var title_f0_6_100="HHV-6 encephalitis MRIs 1";

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" &copy;2013 UpToDate",
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" Post-transplant acute limbic encephalitis caused by HHV-6 - initial magnetic
resonance imaging findings with days from symptom onset indicated",
" </div>",
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" </div>",
" <div class=\"lgnd\">",
" Axial fluid attenuation inversion recovery (FLAIR) (top) and diffusion-
weighted (bottom) sequences demonstrate limbic system involvement, including the
uncus, amygdala, and anterior hippocampus in all patients. For Patient 6, only
coronal FLAIR images from day two were available. An axial FLAIR image from day
six, with findings similar to those on day two, is shown. The left side of each
image corresponds to the right side of the brain.",
" <div class=\"footnotes\">",
" HHV-6: human herpesvirus 6",
" </div>",
" <div class=\"reference\">",
" Reproduced with permission from: Seeley WW, Marty FM, Holmes TH, et al. Post-
transplant acute limbic encephalitis: Clinical features and relationship to HHV6.
Neurology 2007; 69:156. Copyright &copy; 2007 Lippincott Williams &amp; Wilkins.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
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" </div>",
" <div class=\"lgnd\">",
" Multiple small erythematous papules are present around the mouth.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" </div>",
" </div>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 524px\">",
" <div class=\"ttl\">",
" Perioral dermatitis",
" </div>",
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" </div>",
" <div class=\"lgnd\">",
" Clustered small papules are present on the perioral skin.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Reproduced with permission from: www.visualdx.com. Copyright Logical Images,
Inc.",
" </div>",
" </div>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 475px\">",
" <div class=\"ttl\">",
" Perioral dermatitis",
" </div>",
" <div class=\"cntnt\" style=\"width: 455px; height: 583px; background-image:
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);\">",
" </div>",
" <div class=\"lgnd\">",
" Multiple erythematous papules are present around the mouth.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" </div>",
" </div>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 524px\">",
" <div class=\"ttl\">",
" Perioral dermatitis",
" </div>",
" <div class=\"cntnt\" style=\"width: 504px; height: 367px; background-image:
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" </div>",
" <div class=\"lgnd\">",
" Multiple erythematous papules are present around the oral cavity in this
child. Note the relative sparing of skin around the border of the lip.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Reprinted by permission of Edizioni Minerva Medica from G Ital Dermatol
Venereol 2010; 145:433. Copyright &copy; 2010. All rights reserved.",
" </div>",
" </div>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 524px\">",
" <div class=\"ttl\">",
" Perioral dermatitis",
" </div>",
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" </div>",
" <div class=\"lgnd\">",
" Tiny papules and pustules grouped on the chin.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Reproduced with permission from: www.visualdx.com. Copyright Logical Images,
Inc.",
" </div>",
" </div>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 524px\">",
" <div class=\"ttl\">",
" Severe perioral dermatitis",
" </div>",
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);\">",
" </div>",
" <div class=\"lgnd\">",
" Erythematous papules and confluent areas of erythema are present.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Reproduced with permission from: www.visualdx.com. Copyright Logical Images,
Inc.",
" </div>",
" </div>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 524px\">",
" <div class=\"ttl\">",
" Severe perioral dermatitis",
" </div>",
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" </div>",
" <div class=\"lgnd\">",
" Numerous inflammatory papules are present on the perioral skin.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Reproduced with permission from: www.visualdx.com. Copyright Logical Images,
Inc.",
" </div>",
" </div>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 470px\">",
" <div class=\"ttl\">",
" Perioral dermatitis",
" </div>",
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" </div>",
" <div class=\"lgnd\">",
" Multiple acneiform papules can be seen on this young woman. Note the
characteristic sparing around the lips.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Reproduced with permission from: Goodheart, HP, MD. Goodheart's Photoguide of
Common Skin Disorders, 2nd ed. Lippincott Williams &amp; Wilkins, Philadelphia
2003. Copyright &copy;2003 Lippincott Williams &amp; Wilkins.",
" </div>",
" </div>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 470px\">",
" <div class=\"ttl\">",
" Periorificial dermatitis",
" </div>",
" <div class=\"cntnt\" style=\"width: 448px; height: 504px; background-image:
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" </div>",
" <div class=\"lgnd\">",
" Multiple erythematous papules and mild scale are present on the perinasal
skin.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Reprinted by permission of Edizioni Minerva Medica from G Ital Dermatol
Venereol 2010; 145:433. Copyright &copy; 2010. All rights reserved.",
" </div>",
" </div>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 524px\">",
" <div class=\"ttl\">",
" Periorificial dermatitis",
" </div>",
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" Multiple erythematous papules are present in the periorbital region.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Reproduced with permission from: www.visualdx.com. Copyright Logical Images,
Inc.",
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" Endoscopic criteria suggesting malignancy of a polyp",
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" <div class=\"lgnd\">",
" <div class=\"footnotes\">",
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" <tr>",
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" Anabolic steroids",
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" <tr>",
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" <tr>",
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" </tr>",
" <tr>",
" <td>",
" Clonidine withdrawal",
" </td>",
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" <tr>",
" <td class=\"subtitle1_single\">",
" Miscellaneous",
" </td>",
" </tr>",
" <tr>",
" <td>",
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" </td>",
" </tr>",
" <tr>",
" <td>",
" Neuroblastoma",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Hypercalcemia",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Acute intermittent porphyria",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Neuroleptic malignant syndrome",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Neurofibromatosis",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Tuberous sclerosis",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Volume overload",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" <div class=\"lgnd\">",
" <div class=\"footnotes\">",
" PDA: patent ductus arteriosus; AV: arteriovenous; SLE: systemic lupus
erythematosus; PCP: phencyclidine.",
" </div>",
" <div class=\"reference\">",
" Adapted with permission from Linakis JG, Constantine E. Hypertension. In:
Textbook of Pediatric Emergency Medicine, 5th ed, Fleisher GR, Ludwig S, Henretig
FM (Ed), Lippincott Williams &amp; Wilkins, Philadelphia, 2006. Copyright &copy;
2006 Lippincott Williams &amp; Wilkins.",
" </div>",
" <div class=\"contractual\">",
" <br/>",
" <a href=\"file://www.lww.com\">",
" file://www.lww.com",
" </a>",
" </div>",
" </div>",
" </div>",
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" <div class=\"graphic\">",
" <div class=\"figure\">",
" <div class=\"ttl\">",
" Questionnaire for exploring obstructive sleep apnea (OSA) symptoms",
" </div>",
" <div class=\"cntnt\">",
" <table cellspacing=\"0\">",
" <tbody>",
" <tr>",
" <td class=\"subtitle1\">",
" Questions",
" </td>",
" <td class=\"subtitle1\" colspan=\"2\">",
" Circle one",
" </td>",
" </tr>",
" <tr>",
" <td>",
" People tell me that I snore",
" </td>",
" <td>",
" Y",
" </td>",
" <td>",
" N",
" </td>",
" </tr>",
" <tr>",
" <td>",
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" N",
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" </tr>",
" <tr>",
" <td>",
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" </td>",
" <td>",
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" <td>",
" N",
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" </tr>",
" <tr>",
" <td>",
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" </td>",
" <td>",
" Y",
" </td>",
" <td>",
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" <tr>",
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" </td>",
" <td>",
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" </td>",
" <td>",
" N",
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" <tr>",
" <td>",
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" </td>",
" <td>",
" Y",
" </td>",
" <td>",
" N",
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" </tr>",
" <tr>",
" <td>",
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" <td>",
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" <td>",
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" </tr>",
" <tr>",
" <td>",
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" </td>",
" <td>",
" Y",
" </td>",
" <td>",
" N",
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" </tr>",
" <tr>",
" <td>",
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" </td>",
" <td>",
" Y",
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" <td>",
" N",
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" <tr>",
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" </td>",
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" Y",
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" </tr>",
" <tr>",
" <td class=\"sublist_other\">",
" &nbsp;",
" </td>",
" </tr>",
" <tr class=\"divider_top\">",
" <td class=\"subtitle1_single\">",
" High risk",
" </td>",
" <td class=\"subtitle1_single\" colspan=\"2\">",
" Low risk",
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" </tr>",
" <tr>",
" <td>",
" <p>",
" - Male",
" </p>",
" <p>",
" - Body mass index greater than 25 kg/m",
" ^{",
" 2",
"}",
" </p>",
" - Neck circumference:",
" <ul>",
" <li>",
" Greater than 17 inches in men",
" </li>",
" <li>",
" Greater than 16 inches in women",
" </li>",
" </ul>",
" <p>",
" - Habitual snoring/gasping noted by bed partner",
" </p>",
" <p>",
" - Hypertension",
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" </td>",
" <td colspan=\"2\">",
" <p>",
" - No snoring",
" </p>",
" <p>",
" - Premenopausal",
" </p>",
" <p>",
" - Thin",
" </p>",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" <div class=\"lgnd\">",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Reprinted with permission from: Associated Professional Sleep Societies, LLC,
2010. Meoli AL, Rosen CL, Kristo D, et al. Upper Airway Management of the adult
patient with obstructive sleep apnea in the perioperative period-avoiding
complications. Sleep 2003; 26:1060. Copyright &copy; 2003.",
" </div>",
" </div>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\">",
" <div class=\"ttl\">",
" Identification and assessment of obstructive sleep apnea (OSA): American
Society of Anesthesiologists example",
" </div>",
" <div class=\"cntnt\">",
" <table cellspacing=\"0\">",
" <tbody>",
" <tr>",
" <td class=\"subtitle1_single\">",
" Clinical signs and symptoms suggesting the possibility of OSA",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_single\">",
" 1. Predisposing physical characteristics",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" a. Body mass index 35 kg/m",
" ^{",
" 2",
"}",
" (95th percentile for age and gender)*",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" b. Neck circumference 17 inches (men) or 16 inches (women)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" c. Craniofacial abnormalities affecting the airway",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" d. Anatomical nasal obstruction",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" e. Tonsil nearly touching or touching in the midline",
" </td>",
" </tr>",
" <tr class=\"divider_top\">",
" <td class=\"subtitle2_single\">",
" 2. History of apparent airway obstruction during sleep (two or more of the
following are present: if patient lives alone or sleep is not observed by another
person, then only one of the following needs to be present)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" a. Snoring (loud enough to be heard through closed door)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" b. Frequent snoring",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" c. Observed pauses in breathing during sleep",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" d. Awakens from sleep with choking sensation",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" e. Frequent arousals from sleep",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" f. (Intermittent vocalization during sleep)*",
" </td>",
" </tr>",
" <tr class=\"divider_top\">",
" <td class=\"subtitle2_single\">",
" 3. Somnolence (one or more of the following is present)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" a. Frequent somnolence or fatigue despite adequate \"sleep\"",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" b. Falls asleep easily in a non stimulating environment (eg, watching TV,
reading, riding in or driving a car) despite adequate \"sleep\"",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" c. (Parent or teacher comments that child appears sleepy during the day,
is easily distracted, is overly aggressive, or has difficulty concentrating)*",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" d. (Child often difficult to arouse at usual awakening time)*",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" <div class=\"lgnd\">",
" If a patient has signs or symptoms in&nbsp;two or more of the above
categories, there is a significant probability that he or she has obstructive sleep
apnea (OSA). The severity of OSA may be determined by sleep study. If a sleep study
is not available, such patients should be treated as though they have moderate
sleep apnea unless one or more of the signs or symptoms above is severely abnormal
(eg, markedly increased body mass index or neck circumference, respiratory pauses
that are frightening to the observer, patient regularly falls asleep within minutes
after being left unstimulated), in which case they should be treated as though they
have severe apnea.",
" <div class=\"footnotes\">",
" * Item in parentheses refers to pediatric patients.",
" </div>",
" <div class=\"reference\">",
" Reproduced with permission from: American Society of Anesthesiologists Task
Force on Perioperative Management of Patients with Obstructive Sleep Apnea.
Practice guidelines for the perioperative management of patients with obstructive
sleep apnea: a report by the American Society of Anesthesiologists Task Force on
Perioperative Management of Patients with Obstructive Sleep Apnea. Anesthesiology
2006; 104:1081. Copyright &copy; 2006 Lippincott Williams &amp; Wilkins.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
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var outline_f0_6_105=null;
var title_f0_6_106="Morbidity rates for extremely premature infants";
var content_f0_6_106=[" <div id=\"graphicsToolbar\">",
" <div id=\"graphicsCopy\">",
" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
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title=\"Print this page\"/>",
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" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\">",
" <div class=\"ttl\">",
" Rates of common morbidities among survivors in selected studies for infants 22
to 25 weeks gestation during the initial NICU admission",
" </div>",
" <div class=\"cntnt\">",
" <table cellspacing=\"0\">",
" <tbody>",
" <tr>",
" <td class=\"subtitle1\" rowspan=\"2\">",
" Study",
" </td>",
" <td class=\"subtitle1\" colspan=\"5\">",
" Rate (percent) by gestational week",
" </td>",
" <td class=\"subtitle1\" rowspan=\"2\">",
" Comment",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2\">",
" 22",
" </td>",
" <td class=\"subtitle2\">",
" 23",
" </td>",
" <td class=\"subtitle2\">",
" 24",
" </td>",
" <td class=\"subtitle2\">",
" 25",
" </td>",
" <td class=\"subtitle2\">",
" Total",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_left\" colspan=\"7\">",
" Severe intraventricular hemorrhage (&ge;grade 3)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Markestad",
" ^{",
" [1]",
"}",
" </td>",
" <td class=\"centered\">",
" n/a",
" </td>",
" <td class=\"centered\">",
" 11",
" </td>",
" <td class=\"centered\">",
" 16",
" </td>",
" <td class=\"centered\">",
" 10",
" </td>",
" <td class=\"centered\">",
" 12",
" </td>",
" <td>",
" Infants with CUS* scans at &ge;3 weeks",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" EXPRESS",
" ^{",
" [2]",
"}",
" </td>",
" <td class=\"centered\">",
" 20*",
" </td>",
" <td class=\"centered\">",
" 19",
" </td>",
" <td class=\"centered\">",
" 10",
" </td>",
" <td class=\"centered\">",
" 12",
" </td>",
" <td class=\"centered\">",
" 13",
" </td>",
" <td>",
" &nbsp;",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Stoll",
" ^{",
" [3]",
"}",
" </td>",
" <td class=\"centered\">",
" 38",
" </td>",
" <td class=\"centered\">",
" 36",
" </td>",
" <td class=\"centered\">",
" 26",
" </td>",
" <td class=\"centered\">",
" 21",
" </td>",
" <td class=\"centered\">",
" 25",
" </td>",
" <td>",
" Infants with CUS scans within first 28 days",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_left\" colspan=\"7\">",
" Periventricular leukomalacia",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Markestad",
" ^{",
" [1]",
"}",
" </td>",
" <td class=\"centered\">",
" n/a",
" </td>",
" <td class=\"centered\">",
" 0",
" </td>",
" <td class=\"centered\">",
" 14",
" </td>",
" <td class=\"centered\">",
" 8",
" </td>",
" <td class=\"centered\">",
" 10",
" </td>",
" <td>",
" Infants with CUS",
" ^{",
" &bull;",
"}",
" scans at &ge;3 weeks",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" EXPRESS",
" ^{",
" [2]",
"}",
" </td>",
" <td class=\"centered\">",
" 0*",
" </td>",
" <td class=\"centered\">",
" 9.4",
" </td>",
" <td class=\"centered\">",
" 6.2",
" </td>",
" <td class=\"centered\">",
" 5.4",
" </td>",
" <td class=\"centered\">",
" 6.2",
" </td>",
" <td>",
" &nbsp;",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Stoll",
" ^{",
" [3]",
"}",
" </td>",
" <td class=\"centered\">",
" 6",
" </td>",
" <td class=\"centered\">",
" 4",
" </td>",
" <td class=\"centered\">",
" 3",
" </td>",
" <td class=\"centered\">",
" 4",
" </td>",
" <td class=\"centered\">",
" 4",
" </td>",
" <td>",
" Infants with CUS scans within first 28 days",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_left\" colspan=\"7\">",
" Necrotizing enterocolitis (NEC)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist2_start\" colspan=\"6\">",
" Carlo",
" ^{",
" [4]",
"}",
" </td>",
" <td class=\"sublist1_start\">",
" Both medically and surgically treated NEC",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" ANS",
" </td>",
" <td class=\"centered\">",
" 0",
" </td>",
" <td class=\"centered\">",
" 12",
" </td>",
" <td class=\"centered\">",
" 10",
" </td>",
" <td class=\"centered\">",
" 10",
" </td>",
" <td class=\"centered\">",
" 10",
" </td>",
" <td>",
" ANS subgroup treated with antenatal steroids (ANS)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" No ANS",
" </td>",
" <td class=\"centered\">",
" 12",
" </td>",
" <td class=\"centered\">",
" 15",
" </td>",
" <td class=\"centered\">",
" 10",
" </td>",
" <td class=\"centered\">",
" 6",
" </td>",
" <td class=\"centered\">",
" 9",
" </td>",
" <td>",
" No ANS subgroup did not receive antenatal steroids",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Markestad",
" ^{",
" [1]",
"}",
" </td>",
" <td class=\"centered\">",
" n/a",
" </td>",
" <td class=\"centered\">",
" 0",
" </td>",
" <td class=\"centered\">",
" 8.6",
" </td>",
" <td class=\"centered\">",
" 0",
" </td>",
" <td class=\"centered\">",
" 3",
" </td>",
" <td>",
" Surgically treated NEC",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" EXPRESS",
" ^{",
" [2]",
"}",
" </td>",
" <td class=\"centered\">",
" 0*",
" </td>",
" <td class=\"centered\">",
" 1.9",
" </td>",
" <td class=\"centered\">",
" 9.4",
" </td>",
" <td class=\"centered\">",
" 6.0",
" </td>",
" <td class=\"centered\">",
" 6.2",
" </td>",
" <td>",
" Both medically and surgically treated NEC",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Stoll",
" ^{",
" [3]",
"}",
" </td>",
" <td class=\"centered\">",
" 1.7",
" </td>",
" <td class=\"centered\">",
" 8.3",
" </td>",
" <td class=\"centered\">",
" 9.2",
" </td>",
" <td class=\"centered\">",
" 6.2",
" </td>",
" <td class=\"centered\">",
" 7.6",
" </td>",
" <td>",
" Surgically treated NEC",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_left\" colspan=\"7\">",
" Bronchopulmonary dysplasia",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist2_start\" colspan=\"6\">",
" Carlo",
" ^{",
" [4]",
"}",
" </td>",
" <td class=\"sublist1_start\">",
" Oxygen use at 36 weeks PMA",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" ANS",
" </td>",
" <td class=\"centered\">",
" 65",
" </td>",
" <td class=\"centered\">",
" 66",
" </td>",
" <td class=\"centered\">",
" 66",
" </td>",
" <td class=\"centered\">",
" 55",
" </td>",
" <td class=\"centered\">",
" 60",
" </td>",
" <td>",
" ANS sugroup treated with antenatal steroids (ANS)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" No ANS",
" </td>",
" <td class=\"centered\">",
" 58",
" </td>",
" <td class=\"centered\">",
" 70",
" </td>",
" <td class=\"centered\">",
" 54",
" </td>",
" <td class=\"centered\">",
" 47",
" </td>",
" <td class=\"centered\">",
" 54",
" </td>",
" <td>",
" No ANS subgroup did not receive antenatal steroids",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" EPICure",
" ^{",
" [5]",
"}",
" </td>",
" <td class=\"centered\">",
" n/a",
" </td>",
" <td class=\"centered\">",
" 86*",
" </td>",
" <td class=\"centered\">",
" 77",
" </td>",
" <td class=\"centered\">",
" 70",
" </td>",
" <td class=\"centered\">",
" 73",
" </td>",
" <td>",
" Oxygen use at 36 weeks PMA",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Markestad",
" ^{",
" [1]",
"}",
" </td>",
" <td class=\"centered\">",
" n/a",
" </td>",
" <td class=\"centered\">",
" 67",
" </td>",
" <td class=\"centered\">",
" 54",
" </td>",
" <td class=\"centered\">",
" 47",
" </td>",
" <td class=\"centered\">",
" 52",
" </td>",
" <td>",
" Use of oxygen or assisted ventilation at 36 weeks PMA",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" EXPRESS",
" ^{",
" [2]",
"}",
" </td>",
" <td class=\"centered\">",
" 40",
" ^{",
" &bull;",
"}",
" </td>",
" <td class=\"centered\">",
" 26",
" </td>",
" <td class=\"centered\">",
" 31",
" </td>",
" <td class=\"centered\">",
" 29",
" </td>",
" <td class=\"centered\">",
" 41",
" </td>",
" <td>",
" Receipt of &ge;30 percent oxygen at 36 weeks PMA",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Stoll",
" ^{",
" [3]",
"}",
" </td>",
" <td class=\"centered\">",
" 85",
" </td>",
" <td class=\"centered\">",
" 73",
" </td>",
" <td class=\"centered\">",
" 69",
" </td>",
" <td class=\"centered\">",
" 55",
" </td>",
" <td class=\"centered\">",
" 63",
" </td>",
" <td>",
" Oxygen use at 36 weeks PMA",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_left\" colspan=\"7\">",
" Severe retinopathy of prematurity (ROP)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" EPICure",
" ^{",
" [5]",
"}",
" </td>",
" <td class=\"centered\">",
" n/a",
" </td>",
" <td class=\"centered\">",
" 26*",
" </td>",
" <td class=\"centered\">",
" 20",
" </td>",
" <td class=\"centered\">",
" 10",
" </td>",
" <td class=\"centered\">",
" 15",
" </td>",
" <td>",
" Treated with cryotherapy or laser",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Markestad",
" ^{",
" [1]",
"}",
" </td>",
" <td class=\"centered\">",
" n/a",
" </td>",
" <td class=\"centered\">",
" 33",
" </td>",
" <td class=\"centered\">",
" 17",
" </td>",
" <td class=\"centered\">",
" 9",
" </td>",
" <td class=\"centered\">",
" 14",
" </td>",
" <td>",
" Treated with cryotherapy",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" EXPRESS",
" ^{",
" [2]",
"}",
" </td>",
" <td class=\"centered\">",
" 80",
" ^{",
" &bull;",
"}",
" </td>",
" <td class=\"centered\">",
" 62",
" </td>",
" <td class=\"centered\">",
" 48",
" </td>",
" <td class=\"centered\">",
" 32",
" </td>",
" <td class=\"centered\">",
" 42",
" </td>",
" <td>",
" ROP &gt;Stage 2",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Stoll",
" ^{",
" [3]",
"}",
" </td>",
" <td class=\"centered\">",
" 50",
" </td>",
" <td class=\"centered\">",
" 40",
" </td>",
" <td class=\"centered\">",
" 35",
" </td>",
" <td class=\"centered\">",
" 17",
" </td>",
" <td class=\"centered\">",
" 27",
" </td>",
" <td>",
" Infants in hospital at 28 days requiring intervention/surgery",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_left\" colspan=\"7\">",
" Late-onset infection",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Stoll",
" ^{",
" [3]",
"}",
" </td>",
" <td class=\"centered\">",
" 58",
" </td>",
" <td class=\"centered\">",
" 62",
" </td>",
" <td class=\"centered\">",
" 55",
" </td>",
" <td class=\"centered\">",
" 46",
" </td>",
" <td class=\"centered\">",
" 52",
" </td>",
" <td>",
" Among infants who survived &gt;3 days after birth",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" <div class=\"lgnd\">",
" <div class=\"footnotes\">",
" NICU: neonatal intensive care unit; CUS: cranial ultrasound; PMA:
postmenstrual age; n/a: not available; ANS: antenatal steroid therapy.",
" <br/>",
" * &le;23 weeks.",
" <br/>",
" <span class=\"bullet\">",
" &bull;",
" </span>",
" &le;22 weeks.",
" </div>",
" <div class=\"reference\">",
" References:",
" <br/>",
" <ol>",
" <li>",
" Markestad T, Kaaresen PI, R&oslash;nnestad A, et al. Early death,
morbidity, and need of treatment among extremely premature infants. Pediatrics
2005; 115:1289.",
" </li>",
" <li>",
" EXPRESS Group, Fellman V, Hellstr&ouml;m-Westas L, et al. One-year survival
of extremely preterm infants after active perinatal care in Sweden. JAMA 2009;
301:2225.",
" </li>",
" <li>",
" Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely preterm
infants from the NICHD Neonatal Research Network. Pediatrics 2010; 126:443.",
" </li>",
" <li>",
" Carlo WA, McDonald SA, Fanaroff AA, et al. Association of antenatal
corticosteroids with mortality and neurodevelopmental outcomes among infants born
at 22 to 25 weeks' gestation. JAMA 2011; 306:2348.",
" </li>",
" <li>",
" Costeloe K, Hennessy E, Gibson AT, et al. The EPICure study: outcomes to
discharge from hospital for infants born at the threshold of viability. Pediatrics
2000; 106:659.",
" </li>",
" </ol>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
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var title_f0_6_107="Prenatal ultrasound ARKPD";
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title=\"Print this page\"/>",
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" <a class=\"icontxt textLink\" href=\"?imageKey=OBGYN
%2F69859&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\"
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" </a>",
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" </div>",
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" </div>",
" <div class=\"lgnd\">",
" Autosomal recessive polycystic kidney disease (ARPKD)-Bilateral massively
enlarged kidneys with no corticomedullary differentiation. Note associated
oligohydramnios.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Courtesy of Tulin Ozcan, MD.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f0_6_107=[""].join("\n");
var outline_f0_6_107=null;
var title_f0_6_108="FAST subxiphoid normal";
var content_f0_6_108=[" <div id=\"graphicsToolbar\">",
" <div id=\"graphicsCopy\">",
" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
" </div>",
" <div id=\"graphicsLinks\">",
" <a href=\"?imageKey=EM
%2F66281&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=2\" onclick=\"\">",
" <img alt=\"Print this page\" src=\"./../images/icn_print.myextg\"
title=\"Print this page\"/>",
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=EM
%2F66281&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=2\" onclick=\"\"
title=\"Print this page\">",
" Print",
" </a>",
" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
" </a>",
" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 524px\">",
" <div class=\"ttl\">",
" FAST: Subxiphoid normal view",
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" </div>",
" <div class=\"lgnd\">",
" This ultrasound image shows a normal heart as seen using a subxiphoid view as
part of the FAST examination.",
" <div class=\"footnotes\">",
" LA: left atrium; LV: left ventricle; RA: right atrium; RV: right ventricle",
" </div>",
" <div class=\"reference\">",
" Courtesy of Greg Snead, MD.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
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" <ul>",
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" <a class=\"graphic graphic_table\" href=\"UTD.htm?20/59/21435\">",
" Hypothermia",
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" <dl>",
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" The Basics",
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" <a href=\"UTD.htm?30/53/31569\">",
" Patient information: Frostbite (The Basics)",
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" Patient information: Hypothermia (The Basics)",
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" <a class=\"lang\" href=\"./es-419/hypothermia-the-basics?
