.
Inadequate Oral Intake and Cystic Fibrosis

Due to increased work of breathing and pancreatic insufficiency, infants and children with CF have increased caloric needs, as much as 200% above that of the general population. 3,13 Pancreatic insufficiency occurs in most (85%90%) individuals with CF, which causes malabsorption of nutrients.14 The CF Foundation recommends that children with CF who have growth deficits receive oral and enteral supplements to achieve better weight gain, and recommend a BMI of at least the 50th percentile.13 The initiation of enteral feedings is suggested when oral supplementation does not achieve adequate weight gain.14 This is especially important because studies have demonstrated that better weight status is associated with better lung function and improved survival rates.13
Inadequate Oral Intake in Burns, Sepsis/Critical Illness, and HIV

Children with severe burns, sepsis, or advanced HIV may have extremely high metabolic rates that demand full or supplemental tube feedings. 3 Calorie, protein, and micronutrient needs are increased in burn patients to allow wound healing. Individuals with burns affecting over 20% surface area are more likely to require supplemental tube feedings to meet their needs.17 Small bowel feedings are often preferred due to the risk of gastric ileus in this population.17
Enteral Nutrition: Routes of Administration

The route chosen for the administration of EN depends upon the anticipated length of time that tube feeding will
436
Table 34-1 Indications for Enteral Nutrition1

Inadequate Oral Intake Increased Nutrient Needs Increased GI Losses Primary Therapy Oral Motor Dysfunction Structural or Functional Abnormality of GI Tract Injury/Critical Illness
Anorexia nervosa Anorexia related to medical condition Anorexia due to treatment/ medications (eg, chemotherapy) Food aversion Mucositis
Cystic fibrosis BPD FTT (requires catch-up growth) Congenital heart disease Renal disease Infection
Pancreatic insufficiency SBS
Metabolic diseases Intolerance to fasting Unpalatable diet (eg, elemental or metabolic formula) IBD
Prematurity Neuromuscular disorders Neurological impairment (eg, cerebral palsy)
Congenital malformation Intestinal pseudoobstruction TEF Proximal fistula with highoutput Proximal intestinal obstruction
Burn Trauma
Cholestatic liver disease Biliary atresia Malabsorption
Surgery
Oral intubation
be required, the anatomy of the patient, and the disease state. 3 Short-term EN can be administered via nasoenteric route (eg, nasogastric, nasoduodenal, or nasojejunal tube) or placed orally (eg, orogastric). Examples of long-term enteral access include percutaneous endoscopic gastrostomy (PEG), percutaneous endoscopic jejunostomy (PEJ), surgical jejunostomy, or surgical gastrostomy.18 When choosing enteral access one should consider the following: (1) indication for EN, (2) duration of EN, (3) anatomical integrity of the GI tract, (4) functional integrity of the GI tract, and (5) risk of aspiration.1
Gastrointestinal Conditions
Infants born with congenital anomalies of the GI tract generally require PN. Children who develop GI disorders that prohibit the use of enteral feedings rely on PN for their nutrition, either temporarily or permanently. For instance, SBS may result from major surgical resection of the GI tract, or may develop in infants born with gastric anomalies.19 Intestinal atresia that requires extensive resection or gastroschisis that causes necrotic bowel can lead to SBS. Necrotizing enterocolitis (NEC), trauma, and volvulus are other examples of conditions in which SBS can occur. PN is always indicated for SBS in the immediate postoperative period.19,20 Eventually, many individuals with SBS can adapt to enteral feeds with the successful weaning of PN.19 NEC in infants requires PN, as enteral feedings are withheld for a period of time to support bowel healing and recovery. 3,21,22 Those with intestinal failure, as defined by inability of the gut to digest or absorb an adequate amount, or extensive lesions and/or motor dysfunction, usually require
PN. However, in some pediatric intestinal failure cases a semi-elemental or elemental diet may be tolerated. 23,24 The removal or absence of a part of the GI tract will impact the ability to tolerate enteral feeding; for some this intolerance is transient and for others it is long term.23 Obstruction of the GI tract and major surgery that impairs the GI tract also require PN. Other GI conditions such as severe inflammatory bowel disease, severe reflux, motility disorders of the GI tract, severe/acute pancreatitis, intractable diarrhea, intussusception, volvulus, high output fistulas, severe Hirschsprungs disease, and severe GI side effects of chemotherapy including radiation enteritis (as well as cancer cachexia) can in extreme cases require PN support. 3,4,23
Prematurity
Premature and low birth weight infants need a source of nutrition immediately after birth due to low nutrient reserves, increased energy expenditure, immaturity of the GI tract, as well as their increased propensity for acute and chronic illness.8,21 Infants should receive PN if it is anticipated that they will be unable to receive enteral feedings for more than 2 to 3 days. Infants have very limited fat and glycogen stores, and when these have been depleted infants begin to catabolize protein stores for energy. However, EN is commonly withheld if the following conditions are present: severe respiratory failure associated with hypoxia and acidosis; hypotension treated with vasopressors; peri natal asphyxia with signs of organ involvement; clinical signs of NEC or intestinal obstruction; congenital heart disease with decreased left-sided outflow; patent ductus arteriosus with left to right shunt or requiring Indomethacin or surgical ligation; or sepsis-associated paralytic ileus.
437
PN is typically provided, as premature infants may be unable to digest nutrients enterally due to immature intestinal development and low digestive enzyme production. These infants are also prone to reflux, generalized GI dysmotility and delayed gastric emptying.8,21 These GI issues are particularly prevalent in infants who weigh less than 1500 g.4,21 Organized gut motility does not begin until 32 to 34 weeks gestation.25 PN is weaned slowly as EN and/or oral intake increases, so that overall the nutrient intake remains optimal during this transition.
tubes.27 There were no documented cases of NEC or intestinal perforation. Although the parenteral group achieved goal calories first (3.07 days 2.1 days for PN; 4.25 days 2.6 days for enteral), the benefits of EN far outweigh the risks of PN. Pettignano et al concluded that vasoactive drug infusions should not be considered a contraindication to enteral feeding.27
Access for Administering PN

Venous access is not defined by the initial point of entry, but by the position of the catheter tip. With central venous lines (CVL) the catheter tip terminates in the superior vena cava (SVC) or the right atrium of the heart. PN can be administered through a peripheral vein; however, the final osmolality is limited to 900 mOsm/kg to minimize risk of phlebitis and infiltration.29 To do this the dextrose concentration is limited to 10% to 12.5%; this means that the PPN requires a relatively large volume to supply adequate administration of nutrients. In the critically ill infant or child, nutrient requirements often cannot be met with PPN due to the fluid restriction. Adequate PN requires a CVL and allows for administration of a solution with a high osmolality (ie, > 900 mOsm/kg).
Congenital Heart Disease

In infants and children with congenital heart disease, PN may be used until tolerance to EN is established, especially postoperatively due to increased nutrient needs to support recovery.7 In addition to supporting postoperative recovery, the infant or child needs to be anabolic to promote growth; therefore nutrient requirements are especially high in the chronically ill infant and child with congenital heart disease.26 In patients who are receiving vasopressor medications (eg, dopamine, dobutamine, epinephrine), EN may be contraindicated, but this remains an area of controversy. 27 PN is occasionally needed to treat individuals with chyle leaks (ie, chylothorax, chylous effusion, chylous ascites, or chylopericardium) who do not respond to diets restricted in long-chain triglycerides (LCTs) and high in medium-chain triglycerides (MCTs).28 Because the lipids in PN go directly into the bloodstream and bypass the lymph system, they do not increase the volume of chyle produced.
Macronutrients
Parenterally, carbohydrates are administered in the form of dextrose, which provides 3.4 kcal/g. Protein is administered as a crystalline amino acid solution, which provides 4 kcal/g. Specialized amino acid solutions are available for infants and children; these include TrophAmine 6% and 10% (B.Braun), Premasol 6% and 10% (Baxter Healthcare), and Aminosyn-PF 7% and 10% (Hospira). These specialized solutions contain high concentrations of essential amino acids, including histadine and tyrosine; low concentrations of phenylalanine, methionine, and glycine; as well as glutamic acid, aspartic acid, taurine, and N-acetyl-Ltyrosine. The amino acid solutions for infants are designed to replicate plasma amino acids in breastfed infants. They also have a lower pH, which allows higher levels of calcium and phosphate to be added to the solution. Using a more concentrated amino acid solution allows for a smaller volume to be administered, which then allows for a greater volume to be allotted for other solutions (ie, dextrose), as well as electrolytes, minerals, trace elements, vitamins, and intravenous fat emulsion (IVFE). Using a less concentrated amino acid solution may sometimes be necessary because of the difficulty in measuring extremely small volumes of the more concentrated solutions. When an infant or child is severely fluid restricted, it may be difficult
Anorexia Nervosa
Severely malnourished patients with anorexia nervosa who require urgent nutrition rehabilitation may more readily accept PN than EN support. However, this is a last resort because PN is more expensive and carries increased risk for complications.7
Relative Indications for PN

Treatment with extracorporeal membrane oxygenation (ECMO) and use of vasopressor support may not be absolute contraindications to enteral feedings; however, many clinicians are hesitant to enterally feed infants and children with hemodynamic instability due to risk of bowel ischemia. Concerns about NEC and the possible effect of hypoxia on the gut during ECMO have led to the use of PN as the main source of nutrition support in pediatrics. However, a study was done in which infant subjects on ECMO received full-strength, continuous enteral feedings administered via either nasogastric or post-pyloric feeding
438
Table 34-2. Chart Comparing Various Pediatric Amino Acid Solutions
Comparison of Various Pediatric AA Solutions

Ten percent pediatric amino acid formulations Company Product Introduction date (FDA approval date) Amino acid content (gm/100mL) Essential amino acids Isoleucine Leucine Lysine (added as lysine acetate) Methionine Phenylalanine Threonine Tryptophan Valine Cysteine (as cysteine HCI H2O) Histidine Tyrosine (added as tyrosine and N-acetyl-L-tyrosine) Nonessential amino acids Alanine Arginine Proline Serine Glycine L-Aspartic acid L-Glutamic acid Taurine Sodium metabisulfite NF (as an antioxidant) pH adjusted with glacial acetic acid USP pH: Average and (range) Calc. osmolarity (mOsmol/L) Total amino acids (gm/L) Total nitrogen (gm/L) Protein equivalent (gm/L) Electrolytes (mEq/L) Sodium Acetate Chloride B. Braun (McGaw), Bethlehem, PA TrophAmine July 20, 1984 Hospira (Abbott), Abbott Park, IL Aminosyn PF Sept. 6, 1985 Baxter, Deerfield, IL PremaSol June 23, 2003
0.820 1.400 0.820 1.200 0.340 0.480 0.420 0.200 0.780 <0.016 <0.024 0.480 0.240 0.044 0.240 0.540 1.200 0.680 0.380 0.360 0.320 0.500 0.025 <0.050 5.5 (5.0-6.0) 875 100 15.5 97 5 97 <3
0.760 1.200 0.677 -0.180 0.427 0.512 0.180 0.673 --0.312 0.044 --0.698 1.227 0.812 0.495 0.385 0.527 0.820 0.070 0 5.5 (5.0-6.5) 788 100 15.2 100 None 46 None
0.820 1.400 0.820 -0.340 0.480 0.420 0.200 0.780 <0.016 -0.480 0.240 --0.540 1.200 0.680 0.380 0.360 0.320 0.500 0.025 0 5.5 (5.0-6.0) 865 100 15.5 --94 <3
Source: FDA, US Food and Drug Administration
Reprinted with permission from: Nieman Carney L. Neonatal Nutrition Support (CEU Self-Study Course), Nutrition Dimension, Ashland, OR. 2009.
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TABLE 34-3: Comparison of Selected Intravenous Fat Emulsions
Comparing of Comparison ofSelected SelectedIntravenous IntravenousFat Fat Emulsions Emulsions

Product and distributor Oil base Fatty acid content (%) Linoleic Oleic Palmitic Linolenic Stearic Calories/ml 10% 20% Egg yolk phospholipids (%) Glycerin (%) Osmolarity mOsm/L 10% 20% Intralipid 10% and 20% (Clintec) Soybean Liposyn II 10% and 20 % (Abbott) 50% Soybean and 50% safflower 65.8 17.7 8.8 4.2 3.4 1.1 2.0 1.2 2.5 276 258 Liposyn III 10% and 20% (Abbott) Soybean
50 26 10 9 3.5 1.1 2.0 1.2 2.25 260 260
54.5 22.4 10.5 8.3 4.2 1.1 2.0 1.2 2.5 284 292
Source: Drug facts and comparisons. 1998 ed. St. Louis: Wolters Kluwer Co. Source: Drug facts and Comparisons . 1998 ed. St. Louis: Wolters Kluwer Health.
Reprinted with permission from: Nieman Carney L. Neonatal Nutrition Support (CEU Self-Study Course), Nutrition Dimension, Ashland, OR. 2009.
to meet the estimated nutrient needs via PN due to the lack of a concentrated infant amino acid solution (ie, 15%). Research has shown a potential decrease in PN-associated cholestasis with the use of TrophAmine, as compared to Aminosyn- PF. 30 Another benefit of TrophAmine is that when L-cysteine is added, there is an increased solubility of calcium and phosphorus. TrophAmine is the only infant amino acid product available in the United States that has been utilized when conducting stability studies for the addition of cysteine to PN solutions. IVFE consists of either soybean oil or a combination of safflower and soybean oil. These products provide 10 kcal/g, regardless of the product concentration, and are available in 10% (1.1 kcal/mL), 20% (2 kcal/mL), and 30% concentrations. The 20% concentration is preferred over the 10% product because it allows adequate lipid intake in less volume. The 10% solution has a higher phospholipid/ triglyceride weight ratio than the 20% solution, and this higher ratio may affect the activity of lipoprotein lipase,
the primaryenzyme for lipid clearance, resulting in higher triglycerides and other plasma lipids in infants.22 In recent years some institutions have been utilizing 30% lipid solutions without adverse effects, but this is not a common practice. IVFE not only supplies a concentrated source of calories but also provides essential fatty acids (EFAs) for cell membrane integrity and brain development. IVFE also helps to prolong the integrity of peripheral lines because of their lower osmolality. It is crucial to provide infants and children a minimum amount of lipids (0.51 g/kg/d) to prevent essential fatty acid deficiency (EFAD). However, premature infants require at least 0.6 to 0.8 g/kg/d.1 EFAD was historically defined as a triene:tetraene ratio equal to or greater than 0.431; however, Mayo Clinical Laboratories recently developed a new set of standards for assessing the triene:tetraene ratio for various age groups, but this is only applicable if the test is run by its laboratory.
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Table 34-4 Recommendations for Initiation and Advancement of Parenteral Nutrition

Initiation Advance By Goals
Infants (< 1 y) Protein (g/kg/d) CHO (mg/kg/min) Fat (g/kg/d) Children (110 y) Protein (g/kg/d) CHO (mg/kg/min) Fat (g/kg/d) Adolescents Protein (g/kg/d) CHO (mg/kg/min) Fat (g/kg/d)
Preterm 1.53 57 12
Term 1.53 69 12
Preterm 1 12.5% dextrose per day 0.51
Term 1 12 or 2.55% dextrose per day 0.51
Preterm 34 812 (Max 1418) 33.5 (Max 0.17g/kg/hr) 1.53 810 23 0.82.5 56 12.5
Term 23 12 (Max 1418) 3 (Max 0.15g/ kg/hr)
12 10% dextrose 12 0.81.5 3.5 or 10% dextrose 1
1 5% dextrose per day 0.51 1 12 or 5% dextrose per day 1
Electrolytes
Close monitoring of electrolyte status is essential. In newborns, the addition of electrolytes to PN may be deferred until the second day of life in some cases. Potassium is generally added once normal kidney status and good urine output are established, and sodium is often added once diuresis begins.22 Daily adjustments to electrolyte intake are often necessary. Electrolyte requirements of preterm and full-term infants are generally similar, with the exception of calcium and phosphorus. Electrolytes are typically prescribed per kilogram in infants and younger children, and as units per day in larger children and adolescents.
Table 34-5 PN Electrolyte Dosing Guidelines*
Electrolyte Preterm Neonates Infants/ Children Adolescents & Children > 50kg
conditions, such as renal or hepatic disease, some may use custom trace elements.
Table 34-6 Comparison of MTE Products (quantity per 1 mL of solution)
Mineral Multitrace-4 Neonatal Multitrace-4 Pediatric Multitrace-5 Concentrate (Adolescent/ Adult)
Zinc (as Sulfate) Chromium (as Chloride) Selenium (as Selenious Acid) Copper (as Sulfate) Manganese (as Sulfate)
1.5 mg 0.85 mcg none 0.1 mg 25 mcg
1 mg 1 mcg none 0.1 mg 25 mcg
5 mg 10 mcg 60 mcg 1 mg 0.5 mg
Sodium Potassium Calcium Phosphorus Magnesium Acetate Chloride
2-5 mEq/k 2-5 mEq/k 1-2 mEq/kg 2-4 mEq/kg 2-4 mEq/kg 1-2 mEq/kg 0.5-4 mEq/k 10-20 mEq/d 2-4 mEq/kg 0.5-2 mmol/kg 10-40 mmol/d 1-2 mmol/kg 0.3-0.5 mEq/kg 0.3-0.5 mEq/kg 10-30 mEq/d As needed to maintain acid base-balance As needed to maintain acid base-balance
Source: American Regent Product Catalog http://www.americanregent.com/multiple_trace.html
*Assumes normal organ function and losses Reprinted with permission from Mirtallo J, Canada T, Johnson D, et al. Safe practices for parenteral nutrition. J Parenter Enteral Nutr. 2004;28(6):S-39S70.
Vitamins, Minerals, and Trace Elements

Standard infant and pediatric trace element commercial products are available. However, in cases of specific medical
Zinc is important for the maintenance of cell growth and development. When PN is supplemental to EN or of short duration, zinc is the only trace element that requires supplementation. Some conditions that require additional zinc intake include elevated urinary zinc excretion (eg, high-output renal failure) and increased GI excretion (eg, high-volume stool loss and fistula/stoma losses). Copper is an essential constituent of many enzymes. Current daily recommendations are adequate to prevent deficiency. Clinical manifestations of copper deficiency include hypochromic anemia that is unresponsive to iron therapy, neutropenia, and osteoporosis. Conditions requiring higher copper intake include increased biliary losses due to jejunostomy and losses via external biliary
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Table 34-7 Trace Element Requirements*

Trace Element Preterm Neonates < 3 kg (mcg/kg/d) Term Neonates 3-10 kg (mcg/kg/d) Children 10-40 kg (mcg/kg/d) Adolescents > 40 kg (per day)
Zinc Copper Manganese Chromium Selenium
400 20 1 0.05-0.2 1.5-2
50-250 20 1 0.2 2
50-125 5.0-20 1 0.14-0.2 1.0-2
2-5 mg 200-500 mg 40-100 mcg 5-15 mcg 40-60 mcg
*assumes normal organ function and losses In order to meet these trace element needs, one would need to use individual trace element products. Commercially available multi-trace element products would not meet these needs. Reprinted with permission from Mirtallo J, Canada T, Johnson D, et al. Safe practices for parenteral nutrition. J Parenter Enteral Nutr. 2004;28(6):S-39S70.
drainage. Historically, copper was withheld in PN for patients with cholestasis; however, cases of copper deficiency have recently been reported when copper was withheld in PN. 32 In patients with cholestasis, it is recommended to reduce supplementation by 50% of the amount typically provided for age, monitor serum copper levels and ceruloplasmin, and adjust supplementation accordingly. 33 Manganese is an important component of several enzymes. 34 Manganese deficiency has not been documented in humans. However, manganese toxicity has been reported. Manganese supplementation in PN should be withheld in patients with cholestasis or other liver function impairment. 34,35 Fok et al. provided evidence suggesting that high manganese intake contributes to the development of cholestasis. 35 Manganese should therefore be used with caution in PN provided to infants because they are more susceptible to cholestasis. 35 It is recommended to monitor serum manganese levels and adjust supplementation as needed. Selenium is a component of the enzyme glutathione peroxidase, which is involved in protecting cell membranes from peroxidase damage through detoxification of peroxides and free radicals. 34 Supplementation with selenium is recommended when a patient is on long-term PN (ie, longer than 1 month). It is recommended to decrease selenium intake when renal dysfunction is present. 33 Chromium potentiates the action of insulin and plays a role in glucose, protein, and lipid metabolism; therefore, chromium is essential for growth. 34 It is also recommended to decrease chromium intake with renal dysfunction. Molybdenum supplementation is recommended in cases when exclusive PN exceeds 4 weeks. Deficiency of molybdenum has not been reported in pediatrics; however, one adult case of deficiency has been documented. 34 Iodine is often omitted from PN since iodine-containing disinfectants and detergents are used on the skin and absorbed.
Iron supplementation should be considered only among long-term PN-dependent patients who are not receiving frequent blood transfusions. Monitoring iron status is imperative with iron supplementation as there is a risk of iron overload. 36 Parenteral vitamin products for infants and children (<11 years of age) have not been reformulated since their inception in the 1970s and 1980s.1 Currently available commercial products do not meet the vitamin needs of malnourished patients, those affected by renal or liver disease, premature infants, and children with SBS.1 Greene at al explored this issue in depth in 1998; however, new parenteral vitamin products intended for infants and younger children have yet to be released. 37
Table 34-8 Dosing Recommendations for Pediatric Parenteral Multiple Vitamins (MVI-Pediatric)*
Manufacturer Recommendations NAG-AMA Recommendations
Weight (kg) <1 3-Jan >3
Dose (mL) 1.5 3.25 5
Weight (kg) < 2.5 > 2.5
Dose (mL) 2 mL/kg 5 mL
*Assumes normal organ function Nutrition Advisory Group-American Medical Association
PN Additives: Heparin, Carnitine, and Cysteine

Heparin is added to PN solutions to reduce the formation of a fibrin sheath around the catheter and may reduce phlebitis and increases the duration of catheter patency. 22 Heparin also stimulates the release of lipoprotein lipase, which may improve lipid clearance. It is recommended to add heparin in units of 0.25 to 1/mL PN solution. 22 There is an increased risk of anti-coagulation with the higher doses of heparin. Carnitine is responsible for the transport of fatty acids into the mitochondria for oxidation. Carnitine deficiency
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results in impaired fatty acid oxidation and can present as hypertriglyceridemia. Carnitine synthesis and storage are not optimal at birth, when compared to older children and adults. Premature infants less than 34 weeks gestation receiving PN without carnitine can develop carnitine deficiency 6 to 10 days after birth. 38 Carnitor (Sigma-Tau Pharmaceuticals) is available for PN supplementation. An initial, safe dose to consider for infants on exclusive PN for more than 4 weeks is 8 to 10 mg/kg/d.22 A recent study revealed that parenteral supplementation of 20 mg/ kg/d carnitine resulted in plasma total carnitine concentrations that exceeded the reference range, which supports the use of smaller doses of carnitine supplementation. 39 It is recommended to monitor carnitine levels and titrate supplementation from 8 to 10 mg/kg/d, up to a maximum of 20 mg/kg/d. Cysteine, a conditionally essential amino acid, is not a component of crystalline amino acid solutions because it is unstable and will form an insoluble precipitate. 22 In adults, cysteine can be synthesized from methionine; however, preterm infants lack adequate hepatic cystathionase to facilitate this conversion. Commonly recommended dosing for L-cysteine hydrochloride is 40 mg per gram of amino acids. Current practice suggests supplementation with L-cysteine hydrochloride for the first year of life, although practice varies widely. 36 One benefit of the addition of L-cysteine hydrochloride to PN is the decrease in the pH of the solution, which increases the solubility of calcium and phosphorus. It should be noted though that the addition of cysteine to PN warrants close monitoring of acid-base status as it may increase risk for acidosis, and acetate may need to be added to the solution.
Monitoring
Prior to initiation of PN support, it is recommended to check the following biochemical indices: basic metabolic panel (BMP), calcium, magnesium, phosphorus, liver function tests (ie, Alk Phos, ALT, AST, GGT), total bilirubin, conjugated or direct bilirubin, prealbumin, albumin, and triglyceride. Following the initiation of PN the patients require close biochemical monitoring. The monitoring is then slowly decreased in frequency depending on the patients demonstration of stable parameters. Patients on long-term PN, such as those with SBS, need regular monitoring of vitamin and mineral status.
Aluminum in PN
It has come to light that various products utilized during PN compounding contain high levels of aluminum, which can be especially dangerous for infants and children. Preterm infants are extremely vulnerable to aluminum toxicity due to immature renal function and the likelihood for long-term PN. 36 As of July 2004, the Food and Drug Administration (FDA) mandated that products used in compounding PN should state the aluminum content on the label. The FDA identified 5 mcg/kg/d as the maximum amount of aluminum that can be safely tolerated and amounts exceeding this limit may be associated with central nervous system or bone toxicity. 36 It is essential for pharmacists, dietitians, physicians, and nurses to collaborate to minimize the use of higher aluminum content products. However, it is difficult to achieve the recommended aluminum intake level set by the FDA when patients are receiving multiple medications and PN. Providing PN is wrought with unique potential risks and complications and calls for a diligent interdisciplinary team approach. Initiating EN as soon as medically appropriate is the key to minimizing the potential adverse effects of PN support.
Complications of PN
Short-term potential adverse effects of PN include the following: infection, hyperglycemia, electrolyte abnormalities, disturbance of acid-base balance, hypertriglyceridemia, phlebitis, bacterial translocation, and compromised gut integrity. With long-term PN support adverse effects may include infection, PN-associated cholestasis, metabolic complications, disturbance of acid-base balance, osteopenia, risk of vitamin/mineral deficiency or toxicity, and continued risk of bacterial translocation. Nosocomial infections appear to result either from improper care of the catheter and/or frequent use of the catheter for purposes other than delivery of nutrients (eg, blood draws, medication administration).1
Feeding Teams
Pediatric feeding disorders are common, affecting 25% of typically developing children and up to 80% of developmentally delayed children.40 Prolonged feeding disorders have significant short- and long-term medical consequences, including poor growth and development, severe malnutrition, increased susceptibility to illness, and even death.40 Feeding disorders are often confused with eating disorders. The American Psychiatric Association has established criteria for the diagnosis of eating disorders, anorexia nervosa and bulimia, based on DSM-IV criteria that focuses on weight loss, attitudes and behaviors, and
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amenorrhea displayed by patients with eating disorders.41 Eating disorders are more commonly seen in older children with a dysmorphic body image; they do not eat because their focus is the intent to be thin. A feeding disorder has been defined as the inability or refusal to consume certain foods in sufficient quantity or variety to maintain normal growth.42,43 Generally, feeding disorders involve younger children whose intent is not centered on body image they refuse to eat due to lack of desire or lack of oral-motor skills.
Etiologies of Feeding Disorders

Feeding disorders have numerous causes, which are often inter-related. Organic, environmental, and behavioral issues can all adversely impact feeding. Organic factors can be categorized as those affecting the ability to eat, the desire to eat, and the developmental readiness to eat. The ability to eat is a complex process and there are many potential impediments to functional chewing and swallowing. The following are examples of organic causes of feeding disorders: anatomical defects, genetic disorders/ syndromes, and GI issues. Anatomic abnormalities within the oral cavity and airway include aspiration syndromes, micrognathia, cleft lip and palate, vocal cord paralysis (frequently as a complication of cardiac surgery), laryngomalacia, asthma, and Treacher-Collins Syndrome. Many syndromes and chromosomal abnormalities have a high risk for feeding difficulties. Examples include Trisomy 21, Williams syndrome, CHARGE syndrome, WAGR Syndrome, 22 q deletions, Trisomy 13, and Trisomy 18. Some gastroesophageal pathologies that impact feeding include tracheoesophageal fistula, esophageal strictures, malrotation, gastroesophageal reflux, esophagitis (including eosinophilic esophagitis), dysmotility, constipation, cystic fibrosis, and irritable bowel syndrome. Some conditions warrant interventions whose iatrogenic effects adversely impact the desire to eat. These may include side effects from some chemotherapeutic agents and medications for attention deficit hyperactivity disorder, or oral aversion after the prolonged intubation of premature infants. Supplemental tube feedings can also affect the desire to eat orally. Impaired developmental readiness to eat arises from developmental delays and sensory and oral-motor issues. These impact the ability to accept foods, advance textures, and eat in an ageappropriate manner, which is frequently seen in children on the autistic spectrum. Environmental factors impact feeding. The parent-child interaction around food creates the environment in which the child eats. Poor interactions during feeding may present
at any period in an infant or childs lifetime; if this occurs early in life there is an increased risk for long-lasting effects. Examples of inadequate parent-child interaction during feeding may include: a parent not looking at an infant or reading hunger cues during a bottle feeding, and feeding a meal to a toddler separate from the family.44 The familys cultural and religious beliefs surrounding food change how eating and weight is perceived. In addition, the ability to buy food, the quality of food available, and the feeding equipment within the home can impact the success of the feeding experience. Behavioral issues can stem from a combination of any of the aforementioned concerns. Internationally adopted children frequently have feeding issues likely related to the feeding conditions they experienced before adoption. A child with GI pathology may develop a learned avoidance and/or feeding-related anxiety, resulting in limited intake of volume and inconsistent acceptance. An infant who required prolonged intubation may have an oral aversion and food refusal. Patients with significant food allergies may refuse to eat foods to which they are not allergic. Parents who have difficulty setting limits can lose control of the meal and be unable to establish a consistent mealtime structure.
Table 34-9 Commonly Utilized Behavioral Strategies for Treating Feeding Disorders Offer liquids primarily between meals, and limit drinking during meals Encourage a structured and consistent schedule for 3 meals and2to 3 snacks daily Limit meals to 2030 minutes Eliminate grazing behavior on liquids and foods between meals Use a timer to have a child sit at the table for a finite period of time Offer foods on a divided plate Offer 1 new or non-preferred food with 1 to 2 preferred foods Continue to offer non-preferred foods in a positive way (as with all children, repeated exposure to new foods increases acceptance) Encourage exploration of a non-preferred food (touching to lips, touching with fingers) Establish a non-food reward system (for children older than 1215months) where positive behavior is praised and negative behavior is ignored Be as consistent as possible Encourage training and cooperation of all caregivers to support acohesive treatment approach Encourage family mealtimes Provide age-appropriate portions and developmentally appropriatetextures
Evaluation and Treatment of Feeding Disorders

