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The Use of an Inflammation-Modulating Diet in Patients With Acute Lung Injury or Acute Respiratory Distress Syndrome: A Meta-Analysis of Outcome Data

From ¹ Intensive Care Department, Fernandes Távora Hospital, Fortaleza, Ceará, Brazil;² Research and Development, Abbott Nutrition, Abbott Laboratories, Columbus, Ohio; ³ Department of General Intensive Care, Rabin Medical Center, Tel Aviv, Israel.

Address correspondence to: Alessandro Pontes-Arruda, MD, MSc, PhD, Intensive Care Department, Fernandes Távora Hospital, Rua Ildefonso Albano 777/403, Fortaleza, Ceará, Brazil 60.115-000; e-mail: pontes-arruda{at}secrel.com.br.

Background: This meta-analysis of clinical trials compares an inflammation-modulating diet enriched with eicosapentaenoic acid (EPA), -linolenic acid (GLA), and elevated antioxidants (EPA + GLA) vs a control diet to determine the effectiveness of this specialized diet on oxygenation and clinical outcomes in mechanically ventilated patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Methods: MEDLINE, EMBASE, Cochrane Clinical Trials Register, and the U.S. National Institute of Health Clinical Trials databases were searched. The outcome measures assessed were 28-day in-hospital mortality, 28-day ventilator-free and intensive care unit (ICU)-free days, and the development of new organ failures. An evaluation of oxygenation and ventilatory variables was also performed. Outcomes were analyzed using both fixed-effects and random-effects models. Results: Three randomized controlled studies (n = 411 patients) were included in this meta-analysis. Among the most important findings of this evaluation is a significant reduction in the risk of mortality (odds ratio [OR] = 0.40; 95% confidence interval [CI] = 0.24–0.68; P = .001), with significant reductions in the risk of developing new organ failures (OR = 0.17; 95% CI = 0.08–0.34; P < .0001), time on mechanical ventilation (standardized mean difference [SMD] = 0.56; 95% CI = 0.32–0.79; P < .0001), and ICU stay (SMD = 0.51; 95% CI = 0.27–0.74; P < .0001) in patients who received EPA + GLA. Conclusions: The meta-analysis showed a significant reduction in the risk of mortality as well as relevant improvements in oxygenation and clinical outcomes of ventilated patients with ALI/ARDS given EPA + GLA.

Key Words: meta-analysis • eicosapentaenoic acid • -linolenic acid • ARDS • ALI • sepsis • inflammation • borage oil • fish oil • critical care • omega-3 fatty acids

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are acute life-threatening forms of hypoxic respiratory failure due to a persistent pulmonary and systemic inflammation. Contributing factors that may give rise to ALI/ARDS from increased inflammation include sepsis, aspiration, pulmonary contusion, pneumonia, multiple trauma, shock, and burn injury.¹ Although the pathophysiology of ALI/ARDS is increasingly well understood, very little success has been achieved with regard to new and effective treatments. Current therapeutic interventions for ALI/ARDS are supportive in nature, offering encouraging laboratory measurements or early physiologic improvements but without sustained clinical outcome benefits.^2,3 Recent studies have shown that the use of specialized enteral nutrition formulas is becoming one of the primary therapies in the clinical management of critically ill patients.^4,5

Supportive care along with the increasing use of nutrition therapy in patients with ALI/ARDS during the past 10 years has improved morbidity in the intensive care unit (ICU). A primary therapeutic goal for ALI/ARDS is to increase oxygenation by decreasing pulmonary and systemic inflammation while reducing the incidence of organ dysfunction. A growing collection of studies has shown that the use of -3 fatty acids (eicosapentaenoic acid [EPA]) in combination with -linolenic acid (GLA) and higher levels of antioxidants can aggressively reduce a raised inflammatory response while promoting vasodilation and oxygen delivery.^6-10 This type of nutrition formulation should not be confused and associated with the "immune enhancing diets" that contain different active ingredients (L-arginine, fish oil, nucleotides, and L-glutamine) and have been extensively evaluated in the literature for different types of ICU patients.^4,5

Over the past several years, intensive clinical testing of EPA + GLA has resulted in a number of clinical outcome benefits for ALI/ARDS patients. Gadek et al¹¹ performed the pioneering trial assessing the effects of EPA + GLA, showing positive effects on clinical pathophysiology and outcomes in a heterogeneous group of patients with ARDS. In a recent study, Singer et al¹² showed that ventilated postsurgical/trauma patients with ALI who were fed the EPA + GLA diet had significant improvements in oxygenation and pulmonary compliance with fewer ventilator days and a significant reduction in 28-day mortality when compared with patients receiving an isocaloric and isonitrogenous standard diet. Pontes-Arruda et al¹³ performed an additional study in mechanically ventilated patients with ARDS secondary to severe sepsis and septic shock, demonstrating significant improvements in oxygenation and reduction in the development of new organ failures, a significant increase in the number of ventilator-free and ICU-free days, and a significant reduction in mortality observed in patients given the EPA + GLA diet.

Collectively, the aforementioned evidence represents provocative and clinically useful information on improvements in clinical outcomes for the ALI/ARDS patient. Each of the studies, however, was performed in a different patient population, with each sharing a common pathophysiology of respiratory failure due to an increased and persistent systemic inflammation. Our goal was to perform a meta-analysis on the cumulative evidence from a thorough literature search focusing on clinical trials comparing EPA + GLA vs a control standard diet to determine the overall effectiveness of this specialized diet on oxygenation and clinical outcomes in critically ill, mechanically ventilated patients with ALI/ARDS.