source=topic_page\">",
" Spanish",
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editors/patient-information\">",
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" <div id=\"topicText\">",
" <p class=\"headingAnchor\" id=\"H175117909\">",
" <span class=\"h1\">",
" What is hypothermia?",
" </span>",
" &nbsp;&mdash;&nbsp;Hypothermia is when the body gets very cold and
can&rsquo;t warm up on its own. Body temperature is normally around 98.6&ordm;F
(37&ordm;C). Hypothermia is when it drops below 95&ordm;F (35&ordm;C).",
" </p>",
" <p>",
" Hypothermia can happen after being in cold air or water for too long. Young
children and elderly people are more likely to get hypothermia.",
" </p>",
" <p>",
" Hypothermia can cause serious problems, or even death, if it is not treated
quickly.",
" </p>",
" <p class=\"headingAnchor\" id=\"H175117924\">",
" <span class=\"h1\">",
" What are the symptoms of hypothermia?",
" </span>",
" &nbsp;&mdash;&nbsp;Symptoms can include (",
" <a class=\"graphic graphic_table graphicRef83975 \" href=\"UTD.htm?
20/59/21435\">",
" table 1",
" </a>",
" ):",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" Shivering (but if hypothermia becomes severe, the person might actually",
" <strong>",
" stop",
" </strong>",
" shivering)",
" </li>",
" <li>",
" Clumsiness",
" </li>",
" <li>",
" Trouble speaking clearly",
" </li>",
" <li>",
" Confusion",
" </li>",
" <li>",
" Feeling tired",
" </li>",
" <li>",
" Breathing faster than usual",
" </li>",
" <li>",
" Urinating more than usual",
" </li>",
" </ul>",
" </p>",
" <p>",
" Because hypothermia can happen slowly and cause confusion, a person might
not realize that he or she has it.",
" </p>",
" <p class=\"headingAnchor\" id=\"H175117939\">",
" <span class=\"h1\">",
" How can I help a person who might have hypothermia?",
" </span>",
" &nbsp;&mdash;&nbsp;If you think someone might be in danger of hypothermia,
you should:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" Move the person to a warmer place as soon as possible",
" </li>",
" <li>",
" Take off any wet clothing",
" </li>",
" <li>",
" Cover the person with blankets",
" </li>",
" <li>",
" Offer warm beverages if the person is able to drink",
" </li>",
" </ul>",
" </p>",
" <p>",
" If you think you or another person might have frostbite (damage to a body
part caused by cold), do",
" <strong>",
" not",
" </strong>",
" rub or massage the affected skin. This can cause worse damage.",
" </p>",
" <p class=\"headingAnchor\" id=\"H175117954\">",
" <span class=\"h1\">",
" When should I call for help?",
" </span>",
" &nbsp;&mdash;&nbsp;If a person shows signs of moderate or severe
hypothermia, get medical care right away. Signs include passing out, trouble
speaking or thinking clearly, clumsiness, loss of shivering, and trouble breathing.
Waiting to get treatment could cause serious health problems or even death.",
" </p>",
" <p class=\"headingAnchor\" id=\"H175117969\">",
" <span class=\"h1\">",
" How is hypothermia treated?",
" </span>",
" &nbsp;&mdash;&nbsp;It depends on how serious it is. In many cases, getting
out of the cold and warming up with blankets can prevent the need for medical
care.",
" </p>",
" <p>",
" Severe hypothermia needs to be treated in the hospital. Doctors will check
the person&rsquo;s temperature. They will also try to make sure the person keeps
breathing and that his or her heart keeps beating.",
" </p>",
" <p>",
" Hospital treatment of hypothermia might include any of the following:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Blankets, heating pads, warm baths, or heaters that blow warm air &ndash;
These can all be used to help bring a person&rsquo;s body temperature back up.",
" </li>",
" <li>",
" Warm fluids through IV (a thin tube that goes into a vein)",
" </li>",
" <li>",
" Warm oxygen to breathe, or a breathing tube if needed",
" </li>",
" <li>",
" Warming the inside of the body with water &ndash; Warm salt water can be
used to bring heat to the organs. The water goes into the body through a small
tube, then back out.",
" </li>",
" <li>",
" Medicines &ndash; Sometimes medicines are needed to treat related issues
like low blood pressure or heart problems.",
" </li>",
" <li>",
" Blood rewarming &ndash; This is done with a special machine that draws
blood out of the body, warms it up, and then puts it back in.",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H175117984\">",
" <span class=\"h1\">",
" Can hypothermia be prevented?",
" </span>",
" &nbsp;&mdash;&nbsp;Yes. In most cases, you can prevent hypothermia by being
careful not to stay out in the cold for too long. Be sure to dress warmly enough,
and wear layers. Change out of wet clothes as quickly as possible.",
" </p>",
" <p>",
" Babies and young children are more likely than adults to get hypothermia.
That&rsquo;s because their bodies have a harder time keeping warm, and they might
not always notice when they are getting too cold. Make sure that children are
dressed warmly and wear hats and mittens in cold weather. Don&rsquo;t let them play
outside in the cold for too long without taking a break to warm up.",
" </p>",
" <p>",
" Elderly people also have a harder time than younger adults keeping warm, and
they are more likely to have health issues or take medicines that can affect body
temperature. You can help older people by making sure that their homes are kept
warm enough, especially in winter.",
" </p>",
" <p>",
" People who have problems with alcohol also have a higher risk of getting
hypothermia. That&rsquo;s because alcohol can make it harder to notice when your
body is getting too cold. Drinking too much can also cause you to pass out, which
can lead to hypothermia in cold weather. If you think you or someone you know might
have a drinking problem, talk to a doctor or nurse.",
" </p>",
" <p class=\"headingAnchor\" id=\"H336862244\">",
" <span class=\"h1\">",
" More on this topic",
" </span>",
" </p>",
" <p>",
" <a class=\"medical medical_basics\" href=\"UTD.htm?30/53/31569?
source=see_link\">",
" Patient information: Frostbite (The Basics)",
" </a>",
" </p>",
" </div>",
" <div id=\"reviewProcess\">",
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" <a class=\"policy policy_editorialpolicy\" href=\"/home/editorial-
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" <div id=\"innerOutline\">",
" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <div id=\"outline\">",
" <ul>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H175117909\">",
" What is hypothermia?",
" </a>",
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" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H175117924\">",
" What are the symptoms of hypothermia?",
" </a>",
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" How can I help a person who might have hypothermia?",
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" <a class=\"outlineLink\" href=\"#H175117984\">",
" Can hypothermia be prevented?",
" </a>",
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" Patient information: Frostbite (The Basics)",
" </a>",
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var title_f0_6_110="Polidocanol: Drug information";
var content_f0_6_110=[" <noscript>",
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JavaScript is required in order for our site to behave correctly. Please enable
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" <!-- TC:TOPIC_PAGE -->",
" <div id=\"topicContent\">",
" <div id=\"drugTitle\">",
" Polidocanol: Drug information",
" </div>",
" <div id=\"lexiTitleImg\">",
" <img height=\"17\" src=\"./../images/lexiComp/Lexicomp_2012_71x17.myextg\"
width=\"71\"/>",
" </div>",
" <div class=\"clear\">",
" </div>",
" <div id=\"drugCopy\">",
" Copyright 1978-2013 Lexicomp, Inc. All rights reserved.",
" </div>",
" <div id=\"topicText\">",
" (For additional information",
" <a class=\"drug drug_patient\" href=\"UTD.htm?16/60/17347?source=see_link\">",
" see \"Polidocanol: Patient drug information\"",
" </a>",
" )",
" <br/>",
" For abbreviations and symbols that may be used in Lexicomp (",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?23/39/24183\">",
" show table",
" </a>",
" )",
" <div class=\"list ubnlist drugH1Div drugBrandNames\" id=\"F10437705\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Brand Names: U.S.",
" </span>",
" <ul>",
" <li>",
" Asclera&trade;",
" </li>",
" </ul>",
" </div>",
" <div class=\"ex_sect_xr thclist drugH1Div drugBrandNames\" id=\"F10134331\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Pharmacologic Category",
" </span>",
" <ul>",
" <li>",
" Sclerosing Agent",
" </li>",
" </ul>",
" </div>",
" <div class=\"block doa drugH1Div\" id=\"F10192886\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Dosing: Adult",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" <b>",
" Varicose veins:",
" </b>",
" I.V.:",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" <i>",
" Reticular veins (1-3 mm diameter):",
" </i>",
" 0.1-0.3 mL of 1% solution per injection (maximum: 10 mL per session); may
repeat in 7-14 days",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" <i>",
" Spider veins (&le;1 mm diameter):",
" </i>",
" 0.1-0.3 mL of 0.5% solution per injection (maximum: 10 mL per session); may
repeat in 7-14 days",
" </p>",
" </div>",
" <div class=\"block foc drugH1Div\" id=\"F10192890\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Dosage Forms: U.S.",
" </span>",
" <p style=\"text-indent:0em;text-align:justify;display:inline\">",
" Excipient information presented when available (limited, particularly for
generics); consult specific product labeling.",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" Injection, solution [preservative free]:",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;text-align:justify;\">",
" Asclera&trade;: 0.5% (2 mL); 1% (2 mL) [contains ethanol]",
" </p>",
" </div>",
" <div class=\"block geq drugH1Div\" id=\"F10192866\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Generic Equivalent Available: U.S.",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" No",
" </p>",
" </div>",
" <div class=\"block adm drugH1Div\" id=\"F10192887\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Administration",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" For intravenous use only. Avoid extravasation. After injection, apply
compression in the form of a stocking or bandage (maintain for 2-3 days [spider
veins] and 5-7 days [reticular veins]). After applying compression, patient should
walk for 15-20 minutes and be observed for anaphylactic or allergic reaction.",
" </p>",
" </div>",
" <div class=\"block use drugH1Div\" id=\"F10134332\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Use",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Treatment of small, uncomplicated varicose veins of the lower extremities",
" </p>",
" </div>",
" <div class=\"block ars drugH1Div\" id=\"F10192874\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Adverse Reactions Significant",
" </span>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" &gt;10%: Local: Hematoma (42%), irritation (41%), discoloration (38%), pain
(24%), pruritus (19%), warmth (16%)",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" 1% to 10%: Local: Neovascularization (8%), injection site thrombosis (6%)",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Postmarketing and/or case reports: Allergic dermatitis, anaphylactic shock ,
angioedema, asthma, cardiac arrest, cerebrovascular accident, circulatory collapse,
confusion, deep vein thrombosis, dizziness, dyspnea, hot flush, hypertrichosis,
injection site necrosis, loss of consciousness, migraine, nerve injury,
palpitation, paresthesia, pulmonary embolism, pyrexia, skin hyperpigmentation,
syncope (vasovagal), urticaria, vasculitis",
" </p>",
" </div>",
" <div class=\"block coi drugH1Div\" id=\"F10192870\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Contraindications",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Hypersensitivity to polidocanol or any component of the formulation; acute
thromboembolic diseases",
" </p>",
" </div>",
" <div class=\"block war drugH1Div\" id=\"F10192871\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Warnings/Precautions",
" </span>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" <b>",
" <i>",
" Concerns related to adverse effects:",
" </i>",
" </b>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;\">",
" &bull; Anaphylaxis/hypersensitivity reaction: Severe allergic reactions,
including anaphylaxis and fatal anaphylactoid reactions have been reported with
polidocanol. More frequent with larger volumes (&gt;3 mL), therefore, dose should
be minimized. Observe 15-20 minutes following injection to monitor for
hypersensitivity/anaphylactic reaction; emergency resuscitation equipment should be
available.",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" <b>",
" <i>",
" Other warnings/precautions:",
" </i>",
" </b>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;\">",
" &bull; Accidental intra-arterial injection: Severe necrosis, ischemia, or
gangrene can occur, and consult vascular surgeon immediately.",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;\">",
" &bull; Appropriate use: After injection is complete, apply
compression/bandage, and have patient walk for 15-20 minutes.",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;\">",
" &bull; Extravasation: Necrosis of the tissue may occur; pain may occur with
inadvertent perivascular injection and may be resolved with a local anesthetic
(without epinephrine).",
" </p>",
" </div>",
" <div class=\"block cyt drugH1Div\" id=\"F13299895\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Metabolism/Transport Effects",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" None known.",
" </p>",
" </div>",
" <div class=\"block dri drugH1Div\" id=\"F10191661\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Drug Interactions",
" </span>",
" <br/>",
" <br/>",
" <div class=\"lexi\" id=\"lexiInteractAddInfo\">",
" (For additional information:",
" <a class=\"dip\" href=\"./drug-interaction\" target=\"_blank\">",
" Launch Lexi-Interact&trade; Drug Interactions Program",
" </a>",
" )",
" </div>",
" <div class=\"lexi\" id=\"lexiInteractImgB\">",
" <img border=\"0\" height=\"17\"
src=\"./../images/lexiComp/Lexicomp_2012_71x17.myextg\" width=\"71\"/>",
" </div>",
" <div class=\"clear\">",
" </div>",
" <p style=\"text-indent:0em;display:inline\">",
" There are no known significant interactions.",
" </p>",
" </div>",
" <div class=\"block prf drugH1Div\" id=\"F10192867\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Pregnancy Risk Factor",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" C (",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?16/42/17068\">",
" show table",
" </a>",
" )",
" </p>",
" </div>",
" <div class=\"block pri drugH1Div\" id=\"F10192868\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Pregnancy Implications",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Teratogenic effects were reported in some animal reproduction studies. There
are no adequate and well-controlled studies in pregnant women. Polidocanol should
not be used in pregnant women.",
" </p>",
" </div>",
" <div class=\"block lac drugH1Div\" id=\"F10192869\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Lactation",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Excretion in breast milk is unknown/not recommended",
" </p>",
" </div>",
" <div class=\"block fee drugH1Div\" id=\"F16322851\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Pricing: U.S. (Medi-Span&reg;)",
" </span>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" <b>",
" Solution",
" </b>",
" (Asclera Intravenous)",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;text-align:justify;\">",
" 0.5% (2 mL): $27.60",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;text-align:justify;\">",
" 1% (2 mL): $39.60",
" </p>",
" </div>",
" <div class=\"block mop drugH1Div\" id=\"F10192889\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Monitoring Parameters",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Monitor patient for anaphylactic or allergic reaction after injection, and
for signs/symptoms of DVT or PE.",
" </p>",
" </div>",
" <div class=\"list fbnlist drugH1Div drugBrandNames\" id=\"F13733199\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" International Brand Names",
" </span>",
" <ul>",
" <li>",
" AET (AR);",
" </li>",
" <li>",
" Aethoxyscerol (BE, CZ);",
" </li>",
" <li>",
" Aethoxysklerol (AT, AU, CH, DK, FI, NL, NO, PY, SE, TH);",
" </li>",
" <li>",
" Aetoxisclerol (FR);",
" </li>",
" <li>",
" Asklerol (IN);",
" </li>",
" <li>",
" Atossisclerol (IT);",
" </li>",
" <li>",
" Etoxisclerol (VE);",
" </li>",
" <li>",
" Farmaflebon (CR, DO, GT, HN, NI, PA, SV);",
" </li>",
" <li>",
" Optiderm Creme (DE);",
" </li>",
" <li>",
" Recessan (PY);",
" </li>",
" <li>",
" Sclerol (IN);",
" </li>",
" <li>",
" Sclerovein (SE);",
" </li>",
" <li>",
" Solcoseryl (HK);",
" </li>",
" <li>",
" Venodenol (ID);",
" </li>",
" <li>",
" Venoscler (UY)",
" </li>",
" </ul>",
" </div>",
" <div class=\"block pha drugH1Div\" id=\"F10192880\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Mechanism of Action",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Acts by irritation of the vein intimal endothelium and causes thrombosis
formation leading to occlusion of the injected vein",
" </p>",
" </div>",
" <div class=\"block phk drugH1Div\" id=\"F10192882\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Pharmacodynamics/Kinetics",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Half-life elimination: 1.5 hours",
" </p>",
" </div>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_in_page\"
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" </a>",
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" </div>",
" <div id=\"topicVersionRevision\">",
" Topic 9907 Version 29.0",
" </div>",
" </div>",
" <div id=\"footer\">",
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" <a class=\"licenseLink\" href=\"./license\" id=\"sla_footer\">",
" Subscription and License Agreement",
" </a>",
" <span class=\"sfInfo\">",
" <span class=\"pipeSpace\">",
" |",
" </span>",
" Release: 21.6- C21.56",
" </span>",
" <br/>",
" <span class=\"sfInfo\">",
" Licensed to:",
" <span class=\"emphasis\">",
" AsanBook Dig. Med. Lib.",
" </span>",
" </span>",
" <span class=\"sfInfo\">",
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" |",
" </span>",
" Support Tag: [0505-197.136.42.3-5480875BC6-S244013.14]",
" <br/>",
" </span>",
" </div>",
" </div>",
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" </div>",
" <div id=\"innerOutline\">",
" <h1>",
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" </h1>",
" <div id=\"outline\">",
" <ul>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F10437705\">",
" Brand Names: U.S.",
" </a>",
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" <li class=\"plainItem\">",
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" Pharmacologic Category",
" </a>",
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" Dosing: Adult",
" </a>",
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" Dosage Forms: U.S.",
" </a>",
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var title_f0_6_111="Surgical specimen of extraosseous osteosarcoma";
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q+CP+gr4k/wDAiD/4zRRQAf8ADKvgj/oK+JP/AAIg/wDjNH/DKvgj/oK+JP8AwIg/
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q+CP+gr4k/wDAiD/4zRRQAf8ADKvgj/oK+JP/AAIg/wDjNH/DKvgj/oK+Jf8AwIg/
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q+CP+gr4k/wDAiD/4zRRQAf8ADKvgj/oK+JP/AAIg/wDjNH/DKvgj/oK+JP8AwIg/
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q+CP+gr4k/wDAiD/4zRRQB6h8L/h/pXw40C40jQ7i+ntp7prtmvHRnDlEUgFVUYwg7etFFFAH/9k=);\">"
,
" </div>",
" <div class=\"lgnd\">",
" (A) The mammogram of the left breast reveals a 2 cm mass with dense
calcifications (arrow).",
" <br>",
" (B) X-ray of the surgical specimen showing a densely calcified mass with the
needle localizer traversing the mass. The x-ray confirms the heavy calcification,
and histopathology confirmed the diagnosis of an extraosseous osteosarcoma.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Courtesy of Richard Waite, MD.",
" </div>",
" </br>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f0_6_111=[""].join("\n");
var outline_f0_6_111=null;
var title_f0_6_96="Sufentanil: Pediatric drug information";
var content_f0_6_96=[" <noscript>",
" <div id=\"javascriptDisabled\">",
" It seems to us that you have your JavaScript turned off on your browser.