Feeding disorders are best evaluated and treated by interdisciplinary teams with expertise in the complexities inherent
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Figure 34-1
to feeding disorders. Feeding teams usually include medical and behavioral health specialists, registered dietitians, and a variety of therapists and social support personnel. The medical team may consist of a physician (often with specialized training in gastroenterology, neurology, neonatology, otolaryngology, or child development), nurse practitioner, and/or registered nurse. The behavioral health practitioner is commonly a psychologist or family counselor, who may be aided by feeding therapists with training in psychology. The therapists may include occupational therapists, speech pathologists, physical therapists, and respiratory therapists. Social support personnel include social workers, case managers, and child life or recreational therapy specialists. The composition of the team varies by facility and by the needs of the patient (Figure 34-1). Services offered by feeding teams also vary by facility.
They range from an initial evaluation with referrals to outside therapists to intensive inpatient feeding therapy. At the initial evaluation, various members of the team interview the child and primary caregivers. The child undergoes a physical examination, and team members observe the child being fed and eating. The team then collaborates at the end of the evaluation to discuss their findings and synthesize family-centered goals and recommendations. Teams frequently refer patients to other sub-specialists and clinics for evaluation and/or treatment of feedingrelated medical issues if they cannot be addressed within the team setting. Some hospital-based teams offer additional services such as inpatient consults or diagnostic testing (eg, modified barium swallow study, gastrointestinal endoscopy). Most teams either provide or refer patients to outpatient
445
or home-based therapies including occupational, speech, nutrition, and individual or group psychological therapy. These services focus specifically on behavioral feeding issues, sensory processing difficulties, development of selffeeding skills, and oral-motor swallowing function. Therapy goals may include increasing a childs acceptance of a variety of foods, managing food refusal behaviors, texture progression (ie, smooth puree to lumpy puree to soft solids), and establishing developmentally appropriate manipulation of liquid and food. Therapists are also able to recommend adaptive equipment, if appropriate.
Table 34-10 Common Feeding Problems Excessive liquid intake, impeding acceptance of solid foods Grazing, unstructured meals/snacks Prolonged feeding time (> 30 minutes) Inadequate or immature oral-motor skills (unable to handle complex textures) Sensory integration issues (will only consume foods/liquids of one color and/or texture)
well as intensive programs, caregivers are typically present for follow-up appointments to monitor the childs progress, support the childs advancement towards long-term treatment goals, and engage with the team to address any questions or concerns. The frequency of follow-up is determined on an individualized basis.
Conclusion
Every child should be evaluated individually when determining the best way to provide optimal nutrition to promote growth and development. What works for one child and caregiver may not work for another. One must consider many factors when initiating nutrition support including, but not limited to, the patients baseline nutrition status, the functionality of the GI tract, access options, administration schedule, and modality. In pediatrics, one must consider the effect that the nutrition support regimen will have on the infant/child and the caregivers. It is essential to be flexible and supportive when working with caregivers to develop a nutrition plan of care that is best for their child and their lives.
Table 34-11 Nutrition Interventions for Children with Feeding Disorders Initiate a multivitamin with mineral (or age-appropriate vitamin supplement) Offer nutrient-dense snacks and increase the caloric concentration infoods (add butter/oils, modulars) Limit juice to 4-oz per day Recommend using pureed table food in place of jarred baby food toincrease caloric density Gradual increase of the thickness of the pureed food may help advance children with difficulty to advance to more complex textures Initiate nutrition supplementation, either orally or via enteral nutrition, if the patient is unable to sustain age-appropriate weightgain Initiate enteral nutrition immediately if the child is < 80% ideal bodyweight Adjust tube feeding regimen in conjunction with behavioral strategiesto increase oral acceptance
Eating is an integral part of our social interactions, and families can experience significant difficulty coping with the stress of caring for a child with a feeding disorder. Families are therefore commonly referred to support groups, where they may discuss building social supports, strategies for establishing mealtime structure at home, coping mechanisms for handling stress, and strategies for implementing behavior management. 43 For patients who require more intensive intervention, some teams offer outpatient day hospital treatment or inpatient treatment, which allow therapists to work with children at every meal and to monitor their nutrition and medical status closely. For outpatient evaluations and therapies, as
1. Which of the following are common behavioral strategies to address picky eating? A. Offer foods on a divided plate B. Offer 1 new or non-preferred food with 1 or 2 preferred foods C. Be consistent D. Encourage family mealtimes E. All of the above 2. All of the following findings may justify nutrition support in a toddler except: A. Height at the 25th percentile on the growth curve since infancy B. No weight gain for 4 months C. Decrease in 2 weight percentiles channels over the past 6 months D. Eats very slowly 3. A child with CF who has a very good appetite, yet is moderately underweight, should receive: A. PN in addition to oral feedings B. Tube feedings only C. No nutrition intervention D. Oral nutrition supplements in between meals See p. 487 for answers.
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37. Greene HL, Hambidge KM, Schanler R, Tsang RC. Guidelines for the use of vitamins, trace elements, calcium, magnesium, and phosphorus in infants and children receiving total parenteral nutrition: report of the Subcommittee on Pediatric Parenteral Nutrition Requirements from the Committee on Clinical Practice Issues of the American Society for Clinical Nutrition. Am J Clin Nutr. 1998;48(5);13241342. 38. Schmidt-Sommerfield E, Penn D, Wolf H. Carnitine blood concentrations and fat utilization in parenterally alimented premature newborn infants. J Pediatr. 1982;100:260. 39. Crill CM, et al. Relative bioavailability of carnitine supplementation in premature neonates. J Parenter Enteral Nutr. 2006; 30(5):421425. 40. Manikam R. Pediatric Feeding Disorders. J Clin Gastroenter. 2000;30(1):3446. 41. American Academy of Pediatrics. Identifying and treating eating disorders. Pediatr. 2003;111(1):204211. 42. Piazza C, Carrol-Hernendez T. Assessment and Treatment of Pediatric Feeding Disorders. Encyclopedia of Early Childhood Development; 2004. http://www.enfant-encyclopedie. com/Pages/PDF/Piazza-Carroll-HernandezANGxp.pdf. Accessed July 20, 2008.
43. Tobin S, Cheng V, Schumacher C, et al. The role of an interdisciplinary feeding team in the assessment and treatment of feeding problems. Building Block for Life. 2005;28(3):111. 44. Satter E. Child of Mine; Feeding with Love and Good Sense. Bull Publishing; 2000.
Additional Readings
Cloud HH. Recent trends in care of children with special needs: nutrition services for children with developmental disabilities and special health care needs. Topics in Clinical Nutrition. 2001;16(4). Puntis JWL. Specialist feeding clinics. Arch Dis Childhood. 2008;93:164167. Rudolph C, Link T. Feeding disorders in infants and children. Pediatr Clin North Am. 2002;49(1):97112, vi.
Implementation of the Plan

Beth Lyman, RN, MSN, Jennifer M. Colombo, MD, and Jodi L. Gamis, OTR
35
CONTENTS
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446 Parenteral Nutrition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
Type of Intravenous Catheter Needed Site Care Safety Issues Nursing Care Enteral Nutrition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enteral Route Selection Types of Tubes Tube Insertion Verification of Placement Bolus vs. Continuous Feeds. . . . . . . . . . . . . . . . . . . . . . . . Bolus Feedings Continuous Feedings Combination Feedings Initiation and Advancement of Feedings . . . . . . . . . . . . . Bolus Feedings Continuous Feedings Combination Feedings Safety Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Preparation Hang Time for Formula Feeding Pumps Nursing Care. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Securing the Tube Site Care Checking Residual Volumes Flushing the Tube Use of Sterile vs. Non-Sterile Water Reflux Aspiration Precautions Intake and Output Weights Assessment of Feeding Tolerance Medication Administration Oral Nutrition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Learning Objectives
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1. Evaluate the patient for specific issues that can impact the plan of care. 2. Implement an evidence-based nutrition plan of care that blends parenteral, enteral, and oral intake as appropriate for that patient. 3. Discern the key safety measures that are age appropriate and patient specific when implementing the nutrition plan of care.
Background
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Implementation of a nutrition plan of care may involve a combination of parenteral nutrition (PN), enteral nutrition (EN), or oral nutrition therapies in pediatric patients. Inorder to stimulate intestinal growth and adaptation, pediatric patients who require PN need some amount of EN, oral intake, or both. Depending on the patient-specific characteristics that have been discussed elsewhere, a balancing of PN nutrients with EN and/or oral intake is the accepted mode of intervention for most pediatric patients. Goals for each of these interventions are constantly redefined based on patient assessment by all involved health care providers and the parents (or caregivers). Clear communication of the plan and goals is essential for successful implementation of any nutrition support plan. These patients are medically complex and require close observation to accurately assess how they tolerate the interventions. For pediatric patients who receive nutrition support the goal of therapy is to first wean off of PN and on to full enteral feedings. Oral feeding is introduced as developmentally and physiologically appropriate. This careful balance of all 3 modalities requires skilled observation and evaluation by everyone involved with the patient.
IMPLEMENTATION OF THE PLAN
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Malnourished children need PN if they cannot tolerate or safely receive EN for > 3 days.1 Implementation of a nutrition care plan that involves PN begins with the goals of therapy and considers fluid status, appropriate intravenous (IV) access and nutrition needs, and anticipated length of therapy. Fluid status and PN solution composition is discussed previously (see Chapter 34). The anticipated length of therapy often dictates the IV access choice. Generally, the longer the need for PN, the more likely a patient will need a more permanent central vascular access device (VAD). In pediatrics, the use of peripheral parenteral nutrition (PPN) may be the initial nutrition intervention.
Type of Intravenous Catheter Needed

Neonatal and pediatric patients may receive a short course of PPN prior to the initiation of PN. Peripheral intravenous vein (PIV) selection is important in these patients. Avoidance of the antecubital fossa is recommended if peripherally inserted central catheter (PICC) placement is anticipated. PPN use is the most common cause of infiltration-related tissue necrosis in pre-term infants so diligent site assessment is crucial.2 Ideally, PIVs should not be placed in the scalp or feet of infants who receive PPN.2 One study documented an average of 2.2 attempts per PIV for PPN placement with an average duration of 2.19 days in neonates receiving PPN.3 Investigators recommended PICC placement as soon as possible.3 When PICC placement is needed for PPN, placement of the tip in the superior vena cava, right atrium, or inferior vena cava above the level of the diaphragm is recommended to prevent complications such as occlusion and leakage.4 Also, a PICC that has been in place for an extended period of time before being used for PN should have tip placement verified before use as this type of VAD is associated with a higher rate of malposition than other central venous catheters (CVCs). 5 Case reports in the literature document intracranial malpositioning resulting in seizures and stroke in pediatric patients who had a PICC for PN.6,7 As PICCs are the preferred VAD for neonates receiving PN, it is important to discern the best placement; ie, upper extremity (UE) versus lower extremity (LE). One retrospective study documented a preferred site placement of UE by nearly 3 to 1 with UE placement at an average of day of life (DOL) 6 compared to LE placement around DOL 8. This study found a significantly longer duration of usefulness for PICCs placed in the LE. There was also a lower incidence of coagulase-negative Staphylococcus (CoNS) in the LE group.8 Care should be taken in site selection for PICCs in neonates. The antecubital fossa or above is the preferred site for PICC placement in children.
PICCs should be secured to the skin. The use of sutures to secure a PICC has been documented to result in less migration, occlusion, and leakage when compared to the use of tape.9 However, sutures can become inflamed requiring removal. The use of an adhesive securement device has been shown to be easier to place and associated with fewer complications than sutures in pediatric patients.10 Critically ill children who require PN will typically have a temporary VAD placed via the subclavian or internal jugular veins. Reduction of bloodstream infections (BSIs) related to CVCs continues to be an ongoing focus in all health care settings, including critical care units. One approach has been to coat CVCs with antibiotics. This is controversial in pediatrics due to concerns of sensitization and development of drug resistance. One study using antibiotic-coated CVCs shows comparable infection rates but the antibiotic-coated CVCs were in place an average of 18 days compared to 5 days for the non-coated CVCs before infection occurred.11 Many critical care units advocate removal of a temporary CVC after 7 days. The use of antibiotic-coated CVCs in pediatric patients remains controversial. When it is clear long-term PN is needed for a patient, plans for the most appropriate VAD need to be made. A patient who will go home for up to 6 weeks of PN can often use the same PICC already in place. A surgically placed tunneled catheter is most often used for infants and children who require home PN for an extended period of time. Occasionally an implanted VAD is placed when intermittent PN or a few nights per week infusions are prescribed. This VAD has definite benefits for adolescents who are already struggling with body image issues. Once a CVC is in place for PN, it is also used to obtain lab specimens to avoid venipuncture. Vigorous cleaning of the injection cap prior to accessing the CVC is essential to prevent intraluminal contamination. The approaches to obtaining lab specimens are compared in Table 35-1. Two studies in the literature document the safe and reliable method of blood sampling involving repeated pushing and pulling of blood into an empty syringe before obtaining a specimen in a new syringe.12,13 Nursing should have options for specimen collection based on what is best for that patient. It is important for nursing staff to stop all infusions when using a multi-lumen catheter to assure accurate lab sample results. When the waste approach is used, one study does validate the safety of 3 mL versus 5 mL of waste when blood samples are obtained from a tunneled or implanted VAD.14 Regardless of the method used to obtain a blood specimen through a CVC, it is recommended to change the injection cap after every blood sample or within 24 hours.
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Table 35-1 Comparison of Techniques Used to Obtain Blood Samples from a VAD
Type of Technique Description Pros Cons
Traditional
Return the Waste
Push-Pull Method
1. Stop infusion 2. Flush VAD with NS 3. Obtain a waste specimen of 35 mL 4. Obtain blood needed for labs ordered 5. Flush VAD with NS 6. Restart infusion 1. Fill a syringe with heparin and remove it 2. Stop infusion 3. Flush VAD with NS 4. Obtain a waste specimen of 35 mL 5. Have a nurse rotate the waste specimen 6. Obtain blood needed for labs ordered 7. Return the waste specimen to the patient 8. Flush VAD with NS 9. Restart infusion 1. Stop infusion 2. Aspirate 35 mL of blood into a syringe 3. Reinfuse that blood and repeat the aspiration/ reinfuse procedure a total of 3 times 4. Place a new syringe on the VAD and obtain blood needed for ordered labs
Gold standard procedure at this time When done properly, low risk of infection associated with obtaining labs. Decreases the blood loss for the patient
Increases blood loss when doing frequent blood sampling Increases exposure of staff to blood Potential for confusing the waste syringe with the sample syringe Potential for reinfusion of blood clots Potential for contamination of blood being reinfused
Limits patient blood loss from blood sampling
Potential for hemolysis due to turbulence created by the pushing and pulling May not be feasible for some VADs that are difficult to drawfrom
Site Care
Once the CVC is in place, routine skin disinfection and dressing changes are necessary. In 2002, the Guidelines for the Prevention of Intravascular Catheter Infections recommended the use of chlorhexidine gluconate (ChloraprepTM ) for skin antisepsis for all patients over the age of 7 days or 26 weeks gestation.15 Since that time, this product has become the standard antiseptic used for routine VAD dressing change skin antisepsis in this country. It is generally well tolerated. Transparent dressings that are replaced every 7 days or when loose or soiled are the dressing of choice over gauze and tape as the insertion site can easily be inspected. A trial of chlorhexidine gluconate-impregnated dressings (BiopatchTM) in neonates resulted in contact dermatitis making it not recommended for use in this population.16 Another key aspect of the dressing is to place a stress loop in the VAD if it is tunneled or in the extension tubing and tape to provide another method to prevent accidental dislodgement of the CVC.
Safety Issues
BSIs related to the CVC are known to be associated with an increase in cholestasis in infants on PN.17 Therefore, many measures must be in place to assure adequate infection control processes to prevent CVC-related BSIs. Table 35-2
summarizes these recommendations. Aside from institution processes to safeguard the patient, individual patients will require infection prevention measures as well. Attempts must be made to prevent contamination of the catheter hub by draining gastrostomy tubes, a leaking ostomy bag, or other body fluids. Babies who are teething need to have a pacifier to prevent them from sucking on their IV tubing. Children who are suspected or known to be self-destructive should be carefully monitored. Siblings need to be supervised when visiting their brother or sister. For children who have a parent in the room at all times monitoring of the parent and any activity with the CVC is warranted. Parents should not be allowed to access or care for a CVC unless specifically trained to do so and only with the permission of the nurse. One of many reports in the literature described the use of a CVC by parents with Munchausen Syndrome by Proxy.18 This condition is now referred to as Pediatric Condition Falsification which is a form of child abuse where the caregiver is the perpetrator. Because this condition can be life threatening for the child, any suspicion of this condition needs to be addressed prior to placement of a CVC for PN. While this condition is difficult to prove, certain typical behaviors seen in the caregivers include doctor shopping to different health care facilities, discrepancy between reported symptoms and
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Table 35-2 Prevention of CVC-Related Bloodstream Infections

Aspect of Care Action
Hand Hygiene Catheter Insertion
Catheter Accessing
Catheter Dressing Changes
Diagnosis of BSI
IV Tubing Changes Other
Use an antiseptic skin soap to wash hands before placing or accessing a VAD or use an alcohol-based hand sanitizer. Staff involved in CVC placement must be competent to do this procedure. Use maximal sterile barriers including masks, gowns, drapes, sterile gloves, and a kit with all needed supplies. Allow nursing to call a time out for an observed break in sterile technique. Avoid placement of a CVC in a febrile patient. Avoid guidewire replacement of a CVC. Vigorously clean the hub of the catheter with 70% alcohol or chlorhexidine wipes before entering the line. Have a policy on routine injection cap changes. Avoid stopcocks on CVCs. Use sterile, prefilled syringes for CVC flushing. Limit accessing for labs to 1 time per day if possible. Use a kit with all supplies needed. Use ChloraprepTM as preferred skin disinfectant. Use a mask and gown for PICC dressings. Use a transparent dressing preferentially over a gauze and tape dressing to allow for the site to be assessed. Restrain the patient as needed to prevent accidental dislodgement. Place a stress loop in the VAD tubing or extension tubing. Obtain a peripheral and central blood culture. Staff obtaining blood cultures should be specially trained and competent to avoid contamination. Draw a minimum of 1mL for the blood culture. Use clinical and other labs to validate diagnosis. Do not necessarily remove the CVC. Lipidsevery 24 h PNevery 72 h unless a 3-1 solution, then every 24 h or if cycled off a few hours/day Evaluate all supplies used on CVCs for defects that could lead to infections. When using outside pharmacies, surveillance of possible IV fluid related infections is needed. Have a surveillance plan within the institution to trend infections and look for a root cause.
what is observed, caregiver reluctance to leave the child and to allow others to provide care, and overzealous attachment to certain healthcare providers.19
Enteral Nutrition
Enteral Route Selection
Enteral nutrition should be considered in all children with an intact and functional gastrointestinal (GI) tract who can not take in enough calories orally to meet their needs for growth and development. Ideally a multidisciplinary team including a pediatric physician, a nurse, a dietitian, a speech therapist, and/or an occupational therapist should assess each patient and develop a feeding plan. Balancing caloric needs with the childs ability to digest and absorb nutrients is a dynamic process that may necessitate low rates of EN via feeding tube. Once a clearly identified indication for enteral tube feeding has been established, several ways to administer EN exist. Enteral access can be obtained through a nasogastric
Nursing Care
In addition to prevention of VAD-related infections, the nursing care of a child requiring PN is extensive. Table 35-3 summarizes the nursing activities required when taking care of a child who requires PN. Most hospitals and other care settings require competencies in the areas of CVC dressing changes, obtaining lab specimens, and appropriate flushing, etc. Meticulous nursing care for any patient receiving PN is absolutely essential in the pediatric care setting.
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Table 35-3 Nursing Care of the Patient Requiring PN

Action Frequency
Weigh patient using the same scale Weigh babies nude Assure the competency of staff who weigh patients Repeat any weight that is clearly aberrant Vital signs Notify physician for temp > 38.5C Monitor intake and output Note stool/ostomy output and notify physician for excessive losses Assess CVC site Assure the CVC is secure Flush the CVC with the appropriate amount of NS and Heparin if TPN cycled off a few hours/day Only use the appropriate concentration of heparin if needed for pt Change injection cap Shower or bathe patient with consideration for the safety of the CVC Assure the safety of the CVC as age appropriate Infuse the PN as orderedmatch the order with the bag Double check the pump settings to assure the PN is infusing as ordered If the CVC comes out or becomes dysfunctional, contact the physician for orders for dextrose-containing solution Monitor lab results and redraw when results look contaminated by PN Monitor blood glucose Promote normal growth and development of the patient
Daily at approximately the same time. As needed As needed As needed but usually at least every 12 h Every shift and as needed At least every 4 h and more often if warranted At least every 4 h and more often if warranted After every interruption in TPN As needed Within 24 h of drawing blood and per hospital policy Daily At all times Daily Hourly As needed As needed Per hospital policy Ongoing
tube, orogastric tube, gastrostomy tube, nasoduodenal tube, nasojenunal tube, gastro-jejunostomy, and jejunostomy. The choice of access is dependent on several factors (described below) and should be made with the guidance of the multidisciplinary team.20 The family and the older child should be involved in the decision-making process to ease potential fears and concerns related to providing EN and to improve compliance. The expected duration of therapy for EN is key in selecting the most appropriate feeding tube. A child expected to require EN for less than 3 months should have a temporary means of providing formula, such as a nasogastric tube, nasoduodenal tube, or an orogastric tube. More permanent access should be considered in a child requiring enteral formula for greater than 3 months. Anatomic abnormalities of the GI tract may dictate the most appropriate feeding tube for the patient, especially if there are known strictures. The GI tract should be free of an obstruction that would impede normal movement of enteral nutrients. There should be appropriate length to allow for digestion and absorption of nutrients. Proper functioning of the GI tract is necessary for successful administration of EN. Feeding directly into the stomach is preferred as it provides a more normal physiological process, digestively and hormonally. Delayed gastric
emptying or severe gastroesophageal reflux will impair tolerance. Bypassing the stomach by way of nasoduodenal, nasojejunal, gastrojejunal, or direct jejunal feedings may be necessary at times. The last factor that should be considered is aspiration risk. Any patient with a potential risk of aspiration should be evaluated. Preventive measures, such as bypassing the stomach by using nasoduodenal, nasojejunal, gastrojejunal, or jejunal tubes, or by operative fundoplication should be considered by the healthcare team.
Types of Tubes
Nasogastric Tube Nasogastric (NG) tubes are indicated for children who have an intact and functional GI tract and will only require enteral formula for a short period of time. These patients should have minimal gastroesophageal reflux, normal gastric emptying, and low risk of aspiration.20 NG tubes are soft flexible tubes made of Silastic or polyurethane ranging in size from 5 Fr. to 12 Fr. The tube size is chosen based on the patients age, size, and type of formula needed. Small-diameter tubes are more comfortable for the patient, but can become clogged, particularly if the patient receives fiber-containing formula or additives to the formula.
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Nasogastic tubes can be easily placed by the family. However, they can be dislodged as well, especially by an active or agitated child. NG tubes should be replaced or changed every 30 days. Children with NG tubes can be encouraged to eat orally while receiving NG tube feedings. Orogastric Tube Orogastric (OG) tubes are not used as frequently because they restrict oral feedings. Orogastric tubes are most useful in infants to avoid nasal obstruction or in children where an NG tube cannot be passed (ie, choanal atresia). Nasojejunal Tube Nasojejunal (NJ) tubes are similar to NG tubes, but longer for passage through the pylorus, duodenum, and into the jejunum. Nasojejunal tubes are necessary when there is delayed gastric emptying, severe gastroesophageal reflux, or risk of aspiration.20 These tubes are challenging to place and require either a skilled nurse, gastroenterologist, or interventional radiologist to place. They can migrate back into the stomach or duodenum or clog with thickened formulas or medication administered in the tube. Feeding tubes in the small bowel must be given as continuous drips since the reservoir function of the stomach is bypassed. Gastrostomy Tube Gastrostomy (G) tubes or buttons are a more permanent way of administering EN, and are recommended for any child who requires long term (greater than 3 months) EN.20 Formula is directly administered into the stomach similar to an NG tube. These tubes can be placed either endoscopically or surgically. The gastrostomy tube size is usually 14 Fr. to 24 Fr.; however, smaller and larger tubes are available. Gastrostomies are soft pliable devices made of silicone or polyurethane. They are less noticeable to the general public, which is important to some patients and families. The primary gastrostomy may be a G-tube or primary placement G-button. Once the gastrostomy tract has matured (in 2 to 3 months), the gastrotomy may be replaced with a low-profile, skin-level device (Mickey button) that the caregivers can change themselves. Gastrojejunostomy Tube Gastrojejunostomy (GJ) tubes are also permanent tubes that are inserted into the wall of the stomach similar to a G-tube; however, there are two ports: one into the stomach for fluids, medication, and venting and the other into the jejunum. They are recommended for patients who require long-term EN and who cannot tolerate feedings into their
stomach because of delayed gastric emptying, gastroesophageal reflux, or risk of aspiration.20 These must be administered as continuous drip feedings. Jejunostomy Tube Jejunostomy (J) tubes are surgically placed jejunal tubes. These tubes can be inserted directly into the jejunum endoscopically or surgically. Typically, they are used in patients who will require enteral nutrition access for the small bowel for more than 6 months.20 The negative side to jejunostomy tube use includes mandatory continuous feedings as well as surgical emergencies (volvulus) around the tube.
Tube Insertion
Most NG tubes are placed at the bedside. An attempt is made to make the child as comfortable as possible. An infant or young child should be swaddled for comfort and to prevent their arms from flailing about during tube insertion. The cervical spine of the child should be slightly flexed and not hyperextended.21 A small amount of lubricant is applied to the tip of the tube or water may be used. The tip is inserted into a nostril and then slid carefully down the nasopharynx, oropharynx, esophagus, and into the stomach. It is then secured into place at the nares. Parents are taught the technique of inserting NG tubes so the tubes can be replaced at home when necessary. Nasojejunal tubes are inserted in a similar manner; however, they usually require the assistance of radiology or fluoroscopy for accurate placement or confirmation. These tubes cannot be replaced at home. If the tube migrates back into the stomach, it must be replaced. Gastrostomy tubes, gastrojejunostomy tubes, and jejunostomy tubes must be placed endoscopically by a pediatric gastroenterologist, radiologist, or by a pediatric surgeon. If a tube is dislodged, families should be instructed to insert a replacement tube or temporary tube in the tract immediately to avoid premature closure of the tract until a more permanent tube can be replaced.
Verification of Placement
Verifying correct placement of an enteral tube is imperative prior to administering enteral formula. A tube accidentally inserted into the respiratory tract will certainly have disastrous or even deadly consequences. Radiology A chest and abdominal x-ray which identifies the length of the tube is the gold standard for confirming placement. The tip of the feeding tube can be seen within the stomach or
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jejunum. There is concern regarding increasing exposure to X-rays, and alternative methods have been used to confirm placement of feeding tubes.22 Air Insufflation Air is pushed through an NG tube using a syringe, with auscultation over the patients left upper quadrant. If the air bolus is heard in the left upper quadrant, then placement is thought to be in the stomach. This method is inexpensive, but is also the least sensitive. Air pushed into a feeding tube that is mistakenly placed in the thoracic cavity can be heard in the abdomen. 23 Many case reports describe the inability of clinicians to determine gastric versus respiratory placement.22 Gastric Aspirate/pH Testing Aspirating gastric contents and confirming pH is an alternative to the gold standard radiograph and is the recommended bedside method to confirm NG placement. 22,23 The Childrens Hospital in Boston recommends use of gastric pH performed at the bedside. Correct placement may be confirmed if the gastric pH measures less than 5. The use of medications for acid suppression is widely used in pediatrics and would invalidate the confirmation of placement. Delivery of feeds, time of last feed, and medications also impact gastric pH. If the gastric pH is greater than 5, gastric aspirate cannot be obtained, the patient clinically deteriorates during placement, or develops low oxygen saturation, an x-ray would be necessary to confirm placement.24 Colorimetric CO2 Detector The colorimetric CO2 detector was initially used to determine placement of an endotracheal tube within the trachea. It has been used in adults to assess appropriate feeding tube placement. Unfortunately, there are no published studies in children regarding the reliability and validity of colorimetric CO2 detectors verifying placement of enteral feeding tubes.25 Electromagnetic Tube Placement The Cortrak SystemTM assists with feeding tube placement by displaying the approximate location of the feeding tube during real-time placement. This system uses feeding tubes with a specialized stylet that has an electromagnetic transmitter. A receiver unit is placed on the patients xiphoid process and acquires the signal from the stylet. It tracks the course of the stylet as the feeding tube is inserted and displays it on a monitor. Pediatric patients who can tolerate an 8 Fr. or larger feeding tubes are candidates for this device.25
Bolus vs. Continuous Feeds
Enteral formulas can be given through bolus feedings, continuous feedings, or a combination of both depending on a number of factors. These factors include the childs condition and nutrition status, anatomy, type of tube selected, indication for tube feedings, and family schedule. It is important to consider family lifestyle when implementing a feeding plan. The goal is to maximize the benefit of enteral feeding while minimizing the complexity of nutrition support.
Bolus Feedings
Bolus feedings imitate regular mealtimes and, therefore, are more physiologic compared to continuous feedings. A feeding schedule is determined by a dietitian and pediatric physician depending on the childs caloric and fluid requirements. Bolus feedings can only be administered into the stomach and should never be administered past the pylorus. Formula can be administered by gravity or over a pre-determined period of time by a feeding pump. Bolus feedings are often more convenient for the patient and family because the schedule is more flexible and the child is not tethered to an infusion pump.
Continuous Feedings
Continuous feedings are infusions of enteral formula over time. Patients, who cannot tolerate large volumes because of delayed gastric emptying, GERD, or dumping syndrome, are given slow continuous feeds. The continuous feedings are generally smaller volumes infused slowly. A feeding pump is required for these infusions which may limit the childs ability to move. For ambulatory patients, there are smaller feeding pumps that can be carried in a backpack allowing for more flexibility and mobility.
Combination Feedings
Combination feedings are ideal for patients who need a significant amount of calories but cannot tolerate large volumes. Smaller bolus feedings can be given during the day and the remainder can be administered continuously overnight. This method also allows the child and parents to sleep at night.21
Initiation and Advancement of Feedings
Enteral feedings are often started in a hospital to observe feeding tolerance and monitor for complications. A feeding schedule is designed by the health care team which may include a dietitian, attending physician, and an occupational therapist, and a GI nurse. The family receives support and reassurance during the hospitalization from all members
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of the team. The family learns about the formula, feeding schedule, enteral device, and safety concerns regarding feedings. Choice of formula is discussed in other chapters. Fullstrength formula should be used. There is no need to dilute the formula for initiation or advancement of feedings.21 For neurologically intact children, it is important to encourage the child to eat orally to maintain oral motor skills. If oral feeding cannot be done, a referral for occupational therapy is warranted for oral stimulation while receiving enteral feeding.
Daytime feedings are compressed by 1 to 2 hours each day until the desired number of boluses is given (3 to 4 hours apart). Boluses may be given over 30 to 60 minutes if intolerance presents.
Safety Issues
Preparation
Formula should be prepared by personnel and family members who are trained to prepare formula in a clean environment.21 Good hand washing is imperative prior to preparation.21 The warm and nutrient-rich environment of enteral formulas promote the growth of bacteria. Using appropriate handling, hygiene, and adherence to guidelines for hang time will prevent most episodes of contamination.26 Ready-to-feed and formulas from liquid concentrate are and should remain sterile; however, bacteria and other micro-organisms can populate rapidly if the right conditions are met. Powdered, reconstituted formulas or those with additives tend to grow more bacteria and therefore require meticulous attention to principles of aseptic technique in the preparation and administration of the formula. 21
Bolus Feedings
The total calculated volume of formula is based on the childs caloric needs and requirements. This volume is divided into 6 to 8 boluses. It is recommended to give 25% of the childs caloric needs on day 1 and advance by 25% each day until the final caloric goal is achieved.21 The child is monitored closely for tolerance to the increased volume. Signs of intolerance include vomiting, abdominal distention, or pain. Bolus feedings are given over 15 to 20 minutes, however, longer times may be required. Once the child is doing well with the initial feeding schedule and is meeting the caloric goal, boluses can be compressed to 4 to 6 feedings. This allows for ease and flexibility of administration by the family at home. Again, the child is monitored for tolerance during this transition. Boluses may need to be given more frequently in infants or children who have metabolic disorders or increased caloric needs (ie, burns, catch-up growth).
Hang Time for Formula

Contamination of enteral formula can occur at any time, even after it is prepared and placed in a container or bag and ready to be given to the child. Hang time refers to the length of the time that the formula flows through an administration set. During this time, it is possible for bacteria to populate and contaminate the formula. Because bolus feedings are usually administered within 1 hour and have a lower risk of contamination, hang time usually refers to a continuous or overnight feeding. Liquids in an open system, human breast milk, and powdered formula that is reconstituted should not hang for more than 4 hours. Sterile, ready-to-feed formula may hang for up to 8 hours. Liquid formula in a closed system can be safely hung for 24 hours.21,27
Continuous Feedings
It is recommended to start continuous feedings at 1 to 2 mL/kg/h for 24 hours and increase by 0.5 to 1 mL/kg/h every 8 to 12 hours until the final caloric goal is met. 22 When the final goal is achieved, compressing the feeding into a shorter time interval should be considered so the child can have a few hours each day free from the feeding tube. Generally 16 to 18 hours each day should enable a full daily caloric requirement. The child is monitored closely for tolerance to each increase in volume and during compression of feedings.
Feeding Pumps
Feeding pumps are useful for delivering continuous feedings or slower infusions for bolus feedings. Some feeding pumps are small enough to be worn in a small backpack for ease of mobility and flexibility of schedules. The ideal pediatric pump is not position sensitive, can be increased in increments of 0.1 mL up to 5 mL/h, and is relatively light weight. Providers and caregivers need to be aware that enteral feeding pumps are not free of malfunctions.
Combination Feedings
When a child cannot tolerate large volumes of bolus feedings, combination feedings should be considered. The total daily caloric requirement is divided between 3 to 4 smaller bolus feedings during the day followed by a continuous infusion overnight. This can be accomplished starting with continuous feedings and working up to the caloric goal.
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Most manufacturers of feeding equipment and pumps have safeguards in place to prevent flow errors. Pumps should accurately administer formula within 5% of the ordered amount. Periodic calibration of the pump is important to ensure the accuracy of the delivery system.21
Checking Residual Volumes

