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N u t r i t i o n Th e r a p y f o r AL I a n d AR D S

Anna Krzak, RDa, Melissa Pleva, Lena M. Napolitano, MDc,*


KEYWORDS  Nutrition therapy  Enteral nutrition  Acute respiratory distress syndrome  Acute lung injury
PharmD
b

The importance of nutrition support in critically ill patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) cannot be overstated. ALI and ARDS are characterized by a proinflammatory response associated with hypercatabolism that could lead to significant nutrition deficits. Nutrition support is necessary to prevent cumulative caloric deficits, malnutrition, loss of lean body mass, and deterioration of respiratory muscle strength.13 Furthermore, early delivery of enteral nutrition (EN) has been associated with modulation of stress and the systemic immune response as well as attenuation of disease severity.1 Such factors make the delivery of EN in critically ill patients, particularly in high-risk patients, such as those with ALI and ARDS, a vital component of quality care and management.
NUTRITION REQUIREMENTS AND SUBSTRATE USE

Although the importance of nutrition in this patient population is widely accepted, determining nutrition requirements and designing a nutrition support regimen is challenging. Secondary diagnoses in patients with ALI and ARDS, such as sepsis, trauma, major surgery, and multisystem organ failure, significantly alter metabolism.4,5 Various comorbidities, sedation, and neuromuscular blockade use further complicate comprehensive assessment of energy expenditure and implementation of a safe and appropriate nutrition support regimen.5
Determining Energy Requirements

The many metabolic and nutrition-related manifestations associated with ALI, ARDS, and common secondary diagnoses make standard equations for determining energy expenditure highly inaccurate.4 Indirect calorimetry (IC) is considered the gold standard
Conflicts of interests: none. a Nutrition Services, University of Michigan Health System, Ann Arbor, MI, USA b Department of Pharmacy Services, University of Michigan Health System, Ann Arbor, MI, USA c Division of Acute Care Surgery, Department of Surgery, University of Michigan Health System, 1500 East Medical Center Drive, 1C340A-UH, SPC 5033, Ann Arbor, MI 481095033, USA * Corresponding author. E-mail address: lenan@med.umich.edu Crit Care Clin 27 (2011) 647659 doi:10.1016/j.ccc.2011.05.004 0749-0704/11/$ see front matter 2011 Published by Elsevier Inc. criticalcare.theclinics.com

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for assessing energy requirements.1 Unfortunately, because of cost and lack of trained personnel, IC is frequently unavailable. Even when available, technical factors, such as FiO2 greater than or equal to 60%, positive end expiratory pressure greater than 12 cm H2O, and hyperventilation/hypoventilation (acute changes altering body CO2 stores), prohibit accurate study measurement.4,5 When available, IC captures shifts in metabolism during critical illness, allowing clinicians to design safe and appropriate nutrition support regimens while minimizing complications of underfeeding or overfeeding.4,5 Although traditionally respiratory quotient was thought to represent substrate use, it is now more often used to confirm the validity of the study.4 Ideally, the aim is to obtain IC at baseline and repeat when the patient clinical status changes in an effort to provide the safest and most appropriate nutrition therapy.4,5
Hypercapnia and Substrate Use

Previously, high carbohydrate provision was considered most detrimental in terms of hypercapnia associated with overfeeding. However, Talpers and colleagues6 demonstrated that increasing caloric provision rather than excessive carbohydrate substrate correlated more closely with CO2 production (Fig. 1). When the carbohydrate-to-fatcalorie ratio was constant, increasing total calorie intake resulted in a statistically significant increase in VCO2 production.6 Before the Talpers and colleagues study in 1992, a study (n 5 20) reported a reduction in duration of mechanical ventilation with the use of a high-fat, low-carbohydrate formula compared with a standard formula.1,7,8 Additional review of other pertinent literature on this subject demonstrates no improvement in CO2 production or improved outcomes correlated with use of high-fat, low-carbohydrate formulas.1,7,8 Moreover, the American Society for Parenteral and Enteral Nutrition (ASPEN)/Society of Critical Care Medicine (SCCM) consensus guidelines for nutrition support therapy in adult, critically ill patients published in 2009, state that, Specialty high-lipid low-carbohydrate formulations designed to manipulate the respiratory quotient and reduce CO2 production are not recommended for routine use in [intensive care unit] ICU patients with acute respiratory failure.1 Because of a high risk of CO2 retention, patients with ALI and ARDS on nutrition support should be frequently monitored for signs of underfeeding or overfeeding. Attention should be paid to unanticipated acid/base changes or difficulty weaning from mechanical ventilation.5 Nutrition requirements for these patients should be