JavaScript is required in order for our site to behave correctly. Please enable
your JavaScript to continue use our site.",
" </div>",
" </noscript>",
" <div id=\"printHeader\">",
" <div id=\"printHeaderLogo\">",
" <img alt=\"UpToDate\" src=\"./../images/UTD2_masthead.myextg\">",
" <img align=\"right\" alt=\"Wolters Kluwer Health\" height=\"40\"
src=\"./../images/logoWKH.myextg\" width=\"175\">",
" <br>",
" <div id=\"printHeaderText\">",
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" www.uptodate.com",
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" </div>",
" <div id=\"printHeaderLinks\">",
" <a class=\"TOPIC\" href=\"#\" id=\"printHeaderPrint\" rel=\"2\" title=\"Click
here to print\">",
" Print",
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" <a href=\"#\" id=\"printHeaderBack\" title=\"Back to normal view\">",
" Back",
" </a>",
" </div>",
" </div>",
" <!-- TC:TOPIC_PAGE -->",
" <div id=\"topicContent\">",
" <div id=\"drugTitle\">",
" Sufentanil: Pediatric drug information",
" </div>",
" <div id=\"lexiTitleImg\">",
" <img height=\"17\" src=\"./../images/lexiComp/Lexicomp_2012_71x17.myextg\"
width=\"71\"/>",
" </div>",
" <div class=\"clear\">",
" </div>",
" <div id=\"drugCopy\">",
" Copyright 1978-2013 Lexicomp, Inc. All rights reserved.",
" </div>",
" <div id=\"topicText\">",
" (For additional information",
" <a class=\"drug drug_general\" href=\"UTD.htm?14/47/15094?source=see_link\">",
" see \"Sufentanil: Drug information\"",
" </a>",
" and",
" <a class=\"drug drug_patient\" href=\"UTD.htm?43/45/44755?source=see_link\">",
" see \"Sufentanil: Patient drug information\"",
" </a>",
" )",
" <br/>",
" For abbreviations and symbols that may be used in Lexicomp (",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?23/39/24183\">",
" show table",
" </a>",
" )",
" <div class=\"list ubnlist drugH1Div drugBrandNames\" id=\"F223606\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Brand Names: U.S.",
" </span>",
" <ul>",
" <li>",
" Sufenta&reg;",
" </li>",
" </ul>",
" </div>",
" <div class=\"list cbnlist drugH1Div drugBrandNames\" id=\"F223607\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Brand Names: Canada",
" </span>",
" <ul>",
" <li>",
" Sufentanil Citrate Injection, USP;",
" </li>",
" <li>",
" Sufenta&reg;",
" </li>",
" </ul>",
" </div>",
" <div class=\"list_set htclist drugH1Div drugBrandNames\" id=\"F1055535\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Therapeutic Category",
" </span>",
" <ul>",
" <li>",
" <span class=\"list-set-name\">",
" Analgesic, Narcotic",
" </span>",
" </li>",
" <li>",
" <span class=\"list-set-name\">",
" General Anesthetic",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"block don drugH1Div\" id=\"F11445118\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Dosing: Neonatal",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Doses should be titrated to appropriate effects; wide range of doses,
dependent upon desired degree of analgesia or anesthesia.",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" General anesthesia, adjunct (deep intraoperative anesthesia for neonatal
cardiac surgery): Full-term neonates: I.V.: 5-10 mcg/kg/dose as needed; followed by
a continuous I.V. infusion (for postoperative anesthesia): 2 mcg/kg/",
" <b>",
" hour",
" </b>",
" for 24 hours (Anand, 1992)",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Analgesia/sedation in mechanically ventilated patients: Preterm neonates:
I.V.: Loading dose: 0.5 mcg/kg/dose administered over 10 minutes, followed by 0.2
mcg/kg/",
" <b>",
" hour",
" </b>",
" continuous infusion was used in 15 mechanically ventilated premature neonates
(mean GA: 29.1 weeks (26-34 weeks) and produced &ldquo;burst-suppression-
like&rdquo; EEG patterns (Tich, 2010)",
" </p>",
" </div>",
" <div class=\"block dos drugH1Div\" id=\"F1055528\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Dosing: Usual",
" </span>",
" <p>",
" (For additional information",
" <a class=\"drug drug_general\" href=\"UTD.htm?14/47/15094?
source=see_link\">",
" see \"Sufentanil: Drug information\"",
" </a>",
" )",
" </p>",
" <p style=\"text-indent:0em;display:inline\">",
" Doses should be titrated to appropriate effects; wide range of doses,
dependent upon desired degree of analgesia or anesthesia; use lean body weight to
dose patients who are &gt;20% above ideal body weight.",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;margin-top:2em;text-
align:justify;\">",
" Children &lt;12 years: Anesthesia: I.V.: Initial: 10-25 mcg/kg; maintenance:
Up to 25-50 mcg as needed",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" Adults: I.V.:",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;text-align:justify;\">",
" Adjunct to general anesthesia:",
" </p>",
" <p style=\"text-indent:-2em;margin-left:6em;text-align:justify;\">",
" Low dose: Initial: 0.5-1 mcg/kg; maintenance: 10-25 mcg as needed",
" </p>",
" <p style=\"text-indent:-2em;margin-left:6em;text-align:justify;\">",
" Moderate dose: Initial: 2-8 mcg/kg; maintenance: 10-50 mcg as needed",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;text-align:justify;\">",
" Anesthesia: Initial: 8-30 mcg/kg; maintenance: 10-50 mcg as needed",
" </p>",
" </div>",
" <div class=\"block foc drugH1Div\" id=\"F223591\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Dosage Forms: U.S.",
" </span>",
" <p style=\"text-indent:0em;text-align:justify;display:inline\">",
" Excipient information presented when available (limited, particularly for
generics); consult specific product labeling.",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" Injection, solution [preservative free]: 50 mcg/mL (1 mL, 2 mL, 5 mL)",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;text-align:justify;\">",
" Sufenta&reg;: 50 mcg/mL (1 mL, 2 mL, 5 mL)",
" </p>",
" </div>",
" <div class=\"block geq drugH1Div\" id=\"F223577\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Generic Equivalent Available: U.S.",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Yes",
" </p>",
" </div>",
" <div class=\"block csi drugH1Div\" id=\"F223637\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Controlled Substance",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" C-II",
" </p>",
" </div>",
" <div class=\"block adm drugH1Div\" id=\"F1055540\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Administration",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Parenteral: I.V.: Slow I.V. injection or by infusion",
" </p>",
" </div>",
" <div class=\"block scp drugH1Div\" id=\"F223642\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Compatibility",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Stable in D",
" _{",
" 5",
"}",
" W;",
" <b>",
" variable stability (consult detailed reference)",
" </b>",
" in NS.",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" <b>",
" Y-site administration: Compatible:",
" </b>",
" Amphotericin B cholesteryl sulfate complex, atropine, bivalirudin, cefepime,
ceftriaxone, cisatracurium, dexamethasone sodium phosphate, dexmedetomidine,
diazepam, diphenhydramine, etomidate, fenoldopam, haloperidol, hetastarch in
lactate electrolyte injection (Hextend&reg;), hydroxyzine, ketorolac, linezolid,
methotrimeprazine, metoclopramide, midazolam, palonosetron, phenobarbital,
prochlorperazine edisylate, propofol, remifentanil, scopolamine.",
" <b>",
" Incompatible:",
" </b>",
" Lorazepam, phenytoin, thiopental.",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" <b>",
" Compatibility in syringe: Compatible:",
" </b>",
" Atracurium, atropine, bupivacaine, dexamethasone sodium phosphate,
diphenhydramine, haloperidol, hydroxyzine, ketorolac, methotrimeprazine,
metoclopramide, midazolam, prochlorperazine edisylate, scopolamine.",
" <b>",
" Incompatible:",
" </b>",
" Diazepam, lorazepam, phenobarbital, phenytoin.",
" </p>",
" </div>",
" <div class=\"block use drugH1Div\" id=\"F1055539\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Use",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Analgesia; analgesia adjunct; anesthetic agent",
" </p>",
" </div>",
" <div class=\"block mst drugH1Div\" id=\"F223644\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Medication Safety Issues",
" </span>",
" <div class=\"collapsible\">",
" <span class=\"collapsible-title\">",
" Sound-alike/look-alike issues:",
" </span>",
" <div class=\"collapsible-wrap\">",
" <p style=\"text-indent:-2em;margin-left:4em;text-align:justify;\">",
" SUFentanil may be confused with alfentanil, fentaNYL",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;text-align:justify;\">",
" Sufenta&reg; may be confused with Alfenta&reg;, Sudafed&reg;,
Survanta&reg;",
" </p>",
" </div>",
" </div>",
" <div class=\"collapsible\">",
" <span class=\"collapsible-title\">",
" High alert medication:",
" </span>",
" <div class=\"collapsible-wrap\">",
" <p style=\"text-indent:-2em;margin-left:4em;\">",
" The Institute for Safe Medication Practices (ISMP) includes this medication
among its list of drugs which have a heightened risk of causing significant patient
harm when used in error.",
" </p>",
" </div>",
" </div>",
" </div>",
" <div class=\"block arm drugH1Div\" id=\"F223641\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Adverse Reactions",
" </span>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" Cardiovascular: Bradycardia, cardiac arrhythmia, hyper-/hypotension",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" Central nervous system: CNS depression, confusion, somnolence",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" Dermatologic: Pruritus",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" Gastrointestinal: Nausea, vomiting",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" Ocular: Blurred vision",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" Neuromuscular &amp; Skeletal: Chest wall rigidity",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" Rare but important or life-threatening: Anaphylaxis, apnea, arrhythmia,
biliary spasm, bronchospasm, cardiac arrest, chills, circulatory depression; cold,
clammy skin; dizziness, dysesthesia, erythema, itching, laryngospasm, mental
depression, paradoxical CNS excitation or delirium, physical and psychological
dependence with prolonged use, respiratory depression (dose related), seizure,
skeletal muscle rigidity, skin rash, tachycardia, urinary retention, urinary tract
spasm, urticaria",
" </p>",
" </div>",
" <div class=\"block coi drugH1Div\" id=\"F1055544\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Contraindications",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Hypersensitivity to sufentanil or any component; increased intracranial
pressure; severe respiratory depression",
" </p>",
" </div>",
" <div class=\"block pre drugH1Div\" id=\"F1055527\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Precautions",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Use with caution in patients with head injuries, hepatic impairment,
pulmonary disease, or with use of MAO inhibitors within past 14 days; sufentanil
shares the toxic potential of opiate agonists, precautions of opiate agonist
therapy should be observed",
" </p>",
" </div>",
" <div class=\"block war drugH1Div\" id=\"F1055526\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Warnings",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" May cause severe respiratory depression; rapid I.V. infusion may result in
skeletal muscle and chest wall rigidity, impaired ventilation, respiratory
distress, apnea, bronchoconstriction, laryngospasm, arrest; inject slowly over 3-5
minutes; nondepolarizing skeletal muscle relaxant may be required; abrupt
discontinuation after prolonged use may result in withdrawal symptoms",
" </p>",
" </div>",
" <div class=\"block cyt drugH1Div\" id=\"F223631\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Metabolism/Transport Effects",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" <b>",
" Substrate",
" </b>",
" of CYP3A4 (major);",
" <b>",
" Note:",
" </b>",
" Assignment of Major/Minor substrate status based on clinically relevant drug
interaction potential",
" </p>",
" </div>",
" <div class=\"block dri drugH1Div\" id=\"F223586\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Drug Interactions",
" </span>",
" <br/>",
" <br/>",
" <div class=\"lexi\" id=\"lexiInteractAddInfo\">",
" (For additional information:",
" <a class=\"dip\" href=\"./drug-interaction\" target=\"_blank\">",
" Launch Lexi-Interact&trade; Drug Interactions Program",
" </a>",
" )",
" </div>",
" <div class=\"lexi\" id=\"lexiInteractImgB\">",
" <img border=\"0\" height=\"17\"
src=\"./../images/lexiComp/Lexicomp_2012_71x17.myextg\" width=\"71\"/>",
" </div>",
" <div class=\"clear\">",
" </div>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of
Alcohol (Ethyl).",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Alvimopan: Analgesics (Opioid) may enhance the adverse/toxic effect of
Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7
days) opiates prior to alvimopan initiation. Management: Alvimopan is
contraindicated in patients receiving therapeutic doses of opioids for more than 7
consecutive days immediately prior to alvimopan initiation.",
" <i>",
" Risk D: Consider therapy modification",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Ammonium Chloride: May increase the excretion of Analgesics (Opioid).",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Amphetamines: May enhance the analgesic effect of Analgesics (Opioid).",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of
Analgesics (Opioid).",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of
Azelastine (Nasal).",
" <i>",
" Risk X: Avoid combination",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Beta-Blockers: Anilidopiperidine Opioids may enhance the bradycardic effect
of Beta-Blockers. Anilidopiperidine Opioids may enhance the hypotensive effect of
Beta-Blockers.",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Calcium Channel Blockers (Nondihydropyridine): Anilidopiperidine Opioids may
enhance the bradycardic effect of Calcium Channel Blockers (Nondihydropyridine).
Anilidopiperidine Opioids may enhance the hypotensive effect of Calcium Channel
Blockers (Nondihydropyridine).",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" CNS Depressants: May enhance the adverse/toxic effect of other CNS
Depressants.",
" <b>",
" Exceptions:",
" </b>",
" Levocabastine (Nasal).",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Conivaptan: May increase the serum concentration of CYP3A4 Substrates.",
" <i>",
" Risk X: Avoid combination",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4
Substrates.",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4
Substrates.",
" <i>",
" Risk D: Consider therapy modification",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Dasatinib: May increase the serum concentration of CYP3A4 Substrates.",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of
Desmopressin.",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Droperidol: May enhance the CNS depressant effect of CNS Depressants.
Management: Consider dose reductions of droperidol or of other CNS agents (e.g.,
opioids, barbiturates) with concomitant use.",
" <i>",
" Risk D: Consider therapy modification",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants.",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Ivacaftor: May increase the serum concentration of CYP3A4 Substrates.",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Magnesium Sulfate: May enhance the CNS depressant effect of CNS
Depressants.",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" MAO Inhibitors: Anilidopiperidine Opioids may enhance the serotonergic effect
of MAO Inhibitors. This could result in serotonin syndrome. Management: Avoid use
of fentanyl (and other anilidopiperidine opioids when possible) in patients who
have used a monoamine oxidase inhibitor within the past 14 days due to reports of
unpredictable but severe adverse effects.",
" <i>",
" Risk X: Avoid combination",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Metyrosine: CNS Depressants may enhance the sedative effect of Metyrosine.",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Mifepristone: May increase the serum concentration of CYP3A4 Substrates.
Management: Minimize doses of CYP3A4 substrates, and monitor for increased
concentrations/toxicity, during and 2 weeks following treatment with mifepristone.
Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine,
sirolimus, and tacrolimus.",
" <i>",
" Risk D: Consider therapy modification",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Mirtazapine: CNS Depressants may enhance the CNS depressant effect of
Mirtazapine.",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Mixed Agonist / Antagonist Opioids: May diminish the analgesic effect of
Analgesics (Opioid). Management: Seek alternatives to mixed agonist/antagonist
opioids in patients receiving pure opioid agonists, and monitor for symptoms of
therapeutic failure/high dose requirements (or withdrawal in opioid-dependent
patients) if patients receive these combinations.",
" <i>",
" Risk D: Consider therapy modification",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Paraldehyde: CNS Depressants may enhance the CNS depressant effect of
Paraldehyde.",
" <i>",
" Risk X: Avoid combination",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of
Pegvisomant.",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Perampanel: May enhance the CNS depressant effect of CNS Depressants.
Management: Patients taking perampanel with any other drug that has CNS depressant
activities should avoid complex and high-risk activities, particularly those such
as driving that require alertness and coordination, until they have experience
using the combination.",
" <i>",
" Risk D: Consider therapy modification",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Pramipexole: CNS Depressants may enhance the sedative effect of
Pramipexole.",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole.",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine.",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Selective Serotonin Reuptake Inhibitors: Analgesics (Opioid) may enhance the
serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause
serotonin syndrome.",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants.
Management: Consider alternatives to combined use. When combined use is needed,
consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol
or sedative hypnotics is contraindicated.",
" <i>",
" Risk D: Consider therapy modification",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid).",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Thiazide Diuretics: Analgesics (Opioid) may enhance the orthostatic
hypotensive effect of Thiazide Diuretics.",
" <i>",
" Risk C: Monitor therapy",
" </i>",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem.
Management: Reduce the Intermezzo brand sublingual zolpidem dose to 1.75 mg for men
who are also receiving other CNS depressants. No such dose change is recommended
for women. Avoid use with other CNS depressants at bedtime; avoid use with
alcohol.",
" <i>",
" Risk D: Consider therapy modification",
" </i>",
" </p>",
" </div>",
" <div class=\"block prf drugH1Div\" id=\"F223587\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Pregnancy Risk Factor",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" C (",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?16/42/17068\">",
" show table",
" </a>",
" )",
" </p>",
" </div>",
" <div class=\"block pri drugH1Div\" id=\"F5050046\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Pregnancy Implications",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Animal studies suggest embryocidal effects when given I.V. for a period of 10
days to &gt;30 days. No evidence of teratogenic effects observed in animals.
Administration of epidural sufenanil with bupivacaine with or without epinephrine
is indicated in labor and delivery. Intravenous use or larger epidural doses are
not recommended in pregnant women.",
" </p>",
" </div>",
" <div class=\"block mop drugH1Div\" id=\"F1055534\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Monitoring Parameters",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Respiratory rate, blood pressure, heart rate, oxygen saturation, neurological
status (for degree of analgesia/anesthesia)",
" </p>",
" </div>",
" <div class=\"block pha drugH1Div\" id=\"F1055525\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Mechanism of Action",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Binds with stereospecific receptors at many sites within the CNS, increases
pain threshold, alters pain reception, inhibits ascending pain pathways; ultra
short-acting narcotic",
" </p>",
" </div>",
" <div class=\"block phd drugH1Div\" id=\"F1055542\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Pharmacodynamics",
" </span>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" Onset of action: 1-3 minutes",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" Duration: Dose dependent; anesthesia adjunct doses: 5 minutes",
" </p>",
" </div>",
" <div class=\"block phk drugH1Div\" id=\"F1055543\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Pharmacokinetics (Adult data unless noted)",
" </span>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" Distribution: V",
" _{",
" dss",
"}",
" :",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;text-align:justify;\">",
" Children 2-8 years: 2.9 &plusmn; 0.6 L/kg",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;text-align:justify;\">",
" Adults: 1.7 &plusmn; 0.2 L/kg",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" Protein binding (alpha",
" _{",
" 1-",
"}",
" acid glycoprotein):",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;text-align:justify;\">",
" Neonates: 79%",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;text-align:justify;\">",
" Adults:",
" </p>",
" <p style=\"text-indent:-2em;margin-left:6em;text-align:justify;\">",
" Male: 93%",
" </p>",
" <p style=\"text-indent:-2em;margin-left:6em;text-align:justify;\">",
" Postpartum women: 91%",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" Metabolism: Primarily by the liver via demethylation and dealkylation",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" Half-life, elimination:",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;text-align:justify;\">",
" Neonates: 382-1162 minutes",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;text-align:justify;\">",
" Children 2-8 years: 97 &plusmn; 42 minutes",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;text-align:justify;\">",
" Adolescents 10-15 years: 76 &plusmn; 33 minutes",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;text-align:justify;\">",
" Adults: 164 &plusmn; 22 minutes",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" Elimination: &sim;2% excreted unchanged in the urine; 80% of dose excreted in
urine (mostly as metabolites) within 24 hours",
" </p>",
" <p style=\"text-indent:-2em;margin-left:4em;text-align:justify;\">",
" Clearance:",
" </p>",
" <p style=\"text-indent:-2em;margin-left:6em;text-align:justify;\">",
" Children 2-8 years: 30.5 &plusmn; 8.8 mL/minute/kg",
" </p>",
" <p style=\"text-indent:-2em;margin-left:6em;text-align:justify;\">",
" Adolescents: 12.8 &plusmn; 12 mL/minute/kg",
" </p>",
" <p style=\"text-indent:-2em;margin-left:6em;text-align:justify;\">",
" Adults: 12.7 &plusmn; 0.8 mL/minute/kg",
" </p>",
" </div>",
" <div class=\"block pai drugH1Div\" id=\"F1055532\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Patient Information",
" </span>",
" <p>",
" (For additional information",
" <a class=\"drug drug_patient\" href=\"UTD.htm?43/45/44755?