It is not recommended to check residual volumes as there is much debate over their significance. Intolerance to feedings is demonstrated by mood (ie, fussy or irritable), vomiting, retching, or abdominal distention. Residuals are influenced by enteral formulation, gastric emptying, gastroesophageal reflux, respiratory embarrassment, timing of measurement in relation to feed, and delivery method. Residuals that are collected should be re-fed to the patient as this can be a significant source of calorie loss.
Nursing Care
Securing the Tube
Nasoenteric tubes can easily be pulled out of the nose by an infant or a child tugging on the tube, sneezing, or vomiting. To prevent dislodgement, the tube is secured in place on the childs face. It is recommended to fix the excess tubing to the back of the infants or childs shirt (ie, with a tape tab and safety pin). This helps to keep the tube out of sight and prevents the child from grabbing it. Transparent dressing is usually applied to the cheek on the same side of the face as the nasoenteric tube. The enteral tube is inserted as described previously. The portion of the tube that remains outside the body is laid across the DuodermTM and then a transparent dressing is applied over the tube and Duo-dermTM securing the tube to the face. This method protects the childs skin from harsh adhesive tape that may tear the skin.28 J tubes, G tubes, and low-profile skin-level G buttons can also be pulled out by the child, although it is less likely. Most types of permanent feeding devices have an internal retaining device which may be a collapsible rubber stopper or a water-filled balloon. Many permanent feeding devices also have an external retaining device. A similar technique can be used to secure a G or J tube to the childs stomach. There are commercially available products to help keep some tubes in place.
Flushing the Tube

In general, routine flushing of enteral tubes after each bolus feeding or interrupting continuous feeding for water flushes is not recommended in children.21 If a tube becomes clogged, water is readily available and is the preferred flushing solution. Sterile or purified water is preferred over tap water when flushing the tube.21 It is important to take the childs age into account when flushing an enteral feeding tube with water. Immature kidneys cannot remove excess water and too much free water can dilute normal sodium levels causing hyponatremia. Hyponatremia may promote complications (eg, seizures). Typically, 3 to 5 mL is enough to flush an NG tube in children. Smaller volumes may be used in premature and smaller infants.
Use of Sterile vs. Non-Sterile Water

It is generally recommended to use sterile or purified water when preparing formulas for infants or immunocompromised children.26
Reflux
Severe gastroesophageal reflux may be an indication for enteral tube feeding when frequent emesis results in food refusal and failure to thrive. Gastroesophageal reflux can be frustrating and anxiety provoking for both the child and caregivers. Frequent episodes of emesis are a source of calorie loss in young children. Reflux can worsen with enteral tube feedings. Children are unable to self-limit their intake. Their stomach may not be able to accommodate their goal volumes. Also, in older children, the diet is changed from relatively thickened or solid feeds to liquid formula, which can predispose them to more reflux.20 Worsening reflux may be a sign of intolerance to a feeding schedule or formula. Sepsis, respiratory embarrassment, or metabolic abnormalities have an impact on the number of reflux episodes.
Site Care
Keeping the site clean and dry is the most important aspect of caring for an enteral feeding tube. Washing the nose and face with mild soap and water daily is enough to keep the nasoenteric tubes clean. Ostomy sites should be monitored for cleanliness daily. Mild soap and water is enough to keep these sites clean, gently scrubbing off any crusted areas. A 22 gauze dressing that is cut half way through can be placed between the device and the skin to keep the ostomy site dry if there is some leakage. For the most part, a dressing is not required. Antibiotic ointment may be needed if the site becomes erythematous or tender. Caregivers are taught to apply the ointment for up to 3 days and if the symptoms persist, a physician should be contacted.
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The cause and extent of GERD affects nutrition management. Common tests in the evaluation include an esophagram, upper GI study, pH/impedance probe study, or esophagogastroduodenoscopy with biopsies. Changing the enteral formula, slowing the rate of the bolus feedings, or changing to continuous feedings may need to be considered. Medications to treat reflux such as H2 blockers or proton pump inhibitors may be prescribed. If delayed gastric emptying is the cause for increased reflux, prokinetic medications, changing formula, or post-pyloric feeding may be considered.20 If all other methods have failed, a surgical consultation for fundoplication procedure or JT may be necessary.
patterns of the child and be able to discuss them with the multidisciplinary team at follow-up visits. For patients with ostomies, ostomy output should be recorded and a contact given if that amount is exceeded.
Weights
Weights should be monitored daily during the initiation and advancement phases of a feeding plan. The infant or child should be weighed without clothing and on the same scale every day at the same time. Ostomy bags should be emptied just prior to the weight measurement. Individual weights are less important than an overall weight trend. Monitoring a childs weight at every follow-up visit ensures that the child is receiving appropriate calories for growth. If the child fails to gain weight or loses weight, healthcare providers should investigate any potential sources of calorie loss.
Aspiration Precautions
Infants and children lying flat are at increased of refluxing and aspirating. It is important to position the infant or child in a manner to prevent aspiration episodes with the head of the child elevated at least 30 while receiving a feed.20,21 It may also be necessary to feed the child at risk for aspiration transpylorically.
Assessment of Feeding Tolerance

Successful enteral nutrition will allow a child to grow in both weight and length without significant distress. Tolerance to a feeding plan should be assessed during initiation, advancement, and maintenance of feedings. Any issues with feeding intolerance should be addressed early to minimize interruption of nutrition support. Monitoring parameters that should be assessed routinely include vital signs, intake and output, daily weights, enteral access, and physical exam with close attention to abdominal assessment. Laboratory assessment including electrolytes, glucose, calcium, magnesium, and phosphorus should be obtained prior to initiating enteral nutrition. They may need to be monitored frequently until they are stable, especially in the severely malnourished child at risk for refeeding syndrome.21 Parents and caregivers should be made aware of the signs and symptoms of feeding intolerance so that they may seek medical attention in a timely manner. Signs and symptoms of feeding intolerance include changes in mood or behavior (ie, fussiness during feeds), coughing, choking, retching, abdominal distention, vomiting, or diarrhea. Modifications to the feeding plan can be made to decrease these problems.
Intake and Output

During the initiation and advancement of enteral feeding, intake and output should be measured frequently, accurately, and recorded for each 24-hour period. This information helps monitor the childs caloric adequacy and fluid balance, and assists the multidisciplinary teams decision making regarding needed changes to the nutrition plan. Intake should be documented as both oral and enteral feeding. Caregivers should record the name and the amount that was given. They also should include if the feeding was held or for medications or intolerance, or decreased. Output can be in the form of vomiting, voiding, and elimination. A normal voiding pattern ensures that the child is receiving enough fluid and that the childs kidneys are functioning properly. A normal stooling pattern indicates that the child is tolerating the feedings and likely absorbing the appropriate macro- and micronutrients. Patients with an ostomy should have written parameters for when to call the physician. Diarrhea is a cause for concern as it is source of significant fluid and calorie loss. Maintaining a strict intake and output diary can be challenging especially for the family at home. When the child is tolerating maintenance or caloric goal feeds, monitoring of intake and output can be more flexible. The parents or caregivers should note modifications to the feeding schedule, episodes of vomiting, or changes in the voiding or stooling
Medication Administration
Enteral feeding tubes can be utilized for medication administration. Some medications can be given via enteral tube easily (eg, liquid suspension or solution, crushed solid tablets, and capsules). More complex formulations including extended or sustained released products are problematic.
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Liquid forms of medications are preferred. Some solutions and suspensions may be too viscous or thick to safely put through an enteral tube. These medications must be diluted with sterile water. Suspensions must be shaken thoroughly prior to administration.21 Improper administration can lead to inaccurate medication provision. Medications in the solid form such as tablets or capsules must be crushed or opened and mixed with purified water prior to administering through an enteral feeding tube. It is important to mix the medication well to prevent underdosing or overdosing of the prescribed medication. After administering medications through an enteral feeding tube, the tube must be flushed with purified water to prevent the feeding tube from being clogged and to ensure that the entire dose of medication is given to the child. Caregivers should be aware of what medication is being administered and where the medication is being administered. Certain medications including vitamins and minerals require activation in the stomach or are predominantly absorbed in the upper small intestine. Medications that alter gastric pH may also affect the activity of concomitant medications. A consultation with a pharmacist is warranted when deciding to give medications through an NJ tube or a GJ tube as these tubes bypass the stomach and upper small intestine altogether. A pharmacist will also provide information regarding medication compatibility if the decision is made to add the medication directly to an enteral formula.21
Table 35-4 Weaning Off Tube Feedings Using spoon foods, baby foods, or blenderized table food aim for 12 bites swallowed with no vomiting. Increase bite amount if reaching goal 75% of the time, about every 34 days Once 10 bites achieved per meal, go to amounts/quantity. Taking 14 oz per meal consumed, start tube reduction Reduce the tube feeding early in the day to benefit meals. Reduce the bedtime/evening tube feedings last. Continue to advance oral motor and oral sensory but not at mealtimes. Begin activating chewing skills while continuing to spoon feed Introduce cup and straw. When swallowing of chewables is established, offer finger foods at each meal before the spoon feeding. Offer liquid by cup or straw throughout the meal but do not leave on the tray. Naked weights will be needed monthly. This will help determine tube reduction. Reduce 48 oz depending on weight gain/loss. Increase finger foods as skill allows. Add water to tube feedings as needed during reduction. Need 23 months of normal growth without tube use before removing the tube.
Oral Nutrition
A patient is ready to have the tube feedings reduced when he or she can tolerate the amount of calories needed for growth. In transition off tube feeds, it is typical for the child to receive more bolus feedings and to get those feedings in 30 minutes or less. An established meal schedule offered before bolus feedings provides the opportunity to eat orally before tube feeds. Table 35-4 is an example of a tube weaning program. The goal of tube reduction should not be to just get off the tube but to be able to eat a variety of age-appropriate foods with age-appropriate skills and growth. Progress is determined by many factors (eg, ongoing medical complications, cooperation and consistency of caregivers, and realistic expectations). Communication, consistency, and commitment are needed by all providers and the family to achieve the goal of oral eating.
1. A patient who has a documented weight loss of 5%, whose body mass index is < 3rd percentile, and is not expected to have normal gut function for at least 7 more days should receive PN via: A. Peripheral IV B. PICC C. Surgically placed CVC D. No PN 2. A baby with short bowel syndrome is anemic and needs daily lab specimens. The most appropriate technique to obtain the lab specimens for this patient is: A. Return the waste B. Push Pull method C. Traditional method using the least amount of waste possible 3. A toddler with failure to thrive who plots at < 3rd percentile for body mass index needs nasogastric tube feeds due to presumed postviral food aversion. The most appropriate approach to feeding this child is: A. Continuous drip feedings B. Bolus feedings during the day only C. Daytime bolus, nighttime drip D. None of the above. Do an occupational therapy consult for food aversion. See p. 487 for answers.
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References
1. Duggan C, Rizzo C, Cooper A, et al. Effectiveness of a clinical practice guideline for parenteral nutrition: a 5-year follow-up study in a pediatric teaching hospital. J Parenter Enteral Nutr. 2002;26:377381. 2. Wilkins CE, Emmerson AJB. Extravasation injuries on regional neonatal units. Arch Dis Child Fetal Neonatal Ed. 2004;89:F274275. 3. Franck LS, Hummel D, Connell K, et al. The safety and efficacy of peripherally inserted intravenous catheters in ill neonates. Neonatal Network. 2001;20(5):3338. 4. Racadio JM, Doellman DA, Johnson NA, et al. Pediatric peripherally inserted central catheters: complication rates related to catheter tip location. Pediatrics. 2001;107(2):14. 5. DiChicco R, Seidner DL, Brun C, et al. Tip position of long-term central venous access devices used for parenteral nutrition. J Parenter Enteral Nutr. 2007;31(5):382387. 6. Anderson C, Graupman PC, Hall WA. Pediatric intracranial complications of central venous catheter placement. Pediatr Neurosurg. 2004;40:2831. 7. Parikh S, Narayanan V. Misplaced peripherally inserted central catheter: an unusual cause of stroke. Pediatr Neurol. 2004;30(3):210212. 8. Hoang V, Sills J, Chandler M, et al. Percutaneously inserted central venous catheters for total parenteral nutrition in neonates: complication rates related to upper versus lower extremity insertion. Pediatrics. 2008;121(5):11521159. 9. Graf JM, Newman CD, McPherson ML. Sutured securement of peripherally inserted central catheters yields fewer complications in pediatric patients. J Parenter Enteral Nutr. 2006;30(6):532535. 10. Frey AM, Shears GJ. Why are we stuck on tape and suture? J Infusion Nurs. 2006;29(1)3438. 11. Chelliah A, Heydon KH, Zaoutis TE, et al. Observational trial of antibiotic-coated central venous catheters in critically ill pediatric patients. Pediatr Infect Dis J. 2007;26(9):816820. 12. Barton SJ, Chase T, Latham B, et al. Comparing two methods to obtain blood specimens from pediatric central venous catheters. J Pediatr Oncol Nurs. 2004;21(6):320326. 13. Adlard K. Examining the push-pull method of blood sampling from central venous access devices. J Pediatr Oncol Nurs. 2008;25(4):200207. 14. Cole M, Price L, Parry A, et al. A study to determine the minimum volume of blood necessary to be discarded from a central venous catheter before a valid sample is obtained in children with cancer. Pediatr Blood Cancer. 2007;48:687695. 15. Centers for Disease Control and Prevention. Guidelines for the prevention of intravascular catheter-related infections. MMWR Morb Mortal Wkly Rep. 2002;51(RR10):126.
16. Garland JS, Harris MC, Naples M, et al. A randomized trial comparing povidone-iodine to chlorhexidine gluconateimpregnated dressing for prevention of central venous catheter infections in neonates. Pediatrics. 2001;14311437. 17. Sondheimer JM, Asturias E, Cadnapaphornchai M. Infection and cholestasis in neonates with intestinal resection and long-term parenteral nutrition. J Pediatr Gastroenterol Nutr. 1998;27:131137. 18. Feldman KW, Hickman RO. The central venous catheter as a source of medical chaos in Munchausen syndrome by proxy. J Pediatr Surg. 1998;33(4):623627. 19. Ayoub CC, Alexander R. Definitional issues in Munchausen by proxy. APSAC Advisor. 1998;11(1):710. 20. Baker SS, Bakers RD, Davis AM. Pediatric Nutrition Support. Sudbury, MA: Jones and Bartlett Publishers; 2007. 21. Bankhead R, Boullata J, Brantley S, et al. Enteral nutrition practice recommendations. J Parenter Enteral Nutr. 2009;33(2):122167. 22. Wilkes-Holmes C. Safe placement of nasogastric tubes in children. Paediatr Nurs. 2006;18(9):1417. 23. Westhus N. Methods to test feeding tube placement in children. Am J Matern Child Nurs. 2004;29(5):282287. 24. Richardson DS, Branowicki PA, Zeidman-Rogers L, Mahoney J, MacPhee M. An evidence-based approach to nasogastric tube management: special considerations. J Pediatr Nurs. 2006;21(5):388393. 25. Ellett ML. What is known about methods of correctly placing gastric tubes in adults and children. Gastroenterol Nurs. 2004 Nov-Dec;27(6):253259. 26. Smith SL. Guidelines for safety and quality assurance when preparing infant feedings. Newborn Infant Nurs Rev. 2008;8(2):101107. 27. Hustler D. Delivery and bedside management of infant feedings. In: Robbins ST, Beker LT, eds. Infant Feedings: Guidelines for Preparation of Formula and Breastmilk in Health Care Facilities. Chicago, IL: American Dietetic Association; 2003:8895. 28. Guenter P, Silkroski M. Tube Feeding: Practical Guidelines and Nursing Protocols. Sudbury, MA: Jones and Bartlett Publishers; 2001.
Evaluation and Monitoring of Pediatric Patients Receiving Specialized Nutrition Support

Elaina Szeszycki, PharmD, BCNSP, Wendy Cruse, MMSc, RD, CNSD and Michelle Strup, PharmD
36
CONTENTS
Management of Pediatric Patients Receiving Nutrition Support Therapy. . . . . . . . . . . . . . . . . . . . . . . . . 460 Nutrition Monitoring and Evaluation. . . . . . . . . . . . . . . . . 461 Enteral Nutrition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
Monitoring Evaluation of Growth and Nutrition Adequacy Evaluation of Formula Tolerance Monitoring Laboratory Values Oral Feeding Revision of Enteral Plan Parenteral Nutrition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463 Evaluate for Infusion-Related Incidents Evaluate Tolerance of Volume Evaluate Tolerance of Macronutrients Monitoring the Integrity of PN Formulations Comparison of 3-n-1 and 2-n-1 Formulations Combination Enteral and Parenteral Nutrition Reassessment of the Plan. . . . . . . . . . . . . . . . . . . . . . . . . 466
Learning Objectives
1. State objective and subjective data necessary for a thorough evaluation of currently stated nutrition support goals. 2. Identify parameters utilized to evaluate gastrointestinal tolerance of enteral nutrition. 3. Identify parameters utilized to evaluate tolerance to parenteral nutrition. 4. List factors affecting calcium and phosphorus solubility. 5. Discuss the laboratory monitoring required for patients receiving specialized nutrition support.
Evaluate Drug and Nutrient Interactions. . . . . . . . . . . . 466

Compatibility of Medications Guidelines for Monitoring Nutrition Laboratory Values in Children Receiving Enteral and Parenteral Nutrition Physical Data Chemistry Profile Monitoring Nutrition-Related Laboratory Tests Liver Function Tests and Bilirubin Trace Elements Iron Studies and Anemia Vitamins Metabolic Bone Disease Infectious Complications. . . . . . . . . . . . . . . . . . . . . . . . . . 470 Appendix 36-1: PN Limits . . . . . . . . . . . . . . . . . . . . . . . . . 471
Appendix 36-2: Neonatal and Pediatric PN Monitoring Form. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472 Appendix 36-3: Long-Term PN Lab Tracking Sheet . . . . . 473
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Management of pediatric patients receiving nutrition support therapy is based on continuously assessing the tolerance and efficacy of the nutrition intervention based on the initial nutrition care plan. The nutrition care plan must consist of nutrition goals that are both short term and long term. The patient-specific set of goals must be continually monitored to assess the efficacy of therapy and adequacy of growth. When initiating any form of nutrition support in a severely malnourished child, careful monitoring must take place to avoid refeeding syndrome.1 Hypophosphatemia has been reported to be associated with malnutrition in children and in the first 10 days of intensive care hospitalization.2 Although hypophosphatemia is most commonly associated with refeeding syndrome, careful monitoring of phosphorus as well as potassium and magnesium is critical when initiating nutrition support in severely malnourished patients. 3 Baseline electrolyte levels should be obtained and depleted mineral and electrolytes should be replaced
Management of Pediatric Patients Receiving Nutrition Support Therapy
EVALUATION AND MONITORING OF PEDIATRIC PATIENTS RECEIVING SPECIALIZED NUTRITION SUPPORT
461
before initiation of nutrition therapy.1 It has been suggested that electrolyte levels should be monitored thereafter every 6 hours, 12 hours, then daily for the first 3 days or until levels are stable.4,5 Daily monitoring of serum electrolytes, minerals, and vital signs during advancement of nutrition support would be a minimum expectation in malnourished patients. Oral supplements can be administered by mouth or feeding tube as tolerated when patients are being fed enterally. Intravenous (IV) electrolytes can be provided when patients are receiving primarily parenteral nutrition (PN). Should the child experience diarrhea when receiving oral therapy or serum levels are moderately to severely depleted, electrolyte replacement may need to be switched to IV infusion. It is also critical to avoid providing excess or inadequate calories during controlled feeding situations when the child is not utilizing hunger and satiety cues. Children receiving tube feeding do not have the ability to choose more or less calories as their growth and nutrition needs change; therefore, it is critical to monitor growth frequently. It is important to utilize growth charts with serial measurements and growth velocity.6,7 Excessive calories from PN may contribute to cholestatic liver disease, which is discussed later in this chapter. The route of nutrition support needs to be reevaluated frequently. Enteral nutrition (EN) is the preferred route when possible. PN should be used when the gastrointestinal (GI) tract is not functional or if inadequate absorption is apparent and thus adequate nutrition support is not possible via the enteral route.8 Adequacy and appropriateness of the route for nutrition support must be reassessed frequently and adjusted as needed.
malnourished children at risk for refeeding syndrome or during the transition periods between PN, EN, and oral diet may require more frequent monitoring.
Enteral Nutrition
Monitoring
There are many parameters that can be used to monitor patients receiving EN. During the initiation and advancement of EN, monitoring will be more frequent and become less frequent as the child becomes more stable. A proposed monitoring protocol for infants and children receiving EN initially and then stable, both while in hospital and at home, is provided in Table 36-1.9,10
Evaluation of Growth and Nutrition Adequacy

Baseline anthropometric data must be assessed initially, followed by periodic monitoring of growth velocity. Calorie, protein, vitamin, mineral, and fluid intake must be assessed initially, then monitored daily then weekly and later monthly as needed. Fluid status can be assessed by balancing fluid intake with fluid output including urine, stool, or ostomy output, emesis, wound losses, and tube drainage.
Evaluation of Formula Tolerance

Monitoring tolerance to EN includes monitoring changes in GI function. Stool frequency and consistency as well as presence of blood should be recorded daily. If a patient has an ostomy, consistency and volume of ostomy output should also be recorded daily. Volume goal may be < 40 mL/kg/d or < 30% of formula volume.11 A large amount of stool or ostomy output may indicate the need to reduce formula volume or avoid advancement of feeding volume. Large stool volume or ostomy output may require the initiation of IV fluids to avoid dehydration. If small bowel bacterial overgrowth is present based on the presence of D-lactate or a positive breath hydrogen test, a low-carbohydrate formula may be beneficial. Measuring stool for reducing substances also identifies when a patient is experiencing small bowel bacterial overgrowth. Antibiotics administered enterally in a cyclical fashion, probiotics, and avoidance of acid suppression may also be beneficial in patients with bacterial overgrowth. 5 The presence of blood in the stool may require an elemental formula with lower allergenicity or in extreme cases an amino acid-based formula. Other symptoms of GI intolerance may include nausea, vomiting, gastric residuals, abdominal distention, and increase in abdominal girth.
Nutrition Monitoring and Evaluation
Complications associated with the delivery of EN and PN can be prevented with monitoring and timely formula adjustments based on the patients tolerance. Development of enteral and parenteral monitoring guidelines is critical to assure all parameters are being assessed. Monitoring parameters are based on nutrition goals set in the nutrition care plan as well as patient tolerance. Initially, baseline weight, height or length, and head circumference should be plotted on age-appropriate growth curves. Monitoring will include the patients growth, fluid status, clinical status, tolerance to EN and PN, medication changes, and laboratory values. Frequency of monitoring depends on the age, severity of illness, tolerance of specialized nutrition support (SNS), comorbid diseases, and degree of malnutrition. Preterm neonates, infants, critically ill patients, and severely
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Monitoring Laboratory Values

Routine laboratory monitoring may include serum electrolytes, glucose, blood urea nitrogen (BUN), creatinine, calcium, phosphorus, magnesium, albumin, prealbumin, complete blood count with differential, and iron indices as well as assessment of acid-base status. Routine monitoring of laboratory values is not indicated for medically stable pediatric patients receiving EN at advised levels and achieving adequate growth.9 Serum zinc may need to be monitored when fat malabsorption is present. Physical assessment including clinical signs of nutrient excess or deficiency must be assessed periodically.
Oral Feeding
Introduction to oral feeding is critical in all infants receiving EN. Allowing the infant to take a minimal volume of formula orally may reduce the amount of oral aversion so commonly seen in these children. It is also critical in older children receiving tube feeding to be allowed to eat and drink once safety has been established either via observation or oximetry-swallow study.
Table 361 Suggested Parameters to Monitor for Infants and Children Receiving Enteral Nutrition9,10
Initial Week During Hospitalization Outpatient EN-Only Patient Outpatient PN and/ or EN Patient
Growth Parameters Weight NICU Infants Children Length NICU Infants Children Height (> 36 mo) Head circumference (< 36 mo) Weight gain Linear growth Intake Parameters Intake Calories Protein Vitamins Minerals Fluid balance GI Tolerance Abdominal girth Gastric residuals Emesis Stool (volume, frequency, consistency, color) Ostomy (volume, consistency) Physical Temperature Tube placement Tube site care
Daily Daily Daily Baseline Baseline Baseline Baseline Baseline DailyWeekly Monthly Daily
Daily Daily DailyTwice Weekly Weekly Monthly Monthly Monthly WeeklyMonthly DailyWeekly Monthly Weekly
WeeklyMonthly WeeklyMonthly Weekly to Every Clinic Monthly or at Clinic
Weekly Weekly Weekly Monthly or at Clinic
Monthly or at clinic WeeklyMonthly Monthly Monthly
Monthly or at clinic Weekly Monthly Weekly
As indicated As ordered or reported As reported Daily as reported
As indicated As ordered or reported As reported Daily as reported
As indicated As ordered or reported As reported Report changes in stool pattern
As indicated As ordered or reported As reported Report changes in stool pattern
Per nursing policy Prior to each feeding Daily
Per nursing policy Prior to each feeding Daily
Report when > 101F (38.5C) Prior to each feeding Daily
Report when > 101F (38.5C) Prior to each feeding Daily
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Revision of Enteral Plan

Revision of the EN care plan will be based on patients tolerance of the EN regimen and achievement of goals. If goals are not being met, the nutrition care plan must be adjusted according to patients tolerance. When the child has grown and is older the formula type and volume will need to be adjusted based on the childs needs, recommended daily allowance (RDA), and dietary reference intake (DRI). If the EN plan is not supporting appropriate growth and making adjustments to the EN plan does not support the nutrition goals, then supplementation with PN or a transition to all PN may be required. It is important to assess if the patient has achieved the nutrition goals. EN can be transitioned to oral diet should the child be able to tolerate an oral diet.
If nutrition goals are unattainable by EN then PN will need to be considered. As with EN, patient allergy information or any history of infusion-related incidents should be evaluated prior to the initiation of PN.
Evaluate for Infusion-Related Incidents

Patients with an egg allergy may require a test dose of lipid emulsion to better evaluate for any reaction.12 The emulsifier in currently marketed long-chain triglyceride lipid emulsions contains egg phospholipid. Even though reactions to PN components are rare, there are case reports suggesting that multivitamins, lipid emulsions, iron dextran, or preservatives may be the causative agent.13,14 If a reaction does occur and PN is suspected, eliminating 1 agent at a time helps to determine the causative ingredient. If PN is required for more than a week with no EN then alternate routes may need to be identified to provide the particular causative agent. Vitamins may be administered orally or via a feeding tube or topical safflower oil in the case of lipid intolerance. Once the patient allergy profile has been reviewed, IV access needs to be identified. Peripheral parenteral nutrition (PPN) is limited based on osmolarity due to the vesicant properties of PN ingredients. Institutions generally set osmolarity limits for neonatal PPN at 900 to 1200 mOsm/L and pediatric PPN at 600 to 900 mOsm/L.10 Maximum dextrose concentration for pediatric and neonatal PPN is 12.5% but ultimately the osmolarity of the solution dictates the amount of nutrients, electrolytes, and minerals that can be ordered.15 Lower concentrations of dextrose may be necessary in children with poor peripheral access. Amino acids, dextrose, calcium, sodium, and potassium are the main determinants of osmolarity. If PPN is utilized, the IV
site needs to be monitored closely (every 3 to 4 hours) for early signs of infiltration. It is difficult to provide 100% of nutrition goals with a peripheral solution but may be effective for a short period of time. If EN cannot be initiated and advanced to goal within 5 to 7 days, serious consideration should be given to placement of a catheter for central venous access.10 Once central access is obtained it is helpful to note the date of insertion, location, type of catheter, and number of lumens. These initial data will be useful when monitoring for catheter-related complications. Heparin is routinely added to neonatal and pediatric PN solutions to maintain patency of the central venous catheter.16 Lower flow volumes, smaller catheters, and frequent interruptions of PN solutions may play a roll in increased incidence of catheter clotting than in adults.17 Preliminary data suggest that a heparin concentration of 0.5 units/mL in neonatal PN solutions may be as effective for maintaining catheter patency as 1 unit/mL.18 Prospective data are currently being collected to further validate these preliminary results (Elaina Szeszycki, personal communication).
Evaluate Tolerance of Volume

Generally PN volume is based on a patients maintenance volume requirement (refer to Chapter 9). Fluid volume may be restricted or increased depending on disease processes and clinical condition. There are a number of subjective and objective data that can be evaluated to aid in determining if the volume of PN or total fluid intake is appropriate. Weight, intake from all sources, output from all sources, laboratory results (refer to Table 36-7), vitals, and physical assessment should be evaluated on a daily basis initially when PN is started (Table 36-2). Routine weights and laboratory results can be decreased as the patient stabilizes. If a patient is going home on PN or has limited access, total fluid requirement may be incorporated into the PN solution as possible.
Evaluate Tolerance of Macronutrients

Amino acid tolerance can be evaluated by monitoring the BUN level.19 If an elevated BUN cannot be explained by changes in renal function, medications (eg, highdose steroids, amphotericin, aminoglycosides, and diuretics), bleeding, or dehydration then the non-protein calorie:nitrogen (NPC:N) ratio needs to be evaluated. The ideal NPC:N ratio in stable patients is 150250:1.20 The ratio may be less in critically ill patients or higher in renal failure patients. Ammonia levels and mental status are monitored in liver disease patients. Please refer to Chapter 26.
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Table 36-2 Parameters to Evaluate Adequacy of PN Volume

Parameter DehYDRATION FLUID OVERLOAD
Weight Change: Real versus fluid Intake: Intravenous fluids, PN, blood products, medications, EN Output: Urine, gastric, stool, bile, chest tube, wound, skin Laboratory
Rapid weight Total intake < total output Decreased urine output, dark urine Blood urea nitrogen, sodium, serum osmolality, urine specific gravity, albumin or Hgb Heart rate, losses with fever Addition of diuretic or change in frequency Thirst, dry lips, dry mucous membranes, dry skin, headache, dizziness
Rapid weight Total intake > total output Increased urine output in patients with normal renal and liver function sodium, serum osmolality, urine specific gravity albumin or Hgb Respiratory rate Fluid retention with steroids or excessive sodium intake Peripheral, facial, and orbital edema, abdominal girth, shortness of breath
Vitals Medications Physical Exam
Dextrose is best monitored by venous blood glucose and capillary glucose. The frequency of venous or capillary glucose monitoring depends on history of glucose intolerance, presence of diabetes, or concurrent medications affecting blood glucose control. Capillary glucose monitoring is useful for frequent monitoring so that the central line does not have to be accessed an inordinate amount of times during the day or when verifying an abnormal glucose level from a venous sample. The frequency of monitoring can be modified once the patient has established good blood glucose control on the goal PN formula. Ordering dextrose in PN as final dextrose concentration has been the standard for years but there is a push to order dextrose in mg/kg/min or g/kg/d as a glucose infusion rate (GIR). Maximal dextrose infusion varies according to age and there is growing information about the maximal GIR range for differing age groups.21 This should allow for more appropriate dextrose ordering and potentially decrease complications associated with excess carbohydrate intake (eg, hyperglycemia, elevated liver enzymes, cholestasis, and ultimately fatty liver).22 Unexplained hyperglycemia should prompt the calculation of the GIR from the PN solution and other dextrose-containing solutions. Pediatric patients receiving PN for > 2 weeks on a stable regimen may be
cycled 12 to 22 hours per day in an effort to ease daily activities and decrease hepatic complications related to PN. 23 Initially, blood glucose levels should be obtained during the high rate of cyclic PN infusion and 1 to 2 hours after cycle completion to evaluate for hyper- and hypoglycemia. Levels > 150 mg/dL will require a decrease in dextrose amount or lengthening of cyclic infusion to decrease the GIR. Levels < 60 mg/dL or any symptoms of hypoglycemia will require a longer taper period off of the cyclic PN or adjustment of insulin if present in PN solution.24 Triglyceride levels are monitored daily as lipid intake is increased and then decreased to weekly once dose is stable and levels are adequate. Maximal lipid infusion for adults is 0.125 g/kg/h.25 There is limited information regarding maximal infusion rate for pediatrics but it is well-documented that longer infusion rates, 12 to 24 hours, improve tolerance to lipid infusions.26 Decreasing the lipid dose or infusing lipids every other day or 3 to 5 times a week instead of daily in long-term PN patients will allow for further clearance of the lipid and possibly avoid triglyceride levels > 200 mg/dL. Limiting the dose and therefore decreasing phytosterol intake may also reduce the cholestasis commonly noted in pediatric patients receiving long-term PN. 27 Calculating the lipid infusion rate in g/kg/h would be helpful if hypertriglyceridemia is an issue.
Monitoring the Integrity of PN Formulations