Fig. 1. Effect of carbohydrate versus total calories on CO2 production. Increasing caloric provision rather than excessive carbohydrate substrate correlated more closely with CO2 production. When carbohydrate-to-fat-calorie ratio was constant, increasing total calorie intake resulted in a statistically significant increase in VCO2 production. Abbreviations: CHO, carbohydrate; REE, resting energy expenditure. (Adapted from Talpers SS, Romberger DJ, Bunce SB, et al. Nutritionally associated increased carbon dioxide production. Excess total calories vs high proportion of carbohydrate calories. Chest 1992;102:5515; with permission.)

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reevaluated and the nutrition support regimen adjusted frequently as indicated by the patients clinical status.
Complications of Underfeeding and Overfeeding

The fundamental goal of providing adequate nutrition support therapy to critically ill patients is to avoid gross underfeeding or overfeeding. The metabolic implications characteristic of ALI and ARDS place these patients at higher risk for complications related to underfeeding or overfeeding (Table 1). Deleterious effects of underfeeding in patients with ALI and ARDS, such as a reduction in respiratory muscle strength and ventilatory drive, could lead to failure to wean from mechanical ventilation.9 Underfeeding is also associated with immunosuppression, poor wound healing, and increased risk of nosocomial infections.9 The effects of inadequate nutrition in critically ill patients are more frequently highlighted, but it should be recognized that overfeeding may also lead to undesirable outcomes. Similar to the consequences of underfeeding, hypercapnia resulting from overfeeding may delay ventilator weaning.9 Stress hyperglycemia, which is common in critically ill patients, is exacerbated by overfeeding and may also prolong wound healing and increase risk of infection.9
TIMING OF THERAPY: EARLY ENTERAL NUTRITION

Early initiation of enteral nutrition in critical illness is important to achieve clinical benefit. See Box 1 for a summary of the clinical benefits of early enteral nutrition. Once patients are fluid resuscitated and hemodynamically stable, enteral nutrition should be initiated within 24 to 48 hours and advanced to goal over the next 48 to 72 hours.1,10,11 Feeding initiated within 24 to 72 hours of ICU admission, compared with feeding started later, is associated with reduced gastrointestinal permeability; reduced activation and release of inflammatory cytokines; and decreased infectious morbidity, mortality, and hospital length of stay.1,10,11
ROUTE OF DELIVERY (GASTRIC VS SMALL-BOWEL FEEDS)

The most appropriate route of delivery of enteral nutrition is an area of intense debate. Although small-bowel feeding may decrease the incidence of gastroesophageal reflux, meta-analyses evaluating gastric and small-bowel feeding reported no
Table 1 Complications of underfeeding and overfeeding Underfeeding Decreased ventilatory drive Depressed respiratory muscle strength Failure to wean from mechanical ventilation Immunosuppression Poor wound healing Infections Overfeeding Hypercapnia Azotemia Failure to wean from mechanical ventilation Electrolyte imbalances Hyperglycemia Infections Poor wound healing Immunosuppression Hepatic steatosis Data from Refs.
3,6,9