source=see_link\">",
" see \"Sufentanil: Patient drug information\"",
" </a>",
" )",
" </p>",
" <p style=\"text-indent:0em;display:inline\">",
" May be habit-forming; avoid abrupt discontinuation after prolonged use",
" </p>",
" </div>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_in_page\"
target=\"_blank\">",
" Subscription and License Agreement",
" </a>",
" .",
" </div>",
" <div class=\"headingAnchor\" id=\"references\">",
" <h1>",
" REFERENCES",
" </h1>",
" <ol id=\"reference\">",
" <li>",
" <div class=\"reference\">",
" Anand KJ and Hickey PR, \"Halothane-Morphine Compared With High-Dose
Sufentanil for Anesthesia and Postoperative Analgesia in Neonatal Cardiac
Surgery,\"",
" <i>",
" N Engl J Med",
" </i>",
" , 1992, 326(1):1-9.",
" <span class=\"pubmed-id\">",
" [PubMed",
" <a href=\"UTD.htm?0/6/96/abstract-text/1530752/pubmed\" id=\"1530752\"
target=\"_blank\">",
" 1530752",
" </a>",
" ]",
" </span>",
" </div>",
" </li>",
" <li>",
" <div class=\"reference\">",
" Guay J, Gaudreault P, Tang A, et al, &ldquo;Pharmacokinetics of Sufentanil
in Normal Children,&rdquo;",
" <i>",
" Can J Anaesth",
" </i>",
" , 1992, 39(1):14-20.",
" <span class=\"pubmed-id\">",
" [PubMed",
" <a href=\"UTD.htm?0/6/96/abstract-text/1531117/pubmed\" id=\"1531117\"
target=\"_blank\">",
" 1531117",
" </a>",
" ]",
" </span>",
" </div>",
" </li>",
" <li>",
" <div class=\"reference\">",
" Nguyen The Tich S, Vecchierini MF, Debillon T, et al, \"Effects of
Sufentanil on Electroencephalogram in Very and Extremely Preterm Neonates,\"",
" <i>",
" Pediatrics",
" </i>",
" , 2003, 111(1):123-8.",
" <span class=\"pubmed-id\">",
" [PubMed",
" <a href=\"UTD.htm?0/6/96/abstract-text/12509564/pubmed\" id=\"12509564\"
target=\"_blank\">",
" 12509564",
" </a>",
" ]",
" </span>",
" </div>",
" </li>",
" <li>",
" <div class=\"reference\">",
" Seguin JH, Erenberg A, and Leff RD, &ldquo;Safety and Efficacy of Sufentanil
Therapy in the Ventilated Infant,&rdquo;",
" <i>",
" Neonatal Netw",
" </i>",
" , 1994, 13(4):37-40.",
" <span class=\"pubmed-id\">",
" [PubMed",
" <a href=\"UTD.htm?0/6/96/abstract-text/8007923/pubmed\" id=\"8007923\"
target=\"_blank\">",
" 8007923",
" </a>",
" ]",
" </span>",
" </div>",
" </li>",
" </ol>",
" </div>",
" <div id=\"topicVersionRevision\">",
" Topic 12812 Version 36.0",
" </div>",
" </div>",
" <div id=\"footer\">",
" <div id=\"supportFooter\">",
" <span class=\"sfInfo\">",
" &copy; 2013 UpToDate, Inc. All rights reserved.",
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" Subscription and License Agreement",
" </a>",
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" Release: 21.6- C21.56",
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" Licensed to:",
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" AsanBook Dig. Med. Lib.",
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" </span>",
" Support Tag: [1105-83.177.194.223-F706DDF602-S244013.14]",
" <br/>",
" </span>",
" </div>",
" </div>",
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" </a>",
" </div>",
" <div id=\"innerOutline\">",
" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <div id=\"outline\">",
" <ul>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F223606\">",
" Brand Names: U.S.",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F223607\">",
" Brand Names: Canada",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F1055535\">",
" Therapeutic Category",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F11445118\">",
" Dosing: Neonatal",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F1055528\">",
" Dosing: Usual",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F223591\">",
" Dosage Forms: U.S.",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F223577\">",
" Generic Equivalent Available: U.S.",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F223637\">",
" Controlled Substance",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F1055540\">",
" Administration",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F223642\">",
" Compatibility",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F1055539\">",
" Use",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F223644\">",
" Medication Safety Issues",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F223641\">",
" Adverse Reactions",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F1055544\">",
" Contraindications",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F1055527\">",
" Precautions",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F1055526\">",
" Warnings",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F223631\">",
" Metabolism/Transport Effects",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F223586\">",
" Drug Interactions",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F223587\">",
" Pregnancy Risk Factor",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F5050046\">",
" Pregnancy Implications",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F1055534\">",
" Monitoring Parameters",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F1055525\">",
" Mechanism of Action",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F1055542\">",
" Pharmacodynamics",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F1055543\">",
" Pharmacokinetics (Adult data unless noted)",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F1055532\">",
" Patient Information",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a href=\"#references\">",
" REFERENCES",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" <div class=\"openRelatedGraphics\" id=\"DRUG_PED/12812\"
rel=\"outline_link\">",
" GRAPHICS",
" <a class=\"graphics_icon\" href=\"#\" title=\"View All Related Graphics\">",
" View All",
" </a>",
" </div>",
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" <div id=\"relatedGraphics\">",
" <ul>",
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" <div class=\"openRelatedGraphics\" id=\"DRUG_PED/12812|TAB\">",
" <a href=\"#\" title=\"TABLES\">",
" TABLES",
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" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?23/39/24183\"
title=\"Lexicomp clinical abbreviations\">",
" Lexicomp clinical abbreviations",
" </a>",
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" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
" <div id=\"relatedTopics\">",
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var title_f0_6_97="Evaluation and management of neonatal Graves' disease";
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" Evaluation and management of neonatal Graves' disease",
" </div>",
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" Author",
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" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/6/97/contributors\">",
" Stephen LaFranchi, MD",
" </a>",
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href=\"UTD.htm?0/6/97/contributors\">",
" Section Editors",
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0/6/97/contributors\">",
" Joseph A Garcia-Prats, MD",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/6/97/contributors\">",
" Mitchell Geffner, MD",
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" Deputy Editor",
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0/6/97/contributors\">",
" Alison G Hoppin, MD",
" </a>",
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" Oct 2013.",
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" Jan 25, 2013.",
" </div>",
" <div id=\"topicText\">",
" <p class=\"headingAnchor\" id=\"H1\">",
" <span class=\"h1\">",
" INTRODUCTION",
" </span>",
" &nbsp;&mdash;&nbsp;Neonatal Graves&rsquo; disease refers to the
hyperthyroidism that is seen in a small percentage of infants born to mothers with
Graves&rsquo; disease. Although neonatal Graves' disease is usually self-limited,
it can be severe, even life-threatening, and have deleterious effects on neural
development. Maternal Graves' disease is by far the most common cause of neonatal
hyperthyroidism. Active Graves' disease in a pregnant woman can lead to either
hyper- or hypothyroidism in the fetus and neonate, depending on the balance of the
maternal stimulatory and inhibitory antibody and antithyroid drug effect [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/1\">",
" 1",
" </a>",
" ]. Babies destined to develop neonatal Graves' disease, however, are almost
always hyperthyroid at birth (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?41/48/42760?
source=see_link\">",
" \"Hyperthyroidism during pregnancy: Treatment\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H2\">",
" <span class=\"h1\">",
" INCIDENCE",
" </span>",
" &nbsp;&mdash;&nbsp;Graves' hyperthyroidism occurs in approximately 0.2 percent
of women, and it occurs in approximately one to five percent of infants born to
these mothers [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/2-4\">",
" 2-4",
" </a>",
" ]. Thus, neonatal Graves' hyperthyroidism would be expected to occur in
approximately 1:25,000 neonates, and affects males and females equally.",
" </p>",
" <p>",
" Why only two percent of infants of mothers with Graves' hyperthyroidism are
affected is explained by the level of the maternal serum stimulatory TSH receptor
antibody (TSHR-Ab). The higher the maternal stimulatory TSHR-Ab concentration is
during the third trimester, the greater is the likelihood of neonatal Graves'
hyperthyroidism. In practice, neonatal hyperthyroidism is most likely when the
TSHR-Ab activity of maternal serum is above 500 percent of the values in serum of
normal subjects [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/5,6\">",
" 5,6",
" </a>",
" ]. This was illustrated in a study of 29 pregnant women with a history of
Graves' disease that confirmed the relationship of high TSHR-Ab and neonatal
thyrotoxicosis. In the 35 live births, there were six cases of neonatal Graves'
disease resulting in an incidence of 17 percent, a higher rate than previously
reported [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/7\">",
" 7",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H3\">",
" <span class=\"h1\">",
" PATHOGENESIS",
" </span>",
" &nbsp;&mdash;&nbsp;Neonatal (and fetal) Graves' hyperthyroidism results from
the transplacental passage of maternal stimulatory TSHR-Ab [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/3,8,9\">",
" 3,8,9",
" </a>",
" ]. Most neonatal Graves&rsquo; disease occurs in the setting of active Graves'
hyperthyroidism in the mother. However, the disorder also can occur in infants of
women with a history of Graves' hyperthyroidism treated with thyroidectomy or
radioactive iodine in the past [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/10\">",
" 10",
" </a>",
" ]. After a woman with Graves&rsquo; disease undergoes one of these treatments,
the risk of having an infant affected by neonatal Graves&rsquo; disease falls over
time, in conjunction with decreases in TSHR-Ab levels. The risk of neonatal Graves'
disease is low five years after radioactive iodine, but some mothers still have
persistent TSHR-Ab elevation and will deliver babies with neonatal Graves' disease
[",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/11\">",
" 11",
" </a>",
" ]. As described above, measurement of maternal serum TSHR-Ab may be helpful in
predicting whether a newborn will be affected. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?41/48/42760?
source=see_link\">",
" \"Hyperthyroidism during pregnancy: Treatment\"",
" </a>",
" .)",
" </p>",
" <p>",
" Serial in utero ultrasonography with measurement of fetal thyroid size has
also been reported to help determine which neonates are likely to manifest neonatal
hyperthyroidism [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/12\">",
" 12",
" </a>",
" ]. In a report of 20 pregnant women with Graves' disease, the fetal thyroid
gland was enlarged in five pregnancies. In these five patients, the maternal
antithyroid medication dose was decreased resulting in a reduction of the fetal
thyroid gland to a normal size in three cases but in the other two cases the gland
remained enlarged. These latter two infants both developed neonatal Graves' disease
[",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/12\">",
" 12",
" </a>",
" ]. Care must be taken, however, as fetal goiter may be a feature of in utero
hyperthyroidism or hypothyroidism. Another study using ultrasonography reported
that a hyperthyroid fetus was more likely to have a goiter with central
vascularization, along with other findings, including fetal tachycardia, increased
fetal movement, and advanced bone maturity [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/13\">",
" 13",
" </a>",
" ].",
" </p>",
" <p>",
" Given the pathogenesis, one would expect twins to be equally affected.
However, in a single case report, one twin was hyperthyroid and the other was
hypothyroid [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/14\">",
" 14",
" </a>",
" ]. Both eventually recovered to a euthyroid state.",
" </p>",
" <p class=\"headingAnchor\" id=\"H4\">",
" <span class=\"h2\">",
" Natural history",
" </span>",
" &nbsp;&mdash;&nbsp;Neonatal Graves' hyperthyroidism resolves spontaneously in
3 to 12 weeks as the maternal TSHR-Ab disappears from the infant's circulation.",
" </p>",
" <p class=\"headingAnchor\" id=\"H28990652\">",
" <span class=\"h2\">",
" Other causes of neonatal hyperthyroidism",
" </span>",
" &nbsp;&mdash;&nbsp;Rarely, neonatal hyperthyroidism may be caused by genetic
defects of the thyroid stimulating hormone (TSH) receptor or its mediators; these
forms are not associated with maternal Graves&rsquo; disease.",
" </p>",
" <p class=\"headingAnchor\" id=\"H5\">",
" <span class=\"h3\">",
" Thyrotropin-receptor activating mutations",
" </span>",
" &nbsp;&mdash;&nbsp;Activating germline mutations of the TSH receptor are a
rare cause of neonatal hyperthyroidism [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/15-18\">",
" 15-18",
" </a>",
" ]. Neither the infant nor the mother has circulating TSHR-Ab or evidence for
autoimmune thyroid disease. This condition is inherited as an autosomal dominant
trait, and there may be a family history of hyperthyroidism.",
" </p>",
" <p>",
" In contrast to neonatal Graves' hyperthyroidism, this form of hyperthyroidism
persists indefinitely and will recur whenever antithyroid drug treatment is
discontinued. Thus, treatment with either surgery or radioactive iodine (in
children &gt;10 years of age) is indicated eventually.",
" </p>",
" <p class=\"headingAnchor\" id=\"H6\">",
" <span class=\"h3\">",
" Alpha subunit-G-protein activating mutation (McCune-Albright syndrome)",
" </span>",
" &nbsp;&mdash;&nbsp;Another rare cause of neonatal hyperthyroidism is an
activating mutation of the alpha subunit of the G protein that stimulates adenylate
cyclase [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/19-21\">",
" 19-21",
" </a>",
" ]. This typically occurs as part of the McCune-Albright syndrome. As with
thyrotropin-receptor activating mutations, neither mother nor infant has TSHR-Ab.
In contrast to thyrotropin-receptor activating mutations, however, these are
somatic cell mutations, and so this is a sporadic disorder.",
" </p>",
" <p>",
" This form of hyperthyroidism will persist indefinitely, and so surgery or
radioactive iodine treatment is indicated eventually.",
" </p>",
" <p class=\"headingAnchor\" id=\"H7\">",
" <span class=\"h1\">",
" CLINICAL MANIFESTATIONS",
" </span>",
" &nbsp;&mdash;&nbsp;The clinical manifestations of hyperthyroidism in neonates
are those of hyperthyroidism in general plus some features unique to neonates. The
characteristic abnormalities are:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" Low birth weight for gestational age (intrauterine growth restriction) [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/22\">",
" 22",
" </a>",
" ]",
" </li>",
" <li>",
" Premature birth",
" </li>",
" <li>",
" Microcephaly (may be a manifestation of accelerated brain development with
premature completion of neuronal morphogenesis)",
" </li>",
" <li>",
" Frontal bossing and triangular facies",
" </li>",
" <li>",
" Warm, moist skin",
" </li>",
" <li>",
" Irritability, hyperactivity, restlessness, and poor sleep",
" </li>",
" <li>",
" Tachycardia with a bounding pulse, and sometimes cardiomegaly, cardiac
arrhythmias, or heart failure",
" </li>",
" <li>",
" Fetal hydrops (uncommon)",
" </li>",
" <li>",
" Hyperphagia, but poor weight gain, and diarrhea",
" </li>",
" <li>",
" Hepatosplenomegaly",
" </li>",
" <li>",
" Diffuse goiter, usually small, but occasionally large enough to cause
compression of the airway",
" </li>",
" <li>",
" Stare and occasionally exophthalmos (presumably true Graves'
ophthalmopathy)",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H8\">",
" <span class=\"h2\">",
" Timing of symptoms",
" </span>",
" &nbsp;&mdash;&nbsp;The time of onset and severity of symptoms are variable,
depending upon whether the mother is taking an antithyroid drug at the time of
delivery. Infants born to mothers not receiving an antithyroid drug, including
mothers who are euthyroid as a result of previous ablative treatment for Graves'
hyperthyroidism, are hyperthyroid at the time of birth. Infants of mothers taking
an antithyroid drug may be euthyroid or even hypothyroid at birth, and become
hyperthyroid several days later, as the antithyroid drug is metabolized or excreted
[",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/23\">",
" 23",
" </a>",
" ]. In a report of six infants born to mothers with Graves' disease treated
with antithyroid drugs during pregnancy, symptoms and signs of congenital
hyperthyroidism developed between days 10 and 20 of life [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/24\">",
" 24",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H9\">",
" <span class=\"h1\">",
" DIAGNOSIS",
" </span>",
" &nbsp;&mdash;&nbsp;Thyroid function should be assessed in infants born to
mothers with Graves' hyperthyroidism by measurement of serum-free thyroxine (free
T4) and thyroid stimulating hormone (TSH) at delivery or soon thereafter. It is
important to remember the normal range for both serum free T4 and TSH are higher in
the first few days and weeks of life than in older children and adults. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?39/47/40696?
source=see_link\">",
" \"Thyroid physiology and screening in preterm infants\"",
" </a>",
" .) Most cases of neonatal Graves' disease are diagnosed after discovery of
maternal Graves' disease and are recognized during pregnancy. Rare cases of
neonatal Graves' disease have been detected by newborn screening programs measuring
free T4 levels, then leading to discovery of Graves' hyperthyroidism in the mother
[",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/25\">",
" 25",
" </a>",
" ]. &nbsp;",
" </p>",
" <p class=\"headingAnchor\" id=\"H10\">",
" <span class=\"h2\">",
" Measurement of antibodies",
" </span>",
" &nbsp;&mdash;&nbsp;Measurement of maternal serum TSHR-Ab during the third
trimester helps to predict which infants are at higher risk for development of
fetal and neonatal Graves' hyperthyroidism. The most readily available (and least
expensive) assays are measurements of TSH-binding inhibitory antibodies in receptor
assays (thyrotropin binding inhibitory immunoglobulin [TBII]). Although TBII assays
do not indicate biologic activity, women with Graves' disease usually have
stimulatory antibodies and, as noted above, the fetus or infant is more likely to
have Graves' hyperthyroidism when the maternal value is more than 500 percent of
normal values [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/5,26\">",
" 5,26",
" </a>",
" ]. TSHR-Ab can also be detected by the thyroid stimulating immunoglobulin
(TSI) assay, which measures biologic activity through generation of cyclic AMP.",
" </p>",
" <p class=\"headingAnchor\" id=\"H11\">",
" <span class=\"h1\">",
" TREATMENT",
" </span>",
" &nbsp;&mdash;&nbsp;Once neonatal hyperthyroidism is confirmed by clinical and
biochemical evaluation, treatment should be initiated promptly. Therapy should
consist of the following:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" The antithyroid drug",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?20/50/21286?
source=see_link\">",
" methimazole",
" </a>",
" (MMI, 0.25 to 1.0",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" per day), should be administered every eight hours. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?12/25/12696?
source=see_link\">",
" \"Thionamides in the treatment of Graves' disease\"",
" </a>",
" .)",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?14/50/15142?
source=see_link\">",
" Propylthiouracil",
" </a>",
" is also effective, but has more frequent and severe side effects, including
a risk of hepatotoxicity [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/27\">",
" 27",
" </a>",
" ]. Because of these safety concerns, the Endocrine Society, the American
Thyroid Association, and the US Food and Drug Administration recommend",
" <strong>",
" against",
" </strong>",
" the use of PTU as first-line treatment for Graves' disease throughout
childhood [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/28-30\">",
" 28-30",
" </a>",
" ].",
" </li>",
" <li>",
" A beta adrenergic blocker, such as",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?35/62/36840?
source=see_link\">",
" propranolol",
" </a>",
" (2",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" per day every eight hours) is an important adjunct in controlling
neuromuscular and cardiovascular hyperactivity. If a more cardio-specific beta
blocker is preferred,",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?33/58/34726?
source=see_link\">",
" atenolol",
" </a>",
" (1",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" daily) can be used. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?0/17/275?
source=see_link\">",
" \"Beta blockers in the treatment of hyperthyroidism\"",
" </a>",
" .)",
" </li>",
" <li>",
" Iodine, in the form of one drop (8 mg) of Lugol's solution (126 mg",
" <span class=\"nowrap\">",
" iodine/mL)",
" </span>",
" every eight hours orally or SSKI (",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?35/28/36293?
source=see_link\">",
" potassium iodide",
" </a>",
" ) one to two drops daily, can be given to inhibit thyroid hormone release.
Hyperthyroidism is usually controlled within a few weeks using just an antithyroid
drug and a beta blocker. Iodine, if added, is generally used for only one to two
weeks. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?10/38/10852?
source=see_link\">",
" \"Iodine in the treatment of hyperthyroidism\"",
" </a>",
" .)",
" </li>",
" <li>",
" Glucocorticoids can also be given in extremely ill infants. In addition to
their antiinflammatory actions, glucocorticoids inhibit thyroid hormone secretion
and decrease peripheral conversion of T4 to triiodothyronine (T3).",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?26/24/27017?
source=see_link\">",
" Digoxin",
" </a>",
" may be helpful if heart failure is present.",
" </li>",
" </ul>",
" </p>",
" <p>",
" Once improvement is evident, treatment should be gradually decreased and then
discontinued. This may require frequent (ie, weekly) monitoring of thyroid function
tests to allow adjustment of the antithyroid drug dose to maintain normal serum
free T4 and T3 levels. As noted above, neonatal Graves' hyperthyroidism usually
resolves spontaneously between 3 and 12 weeks of life, although it can persist for
six months or even longer.",
" </p>",
" <p class=\"headingAnchor\" id=\"H12\">",
" <span class=\"h1\">",
" PROGNOSIS",
" </span>",
" &nbsp;&mdash;&nbsp;With adequate therapy, initiated promptly, most neonates
with hyperthyroidism improve rapidly. Nevertheless, some of these patients have IQs
in the 80s when measured at school age, even if they were treated promptly for
hyperthyroidism during the neonatal period. These observations suggest that fetal
or neonatal hyperthyroidism has adverse effects on the developing nervous system.
Growth retardation, craniosynostosis, hyperactivity, and developmental and
behavioral problems have been described as long-term sequelae of neonatal Graves'
hyperthyroidism; the relationship between these findings and the adequacy of
treatment is uncertain [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/31\">",
" 31",
" </a>",
" ].",
" </p>",
" <p>",
" A few infants with neonatal Graves' hyperthyroidism later have diminished TSH
secretion, which may result in central hypothyroidism [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/32\">",
" 32",
" </a>",
" ]. This is thought to be secondary to prenatal exposure of the hypothalamus
and pituitary to high serum thyroid hormone concentrations during a critical stage
of development. There is evidence that insufficient antithyroid drug treatment
during pregnancy increases the risk of permanent central hypothyroidism, drawing
attention to the importance of careful monitoring of maternal thyroid function and
appropriate antithyroid drug dosing during pregnancy [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/33\">",
" 33",
" </a>",
" ]. There is also evidence that decreased TSH secretion might impair normal
fetal thyroid gland development, in a process described as
thyroid \"disintegration\" [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/34\">",
" 34",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H13\">",
" <span class=\"h1\">",
" FETAL HYPERTHYROIDISM",
" </span>",
" &nbsp;&mdash;&nbsp;High maternal serum TSHR-Ab concentrations may cause fetal
hyperthyroidism. It is characterized by fetal hyperactivity, tachycardia (&gt;160",
" <span class=\"nowrap\">",
" beats/min)",
" </span>",
" after 22 weeks gestation, advanced bone maturation, and a goiter. If these
abnormalities are present, corrective therapy (eg, cautious administration of an
antithyroid drug to the mother) may be indicated [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/35\">",
" 35",
" </a>",
" ]. Besides the untoward hypermetabolic effects, fetal hyperthyroidism may
accelerate fetal central nervous system maturation, causing disorganization of
brain development and therefore intellectual disability (mental retardation). The
diagnosis and treatment of fetal hyperthyroidism is discussed elsewhere in the
program. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?41/48/42760?
source=see_link&amp;anchor=H13#H13\">",
" \"Hyperthyroidism during pregnancy: Treatment\", section on 'Fetal
hyperthyroidism'",
" </a>",
" .)",
" </p>",
" <p>",
" Maternal antithyroid drug treatment may also result in fetal goiter and
hypothyroidism. Such cases may be managed by decreasing the maternal antithyroid
dose (if safe), or by intra-amniotic injections of thyroid hormone [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/97/abstract/36,37\">",
" 36,37",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?41/48/42760?
source=see_link&amp;anchor=H5#H5\">",
" \"Hyperthyroidism during pregnancy: Treatment\", section on 'Thionamides'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H28990585\">",
" <span class=\"h1\">",
" SUMMARY AND RECOMMENDATIONS",
" </span>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Neonatal Graves&rsquo; disease develops in about 2 percent of infants born
to mothers with Graves&rsquo; hyperthyroidism, and is caused by the transplacental
passage of maternal stimulatory TSH receptor antibodies (TSHR-Ab). Of the very
small percentage of babies who are exposed to high titers of TSHR-AB, hyperthyroid
symptoms typically present at birth, but the infant may also have hypothyroidism
following delivery, depending on the balance of the TSHR-SAb, TSHR inhibitory
antibodies, and maternal antithyroid drug (if given). Neonatal Graves'
hyperthyroidism resolves spontaneously within 3 to 12 weeks after birth as the
maternal TSHR-Ab disappears from the infant's circulation. (See",
" <a class=\"local\" href=\"#H2\">",
" 'Incidence'",
" </a>",
" above and",
" <a class=\"local\" href=\"#H3\">",
" 'Pathogenesis'",
" </a>",
" above.)",
" </li>",
" <li>",
" The clinical manifestations of hyperthyroidism in neonates include premature
birth",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" low birth weight for gestational age, microcephaly, irritability,
hyperactivity, tachycardia and arrhythmias, hyperphagia, diarrhea,
hepatosplenomegaly, goiter, and stare. The time of onset and severity of symptoms
are variable, depending upon whether the mother is taking an antithyroid drug at
the time of delivery. (See",
" <a class=\"local\" href=\"#H7\">",
" 'Clinical manifestations'",
" </a>",
" above.)",
" </li>",
" <li>",
" To estimate the risk of neonatal Graves&rsquo; disease in infants born to
mothers with a history of Graves&rsquo; disease, maternal serum TSHR-Ab should be
measured during the third trimester. Neonatal hyperthyroidism is most likely when
the TSHR-Ab activity of maternal serum is above 500 percent of the values in serum
of normal subjects. (See",
" <a class=\"local\" href=\"#H10\">",
" 'Measurement of antibodies'",
" </a>",
" above.) &nbsp;",
" </li>",
" <li>",
" High maternal serum TSHR-Ab concentrations may cause fetal hyperthyroidism,
which is characterized by fetal hyperactivity, tachycardia after 22 weeks
gestation, advanced bone maturation, and a goiter. If these abnormalities are
present, corrective therapy may be indicated because fetal hyperthyroidism may
cause untoward effects, particularly on the cardiovascular system, and may also
disrupt fetal central nervous system development. (See",
" <a class=\"local\" href=\"#H13\">",
" 'Fetal hyperthyroidism'",
" </a>",
" above.)",
" </li>",
" <li>",
" All infants born to mothers with a history of Graves&rsquo; disease should
be assessed by measuring serum free thyroxine (free T4) and thyroid stimulating
hormone (TSH) at birth or soon thereafter. This includes infants whose mothers are
euthyroid as a result of previous ablative treatment for Graves' hyperthyroidism.