Changes in any of the PN ingredients may affect the stability or solubility of the formulation and thus warrants constant surveillance during compounding and administration. There are a number of factors that influence solubility of minerals such as calcium and phosphorus, the compatibility of PN solutions, and the integrity of total nutrient admixtures (TNA). Factors that influence calcium and phosphorus solubility are listed in Table 36-3. The pH of the amino acid solution drives the pH of the PN solution. The ideal pH for calcium and phosphorus solubility is ~ 56.28 Solubility will decrease as the pH becomes more acidic or alkaline. Higher concentrations of amino acid allow for higher calcium and phosphorus doses to be admixed in a 2-n-1 or 3-n-1 solution. There is a myth that the amount of lipid emulsion influences how much calcium and phosphorus that can be admixed together in PN solutions but the concentration of lipid emulsion is not a variable evaluated in calcium/phosphorus solubility graphs. Solubility graphs in Trissels and Kings reference texts have been a primary source for determining adequacy of calcium and phosphorus amounts ordered in various PN solutions. 29,30 Today, some of the order-entry software utilized with the
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automated compounding hardware has incorporated the calcium/phosphorus solubility graphs into alerts. The order entry pharmacist is alerted when the solubility graphs are exceeded. This feature eliminates manual plotting of concentration points but still requires critical evaluation of all graphs to determine if each individual solution is appropriate for compounding.
Table 36-3 Factors Affecting Calcium and Phosphorus Solubility Temperature Concentrations of calcium and phosphorus Type of amino acid product and concentration Dextrose concentration pH of final solution Cysteine Lighting Order of mixing
integrity of TNA. 35 Refer to Appendix 36-1 for an example of institutional-derived dosing and stability limits.
Table 36-4 Factors Affecting Total Nutrient Admixture Stability Final pH (56) Optimal pH for stability Divalent cation concentration Maximum concentration limits (calcium, magnesium, zinc) required Trivalent cations (iron dextran) Not stable in TNA Type of amino acid & Higher concentrations improve concentration stability Dextrose concentration Lower concentrations will limit stability Anionic emulsifier Protects emulsion integrity Multivitamin products Protects emulsion integrity Temperature Avoid administration in warm areas Order of mixing Critical to avoid precipitation & instability Product packaging Lipids in plastic ? affect on stability
Calcium and phosphorus amounts are limited in PPN solutions when low amino acid concentrations are ordered (initial PN solutions, renal insufficiency or disease, and dilute solutions). Once amino acid concentrations can be safely advanced, calcium and phosphorus solubility should improve and these mineral doses can be increased. Increasing concentrations of dextrose affects the solubility curve positively as well.29 Some institutions set maximum concentrations allowed for calcium and phosphorus in addition to evaluating the solubility curves to avoid excessive dosing and avoid infiltrations with PPN (Appendix 36-1). Practitioners were reminded in a tragic fashion how important order of mixing is when compounding PN solutions. At least 2 deaths have been associated with calciumphosphorus precipitation in PN solutions. 31 Temperature and lighting also play a role and need to be investigated when precipitation occurs, PN solutions look abnormal or become discolored, PN filters occlude, and when the solution otherwise meets all solubility and stability limits. Neonatal PN solutions are particularly at risk for stability issues due to bilirubin lights, heat from the extensive amount of equipment utilized in these units, and frequent co-infusion of medications with limited intravenous access. TNAs are complex solutions that require additional scrutiny and compounding limits due to their opaque nature. Factors involved for ensuring the integrity of the emulsion are listed in Table 36-4. Minimum concentrations of the macronutrients should be determined, especially for TNA, to maintain the integrity of the emulsion. 32,33 A minimum amount of IV lipid is required to provide adequate emulsifier for a TNA. 34 It is yet to be determined how product packaging of current lipid formulations will affect the
Comparison of 3-n-1 and 2-n-1 Formulations

PN is a general term referring to IV PN whereas 2-n-1 refers to PN compounded with amino acids and dextrose. TNA or 3-n-1 refers to PN solutions compounded with amino acids, dextrose, and lipids. The opaque nature of a TNA or 3-n-1 is considered a disadvantage due to the inability to see obvious precipitates. Calcium and phosphorus intakes are felt to be less with TNA but again lipid is not a limiting factor in the solubility of these two minerals. Divalent cations such as calcium, magnesium, and zinc may be somewhat limited in TNA due to the anionic nature of the lipid emulsions. 33 It may be difficult to provide higher doses of these divalent cations in low-volume solutions or for patients receiving magnesium-wasting medications. As with calcium and phosphorus solubility, higher concentrations of amino acid and dextrose provide a protective effect on the emulsion. The amino acids form a protective layer around the lipid globules while the hypertonicity of the dextrose prohibits excessive movement and possible coalescence of globules. 36 The most problematic TNAs are the initial neonatal formulations for extremely low birth weight (ELBW) infants with low dextrose and lipid concentrations. Centers that compound TNAs or 3-n-1 formulations must invest in automated compounding systems that interface with advanced order-entry software containing multiple manufacturer and institutional limits. These dosing and stability limits will aid in identifying solutions potentially unsafe for patient administration. Although TNAs require rigorous review, they do allow for all nutrients to be in one bag and therefore only
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one infusion pump. Nursing time is less compared to lipids administered separately in syringes every 12 hours and co-infused with a 2-n-1 solution. Some institutions infuse lipids in syringes over 24 hours but the latest Centers for Disease Control and Prevention (CDC) recommendation states IV lipids should not be infused longer than 12 hours to avoid microbial growth. 37 There is a concern for increase in lipid peroxidation once lipids are transferred from their original container. 38 Clinical consequence is not known at this time and it is not clear whether peroxidation occurs at a quicker rate in TNA or lipids administered via syringe. Another advantage of TNA is 24-hour infusion of lipid and decreased risk of microbial growth compared to lipid alone. 37 Table 36-5 outlines the advantages and disadvantages of 3-n-1 or TNA over 2-n-1 solutions. Each institution needs to determine which mode of PN ordering works best for its patient populations.
Table 36-5 Advantages and Disadvantages of Total Nutrient Admixtures
Advantages Disadvantages
surgical history, feeding tolerance, or any sign/symptoms of nutrient deficiencies. Transitioning from EN via a feeding tube to oral nutrition requires periodic monitoring of weight, length or height, and skinfold thickness to determine how quickly the transition can occur and its success. A key point for monitoring is follow-up once a plan is in place.
Reassessment of the Plan
Allows for 24-hour lipid infusion Decrease labor costs Decreased equipment and supplycost Decreases microbial growth opportunity
Prohibits visual inspection Limited compatibility information Minimum macronutrient amount required forstability
Patients receiving SNS require periodic reassessment of their progress and goals. Pediatric patients differ from adults in that growth and development is a dynamic process and these 2 elements should be taken into account when assessing the patient. Weight, fluid, calorie, protein, vitamin, and mineral goals all need to be adjusted as the patient grows, with subsequent adjustment in his or her SNS regimen. Ideally these restated goals and therapy recommendations should be communicated to all physicians involved in the patients care so that evaluation of changes can be monitored. If the current nutrition regimen is not successful, an alternative plan needs to be developed, initiated, and monitored. Assessment, recommendation of a plan, activation of the plan, and evaluation of the plan is a continuous cycle that needs to be followed by practitioners involved with patients requiring SNS.
Figure 36-1
Combination Enteral and Parenteral Nutrition

Once EN is initiated along with current PN, the amount of monitoring and evaluation of specialized nutrition support (SNS) increases during this transition phase. The plan is to advance EN to goal as soon as possible while scaling back on PN but still maintaining adequate nutrition intake. Monitoring of weight, enteral tolerance, linear growth, skinfold thickness, protein stores, electrolytes, minerals, and other laboratory values will aid in determining if the EN regimen is appropriate. This can occur through once or twice weekly lab draws and communication with parents or caregivers. This is in addition to monthly clinic visits. Frequent communication regarding the patients progress with the medical team will allow for quicker advancement of enteral feedings per patient tolerance. When adequate nutrient intake can be achieved enterally and/or orally and appropriate growth demonstrated, then PN can be discontinued and vascular access removed. EN can be gradually decreased as oral intake improves. When the patient is stable on a goal EN regimen and PN is discontinued, the frequency of monitoring can be decreased. Laboratory monitoring is required periodically depending on other pertinent medical history,
Evaluate Drug and Nutrient Interactions
The process of evaluating for drug-nutrient interactions begins with the patient medication profile and nutrition regimen. There are a number of excellent published
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resources and pharmacy computer databases that can be utilized to identify drug-drug and drug-nutrient interactions. 39,40 Pharmacy order entry systems can provide alerts for particular medications (eg, fluoroquinolones and phenytoin) when patients are receiving enteral feedings. Once an interaction is identified, the severity along with the source of the interaction needs to be evaluated closely to determine a course of action. A number of interactions may be avoided by administering the drug and the particular nutrient, vitamin, or mineral at separate times during the day. If enteral formula ingredients interfere with drug absorption, consultation with a pharmacist and dietitian can aid in developing a revised enteral regimen for the patient that will allow for improved drug absorption. Particular medications may induce certain electrolyte and mineral wasting or retention. Oral, enteral, or parenteral electrolyte and mineral supplementation may be required while a patient is receiving these offending agents. PN is not meant to be a vehicle for acute electrolyte and mineral replacement but can aid in supplementing patients with chronic electrolyte and mineral abnormalities. Electrolyte and mineral supplementation should not be added directly to enteral formulas due to the potential for instability but should be diluted and given orally or flushed via a feeding tube. Table 36-6 lists some common drug-induced metabolic disorders.41,42 Patients on these particular medications require at least weekly laboratory monitoring. Frequency of monitoring is dependent on renal and hepatic function as well.
Table 36-6 Drug-Induced Metabolic Disorders Loop Diuretics hyponatremia, hypokalemia, hypocalcemia, metabolic alkalosis H2 antagonists hyponatremia Corticosteroids hypokalemia, hypocalcemia, hypophosphatemia, metabolic alkalosis Amphotericin B hypokalemia, hypomagnesemia, metabolic acidosis Cyclosporine, Tacrolimus hypomagnesemia, hyperkalemia, hypertriglyceridemia Aminoglycosides metabolic acidosis Citrate hypocalcemia
and compatible medications that can be safely added to PN solutions. Certain medications may be co-infused with PN or TNA if no other access is available. There are a number of published compatibility charts but it is still a good practice to compare your own institutions PN solutions against published charts and studies.43,44 A range of PN solutions and TNA have been tested but there is no way to test each individual solution for stability that may be prescribed in clinical practice.
Guidelines for Monitoring Nutrition Laboratory Values in Children Receiving Enteral and Parenteral Nutrition
The goals for monitoring patients receiving SNS are to ensure the efficacy of the regimen and to identify and prevent potential complications. It is important that the nutrition support team (physician, nurse, pharmacist, and dietitian) establish goals for the patient prior to initiating SNS. The monitoring of patients requiring EN and/or PN must include both clinical data and laboratory testing. Sample patient data sheets are included (Appendices 36-2 and 36-3). Appendix 36-2 may be utilized for patients started on PN or a combination of PN/EN. Appendix 36-3 can be utilized in addition to Appendix 36-2 for those patients receiving PN for greater than 3 months. Every patient must have documented baseline data in order for appropriate evaluation and monitoring to take place. It is important to note that it is impossible to create a one size fits all set of monitoring guidelines. Each patients monitoring regimen must be created based on the specific disease state and individualized long-term goals. New patients will require the most frequent monitoring, while stable long-term SNS patients may require less intense monitoring. EN-only patients will require less laboratory monitoring while those on PN will require regular laboratory testing. The following information should be used as a general guideline and can be customized to the specific patient needs. Please refer to disease-specific chapters in this book for additional monitoring that may be required. Tables 36-7 and 36-8, which appear at the end of this chapter, are examples of suggested monitoring for shortand long-term laboratory testing.
Compatibility of Medications
In addition to calcium and phosphorus solubility, stability of the PN solution needs to be evaluated at order entry. Critical review of available PN stability literature, parenteral product manufacturer studies, and in-house stability studies are what nutrition support practitioners rely on to determine maximum concentrations for micronutrients
Physical Data
There are a number of objective physical pieces of data that can be collected to aid in evaluating adequacy and tolerance to SNS. Developing standards of practice, order sets, policies, and procedures in all institutions caring for patients requiring SNS can assist those individuals responsible for monitoring these complex patients. Table 36-1
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delineates some general guidelines but individual patient needs and clinical situation should dictate specific monitoring parameters and the frequency.
Chemistry Profile Monitoring4550

The monitoring of electrolytes, minerals, renal function, glucose, and acid-base balance is essential in PN. When initiating a patient on PN, a baseline basic metabolic panel (BMP), magnesium, phosphorous, and triglyceride level should be ordered and monitored daily until the patient has reached the calorie goal established at initial assessment. The frequency may be decreased to twice weekly in which one day includes the comprehensive metabolic panel (CMP), which encompasses the hepatic function along with the BMP. As the patient stabilizes, labs may be decreased to weekly. Finally, these labs may be reduced to every 2 to 4 weeks when the PN formula is stable and if appropriate goals are being met for the current condition and growth needs.
patient receiving PN for > 7 days. 56 Although most EN formulas contain adequate dietary carnitine, supplementation can be considered in EN patients with malabsorption or bowel resection if deficiency is suspected or confirmed by laboratory testing. A carnitine profile, including ester/ free ratio, should be monitored every 3 to 6 months if the patient is being supplemented. A yearly carnitine profile is sufficient for patients not receiving supplementation. There are 2 fatty acids in humans that must be supplied via the diet primarily from plants. They are linoleic and -linolenic acid and are known as essential fatty acids (EFAs). Patients receiving EN and PN must be adequately supplemented with both EFAs because their oral intake may be minimal. If inadequate amounts are provided, an essential fatty acid deficiency (EFAD) may eventually occur. If lipid-free PN is provided for a significant amount of time or there is clinical manifestation of an EFAD, it is possible to order an EFA profile. The resulting triene:tetraene ratiocan determine if an EFAD exists. 26,6062
Nutrition-Related Laboratory Tests

(see also Chapters 4 and 5) Prealbumin is commonly used to monitor protein status due to its shorter half-life of 2 to 3 days in comparison to albumin. 51 However; there are other factors that can influence prealbumin levels such as inflammatory states, end-stage liver disease, untreated thyroid disease, renal disease, and zinc deficiency. These limitations should be considered when interpreting a patients prealbumin level. 5254 Monitoring of prealbumin levels can be helpful especially for long-term stable patients. Prealbumin can be monitored on a weekly basis initially and then monthly in stable patients. Changes in triglyceride levels can be influenced by a variety of factors including disease state, organ function, medications, nutrition status, and current nutrient intake. They should be monitored daily when SNS is initially started, followed by a weekly level, and then increased to monthly.19,26,45,55 Carnitine is often supplemented in the formula of PN patients, particularly neonates and infants due to their inability to synthesize an adequate amount. In addition, premature neonates will also have limited carnitine stores that are needed for long-chain fatty acid transport. 56 A deficient patient may present with increased triglyceride levels, hyperbilirubinemia, or decreased weight gain along with a multitude of other clinical symptoms. 5759 Currently a carnitine dose of 10 to 20 mg/kg/d is recommended for IV or oral supplementation and should be initiated in any
Liver Function Tests and Bilirubin

Liver complications are a well-documented adverse effect of PN in children. 6366 It is necessary to monitor liver function enzymes, which generally include alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase, on a weekly basis when initiating PN. A total bilirubin should also be followed. If prolonged PN is anticipated or the patient becomes jaundiced, a direct or conjugated bilirubin level is helpful to monitor for cholestasis. 24 A direct bilirubin > 2 mg/dL may prompt earlier monitoring of the trace elements, copper, and manganese. 67 The liver function enzymes and total bilirubin are included when ordering the CMP as previously discussed. Once stabilized these laboratory tests can be monitored every 2 to 4 weeks. Gamma glutamyl transpeptidase (GGTP) is another liver enzyme that is more specific for liver and biliary tract problems. 24 GGTP is the most sensitive liver enzyme for detecting biliary obstruction, cholangitis, or cholecystitis. 51 It can be ordered for further diagnosis when the traditional liver enzymes are elevated or as a regularly monitored monthly test if the patient is at risk for biliary problems. The prothrombin time (PT) and international normalized ratio (INR) can be utilized in long-term monitoring of PN. The PT can be elevated in a patient who is developing hepatocellular disease or obstructive biliary disease or more rarely a vitamin K deficiency. 24,68,69 A baseline and then monthly check of the PT/INR is adequate.
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Trace Elements
(see also Chapter 6) When a patient is receiving PN for several months, it is important to assess the status of trace elements due to the standardized way in which they are initially ordered in PN patients and the known contamination of commercial products used to compound PN.70 After 3 consecutive months on PN (unless clinically indicated earlier),71 a patient should be assessed for zinc, selenium, manganese, copper, and chromium.45 Long-term use of standard multi-trace products can result in both excessive and deficient concentrations, especially in patients who have abnormalities in the GI tract. Although measuring blood concentrations of these trace elements is not necessarily the most accurate due to the bodys ability to store these elements, it is generally the easiest and least costly way to monitor.72 It is also important to note that these elements should not be checked during times of acute inflammatory type conditions due to the bodys sequestration of some elements during this time. Levels may be falsely decreased in these types of situations.73 Assessment of these elements should occur every 3 to 12 months while receiving PN.45,72 If a patient is found to have an elevated level of any standard element, the multi-trace element of the PN can be omitted and separate elements may be added. Additionally, if any element is found to be deficient, it can be added in addition to the standard multi-trace. There are limits to concentrations of trace elements in PN so this must be considered, and in that situation, oral supplementation may be an option. After altering the dosage of any element it should be rechecked in approximately 1 to 3 months. If a patients condition has completely stabilized, it is reasonable to monitor only once per year. Aluminum, considered an ultratrace element, is a known contaminant of PN products. It is important to monitor due to the patients continued exposure and risk for toxicity. It is reasonable to check an aluminum level each year during PN therapy. If the aluminum is elevated, the PN pharmacist can look at the current PN components and make adjustments if possible since aluminum contamination varies even between different PN product manufacturers.74 Molybdenum deficiency is rare but can occur in a PN patient, especially those with decreased intestinal absorption.75,76 If desired, a molybdenum level may be checked yearly unless otherwise clinically indicated. If a deficiency is detected, molybdenum may be supplemented via PN in the form of ammonium molybdate.
Iodine is an element not supplied by standard multitrace products in PN. Therefore it is possible, although unlikely, for a SNS patient to become deficient.77,78 This can routinely be assessed with a yearly thyroid stimulating hormone (TSH), triiodothyronine (T3) test, or urine iodine concentration.
Iron Studies and Anemia

(see also Chapters 68) When patients are dependent on EN and/or PN, there is always the potential for the patient to become anemic. The 4 nutrients that are most likely to be the reason for an anemia are iron, copper, vitamin B12 , and folic acid. Standard PN contains 3 of the previous nutrients with the exception being iron. Enterally fed patients typically are provided with all 4 nutrients. However, the standard quantities provided may not always be adequate for the specific disease process that is being treated. For example, a patient who has shortened bowel will generally have less absorption of the nutrients from EN and may become deficient over time. Iron deficiency can be recognized by abnormalities in the complete blood count (CBC). In general there is a decrease in hemoglobin and mean corpuscular volume (MCV).45 It may take some time for the deficiency to occur so a routine CBC (at least monthly) is recommended to monitor for these changes.46,47,50 When these abnormalities are present an iron panel can be ordered if indicated to confirm the deficiency. An iron panel should include serum iron, ferritin, transferrin saturation, and iron-binding capacity. In a deficient patient, the iron and ferritin may be reduced and the binding capacity elevated. After confirming the deficiency, the iron may be supplemented orally. If the patient does not respond to oral iron, parenteral iron may be used as a separate infusion or added to the PN. The only parenteral iron that may be used in PN is iron dextran, and it can only be used in the absence of lipids in the formulation for stability reasons.44 Monitoring of iron status should occur every 3 to 6 months in a deficient patient or a patient receiving supplementation. Copper deficiency can also present with anemia and neutropenia.79,80 This can result from decreased absorption or increased losses from the intestinal tract. Copper deficiency can also occur due to high zinc, vitamin C, or iron supplementation or from the use of gastric acid suppressing medications. 81 Iatrogenic copper deficiency may occur with inadequate amounts in PN due to concern for accumulation in patients with cholestasis. Measuring serum copper or serum cerulosplasmin levels can assess
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the patients copper status.72 This can be performed with the other multi-trace elements as previously discussed. Both vitamin B12 and folic acid deficiencies can present as a macrocytic anemia with an elevated MCV. Because these 2 nutrients have an intertwined relationship in the body, it is recommended to assess the status of both whenever either is measured. Patients without an ileal cecal valve are particularly at risk for development of vitamin B12 deficiency since this is a site for absorption. It is possible for the body to maintain serum vitamin B12 levels even though storages have been depleted. Therefore, it can also be beneficial to check methylmalonic acid and homocysteine levels when vitamin B12 deficiency is truly suspected. These 2 tests will be elevated in most patients even with a minimal vitamin B12 deficiency. 82 However, homocysteine levels may also be elevated in the presence of folic acid and vitamin B6 deficiency, therefore it is not a specific indicator of vitamin B12 deficiency. 83 A yearly measure of these vitamins is normally sufficient unless deficiency is suspected71 or in evaluating after increased supplementation.
pain or non-traumatic fracture, the following laboratory tests may indicate MBD: low to normal PTH, elevated alkaline phosphatase, altered vitamin D levels, changes in serum calcium levels, and hypercalciuria. 50,84,85 Therefore, monitoring a yearly PTH along with vitamin D may be indicated in long-term PN patients. Catheter-related bloodstream infections (CRBSIs) are a well-known complication of vascular access devices. By monitoring for fever and changes in the CBC, potential infections can be identified and treated promptly.45 The most recent CDC guidelines for catheter maintenance were published in 2002.86 The replacement of the infected catheter is recommended in most CRBSIs. However, continual replacement of the catheter can lead to the loss of venous access sites. This can be problematic for many PN patients due to their long-term need for a vascular access device. One strategy used to prevent CRBSIs has been the use of agents to sterilize the catheter lumen. The first of these was antibiotic lock therapy (ALT), which has been studied since the late 1980s.87 This method involves using concentrated antibiotic solutions and dwelling the solution in the catheter lumen for a period of time. Problems associated with ALT are the development of antibiotic resistance with long-term use, lack of documented stability, and expense. 88 A newer agent that has been shown to reduce CRBSI is ethanol. Opilla MT et al specifically studied the use of ethanol for the home PN patient and showed a statistically significant reduction in CRBSIs and catheter exchanges. 89 The use of an ethanol lock has been shown to be safe for the pediatric patient.9092 Currently, there is not a standardized dose, concentration, frequency, or dwell time for the use of ethanol lock. Factors that must be considered when choosing to utilize an ethanol lock include catheter material, catheter age, and compliance.93 Bacterial overgrowth can be a complication of patients with intestinal failure receiving PN and requires treatment when identified. Abdominal discomfort, bloating, cramps, gas, changes in stool color, consistency, and odor are common signs and symptoms. When the preceding signs and symptoms are identified, the patient should be treated. If a fever is also present, the patient should be evaluated for bacteremia due to possible translocation from the GI.45 (See Chapter 27.)
Infectious Complications
Vitamins
(see also Chapters 7 and 8) Fat-soluble vitamins A, D, E, and K are standard components of most parenteral multivitamin products and EN products. It is possible for a patient to accumulate excessive amounts due to the bodys storage of these vitamins, but it is also possible for deficiency to occur with certain disease states. Monitoring the levels of vitamins A, D, and E once yearly is recommended unless otherwise clinically indicated.45 Vitamin K status is more commonly assessed by the PT as previously discussed. The water-soluble vitamins including B1, B2 , B6, B12 , niacin, folic acid, pantothenic acid, biotin, and vitamin C are also components of parenteral multivitamins and EN. Routine monitoring of these vitamins is not indicated (except for B12 and folic acid as previously discussed) unless there is a clinical reason to believe that there is a deficiency or toxicity.71
Metabolic Bone Disease

Metabolic bone disease (MBD) is a complication that may result from long-term PN. It may present as osteomalacia, osteopenia, or osteoporosis. Several factors may increase the incidence of MBD. Those include medications, calcium, and vitamin D malabsorption, metabolic acidosis, high aluminum concentrations in PN, and other nutrient deficiencies. In addition to the presence of bone
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Table 36-7
Parameter Initial Followup
Table 36-8
Parameter Initial Followup
BMP CMP Magnesium Phosphorous Prealbumin Triglycerides PT/INR CBC differential/ platelets GGT
Daily Weekly Daily to Weekly Daily to Weekly Weekly Daily to Weekly Weekly Weekly Baseline if indicated
Included in CMP Every 1 to 4 weeks Every 1 to 4 weeks Every 1 to 4 weeks Monthly Monthly Monthly Every 1 to 4 weeks Monthly
Iron Studies Zinc Selenium Manganese Copper Chromium Vitamins A, D, and E Vitamin B12 and Folate Carnitine TSH
3 mo 3 mo 3 mo 3 mo 3 mo 3 mo 6 mo 6 mo 3 mo Baseline if indicated
Every 36 mo Every 36 mo Every 36 mo Every 36 mo Every 36 mo Every 36 mo Every 12 mo Every 12 mo Every 312 mo Every 12 mo
Appendix 36-1 PN Limits