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Box 1 Benefits of early enteral nutrition Attenuation of hypercatabolism Decreased gastrointestinal permeability Improved hepatic and visceral blood flow Reduced activation and release of inflammatory cytokines Decreased infectious morbidity Decreased mortality Shorter hospital length of stay Data from Refs.1,10,11

significant difference in pneumonia, ICU length of stay, or mortality.1215 Some of the benefits of gastric feeding include ease of tube placement and earlier feeding initiation.13 In fact, ASPEN/SCCM guidelines recognize that gastric feeding is appropriate for many critically ill patients.1 However, at the height of critical illness, patients are prone to gastrointestinal dysfunction, gastroparesis, and potential feeding intolerance.1 Therefore, small-bowel feeding tube placement should be considered for high-risk patients, particularly those with a history of aspiration or intolerance to gastric feeding.1,5 Frequent withholding of EN because of elevated gastric residual volumes also warrants evaluation for small-bowel feeding.1

SPECIAL CONSIDERATIONS FOR NUTRITION SUPPORT IN ALI AND ARDS

ALI and ARDS are characterized by a persistent production of oxygen free radicals and arachidonic acid (AA)-derived inflammatory mediators.1620 These mediators result in lung inflammation, edema, and diffuse alveolar damage. A key aim in treating patients with ALI and ARDS is to modulate pulmonary inflammation and permeability characteristic of the disease, thereby improving oxygenation.16 A diet enriched with eicosapentaenoic acid (EPA) and g-linolenic acid (GLA) has been shown to modify the availability of AA in tissue and cell phospholipids as well as stimulate proinflammatory eicosanoid production from AA.1620 Additionally, EPA shifts production of cytokines from the highly proinflammatory 4-series leukotrienes and dienoic prostaglandins to the less-inflammatory 5-series leukotrienes and trienoic prostaglandins. Through a series of pathways, GLA is metabolized to prostaglandin E1, a potent vasodilator of pulmonary and systemic circulation. Consequently, a combination of EPA and GLA may favorably reduce the pulmonary inflammatory response and support vasodilation and oxygenation (Fig. 2).1620

CLINICAL TRIALS WITH IMMUNE-MODULATING NUTRITION IN ALI/ARDS

Several studies in patients with ALI or ARDS have shown that the use of omega-3 fatty acids, specifically EPA and GLA, and antioxidants may prevent oxidative cellular injury, modify the metabolic response caused by stress, and modulate immunity and inflammation.1620 This specialized nutrition support therapy was associated with improved outcomes, including improved ventilation and oxygenation, shorter ICU length of stay, and decreased morbidity and mortality.2123

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Fig. 2. Pathophysiology: metabolism of omega-6 fatty acids and omega-3 fatty acids. The major product of omega-6 fatty acid metabolism is arachidonic acid. Cyclooxygenase and lipoxygenase enzymes use arachidonic acid to form prostaglandins of the 2 series and leukotrienes of the 4 series. These compounds are known to be proinflammatory. The metabolites of omega-3 fatty acids (primarily EPA and docosahexaenoic acid) compete with arachidonic acid for use of the same enzymes. As a result, more omega-3 fatty acids lead to both an increase in antiinflammatory mediators and a decrease in proinflammatory mediators. (Created by Todd W. Rice, MD, MSc and Arthur P. Wheeler, MD and Presented at A.S.P.E.N. Clinical Nutrition Week 2011; with permission.)

Three prospective, randomized clinical trials highlighted the use of omega-3 fatty acids and antioxidants in patients with ALI and ARDS. Two of these studies were single-center studies and one study was completed at 5 sites in the United States. The sample size in each study ranged from 100 to 165 patients. All three trials followed a similar study design comparing a diet enriched with EPA, GLA, and antioxidants (Oxepa; Abbott Nutrition, Abbott Laboratories, Columbus, OH, USA) with an isocaloric and isonitrogenous control diet (Pulmocare; Abbott Nutrition, Abbott Laboratories).4,5,9,16 In a meta-analysis of these 3 trials, the diet enriched with EPA, GLA, and antioxidants was associated with the following outcomes: (1) a 60% reduction in 28-day, in-hospital, all-cause mortality (odds ratio [OR] 0.404; 95% confidence interval [CI] 0.2410.678; P 5 .001); (2) a mean increase of 4.9 ventilator-free days; (3) a mean increase of 4.3 ICU-free days; (4) an 83% reduction in the risk of developing new organ failures, (The study reported by Singer and colleagues was excluded because it did not assess the development of new organ failures); and (5) improvement in oxygenation status (Figs. 3 and 4).16,2123 However, a recent study reported different findings. The ARDSNet EDEN-Omega study was entitled Early Versus Delayed Enteral Feeding and Omega-3 Fatty Acid/ Antioxidant Supplementation for Treating People With Acute Lung Injury or Acute Respiratory Distress Syndrome.24 This phase III clinical trial was a prospective, randomized trial of initial trophic enteral feeding followed by advancement to fullcalorie enteral feeding versus early advancement to full-calorie enteral feeding. This trial was run simultaneously with a trial of omega-3 fatty acid, GLA, and antioxidant