It is important to remember the normal range for both serum free T4 and TSH
concentrations is higher in the first few days and weeks of life than in older
children and adults. (See",
" <a class=\"local\" href=\"#H9\">",
" 'Diagnosis'",
" </a>",
" above and",
" <a class=\"medical medical_review\" href=\"UTD.htm?39/47/40696?
source=see_link\">",
" \"Thyroid physiology and screening in preterm infants\"",
" </a>",
" .)",
" </li>",
" <li>",
" If neonatal hyperthyroidism is confirmed by clinical and biochemical
evaluation, treatment should be initiated promptly. We recommend that these infants
be treated with a combination of the antithyroid drug",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?20/50/21286?
source=see_link\">",
" methimazole",
" </a>",
" and a beta adrenergic blocker such as",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?35/62/36840?
source=see_link\">",
" propranolol",
" </a>",
" or",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?33/58/34726?
source=see_link\">",
" atenolol",
" </a>",
" , rather than no treatment or monotherapy (",
" <a class=\"grade\" href=\"._grade_2?title=Grade 1B\">",
" Grade 1B",
" </a>",
" ). Iodine can be given to inhibit thyroid hormone release; iodine is
generally reserved for neonates whose hyperthyroidism is not controlled with an
antithyroid drug and beta blocker.",
" </li>",
" <li>",
" With adequate therapy, most neonates with hyperthyroidism improve rapidly.
Nevertheless, there may be some long-term adverse effects on cognitive development
even with prompt treatment. Some individuals later develop central hypothyroidism
due to prenatal exposure of the hypothalamus and pituitary to high serum thyroid
hormone concentrations. (See",
" <a class=\"local\" href=\"#H12\">",
" 'Prognosis'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_in_page\"
target=\"_blank\">",
" Subscription and License Agreement",
" </a>",
" .",
" </div>",
" <div class=\"headingAnchor\" id=\"references\">",
" <h1>",
" REFERENCES",
" </h1>",
" <ol id=\"reference\">",
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" Duprez L, Parma J, Van Sande J, et al. Germline mutations in the thyrotropin
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" Yoshimoto M, Nakayama M, Baba T, et al. A case of neonatal McCune-Albright
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" Weinstein LS, Shenker A, Gejman PV, et al. Activating mutations of the
stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 1991;
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" Farrehi C. Accelerated maturity in fetal thyrotoxicosis. Clin Pediatr
(Phila) 1968; 7:134.",
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" Zakarija M, McKenzie JM, Hoffman WH. Prediction and therapy of intrauterine
and late-onset neonatal hyperthyroidism. J Clin Endocrinol Metab 1986; 62:368.",
" </a>",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/97/abstract/24\">",
" Weber G, Ielo V, Vigone MC, et al. Neonatal hyperthyoidism: Report of eight
cases. Ital J Pediatr 2001; 27:757.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/97/abstract/25\">",
" Tajima T, Jo W, Fujikura K, et al. Elevated free thyroxine levels detected
by a neonatal screening system. Pediatr Res 2009; 66:312.",
" </a>",
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" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/97/abstract/26\">",
" Skuza KA, Sills IN, Stene M, Rapaport R. Prediction of neonatal
hyperthyroidism in infants born to mothers with Graves disease. J Pediatr 1996;
128:264.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/97/abstract/27\">",
" Rivkees SA, Szarfman A. Dissimilar hepatotoxicity profiles of
propylthiouracil and methimazole in children. J Clin Endocrinol Metab 2010;
95:3260.",
" </a>",
" </li>",
" <li>",
" U.S. Food and Drug Administration, update 4/21/2010:
file://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalPro
ducts/ucm164162.htm (Accessed on September 09, 2010).",
" </li>",
" <li>",
" Endocrine Society statement, April 14th, 2009. file://www.endo-
society.org/advocacy/legislative/SocietyStatementontheNEJMLettetotheEditoronPTUUseI
nChildren.cfm.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/97/abstract/30\">",
" Bahn RS, Burch HS, Cooper DS, et al. The Role of Propylthiouracil in the
Management of Graves' Disease in Adults: report of a meeting jointly sponsored by
the American Thyroid Association and the Food and Drug Administration. Thyroid
2009; 19:673.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/97/abstract/31\">",
" Daneman D, Howard NJ. Neonatal thyrotoxicosis: intellectual impairment and
craniosynostosis in later years. J Pediatr 1980; 97:257.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/97/abstract/32\">",
" Mandel SH, Hanna CE, LaFranchi SH. Diminished thyroid-stimulating hormone
secretion associated with neonatal thyrotoxicosis. J Pediatr 1986; 109:662.",
" </a>",
" </li>",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/97/abstract/33\">",
" Kempers MJ, van Tijn DA, van Trotsenburg AS, et al. Central congenital
hypothyroidism due to gestational hyperthyroidism: detection where prevention
failed. J Clin Endocrinol Metab 2003; 88:5851.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/97/abstract/34\">",
" Kempers MJ, van Trotsenburg AS, van Rijn RR, et al. Loss of integrity of
thyroid morphology and function in children born to mothers with inadequately
treated Graves' disease. J Clin Endocrinol Metab 2007; 92:2984.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/97/abstract/35\">",
" Srisupundit K, Sirichotiyakul S, Tongprasert F, et al. Fetal therapy in
fetal thyrotoxicosis: a case report. Fetal Diagn Ther 2008; 23:114.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/97/abstract/36\">",
" Miyata I, Abe-Gotyo N, Tajima A, et al. Successful intrauterine therapy for
fetal goitrous hypothyroidism during late gestation. Endocr J 2007; 54:813.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/97/abstract/37\">",
" Bliddal S, Rasmussen &Aring;K, Sundberg K, et al. Graves' disease in two
pregnancies complicated by fetal goitrous hypothyroidism: successful in utero
treatment with levothyroxine. Thyroid 2011; 21:75.",
" </a>",
" </li>",
" </ol>",
" </div>",
" <div id=\"topicVersionRevision\">",
" Topic 5839 Version 7.0",
" </div>",
" </div>",
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var outline_f0_6_97=[" <div id=\"toggleOutline\">",
" <a href=\"#\" title=\"Collapse Topic Outline\">",
" <img alt=\"\" src=\"./../images/orange_arrow_left.myextg\"/>",
" </a>",
" </div>",
" <div id=\"innerOutline\">",
" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <div id=\"outline\">",
" <ul>",
" <li>",
" <a class=\"sr_button\" href=\"#H28990585\" id=\"summRecButton\">",
" <span>",
" SUMMARY &amp; RECOMMENDATIONS",
" </span>",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H1\">",
" INTRODUCTION",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H2\">",
" INCIDENCE",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H3\">",
" PATHOGENESIS",
" </a>",
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" Natural history",
" </a>",
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" Other causes of neonatal hyperthyroidism",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H5\">",
" - Thyrotropin-receptor activating mutations",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H6\">",
" - Alpha subunit-G-protein activating mutation (McCune-Albright syndrome)",
" </a>",
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" <a class=\"outlineLink\" href=\"#H7\">",
" CLINICAL MANIFESTATIONS",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H8\">",
" Timing of symptoms",
" </a>",
" </li>",
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" <a class=\"outlineLink\" href=\"#H9\">",
" DIAGNOSIS",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H10\">",
" Measurement of antibodies",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H11\">",
" TREATMENT",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H12\">",
" PROGNOSIS",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H13\">",
" FETAL HYPERTHYROIDISM",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H28990585\">",
" SUMMARY AND RECOMMENDATIONS",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a href=\"#references\">",
" REFERENCES",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
" <div id=\"relatedTopics\">",
" <ul>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?0/17/275?
source=related_link\">",
" Beta blockers in the treatment of hyperthyroidism",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?41/48/42760?
source=related_link\">",
" Hyperthyroidism during pregnancy: Treatment",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?10/38/10852?
source=related_link\">",
" Iodine in the treatment of hyperthyroidism",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?12/25/12696?
source=related_link\">",
" Thionamides in the treatment of Graves' disease",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?39/47/40696?
source=related_link\">",
" Thyroid physiology and screening in preterm infants",
" </a>",
" </li>",
" </ul>",
" </div>",
" </div>"].join("\n");
var title_f0_6_98="Randomized clinical trials of combinations of nonbiologic DMARDs
in rheumatoid arthritis";
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" Randomized clinical trials of combinations of nonbiologic DMARDs in rheumatoid
arthritis",
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" </a>",
" <span>",
" is complete.",
" </span>",
" </div>",
" <div id=\"literatureReviewDate\">",
" <span class=\"emphasis\">",
" Literature review current through:",
" </span>",
" Oct 2013.",
" <span class=\"pipeSpace\">",
" |",
" </span>",
" <span class=\"emphasis\">",
" This topic last updated:",
" </span>",
" Feb 28, 2012.",
" </div>",
" <div id=\"topicText\">",
" <p class=\"headingAnchor\" id=\"H1\">",
" <span class=\"h1\">",
" INTRODUCTION",
" </span>",
" &nbsp;&mdash;&nbsp;More than a dozen traditional disease modifying
antirheumatic drugs (DMARDs) and biologic agents, respectively termed nonbiologic
and biologic DMARDs, are currently available; thus, there are more than 100 and
1000 potential combinations of two and three DMARDs, respectively. Of these, only a
few have been directly compared in randomized clinical trials. Some well-designed
studies have demonstrated clinically significant efficacy with a generally
acceptable risk of toxicity.",
" </p>",
" <p>",
" Representative clinical trials of various combinations of nonbiologic DMARDs
in early and established rheumatoid arthritis (RA) will be reviewed here. The
general approach to management of RA and randomized controlled trials of biologic
agents in this disease are discussed separately. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?38/11/39098?
source=see_link\">",
" \"General principles of management of rheumatoid arthritis in adults\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?10/10/10410?
source=see_link\">",
" \"Randomized clinical trials of tumor necrosis factor inhibitors in
rheumatoid arthritis\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?20/40/21130?
source=see_link\">",
" \"Rituximab and other B cell targeted therapies for rheumatoid arthritis\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?9/0/9223?
source=see_link\">",
" \"T cell targeted therapies for rheumatoid arthritis\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?34/12/35016?
source=see_link\">",
" \"Randomized clinical trials in rheumatoid arthritis of biologic agents that
inhibit IL-1, IL-6, and RANKL\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H2\">",
" <span class=\"h1\">",
" METHOTREXATE BASED COMBINATIONS",
" </span>",
" </p>",
" <p class=\"headingAnchor\" id=\"H3\">",
" <span class=\"h2\">",
" Gold and MTX",
" </span>",
" &nbsp;&mdash;&nbsp;The clinical effectiveness of the combination of
intramuscular gold when added to ongoing",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" (MTX) was best illustrated in a study in which 65 patients with RA and a
partial response to MTX (mean dose of 18.5",
" <span class=\"nowrap\">",
" mg/week)",
" </span>",
" continued MTX therapy and were randomly assigned to receive gold sodium
thioglucose (initial dose of 10 mg, followed by 25 mg at week one and 50 mg per
week thereafter) or placebo injections for 48 weeks [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/1\">",
" 1",
" </a>",
" ]. At the end of the trial, those who received gold injections did
significantly better than the placebo group:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" ACR20 responses occurred in a significantly greater proportion of gold plus
MTX treated subjects (61 versus 30 percent).",
" </li>",
" <li>",
" ACR50 responses also occurred more often in those receiving gold (26 versus
4 percent).",
" </li>",
" <li>",
" ACR70 responses were only seen in those receiving gold (21 versus 0
percent).",
" </li>",
" <li>",
" Fewer withdrawals in the gold plus MTX group than in the placebo group were
due to lack of efficacy (3 of 9 versus 10 of 14, respectively).",
" </li>",
" <li>",
" Withdrawals due to adverse events were not significantly more frequent in
the gold plus MTX group (10 versus 3 percent).",
" </li>",
" </ul>",
" </p>",
" <p>",
" Mucocutaneous side effects occurred in 17 of 38",
" <span class=\"nowrap\">",
" gold/",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?
source=see_link\">",
" methotrexate",
" </a>",
" </span>",
" treated patients, leading to temporary suspension of therapy with gold.
However, in 15 of 17 patients, gold was reintroduced (at one-half the dose at which
the adverse effect occurred, followed by a gradual increase by 5 mg per week to the
maximum tolerated dose or 50 mg per week) without recurrent rash or mucositis.",
" </p>",
" <p>",
" Intramuscular gold is rarely used in the treatment of RA because of its slow
onset of action and difficulty of administration compared with many newer
therapies.",
" </p>",
" <p class=\"headingAnchor\" id=\"H4\">",
" <span class=\"h2\">",
" SSZ and MTX",
" </span>",
" &nbsp;&mdash;&nbsp;There are conflicting data on the efficacy of the two drug
combination of",
" <a class=\"drug drug_general\" href=\"UTD.htm?8/28/8647?source=see_link\">",
" sulfasalazine",
" </a>",
" (SSZ) and",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" (MTX).",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Forty patients with RA unresponsive to",
" <a class=\"drug drug_general\" href=\"UTD.htm?8/28/8647?source=see_link\">",
" sulfasalazine",
" </a>",
" alone were randomized to combination therapy consisting of sulfasalazine
and",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?
source=see_link\">",
" methotrexate",
" </a>",
" or to methotrexate alone [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/2\">",
" 2",
" </a>",
" ]. At 24 weeks, combination therapy resulted in a significant decrease in
disease activity compared with methotrexate alone. No difference in toxicity was
observed between the two treatment groups.",
" </li>",
" <li>",
" A multicenter study in Europe enrolled 205 patients with RA who had not
previously been treated with any DMARD(s) and randomly assigned them to",
" <a class=\"drug drug_general\" href=\"UTD.htm?8/28/8647?source=see_link\">",
" sulfasalazine",
" </a>",
" ,",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?
source=see_link\">",
" methotrexate",
" </a>",
" , or a combination of the two agents [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/3\">",
" 3",
" </a>",
" ]. After one-year of concealed treatment, 146 were followed for an
additional four years in an unblinded fashion and with whatever treatment was
chosen by the clinicians managing their care. Five years after initial enrollment,
disease activity, functional status, and radiographic scores were assessed [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/4\">",
" 4",
" </a>",
" ]. These outcomes were not significantly different among the three groups at
the one- or five-year points.",
" </li>",
" <li>",
" A molecular rationale for the failure of",
" <a class=\"drug drug_general\" href=\"UTD.htm?8/28/8647?source=see_link\">",
" sulfasalazine",
" </a>",
" (SSZ) and",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?
source=see_link\">",
" methotrexate",
" </a>",
" given in combination to be more efficacious than either drug given alone was
provided in a Dutch study [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/5\">",
" 5",
" </a>",
" ]. SSZ was found to be a potent inhibitor of the principal cell membrane
transporter for folates as well as methotrexate, along with inducing cellular
folate depletion. These observations led to recommendations that the drugs should
not be given in combination and that folate supplementation should be administered
to patients on either drug.",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H5\">",
" <span class=\"h2\">",
" SSZ, HCQ, and MTX",
" </span>",
" &nbsp;&mdash;&nbsp;A well-controlled, prospective study of 102 patients with
established RA found that triple therapy with",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" (MTX, 7.5 to 17.5 mg per week, titrated for response),",
" <a class=\"drug drug_general\" href=\"UTD.htm?8/28/8647?source=see_link\">",
" sulfasalazine",
" </a>",
" (SSZ, 500 mg twice daily), and",
" <a class=\"drug drug_general\" href=\"UTD.htm?2/26/2471?source=see_link\">",
" hydroxychloroquine",
" </a>",
" (HCQ, 200 mg twice daily) was superior to MTX alone or to SSZ plus HCQ [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/6\">",
" 6",
" </a>",
" ]. The primary end-point was at least 50 percent improvement at nine months, a
benefit which had to be sustained for two years without the development of
significant drug toxicity. Response was realized in 77, 40, and 33 percent of
patients randomized to triple, double, or single agent therapy, respectively (p =
0.003 for comparisons with the triple agent group).",
" </p>",
" <p class=\"headingAnchor\" id=\"H6\">",
" <span class=\"h2\">",
" HCQ/MTX versus SSZ/MTX versus HCQ/SSZ/MTX",
" </span>",
" &nbsp;&mdash;&nbsp;The question of whether a two drug or a three drug
combination that included",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" (MTX) was more efficacious for patients with RA who had an inadequate response
to MTX alone was addressed in a study that randomized 171 patients to one of three
groups: a three drug combination of MTX,",
" <a class=\"drug drug_general\" href=\"UTD.htm?2/26/2471?source=see_link\">",
" hydroxychloroquine",
" </a>",
" (HCQ) and",
" <a class=\"drug drug_general\" href=\"UTD.htm?8/28/8647?source=see_link\">",
" sulfasalazine",
" </a>",
" (SSZ); a two drug regimen of MTX plus HCQ (plus placebo); or MTX plus SSZ
(plus placebo) [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/7\">",
" 7",
" </a>",
" ].",
" </p>",
" <p>",
" Patients all had active disease and were followed for two years. The",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" dose was escalated from 7.5 mg per week to a maximum of 17.5 mg per week.",
" <a class=\"drug drug_general\" href=\"UTD.htm?8/28/8647?source=see_link\">",
" Sulfasalazine",
" </a>",
" was initially given at a dose of 500 mg BID and increased to 1 gram BID. The",
" <a class=\"drug drug_general\" href=\"UTD.htm?2/26/2471?source=see_link\">",
" hydroxychloroquine",
" </a>",
" dose was 200 mg BID.",
" </p>",
" <p>",
" Patients on the three drug combination had a significantly greater proportion
of ACR 20 and 50 responses than those on either of the two drug plus placebo
combinations (ACR20 responses of 78 percent, 60 percent, and 49 percent for those
receiving three drugs, MTX plus HCQ, and MTX plus SSZ, respectively; ACR50
responses of 55, 40, and 29 percent, respectively). There was no significant
difference in toxicity among the three groups.",
" </p>",
" <p class=\"headingAnchor\" id=\"H7\">",
" <span class=\"h2\">",
" SSZ, prednisolone, and MTX",
" </span>",
" &nbsp;&mdash;&nbsp;A double-blind study randomized 155 patients with early
onset RA to combination therapy consisting of",
" <a class=\"drug drug_general\" href=\"UTD.htm?8/28/8647?source=see_link\">",
" sulfasalazine",
" </a>",
" (SSZ, 2",
" <span class=\"nowrap\">",
" g/day),",
" </span>",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" (MTX, 7.5",
" <span class=\"nowrap\">",
" mg/week),",
" </span>",
" and",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/48/33536?source=see_link\">",
" prednisolone",
" </a>",
" (initial dose of 60",
" <span class=\"nowrap\">",
" mg/day",
" </span>",
" which was lowered over six weeks to 7.5",
" <span class=\"nowrap\">",
" mg/day)",
" </span>",
" or to SSZ alone [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/8,9\">",
" 8,9",
" </a>",
" ]. Prednisolone and MTX were withdrawn at weeks 28 and 40, respectively.
Evaluation of therapeutic efficacy was assessed via a pooled index of five disease
activity measures and via radiographic outcomes. At week 28, combination therapy
resulted in significant clinical benefits as determined by the pooled index when
compared with sulfasalazine alone (p&lt;0.0001). In addition, 72 and 49 percent of
patients treated with combination therapy and sulfasalazine alone had improved,
respectively. These benefits were not statistically significant once prednisolone
was withdrawn, and the clinical differences between the groups were unchanged after
methotrexate was stopped. Nevertheless, radiographic benefits due to combination
therapy were statistically significant at multiple time periods (weeks 28, 56, and
80).",
" </p>",
" <p class=\"headingAnchor\" id=\"H8\">",
" <span class=\"h2\">",
" SSZ, HCQ, prednisolone, and MTX",
" </span>",
" &nbsp;&mdash;&nbsp;In a multicenter trial (FIN-RACo), 199 patients were
randomly assigned either to combination therapy consisting of",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" (MTX),",
" <a class=\"drug drug_general\" href=\"UTD.htm?8/28/8647?source=see_link\">",
" sulfasalazine",
" </a>",
" (SSZ),",
" <a class=\"drug drug_general\" href=\"UTD.htm?2/26/2471?source=see_link\">",
" hydroxychloroquine",
" </a>",
" , and",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/48/33536?source=see_link\">",
" prednisolone",
" </a>",
" or to single agent therapy [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/10\">",
" 10",
" </a>",
" ]. Patients randomized to single agent therapy were initially treated with
SSZ, but MTX was later substituted for SSZ in 51 patients. In addition,
prednisolone was required in 63 individuals. After two years, remission was
realized in 36 and 18 percent of the combination and single-agent therapy group,
respectively (p = 0.003). In addition, 7 percent of those assigned single therapy,
but none who received combination therapy developed radiographically apparent
atlantoaxial subluxation (p = 0.029) [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/11\">",
" 11",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H25246332\">",
" <span class=\"h2\">",
" Calcineurin inhibitor plus MTX",
" </span>",
" &nbsp;&mdash;&nbsp;The calcineurin inhibitors (CNI),",
" <a class=\"drug drug_general\" href=\"UTD.htm?31/39/32368?source=see_link\">",
" cyclosporine",
" </a>",
" and",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/14/32992?source=see_link\">",
" tacrolimus",
" </a>",
" , have each been studied in RA in combination with MTX. These drugs are rarely
used in RA because of the availability of effective medications that lack the
degree of renal risk associated with the CNIs.",
" </p>",
" <p class=\"headingAnchor\" id=\"H9\">",
" <span class=\"h3\">",
" Cyclosporine and MTX",
" </span>",
" &nbsp;&mdash;&nbsp;The combination of",
" <a class=\"drug drug_general\" href=\"UTD.htm?31/39/32368?source=see_link\">",
" cyclosporine",
" </a>",
" and",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" has generally been more effective than either agent used individually [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/12-15\">",
" 12-15",
" </a>",
" ]. The following studies are illustrative:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" A six-month study evaluated the clinical response of 148 patients with
severe RA randomized to",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?
source=see_link\">",
" methotrexate",
" </a>",
" (at the maximal tolerated dose) plus",
" <a class=\"drug drug_general\" href=\"UTD.htm?31/39/32368?
source=see_link\">",
" cyclosporine",
" </a>",
" (2.5 to 5",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" per day) or to methotrexate plus placebo [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/16\">",
" 16",
" </a>",
" ]. Compared with methotrexate alone, combination therapy resulted in fewer
tender joints (average decrease of 4.8 joints, p = 0.02), fewer swollen joints
(average decrease of 3.8 joints, p = 0.005), and improvement in disease activity as
determined by both the clinician and patient. Clinical improvement was maintained
when this study was extended for another 24 weeks [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/12\">",
" 12",
" </a>",
" ].",
" </li>",
" <li>",
" Another study that randomly assigned 120 patients with active RA either to
the combination of",
" <a class=\"drug drug_general\" href=\"UTD.htm?31/39/32368?