Adult Pediatric NICU Stability Usual Dose Comments
Na K Ca PO4 Mg Cl Ac Zn Cysteine Vitamin K Ranitidine Famotidine Folic Acid Heparin Vitamin C Carnitine Amino Acid Dextrose Lipid
180 150 30 35 24 300 300 10
180 06 150 06 30 02 30 02 24 00.5 250 08 250 08 5 300 10 100 06 n/a 2.5 10 1000 700 50 Min 10 g/L or DC Lipids Min 50 g/L Min 5 g/L
10 n/a 40
180 06 150 05 30 04.5 30 02 13 01 250 010 250 010 5 400 120 n/a 100 2 n/a 2.5 10 1000 700 50 Min 10 g/L or DC Lipids Min 50 g/L Min 5 g/L
1000 500 50 Min 20 g/L Min 50 g/L Min 5 g/L
mEq/L mEq/kg mEq/L mEq/kg mEq/L mEq/kg mmol/L mmol/kg mEq/L mEq/kg mEq/L mEq/kg mEq/L mEq/kg mg/L Mcg/kg mg/kg ***mg*** mg/L mg/kg mg/L mg/kg ***mg*** mg/d units/L mg/d mg/kg/d
X X X X X X X X X X X X X X X X X X
Osmolarity
Total zinc or DC fat mg/day
Not mg/L X X X X X X X Total dose X Need 20 g/L if Dextrose < 10% or DC Lipids DC Lipids if < 50 g/L DC Lipids if < 5 g/L
472
Appendix 36-2 Neonatal and Pediatric PN Monitoring Form Name: MRN: DOB: Age:___y____m____d Goals: Calories (kcal/d):_ ___________________ Protein (g/d):_______________________ Fluid (mL/d):_ ______________________ Date Weight (kg) Sodium / Potassium Chloride / Carbon Dioxide BUN / Creatine Glucose / Calcium Phosphorous / Magnesium Total/conj. Bilirubin Cholesterol / Triglyceride AST / ALT AlkPhos / GGT Hgb / Hct WBC / platelets INR Zinc Albumin / Prealbumin AA/Dex/lipid Na (mEq/kg) K (mEq/kg) Cl (mEq/kg) Anions (A,C) Ca (mEq/kg) P (mmol/kg) Mg (mEq/kg) Heparin MVI:Peds/Adult TMS:Peds/Adult Zinc (mcg/kg) Copper (mcg/kg) Manganese (mcg/kg) Chromium (mcg/kg) Selenium (mcg/kg) Carnitine (mg/kg) Rate/Cycle Total Volume/day Total Calories/day kcal/kg GIR NPC:N Wt used for script kcal/mL Formula Rate/Cycle Route mL PN/EN kcal / kcal/kg % PN/EN Protein (g) Protein (g/kg) UOP mL/kg/h Emesis Stool Ostomy mL/d / mL/kg Total mL /
Admit Date: DX:
kcal/kg: ________________________________ g/kg: __________________________________ mL/kg:_ ________________________________ LABS
MD: Date: wt_____ :____%ile ht/lt_ __ :____%ile wt/ht_ _______%ile dry wt__________
WA_______ HA________ BMI_______ IBW_______
/ / / / / / / / / / / / / /
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TPN SCRIPT / /
ENTERAL / / / / / / TOTALS / / / / / / / / / /
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OUTPUT
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Appendix 36-3 Long-Term PN Lab Tracking Sheet Patient: TPN start date: Enteral Formula: Lab Location: Date: Every Month Pre-Albumin Triglyceride GGT MCV Every 3 Months Selenium Manganese Copper Chromium Zinc Ferritin Iron Serum TIBC Transferrin Saturation Carnitine Total Carnitine Free Carnitine Ratio Every 12 Months Vitamin A Vitamin D Vitamin E Vitamin B12 RBC Folate TSH Free T4 Aluminum Recorded By: Reviewed By: Date Faxed to Physician: D.O.B. Physician: Fax: Pager: Other Contact: Phone: Diagnosis: Home Health Care: Lab Location / Phone: Family Contact: Medical Record Number:
474
1. Meeting a weight goal is the primary goal for SNS patients. A. True B. False 2. Bloating, fullness, and abdominal cramping may be related to the rate of enteral nutrition infusion. A. True B. False 3. Examining the GIR from PN may provide insight to hyperglycemia of unknown etiology. A. True B. False 4. Final amino acid and dextrose concentrations do not affect calcium and phosphorus solubility. A. True B. False 5. Only selenium and zinc levels should be monitored periodically in patients receiving PN with cholestasis or specifically a direct bilirubin > 2 mg/dL. A. True B. False See p. 487 for answers.
References
1. A.S.P.E.N. Enteral Nutrition Practice Recommendations Task Force. Enteral nutrition practice recommendations. J Parenter Enteral Nutr. 2009;33(2):122167. 2. Santanan e Meneses JF, Leite HP, de Carvalho WB, et al. Hypophosphatemia in critically ill children: prevalence and associated risk factors. Pediatr Crit Care Med. 2009;10:234238. 3. Dickerson R. Refeeding syndrome in the intensive care unit. Hosp Pharm. 2002;37(7):770775. 4. Parrish CR. The refeeding syndrome in 2009: prevention is the key to treatment. J Support Oncol. 2009;7:2021. 5. McCray S, Walker S, Parrish CR. Much ado about refeeding. Practical Gastroenterol. 2005;30(1):2644. 6. Danner E, Joeckel R, Michalak S, et al. Weight velocity in infants and children. Nutr Clin Pract. 2009;24:7679. 7. Guo S, Roche AF, Fomon SJ, et al. Reference data on gains in weight and length during the first two years of life. J Pediatr. 1991;119:355362. 8. A.S.P.E.N. Board of Directors and Task Force on Standards for Specialized Nutrition Support for Hospitalized Pediatric Patients. Standards for specialized nutrition support: hospitalized pediatric patients. Nutr Clin Pract. 2005;20:103116. 9. Moyer-Mileur L. Anthropometric and laboratory assessment of very low birth weight infants: the most helpful measurements and why. Semin Perinatol. 2007;31:96103. 10. A.S.P.E.N. Board of Directors and the Clinical Guidelines Task Force. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J Parenter Enteral Nutr. 2002;1SA.
11. Wessel JJ, Kocoshis SA. Nutritional management of infants with short bowel syndrome. Semin Perinatol. 2007;31:104111. 12. Intralipid 20% A 20% I.V. Fat Emulsion [package insert]. Clayton, NC: Kabi Pharmcia; 1991. 13. Bullock L, Etchason E, Fitzgerald JF, et al. Case report of an allergic reaction to parenteral nutrition in a pediatric patient. J Parenter Enteral Nutr. 1990;14:98100. 14. Market AD, Lew DB, Schropp KP, et al. Parenteral nutrition-associated anaphylaxis in a 4-year-old child. J Pediatr Gastroenterol Nutr. 1998; 26(2):229231. 15. Seashore JH, Hoffman M. Use and abuse of peripheral parenteral nutrition in children. Nutr Support Serv. 1983; 3(10):813. 16. Imperial J, Bistrain BR, Bothe A Jr, et al. Limitation of central vein thrombosis in total parenteral nutrition by continuous infusion of lowdose heparin. J Am Coll Nutr. 1983;2:6373. 17. Kakzanov V, Monagle P, Chan A. Thromboembolism in infants and children with gastrointestinal failure receiving long-term parenteral nutrition. J Parenter Enteral Nutr. 2008;32:8893. 18. Szeszycki E, Kastner A, Mobley L, Gervasio J. A comparison of the efficacy of 0.5 units/mL versus 1 unit/mL of heparin in neonatal parenteral nutrition. A.S.P.E.N. 2009, Nutrition Practice Poster Presentation. 19. Shulman RJ, Phillips S. Parenteral nutrition in infants and children. J Pediatr Gastroenterol Nutr. 2003;36(5):588607. 20. Wesley JR, Coran AG. Intravenous nutrition for the pediatric patient. Semin Pediatr Surg. 1992;1:212. 21. Koletzko B, Goulet O, Hunt J, et al. 1. Guidelines on paediatric parenteral nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), supported by the European Society of Paediatric Research (ESPR). J Pediatr Gastroenterol Nutr. 2005;41:S28S32. 22. Burke JF, Wolfe RR, Mullany CJ, et al. Glucose requirements following burn injury. Ann Surg. 1979;190(3):274285. 23. Jensen AR, Goldin AB, Koopmeiners JS, et al. The association of cyclic parenteral nutrition and decreased incidence of cholestatic liver disease in patients with gastroschisis. J Pediatr Surg. 2009;44(1):183189. 24. Btaiche IF, Khalidi N. Parenteral nutrition-associated liver complications in children. Pharmacotherapy. 2002;22:188211. 25. Mirtallo J, Canada T, Johnson D, et al. Task Force for the Revision of Safe Practices for Parenteral Nutrition. Safe practices for parenteral nutrition. J Parenter Enteral Nutr. 2004;28(6):S39S70. Erratum 2006; 30:177. 26. Kerner JA, Poole RL. The use of IV fats in neonates. Nutr Clin Pract. 2006;21:374380. 27. Pianese P, Salvia G, Campanozzi A, et al. Sterol profiling in red blood cell membranes and plasma of newborns receiving total parenteral nutrition. J Pediatr Gastroenterol Nutr. 2008;47(5):645651. 28. Clintec Nutrition Company in cooperation with Wagner DR and Atkins J. Total Nutrient Admixtures: Clinical and Practical Guidelines. USA: Clintec Nutrition Co; 1992.
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29. Trissel LA, ed. Handbook on Injectable Drugs. 11th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2001:195205. 30. IV Compatibility. King Guide to Parenteral Admixtures. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at: http://online.lexi.com/crlonline. Accessed January 2009. 31. Food and Drug Administration. Safety Alert: Hazards of precipitation associated with parenteral nutrition. Am J Hosp Pharm. 1994;51:14271428. 32. Bullock L, Fitzgerald JF, Walter WV. Emulsion stability in total nutrient admixtures containing a pediatric amino acid formulation. J Parenter Enteral Nutr. 1992;16:6468. 33. Driscoll DF, Bhargava HN, Zaim RH, et al. Physicochemical stability of total nutrient admixtures. Am J Health Syst Pharm. 1995;52:623634. 34. Driscoll DF, Giampietro K, Wichelhaus DP, et al. Physicochemical stability assessments of lipid emulsions of varying oil composition. Clin Nutr. 2001;20:151157. 35. Driscoll DF, Ling PR, Bistrain BR. Physical stability of 20% lipid injectable emulsions via simulated syringe infusion: effects of glass vs. plastic product packaging. J Parenter Enteral Nutr. 2007;31:148153. 36. Warshawsky KY. Intravenous fat emulsions in clinical practice. Nutr Clin Pract. 1992;7(4):187196. 37. OGrady NP, Alexander M, Dellinger EP, et al. Guidelines for the prevention of intravascular catheter-related infections. Infect Control Hosp Epidemiol. 2002;23:759769. 38. Neuzil J, Darlow BA, Inder TE, et al. Oxidation of parenteral lipid emulsion by ambient and phototherapy lights: potential toxicity of routine parenteral feeding. J Pediatr. 1995;126:785790. 39. Nyffeler MS, Frankel E, Hayes E, et al. Drug-nutrient interactions. In: Merritt R, DeLegge MH, Holcombe B, et al., eds. The A.S.P.E.N. Nutrition Support Practice Manual. 2nd ed. USA: American Society for Parenteral and Enteral Nutrition; 2005:118136. 40. Drug Interactions. Thomson Micromedex. Greenwood Village, CO. http://thomsonhc.com. Accessed January 2009. 41. Navaneethan SD, Sankarasubbaiyan SG, Jeevanantham VM. Tacrolimus-associated hypomagnesemia in renal transplant receipients. Transplantation Proc. 2006;38(5):13201322. 42. Brown RO. Drug-nutrient interactions. In: Cresci G., ed. Nutrition Support for the Critically Ill Patient: A Guide to Practice. Boca Raton, FL: CRC Press; 2005:341355. 43. Robinson CA, Lee JE. Y-site compatibility of medications with parenteral nutrition. In: Phelps SJ, Hak EB, Crill CM, eds. Teddy Bear Book: Pediatric Injectable Drugs. 8th ed. Bethesda, MD: American Society of HealthSystem Pharmacists; 2007:459463. 44. Trissel LA. Compatibility of medications with 3-in-1 parenteral nutrient admixtures. J Parenter Enteral Nutr. 1999;23:6774. 45. Siepler J. Principles and strategies for monitoring home parenteral nutrition. Nutr Clin Pract. 2007;22:340350. 46. Kovacevish D, Canada T, Lown D. Monitoring home and other alternate site nutrition support. In: Gottschlich M, ed., Fuhrman M, ed, et al. The Science and Practice of Nutrition Support. Dubuque, IA: Kendell/Hunt Publishing Co; 2000:731756.
47. Vanderhoof J, Young R. Overview of considerations for the pediatric patient receiving home parenteral and enteral nutrition. Nutr Clin Pract. 2003;18:221226. 48. Sacks G, Mayhew S, Johnson D. Parenteral nutrition implementation and management. In: Merritt R, ed, et al. The A.S.P.E.N. Nutrition Support Practice Manual. 2nd ed. USA: American Society for Parenteral and Enteral Nutrition; 2005:108117. 49. American Society for Parenteral and Enteral Nutrition Board of Directors and the Standards for Specialized Nutrition Support Task Force, Kovacevich DS, Frederick A, Kelly D, Reid N, Young L. Standards for specialized nutrition support: home care patients. Nutr Clin Pract. 2005;20:579590. 50. Ireton-Jones C, DeLegge MH, Epperson LA, et al. Management of the home parenteral nutrition patient. Nutr Clin Pract. 2003;18:310317. 51. Pagana KD, Pagana TJ, eds. Mosbys Diagnostic and Laboratory Test Reference. 8th ed. St Louis, MO: Mosby; 2007:755756. 52. Fuhrman MP, Charney P, Mueller CM. Hepatic proteins and nutrition assessment. J Am Diet Assoc. 2004;104:12581264. 53. Marshall WJ. Nutritional assessment: its role in the provision of nutrition support. J Clin Pathol. 2008;61:10831088. 54. Johnson AM, Merlini G, Sheldon J, et al. Clinical indications for plasma protein assays: transthyretin (prealbumin) in inflammation and malnutrition. Clin Chem Lab Med. 2007;45:419426. 55. Crook MA. Lipid clearance and total parenteral nutrition: the importance of monitoring plasma lipids. Nutrition. 2000;16:774775. 56. Crill CM, Helms RA. The use of carnitine in pediatric nutrition. Nutr Clin Pract. 2007;22:204213. 57. Borum PR. Carnitine in neonatal nutrition. J Child Neurol. 1995;10(suppl):2S252S31. 58. Winter SC, Szabo-Aczel S, Curry CJ, et al. Plasma carnitine deficiency: clinical observations in 51 pediatric patients. Am J Dis Child. 1987;141:660665. 59. Tao RC, Yoshimura NN. Carnitine metabolism and its application in parenteral nutrition. J Parenter Enteral Nutr. 1980;4:469486. 60. Hamilton C, Austin T, Seidner DL. Essential fatty acid deficiency in human adults during parenteral nutrition. Nutr Clin Pract. 2006;21:387394. 61. Postuma R, Pease PW, Watts R, et al. Essential fatty acid deficiency in infants receiving parenteral nutrition. J Pediatr Surg. 1978;13:393398. 62. Panel on Macronutrients, Panel on the Definition of Dietary Fiber, Subcommittee on Upper Reference Levels of Nutrients, Subcommittee on Interpretation and Uses of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary Reference Intakes for Energy, Carbohydrate, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington DC: The National Academies Press; 2005:422541. 63. Postuma R, Trevenen CL. Liver disease in infants receiving parenteral nutrition. Pediatrics. 1979;63:110115. 64. Kelly DA. Liver complications of pediatric parenteral nutrition-epidemilogy. Nutrition. 1998;14:153157.
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65. Quigley EM, Marsh MN, Shaffer JL, Markin RS. Hepatobiliary complications of total parenteral nutrition. Gastroenterology. 1993;104:286301. 66. Payne-James JJ, Silk DB. Hepatobiliary dysfunction associated with total parenteral nutrition. Dig Dis. 1991;9:106124. 67. McMillan NB, Mulroy C, MacKay MW, et al. Correlation of cholestasis with serum copper and whole-blood manganese levels in pediatric patients. Nutr Clin Pract. 2008;23:161165. 68. Duerksen DR, Papineau N. The prevalence of coagulation abnormalities in hospitalized patients receiving lipid-based parenteral nutrition. J Parenter Enteral Nutr. 2004;28:3033. 69. Deitcher SR. Interpretation of the international normalized ratio in patients with liver disease. Lancet. 2002;359:4748. 70. Pluhator-Murton MM, Fedorak RN, Audette RJ, et al. Trace element contamination of total parenteral nutrition. 1. Contribution of component solutions. J Parenter Enteral Nutr. 1999;23:222227. 71. Jensen GL, Binkley J. Clinical manifestations of nutrient deficiency. J Parenter Enteral Nutr. 2002;26:S29S33. 72. Fuhrman MP. Micronutrient assessment in long-term home parenteral nutrition patients. Nutr Clin Pract. 2006;21:566575. 73. Prelack K, Sheridan RL. Micronutrient supplementation in the critically ill patient: strategies for clinical practice. J Trauma. 2001;51:601620. 74. Poole RL, Hintz SR, Mackenzie NI, et al. Aluminum exposure from pediatric parenteral nutrition: meeting the new FDA regulation. J Parenter Enteral Nutr. 2008;32(3):242246. 75. Heimburger DC, McLaren DS, Shils M. Clinical manifestations of nutrient deficiencies and toxicities: a resume. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern Nutrition in Health and Disease. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:595612. 76. Nielsen FH. Boron, manganese, molybdenum, and other trace elements. In: Bowman BA, Russel RM, eds. Present Knowledge in Nutrition. 8th ed. Washington, DC: ILSI Press; 2001:384400. 77. Ibrahim M, Morreale de Escobar GM, Visser TJ, et al. Iodine deficiency associated with parenteral nutrition in extreme preterm infants. Arch Dis Child Fetal Neonatal Ed. 2003;88:F5657. 78. Moukarzel AA, Buchman AL, Salas JS, et al. Iodine supplementation in children receiving long-term parenteral nutrition. J Pediatr. 1992;121:252254. 79. Nagano T, Toyoda T, Tanabe H, et al. Clinical features of hematological disorders caused by copper deficiency during long-term enteral nutrition. Intern Med. 2005;44:554559.
80. Fuhrman MP, Herrmann V, Masidonski P, et al. Pancytopenia after removal of copper from total parenteral nutrition. J Parenter Enteral Nutr. 2000;24:361366. 81. Beshgetoor D, Hambidge M. Clinical conditions altering copper metabolism in humans. Am J Clin Nutr. 1998;67:10171021S. 82. Hoffbrand AV. Chapter 100 Megaloblastic anemias. In: Harrisons Online. http://www.accessmedicine.com/content. aspx?aID=2893392. Accessed October 21, 2009. 83. Clark SF. Vitamins and trace elements. In: Gottschlich MM, DeLegge, MH, Mattox T, Mueller C, Worthington P, eds. The A.S.P.E.N. Nutrition Support Core Curriculum: A CaseBased Approach The Adult Patient. Silver Spring, MD: American Society for Parenteral and Enteral Nutrition; 2007:129159. 84. Ferrone M, Geraci M. A review of the relationship between parenteral nutrition and metabolic bone disease. Nutr Clin Pract. 2007;22:329339. 85. Klein GL. Metabolic bone disease of total parenteral nutrition. Nutrition. 1998;14:149152. 86. Centers for Disease Control and Prevention. Guidelines for the Prevention of Intravascular Catheter-Related Infections. MMWR Recomm Rep. 2002;51(RR10):129. 87. Messing B, Peitra-Cohen S, Debure A, Bernier J. Antibioticlock technique: a new approach to optimal therapy for catheter-related sepsis in home-parenteral nutrition patients. J Parenter Enteral Nutr. 1988;12:185189. 88. Bestul MB, VandenBussche HL. Antibiotic lock technique: review of the literature. Pharmacotherapy. 2005;25:211227. 89. Opilla MT, Kirby DF, Edmond MB. Use of ethanol lock therapy to reduce the incidence of catheter-related bloodstream infections in home parenteral nutrition patients. J Parenter Enteral Nutr. 2007;31(4):302305. 90. Mouw E, Chessman K, Lesher A, Tagge E. Use of an ethanol lock to prevent catheter-related infections in children with short bowel syndrome. J Pediatr Surg. 2008;43(6):10251029. 91. Onland W, Shin CE, Fustar S, Rushing T, Wong WY. Ethanol-lock technique for persistent bacteremia of long term intravascular devices in pediatric patients. Arch Pediatr Adolesc Med. 2006 Oct;160(10):10491053. 92. Dannenberg C, Bierbach U, Rothe A, Beer J, Korholz D. Ethanol-lock technique in the treatment of bloodstream infections in pediatric oncology patients with broviac catheter. J Pediatr Hematol Oncol. 2003;Aug;25(8):616621. 93. Crnich CJ, Halfmann JA, Crone WC, Maki DG. The effects of prolonged ethanol exposure on the mechanical properties of polyurethane and silicone catheters used for intravascular access. Infect Control Hosp Epidemiol. 2005;26:708714.
Ethical Issues in the Provision ofNutrition

Patrick M. Jones, MD, MA and Brian Carter, MD
37
CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485 Clinical Care as a Team Approach . . . . . . . . . . . . . . . . . . 486 Approaching the Pediatric Patient: WhatShould We Let Them Know?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
The Good Shepherds The Liberators The Educators
Learning Objectives
1. Explain 3 models of sharing information with a pediatric patient. 2. Define natural versus medical provision of nutrition. 3. Review the importance of determining goals of treatment. 4. Examine the unique values associated with providing nutrition to children.
Natural versus Medical Provision ofNutrition . . . . . 487 Determining the Goals of Nutrition. . . . . . . . . . . . . . . . . . 487 Values Ascribed to Feeding. . . . . . . . . . . . . . . . . . . . . . . . 488
Do we tend to see medical feeding in a different light from other interventions? Why is unique value assigned to feeding?
Introduction
Ethical Dimensions of Clinical Nutrition Issues. . . . . . . . 489

The Intensive Care Environment: Neonatal and Beyond Palliative Care The Special Needs Infant and Toddler Vegetarian Diets, Fad Diets, and Feeding Disorders Childhood Obesity The Adolescent Summary
Case Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491

A Decision Not to Start Medical Nutrition Support? The Withdrawal of Nutrition Support
There are ever-expanding clinical applications to ethics in the practice of the healing arts. The uniqueness of the pediatric patient, who is dynamic in her growth, development, and communication and cognitive capacities, requires special sensitivity on the part of all healthcare professionals. Similarly, decisional processes that early on rely solely on parents/ guardians gradually must change to incorporate the child and, ultimately, yield to the child as a maturing and autonomous young adult. As interdisciplinary team members work together to bring about cure, prolong function, and provide comfort to children living with acute and chronic health care conditions, a common approach, language, and understanding of values that are important to patients, families, and health care professionals will serve everybody. Like other specialty areas, pediatric nutrition comes with its own set of ethical challenges. Approaching these challenges requires that the clinician be able to communicate effectively with patients, families, and other caregivers. This chapter is not intended to make a person competent to handle any or all situations, but instead it intends to help the reader become more comfortable when engaging in conversations regarding ethics so that the important voice of the nutritionist is heard by families and caregivers discussing these issues.
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Clinical Care as a Team Approach
The practice of medicine, even when dealing with decisions that raised fundamental ethical and social questions, was historically the domain of an individual physician. Physicians would decide if a critically ill baby had enough potential to continue on the ventilator, whether an organ should be given to a patient in heart failure, or if the elderly womans pneumonia should be treated with antibiotics. However, events such as abuses in human experimentation and the formation of a national commission to explore medical ethics in the late 1960s and early 1970s began to change the number of persons gathering around the bedside. During the 1970s and 1980s, institutional review boards (IRBs) examined research protocols to ensure subject protection; orders to limit life-saving interventions began to be documented and justified in the medical chart; and ethics committees discussed situations that spurred moral disagreement in the medical staff and/or the family. The result has been a dramatic shift in how health care interacts with the medical patient.1 Today, health care is not only affected by this history but also the increasing role of the medical specialist. Any or all of the following caregivers may be found participating in the care of a sick child and her family: bedside nurse, charge nurse, respiratory therapist, physician (including various physician subspecialists and trainees), dietitian, physical therapist, occupational therapist, speech pathologist, social worker, case manager, psychologist, nurse practitioner, physician assistant, chaplain, child life specialist, and music therapist. The potential for benefit is high, as many professionals focus on specific aspects of that patients care, but an obvious, and frequent, drawback is a lack of true teamwork. Most of the time, this problem originates from a lack of defined roles mixed with poor communication; the result may be conflicting messages presented to the family. It is important to acknowledge that within the team lies people with individual experiences and personal circumstances. Cultivating an environment where the team can openly discuss concerns about patient care is a formidable, but extremely valuable undertaking. As a participating member of a health care team, it is each persons responsibility to form this team environment by communicating effectively, understanding the underlying issues at hand, and maintaining a complete picture of the goals and objectives of the clinical care of a patient.
Pediatric medicine has at its core a unique figure: the ever-changing and developing child. Most of the time, the medical communitys interaction with children is brief they get sick, they recover, they blissfully run off to their old routines. Occasionally, however, the encounters last much longer and involve illnesses that do not allow a quick recovery or even a return home. A foundational concern for the caregivers of these patients is that of knowing what information, if any, to give the child regarding an illness. There are certain children for which this question is rather straightforward; an example being a child who is unable to comprehend the world around her (eg, a newborn or a child with severe traumatic brain injury). However, an 8-yearold with leukemia is able to understand some aspects of her illness, and may need to participate in conversations regarding her disease and its treatment. To help summarize the best approach to involving the pediatric patient, it is useful to turn to the work of Robert Cassidy in his chapter on truth-telling.2 Cassidy describes 3 broad communication strategies for communicating with a sick child. His first 2 models are described as the good shepherd and the liberator models. After discussing the history of these approaches and providing critiques, he offers up a compromise, the educator model of pediatric engagement, which best describes the approach used by most pediatricians today.
Approaching the Pediatric Patient: WhatShould We Let Them Know?
The Good Shepherds

This model is rooted in the historical model of patient-physician interaction in which the physician, because of his or her special knowledge concerning health and the human body, primarily made all decisions regarding a patients treatment, sometimes even choosing not to inform the patient of an underlying medical condition. With the emphases of patient autonomy in the late 1960s and early 1970s, this paternalistic practice began to disappear, and patients became intimately involved in choices regarding their medical care. However, the autonomy movement was not quick to trickle down to the pediatric population, as medical providers and parents continued to treat children in a similar manner. These adults viewed it as their duty to take responsibility for all decisions, due to their more advanced level of knowledge and maturity. Caregivers feared that telling the truth to a sick child about her condition would be harmful, and therefore selfish and irresponsible, so they adamantly guarded the child from any discussions about their medicalcare.
ETHICAL ISSUES IN THE PROVISION OFNUTRITION
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The Liberators
Cassidy describes the liberators are those who fought to counter the arguments of the Good Shepherds, especially as researchers in the medical and social sciences made the following important discoveries: Withholding illness-related information from children tends to increase their anxiety and fear. 3 Some sick children feel pressure to continue the faade of not knowing about their illness in order to protect their parents.4 Children are exceptionally observant and adept at discovering the truth, regardless of the intent of parents or health care providers to shield them from it. 5,6 Although a mature concept of death was thought to be unattainable by a child, a majority of children reach such an understanding by the age of 7 years.7 While this information argued for children to be given information about their illness, the liberators erred in assuming that the solution was to apply adult standards to the pediatric population. The result was a standoff between 2 approaches that stood at opposing ends of the spectrum: either tell children nothing in order to protect them from a harsh reality, or tell children everything and potentially bombard them with age-inappropriate information.
4. Soliciting an expression of the patients willingness to accept the proposed care. 8 A frequent objection to obtaining assent is the fear that the child may refuse to assent to a needed procedure. However, as noted by Cassidy, this potential roadblock for the care team may be extremely beneficial for the patient. As children are typically eager to please the important figures in their lives, a refusal to give assent could be an important signal that a misunderstanding or fear needs to be addressed by the parent or care team prior to the procedure being performed. The result is improved communication and trust (and potentially an improved outcome).2
The Educators
A compromise is forged by approaching the patient in a manner that makes use of a skill already rooted within the practice of pediatrics: the assessment of a childs development. In this approach, caregivers interact with the pediatric patient in a manner that is appropriate to her level of development; autonomy is not given fully and freely to the child, but caregivers act in a manner that will inform and foster the development of her increasing autonomy. This gradual approach, especially in children with chronic, yet survivable medical conditions (eg, diabetes) makes the transition to adulthood more realistic than the sudden placement of full responsibility upon a patient when she becomes an adult. Used within this model is the concept of obtaining assent from the pediatric patient. The American Academy of Pediatrics (AAP) describes assent as having 4 elements: 1. Helping the patient achieve a developmentally appropriate awareness of the nature of his or her condition 2. Telling the patient what he or she can expect with tests and treatment(s) 3. Making a clinical assessment of the patients understanding of the situation and the factors influencing how he or she is responding (including whether there is appropriate pressure to accept testing or therapy)
When discussing ethical issues it is helpful to begin the conversation by making sure that the terms and phrases being used are understood in the same manner. Therefore, prior to looking at individual clinical examples, it is important to discuss what is meant by the natural provision of nutrition as opposed to the medical provision of nutrition. These terms can be used in various manners, but for the purposes of this chapter, the definitions put forth by Nicolas Porta and Joel Frader are helpful as they describe their typical usage in the clinical and bioethical literature.9 The natural provision of nutrition refers to all feedings that do not require medical intervention, specifically breast, bottle, cup, and other oral feedings. Medical provision of nutrition refers to nutrition that requires a special physician order (eg, the usage of a nasogastric tube, central intravenous catheter, or the placement of a gastrostomy feeding tube). As they are quick to point out, these classifications into natural and medical do not connote that one is ethically optional while the other is not.9 For example, medical nutrition is frequently used in premature infants until they develop the ability to suck and swallow safely; discontinuation of such feedings to a child without another complication (such as a fatal underlying condition) would be unacceptable.
Natural versus Medical Provision ofNutrition
Determining the Goals of Nutrition
Another useful practice prior to discussing an ethical question, particularly one that focuses on the use or disuse of a particular medical intervention, is to define the goals of the act in question. For instance, when a child is placed on a ventilator, certain goals are set for the usage of that intervention (although this process is rarely formalized). Often the goal is the provision of oxygen and the removal of carbon dioxide until appropriate lung healing, or maturation, can take place. Once that goal is no longer served because the
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lungs have developed enough to sustain life, the ventilator is discontinued. On a similar, yet more tragic vein, if the infant is found to have a genetic condition that will prevent the lungs from ever healing or maturing to the point that the ventilator is unnecessary, it can be said that the intervention (assisted ventilation) is not serving the initial goal. The physiological purpose of the ventilator, to provide oxygen and remove carbon dioxide, is still being met, but the overarching goal of using the ventilator to support the infant until lung healing or maturation is achieved is no longer applicable. While the ventilator may be continued, it is now with a completely different set of goals in mind. This may be to sustain life at all costs; however this longterm management goal is often fraught with complications. The new goal might be to briefly continue physiological support until the family has adjusted to the terminal nature of the childs condition. This could include waiting for other family members to come together, perhaps from a distance, to provide emotional support and assist with funeral plans. Regardless of the decision made, it should be recognized that the underlying goal has changed, and it is no longer to support until a cure. Thus, when discussing nutrition in light of ethical dilemmas posed by individual cases, it is important to consider the underlying goal of providing nutrition. In its very basic form, the goal of providing pediatric patients with nutrition (natural or medical) is to provide them with the substrate, vitamins, and minerals needed to meet basic metabolic demands for appropriate growth and development. Of course, there are many other goals for nutrition in addition to this rather basic purpose. For example, in the patient with cystic fibrosis, adequate nutrition to meet increased needs becomes a key factor in decreasing morbidity and mortality. Also, in a patient with liver failure, the goals of providing nutrition include optimizing his chance for a successful transplant. However, just as in the aforementioned example with the ventilator, should the clinical situation change, it is important to reevaluate the goals of nutrition therapy as they may no longer apply and the team may find itself pursuing a nutritional strategy based on an outdated set of goals. As an example of this, if a child with liver failure suffers a new complication that makes transplant impossible, the goal of nutrition would no longer be to optimize the patient for surgery. The realization of new goals, such as improving quality of life, may allow the team to be less aggressive (no central lines, less emphasis on caloric intake) and begin to de-medicalize the family and the child during the final months of life.
Values Ascribed to Feeding

Do we tend to see medical feeding in a different light from other interventions?
Although identifying the goals of medically provided nutrition is critical, to limit the discussion to this process alone fails to address the complete picture. Outside of the intended goals, the provision of nutrition to a pediatric patient often has values assigned to it that make this intervention unique from other life-sustaining interventions. An example of this assignment of value can be seen in the description of withholding nutrition as starving the patient to death. This is a phase rather unique to discussions on nutrition; rarely is the removal of a ventilator described as suffocating the patient to death or the decision to forgo dialysis as drowning the patient to death. The tendency to use this language shows that a certain value is being placed upon the provision of medical feeding.10 Another example of this perspective of value assigned to feeding and nutrition is seen in a pair of surveys done with pediatric health care providers. The Pediatric Section of the Society for Critical Care Medicine found that 98% of physicians were apt to withhold cardiopulmonary resuscitation (CPR), 86% withdrew ventilators, but only 42% would withdrawal tube feedings.11 Likewise, a survey of pediatric residents in their third year of training demonstrated that 100% would withhold CPR and vasoactive medicines, 97% would withdraw ventilator support, but only 45% would withdrawal fluids and nutrition.12 Again, it appears that there are underlying values assigned to providing a child with nutrition that reach beyond the set medical goals. Because of this, ethical issues involving the provision or withholding of nutrition often take place in a unique and complex social dynamic, charged with emotion.
Why is unique value assigned to feeding?

What is it about feeding that makes it more likely to have additional value ascribed to it as opposed to dialysis? A possibility is that providing nutrition to a child is a fundamental responsibility of the caregiver. A child is born unable to provide himself with nutrition, and several years of development must take place before he is able to independently obtain and consume nutrition. Perhaps this responsibility is so ingrained in the caregivers being, that limiting its provision, no matter how beneficent the motives, causes feelings of guilt or neglect in attending to care-giving duties. Contrast this to the act of breathing: should assistance be needed with this life-sustaining function, its provision is beyond the usual parental duty. Therefore, while the discontinuation of
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a ventilator is difficult for all who care for the child, perhaps the feeling that all natural caregiving responsibilities have been fulfilled allows this to be more palatable limitation of treatment than the withholding of nutrition.10 Another potential reason for the uniqueness of feeding is the typical time course and physical appearance of a person who dies from starvation or dehydration. This is not to imply that starvation is not a natural part of the dying process, in fact the bodys reaction to a deprivation of nutrition may actually serve to ease a persons death. However, for families who are caring for a child who is not being adequately fed, the visual appearance and the prolonged time course prior to death may be too difficult to endure regardless of any medical considerations. Additionally, the supportive care programs that could provide palliative care throughout the dying process for these children are unavailable in many geographic locales.13,14 Therefore, it is understandable why the medical provision of nutrition may be seen as such an essential element of care.
Ethical Dimensions of Clinical Nutrition Issues

The Intensive Care Environment: Neonatal and Beyond
Common practice in the neonatal intensive care unit (NICU) includes a nutrition plan that facilitates growth, development, healing, and immune function. All newborns are born dependent upon caregivers for nutrition support. Those with special considerations such as prematurity, congenital anomalies requiring surgery, and numerous disease states all may require medically delivered nutrition and hydration. In a similar light, pediatric intensive care unit (PICU) patients may also be in need of nutritional support as infants, surgical patients, trauma victims, or because of chronic and debilitating conditions that may be associated with increased energy and nutrient demands or special needs for nutritional delivery. In the ICU, medically administered nutrition may well be the norm. As such, its goals and decided benefits must be reexamined as the patients condition changes. Risks (or burdens), as well as benefits of nutritional delivery systems must be acknowledged and clarified for the pediatric patient and his/her parents.15,16 The mere capability to do something does not equate with the absolute medical indication, or prerogative, to do so. Ethical challenges in nutrition management for neonatal and pediatric ICU patients, then, can be evaluated in the context of goals and values, and warrant open communication and a collaborative approach among the medical team involved. In a family-centered context, parental input may
be important in making certain choices about the appropriateness of medically delivered nutrition in the hospital or at home. At the very least, open and transparent decisional processes and communication with parents that allow for their understanding of why, and how, and for how long a certain method may be used, is required. When surgically placed devices (eg, central venous catheters, gastrostomy, or jejunostomy feeding tubes) are considered, the risks and benefits require special attention as the potential for pain, wound healing, aspiration, infection, thrombosis, or other complications must be weighed against the patient and family goals. For most patients the benefits are clear and the health care team makes reasonable decisions with the family to proceed with placement of such devices. But on occasion, the initial placement, or their replacement, become burdensome and cause all involved to pause and reconsider their appropriateness. This may be especially true in the terminal stages of many chronic and debilitating conditions. In these cases, adequate time needs to be devoted to discerning the best interests of the pediatric patientoften addressed differently by the patient, parents, and clinicians. Clinicians sensitivity to parental or patient goals and values that differ from their own, whether in matters of culture and custom, faith and religious tradition, or social and family norms and expectations must be present and allow for considerations beyond what may be simply metabolically or physiologically apparent as a best course of action. With long-term care and chronic debilitation, one may need to ask Does more always equate to better?17 Perhaps the most heated ethical debates in nutrition management of patients dependent upon medically delivered nutrition and hydration are in the context of the withholding or withdrawal (WH/WD) of such nutrition. For children, especially those in whom a cognitive capacity is not appropriate for them to participate in decisions, parents normally serve as surrogate decision makers as they are entrusted by society with discerning and acting upon their childs best interests. These interests, though not always knowable, certainly include not being treated as mere passive objects, and the same ethical and legal posture toward WH/WD medical nutrition is due them that is due adult patients.10 Decisions that are made concerning medical nutrition should be made like all other decisions about WH/WD life-sustaining treatments, although as previously noted these decisions may be fraught with greater psychological and emotional duress among all partiesespecially when the patient is not imminently dying.18, 19 As noted by Porta and Frader, clinicians should neither demand nor reject
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medical nutrition without examining and considering each situations context (eg, goals, values, burdens, and benefits), through which the provision of medical nutrition may be found morally optional.9
Palliative Care
The subject of palliative, and end-of-life, care has been of increasing interest in pediatric medicine over the past decade. Among resources that address what pediatric palliative care should entail, the 2003 Institute of Medicine Report When Children Die is among the most often cited.20 Among issues noted therein, the attention to medically administered [artificial] nutrition and hydration (ANH) is noted as one that warrants acknowledgement by clinicians of some residual controversy and continued need for inquiry. The recent AAP Clinical Report, Forgoing Medically Provided Nutrition and Hydration in Children, helps by providing further guidance in this sensitive area.21 Both of these resources, and numerous articles that have been published in the peer-reviewed medical literature, address aspects of ANH in the context of life-limiting or threatening conditions, and specifically at the end of life.22,23 Matters of values, open communication, assigned meanings to feeding, and the overall goals of care require attention in addressing this matter as much as any other life-sustaining interventions. The dietician may need to be a resource for parents, families, other care team members, and for physicians in particular as the issue of ANH is examined in the acute care setting (hospital or clinic), home health, or home palliative and hospice care. Attention to the normalcy of assisted feeding devices, such as gastrostomy feeding tubes, is another sensitive area that may require education as well as a values clarification. Petersen and colleagues reported a different perspective on feeding through a gastrostomy tube by a majority of daily caregivers of children with cerebral palsy.24
The Special Needs Infant and Toddler