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Fig. 3. Effect of inflammation-modulating diet on mortality in ALI/ARDS. Effect of the EPA and GLA diet when compared with the control diet on 28-day, in-hospital, all-cause mortality. Data are presented as OR for each study (boxes), 95% CI (horizontal lines), and summary as OR with 95% CI (diamond). (Adapted from Pontes-Arruda A, Demichele S, Seth A, et al. The use of an inflammation-modulating diet in patients with acute lung injury or acute respiratory distress syndrome: a meta-analysis of outcome data. JPEN J Parenter Enteral Nutr 2008;32:596; with permission.)

Nutrition Therapy for ALI and ARDS

Fig. 4. Effect of inflammation-modulating diet on ventilator-free (A) and ICU-free days (B) in patients with ALI and ARDS. Std diff, standard difference. (Adapted from Pontes-Arruda A, Demichele S, Seth A, et al. The use of an inflammation-modulating diet in patients with acute lung injury or acute respiratory distress syndrome: a meta-analysis of outcome data. JPEN J Parenter Enteral Nutr 2008;32:596; with permission.)

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supplementation versus comparator enteral solution. The primary outcome measures were number of ventilator-free days and mortality before hospital discharge with unassisted breathing. This trial added an omega-3 fatty acid and antioxidant supplement to usual feeding (did not use a commercially available product). This difference is important in this trial design from prior studies in that it separated the immunemodulating nutrients from the continuous delivery of EN. Participants assigned to initial minimal enteral feedings received feedings at 10 mL/h and continued at this rate for 144 hours, provided that the participant remained on mechanical ventilation. After 144 hours, the feeding rate was advanced to the full-calorie target rate. Participants assigned to initial full-calorie enteral feedings received feedings at 25 mL/h, and the feeding rate was increased by 25 mL increments every 6 hours until the goal rate was reached. Omega-3 fatty acid, antioxidant, and placebo supplements were administered with a syringe into the participants feeding tube every 12 hours until day 21 or discontinuation of the ventilator. The Data Safety and Monitoring Board performed an interim analysis and examined the data of the EDEN-Omega study. The study was terminated early for futility. In a brief report in Surgery News,25 the preliminary data was reviewed. The mortality rate at 60 days was significantly lower at 16.3% in the control group versus 26.6% in the experimental cohort (P 5 .05). In addition, patients randomized to the omega3 fatty acidsupplement group had significantly fewer ventilator-free days within 28 days (14.6 days, compared with 17.4 days for the control group, P 5 .03) and significantly fewer ICU-free days within 28 days (13.9 days, compared with 16.8 days for the control group, P 5 .02; Tables 2 and 3). Further review of the data from this prospective clinical trial awaits peer-reviewed publication.
CONTROVERSIES WITH IMMUNE-MODULATING NUTRITION IN ALI/ARDS