source=see_link\">",
" cyclosporine",
" </a>",
" (2.5",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" increased to 5",
" <span class=\"nowrap\">",
" mg/kg/day,",
" </span>",
" if tolerated) and",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?
source=see_link\">",
" methotrexate",
" </a>",
" (7.5",
" <span class=\"nowrap\">",
" mg/week,",
" </span>",
" increased to 15",
" <span class=\"nowrap\">",
" mg/week,",
" </span>",
" if tolerated) or to cyclosporin and placebo [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/13\">",
" 13",
" </a>",
" ]. The combination of cyclosporine and methotrexate tended to produce better
clinical responses. In those followed for 48 weeks, significantly less radiographic
damage occurred in the combination group than in the group on cyclosporine alone
(median Larsen scores of 10 and 4, respectively, p = 0.004) [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/13\">",
" 13",
" </a>",
" ]. Remissions were uncommon in both groups (four versus six patients,
respectively).",
" </li>",
" <li>",
" In another study, 61 patients with active RA of less than two years duration
who had not received DMARDs or",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?
source=see_link\">",
" prednisone",
" </a>",
" in a dose of more than 10",
" <span class=\"nowrap\">",
" mg/day",
" </span>",
" were randomly assigned to receive",
" <a class=\"drug drug_general\" href=\"UTD.htm?31/39/32368?
source=see_link\">",
" cyclosporine",
" </a>",
" (3",
" <span class=\"nowrap\">",
" mg/kg/day",
" </span>",
" initially with an increase to 4",
" <span class=\"nowrap\">",
" mg/kg/day)",
" </span>",
" plus",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?
source=see_link\">",
" methotrexate",
" </a>",
" (10 to 15 mg intramuscularly weekly with an increase to 20",
" <span class=\"nowrap\">",
" mg/week,",
" </span>",
" if necessary) or methotrexate and placebo [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/14\">",
" 14",
" </a>",
" ]. ACR 20, ACR 50, and ACR 70 response rates in the combination and
methotrexate alone groups were 53 versus 61 percent, 50 versus 42 percent, and 47
versus 19 percent, respectively. There was significantly less progression in
radiographic joint damage during one year of treatment in the combination than in
the methotrexate-only groups (change in joint damage score 1.9 versus 7.5,
respectively). There were more withdrawals from the combination group due to
adverse effects (7 patients, 23 percent) than the methotrexate-only group (2
patients, 6 percent). Although patients were aware of their assigned treatment, the
scoring of radiographs was performed by an investigator who was unaware of this
factor.",
" </li>",
" </ul>",
" </p>",
" <p>",
" However, another study comparing",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" and",
" <a class=\"drug drug_general\" href=\"UTD.htm?31/39/32368?source=see_link\">",
" cyclosporine",
" </a>",
" with",
" <a class=\"drug drug_general\" href=\"UTD.htm?8/28/8647?source=see_link\">",
" sulfasalazine",
" </a>",
" alone found no significant difference at 48 weeks in clinical and radiographic
outcome with the two regimens [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/17\">",
" 17",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H10\">",
" <span class=\"h3\">",
" Tacrolimus and MTX",
" </span>",
" &nbsp;&mdash;&nbsp;The combination of",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/14/32992?source=see_link\">",
" tacrolimus",
" </a>",
" (3 mg per day) and",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" (MTX, mean of 15 mg per week) may have some benefit, as suggested by the
results of an uncontrolled multicenter trial in 80 patients with RA that was still
active despite ongoing methotrexate therapy [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/18\">",
" 18",
" </a>",
" ]. ACR20 responses were noted in 52.5 percent of those receiving the
combination at the end of six months of treatment. Increases in serum creatinine of
&ge;30 percent were seen in 29 percent of patients. Withdrawals from the study were
predominantly due to possible or probable adverse effects from tacrolimus and lack
of efficacy (12.5 and 5 percent, respectively).",
" </p>",
" <p>",
" Careful monitoring of renal function is required if this combination is
utilized, as the renal dysfunction that is a common adverse effect of",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/14/32992?source=see_link\">",
" tacrolimus",
" </a>",
" , may lead to a prolongation of the half-life of",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" and could increase the risk of myelosuppression. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?27/27/28090?
source=see_link\">",
" \"Pharmacology and side effects of cyclosporine and tacrolimus\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?40/61/41945?
source=see_link\">",
" \"Cyclosporine and tacrolimus nephrotoxicity\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H11\">",
" <span class=\"h2\">",
" Leflunomide and MTX",
" </span>",
" &nbsp;&mdash;&nbsp;The administration of",
" <a class=\"drug drug_general\" href=\"UTD.htm?18/36/19015?source=see_link\">",
" leflunomide",
" </a>",
" (LEF) in combination with",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" (MTX) is based upon the premise that it may be useful to combine an agent
whose mode of action is different from that of MTX. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?9/59/10169?
source=see_link\">",
" \"Leflunomide in the treatment of rheumatoid arthritis\"",
" </a>",
" .) An initial open label study of 30 patients with active RA suggested benefit
from this combination and provided the rationale for further studies [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/19\">",
" 19",
" </a>",
" ].",
" </p>",
" <p>",
" A subsequent trial randomly assigned 263 patients with persistent disease
activity despite use of MTX (mean 17",
" <span class=\"nowrap\">",
" mg/week)",
" </span>",
" to groups that received either",
" <a class=\"drug drug_general\" href=\"UTD.htm?18/36/19015?source=see_link\">",
" leflunomide",
" </a>",
" (100 mg per day for two days, followed by 10 mg per day with titration upward
to 20 mg per day or down to 10 mg every other day as indicated by clinical response
or adverse effects) or placebo [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/20\">",
" 20",
" </a>",
" ]. More than three-quarters of the subjects were women, the mean age
approximately was 56 years, and disease duration averaged 10 to 12 years. Eighty to
90 percent of the patients were rheumatoid factor positive. Blood counts, serum
aminotransferase enzyme levels, and serum albumin were followed carefully, and the
dose of leflunomide adjusted accordingly.",
" </p>",
" <p>",
" After six months, an ACR20 response was noted in significantly more patients
in the LEF plus MTX group than in the placebo plus MTX group (46 versus 19 percent,
respectively). LEF plus MTX treated patients also had more frequent ACR 50 (26
versus 6 percent) and ACR 70 (10 versus 2 percent) responses than did those who
received MTX and placebo.",
" </p>",
" <p>",
" At the end of the study, a majority of patients in the LEF plus MTX group were
receiving 20",
" <span class=\"nowrap\">",
" mg/day",
" </span>",
" of",
" <a class=\"drug drug_general\" href=\"UTD.htm?18/36/19015?source=see_link\">",
" leflunomide",
" </a>",
" (55 percent), while a minority were on 10",
" <span class=\"nowrap\">",
" mg/day",
" </span>",
" or every other day (39 and 6 percent, respectively). Adverse events were
common in both groups, but only diarrhea was more common in the leflunomide plus",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" group (25 versus 13 percent).",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" There were fewer infections in the combination group, and there were no
opportunistic infections in either group of patients.",
" </li>",
" <li>",
" There were more discontinuations of treatment due to adverse events in the
combination group and more withdrawals due to lack of efficacy in the",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?
source=see_link\">",
" methotrexate",
" </a>",
" plus placebo group. The proportion of withdrawals from the study was similar
in the two groups (23 and 25 percent, respectively).",
" </li>",
" <li>",
" Elevation of serum aminotransferase enzyme levels (more than 1.2-fold
greater than the upper limit of normal) was more frequent in the combination group
than in the",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?
source=see_link\">",
" methotrexate",
" </a>",
" plus placebo group (31 versus 7 percent).",
" </li>",
" <li>",
" Mild or moderate decreases in leukocyte",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" neutrophil counts were more frequently noted in those receiving the",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?
source=see_link\">",
" methotrexate",
" </a>",
" -",
" <a class=\"drug drug_general\" href=\"UTD.htm?18/36/19015?
source=see_link\">",
" leflunomide",
" </a>",
" combination, but none of the patients experienced severe leukopenia or
neutropenia.",
" </li>",
" </ul>",
" </p>",
" <p>",
" At the conclusion of the double-blind portion of this study, an open-label
extension was conducted for an additional 24 weeks [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/21\">",
" 21",
" </a>",
" ]. Responses noted in 96 patients who initially received",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" plus",
" <a class=\"drug drug_general\" href=\"UTD.htm?18/36/19015?source=see_link\">",
" leflunomide",
" </a>",
" were generally maintained, while 96 others who had received placebo plus
methotrexate for 24 weeks experienced a gradual improvement after leflunomide was
substituted for placebo. Among the latter group, those who did not receive a
loading dose of leflunomide had less nausea and diarrhea and less often had
elevations of serum aminotransferases than those who did receive a loading dose.",
" </p>",
" <p>",
" Overall, addition of",
" <a class=\"drug drug_general\" href=\"UTD.htm?18/36/19015?source=see_link\">",
" leflunomide",
" </a>",
" to",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" therapy had moderate efficacy. However, scrupulous monitoring of serum
aminotransferase levels and adjustment of leflunomide or methotrexate dose are
necessary, since the combination of these two agents frequently led to enzyme
elevations.",
" </p>",
" <p class=\"headingAnchor\" id=\"H13\">",
" <span class=\"h2\">",
" Doxycycline and MTX",
" </span>",
" &nbsp;&mdash;&nbsp;Clinical trials of",
" <a class=\"drug drug_general\" href=\"UTD.htm?2/41/2714?source=see_link\">",
" doxycycline",
" </a>",
" have not demonstrated efficacy of this agent for signs and symptoms of
arthritis when used alone in patients with RA. It is rarely used in the treatment
of RA because of the availability of more effective therapies. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?0/35/566?
source=see_link\">",
" \"Miscellaneous novel therapies in rheumatoid arthritis\"",
" </a>",
" .)",
" </p>",
" <p>",
" However,",
" <a class=\"drug drug_general\" href=\"UTD.htm?2/41/2714?source=see_link\">",
" doxycycline",
" </a>",
" may enhance the effectiveness of",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" when used early in the course of disease. This was illustrated in a trial that
enrolled 66 patients with early seropositive RA, each of whom received escalating
doses of methotrexate (initial dose 7.5",
" <span class=\"nowrap\">",
" mg/week,",
" </span>",
" mean final dose approximately 15",
" <span class=\"nowrap\">",
" mg/week)",
" </span>",
" [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/98/abstract/22\">",
" 22",
" </a>",
" ]. Patients were randomly assigned to one of three groups: placebo, low dose
doxycycline (20 mg twice daily), or high-dose doxycycline (100 mg twice daily).
After two years of treatment, the ACR50 response rates in the placebo, low-dose
doxycycline, and high-dose doxycycline groups were 12.5, 39, and 41.6 percent,
respectively, a statistically and clinically significant difference.",
" </p>",
" <p class=\"headingAnchor\" id=\"PATIENT_INFORMATION\">",
" <span class=\"h1\">",
" INFORMATION FOR PATIENTS",
" </span>",
" &nbsp;&mdash;&nbsp;UpToDate offers two types of patient education materials,
&ldquo;The Basics&rdquo; and &ldquo;Beyond the Basics.&rdquo; The Basics patient
education pieces are written in plain language, at the 5",
" ^{",
" th",
"}",
" to 6",
" ^{",
" th",
"}",
" grade reading level, and they answer the four or five key questions a patient
might have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10",
" ^{",
" th",
"}",
" to 12",
" ^{",
" th",
"}",
" grade reading level and are best for patients who want in-depth information
and are comfortable with some medical jargon.",
" </p>",
" <p>",
" Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on
&ldquo;patient info&rdquo; and the keyword(s) of interest.)",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Beyond the Basics topics (see",
" <a class=\"medical medical_patient\" href=\"UTD.htm?20/61/21463?
source=see_link\">",
" \"Patient information: Rheumatoid arthritis symptoms and diagnosis (Beyond
the Basics)\"",
" </a>",
" and",
" <a class=\"medical medical_patient\" href=\"UTD.htm?23/44/24264?
source=see_link\">",
" \"Patient information: Rheumatoid arthritis treatment (Beyond the
Basics)\"",
" </a>",
" and",
" <a class=\"medical medical_patient\" href=\"UTD.htm?26/40/27266?
source=see_link\">",
" \"Patient information: Disease-modifying antirheumatic drugs (DMARDs)
(Beyond the Basics)\"",
" </a>",
" and",
" <a class=\"medical medical_patient\" href=\"UTD.htm?38/29/39378?
source=see_link\">",
" \"Patient information: Complementary therapies for rheumatoid arthritis
(Beyond the Basics)\"",
" </a>",
" )",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H256643174\">",
" <span class=\"h1\">",
" SUMMARY AND RECOMMENDATIONS",
" </span>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" In patients with a partial response to",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?
source=see_link\">",
" methotrexate",
" </a>",
" (MTX) alone, the addition of intramuscular gold resulted in greater benefit
than placebo, although mucocutaneous side effects were common and required
adjustments in dosing. Gold therapy is rarely used because of its disadvantages
compared with other available therapies. (See",
" <a class=\"local\" href=\"#H3\">",
" 'Gold and MTX'",
" </a>",
" above.)",
" </li>",
" <li>",
" The drug combination of MTX,",
" <a class=\"drug drug_general\" href=\"UTD.htm?8/28/8647?source=see_link\">",
" sulfasalazine",
" </a>",
" (SSZ), and",
" <a class=\"drug drug_general\" href=\"UTD.htm?2/26/2471?source=see_link\">",
" hydroxychloroquine",
" </a>",
" (HCQ) results in greater clinical benefit than MTX alone, MTX plus HCQ, or
MTX plus SSZ in patients with an inadequate response to MTX or another disease
modifying antirheumatic drug (DMARD) alone. The efficacy of SSZ plus MTX is
uncertain compared with either drug alone. (See",
" <a class=\"local\" href=\"#H4\">",
" 'SSZ and MTX'",
" </a>",
" above and",
" <a class=\"local\" href=\"#H5\">",
" 'SSZ, HCQ, and MTX'",
" </a>",
" above and",
" <a class=\"local\" href=\"#H6\">",
" 'HCQ/MTX versus SSZ/MTX versus HCQ/SSZ/MTX'",
" </a>",
" above.)",
" </li>",
" <li>",
" Treatment with combinations of DMARDs plus glucocorticoids provides greater
benefit clinically and results in less radiographic progression compared with DMARD
monotherapy. (See",
" <a class=\"local\" href=\"#H7\">",
" 'SSZ, prednisolone, and MTX'",
" </a>",
" above and",
" <a class=\"local\" href=\"#H8\">",
" 'SSZ, HCQ, prednisolone, and MTX'",
" </a>",
" above.)",
" </li>",
" <li>",
" Combination therapy with MTX plus",
" <a class=\"drug drug_general\" href=\"UTD.htm?31/39/32368?
source=see_link\">",
" cyclosporine",
" </a>",
" , a calcineurin inhibitor (CNI), generally results in greater clinical and
radiographic benefit compared with either therapy alone. Limited data suggest that
the combination of MTX with another CNI,",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/14/32992?
source=see_link\">",
" tacrolimus",
" </a>",
" , may also be of benefit. CNIs are rarely used in RA because of their
greater risks compared with other available therapies. (See",
" <a class=\"local\" href=\"#H9\">",
" 'Cyclosporine and MTX'",
" </a>",
" above and",
" <a class=\"local\" href=\"#H10\">",
" 'Tacrolimus and MTX'",
" </a>",
" above.)",
" </li>",
" <li>",
" In patients who have not responded adequately to MTX alone, the addition
of",
" <a class=\"drug drug_general\" href=\"UTD.htm?18/36/19015?
source=see_link\">",
" leflunomide",
" </a>",
" resulted in greater benefit compared with placebo. Diarrhea was the only
adverse event that was more common in the combination therapy group, although
scrupulous monitoring of serum aminotransferase levels and adjustment of
leflunomide or",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?
source=see_link\">",
" methotrexate",
" </a>",
" dose are necessary in patients receiving both drugs, since the combination
frequently led to liver enzyme elevations. (See",
" <a class=\"local\" href=\"#H11\">",
" 'Leflunomide and MTX'",
" </a>",
" above.)",
" </li>",
" <li>",
" <a class=\"drug drug_general\" href=\"UTD.htm?2/41/2714?source=see_link\">",
" Doxycycline",
" </a>",
" may enhance the effectiveness of MTX when used early in the course of
seropositive disease, but it is rarely used because of the greater efficacy of
other available therapies. (See",
" <a class=\"local\" href=\"#H13\">",
" 'Doxycycline and MTX'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_in_page\"
target=\"_blank\">",
" Subscription and License Agreement",
" </a>",
" .",
" </div>",
" <div class=\"headingAnchor\" id=\"references\">",
" <h1>",
" REFERENCES",
" </h1>",
" <ol id=\"reference\">",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/1\">",
" Lehman AJ, Esdaile JM, Klinkhoff AV, et al. A 48-week, randomized, double-
blind, double-observer, placebo-controlled multicenter trial of combination
methotrexate and intramuscular gold therapy in rheumatoid arthritis: results of the
METGO study. Arthritis Rheum 2005; 52:1360.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/2\">",
" Haagsma CJ, van Riel PL, de Rooij DJ, et al. Combination of methotrexate and
sulphasalazine vs methotrexate alone: a randomized open clinical trial in
rheumatoid arthritis patients resistant to sulphasalazine therapy. Br J Rheumatol
1994; 33:1049.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/3\">",
" Dougados M, Combe B, Cantagrel A, et al. Combination therapy in early
rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial
of sulphasalazine and methotrexate compared with the single components. Ann Rheum
Dis 1999; 58:220.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/4\">",
" Maillefert JF, Combe B, Goupille P, et al. Long term structural effects of
combination therapy in patients with early rheumatoid arthritis: five year follow
up of a prospective double blind controlled study. Ann Rheum Dis 2003; 62:764.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/5\">",
" Jansen G, van der Heijden J, Oerlemans R, et al. Sulfasalazine is a potent
inhibitor of the reduced folate carrier: implications for combination therapies
with methotrexate in rheumatoid arthritis. Arthritis Rheum 2004; 50:2130.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/6\">",
" O'Dell JR, Haire CE, Erikson N, et al. Treatment of rheumatoid arthritis
with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of
all three medications. N Engl J Med 1996; 334:1287.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/7\">",
" O'Dell JR, Leff R, Paulsen G, et al. Treatment of rheumatoid arthritis with
methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a
combination of the three medications: results of a two-year, randomized, double-
blind, placebo-controlled trial. Arthritis Rheum 2002; 46:1164.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/8\">",
" Boers M, Verhoeven AC, Markusse HM, et al. Randomised comparison of combined
step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone
in early rheumatoid arthritis. Lancet 1997; 350:309.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/9\">",
" Garnero P, Landew&eacute; R, Boers M, et al. Association of baseline levels
of markers of bone and cartilage degradation with long-term progression of joint
damage in patients with early rheumatoid arthritis: the COBRA study. Arthritis
Rheum 2002; 46:2847.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/10\">",
" M&ouml;tt&ouml;nen T, Hannonen P, Leirisalo-Repo M, et al. Comparison of
combination therapy with single-drug therapy in early rheumatoid arthritis: a
randomised trial. FIN-RACo trial group. Lancet 1999; 353:1568.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/11\">",
" Neva MH, Kauppi MJ, Kautiainen H, et al. Combination drug therapy retards
the development of rheumatoid atlantoaxial subluxations. Arthritis Rheum 2000;
43:2397.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/12\">",
" Stein CM, Pincus T, Yocum D, et al. Combination treatment of severe
rheumatoid arthritis with cyclosporine and methotrexate for forty-eight weeks: an
open-label extension study. The Methotrexate-Cyclosporine Combination Study Group.
Arthritis Rheum 1997; 40:1843.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/13\">",
" Gerards AH, Landew&eacute; RB, Prins AP, et al. Cyclosporin A monotherapy
versus cyclosporin A and methotrexate combination therapy in patients with early
rheumatoid arthritis: a double blind randomised placebo controlled trial. Ann Rheum
Dis 2003; 62:291.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/14\">",
" Marchesoni A, Battafarano N, Arreghini M, et al. Radiographic progression in
early rheumatoid arthritis: a 12-month randomized controlled study comparing the
combination of cyclosporin and methotrexate with methotrexate alone. Rheumatology
(Oxford) 2003; 42:1545.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/15\">",
" Hetland ML, Stengaard-Pedersen K, Junker P, et al. Combination treatment
with methotrexate, cyclosporine, and intraarticular betamethasone compared with
methotrexate and intraarticular betamethasone in early active rheumatoid arthritis:
an investigator-initiated, multicenter, randomized, double-blind, parallel-group,
placebo-controlled study. Arthritis Rheum 2006; 54:1401.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/16\">",
" Tugwell P, Pincus T, Yocum D, et al. Combination therapy with cyclosporine
and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporine
Combination Study Group. N Engl J Med 1995; 333:137.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/17\">",
" Proudman SM, Conaghan PG, Richardson C, et al. Treatment of poor-prognosis
early rheumatoid arthritis. A randomized study of treatment with methotrexate,
cyclosporin A, and intraarticular corticosteroids compared with sulfasalazine
alone. Arthritis Rheum 2000; 43:1809.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/18\">",
" Kremer JM, Habros JS, Kolba KS, et al. Tacrolimus in rheumatoid arthritis
patients receiving concomitant methotrexate: a six-month, open-label study.
Arthritis Rheum 2003; 48:2763.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/19\">",
" Weinblatt ME, Kremer JM, Coblyn JS, et al. Pharmacokinetics, safety, and
efficacy of combination treatment with methotrexate and leflunomide in patients
with active rheumatoid arthritis. Arthritis Rheum 1999; 42:1322.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/20\">",
" Kremer JM, Genovese MC, Cannon GW, et al. Concomitant leflunomide therapy in
patients with active rheumatoid arthritis despite stable doses of methotrexate. A
randomized, double-blind, placebo-controlled trial. Ann Intern Med 2002; 137:726.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/21\">",
" Kremer J, Genovese M, Cannon GW, et al. Combination leflunomide and
methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing
MTX monotherapy: open-label extension of a randomized, double-blind, placebo
controlled trial. J Rheumatol 2004; 31:1521.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/98/abstract/22\">",
" O'Dell JR, Elliott JR, Mallek JA, et al. Treatment of early seropositive
rheumatoid arthritis: doxycycline plus methotrexate versus methotrexate alone.