Among the varied special needs children cared for by dieticians, perhaps the most labor-intensive and demanding are graduates from the NICU. These children may be followed by an interdisciplinary team in NICU Graduate Follow-up Clinics that include a dietitian, may be seen only by primary care clinicians (pediatricians, family physicians, nurse practitioners, physician assistants), in county health department clinics, or they may be altogether lost to follow-up. Their nutrition needs are fundamental to their care as continued growth, physical development, neurodevelopment, resilience with acute illness, and overall health are all predicated on good nutrition.25,26
On occasion an ethical dilemma may arise in determining that the placement of a medical nutrition device (feeding gastrostomy tube), is in the best interests of the patient. The dietician as a key interdisciplinary health care team member, or consultant, may bring clarity to decisions to go forward with such a plan, or to reconsider it. Goals clarification may be the greatest contribution to be made. The dietician may also be called to advocate for correct ethical action in beginning, sustaining, or advancing nutrition support for special needs children. She may find herself in tension with primary or specialty clinicians who have not prioritized nutrition for the NICU graduate, missed faltering growth, or are uncertain about what to do next for a child in whom a medical feeding device is not being used and oral nutrition is inadequate to secure the goals of health. Ethical action here requires professional competence, self-confidence, and a stance of advocacy for the child. Effectively communicating with involved clinicians, and parents, may include the provision of past and present goals of nutrition, observed and documented failures (growth curves, illness, and other outcomes), and recommendations with evidence-based expectations for measurable outcomes in an appropriate timetable. Additionally, some NICU graduates have chronic gastrointestinal illnesses such as cholestatic jaundice, liver disease, or short bowel syndrome (SBS) following neonatal surgery. The care of the child with SBS requires attentiveness to detail and elements of psychosocial support for the child and family that complement the necessary medical, nutrition, and pharmacy (home parenteral nutrition) management of this condition. Those who await eventual liver-bowel transplantation have lengthy waiting periods and high morbidity and mortality.27 Other children with special nutrition needs include those born with an inborn error of metabolism. Perhaps diagnosed prenatally, or even after discharge home from the hospital, many metabolic conditions result in acute illness and nearly all have significant impact upon child growth and development. The nutritionist must remind himself that he is part of a team and work collaboratively in addressing parent education, child health, and the provision of special nutrition products. In extreme cases, such as certain urea cycle disorders, liver transplantation may be the ultimate goal and nutrition assessment and daily management brings the nutritionist in close and frequent contact with the family. Should such contact lead to shared feelings about the childs illness, goals, and values, it is the nutritionists duty to raise issues that might seem contrary to the goals of the current care plan with the responsible physician or team leader.
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Vegetarian Diets, Fad Diets, and Feeding Disorders

The dietician is a key team member in addressing nutrition education for children of all ages. While this chapter cannot address the broad concerns raised and management issues required for children with feeding disorders such as bulimia and anorexia (Chapter 19), the dietician must attend to the priority of care being focused on the patients well-being and best interests as they can best be discerned. In conjunction with other clinicians and behavioral health specialists, the nutritionist may need to address facts, falsehoods, and fallacies about the goals of nutrition, nutrition essentials, and how all concerned parties may help children attain and maintain good health. When addressing vegetarian diets, it may be important to understand the rationale for such dieting can be clinical (eg, improved cardiovascular health and longevity), a means of addressing weight control, upholding religious tenets, or ethical life-style choices (addressing concern for the ecosystems on the planet, and for animal well-being).28 At the same time vegetarianism may be a marker for disordered eating practices (or tendencies) and a preoccupation with weight that may not serve the childs overall interests. 29 The dietician must balance appropriate support of choices and dieting habits with responsibilities of addressing potential clinical and behavioral health matters.
from parents and siblings but also a claim to independent thinking. For some, this may include the choice of separate dietary preferences, vegetarian dieting (while the remainder of their family, or even circle of friends continue omnivorous dieting), or participation in fad dieting that may actually reflect issues of reckoning with bodily changes of adolescence, or even self-image and psychological well-being. In this period of life, clinicians need to attend to the complexity of intersecting issuesclinical, social, and behavioralwhich affect dieting and overall nutritional well-being. A balance of respect for the adolescent accomplishing individual identity and independence must be met with informing and educating the young person about healthy habits and avoidance of negative behaviors. While matters of eating disorders exceed the subject of this chapter and are discussed elsewhere (Chapter 19), ethical precepts of respect for persons, doing good and avoiding harm, and attending to the fine line of confidentiality for and with the adolescent patient and his or her family must be recognized by all health care team members.
Summary
The timely, appropriate, and beneficial provision of pediatric nutrition requires attention to the pediatric patient and his or her parents and family. Ethical challenges may best be met with open dialogue, respectful listening, clarity of communication, and sensitive provision of support directed toward mutually derived nutrition goals. The dietician has an integral role to play in these matters as a valued interdisciplinary team member across diverse diagnostic categories, care environments, and the age continuum of pediatrics.
Childhood Obesity
The recent increase in childhood obesity may be seen by some as a mere medical, or strictly nutrition, condition. This is far from the reality of complex social, behavioral, educational, and even economic contributors to this growing concern. Some have raised the issue of obesity constituting medical neglect, and thereby warranting interventions that include social and legal actions akin to those expected in physical or sexual child abuse, or gross parental neglect of meeting a childs due needs (eg, food, clothing, shelter, education, and health care). Recently, Varness and colleagues have addressed the nature of these concerns and how they are rarely borne out in such a manner that obesity could legitimately be considered neglect. 30
Case Studies
A Decision Not to Start Medical Nutrition Support?
A term infant is delivered by emergency cesarean section for fetal bradycardia to a 25-year-old gravida I mother with diabetes mellitus. He required extensive resuscitation and had Apgar scores of 0, 0, and 3 at 1, 5, and 10 minutes after birth, respectively. He is admitted to the NICU with respiratory distress and hypoglycemia. His birth weight is 4.5 kg. He has poor cardiovascular function, hypotension, and metabolic acidosis. His respiratory depression and apnea require assisted ventilation. At 2 hours of age he has a convulsion and after receiving an anticonvulsant he is placed on a head-cooling protocol for severe birth asphyxia. An MRI confirms diffuse and devastating ischemic brain injury. On postnatal day 4 he fails a trial of extubation due to apnea and inability to handle his own secretions. He has
The Adolescent
The period of adolescence is accompanied by major developmental and cognitive goals, not the least of which are individuationthe process in which the young person engages in developing his or her own self-identity and strives to become an individual, distinct from parents and siblingsand independence, whereby the young person takes actions that allow for not only a separate identity
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no urine output for 7 days and after receiving initial intravenous dextrose the question of providing parenteral nutrition or a trial of nasogastric tube feedings is raised on morning ICU rounds. A discussion follows in which his prognosis for recovery is described as bleakhis future survival is contingent on the provision of a tracheostomy and placing a feeding gastrostomybut his potential for future neurological function (motor, cognitive, and communicative) and development is gone and he will remain infantile. This infant presents a number of opportunities for evaluating nutrition support: a large for gestational age infant of a diabetic mother (complicated by hypoglycemia), birth asphyxia (with circulatory shock, acidosis, and likely impaired gastrointestinal perfusion, mucosal barrier function, and poor gut motility), neurological injury, and renal failure. At a week of age he evidences multiple organ system injury and failure of function. His prognosis for successful oral feeding is nil, and in the face of renal failure the provision of parenteral nutrition must be questioned. 1. What is the ethical rationale for placing a central line and providing parenteral nutrition? 2. What is the burden:benefit analysis of pursuing a feeding gastrostomy and fundoplication? 3. What are the goals of nutrition support for this baby? 4. Can palliative care be provided without a specific feeding regimen?
The Withdrawal of Nutrition Support

Jill, a 3-year-old girl with severe cerebral palsy (spastic quadriplegia), seizures, and mental retardation after infantile meningitis, has recently required management in the PICU following a fourth episode of aspiration pneumonia. She is sedated in order to allow adequate assisted ventilation, and has been receiving medically administered intravenous nutrition and hydration for the past 5 days. Her parents meet with the PICU team to discuss the prognosis and plan of care. The team states they are hoping for the best for Jill, as nobody knows how long she was hypoxic after she arrested at home. A trial of lifting her sedation, reducing ventilator support, extubating Jill, and providing enteral nutrition through a transpyloric nasal feeding tube is agreed to by Jills parentswho are anxious to see any signs of Jill getting better. Two days later, however, Jills respiratory condition worsens after failing a trial of extubation and a tracheostomy must now be considered. Jills mother and father are overwhelmed by her decompensation following this most recent aspiration event. She is not responding to their voice or touch. At a follow-up family meeting her attending physician discusses his concern for
Jills neurological status. Unlike prior hospitalizations with aspiration pneumonia, this time she has never opened her eyes, is only reflexively responsive to pain, and he fears she may never improve, or even assume her prior level of infantile function. He also believes that Jills overall condition warrants not only the tracheostomy but that she will need a fundoplication to protect her airway if she were to receive gastric feedingsstating for clarification that feeding should now only be pursued via a gastrostomy tube. In realizing the extent of Jills injury and poor prognosis, the parents begin to sob, We knew this day might come. After a minute, the physician re-appraises the matter of nutrition support for Jill, stating, Just because we can place a feeding gastrostomy does not necessarily mean we should. And frankly, that is true for the tracheostomy as well. This gives the parents initial pause, but then they express a desire to speak with extended family members, their church, and be given some time. The physician leaves them alone to talk with the unit social worker. 1. What are the key considerations for this family to consider in making their decision for Jill? 2. How does the ethical standard of doing what is in the childs best interest pertain to this case? 3. What level of burden, pain, or suffering might be acceptable in doing surgery for Jill? 4. If the parents elect not to have a gastrostomy, fundoplication, and tracheostomy done, what nutrition support goals should exist for this patient?
1. When a developmentally appropriate child with cystic fibrosis asks questions to the medical team regarding his or her disease, the method of communication thought to be most beneficial is to: A. Carefully talk to the child, trying to stay positive, while also avoiding any potentially negative information. B. Try to give the child the worse case scenarios in hopes of preparing him or her for the worst. C. Tell the child that you are going to focus on todays plan of care, but that you will schedule an appointment with the nurse educator. D. With the guardians permission, try to answer the questions in an honest, but developmentally appropriate, manner. E. All of the above.
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2. How do Porta and Frader distinguish between natural and medical nutrition? A. Natural nutrition is a mandatory act. B. Medical nutrition is a mandatory act. C. Natural nutrition is always optional. D. Medical nutrition is always optional. E. None of the above. 3. Which of the following actions is not recommended as a way to help reach an ethical decision regarding the provision of nutrition? A. Make sure everyone on the team is using the same definition for commonly used medical and ethical terms. B. Avoid talking to the family or the patient until a decision is made so that the team does not appear uncertain. C. Define the long-term goal of providing nutrition to the patient. D. Discuss with the family their views and beliefs regarding feeding and/or the provision of nutrition. E. Carefully examine the context (goals, values, burdens, and benefits) of the nutrition dilemma. See p. 487 for answers.
References
1. Rothman DJ. Strangers at the Bedside. New York, NY: Walter de Gruyter, Inc; 2003. 2. Cassidy RC. Tell all the truth? Shepherds, liberators, or educators. In: Cassidy R, Fleischman A, eds. Pediatric Ethics: From Principles to Practice. Amsterdam, The Netherlands: Harwood Academic; 1996:6782. 3. Slavin LA, OMalley JE, Koocher GP, Foster DJ. Communication of the cancer diagnosis to pediatric patients: Impact on long-term adjustment. Am J Psychiatry. 1982;139(2):179183. 4. Bluebond-Langner M. The Private Worlds of Dying Children. Princeton, NJ: Princeton University Press; 1978. 5. Spinetta JJ, Rigler D, Karon M. Anxiety in the dying child. Pediatrics. 1973; 52(6):841845. 6. Spinetta JJ, Maloney MS. Death and anxiety in the outpatient leukemic child. Pediatrics. 1975;56(6):10341037. 7. Speece MW, Brent SB. Childrens understanding of death: A review of three components of a death concept. Child Dev. 1984;55:16711686. 8. American Academy of Pediatrics, Committee on Bioethics. Informed consent, parental permission, and assent in pediatric practice. Pediatrics. 1995;95(2):314317. 9. Porta N, Frader J. Withholding hydration and nutrition in newborns. Theor Med Bioeth. 2007;28:443451. 10. Carter BS, Leuthner SR. The ethics of withholding/ withdrawing nutrition in the newborn. Semin Perinatol. 2003;27(6):480487.
11. Society of Critical Care Medicine, Task Force on Ethics. Consensus report on the ethics of forgoing lifesustaining treatments in the critically ill. Crit Care Med. 1990;18(12):14351439. 12. Rubenstein JS, Unti SM, Winter RJ. Pediatric resident attitudes about technologic support of vegetative patients and the effect of parental inputa longitudinal study. Pediatrics. 1994;94(1):812. 13. Contro N, Larson J, Scofield S, Sourkes B, Cohen H. Family perspectives on the quality of pediatric palliative care. Arch Pediatr Adolesc Med. 2002;156:1419. 14. Liben S, Papadatou D, Wolfe J. Paediatric palliative care: Challenges and emerging ideas. Lancet. 2008;371(9615):852864. 15. Hobbs N. Decisions for a baby in foster care. J Clin Ethics. 2004;15(3):292295. 16. Mello M. The experience of a community representative on an Ethics Consult Team. J Clin Ethics. 2004;15(3):296301. 17. Essex C. More is not necessarily better. Arch Dis Child. 2006;91:202. 18. Mitchell C, Truog RD, Ethics Advisory Committee at Childrens Hospital Boston. Excerpts from the ethics consult report: MT. J Clin Ethics. 2004;15(3):302306. 19. Johnson JA. Withdrawal of medically administered nutrition and hydration: the role of benefits and burdens, and of parents and ethics committees. J Clin Ethics. 2004;15(3):307311. 20. Field MJ, Behrman RE, eds. When Children Die: Improving Palliative and End-of-Life Care for Children and Their Families. Washington, DC: National Academies Press; 2003:39, 143, 298299. 21. Diekema DS, Botkin JR, American Academy of Pediatrics Committee on Bioethics. Clinical ReportForgoing medically provided nutrition and hydration in children. Pediatrics. 2009;124(2):813822. 22. Levi BH. Withdrawing nutrition and hydration from children: legal, ethical and professional issues. Clin Pediatr. 2003;42:139145. 23. Truog RD, Cochrane TI. Refusal of hydration and nutrition: irrelevance of the artificial vs natural distinction. Arch Intern Med. 2005;165:25742576. 24. Petersen MC, Kedia S, Davis P, Newman L, Temple C. Eating and feeding are not the same: caregivers perceptions of gastrostomy feeding for children with cerebral palsy. Dev Med Child Neurol. 2006;48:713717. 25. Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Pool WK and the NICHD Neonatal Research Network. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics. 2006;117(4):12531261. 26. Bhatia J. Post-discharge nutrition of preterm infants. J Perinatol. 2005;25:S15S16. 27. Horlsen S. Organ allocation for liver-intestine candidates. Liver Tranpl. 2004;10:S86S89. 28. Klopp SA, Heiss CJ, Smith HS. Self-reported vegetarianism may be a marker for college women at risk for disordered eating. J Am Diet Assoc. 2003;103:745747. 29. Perry CL, McGuire MT, Neumark-Sztainer D, Story M. Characteristics of vegetarian adolescents in a multiethnic urban population. J Adolesc Health. 2001;29:406416.
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30. Varness T, Allen DB, Carrel AL, Fost N. Childhood obesity and medical neglect. Pediatrics. 2009;123:399406.
Additional Readings of Interest

Carrese JA. Refusal of care: patients well-being and physicians ethical obligations. JAMA. 2006;296(6):691695. Ferrie S. A quick guide to ethical theory in healthcare: solving ethical dilemmas in nutrition support situations. Nutr Clin Pract. 2006 21:113117. Fine RL. Ethical issues in artificial nutrition and hydration. Nutr Clin Pract. 2006;21:118125 MacDonald C. Treatment resistance in anorexia nervosa and the pervasiveness of ethics in clinical decision making. Can J Psychiatry. 2002;47:267270. OSullivan Maillet J, Vyas A, Rodrigues J. Ethical issues in nutrition and human immunodeficiency virus. Nutr Clin Pract. 2004;19:365374. Sayers GM, Lloyd DA, Gabe SM. Parenteral nutrition: ethical and legal considerations. Postgrad Med J. 2006 Feb;82(964):7983. Sharp HM, Bryant KN. Ethical issues in dysphagia: When patients refuse assessment or treatment. Semin Speech Lang. 2003;24(4):285299. Thomson C, Diekman C, Fragakis AS, Meerschaert C, Holler H, Devlin C. Guidelines regarding the recommendation and sale of dietary supplements. J Am Diet Assoc. 2002;102:11581164. Unknown. Artificial feeding for a child with a degenerative disorder: a familys view. The mother and grandmother of Frances. Arch Dis Child. 2005 Sep;90(9):979.
Ethical Issues and Nutrition Therapy in General
Donnelly JP, Huff SM, Lindsey ML, McMahon KA, Schumacher JD. The needs of children with life-limiting conditions: a healthcare-provider-based model. Am J Hosp Palliat Care. 2005;22(4):259267. Fleischman AR, Collogan L. Addressing ethical issues in everyday practice. Pediatr Ann. 2004;33(11):740745. Frader JE. Discontinuing artificial fluids and nutrition: discussions with childrens families. Hastings Cent Rep. 2007;37(1):49. Glover JJ, Caniano DA, Balint J. Ethical challenges in the care of infants with intestinal failure and lifelong total parenteral nutrition. Semin Pediatr Surg. 2001;10(4):230236. Heine RG, Bines JE. New approaches to parental nutrition in infants and children. J Paediatr Child Health. 2002;38(5):433437. National Hospice and Palliative Care Organization. Standards of Practice for Pediatric Palliative Care and Hospice. Alexandria, VA: National Hospice and Palliative Care Organization; 2009. Nelson LJ, Rushton CH, Cranford RE, Nelson RM, Glover JJ, Truog RD. Forgoing medically provided nutrition and hydration in pediatric patients. J Law Med Ethics. 1995;23(1):3346. Repenshek M, Slosar JP. Medically assisted nutrition and hydration: a contribution to the dialogue. Hastings Cent Rep. 2004;34(6):1316. Saad L. Americans choose death over vegetative state: most would have feeding tube removed for their child, spouse, or themselves. In: Gallup A, Newport F, eds. The Gallup Poll: Public Opinion March 29, 2005. Lanham, MD: Rowman & Littlefield; 2006:116118. Velez G Jr. Death of John Paul II and the basic human care for the sick and the dying. Ethics Med. 2005;Fall;21(3):167177.
Ethical Issues and Nutrition Therapy: Pediatric End of Life
Test Your Knowledge Answers
Chapter 1: Mechanics of Nutrient Intake

1. The correct answer is C. 2. The correct answer is B. 3. The correct answer is A .
Chapter 4: Fats
1. The correct answer is B. The problems of overweight and obesity are the result of excess calories and not simply too much fat. In addition to customizing the caloric intake to meet the individual patients needs, the ideal nutritional support will provide appropriate ratios of preformed LA, -LA, ARA, EPA, and DHA that cannot be made in adequate amounts by the patient. 2. The correct answer is D. Medium-chain fatty acids and long-chain fatty acids are oxidized in mitochondria. Very long-chain fatty acids are oxidized in peroxisomes and mitochondria. Although it is normally a minor pathway, omega-oxidation in the endoplasmic reticulum of the cytoplasm becomes important if there is mitochondrial dysfunction. 3. The correct answer is D. The neonate cannot synthesize LA or -LA. Although the enzymes are present to convert LA to ARA and -LA to EPA and DHA, the capacity to do so is not adequate to meet the needs of the neonate.
Chapter 2: Gross Digestion Principles: Gastric Grinding and Gastrointestinal Motility

1. The correct answer is C. Liquids empty from the stomach faster than solids; feeding higher in fiber, fat, and protein will empty more slowly. 2. The correct answer is B. The other three answers each describe characteristics of one of the 3 phases of the migrating motor complex seen in the fasting state. 3. The correct answer is D. It has been demonstrated that even small amounts of enteral feeding in the premature infant will encourage maturation of intestinal motility. Bolus feeds will actually cause a cessation of contractions in the proximal small bowel of the premature infant. Both gastric emptying and intestinal transit are slower in the premature infant.
Chapter 3: Carbohydrates: Changes with Development

1. The correct answer is D. Lactose, sucrose, and maltose are disaccharides. Amylose is a polysaccharide consisting of multiple glucose units and is a component of starch. 2. The correct answer is B. 3. The correct answer is B. Lactase activity at the start of the third trimester is < 25% of that at term. 4. The correct answer is D. The prevalence of hypolactasia amongst individuals of different ethnic backgrounds is as follows: 90% Asians, 80% African-Americans, 53% Hispanics, and 15% to 25% non-Hispanic whites.
Chapter 5: Protein Digestion, Absorption, and Metabolism

1. 2. 3. 4. 1. 2. 3. 4. The correct answer is C. The correct answer is A . The correct answer is A . The correct answer is C. The correct answer is E . The correct answer is E . The correct answer is E . The correct answer is D.
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Chapter 6: Minerals
488
5. The correct answer is B. 6. The correct answer is A .
Chapter 10: Nutrition and Early Development

1. The correct answer is D. 2. The correct answer is C. 3. The correct answer is B.
Chapter 7: Water-Soluble Essential Micronutrients

1. 2. 3. 4. 5. 1. 2. 3. 4. 5. The correct answer is D. The correct answer is E . The correct answer is C. The correct answer is D. The correct answer is A . The correct answer is A . The correct answer is E . The correct answer is C. The correct answer is D. The correct answer is E .
Chapter 11: Human Milk

1. The correct answer is E . Some of these infants have been shown to have an insufficient suck and negative pressure needed for good milk extraction. They may fool mothers and as this problem persists, the mothers milk supply may dwindle. This may cause dehydration as well as poor growth and create a cycle that can lead to lactation failure. Encouraging mothers to pump to stimulate milk supply is helpful; also, the use of teat weights to determine whether there is sufficient milk transferred can also be helpful. Further information is included in references 39 and 40. 2. The correct answer is B. Although calories are important which will be supplied in greater amounts with the higher fat content of hind milk, the premature infant needs fortification for protein, calcium, phosphorus, magnesium, and zinc. 3. The correct answer is A . Donor banked human milk may often be from donations of mothers of term infants. This milk would have lower protein content than the milk from a mother of a preterm infant. The pasteurization process alters some of the properties of human milk as well. There will be increased needs for supplemental protein, calcium, and phosphorus.
Chapter 8: Fat-Soluble Vitamins
Chapter 9: Fluids and Electrolytes

1. The correct answer is C. Fluid gains in the body compartments depend on the volume and osmolarity of the fluid administered. Administering 100 mL of 0.9% sodium chloride (154 mEq/L of sodium) will not alter the plasma osmolarity because it is iso-osmotic. The sodium will be held in the ECF by the Na+-K+-ATPase pump, and the water stays with the sodium. Therefore, all of the administered volume (100 mL) will stay in the ECF compartment. Because 25% of the ECF compartment is intravascular volume, the intravascular volume will increase by 25 mL. 2. The correct answer is A . A low serum sodium concentration is the result of either an increase in TBW or a decrease in total body sodium with a subsequent decrease in TBW. The weight has not changed significantly over the past 3 days and the sodium intake (3 mEq/kg/d) may not be sufficient for a 1250-g neonate. Therefore, the renal and GI losses are probably exceeding the sodium intake, resulting in the decreased serum sodium concentration. The correct treatment would be to increase the sodium concentration in the maintenance IV fluids. 3. The correct answer is C. The low serum phosphorus concentration is cause for concern and needs to be treated acutely. A supplemental IV infusion of sodium phosphate would be more appropriate than adding sodium phosphate to the maintenance IV solution. A serum potassium concentration of 3.4 mEq/L does not necessitate acute treatment; increasing the potassium in the maintenance IV fluids would be most appropriate to address this issue.
Chapter 12: Infant Formulas and ComplementaryFeeding

1. 2. 3. 4. The correct answer is C. The correct answer is B. The correct answer is A . The correct answer is D.
Chapter 13: Growth Assessment and Monitoring

1. False. BMI not available for children age < 2 years. BMI patterns after age 2 years can be linked to adolescent. 2. False. BMI percentile 85th 95th represents risk for overweight. BMI percentile > 95th represents overweight. 3. True. The CDC recommends using terminology obesity for BMI 95th percentile or calculated BMI 30 kg/m2 . This is a change from Expert Committee recommendations in 1998 that discouraged use of obesity terminology in children. The term obesity denotes excess body fat and the associated serious health
TEST YOUR KNOWLEDGE ANSWERS
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4.
5. 6. 7.
risks. It also provides continuity with adult definitions and avoids the vagueness of previous terminologies of risk for overweight for BMI 85th to 94th percentile and overweight for BMI > 95th percentile. The correct answer is D. FTT or wasting is an involuntary decline falling below 2 or more major percentile channels. The major percentile channels are 90th, 75th, 50th, 25th, 10th, and 5th. The correct answer is C. The 50th percentile is the mean and median value. This corresponds to a z score of 0. The correct answer is D. Timeline of progression was not given; otherwise, answer B is also potentially life threatening if rapid in onset (ie, < 1 to 2 months). The correct answer is B. Length refers to linear measurements taken with the subject in a supine position. Lengths are longer than heights. Linear growth in the birth to age 36-month growth reference charts is based on length measurements. Linear growth in the 2- to 20-year growth reference charts is based on height measurements.
Chapter 14: Obesity and Metabolic Disorders

1. The correct answers are A, B (as relates to cut-points), D, and E . 2. The correct answer is B. 3. The correct answers are E and F.
where the child sleeps, and no television if the child is < 2 years of age; and 1 hour of physical activity per day. 3. The correct answer is B. The Traffic Light Diet was designed to promote weight loss, provide adequate kilocalories and nutrients for growth and development, and be easy to follow. The Food Guide Pyramid was designed as a general guide for diet and exercise in adults; however it was used as a dietary component in childhood weight management in one study of adolescents. 4. The correct answer is D. For children and adolescents, these diets have not been studied due to potential risks for growing children and adolescents from elimination of key food groups, greater than recommended caloric restriction, adverse behavioral patterns of eating and/ or lack of scientific evidence for the basis of the diets recommendations. The key requirement for dietary treatment of overweight children and adolescents is to initiate and maintain lifelong healthy eating habits that focus on unhealthy weight in the short term and foster improved health outcomes in the long term.
Chapter 17: Sports Nutrition

1. 2. 3. 4. The correct answer is B. The correct answer is C. The correct answer is A . The correct answer is D.
Chapter 15: Lipid Disorders

1. The correct answer is B. 2. The correct answer is D. 3. The correct answer is B.
Chapter 18: Developmental Delay

1. The correct answer is D. 2. The correct answer is C. 3. The correct answer is B.
Chapter 16: Use of Popular and Fad Diets

1. The correct answer is C. The ADA evidence-based analysis of pediatric overweight literature on intervention programs reported positive effects from 2 specific kinds of interventions: multi-component, family-based programs for children between the ages of 5 and 12 and multi-component school-based programs for adolescents. The components included were behavioral counseling, promotion of physical activity, parent training/modeling, dietary counseling, and nutrition education. 2. The correct answer is A . Interventions should be based on the familys readiness to change and include the following recommendations: consumption of 5 servings of fruits and vegetables per day; minimization or elimination of sugar-sweetened beverages; limits of 2 hours of screen time per day, no television in the room
Chapter 19: Eating Disorders

1. The correct answer is C. Physical presentation of a person with anorexia nervosa includes lanugo-type hair, muscle wasting, dry skin, cyanosis of extremities, bradycardia less than 60 beats/min, and cachexia. When anorexia develops in childhood, the first clinical sign may be failure to make weight gains while continuing to grow in height as opposed to documented weight loss. Growth charts should be evaluated for typical growth patterns of the individual 2. The correct answer is B. Parenteral nutrition (PN) is only indicated in cases of digestive inability as it leads to a continued loss of hunger cues in the eating-disordered individual. 3. The correct answer is A . Patients with a weight loss of 10% within 2 to 3 months or those at or below 70%
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ideal body weight are at the greatest risk. Categories of patients who may meet these criteria include those with anorexia nervosa, alcoholics, cancer patients, postoperative patients, the elderly, uncontrolled diabetics, marasmus, prolonged fasting, morbid obesity with profound weight loss, patients NPO greater than 5 to 7 days, malabsorptive syndrome (such as pancreatitis, cystic fibrosis, short bowel), prolonged antacid use (due to binding of phosphorus), and long-term diuretic use (due to electrolyte losses).
milk is the most important therapy. A protein hydrolysate formula would be an effective substitute and if not tolerated, an elemental formula.
Chapter 21: Diabetes Mellitus and Other EndocrineDisorders

1. The correct answer is D. The concentration of dextrose used in the PN should be chosen based on the optimal formulation of the PN, rather than on the fact that the child has diabetes mellitus. 2. The correct answer is A . The hospitalized child with CF-related diabetes mellitus often has increased insulin resistance and therefore requires a larger amount of insulin to control blood glucose excursions. 3. The correct answer is C. Acceptable blood glucose control in children with diabetes mellitus on EN can usually be obtained by using subcutaneous insulin. Insulin is usually not administered enterally. 4. The correct answer is D. Acceptable serum sodium concentrations in a child with diabetes insipidus on nutrition support can usually be obtained by using an intravenous drip of aqueous vasopressin.
Chapter 20: Food Allergies

1. The correct answer is D. Allergens are usually proteins or glycoproteins. Allergies do not develop to carbohydrates. Allergies to intravenous lipid, amino acid solution, and the multivitamin solution have all been described. 2. The correct answer is B. Children under 2 years of age and avoiding milk and soy protein are at increased risk of consuming insufficient fat, protein, calcium, vitamin D, zinc, iron, and total energy. Enriched rice milk provides adequate vitamin D and calcium but does not provide appropriate fat, protein, and energy intake. Appropriate substitute for liquid intake would be a hydrolysate formula or if that is not tolerated, an elemental formula. 3. The correct answer is D. In a patient with a history of anaphylaxis to a food, a food challenge at home should never be recommended. Follow-up with an allergist is the only safe way to assess if a patient has outgrown or developed tolerance to the food. Annual follow-up assessment with an allergist is recommended for children with food allergies. The nutrition assessment of a these children should always review growth and nutrient intake. By obtaining a 24-hour recall and reviewing common foods consumed, exposures to food allergens can be identified. If a patient is tolerating exposures to foods that were allergenic, again the patient must follow up with the allergist to clarify the allergen list. Liberalizing a patients diet will provide more options for improving the overall nutrition intake. 4. The correct answer is A . In IgE-mediated anaphylaxis, there are usually cutaneous signs such as an urticarial rash. The absence of cows milk-specific IgE on RAST testing makes an IgE-mediated mechanism unlikely. This clinical scenario is consistent with food proteininduced enterocolitis syndrome and avoidance of cows
Chapter 22: Inborn Errors of Metabolism

1. The correct answer is D. Disorders selected for newborn screening programs must be cost-effective and reliably detected by population-based screening methods. Realistic and effective treatment modalities should be available for the disorder to prevent severe sequelae of the disease. 2. The correct answer is C. Specialty total parenteral nutrition solutions for MMA provide all essential amino acids except met, val, ile, and thr. As metabolic control improves, standard total parenteral nutrition may need to be added in limited quantities to prevent protein deficiency. 3. The correct answer is B. Individuals with VLCADD cannot metabolize long-chain fats effectively and Intralipid is a long-chain fat source. Answer A is incorrect because MCTs provide a source of fat that can be metabolized to meet caloric needs. Answer C is incorrect because carbohydrates provide an energy source that can be utilized without fatty acid oxidation. Answer D is incorrect because cornstarch is a slowly digested carbohydrate source that can be effective to prevent low glucose concentrations during fasting.
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Chapter 23: Cardiac Disease

1. The correct answer is D. Surgical correction has emerged as the most efficient method to improve the nutrition status of these infants. Surgical correction eliminates the cardiac factors contributing to malnutrition. 2. The correct answer is D. Considering the diversity of the population and varying degrees of anomalies, an infant with congenital heart disease may require energy intakes of 140200 kcal/kg/d body weight to induce growth. 3. The correct answer is D. The exact etiology for growth impairment in children with congenital heart disease remains unclear. Many factors have been identified as contributing to growth failure in this population. 4. The correct answer is C. The use of a medium-chain triglyceride enriched diet is based on the understanding that enterocytes directly absorb MCT into circulation allowing adequate calories while reducing lymphatic flow to allow for healing. At least 3% to 4% of fat calories should come from LCT to prevent essential fatty acid deficiency.
3. The correct answer is C. Cardiovascular disease is the major cause of mortality in patients with CKD. Not only do CKD patients typically have traditional risk factors including hypertension, dyslipidemia, and left ventricular hypertrophy they also have non-traditional markers or uremic factors that can contribute to CVD in adult patients. These factors include inflammation, anemia, fluid overload, proteinuria, abnormal calcium and phosphorus levels, dyslipidemia, and vascular injury. 4. The correct answer is A . Recent studies indicate nPCR is a superior marker of nutrition status in children on maintenance hemodialysis. In these studies, serum albumin was a poor indicator of nutrition status. An nPCR of < 1 g/kg/d was a strong predictor of weight loss in adolescent patients. However, increased risk of mortality has been associated with hypoalbuminemia. Therefore, serum albumin may be used as a nutrition status marker, but with caution if hypoalbuminemic factors are present.
Chapter 25: Gastrointestinal Disease