Despite several reports regarding the positive effects of omega-3 fatty acids on the inflammatory response in patients with ALI and ARDS, there are still areas of uncertainty and controversy. First, in the original 3 trials on omega-3 fatty acids, the medical management of the patients is not consistently controlled or reported. The recent ARDSNet EDEN-Omega study was the first to report important components of medical management, such as fluid therapy and tidal volume.5,16,24 Second, many studies on the use of enteral omega-3 fatty acids used a comparator formula (Pulmocare) that was high in fat and low in carbohydrate. The fat source in this comparator formula is primarily omega-6 fatty acids.16 Omega-6 fatty acids have been associated with proinflammatory characteristics in critically ill patients.1,2628 It could be presumed that the results reported in studies using this high-fat, low-carbohydrate formula as the control were distorted because of the potential proinflammatory characteristics of omega-6 fatty acids. Third, timing of initiation of therapy, optimal dose, and duration of therapy remain uncertain. As previously mentioned, early delivery of EN is pivotal to obtain clinical benefit.1,10,11 The same is true when using immune-modulating, specialized nutrition support. Studies suggest that delivery of more than 50% to 65% of goal calories is more closely associated with positive outcomes of EN, when compared with lower calorie provision.1 The period of time needed from delivery to clinical effect may vary based on the dose and the route of delivery. See Table 3 for more information regarding the dosing ranges of EPA, docosahexaenoic acid, and GLA in important trials. Additional studies are needed to come to a definitive conclusion.

Table 2 Antiinflammatory immune-modulating enteral nutrition versus standard enteral nutrition in ALI, ARDS, and sepsis Study Gadek et al,21 1999 Population ARDS (n 5 146) Study Groups EPA/GLA/AO Control EN EPA/GLA/AO Control EN EPA/GLA/AO Control EN EPA/GLA/AO Control EN Mortality 11/70 (16%) 19/76 (25%) ICU mortality 14/46 (30%)a 26/49 (53%) 28d mortality 26/83 (31%)a 38/82 (46%) 28d mortality LOS Days, Mean SD 11.0 14.8 27.9 31.1 0.9 ICUa 1.3 ICU 2.1 Hospital 2.4 Hospital Ventilator Days, Mean SD 9.6 0.9a 13.2 1.4 New Organ Dysfunction 7/70 (10%)a 19/76 (25%)

Singer et al,22 2006

ARDS and ALI (n 5 100) Severe sepsis (n 5 165)

13.5 11.8 ICU 15.6 11.8 ICU 17.2 4.9 ICUa 23.4 3.5 ICU

12.1 11.3 14.7 12.0 14.6 4.3a 22.2 5.1

NR

Pontes-Arruda et al,23 2006

32/83 (39%)a 66/82 (80%)

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Abbreviations: AO, antioxidants; EN, enteral nutrition; EPA, eicosapentaenoic acid; GLA, g-linolenic acid; LOS, length of stay; NR, not reported; SD, standard deviation. a P .05. Data from McClave SA, Martindale RG, Vanek VW, et al; A.S.P.E.N. Board of Directors; American College of Critical Care Medicine; Society of Critical Care Medicine. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr 2009;33(3):277316.

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Table 3 Summary of clinical studies Gadek et al21 Design P, R, C, DB Full feeds Multicenter 146 ARDS Omega-3 FA 1 AO 6.9 2.9 5.8 Continuous High fat (omega-6, 9) Uncontrolled Uncontrolled X X X X Singer et al22 P, R, C Full feeds Single center 100 ALI Omega-3 FA 1 AO 5.4 2.5 5.1 Continuous High fat (omega-6, 9) Uncontrolled Uncontrolled X X X Not assessed X PontesArruda et al23 P, R, C, DB Full feeds Single center 165 severe sepsis/ septic shock Omega-3 FA 1 AO 4.9 2.2 4.6 Continuous High fat (omega-6, 9) Uncontrolled Uncontrolled X X X X X ARDSNet EDEN-Omega24 P, R, C Full feeds/ trophic feeds Multicenter 272 ALI/ARDS Omega-3 FA 1 AO 6.8 3.4 5.9 Bolus BID High carbohydrate 6 mL/kg PBW Conservative X X

Setting Patients Interventions

Mean fatty-acid intake EPA (g/d) DHA (g/d) GLA (g/d) Omega-3 delivery Control formula Tidal volume Fluid therapy Outcomesa Improved oxygenation Reduced vent days Reduced ICU length of stay Reduced new organ failure Reduced 28-day mortality

Abbreviations: AO, antioxidants; C, controlled; CD, control diet; DB, double blind; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FA, fatty acid; GLA, g-linolenic acid; P, prospective; PBW, predicted body weight; R, randomized. a X: statistically significant (P<.05) for EPA 1 GLA versus control diet. Data from Pontes-Arruda A, Demichele S, Seth A, et al. The Use of an inflammation-modulating diet in patients with acute lung injury or acute respiratory distress syndrome: a meta-analysis of outcome data. JPEN J Parenter Enteral Nutr 2008;32:596.