Arthritis Rheum 2006; 54:621.",
" </a>",
" </li>",
" </ol>",
" </div>",
" <div id=\"topicVersionRevision\">",
" Topic 7484 Version 9.0",
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" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <div id=\"outline\">",
" <ul>",
" <li>",
" <a class=\"sr_button\" href=\"#H256643174\" id=\"summRecButton\">",
" <span>",
" SUMMARY &amp; RECOMMENDATIONS",
" </span>",
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" <a class=\"outlineLink\" href=\"#H1\">",
" INTRODUCTION",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H2\">",
" METHOTREXATE BASED COMBINATIONS",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H3\">",
" Gold and MTX",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H4\">",
" SSZ and MTX",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H5\">",
" SSZ, HCQ, and MTX",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H6\">",
" HCQ/MTX versus SSZ/MTX versus HCQ/SSZ/MTX",
" </a>",
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" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H7\">",
" SSZ, prednisolone, and MTX",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H8\">",
" SSZ, HCQ, prednisolone, and MTX",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H25246332\">",
" Calcineurin inhibitor plus MTX",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H9\">",
" - Cyclosporine and MTX",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H10\">",
" - Tacrolimus and MTX",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H11\">",
" Leflunomide and MTX",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H13\">",
" Doxycycline and MTX",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#PATIENT_INFORMATION\">",
" INFORMATION FOR PATIENTS",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H256643174\">",
" SUMMARY AND RECOMMENDATIONS",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a href=\"#references\">",
" REFERENCES",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
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" </a>",
" </li>",
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" <a class=\"medical medical_patient\" href=\"UTD.htm?38/29/39378?
source=related_link\">",
" Patient information: Complementary therapies for rheumatoid arthritis
(Beyond the Basics)",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_patient\" href=\"UTD.htm?26/40/27266?
source=related_link\">",
" Patient information: Disease-modifying antirheumatic drugs (DMARDs) (Beyond
the Basics)",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_patient\" href=\"UTD.htm?20/61/21463?
source=related_link\">",
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Basics)",
" </a>",
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" Patient information: Rheumatoid arthritis treatment (Beyond the Basics)",
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" <a class=\"medical medical_review\" href=\"UTD.htm?27/27/28090?
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" Pharmacology and side effects of cyclosporine and tacrolimus",
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" Randomized clinical trials in rheumatoid arthritis of biologic agents that
inhibit IL-1, IL-6, and RANKL",
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" <a class=\"medical medical_review\" href=\"UTD.htm?10/10/10410?
source=related_link\">",
" Randomized clinical trials of tumor necrosis factor inhibitors in rheumatoid
arthritis",
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" <a class=\"medical medical_review\" href=\"UTD.htm?20/40/21130?
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" T cell targeted therapies for rheumatoid arthritis",
" </a>",
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" </div>",
" </div>"].join("\n");
var title_f0_6_99="Heart-lung transplantation";
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" Heart-lung transplantation",
" </div>",
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" Authors",
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0/6/99/contributors\">",
" Roland G Nador, MD",
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" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/6/99/contributors\">",
" Dale Lien, MD",
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href=\"UTD.htm?0/6/99/contributors\">",
" Section Editor",
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" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/6/99/contributors\">",
" Sharon A Hunt, MD",
" </a>",
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href=\"UTD.htm?0/6/99/contributors\">",
" Deputy Editor",
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0/6/99/contributors\">",
" Susan B Yeon, MD, JD, FACC",
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" Oct 2013.",
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" Jul 18, 2012.",
" </div>",
" <div id=\"topicText\">",
" <p class=\"headingAnchor\" id=\"H1\">",
" <span class=\"h1\">",
" INTRODUCTION",
" </span>",
" &nbsp;&mdash;&nbsp;The first heart-lung transplantation was performed in 1981
in a patient with pulmonary arterial hypertension [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/1\">",
" 1",
" </a>",
" ]. The indications for the procedure were subsequently expanded to include
patients with severe parenchymal lung disease and congenital heart disease
complicated by Eisenmenger syndrome. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?7/20/7496?
source=see_link&amp;anchor=H20#H20\">",
" \"Medical management of Eisenmenger syndrome\", section on
'Transplantation'",
" </a>",
" .)",
" </p>",
" <p>",
" Some early recipients of heart-lung transplants had normally functioning
hearts and underwent a \"domino procedure\" in which the normal recipient heart was
explanted along with the diseased lungs and then implanted into a separate patient
awaiting a heart transplant.",
" </p>",
" <p>",
" The domino procedure is now rarely performed because combined heart and lung
transplantation is limited to patients in whom it offers the only surgical option
for their end-stage cardiac and pulmonary disease. The procedure of choice for
pulmonary parenchymal and vascular diseases in the absence of left heart
dysfunction is single or double lung transplantation. (See",
" <a class=\"local\" href=\"#H4\">",
" 'Indications'",
" </a>",
" below and",
" <a class=\"medical medical_review\" href=\"UTD.htm?26/20/26953?
source=see_link\">",
" \"Lung transplantation: General guidelines for recipient selection\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H2\">",
" <span class=\"h2\">",
" Declining use",
" </span>",
" &nbsp;&mdash;&nbsp;The preference for single and double lung transplantation
has markedly reduced the need for the combined heart-lung procedure. The magnitude
of this effect was shown in the 28th report of the Registry of the International
Heart and Lung Transplantation (ISHLT) published in 2011, which noted a 40 percent
decrease in the number of centers performing heart-lung transplants since 1994 [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/2\">",
" 2",
" </a>",
" ]. The total number of procedures has stabilized since 2003, ranging from 84
to 114 per year, compared to an increasing number of single and double lung
transplants (2008 in 2003 to 3272 in 2009).",
" </p>",
" <p>",
" In addition to the availability of single and double lung transplantation, the
decline in the number of patients requiring combined heart-lung transplantation is
also due to new medical therapies for patients with pulmonary arterial hypertension
and congenital heart disease with Eisenmenger syndrome. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?34/24/35210?
source=see_link\">",
" \"Treatment of pulmonary hypertension in adults\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?7/20/7496?
source=see_link\">",
" \"Medical management of Eisenmenger syndrome\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H3\">",
" <span class=\"h2\">",
" Disadvantages",
" </span>",
" &nbsp;&mdash;&nbsp;A major disadvantage to heart-lung transplantation is the
need to procure a heart&ndash;lung bloc for patients who are competing for hearts
with patients on the heart transplant waiting list. This can lead to increased
waiting time and increased mortality among patients awaiting combined heart-lung
transplantation. Other disadvantages (which are not encountered with lung
transplantation) include the requirement for cardiopulmonary bypass during surgery,
the implantation of a denervated heart, and the potential later development of
cardiac graft coronary artery vasculopathy. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?33/31/34297?
source=see_link\">",
" \"Indications and contraindications for cardiac transplantation\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H4\">",
" <span class=\"h1\">",
" INDICATIONS",
" </span>",
" &nbsp;&mdash;&nbsp;The 2011 ISHLT Registry summarized the distribution of
diagnoses leading to heart-lung transplantation from January 1982 to June 2010
(slides available at",
" <a class=\"external\" href=\"file://www.ishlt.org/registries/slides.asp?
slides=heartlungregistry\">",
" file://www.ishlt.org/registries/slides.asp?slides=heartLungRegistry",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/2\">",
" 2",
" </a>",
" ]. The three leading indications were:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" Congenital heart disease with Eisenmenger syndrome &mdash; 35.9 percent",
" </li>",
" <li>",
" Idiopathic pulmonary arterial hypertension &mdash; 27.5 percent",
" </li>",
" <li>",
" Cystic fibrosis &mdash; 14.3 percent",
" </li>",
" </ul>",
" </p>",
" <p>",
" During the period from January 2000 to June 2010, overall there were fewer
procedures performed for cystic fibrosis and more procedures performed for acquired
heart disease and congenital heart disease compared to earlier eras. Congenital
heart disease with Eisenmenger syndrome was the most common indication.",
" </p>",
" <p>",
" During the period from January 2000 and to June 2010, in Europe and other non-
North American regions, cystic fibrosis was a more frequent diagnosis among heart-
lung recipients than in North America, but congenital heart disease was the
dominant diagnosis for all regions.",
" </p>",
" <p>",
" Heart-lung transplantation may also be required in patients with end-stage
parenchymal lung disease who also have severely compromised left ventricular
function (eg, sarcoidosis). The joint guidelines from the American Thoracic",
" <span class=\"nowrap\">",
" Society/American",
" </span>",
" Society for Transplant",
" <span class=\"nowrap\">",
" Physicians/European",
" </span>",
" Respiratory Society and the ISHLT guidelines suggest an age limit for heart-
lung transplantation of 55 years. Among patients with severe lung disease, referral
for heart-lung transplantation should be made if the patient has NYHA class III or
IV heart failure despite optimal surgical and medical treatment (",
" <a class=\"graphic graphic_table graphicRef52683 \" href=\"UTD.htm?
3/2/3117\">",
" table 1",
" </a>",
" ).",
" </p>",
" <p>",
" End-stage lung disease with malignant ventricular arrhythmias not amenable to
pharmacologic or electrophysiologic interventions (including implantable
cardioverter-defibrillator) is a rare indication for the combined procedure.",
" </p>",
" <p>",
" Patients with idiopathic pulmonary arterial hypertension with preserved left
ventricular function are best treated with double-lung transplantation [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/3\">",
" 3",
" </a>",
" ].",
" </p>",
" <p>",
" A preliminary UNOS database analysis comparing the outcome of heart-lung
transplantation with double-lung transplantation for pulmonary hypertension
demonstrated similar survival between the two groups. Heart-lung recipients were
younger, were more likely admitted to the ICU prior to transplant and had shorter
ischemia time [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/4\">",
" 4",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H5\">",
" <span class=\"h2\">",
" Congenital heart disease",
" </span>",
" &nbsp;&mdash;&nbsp;Combined heart-lung transplantation is the preferred
procedure for patients with complex congenital heart disease with Eisenmenger
syndrome, including those with single ventricle anatomy, unsuccessfully repaired or
uncorrectable lesions,",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" severely depressed left ventricular function. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?7/20/7496?
source=see_link&amp;anchor=H20#H20\">",
" \"Medical management of Eisenmenger syndrome\", section on
'Transplantation'",
" </a>",
" .)",
" </p>",
" <p>",
" On the other hand, bilateral lung transplantation with repair of the
congenital defect is the recommended procedure in patients with simple congenital
heart disease. These lesions include [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/5\">",
" 5",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Atrial or ventricular septal defect",
" </li>",
" <li>",
" Scimitar syndrome, which refers to the triad of partial anomalous pulmonary
venous return, hypoplasia or aplasia of a lobe of the right lung (most often), and
the presence of thoracic aorta to pulmonary artery collaterals to the small lung",
" </li>",
" <li>",
" Pulmonary venous stenosis",
" </li>",
" <li>",
" A functionally inadequate vascular bed as with multiple peripheral pulmonary
arterial stenoses or pulmonary arteriovenous malformations.",
" </li>",
" </ul>",
" </p>",
" <p>",
" Orthotopic heart transplantation alone has been performed in patients with
congenital heart disease and a physiologic single lung (eg, unilateral pulmonary
venous stenosis, or due to previous aortopulmonary shunt procedure) [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/6\">",
" 6",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H6\">",
" <span class=\"h2\">",
" Organ allocation",
" </span>",
" &nbsp;&mdash;&nbsp;Heart-lung transplant recipients receive an \"en bloc\"
harvested heart and lung allograft and can be listed under both the lung and heart
allocation systems. The lung allocation system in the United States was changed by
UNOS (",
" <a class=\"external\" href=\"file://www.unos.org/\">",
" www.unos.org",
" </a>",
" ) in 2005 from a system that prioritized patients by the amount of time
accumulated on the waiting list to a system that incorporates the severity of
disease and the likelihood of survival following transplantation into a \"lung
allocation score.\" This score, which includes many variables, dictates a patient's
priority for organ allocation; time on the waiting list is no longer the driving
factor. The lung allocation scoring system has no equivalent to the status 1A
listing by which cardiac recipients obtain the highest priority for allocation of
donor hearts. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?3/25/3480?
source=see_link&amp;anchor=H2#H2\">",
" \"Lung transplantation: An overview\", section on 'Activity'",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?33/31/34297?
source=see_link&amp;anchor=H2#H2\">",
" \"Indications and contraindications for cardiac transplantation\", section on
'Waiting list and allocation'",
" </a>",
" .)",
" </p>",
" <p>",
" The lung allocation scoring system does not adequately reflect the severity of
disease in patients with pulmonary arterial hypertension who are better served by
the cardiac listing criteria. Thus, patients listed for combined heart-lung
transplantation may in some areas be listed as a status 1A heart and obtain a heart
and lung bloc via this mechanism. However, the criteria for 1A heart listing are
not always applicable to patients with pulmonary hypertension or complex cyanotic
congenital heart disease; as a result, an application for 1A status with exemption
may be necessary.",
" </p>",
" <p>",
" In order to alleviate this problem, upon appeal, a modification of the lung
allocation score can be made available for patients with pulmonary hypertension.
Transplant candidates can receive an increase in their lung allocation score to the
90th percentile of all the allocation scores nationally at the time of request if
they meet all of the following criteria:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" Deterioration on optimal therapy",
" </li>",
" <li>",
" Right atrial pressure &gt;15 mmHg",
" </li>",
" <li>",
" Cardiac index &lt;1.8",
" <span class=\"nowrap\">",
" L/min/m2",
" </span>",
" </li>",
" </ul>",
" </p>",
" <p>",
" Additional impact on the lung allocation score can be obtained from total
bilirubin (&ge;1.0",
" <span class=\"nowrap\">",
" mg/dL)",
" </span>",
" and a &ge;50 percent increase of total bilirubin within six months (the latter
exclusively for Group B patients which includes candidates with pulmonary vascular
disease).",
" </p>",
" <p class=\"headingAnchor\" id=\"H7\">",
" <span class=\"h1\">",
" CONTRAINDICATIONS",
" </span>",
" &nbsp;&mdash;&nbsp;Relative contraindications to combined heart-lung
transplantation are similar to those for isolated heart or lung transplantation.
These issues are discussed elsewhere. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?33/31/34297?
source=see_link&amp;anchor=H17#H17\">",
" \"Indications and contraindications for cardiac transplantation\", section on
'Criteria for patient exclusion'",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?26/20/26953?
source=see_link&amp;anchor=H4#H4\">",
" \"Lung transplantation: General guidelines for recipient selection\", section
on 'Contraindications'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H8\">",
" <span class=\"h1\">",
" POSTOPERATIVE MANAGEMENT",
" </span>",
" &nbsp;&mdash;&nbsp;The management of heart-lung transplant recipients is
similar to that of double and single lung transplant patients. The majority of the
postoperative complications, including acute and chronic rejection and infection,
are related to the lung allograft not the cardiac allograft. The level of
immunosuppression is similar to that employed in lung transplant recipients, which
is more profound than in heart transplant recipients. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?3/38/3688?
source=see_link\">",
" \"Induction immunosuppression following lung transplantation\"",
" </a>",
" .)",
" </p>",
" <p>",
" Bleeding in the immediate postoperative period in patients with complex
congenital heart disease may arise from chest wall and aortopulmonary collaterals
as well as adhesions from previous thoracic surgeries. Another contributing factor
may be impaired hepatic function, which is a frequent finding in heart-lung
transplant recipients due to longstanding hepatic congestion secondary to poor
right ventricular function",
" </p>",
" <p>",
" Maintenance immunosuppressive therapy in heart-lung transplant recipients
follows the recommendations for single and double lung transplantation. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?3/38/3688?
source=see_link\">",
" \"Induction immunosuppression following lung transplantation\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H9\">",
" <span class=\"h2\">",
" Surveillance studies",
" </span>",
" &nbsp;&mdash;&nbsp;Heart-lung transplantation recipients are followed closely
with frequent pulmonary function tests, chest radiographs, laboratory testing, and
clinic visits. Surveillance bronchoscopy with transbronchial biopsies is performed
to permit the early diagnosis of acute rejection and infection [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/7-9\">",
" 7-9",
" </a>",
" ]. There is no consensus regarding biopsy frequency. Surveillance biopsies are
most often performed in the first three months after transplantation when the rates
of acute rejection and infection are high, and whenever clinically indicated
thereafter [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/10,11\">",
" 10,11",
" </a>",
" ]. Biopsy proven acute cellular rejection in the lung transplant can occur in
stable asymptomatic patients who have survived two years but the frequency after
four years appears to be very low [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/10\">",
" 10",
" </a>",
" ].",
" </p>",
" <p>",
" Acute cellular rejection of the heart allograft might occur simultaneously or
independently from that of the lung allograft. Isolated acute cellular rejection of
the heart, however, is infrequent and much less common than after isolated heart
transplantation [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/12-14\">",
" 12-14",
" </a>",
" ]. Most episodes occur early [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/12,13,15\">",
" 12,13,15",
" </a>",
" ] and asymptomatic episodes detected by surveillance biopsy are rare later
than four to six months after transplantation [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/16\">",
" 16",
" </a>",
" ]. (See",
" <a class=\"local\" href=\"#H11\">",
" 'Acute cellular rejection'",
" </a>",
" below.)",
" </p>",
" <p>",
" Based upon these observations, surveillance endomyocardial biopsies to detect
asymptomatic heart rejection, which are routinely performed after heart
transplantation, are not recommended in most centers after heart-lung
transplantation, particularly after four to six months [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/16\">",
" 16",
" </a>",
" ]. However, endomyocardial biopsy is indicated at any time in patients who
exhibit symptoms consistent with heart failure",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" have left ventricular or biventricular dysfunction on echocardiography. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?27/24/28040?
source=see_link\">",
" \"Acute cardiac allograft rejection: Diagnosis\"",
" </a>",
" .)",
" </p>",
" <p>",
" Annual comprehensive evaluation of heart-lung transplant recipients is
recommended with pulmonary function testing, chest radiograph, bronchoscopy,
echocardiography, bone density scan, and coronary angiography or",
" <a class=\"drug drug_general\" href=\"UTD.htm?24/57/25494?source=see_link\">",
" dobutamine",
" </a>",
" stress echocardiography to rule out cardiac allograft vasculopathy. Other than
yearly coronary angiography or dobutamine stress echocardiography, general health
maintenance and surveillance requirements are similar to that of patients with lung
transplantation. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?18/9/18585?
source=see_link\">",
" \"Natural history and diagnosis of cardiac allograft vasculopathy\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H10\">",
" <span class=\"h1\">",
" COMPLICATIONS",
" </span>",
" </p>",
" <p class=\"headingAnchor\" id=\"H11\">",
" <span class=\"h2\">",
" Acute cellular rejection",
" </span>",
" &nbsp;&mdash;&nbsp;There appears to be less acute cellular rejection in both
organs following combined heart-lung transplantation compared to the rate of
rejection in lungs or hearts that are transplanted alone [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/2,12,17\">",
" 2,12,17",
" </a>",
" ]. Furthermore, the rate of acute cellular rejection is higher in the lung
than the heart following heart-lung transplantation [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/7,12,13,15\">",
" 7,12,13,15",
" </a>",
" ]. Asymptomatic acute cellular heart transplant rejection detected by
surveillance biopsy appears to be a rare event more than four months after
transplantation [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/16\">",
" 16",
" </a>",
" ].",
" </p>",
" <p>",
" These relationships were illustrated in a review of 348 heart transplant
recipients, 82 double-lung transplant recipients, and 24 heart-lung transplant
recipients who were transplanted between 1990 and 2002 [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/12\">",
" 12",
" </a>",
" ]. The following findings were noted:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" With respect to the heart, the probability of acute cellular rejection
(defined by endomyocardial biopsy [grade &ge;3A] or a clinical episode requiring
increased immunosuppression) was significantly lower in heart-lung compared to
heart transplant recipients in the first three months (22 versus 81 percent) and,
at two years, there were significantly fewer acute rejection episodes in heart-lung
transplant recipients (0.3 versus 2.8 episodes).",
" </li>",
" <li>",
" With respect to the lung, there were significantly fewer acute cellular
rejection episodes in heart-lung transplant compared to lung transplant recipients
at two years (1.0 versus 2.4 episodes). Although this observation suggests that
combined heart-lung transplantation may have a protective immunologic effect in
terms of the development of acute rejection [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/12,18\">",
" 12,18",
" </a>",
" ], this conclusion has been disputed in other studies [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/19,20\">",
" 19,20",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p>",
" Possible reasons for the higher rate of acute cellular lung compared to heart
transplant rejection include the presence of donor bronchus-associated lymphoid
tissue (BALT), increased immunogenicity of the lungs, and frequent infectious
insults with suppressed defense mechanisms.",
" </p>",
" <p>",
" Acute cellular lung allograft rejection can be symptomatic or asymptomatic and
diagnosed only on surveillance transbronchial biopsy [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/7-9,20,21\">",
" 7-9,20,21",
" </a>",
" ]. Not surprisingly, rejection is more likely to be present when biopsy is
performed for clinical indications (38 versus 4 percent on surveillance biopsy in
one series, with biopsy detecting infection in another 45 percent of symptomatic
patients) [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/7\">",
" 7",
" </a>",
" ].",
" </p>",
" <p>",
" The clinical presentation of symptomatic acute lung rejection is nonspecific
and indistinguishable from infection. Cough, dyspnea, low-grade fever, and general
malaise are frequent presenting symptoms. Diagnostic tests that may suggest the
presence of acute rejection but are nonspecific include a low arterial PO2,
desaturation on exercise oximetry, or diffuse infiltrates with or without pleural
effusions on chest radiograph. A decrease in dynamic lung volumes on pulmonary
function tests (&gt;10 percent for FEV1 or &gt;25 percent of FEF25-75) should raise
the possibility of acute rejection or infection (",
" <a class=\"graphic graphic_table graphicRef54968 \" href=\"UTD.htm?
5/0/5131\">",
" table 2",
" </a>",
" ). (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?3/57/3994?
source=see_link\">",
" \"Evaluation and treatment of acute lung transplant rejection\"",
" </a>",
" .)",
" </p>",
" <p>",
" The treatment of acute cellular lung rejection depends upon the histologic
grade and the principles are similar to those with rejection in isolated lung
transplantation (",
" <a class=\"graphic graphic_table graphicRef61800 \" href=\"UTD.htm?