1. The correct answer is D. This patient has Crohns disease. Diet therapy is effective in the treatment of Crohns disease. There is no difference in effectiveness of the polymeric vs elemental diets. A clear liquid diet is inadequate. 2. The correct answer is A . Patients with inflammatory bowel disease often have deficits of several nutrients. This patient has disease of the ileum and is therefore at greater risk of B12 malabsorption. The combination of anemia and low MCV are suggestive of iron deficiency. Both sulphasalazine and methotrexate interfere with folate metabolism and therefore routine supplementation with folate is recommended. It should be mentioned that patients with inflammatory bowel disease are also at risk for bone disease and vitamin D and calcium may also be considered. 3. The correct answer is C. Currently a strictly glutenfree diet is the sole recommended treatment for celiac disease and it should be maintained lifelong. (AGA Institute Medical Position Statement Diagnosis and Management of Celiac Disease 2006; 131:1977-80). There is ongoing research to discover alternative treatments including enzyme therapy and immune agents but as yet none are recommended (Sollid LM, Khosla C. Future therapeutic options for celiac disease. Nat Clin Pract Gastroenterol Hepatol. 2005; 2:140145). It
Chapter 24: Renal Disease

1. The correct answer is C. The use of CRRT provides greater solute clearance and thus electrolytes typically do not need to be limited and are often supplemented. Therefore, use of a regular formula as opposed to a lowelectrolyte renal formula is appropriate. Additionally, enteral products designed for renal patients often are more concentrated, which can cause GI discomfort. GI side effects are common in this population and use of trans-pyloric feeding improves tolerance. Only if continued tolerance problems or poor gut perfusion is suspected should PN be considered. 2. The correct answer is D. Although dialysis losses may be minimal, vitamin B6 intake is often inadequate, likely due to restriction of high-protein foods to limit excess intake of phosphorus and potassium. Recent studies indicate that 25-hydroxyvitamin D may have a role, in addition to well-known 1,25-(OH)2D, with bone metabolism and prevention of hyperparathyroidism. Supplementation to keep serum levels in the appropriate reference range is recommended. Folic acid, although controversial in its role with homocysteine reduction and cardiovascular implications, may have a role with anemia management.
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should be emphasized that the gluten-free diet should be continued even after all symptoms have abated. 4. The correct answer is B. 5. The correct answer is D.
Chapter 26: Hepatic Disease

1. 2. 3. 4. The correct answer is B. The correct answer is B. The correct answer is D. The correct answer is E .
Chapter 27: Intestinal Failure

1. The correct answer is C. The small intestine doubles in length during the last trimester. Therefore, the remaining length of small bowel has a greater inherent capacity to increase in length when the bowel resection occurred earlier in the third trimester. 2. The correct answer is B. Features associated with enteral autonomy include absence of cholestasis, an intact ilealcecal valve, bowel in continuity, shorter duration of PN, residual intestinal length > 15 cm, and an intact colon. Stool number, by itself, is not a predictor. 3. The correct answer is D. The cause of PN-related liver disease is likely multi-factorial and not related to just one issue. 4. The correct answer is D. Oral feedings not only enable the infant to maintain oral feeding skills and decrease the likelihood of developing oral aversion, but oral feedings will stimulate salivary secretion of hormones such as epidermal growth factor which is important to the intestinal adaptive process.
4. The correct answer is B. Energy requirements are increased and are in the range of 125 to 150 kcal/kg/d. Vitamin A supplementation is important and is often used in the intensive care unit to prevent BPD. Vitamin E supplementation is not helpful. These patients also have large insensible water losses and need extra fluid, which results in opening of the patent ductus arteriosus and further stress on the lungs. Fluid restriction often results in inadequate nutrition intake. Calcium status is poor due to decreased intake and increased losses due to diuretics. Adequate intakes of calcium and phosphorus, protein (33.5 g/kg/d), and antioxidants (copper, zinc, and manganese) are required, and it is important to avoid excessive carbohydrate intake because it can impact pulmonary function.
Chapter 29: Organ Transplantation

1. The correct answer is C. Immunosuppressive therapy after transplant can exacerbate or cause problems with hyperglycemia, renal insufficiency, electrolyte and fluid provision, and hyperlipidemia. Moreover, tacrolimus has been shown to cause hyperkalemia and hypomagnesemia. All of these imbalances may necessitate a change in nutrition therapy. Close nutrition monitoring is essential. 2. The correct answer is D. The use of corticosteroids after renal transplant can result in hyperglycemia, hyperlipidemia, and obesity. Biochemical testing should include a lipid profile and glucose levels. A healthy diet including unsaturated fats and exercise as tolerated should be encouraged in an effort to prevent these complications. 3. The correct answer is B. Children with cystic fibrosis and pancreatic insufficiency will continue to have pancreatic disease after lung transplantation. Therefore, pancreatic enzyme supplementation with meals and snacks will need to continue. In general, a semi-elemental enteral formula should be provided if kilocalorie requirements cannot be met with oral intake alone. Parenteral nutrition may be needed if neither enteral nor oral intake is sufficient.
Chapter 28: Pulmonary Disorders

1. The correct answer is C. Acidity in the GI tract may prevent or retard dissolution of enteric-coated pancreatic enzymes. If activation does not occur in the small intestine, then it may be difficult for a person with CF to absorb macro- and micronutrients. 2. The correct answer is B. Blood levels of fat-soluble vitamins should be measured to assure adequacy (vitamins A, E, D). Prothrombin time is insensitive to vitamin K deficiency in CF. PIVKA II provides a better indicator of vitamin K nutrition. 3. The correct answer is A . All risk factors need to be evaluated. Treatment includes optimizing nutrition, increasing physical activity, controlling underlying inflammation, decreased corticosteroid use, and addressing hormone deficiencies.
Chapter 30: Oncology, Hematopoietic Transplant, andSurvivorship

1. The correct answer is A . Methotrexate leads to the development of mucositis which severely compromises oral intake. 2. The correct answer is B. Weight gain, ascites, hyperbilirubinemia, hepatomegaly, and increased transaminases
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are all symptoms of the development of SOS. Nutrition management includes fluid and sodium restriction of the diet, EN, or PN solution. 3. The correct answer is D. EN through the use of feeding tubes is often discouraged among the pediatric hematopoietic transplant population because of the need for frequent tube replacement as a result of vomiting, the risk of bleeding in the presence of thrombocytopenia and pancytopenia with mucositis, dislodgement of the feeding tube, the presence of delayed gastric emptying, and malabsorption of nutrients. 4. The correct answer is D (increase or decrease the absorption of other drugs). 5. The correct answer is D. All of the above can contribute to osteoporosis in the cancer survivor.
Chapter 31: Trauma and Burns

1. The correct answer is C. Solid organ injuries are common in the child due to the exposure of the liver and spleen in the upper abdomen. Unless there is hemodynamic instability, these rarely require operative intervention and can be managed with physical limitations. Nutrition support generally consists of resumption of an age-appropriate diet with caloric supplementation, when caloric intake is inadequate. 2. The correct answer is D. While the extent of pancreatic trauma is quite variable, it is often accompanied by chemical pancreatitis and ileus. When resection occurs, it is usually over the neck of the pancreas and leaves sufficient endocrine tissue for normal glucose control, but may impact exocrine function as evidenced by steatorrhea. 3. The correct answer is B. While the concept of immunonutrition is appealing in this population of patients, randomized clinical studies have failed to show benefit. 4. The correct answer is A . TBSA remains a predictor of mortality. In children, age under 4 years, inhalation injury combined with a TBSA injury of > 30% defines the highest mortality risk group. It is not clearly proportional to the extent of the stress response, which is mediated by multiple additional factors. Estimates of energy needs based on TBSA are consistently inaccurate in their targets.
Chapter 32: Surgery

1. The correct answer is D. The initiation of enteral feedings is the most effective intervention to stimulate
hepatobiliary secretions and lead to resolution of cholestasis. Excessive lipid and carbohydrate calories are considered provocateurs of cholestasis. Cycling of PN has been touted to reduce cholestasis. 2. The correct answer is D. Persistent bilious drainage from the stomach implies distal obstruction. The exception to this rule is congenital duodenal atresia due to congenital dilation and incompetence of the pyloric channel. Despite evacuation of duodenal content in a prograde manner there may be some retrograde flow into the stomach. Contrast extravasation in esophageal atresia should initially be managed with continued NPO to allow the leak to seal without exogenous contamination of the mediastinum. Passage of a transpyloric feeding tube would require excessive manipulation. Abdominal distention with lack of stoma output is indicative of ileus or intestinal obstruction. 3. The correct answer is A . Advancement of enteral feedings is safe when there is no evidence of diarrhea or malabsorption. Reducing substances < 1/2% and fecal pH > 7 are indicative of appropriate absorption. Mucoid stools are a nonspecific finding that only becomes concerning if they contain gross blood. Increased frequency of bowel movements is a generic indicator for feeding intolerance; however, consideration must also be given to the quantity and nature of the stool. Small smears should not be considered as bowel movements whereas large-volume watery output is of concern. 4. The correct answer is A . The hallmark of gastroschisis is that in the majority of patients there is intestinal wall edema and serositis resulting in the inability to determine whether there is continuity or an atresia present. This is further compounded by the fact that this intestine returns to normal morphology over a variable period of time that ranges from 4 to 10 weeks. The intestine in omphalocele is normal other than its covered extra-abdominal location. In the absence of other disorders, these infants tolerate enteral feedings promptly. Hirschsprungs disease patients have impaired motility but once diagnosed either undergo primary reconstruction or diverting colostomy and therefore should have no extended dependence on total parenteral nutrition. The intestine in congenital malrotation is functionally normal although there may be some delayed gastric emptying associated with Ladds bands. If midgut volvulus occurs the patient is at risk for loss of the entire midgut intestine.
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Chapter 33: Assessment of Nutrition Status by Age andDetermining Nutrient Needs

1. The correct answer is D. Components of a detailed nutrition assessment include anthropometric measurements with comparison to reference standards, a detailed diet history, laboratory monitoring, and physical examination. 2. The correct answer is C. Rickets and vitamin D deficiency continue to be a concern in the United States and other Western countries due to exclusively breastfed infants and decreased sun exposure. As a result, on October 13, 2008, the American Academy of Pedia trics issued updated guidelines for vitamin D intake for infants, children, and adolescents to prevent vitamin D deficiency and the incidence of rickets. These new recommendations report a daily intake of 400 International Units of vitamin D for all infants, children, and adolescents starting from the first few days of life. 3. The correct answer is D. Depleted levels of Hgb and Hct, along with spoon-shaped nails, may be an indication of iron deficiency anemia.
Chapter 35: Implementation of the Plan

1. The correct answer is B as the expected need for the CVC is short term. 2. The correct answer is B as there is no waste and minimal risk of contamination during the procedure. 3. The correct answer is Bbolus feed during the day after being offered food and nighttime drip feedings.
Chapter 36: Evaluation and Monitoring of Pediatric Patients Receiving Specialized Nutrition Support
1. False. There are many goals in addition to weight that may be identified for a patient such as wound healing, increased energy, improved protein stores, etc. 2. True. Decreasing the rate and extending the time of infusion may improve the symptoms. 3. True, evaluating the GIR in addition to calorie content will help determine if PN is contributing to hyperglycemia. 4. False. Higher concentrations of amino acids and dextrose can improve calcium and phosphorus solubility. 5. False. Copper and manganese are excreted via the biliary system and these levels should be monitored periodically in patients with cholestasis receiving PN.
Chapter 34: Parenteral and Enteral Nutrition Support: Determining the Best Way to Feed
1. The correct answer is E . All of the above are common behavioral strategies to address picky eating. A divided plate helps children to feel more in control, because they dont want the non-preferred foods touching the preferred foods. Offering a new food with preferred foods encourages a child to try the new food, but keeps the situation from being overwhelming. Family mealtimes are an opportunity for caregivers and siblings to model healthy, positive mealtime behaviors. 2. The correct answer is A . A height at the 25th percentile is within normal growth parameters. It is not normal for a toddler to have no weight gain for an extended period of time. A decrease of 2 weight channels and taking longer than 4 hours to eat in a day are both considered criteria for supplemental nutrition support in children. 3. The correct answer is D. Children with CF have increased calorie needs. If they are unable to maintain a good weight with oral intake alone, then the next step is to provide nutrition supplements. Parenteral Nutrition is not indicated if the child is able to digest/absorb food. Tube feedings may be needed in the future to supplement oral intake, if the initiation of oral nutrition supplements does not produce the desired results.
Chapter 37: Ethical Issues in the Provision of Nutrition