RECOMMENDATIONS FOR NUTRITION SUPPORT IN CRITICALLY ILL PATIENTS WITH ALI AND ARDS General

 EN is preferred when the gastrointestinal tract is functional.  Initiate early EN after patients are resuscitated.  Initiate within 24 to 48 hours and advance to the goal over the next 48 to 72 hours.  Withhold EN if patients are hypotensive or on increasing doses of vasopressors.  Polymeric formula is preferred.

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 Either gastric or small-bowel feeds are acceptable.  Consider small-bowel feeding tube placement in high-risk patients with history of aspiration or intolerance to gastric feeding.  Consider prokinetics in patients with feeding intolerance.  Provide antioxidants and trace minerals.  Fluid-restricted formulas should be considered in patients with respiratory failure.  Aggressively replace phosphorus in patients with normal renal function. Evidence-based consensus guidelines on nutrition support in adult, critically ill patients endorse the following:
ASPEN/SCCM Guidelines

The ASPEN/SCCM Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient published in 20091,2 recommend the following: Patients with ARDS and severe ALI should be placed on an enteral formulation characterized by an anti-inflammatory lipid profile (ie, omega-3 fish oils, borage oil) and antioxidants.
Canadian Clinical Practice Guidelines

The Canadian Clinical Practice Guidelines for Nutrition Support in Mechanically Ventilated, Critically Ill Adult Patients, published in the January 2009 update, recommends the following:10 Based on one level 1 study and four level 2 studies, we recommend the use of an enteral formula with fish oils, borage oils and antioxidants in patients with ALI and ARDS.
SUMMARY

Nutrition support is a critical component of care in patients with ALI/ARDS. Early EN support is recommended, using either gastric or small-bowel feeding dependent on patient tolerance. Indirect calorimetry is the ideal method for determination of caloric requirements in patients with ALI/ARDS. Specialized nutrition support, with an enteral diet enriched with omega-3 fatty acid, GLA, and antioxidant supplementation, should be considered in patients with ALI and ARDS based on the available clinical trial data. However, results from the recent ARDSNet EDEN-Omega study are not yet published. The optimal dosage, composition of fatty acids, and the ratio of individual immunemodulating nutrients in specialized enteral formulations remain controversial.
REFERENCES

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21. Gadek JE, DeMichele SJ, Karlstad MD, et al. Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Crit Care Med 1999;27:140920. 22. Singer P, Theilla M, Fisher H, et al. Benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in ventilated patients with acute lung injury. Crit Care Med 2006;34:10338. 23. Pontes-Arruda A, Aragao AM, Albuquerque JD. Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock. Crit Care Med 2006; 34:232533. 24. Early versus delayed enteral feeding and omega-3 fatty acid/antioxidant supplementation for treating people with acute lung injury or acute respiratory distress syndrome (The EDEN-Omega Study). Available at: http://clinicaltrials.gov/ct2/ show/NCT00609180. Accessed April 24, 2011. 25. Available at: http://www.facs.org/surgerynews/1209.pdf. Accessed April 24, 2011. 26. Battistella FD, Widergren JT, Anderson JT, et al. A prospective, randomized trial of intravenous fat emulsion administration in trauma victims requiring total parenteral nutrition. J Trauma 1997;43:528. 27. Mayer K, Kiessling A, Ott J, et al. Acute lung injury is reduced in fat-1 mice endogenously synthesizing n-3 fatty acids. Am J Respir Crit Care Med 2009; 179:47483. 28. Pluess T, Hayoz D, Berger MM, et al. Intravenous fish oil blunts the physiological response to endotoxin in healthy subjects. Intensive Care Med 2007;33:78997.