13/10/13484\">",
" table 3",
" </a>",
" ). (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?3/57/3994?
source=see_link\">",
" \"Evaluation and treatment of acute lung transplant rejection\"",
" </a>",
" .)",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Minimal (A1) acute rejection is usually observed and followed up with
transbronchial biopsy in four weeks.",
" </li>",
" <li>",
" Mild and moderate rejection episodes (A2 and A3) are initially treated with
high dose",
" <a class=\"drug drug_general\" href=\"UTD.htm?30/25/31129?
source=see_link\">",
" methylprednisolone",
" </a>",
" (10",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" per day) for three days followed by oral",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?
source=see_link\">",
" prednisone",
" </a>",
" (0.6",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" per day in divided doses) that is tapered over four weeks. Transbronchial
biopsy is usually repeated at the end of the steroid taper [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/22\">",
" 22",
" </a>",
" ] and if persistent rejection is seen either the steroid regimen is repeated
or the patient is treated with a T cell depleting agent such as",
" <a class=\"drug drug_general\" href=\"UTD.htm?2/36/2629?source=see_link\">",
" rabbit antithymocyte globulin",
" </a>",
" (RATG, Thymoglobulin&reg;) or OKT3 (Muromonab-CD3).",
" </li>",
" <li>",
" Severe acute rejection (A4) may be managed with the corticosteroid regimen
used for mild to moderate rejection plus either RATG or OKT3.",
" </li>",
" </ul>",
" </p>",
" <p>",
" Total lymphoid irradiation and",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" are options for refractory acute rejection.",
" </p>",
" <p>",
" Patients at risk for cytomegalovirus (CMV) infection are usually
prophylactically treated with anti-CMV therapy while undergoing treatment for
rejection. Antifungal prophylaxis is usually warranted in patients who receive
repeated high dose steroid regimens. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?10/29/10714?
source=see_link\">",
" \"Prophylaxis of infections in solid organ transplantation\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H12\">",
" <span class=\"h2\">",
" Acute antibody mediated rejection",
" </span>",
" &nbsp;&mdash;&nbsp;In addition to T cell mediated cellular rejection,
alloantibody reactivity to donor antigens can result in tissue injury and rejection
mostly via complement fixation. Acute antibody mediated rejection (AMR) is now a
recognized entity in renal and cardiac transplantation. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?27/24/28040?
source=see_link&amp;anchor=H15#H15\">",
" \"Acute cardiac allograft rejection: Diagnosis\", section on 'Acute antibody-
mediated (humoral) rejection'",
" </a>",
" .)",
" </p>",
" <p>",
" Among heart-lung transplants, AMR can occur early or late in the post-
transplant period and it may accompany acute cellular rejection or present
independently. AMR can affect both transplanted organs, resulting in graft
dysfunction.",
" </p>",
" <p>",
" The diagnosis of AMR is usually based upon allograft dysfunction, the presence
of circulating donor specific antibodies (HLA- and non-HLA antibodies), and, in
cardiac transplants, histopathologic evidence of graft injury by capillary
endothelial changes, recruitment of macrophages, neutrophils and complement
activation demonstrated by positive C4d, C3d or C1q immunofluorescence or
immunohistochemistry [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/23\">",
" 23",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?27/24/28040?
source=see_link&amp;anchor=H15#H15\">",
" \"Acute cardiac allograft rejection: Diagnosis\", section on 'Acute antibody-
mediated (humoral) rejection'",
" </a>",
" .)",
" </p>",
" <p>",
" Similar serologic and histologic changes of AMR can also occur in lung
allografts [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/24-26\">",
" 24-26",
" </a>",
" ]. Studies examining the specificity of C4d staining in lung biopsies and its
association with circulating donor specific alloantibodies have led to conflicting
results [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/26-29\">",
" 26-29",
" </a>",
" ]. Thus, the diagnostic criteria for AMR are less established in lung
transplantation.",
" </p>",
" <p>",
" Optimal therapy of AMR is not well defined. Treatment may include high dose
glucocorticoid therapy, plasmapheresis, high dose intravenous immune globulin,",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/12/41161?source=see_link\">",
" rituximab",
" </a>",
" , and most recently",
" <a class=\"drug drug_general\" href=\"UTD.htm?10/63/11257?source=see_link\">",
" bortezomib",
" </a>",
" . (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?14/6/14441?
source=see_link&amp;anchor=H15#H15\">",
" \"Acute cardiac allograft rejection: Treatment\", section on 'Acute antibody-
mediated (humoral) rejection'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H13\">",
" <span class=\"h2\">",
" Infection",
" </span>",
" &nbsp;&mdash;&nbsp;Most infectious complications following heart-lung
transplantation occur at rates similar to those seen in lung transplantation alone
and primarily affect the lungs. Approaches to treatment of infectious complications
and prophylactic measures to prevent them in heart-lung transplant recipients are
the same as those employed following lung transplantation. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?5/59/6073?
source=see_link\">",
" \"Prevention of cytomegalovirus infection in lung transplant recipients\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?12/30/12778?
source=see_link\">",
" \"Bacterial infections following lung transplantation\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?15/34/15914?
source=see_link\">",
" \"Fungal infections following lung transplantation\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?12/26/12712?
source=see_link\">",
" \"Tuberculosis in solid organ transplant candidates and recipients\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?30/30/31207?
source=see_link\">",
" \"Nontuberculous mycobacterial infections in solid organ transplant
candidates and recipients\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H14\">",
" <span class=\"h2\">",
" Chronic rejection",
" </span>",
" &nbsp;&mdash;&nbsp;Chronic rejection can affect both the heart and lungs.
Chronic rejection of heart is manifested as coronary allograft vasculopathy and is
usually diagnosed by surveillance angiographic monitoring before the patient is
symptomatic. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?18/9/18585?
source=see_link\">",
" \"Natural history and diagnosis of cardiac allograft vasculopathy\"",
" </a>",
" .)",
" </p>",
" <p>",
" Chronic rejection of the lungs is manifested histologically as bronchiolitis
obliterans (BO) which is diagnosed and graded via spirometry and known as
bronchiolitis obliterans syndrome (BOS) (",
" <a class=\"graphic graphic_table graphicRef70127 \" href=\"UTD.htm?
24/21/24923\">",
" table 4",
" </a>",
" )&nbsp;[",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/30\">",
" 30",
" </a>",
" ]. Characteristic clinical features include progressive dyspnea, cough,
negative sputum cultures, a normal chest radiograph, and worsening airflow
obstruction without other obvious cause (",
" <a class=\"graphic graphic_table graphicRef58663 \" href=\"UTD.htm?
19/14/19691\">",
" table 5",
" </a>",
" ). (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?18/25/18841?
source=see_link\">",
" \"Chronic lung transplant rejection: Bronchiolitis obliterans\"",
" </a>",
" .)",
" </p>",
" <p>",
" As with acute rejection, chronic rejection of the heart is less common after
heart-lung transplantation compared to heart transplantation alone. In contrast,
chronic rejection of the lungs occurs as often in heart-lung recipients as it does
in single or double lung recipients [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/2,12,20\">",
" 2,12,20",
" </a>",
" ].",
" </p>",
" <p>",
" These relationships were illustrated in the 2011 ISHLT registry report in
which the following findings were noted in adult heart-lung transplant recipients
with follow-up between April 1994 and June 2010 [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/2\">",
" 2",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" The rate of BOS at five years was higher than that of cardiac allograft
vasculopathy (41 versus 11 percent) [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/2\">",
" 2",
" </a>",
" ]. For additional information see",
" <a class=\"external\" href=\"file://www.ishlt.org/registries/slides.asp?
slides=heartLungRegistry\">",
" file://www.ishlt.org/registries/slides.asp?slides=heartLungRegistry",
" </a>",
" .",
" </li>",
" <li>",
" The rate of cardiac allograft vasculopathy at five years was lower with
heart-lung compared to heart transplant recipients (11 versus 30 percent) [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/2,17\">",
" 2,17",
" </a>",
" ].",
" </li>",
" <li>",
" The rate of BOS at five years in heart-lung transplant recipients was
similar to that of in lung transplant recipients (41 versus 49 percent).",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H15\">",
" <span class=\"h2\">",
" Other",
" </span>",
" &nbsp;&mdash;&nbsp;Heart-lung transplantation shares most of the complications
of single or double lung transplantation. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?11/60/12233?
source=see_link\">",
" \"Noninfectious complications following lung transplantation\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?28/47/29433?
source=see_link\">",
" \"Infection in the solid organ transplant recipient\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?33/23/34170?
source=see_link\">",
" \"Development of malignancy following solid organ transplantation\"",
" </a>",
" .)",
" </p>",
" <p>",
" In addition, there are a few complications that appear to be more common
following heart-lung transplantation, including phrenic nerve dysfunction,",
" <span class=\"nowrap\">",
" gastroparesis/gastroesophageal",
" </span>",
" reflux disease (GERD), and chylothorax. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?11/60/12233?
source=see_link\">",
" \"Noninfectious complications following lung transplantation\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H16\">",
" <span class=\"h3\">",
" Phrenic nerve dysfunction",
" </span>",
" &nbsp;&mdash;&nbsp;Phrenic nerve dysfunction (PND) is thought to result from
hypothermia from cold ice slush, pericardial retraction, and electrocautery for
dissection during the heart-lung operation. There is a higher prevalence of PND
among heart-lung transplant recipients compared to those undergoing lung
transplantation alone [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/31,32\">",
" 31,32",
" </a>",
" ]. In one series, for example, the respective rates were 43 and 9 percent.",
" </p>",
" <p>",
" PND may be associated with more days of mechanical ventilation, prolonged ICU
stays, and an increased likelihood of tracheostomy [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/32\">",
" 32",
" </a>",
" ]. Only a minority of patients recover diaphragmatic function following injury
to the phrenic nerve.",
" </p>",
" <p class=\"headingAnchor\" id=\"H17\">",
" <span class=\"h3\">",
" Gastroparesis",
" </span>",
" &nbsp;&mdash;&nbsp;Surgical manipulation of the posterior mediastinum can
injure the vagus nerve and lead to gastroparesis [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/33,34\">",
" 33,34",
" </a>",
" ]. Heart-lung transplant recipients are at higher risk for this complication
due to the surgical techniques employed for the tracheal anastomosis. Consequences
of gastroparesis include an increased risk of aspiration, gastroesophageal reflux
disease (GERD), malnutrition, and poor absorption of medications. Recurrent
aspiration can result in lung injury leading to graft dysfunction, especially in
the early post-transplant period, and GERD has been implicated in the development
of chronic lung rejection [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/33,34\">",
" 33,34",
" </a>",
" ].",
" </p>",
" <p>",
" The diagnosis and treatment of gastroparesis are discussed separately. Options
in heart-lung transplant recipients who do not respond to conventional therapy,
include gastric pacing and, in an initial report, transcutaneous electrical nerve
stimulation (TENS) [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/35,36\">",
" 35,36",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H18\">",
" <span class=\"h3\">",
" Chylothorax",
" </span>",
" &nbsp;&mdash;&nbsp;Chylothorax is caused by the accumulation of chyle in the
pleural space after surgical trauma to the thoracic duct or its collaterals.
Patients with congenital heart disease frequently have abnormally developed
lymphatics that can be susceptible to inadvertent interruption during heart-lung
transplantation [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/37\">",
" 37",
" </a>",
" ]. Depending upon the level of injury chylous effusions can be right-sided,
left-sided, or bilateral.",
" </p>",
" <p>",
" The diagnosis and management of chylothorax are discussed separately. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?36/20/37192?
source=see_link\">",
" \"Etiology, clinical presentation, and diagnosis of chylothorax\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H19\">",
" <span class=\"h1\">",
" OUTCOMES",
" </span>",
" &nbsp;&mdash;&nbsp;Given the relatively low rate of acute and chronic cardiac
transplant rejection cited above [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/2,12\">",
" 2,12",
" </a>",
" ], short-term and long-term morbidity and mortality relate primarily to lung
allograft pathology as they do in lung transplant recipients. (See",
" <a class=\"local\" href=\"#H11\">",
" 'Acute cellular rejection'",
" </a>",
" above and",
" <a class=\"local\" href=\"#H14\">",
" 'Chronic rejection'",
" </a>",
" above.)",
" </p>",
" <p class=\"headingAnchor\" id=\"H20\">",
" <span class=\"h2\">",
" Survival",
" </span>",
" &nbsp;&mdash;&nbsp;The following findings with respect to patient survival
were noted in the 2011 ISHLT registry report of 3303 adult patients who underwent
heart-lung transplantation between January 1982 and June 2009 [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/2\">",
" 2",
" </a>",
" ] (for additional information see",
" <a class=\"external\" href=\"file://www.ishlt.org/registries/slides.asp?
slides=heartLungRegistry\">",
" file://www.ishlt.org/registries/slides.asp?slides=heartLungRegistry",
" </a>",
" ):",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" There is a high rate of early mortality, with survival rates of 73 percent
at three months and 68 percent at one year between 1982 and 2009. Overall survival
was 49.7 percent at five years and 37.7 percent at 10 years. These survival rates
remain lower than those seen with lung transplantation alone even in the latest
period from 2000 to 2009 (75 versus 88 percent at three months and, 70 versus 81
percent at one year, respectively).",
" </li>",
" <li>",
" The overall half-life improved slightly from 4.8 years to 5.5 years in the
modern era.",
" </li>",
" <li>",
" Among patients who survived one year, there was a low but steady mortality
rate with a survival conditional half-life (contingent on survival to one year) of
12 years. Conditional half-life, however, actually decreased in the most recent era
(2000 to 2009) to 10 years. This perhaps reflects the differences in age and
diagnoses of heart&ndash;lung transplant recipients in the modern era. The greater
conditional half life in heart-lung transplant recipients compared to lung
transplant alone (7.8 years for all lung transplants and 9.3 years for double lung
transplants) is likely due to the younger age of the recipients.",
" </li>",
" <li>",
" The mortality rate in the early post-transplant period was similar with
Eisenmenger syndrome and idiopathic pulmonary arterial hypertension, but higher
with other congenital abnormalities. The overall survival and survival rates beyond
one year were the highest for Eisenmenger syndrome.",
" </li>",
" </ul>",
" </p>",
" <p>",
" The main causes of death varied with the time after transplantation:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" In the first 30 days, the time of highest risk, graft failure (28.7
percent), technical complications (22.1 percent), and non-CMV infections (16.2
percent) were the leading causes of deaths.",
" </li>",
" <li>",
" From 31 days to one year, non-CMV infections and graft failure together
accounted for 53.8 percent of deaths. Although acute rejection and CMV infection
are common, they were together responsible for only 3.6 percent of deaths.",
" </li>",
" <li>",
" After the first year, BOS accounted for 16.9 to 22.4 percent of deaths and
graft failure for 13.8 to 17.9 percent of deaths; non-CMV infection caused 24.6 to
30 percent of deaths.",
" </li>",
" <li>",
" In all time periods, cardiovascular disease accounted for 4.4 to 11.5
percent of deaths.",
" </li>",
" </ul>",
" </p>",
" <p>",
" Large case series have shown better overall actuarial survival for heart-lung
transplantation than the ISHLT registry [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/19,20,38,39\">",
" 19,20,38,39",
" </a>",
" ]. In two reports, for example, one-year survival was 87 and 78 percent
compared to 64 percent in the registry [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/20,38\">",
" 20,38",
" </a>",
" ]. In addition, survival following heart-lung transplantation in all the case
series was comparable to that following double or single lung transplantation in
contrast to the better outcomes cited above with lung transplantation in the ISHLT
registry.",
" </p>",
" <p>",
" A possible explanation is that the ISHLT registry includes data from the early
era of transplantation (beginning in 1982) when there were higher rates of
immediate surgical complications and an accompanying increase in early mortality.
This is reflected in improved early survival rates of adult heart-lung transplants
between 2000 and 2009 in the 2011 ISHLT registry report [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/2\">",
" 2",
" </a>",
" ]. Although the five-year survival rate was similar at 51 percent in this era
compared to 50 percent between 1996 and 1999, the overall half-life improved
slightly from 4.8 years in the era of 1982 to 1995 to 5.5 years between 2000 and
2009.",
" </p>",
" <p>",
" Thus, all of the survival benefit occurred in the first year and was then
maintained over time. This suggests that improvements occurred in surgical
technique and in the prevention and treatment of early complications, but not in
the management of late problems such as chronic rejection.",
" </p>",
" <p class=\"headingAnchor\" id=\"H21\">",
" <span class=\"h2\">",
" Morbidity",
" </span>",
" &nbsp;&mdash;&nbsp;The 2010 ISHLT registry also provided information about
morbidity in addition to chronic lung or heart rejection [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/2\">",
" 2",
" </a>",
" ]. The following one and five year rates among survivors were noted:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" Hypertension &mdash; 58.5 and 87.6 percent",
" </li>",
" <li>",
" Hyperlipidemia &mdash; 26.4 and 68.8 percent",
" </li>",
" <li>",
" Diabetes &mdash; 19.1 and 26.1 percent",
" </li>",
" </ul>",
" </p>",
" <p>",
" Renal dysfunction was also common (18.4 and 26.3 percent), and a small number
of patients (3.2 percent at one year) required dialysis or renal transplantation.
Nephrotoxicity from calcineurin inhibitor therapy is a major cause of this problem,
which is also seen in other nonrenal solid organ transplants. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?33/28/34250?
source=see_link\">",
" \"Renal function and nonrenal solid organ transplantation\"",
" </a>",
" .)",
" </p>",
" <p>",
" The prevalence of all malignancies was 6.2 percent in one-year survivors and
posttransplant lymphoproliferative disease (PTLD) accounted for about 70 percent of
first year malignancies [",
" <a class=\"abstract\" href=\"UTD.htm?0/6/99/abstract/2\">",
" 2",
" </a>",
" ]. PTLD remained the most common malignancy in five-year survivors. This is in
contrast to the findings in lung transplantation where PTLD accounts for about 50
percent of malignancies in one-year survivors and skin malignancies were most
common in five-year survivors. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?22/50/23338?
source=see_link\">",
" \"Treatment and prevention of post-transplant lymphoproliferative
disorders\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?33/23/34170?
source=see_link\">",
" \"Development of malignancy following solid organ transplantation\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H22\">",
" <span class=\"h1\">",
" SUMMARY",
" </span>",
" &nbsp;&mdash;&nbsp;Despite the small number of heart-lung transplants that are
performed, it is still the only option for some patients with end stage
cardiopulmonary disease. Postoperative management of heart-lung transplant
recipients is similar to that for patients who have undergone single or double lung
transplantation, as monitoring of lung function using pulmonary function tests,
chest radiographs, and bronchoscopy all play an important role.",
" </p>",
" <p>",
" Acute rejection occurs fairly frequently in the lung allograft but
infrequently in the cardiac allograft; as a result, surveillance endomyocardial
biopsy, unlike lung biopsy, is not routinely recommended. Similarly, chronic
rejection of the heart allograft (cardiac allograft vasculopathy) is diagnosed in
only 10 percent of heart-lung transplant recipients. However, chronic rejection in
the lungs, manifested as bronchiolitis obliterans syndrome occurs in almost one-
half of heart-lung transplant recipients by five years and represents the most
important obstacle to improved long-term survival.",
" </p>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_in_page\"
target=\"_blank\">",
" Subscription and License Agreement",
" </a>",
" .",
" </div>",
" <div class=\"headingAnchor\" id=\"references\">",
" <h1>",
" REFERENCES",
" </h1>",
" <ol id=\"reference\">",
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" Reed EF, Demetris AJ, Hammond E, et al. Acute antibody-mediated rejection of
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" Miller GG, Destarac L, Zeevi A, et al. Acute humoral rejection of human lung
allografts and elevation of C4d in bronchoalveolar lavage fluid. Am J Transplant
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" Girnita AL, McCurry KR, Iacono AT, et al. HLA-specific antibodies are
associated with high-grade and persistent-recurrent lung allograft acute rejection.
J Heart Lung Transplant 2004; 23:1135.",
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" Ionescu DN, Girnita AL, Zeevi A, et al. C4d deposition in lung allografts is
associated with circulating anti-HLA alloantibody. Transpl Immunol 2005; 15:63.",
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posttransplantation septal capillary injury syndrome as a common form of pulmonary
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" Magro CM, Pope Harman A, Klinger D, et al. Use of C4d as a diagnostic
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" Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome
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" Sheridan PH Jr, Cheriyan A, Doud J, et al. Incidence of phrenic neuropathy
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Heart Lung Transplant 1995; 14:684.",
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" Ferdinande P, Bruyninckx F, Van Raemdonck D, et al. Phrenic nerve
dysfunction after heart-lung and lung transplantation. J Heart Lung Transplant
2004; 23:105.",
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" Berkowitz N, Schulman LL, McGregor C, Markowitz D. Gastroparesis after lung
transplantation. Potential role in postoperative respiratory complications. Chest
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" Sodhi SS, Guo JP, Maurer AH, et al. Gastroparesis after combined heart and
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" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/99/abstract/35\">",
" Yiannopoulos A, Shafazand S, Ziedalski T, et al. Gastric pacing for severe
gastroparesis in a heart-lung transplant recipient. J Heart Lung Transplant 2004;
23:371.",
" </a>",
" </li>",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/99/abstract/36\">",
" Weinkauf JG, Yiannopoulos A, Faul JL. Transcutaneous electrical nerve
stimulation for severe gastroparesis after lung transplantation. J Heart Lung
Transplant 2005; 24:1444.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?0/6/99/abstract/37\">",
" Ziedalski TM, Raffin TA, Sze DY, et al. Chylothorax after heart/lung
transplantation. J Heart Lung Transplant 2004; 23:627.",
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" Harringer W, Wiebe K, Str&uuml;ber M, et al. Lung transplantation--10-year
experience. Eur J Cardiothorac Surg 1999; 16:546.",
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" Burton CM, Milman N, Carlsen J, et al. The Copenhagen National Lung
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transplantation. J Heart Lung Transplant 2005; 24:1834.",
" </a>",
" </li>",
" </ol>",
" </div>",
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" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <div id=\"outline\">",
" <ul>",
" <li>",
" <a class=\"sr_button\" href=\"#H22\" id=\"summRecButton\">",
" <span>",
" SUMMARY",
" </span>",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H1\">",
" INTRODUCTION",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H2\">",
" Declining use",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H3\">",
" Disadvantages",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H4\">",
" INDICATIONS",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H5\">",
" Congenital heart disease",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H6\">",
" Organ allocation",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H7\">",
" CONTRAINDICATIONS",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H8\">",
" POSTOPERATIVE MANAGEMENT",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H9\">",
" Surveillance studies",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H10\">",
" COMPLICATIONS",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H11\">",
" Acute cellular rejection",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H12\">",
" Acute antibody mediated rejection",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H13\">",
" Infection",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H14\">",
" Chronic rejection",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H15\">",
" Other",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H16\">",
" - Phrenic nerve dysfunction",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H17\">",
" - Gastroparesis",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H18\">",
" - Chylothorax",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H19\">",
" OUTCOMES",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H20\">",
" Survival",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H21\">",
" Morbidity",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H22\">",
" SUMMARY",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a href=\"#references\">",
" REFERENCES",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" <div class=\"openRelatedGraphics\" id=\"CARD/3525\" rel=\"outline_link\">",
" GRAPHICS",
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" View All",
" </a>",
" </div>",
" </h1>",
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" <li class=\"plainItem\">",
" <div class=\"openRelatedGraphics\" id=\"CARD/3525|TAB\">",
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" TABLES",
" </a>",
" </div>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?3/2/3117\" title=\"table
1\">",
" Methods to assess cardiovascular disability",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?5/0/5131\" title=\"table
2\">",
" Signs and symptoms of rejection",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?13/10/13484\" title=\"table
3\">",
" Pulmonary allograft rejection",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?24/21/24923\" title=\"table
4\">",
" Classification of BOS",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?19/14/19691\" title=\"table
5\">",
" Clinical presentation of BO",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
" <div id=\"relatedTopics\">",
" <ul>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?27/24/28040?
source=related_link\">",
" Acute cardiac allograft rejection: Diagnosis",
" </a>",
" </li>",
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" <a class=\"medical medical_review\" href=\"UTD.htm?14/6/14441?
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" Acute cardiac allograft rejection: Treatment",
" </a>",
" </li>",
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" Chronic lung transplant rejection: Bronchiolitis obliterans",
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" Etiology, clinical presentation, and diagnosis of chylothorax",
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" Evaluation and treatment of acute lung transplant rejection",
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source=related_link\">",
" Indications and contraindications for cardiac transplantation",
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" <a class=\"medical medical_review\" href=\"UTD.htm?3/38/3688?
source=related_link\">",
" Induction immunosuppression following lung transplantation",
" </a>",
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" <a class=\"medical medical_review\" href=\"UTD.htm?28/47/29433?
source=related_link\">",
" Infection in the solid organ transplant recipient",
" </a>",
" </li>",
" <li class=\"plainItem\">",
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