1. The correct answer is D. 2. The correct answer is E . 3. The correct answer is B.
Index
Page numbers followed by f or t indicate figures or tables, respectively.
A
Abdominal injuries, 381382 Absorption of carbohydrates, 20 of fats, 26 of minerals, 4647 of proteins, 3334 of vitamins, 57 Academy of Breastfeeding Medicine, 121 Acanthosis nigricans, 154 Acute kidney injury (AKI) classification postrenal, 257 prerenal, 257 renal, 257 defined, 269 electrolyte and fluid restrictions, 270 neonatal issues, 271272 nutrition assessment, 270 Adolescents acne treatment, 78 calcium requirements, 413 dietary habits, 412 nutrition assessment, 412414 protein requirements, 40 Adrenal glands, injury to, 381 Alagille syndrome, 304, 305
Allergy testing, 216 Aluminum in antacids, 49 infant formula content, 273 toxicity, 268, 273 American Academy of Pediatric Dentistry (AAPD), 414 American Academy of Pediatrics (AAP) breastfeeding policy, 120 dietary calcium needs, 413 hydration guidance, 181t American College of Sports Medicine hydration guidance, 181t American Dietetic Association (ADA) breast milk guidelines, 124 pediatric obesity, 170 American Institute for Cancer Research Recommendations for Cancer Prevention, 364 American Psychiatric Association, 205 Amino acid(s) classification, 38t conditionally essential, 35t, 3637 essential, 35t in fetal development, 106
metabolism role of kidney, 39 role of liver, 3839 and nitrogen balance, 35 non-essential, 35t placental concentrations, 106 urea cycle, 3738 Amylase in pancreatic trauma, 381 Anaphylaxis, 214t, 215216 Anemia, 413 in transplant recipients, 343 Animal models fetal origins of disease, 110 glucocorticoid exposure, 114 iron-deficient diets, 113 nutrient-restricted diets, 112113 of dietary manipulation, 112113 uterine artery ligation, 114 Anorexia nervosa, 205 diagnostic criteria, 205f diet-induced thermogenesis, 206 energy requirements, 206 in childhood, 205 liver disease and, 303 physical presentation, 205 zinc deficiency, 207
495
496
INDEX
Anthropometric measurements body mass index-for-age, 146, 415, 415t head circumference, 144t, 145, 415 length/height, 144145, 414415 parental stature, 415 using knee height, 415 using length board, 414 using standiometer, 414415 using tibial length, 415 mid-arm circumference, 415416 triceps skinfold, 415416 percentiles, 421t upper arm circumference percentiles, 420t weight, 414 method for obtaining, 144, 414 Appetite control, 4 cultural aspect, 3 development during infancy, 4 hypothalamus role, 4 nutrient intake and, 34 phases cephalic, 4 gastric, 4 intestinal, 4 programming of, 113 Arachidonic acid (ARA) in infant formulas, 135136 Arginine hyperammonemia and, 37 in fetal development, 106 Asthma, 333
B
Baby Friendly Hospital Initiative (BFHI), 121 Ballard score, 409410, 410t Bartters syndrome, 277 Bifidobacteria lactus, 137 Bifidobacterium bifidum, 120 Bile acid malabsorption, 316 Binge-eating disorder diagnostic criteria, 206f energy requirements, 206 Biotin absorption, 6970 biochemistry, 69
deficiency state, 70 dietary reference intake, 58t excretion, 6970 metabolism, 6970 physiology, 69 source, 69 supplementation, 70 Bloodstream infections, 317, 449, 470 Body mass index (BMI) developmental delay and, 195 in growth assessment, 146 Body mass index-for-age, 415, 415t Breast milk adding infant formula to, 138 in chronic kidney disease, 273 cytomegalovirus in, 125 fortification, 122123, 122t hang time, 124 hind milk, 122123 intestinal adaptation and, 313314 labeling, 124 maternal medications and, 125 preterm, 122, 122t pumping, 122 safety, 124125 storage, 124, 124t in tube feedings, 124 Breastfeeding advocacy of, 120 appetite development exposure to taste, 4 benefits of, 120121, 121t dyad management, 121 effect on later obesity, 111 infant growth and, 123124 steps for successful, 121t Bronchopulmonary dysplasia (BPD), 332333 Bulimia nervosa diagnostic criteria, 205f energy requirements, 206 physical presentation, 205206 Russells sign, 205 zinc deficiency, 207 Burn(s) inhalation injury, 383 pediatric vs adult, 383 total body surface area, 383
Burn patient energy requirements, 383384 hyperalbuminemia, 384 hyperglycemia in, 384 nutrition support, 384 pediatric, 383 postpyloric feeding, 384 protein requirements, 384 resting energy expenditure, 384
C
Calcium absorption, 4849 body content, 45, 48 deficiency, 47, 49 deposits in kidney, 276 dietary reference intake, 46t excess intake, adverse effects, 50 excretion, 49 homeostasis, 49 in chronic kidney disease, 267 medication interactions, 50 physiological functions, 48 requirements, 413 sources, 47t, 48 Campylobacter, 346t Canadian Pediatric Society, 120 Cancer Childrens Oncology Group LongTerm Follow-Up Guidelines for Survivors, 362 complementary and alternative medicine, 354 disease outcome, 353 gastrointestinal supportive care medications acid-blockers, 368369 antiemetics, 369 antihistamines, 371 appetite stimulants, 371372 atypical antipsychotics, 371 cannabinoids, 371 glucocorticoids, 370 motility agents, 368 pheothiazines, 370 malnutrition in, 349350 mucositis medications, 372373 nutrition aspects metabolic, 351
INDEX
497
physiological, 351 psychological, 351 nutrition assessment, 352353, 352t nutrition intervention, 365f, 366t367t overview, 349 survivors gastrointestinal problems, 362363 heart health, 363364 osteoporosis, 363 treatment complications, 354 tolerance, 353 chemotherapy, 350351 radiation therapy, 350, 350t surgery, 350 Cancer cachexia, 351, 351t Candida esophagitis, 315 Carbohydrate(s) absorption, 20 as energy source, 17 classification, 17 complex, 17 digestion lactose, 1719 starch, 19 malabsorption, 20 disorders, 20t metabolism, 20 in sports nutrition, 179180, 180t starches oligosaccharides, 17 polysaccharides, 17 storage, 17 sugars disaccharides, 17 monosaccharides, 17 Cardiovascular disease (CVD) in chronic kidney disease, 268, 269 lipid management and, 268 in pediatric patients, 252254 risk factors, 162, 268 Celiac disease, 287289 at-risk groups, 288t symptoms, 288t
Centers for Disease Control and Prevention (CDC) breast milk guidelines, 124 Epi-Info nutrition calculator, 146 food allergies statistics, 214 growth charts, 143, 411, 416, 423f430f Central diabetes insipidus, 229 Cerebral palsy abnormal energy expenditure, 193 inappropriate dietary intake and, 192 oral motor dysfunction, 192 Child abuse, 381 Cholestasis, 439 Cholesterol, 162, 253t Cholestyramine, 315 Choline absorption, 7071 biochemistry, 70 deficiency state, 71 dietary reference intake, 58t metabolism, 7071 physiology, 70 sources, 70 supplementation, 71 Chyle loss, 294 Chylothorax, 252 Chylous ascites, 341 Chyme, 12 Colon injury, 382 Complementary and alternative medicine (CAM) in cancer treatment, 354 drug interactions, 194 Congenital heart disease acyanotic, 247, 247t cyanotic, 247, 247t Fontan procedure, 251 growth impairment, 248249, 248t malnutrition, 248 nutrition management, 250 bolus tube feeds, 250 postsurgical complications chylothorax, 252 feeding difficulties, 251 nutrition management, 251252 protein-losing enteropathy, 251
Congenital posterior urethral valves, 256 Constipation, 296 Continuous feedings, 454 Continuous renal replacement therapy (CRRT) caloric needs, 270 defined, 270 enteral nutrition and, 270 Copper, in Wilsons disease, 306 Cornstarch, 306 Cows milk phosphorus content, 51 protein allergy, 222 Creatinine clearance, 257 Critically ill patient hyperglycemia in, 227228 nutrition needs, 378379 Cyclic vomiting syndrome, 296 Cysteine as parenteral nutrition additive, 442 intake requirements, 36 Cystic fibrosis clinical features, 324t diagnosis, 324t eating behaviors in, 330331 fat-soluble vitamin requirements, 326, 327t gastroesophageal reflux, 332 gastrointestinal complications, 332 lung transplantation, 332 nutrition-related complications cystic fibrosis related diabetes, 331332 osteoporosis, 331 pancreatic insufficiency in, 324 pathophysiology, 323324 sodium chloride supplementation, 328 transplant complications distal intestinal obstruction syndrome, 345 zinc loss in, 328 Cystic fibrosis-related diabetes (CFRD), 227, 229, 324, 331332 Cystine stones, 274 Cystinuria, 276
498
INDEX
D
D-lactic acidosis, in intestinal failure, 316 Dental caries, 414 Dentition, 45 by age of eruption, 5t Depression, 205 Developmental delay abnormal energy expenditure, 193 clinical features, 193 determining dietary energy needs, 197t inappropriate dietary intake, 192 micronutrient deficiencies, 193194 nutrient loss, 193 nutrition assessment diagnostic studies, 196 growth and anthropometric measurements, 195 growth history, 194 meal observation, 196 medical history, 194 medications, 194 physical examination, 195 review of systems, 194 social history, 194195 nutrition problems growth failure, 192 osteopenia, 194 overweight, 192 pathophysiology of, 192 prevalence of, 192 undernutrition, 192 nutrition support behavioral modification, 197 enteral tube feeding, 197198 feeding intolerance, 199 formula administration, 198 nutrition requirements, 196197 positioning and oral feeding, 197 oral motor dysfunction, 192193 z scores, 192, 193 Developmental origins of health and disease (DOHaD), 112, 115 animal models, 112114 fetal salvage hypothesis, 112
future health implications, 115 premature infant, early programming, 112 research needs, 116 thrifty phenotype hypothesis, 112 Diabetes mellitus cystic fibrosis related, 227 glucose control in healthy children, 228 on enteral nutrition, 229 on parenteral nutrition, 228229 type 1, 226227 type 2, 227 Diarrhea, 291292, 291t Diet-induced thermogenesis (DIT), 206 Dietary manipulation animal models low-protein, 113 programmed hypertension, 113 severe food restriction, 113 Dietary reference intakes (DRIs) during pregnancy, 108t for minerals, 46t in neurologically impaired children, 197t for vitamins, 58t, 75t Diets, 169176 Atkins Diet, 172 Dean Ornish Diet, 173 Eat Right for Your Type, 174 for children balanced macronutrient lowkilocalorie, 174 Food Guide Pyramid, 175 multidisciplinary programs Kidshape, 175 SHAPEDOWN, 175 Traffic Light Diet, 174175 French Women Dont Get Fat Diet, 171172 Pritikin Diet, 173 South Beach Diet, 172 Suzanne Somers Diet, 173 types behavioral weight-loss plans, 171172
commercial meal/snack replacements, 173174 food group guides/exchange systems, 173 food timing/meals and snacks combinations, 173 food-focused weight loss plans, 172 reduced macronutrient content plans, 172173 WeightWatchers, 173174 Digestion carbohydrates, 17 fats, 25 motor activity factors caloric density, 13 consistency, 13 nutrient content,13 osmolarity, 13 physiology of, 12 proteins, 3233 small bowel motility, 12-13 Distal intestinal obstruction syndrome, 324, 345 Docosahexaenoic acid (DHA), 135136 Drug-nutrient interactions, 466467 Duodenal hematoma, 381382 Duodenal injuries, 381382 Duodenal perforation, 381382 Dutch famine, 114115 Dyslipidemia, 268 Dysphagia, 8
E
Eating disorder(s) anthropometric monitoring, 208209 classification of, 205 etiology, 206 laboratory tests for, 207t meal-planning guidelines, 208 oral nutrition, 208 prevalence, 204 Eating disorder not otherwise specified, 206f Egg allergy, 233, 463 Electrolyte(s) assessment, 90, 90t
INDEX
499
dosing guidelines, 440t in parenteral nutrition, 440 in renal disease, 267 Energy requirements in acute kidney injury, 271 in anorexia nervosa, 206 in binge-eating disorder, 206 in burn patient, 383384 in cancer patient, 367t in chronic kidney disease, 263, 277t in congenital heart disease, 249 in cystic fibrosis, 325-326 in eating-disordered patient, 206 in hematopoietic stem cell transplant patient, 356, 356t in liver disease, 307 in premature infant, 410 Enteral nutrition aspiration precautions, 457 bolus feedings, 454, 455 in bronchopulmonary dysplasia, 436 in cancer patients, 353354 in chronic kidney disease, 272 in congenital heart disease, 250, 436 combination feedings, 454, 455 continuous feedings, 454, 455 in continuous renal replacement therapy, 270 in critically ill patients, 435 in cystic fibrosis, 436 in developmental delay, 197198 in diabetes mellitus choice of formula, 229 insulin administration, 229 evaluation and monitoring anthropometric measurements, 462t formula tolerance, 461 laboratory values, 462, 462t oral feeding, 462 parameters, 462t revision of plan, 463 feeding advancement, 454455 feeding pumps, 455456
feeding tolerance assessment, 457 in food allergies, 223 for eating-disordered patients bolus feedings, 208 formula type, 208 manipulative behaviors, 208 route of feeding, 208 formula hang time, 455 preparation, 455 in hematopoietic stem cell transplant recipients, 358 indications for, 436t intake and output, 457 in intestinal failure/short bowel syndrome, 313314 in liver disease, 308 in renal disease, 435 medication administration, 457458 nursing care, 456 reflux, 456457 residuals, 456 route of administration, 435436 route selection, 451452 safety issues, 455456 site care, 456 transplant recipients intestine, 340341 kidney, 342343 liver, 341 lung, 344 tube flushing, 456 tube placement, 453 verification methods, 453454 tube securement, 456 tube weaning, 458, 458t types of tubes gastrojejunostomy, 453 gastrostomy, 453 jejunostomy, 453 nasogastric tube, 452453 orogastric, 453 when to use, 433434 Enterobacter sakazakaii, 123, 124, 137 Eosinophilic esophagitis, 222223 Eosinophilic gastroenteritis, 296-297, 297t
Epi-Info nutrition calculator, 146 Escherichia coli, 346t Essential fatty acid deficiency (EFDA) in cystic fibrosis, 326 in developmental delay, 193 infant formulas and, 135 in liver disease, 304 in parenteral nutrition, 439 Ethics case studies, 483484 childhood obesity, 483 clinical care as team approach, 485 in feeding disorders, 483 in intensive care environment, 481 models educators, 479 good shepherds, 478479 liberators, 479 natural vs. medical nutrition provision, 479 nutrition goals determination, 479480 overview, 477 palliative care, 482 special needs, infants and toddlers, 482 truth-telling, 478 values ascribed to feeding, 480481 Extrauterine growth retardation, 116
F
Failure to thrive, 145, 286 Familial hypercholesterolemia (FH), 163 Fat(s) absorption, 26 adipose tissue, 24 classification, 23f digestion, 25 in eating disorders, 207 fuel for preterm infant, 27 functions, 24f in sports nutrition, 181 trans, 23 triglycerides, 22 Fatty acid(s) essential, 2324
500
INDEX
long chain, 23 medium chain, 23 monounsaturated, 2223 oxidation, 2627 polyunsaturated, 23 Vitamin E intake, 23 saturated, 22, 23f short chain, 23 synthesis, 26 Feeding difficulties aspiration, 193 nutrient losses, 193 solid foods, 4 Feeding disorders ethical considerations, 483 etiology of, 443 evaluation and treatment, 443444 nutrition intervention, 445t posttransplant liver, 342 treating, 443t Feeding teams, 89, 442443, 444, 444f Female Athlete Triad, 185t Fenton fetal-infant growth chart, 422f Fetal development epigenetic changes, 107 glucose supply, 106 growth, effect of calcium, 108 effect of iron, 108 effect of protein, 107108 effect of vitamin E, 108109 folic acid and, 108 vitamin B12, 108 hypothalamic-pituitary-adrenal (HPA) axis, 107, 109110 insulin-responsive tissues, 106 intrauterine insults, 107 liver, 106 macronutrients in amino acids, 106 glucose, 106 maternal nutrition and calcium, 108 folic acid, 108 iron, 108
macronutrients, 107108 vitamin B12, 108 vitamin E, 108109 metabolic mediators cortisol, 106 insulin, 106 insulin-like growth factors, 106 prenatal stress, impact of, 109110 substrate metabolism, 106 Fetal origins of adult disease, 110111 Fluid(s) body distribution, 8788, 88t deficit calculation, 89 imbalance, 90 maintenance, 412, 412t regulation, 8889 requirements in chronic kidney disease, 265 in hematopoietic stem cell transplantation patient, 357 Holliday-Segar Formula, 89t in intestinal failure/short bowel syndrome, 314 in kidney transplant, 269, in liver disease, 308 pediatric, 8990 Fluoride drinking water levels, 414t requirements, in adolescents, 414 supplementation, 414, 414t topical, 414 Folate, 6566 absorption, 6566 biochemistry, 65 deficiency state, 66 dietary reference intake, 58t excretion, 6566 metabolism, 6566 physiology, 65 source, 65 supplementation, 66 Folic acid, 108, 264 Food Allergen and Consumer Protection Act (FALCPA), 221 Food allergens alternative substitutes, 219t cross-contamination, 221 hidden, 221, 222t
mandatory food labeling, 221 Food allergies, 213224 algorithm for evaluation of, 217f anaphylaxis, 214t, 215216 and other allergic conditions, 215 Centers for Disease Control and Prevention statistics, 214 clinical assessment, 218 clinical presentation, 215216 common definitions, 214t cows milk protein allergy, 222 definitions, 213214, 214t eosinophilic esophagitis, 222223 epidemiology, 214215 food protein-induced enterocolitis syndrome, 216 immunoglobulin E mechanisms, 213214 laboratory assessment, 218 major allergens, 215 management, 216217 micronutrient supplementation, 221222 milk substitutes, 221 National Health and Nutrition Examination Survey results, 215 nutrition assessment, 217218 nutrition intervention, 220 nutrition risk, 218t oral allergy syndrome, 214t, 215 pathophysiology, 215 pediatric formulas, 220t radioallergosorbent test, 216 resources, 220t skin prick testing, 216 toddler diets, case scenarios, 219t tolerance, 213 Food and Drug Administration (FDA) aluminum content labeling, 442 breast milk safety, 124 regulation of dietary supplements, 46 Food protein-induced enterocolitis syndrome (FPIES), 216 Food safety, 345 Foodborne pathogens, 346t
INDEX
501
G
Galactosemia etiology, 241242 management acute, 242 chronic, 242 diet, 242t Gastroesophageal reflux (GER), 286, 332, 390 Gastrointestinal disease disordered ingestion, 283-284 failure of absorption, 284 failure of digestion, 284 functional disorders, 295-296 increased needs, 284 nutrition assessment, 284-285, 285t Gastrojejunostomy tube(s), 198, 404, 453 Gastroparesis, 295-296, 295t Gastrostomy (G) tube button device, 198t in esophageal atresia, 393 insertion, 404, 453 PERT supplements, 330 safety issues, 450 Glucocorticoids effect on fetus, 109110 as preterm delivery treatment, 109 Glucose as fetal energy source, 106 in trauma response, 378379 Glycogen storage diseases (GSDs), 306 Graft versus host disease, 360361, 361t Growth average daily intrauterine weight gain, 411t breastfed infants, 123124 chronic kidney disease and, 259260 overview, 143144 of premature infant, 410 Growth assessment body mass index, 146 failure to thrive (FTT), 145 head circumference, 144t, 145
height (length/stature), 144145, 144t ideal body weight, 146 percentiles z score comparisons, 146t time intervals, 144t weight, 144, 144t weight-for-length percentiles, 145 Growth charts Fenton fetal-infant, 422f interpreting, 146147 limitations, 147 Lubchenco, 410 National Center for Health Statistics, Centers for Disease Control and Prevention, 143, 411, 416, 423f430f World Health Organization, 143144 Growth hormone (GH) therapy, 260f Growth velocity, 411t
H
Healthy People 2010, 120 Heart transplantation biochemical tests, 339t recipient dietary modificiation, 344 nutrition requirements, 344 Hematopoietic stem cell transplantation (HSCT), 354362 complications bacterial overgrowth, 361 graft versus host disease, 360361, 361t hemorrhagic cystitis, 362 infections, 361 mucositis, 360, 372373 pancreatic insufficiency, 361 sinusoidal obstruction syndrome, 362 diet restrictions, 357358 medication side effects, 359t nutrition support, 358-360 enteral nutrition, 358 oral, 357 procedure, 355
recipient anthropometric assessment, 356 caloric requirements, 356, 356t fluid requirements, 357 mineral requirements, 357 nutrition evaluation, 355356 protein requirements, 356, 356t vitamin requirements, 357 Hemodialysis (HD) in chronic kidney disease, 258259 in hypercalcemia, 97 for hypermagnesemia, 96 phosphorus clearance, 267 Holliday-Segar Formula, 49t Honey, 139 Human milk, 120124 banked, 123 calcium content, 48 fortification, 122123, 122t hind milk, 122123 iron content, 123 phosphorus content, 51 vitamin D content, 123 Human Milk Banking Association of North America, 124 Hydration guidance, 181t in sports nutrition, 181182 Hydrochloric acid, 32 Hyperalbuminemia in burn patients, 384 Hyperammonemia treatment of, 37 Hypercalcemia, 50 Hypercalciuria kidney stones and, 275 Hypergastinemia, 316 Hyperglycemia in burn patient, 384 in critically ill patient, 227228 in refeeding syndrome, 209 in organ transplant recipient, 269, 341, 343, 344, 345 in trauma patient, 380 Hyperhomocysteinemia, 264 Hyperkalemia, 341
502
INDEX
Hyperlipidemia, 341, 343 Hypermagnesemia manifestations, 53 neonatal, 53 Hypermetabolism in cirrhotic patients, 304305 in liver disease, 304305 Hypernatremia in nephrogenic diabetes insipidus, 277 Hyperphosphatemia, 52 Hypertension in transplant recipients, 341, 343, 344 Hypervolemia, 89 Hypocalcemia, 49 Hypoglycemia in liver disease, 302 in young children, 228 Hypokalemia in chronic kidney disease, 266 in refeeding syndrome, 209, 210 Hypomagnesemia definition, 53 etiology, 53 in refeeding syndrome, 209, 210 in transplant recipients, 341 manifestations adults, 53 infants, 53 Hypophosphatemia etiology, 51 in chronic kidney disease, 266 in refeeding syndrome, 209 manifestations, 51 Hypothalamic-pituitary-adrenal (HPA) axis, 107 prenatal programming, 109-110, 110f in trauma response, 378 Hypothalamus, 4 Hypovolemia, 89
I
Immunoglobulin E (IgE) in food allergies, 214 mediated allergic diseases, 215216 reaction, 214
Immunosuppressive medications, 344, 345 kidney damage from, 269 side effects, 269 Immunosuppressive therapy noncompliance with, 346 Inborn errors of metabolism (IEM), 232-242 defined, 232 newborn screening, 233 nutrition management, 233f symptoms, 233t Indirect calorimetry, 197t Infant formula as breast milk additive, 138 calcium salts, 48 concentrating, 250t contamination, 124, 137 design of, 129130 forms liquid concentrate, 137 powder, 137138 ready-to-feed, 137 functional ingredients arachidonic acid (ARA), 135136 docosahexaenoic acid (DHA), 135136 nucleotides, 136 prebiotics, 136 probiotics, 136137 lactose in, 17 magnesium requirements, 52 manufacturers Web sites, 130t medium-chain triglyceride, 252t mixing increasing caloric concentration, 138, 138t modular macronutrients, 138 standard dilution, 138 water, 138 phosphorus content, 51 Portagen, 124 regulation, 130 specialized amino acid based, 134135, 136t, 220, 220t carbohydrate free, 135, 136t
extensively hydrolyzed protein, 134, 135t reduced fat/modified fat, 135, 137t reduced mineral, 135, 137t types for symptoms of intolerance, 130, 132t added rice starch, 132133, 132t lactose-free, 132, 132t, 220, 220t partially hydrolyzed protein,130-131, 132t, 220, 220t premature discharge, 134, 135t premature or low birth weight, 133, 134t soy-based,133, 133t, 220, 220t standard milk-based, 130, 131t whey-based, for chronic kidney disease, 273 Infant(s) appetite development, 4 complementary foods, 139 feeding problems, 67 feeding skills, 56 hypomagnesemia, 53 iron deficiency, 123 neonatal cholestasis, 305 neophobia, 4 premature birth weight classification, 410t calcium requirements, 413 delayed gastric emptying, 13 magnesium overdose, 53 necrotizing enterocolitis, 18 nutrition assessment, 409411 Inflammatory bowel disease, 289291 Inhalation injury, 383 Insensible water loss, 90, 332 Insulin in enteral nutrition, 229 in parenteral nutrition, 229 Intestinal adaptation role of ileal-cecal valve, 313 surgical procedures Bianchi procedure, 313
INDEX
503
longitudinal intestinal lengthening and tailoring (LILT), 315 Serial Transverse Enteroplasty (STEP), 313, 315 Intestinal failure (IF) causes, 312t complications bacterial overgrowth, 316 bile acid malabsorption, 316 D-lactic acidosis, 316 hypergastinemia, 316 nephrolithiasis, 316 rapid intestinal transit, 316 definition, 312 etiology of, 313 management enteral nutrition, 313314 fluids, 314 general principles, 315316 medications, 314315 parenteral nutrition, 314 nutrition deficiencies, 316 prevalence of, 312 Intestine transplantation, 318, 339t, 340, 341 Intrauterine growth restriction (IUGR), 106, 410 maternal dietary deficiencies, 107 placental transport insufficiency and, 106 placental weight, 106 Intravenous fat emulsion (IVFE), 437, 439, 439t Irritable bowel syndrome, 296 Iron human milk fortifier, 123 deficiency, 113, 413 fetal growth and, 108 lactoferrin and, 123 requirements adolescents, 413 premature infants, 413 Iron deficiency anemia, 413
K
Kidney(s) amino acid metabolism, 39 functions, 257 injury, 381 nephrogenesis, 257 phosphorus homeostatis and, 51 transplantation biochemical tests 339t calcium intake, 269 cardiovascular disease and, 269 complications, 343344 fluid intake, 269 recipient nutrition requirements, 342343, 343t trauma to, 381 Kidney disease. See also Acute kidney injury chronic effect on growth, 259260 incidence, 256 nutrition assessment, 261268 primary diagnosis, 258t stages of, 257t, 258 nephrotic syndrome, 274 stages, 257t, 258 Kidney stones. See Renal stones
L
Lactase, 17, 18, 18f Lacto engineering, 122 Lactobacillus, 120 Lactobacillus GG, 137 Lactoferrin, 123 Lactose, 1719 Lanthanum carbonate, 267 Length board, 414 Leptin appetite control, 4 food intake and adiposity, 113 liver disease and, 303 Leucine, 35 in fetal development, 106 Lipase gastric, 25, 32 in pancreatic trauma, 381
J
Jejunostomy tube, 453
Lipid disorders, 162167 fasting lipid profile interpretation, 164t genetic familial hypercholesterolemia, 163 lipoprotein lipase deficiency, 163 nutrition management antioxidants, 166 dietary cholesterol, 164, 166t fiber, 165 garlic, 166 monounsaturated fats, 165 omega-3 fatty acids, 166, 166t plant sterols/stanols, 165166 polyunsaturated fats, 165 saturated fats, 164165, 166t simple carbohydrates, 165, 166t soy protein, 166 trans fats, 165, 166t pharmacologic intervention, 167 physical activity, 166, 166t polygenic hypercholesterolemia (nonfamilial), 163 screening for, 163t Lipoprotein lipase (LPL) deficiency, 163 Listeria monocytogenes, 346t Liver amino acid metabolism, 3839 functions, 302 injuries to, 380381 transplantation biochemical tests, 339t recipient feeding disorders, 342 growth and development, 342 nutrition requirements, 341 parenteral nutrition, 341, 342t Liver disease, 302309 anorexia in, 303 energy requirements, 307 fat-soluble vitamin supplementation, 307308, 308t
504
INDEX
fluid requirements, 308 glycogen storage diseases, 306 malnutrition in hypermetabolism, 304305 iatrogenic factors, 303304 inadequate dietary intake, 303 malabsorption, 304 non-cholestatic, 305306 nonalcoholic fatty liver disease (NAFLD), 306 parenteral nutrition and, 308, 317 protein requirements, 307 salt depletion syndrome, 303 Wilsons disease, 306 Lung disease asthma, 333 bone health and, 334 bronchopulmonary dysplasia, 332333 nutrition assessment, 333 nutrition recommendations, 334 pathophysiology, 332 technology dependent, 333 Lung transplantation biochemical tests, 339t complications, 344345 in cystic fibrosis, 332, 344
M
Magnesium absorption, 52 body content, 45, 52 deficiency, 53 dietary reference intake, 46t excess intake, adverse effects, 53 excretion, 52 in infant formulas, 52 metabolism, 5253 in chronic kidney disease, 268 physiological function of, 52 renal transport, 52 sources, 52 tissue distribution, 52 Malnutrition in chronic kidney disease, 258 in liver disease, 303305 Waterlow criteria, 411, 411t World Health Organization classification, 145t
Malnutrition, inflammation, and atherosclerosis syndrome (MIA), 268 Mastication, 45 Meconium ileus, 324 Medium-chain triglyceride(s) (MCTs) in chylothorax management, 252 in enteral nutrition, for liver disease, 308 formulas, 252t Metabolic bone disease, 263, 470 Metabolic disorders, 149158, 467t Metabolic syndrome Acanthosis nigricans, 154 cluster pediatric population and, 153 in adults, 150151 controversies cut-points, 151 etiology, 151 risk and treatment, 151 diagnostic criteria, 150t etiology, 150t in children, 151153 controversies cut-points, 152 non-traditional cardiovascular risk factors, 152153 puberty, 152 Northern Manhattan Family Study, 154 overview, 149150 risk factor profile, 153155 Methylmalonic acidemia etiology, 237, 238f management acute, 238 chronic, 238239 Migrating motor complex (MMC), 12 Milk substitutes, 221 nutrition comparison with whole milk, 221t Mineral(s), 4555 absorption intestinal, 46 renal, 46
deficiency states, 4748 dietary requirements, 46 metabolism, 47 serum concentrations, 45 sources, 46 in sports nutrition, 182 supplements, 46 Minimal change disease, 274 Motility delayed gastric emptying, 1314 dumping, 14 gastric, 12 intake and motor activity caloric density, 13 consistency, 13 nutrient content, 13 osmolarity, 13 rapid intestinal transit, 14 slow intestinal transit, 14 small bowel, 1213 in trauma patients, 379 Mucositis, 360, 372373 Munchausen Syndrome by Proxy, 450 Myelomeningocele, 192, 193, 333
N
Nasogastric tube, 329, 452453 Nasojejunal tube, 453 National Cholesterol Education Program, Adult Treatment Panel III (NCEP-ATP III) metabolic syndrome, 150t recommendations, 155156, 157 risk factor profile, 153155 National Health and Nutrition Examination Survey food allergies, 215 National Kidney Foundation, 258 National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI), 257, 266 Necrotizing enterocolitis (NEC) breast milk and, 121 in premature infants, 18 Neonatal hypermagnesemia, 53 Neonatal cholestasis, 305
INDEX
505
Neonatal iron storage disease, 305 Nephrocalcinosis, 276, 278 Nephrogenesis, 257 Nephrogenic diabetes insipidus (NDI), 277278 Nephrolithiasis, 276, 316 defined, 274 risk factors, 274 Nephrotic syndrome, 274 Neural tube defects, 108 Niacin, 6364 absorption, 6364 biochemistry, 63 deficiency state, 64 dietary reference intake, 58t excretion, 6364 metabolism, 6364 physiology, 63 source, 63 supplementation, 64 Non-cholestatic liver disease, 305306 Non-insulin-dependent diabetes mellitus, 110111 Nonalcoholic fatty liver disease (NAFLD), 306 Normalized protein catabolic rate (nCPR), 258259 Norovirus, 346t North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS), 257 Northern Manhattan Family Study, 154 Nutrition assessment of adolescents, 412414 biochemical indices, 416417 of children, 411t , 411412 in cancer patients, 352353, 352t in cystic fibrosis, 325, 325t in chronic lung disease, 333 in congenital heart disease, 249250, 249t in developmental delay, 194196 in food allergies, 217218 of full-term infants, 411t, 411412 in gastrointestinal disease, 284285, 285t in liver disease, 307, 413414
of premature infants Ballard score, 409410, 410t classification parameters, 409410 Lubchenco growth chart, 410 physical examination, 417, 417t pretransplant, 339340 Waterlow criteria stunting, 411, 411t wasting, 411, 411t Nutrition intervention in cancer patients, 352, 353t feeding disorders, 445t Nutrition support in burn patients, 384 closed head injuries, 380 for cystic fibrosis, 329330 developmental delay, 196199 during trauma, 379 for eating disorders, 208 pancreatic trauma, 381 traumatic brain injury, 380
nutrition assessment, 339340 nutrition requirements, 340341, 342343, 344 survival rates, 346 Ornithine transcarbamylase deficiency etiology, 239 management acute, 239 chronic, 240 urea cycle, 239f Orogastric tube, 453 Osteopenia, 46, 194, 442 Osteoporosis and cystic fibrosis, 331 in pediatric cancer patients, 363 in transplant recipients, 344, 345
P
Pancreas fetal, 106 injury to, 381, 385 Pancreatic enzyme replacement therapy (PERT), 330 posttransplant, 344 Pancreatic insufficiency, 292293, 292t Pancreatic pseudocyst, 381 Pancreatitis, 293294 Panhypopituitarism, 230 Pantothenic acid absorption, 69 biochemistry, 69 deficiency state, 69 dietary reference intake, 58t excretion, 69 metabolism, 69 physiology, 69 source, 69 supplementation, 69 Parenteral nutrition access, 437 additives carnitine, 441442 cysteine, 442 cysteine hydrochloride salt, 36 heparin, 441 aluminum in, 442 amino acid solutions, 37
O
Obesity breastfeeding, 111 cardiovascular disease, 252254, 268 childhood, 169170 clinical approach, 170 ethical considerations, 483 postnatal weight gain and, 111 in trauma patients, 379, 384385 Oral allergy syndrome, 214t, 215 Oral motor dysfunction, 192193 Organ transplantation biochemical tests pretransplant, 339t complications, 343, 346 foodborne illnesses, 345 immunosuppressive therapy, 344, 346 indications for, 338339, 338t physical examination, 339 quality of life, posttransplant, 346 recipient anthropometric assessment, 338 dietary modification, 344
506
INDEX
in anorexia nervosa, 437 in burn patients, 384 in cancer, 354 central parenteral nutrition, 433 central venous lines, 437 cholestasis, 389390, 439 in chronic kidney disease, 274 complications, 442 metabolic bone disease, 470 in congenital heart disease, 250251, 437 in diabetes mellitus, 228 choice of dextrose solution, 228 insulin infusion, 228229 in eating-disorders, 208 egg allergy, 233 electrolyte dosing guidelines, 440t evaluation and monitoring blood urea nitrogen level, 463 calcium solubility, 465t calcium-phosphorus precipitation, 465, 465t form, 472f formulation integrity, 464465 infusion-related incidents, 463 macronutrient tolerance, 463464 parameters, 464t phosphorus solubility, 465t total nutrient admixtures, 464465, 465t, 466t volume tolerance, 463 for food allergic patient, 223224 gastrointestinal conditions, 436 in hematopoietic stem cell transplant, 358 indicators for, 437 initiation and advancement of, 440t in intestinal failure/short bowel syndrome, 314 intradialytic, 274 intravenous catheters central venous catheter, 449 peripherally inserted central catheter, 449 intravenous fat emulsion, 437, 439, 439t laboratory tracking sheet, 473f
limits, 471t in liver disease, 308, 317 macronutrients amino acids, 437439, 438t carbohydrates, 437 magnesium overdose, 53 medications compatability of, 467 drug-nutrient interactions, 466467, 467t nursing care, 451, 452t peripheral, 433, 449 in premature infants, 410, 436437 safety issues bloodstream infections, 317, 450, 470 prevention of, 451t Munchausen Syndrome by Proxy, 450 site care, 450 chlorhexidine gluconate, 450 Guidelines for the Prevention of Intravascular Cather Infections recommendations, 450 total nutrient admixtures advantages and disadvantages, 466t factors affecting stability, 465t in trauma, 379 trace elements chromium, 441, 441t copper, 440, 441t manganese, 441, 441t selenium, 441, 441t zinc, 440, 441t in transplantation intestine, 340341 liver, 341, 342t vitamins, 441t when to use, 433434 Pelvic injury, 382 Pepsinogen, 3233 Peptide, 32, 32t Peripheral blood stem cell transplantation (PBSCT). See Hematopoietic stem cell transplantation (HSCT)
Peripheral parenteral nutrition (PPN), 433, 437, 449 Peripherally inserted central catheter (PICC), 449 Peristalsis, 12 Peritoneal dialysis (PD), 259 Phenylalanine, 35 Phenylketonuria (PKU) etiology, 234, 234f low-phe formula calculation, 235f management acute, 234235 chronic, 235 maternal, 234 meal plan for, 236t recommended nutrient intakes, 235t supplementation cofactors, 237 large neutral amino acids, 237 tyrosine requirement in, 37 Phosphorus absorption, 51 binding medications, 51 biochemistry, 50 body content, 45, 50 deficiency, 51 dietary reference intake, 46t effect on calcium, 49 excess intake, adverse effects, 5152 excretion, 51 glomerular filtration rate and, 51 human milk content, 51 intake from soft drinks, 50 kidney as regulator as, 51 management, in chronic kidney disease, 266267 physiological function of, 50 serum concentration, 50 sources, 5051 tissue distribution, 50 Phosphorus binders, 267 Placental transport insufficiency, 106 Prebiotics 136 Pregnancy dietary reference intakes, 108t epigenetic changes, 107 intergenerational effects, 114115
INDEX
507
intrauterine growth restriction, 106 intrauterine insults, 107 maternal nutrition effect on fetus, 107109 nutrition physiology, 105107 recommended daily nutrient intakes, 108t Primary hyperoxaluria, 278 Probiotics, 136137 Protein catabolic rate (PCR), 258 Protein(s) absorption, 3334 dietary reference intake, 412t digestion, 3233 effect on fetal growth, 107108 ontogeny and gastrointestinal tract, 3132 requirements in acute kidney injury, 271 in burn patient, 384 in chronic kidney disease, 263, 277t in continuous renal replacement therapy, 270 in cystic fibrosis, 326 in eating disorders, 207 in hematopoietic stem cell transplant patient, 356, 356t in liver disease, 307 in sports nutrition, 180181, 180t in transplant recipients, 340, 344 Protein-losing enteropathy (PLE), 251 Pulmonary disorders, 323334 Purine, in uric acid stones, 276
R
Refeeding syndrome definition, 209 hyperglycemia, 209 hypokalemia, 209, 210 hypomagnesemia, 209, 210 hypophosphatemia, 209 incidence of, 209 preventing, 210211, 210t treatment, 210211, 210t
Renal failure creatinine clearance, 257 nutrition management, 277t oxalosis, 278 Renal stones 2,8-dihydroxyadenine calculi, 276 calcium-based, 275276 cystine stones, 274 cystinuria, 276 infection stones, 276 nutrition management, 275t in pediatric patients, 275 struvite calculi, 274, 276 uric acid, 274, 276 xanthine stones, 276 Renal tubular acidosis, 276277 Renal tubular disorders Bartters syndrome, 277 nephrogenic diabetes insipidus, 277278 renal tubular acidosis, 276277 Resting energy expenditure (REE) in burn patient, 384 in developmentally delayed child, 193 in liver disease, 304 in trauma patients, 379 World Health Organization equation, 412, 412t Rett syndrome, 192, 193 Riboflavin, 6263 absorption, 6263 biochemistry, 62 deficiency state, 63 dietary reference intake, 58t excretion, 6263 metabolism, 6263 physiology, 62 source, 62 supplementation, 63 Rickets, 46, 413
S
Salmonella, 346t Seatbelt injury, 381, 382 Serial transverse enteroplasty (STEP), 313, 315 Serum albumin, 262 Sevelamer carbonate, 267
Short bowel syndrome (SBS), 312 Shwachman-Diamond syndrome, 304 Sinusoidal obstruction syndrome (SOS), 359 Sirolimus, 269, 343 Skeleton as mineral reservoir, 4546 growth, 46 injuries to, 382 Skin prick testing, 216 Small intestine injuries, 382 motility, 1213 Sodium absorption, 91 balance, 91 deficiency, in cholestatic liver disease, 303 losses, 91, 182 management, in chronic kidney disease, 265 physiological effects, 91 serum level normal, 91 Spastic hemiplegia, 192 Spastic quadriplegia, 192 Specialized nutrition support (SNS) chemistry profiles, 468 evaluation and monitoring of, 460473 laboratory values, 467, 471t, 473f liver function tests, 468 nutrition-related laboratory tests, 468 physical data, 462t, 467468 reassessment of plan, 466, 466f Spinal cord trauma, 380 Spleen injury, 380 Sports nutrition at bedtime, 183 carbohydrates, 179180 practical application, 180, 180t challenges, 183, 185t fat, 180t, 181 practical application, 180t, 181 Female Athlete Triad, 185t fueling for competition, 184t hydration, 181182, 181t
508
INDEX
practical application, 182 hyponatremia, 182 minerals, 182 overview, 178179 protein, 180181 practical application, 180t, 181 recovery nutrition, 183 resources, 183, 186t timing to sport, 182183, 184t vitamins, 182 Standiometer, 414415 Starvation pathophysiology, 209 Stomach and food intake, 12 injury to, 381 motility, 12 Stool, monitoring, 461, 462t Stunting, 411, 411t Surgery airway disorders, 400401 anorectal malformations, 397 biliary atresia, 399400 choledochal cyst, 400 colon atresia, 396 congenital diaphragmatic hernia, 399 congenital heart disease, 251252 distal intestinal obstruction, 395396 duodenal atresia, 394395 esophageal atresia, 393394 gastroschisis, 397399 Hirschsprungs disease, 396397 intestinal malrotation, 402 intestinal perforation, 402 meconium ileus, 396 midgut volvulus, 402 necrotizing enterocolitis, 401402 neonatal, 388389 neurosurgical disorders, 400 nutrient considerations, 387388 omphalocele, 397 orthopedic disorders, 400 proximal intestinal obstruction, 393 pyloric stenosis, 402403 thoracic disorders, 400 urologic disorders, 400
Swallowing esophageal phase, 5 oral phase, 5 pharyngeal phase, 5 Syndrome of inappropriate antidiuretic hormone (SIADH), 89, 380
T
Tacrolimus, 53, 269, 341, 345 magnesium deficiency and, 53 Thiamin, 6162 absorption, 61 biochemistry, 61 deficiency state, 6162 dietary reference intake, 58t excretion, 61 metabolism, 61 physiology, 61 source, 61 supplementation, 62 toxicity, 78 Thoracic injuries, 382 Toddler(s) feeding problems, 78 feeding skills, 7 formula, 139, 140t Total body water (TBW), 87, 88t Total nutrient admixtures (TNAs), 464465, 465t, 466t Trans-fatty acids, 23 Transsulfuration pathway, 36 Trauma adrenal hemorrhage, 381 age-related injuries, 379 anatomical classification, 379 blunt abdominal, 380381 hollow visceral injuries, 381382 solid visceral injuries, 380381 brain injury, 380 child abuse, 381 childhood, 379 clinical examples, 384385 closed head injuries, 380 duodenal injuries, 381382 extremity injury, 382 facial, 382 hyperglycemia and, 380
metabolic response, 378379 obesity and, 384385 pancreatic, 381 pelvic injury, 382 physiological response, 378379 renal, 381 small intestine and colon injuries, 382 spinal cord injury, 380 syndrome of inappropriate antidiuretic hormone (SIADH) in, 380 thoracic injuries, 382 traumatic brain injury, 380 Traumatic brain injury, 380 Triglyceride(s) defined, 22 Tube feeding. See Enteral nutrition Tumor necrosis factor (TNF) in trauma response, 378 Type IIa Na/phosphate cotransporter (Npt2a) protein, 51 Tyrosine intake requirements, 37 N-acetyl-tyrosine (NAT), 37 phenylketonuria and, 37
U
U.S. Department of Agriculture, Food Safety and Inspection Service, 345 Umbilical cord blood transplantation (UCBT). See Hematopoietic stem cell transplantation (HSCT) United Nations International Childrens Fund (UNICEF), 121 Baby Friendly Hospital Initiative, 121 Urea cycle, 38f, 239f Uric acid stones, 274, 276 Urinary extravasation, 381
V
Vascular access device (VAD), 449 blood sample techniques, 450t Very long chain acyl-CoA dehydrogenase deficiency (VLCADD) etiology, 240
INDEX
509
fatty acid oxidation and, 240f management acute, 240 chronic, 241 Video feeding study, 340 Vitamin(s) allergen-free, 222, 222t fat-soluble, 7486 in sports nutrition, 182 water soluble, 5671 Vitamin A absorption, 7677 biochemistry, 76 deficiency, 7778 dietary reference intake, 75t metabolism, 7677 physiology, 76 sources, 76 toxicity, 78 Vitamin B1. See Thiamin Vitamin B2 . See Riboflavin Vitamin B3. See Niacin Vitamin B5. See Pantothenic acid Vitamin B6 absorption, 6465 biochemistry, 64 deficiency state, 65 dietary reference intake, 58t excretion, 6465 metabolism, 6465 physiology, 64 source, 64 supplementation, 65 Vitamin B7. See Biotin Vitamin B9. See Folate Vitamin B12 absorption, 6667 biochemistry, 66 in cystic fibrosis, 328 deficiency state, 67 dietary reference intake, 58t excretion, 6667 metabolism, 6667 physiology, 66 source, 66 supplementation, 67 Vitamin C absorption, 68 biochemistry, 6768
in chronic kidney disease, 264 deficiency state, 68 dietary reference intake, 58t excretion, 68 metabolism, 68 physiology, 6768 source, 68 supplementation, 69 Vitamin D absorption, 7980 biochemistry, 7879 in chronic kidney disease, 263264, 266 in cystic fibrosis-specific multivitamins, 328, 327t deficiency, 80, 413-414 dietary reference intake, 75t metabolism, 7980 physiology, 7879 sources, 79 toxicity, 80 Vitamin E absorption, 8182 biochemistry, 81 in chronic kidney disease, 264 in cystic fibrosis-specific multivitamins, 328, 327t deficiency, 82 dietary reference intake, 75t metabolism, 8182 physiology, 81 sources, 81 toxicity, 8283 Vitamin K absorption, 83 biochemistry, 83 in chronic kidney disease, 264 in cystic fibrosis-specific multivitamins, 328, 327t deficiency, 8384 dietary reference intake, 75t metabolism, 83 physiology, 81 sources, 83 toxicity, 84
Winkler, Marion, 3 World Health Organization breastfeeding, 120, 129 growth charts, 143144 malnutrition classification, 145t metabolic syndrome, 150t resting energy expenditure equation, 412, 412t
X
Xanthine stones, 276
Z
z scores in developmental delay, 192, 193 percentile comparisons, 146t Zinc in chronic kidney disease, 265 in cystic fibrosis-specific multivitamins, 327t, 328 in eating disorders, 207 in liver disease, 303, 308
W
Wasting, 411, 411t Wilsons disease, 306

ASPEN Nutricion Pediatrica

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The A.S.P.E.N.

Pediatric Nutrition Support Core Curriculum

AMERICAN SOCIETY FOR PARENTERAL AND ENTERAL NUTRITION

7. Water-Soluble Essential Micronutrients. . . . . . . . . . . . . . 56

PART I INTRODUCTORY AND BASIC PHYSIOLOGY

9. Fluids and Electrolytes. . . . . . . . . . . . . . . . . . . . . . . . . . . 87

2. Gross Digestion Principles: Gastric Grinding and Gastrointestinal Motility. . . . . . . . . . . . . . . . . . . . . . 11

PART II AGE-SPECIFIC NUTRITION FOR GROWTH ANDDEVELOPMENT

3. Carbohydrates: Changes with Development. . . . . . . . . . . 17

4. Fats. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 5. Protein Digestion, Absorption, and Metabolism. . . . . . . . 31

15. Lipid Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162

16. Use of Fad and Popular Diets. . . . . . . . . . . . . . . . . . . . 169

30. Oncology, Hematopoietic Transplant, and Survivorship. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349

17. Sports Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

PART III DISEASE STATES AND NUTRITION

31. Trauma and Burns . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378 32. Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

19. Eating Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

20. Food Allergies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

PART IV NUTRITION CARE OF THE PEDIATRIC PATIENT

21. Diabetes Mellitus and Other Endocrine Disorders. . . . 226

22. Inborn Errors of Metabolism . . . . . . . . . . . . . . . . . . . . 232

23. Cardiac Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

24. Renal Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256

35. Implementation of the Plan. . . . . . . . . . . . . . . . . . . . . 448

25. Gastrointestinal Disease . . . . . . . . . . . . . . . . . . . . . . . 283

26. Hepatic Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

37. Ethical Issues in the Provision of Nutrition . . . . . . . . . 477

27. Intestinal Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 28. Pulmonary Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 323

Test Your Knowledge Answers . . . . . . . . . . . . . . . . . . . . . . . . 487 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495

29. Organ Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . 337

Acknowledgments & Dedication

INTRODUCTORY AND BASIC PHYSIOLOGY

Mechanics of Nutrient Intake

Dysphagia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Feeding Teams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

THE A.S.P.E.N. PEDIATRIC NUTRITION SUPPORT CORE CURRICULUM

MECHANICS OF NUTRIENT INTAKE

610 mo 812 mo 913 mo 1016 mo 1319 mo 1418 mo 1622 mo 1723 mo 23 y

67 y 67 y 67 y 78 y 78 y 89 y 910 y 1011 y 1012 y 1012 y 1112 y 1112 y

Feeding Skills in the First Year

THE A.S.P.E.N. PEDIATRIC NUTRITION SUPPORT CORE CURRICULUM

MECHANICS OF NUTRIENT INTAKE

Feeding Skills in the Second Year

THE A.S.P.E.N. PEDIATRIC NUTRITION SUPPORT CORE CURRICULUM

MECHANICS OF NUTRIENT INTAKE

Test Your Knowledge Questions

2010 A.S.P.E.N. www.nutritioncare.org

THE A.S.P.E.N. PEDIATRIC NUTRITION SUPPORT CORE CURRICULUM

2010 A.S.P.E.N. www.nutritioncare.org

Gross Digestion Principles: Gastric Grinding and Gastrointestinal Motility

Altered Patterns of Motility and Potential Interventions . 13

THE A.S.P.E.N. PEDIATRIC NUTRITION SUPPORT CORE CURRICULUM

Small Bowel Motility

GROSS DIGESTION PRINCIPLES: GASTRIC GRINDING AND GASTROINTESTINAL MOTILITY

Effect of Intake on Motor Activity

Altered Patterns of Motility and Potential Interventions

Delayed Gastric Emptying

THE A.S.P.E.N. PEDIATRIC NUTRITION SUPPORT CORE CURRICULUM

Rapid Intestinal Transit

Test Your Knowledge Questions

Slow Intestinal Transit

GROSS DIGESTION PRINCIPLES: GASTRIC GRINDING AND GASTROINTESTINAL MOTILITY

2010 A.S.P.E.N. www.nutritioncare.org

THE A.S.P.E.N. PEDIATRIC NUTRITION SUPPORT CORE CURRICULUM

2. Gross Digestion Principles: Gastric Grinding and Gastrointestinal Motility. . . . . . . . . . . . . . . . . . . . . . 11

4. Fats. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 5. Protein Digestion, Absorption, and Metabolism. . . . . . . . 31

30. Oncology, Hematopoietic Transplant, and Survivorship. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349