	Materials and Methods

Top Materials and Methods Results Discussion

 
Inclusion Criteria and Quality Assessment
An earlier meta-analysis found an important degree of heterogeneity between critically ill and non–critically ill populations.¹⁴ Only those clinical trials that included critically ill patients, defined as patients recruited in an ICU and in need of intensive care support as previously described,¹⁵ were considered in this meta-analysis. In addition, patients had to have respiratory failure requiring mechanical ventilation due to a lung inflammatory process (such as ALI or ARDS). Patients had to be prospectively randomized to receive either an inflammation-modulating diet (EPA + GLA; without any amount of L-arginine, L-glutamine, and/or nucleotide supplementation) or a control standard diet that was not supplemented with the above-mentioned substances. Studies had to fulfill the following quality indicators for critically ill patient trials: be published in an indexed, peer-reviewed journal; must mention at least 1 severity of illness score; must have clearly defined inclusion and exclusion criteria; include 28-day all-cause mortality as one of the study endpoints; and adequately maintain allocation concealment during randomization.^16-21 To have a comprehensive meta-analysis of the studies included, the authors were contacted if additional information from their trials was needed.

Data Collection
An extensive computer search of the literature was conducted, including MEDLINE (www.pubmed.org; 1950–2006, week 44), EMBASE (www.ovid.com; 1974–2006, week 44), the Cochran Controlled Trials Register (fourth quarter, 2006), and the ClinicalTrials.gov database of the U.S. National Institutes of Health. Databases were cross-searched using sensitive (broad) search statements so as not to miss all randomized controlled trials²² performed in critically ill patients requiring mechanical ventilation due to a lung inflammatory disease and also administered EPA + GLA diet. Manual searches of journals and Index Medicus were also performed. Searches were performed using multiple terms, including critically ill patients, fish oil, -3, antioxidants, EPA, DHA, GLA, borage oil, eicosapentaenoic acid, -linolenic acid, ARDS, ALI, mechanical ventilation, sepsis, severe sepsis, septic shock, random allocation, and randomized controlled trials.

Clinical Parameters and Outcomes
The major outcome measures assessed were 28-day in-hospital all-cause mortality, 28-day ventilator-free and ICU-free days, and the development of new organ failures. In addition, assessment of clinical parameters such as oxygenation and ventilatory variables (FiO₂, positive end-expiratory pressure [PEEP], peak inspiratory pressure [PIP], minute ventilation, PaO₂/FiO₂, and tidal volume) was performed. Time on mechanical ventilation and time in the ICU were defined as the number of days from study entry (baseline) to the actual last day that a patient remained on the ventilator or in the ICU, respectively, during the 28-day follow-up period. The development of any new organ dysfunction during the 28-day follow-up, such as cardiovascular, renal, hematological, hepatic, and/or neurological failure, was defined by previously published criteria.²³ An intent-to-treat (ITT) analysis on 28-day in-hospital all-cause mortality was also undertaken. This was the only ITT data available from either the original publications or in all 3 of the original databases.

Statistical Analyses
The synthesis of data was performed using, a priori, the fixed-effects model with its validity confirmed using the ² test (fixed-effects model vs random-effects model).²⁴ To confirm the findings, the data were evaluated via a random-effects model as well. The P value corresponding to the ² test measures heterogeneity among observed odds and standardized differences or any other chosen effect size measure. The fixed-effects model is suitable for the current meta-analysis because the model assumes that all studies included come from a common population (critically ill, mechanically ventilated patients suffering from systemic inflammation and respiratory failure). The implication is that the observed effect size varies from one study to another because of the random error inherent in each study.²⁵ In addition to using the ² test for assessing heterogeneity, I² was also used, which varies from 0% to 100%. I² reflects the magnitude of heterogeneity present with proportion of total variation in estimating treatment effect because of heterogeneity between studies.

For categorical outcomes, odds ratio (OR) summarized the size of the treatment effect, and for continuous variables, the standardized mean difference (SMD) was used. OR is a commonly used index for binary data and has convenient mathematical properties, which makes it attractive for use in combining data across studies and to test the overall effect. In addition, relative risk (RR) was used to further confirm the findings based on OR. SMD is a raw mean difference divided by the within-group standard deviation. SMD is a common treatment effect index for continuous data. The standard deviation could be either a pooled standard deviation or a standard deviation of the control population.

All analyses were done using Comprehensive Meta-Analysis program, version 2.0 (Biostat Inc, Englewood, NJ). Significant differences are reported at P < .05.

A funnel plot was created for mortality data using log OR vs standard error (SE). The funnel plot is a scatter-plot of treatment effect against a measure of study size. It is used primarily as a visual aid for detecting bias or systematic heterogeneity. A symmetric inverted funnel shape arises from a data set in which the likelihood of publication bias is minimal. An asymmetric funnel plot indicates the possibility of either publication bias or some type of systematic difference between the sizes of the studies. An asymmetric funnel plot would cast doubts over the appropriateness of a meta-analysis and suggests investigation of possible causes of bias or systematic differences.

	Results

Top Materials and Methods Results Discussion

 
Study Selection
Five randomized controlled studies were found, out of which 3 fulfilled all the inclusion and quality criteria: 1 in ARDS patients,¹¹ 1 in ALI patients,¹² and 1 in ARDS patients with severe sepsis or septic shock requiring mechanical ventilation.¹³ The other 2 studies were published only as abstracts,^26,27 but were excluded from the final analysis because they did not fulfill the prospectively defined quality inclusion criteria. The 3 trials included in this meta-analysis followed a similar study design comparing not only the same study diet enriched with EPA + GLA + antioxidants (Oxepa; Abbott Nutrition, Abbott Laboratories, Columbus, OH) but also a similar control diet (Pulmocare; Abbott Nutrition, Abbott Laboratories), which is isocaloric and isonitrogenous with equal amounts of lipid when compared with EPA + GLA and differing only in terms of its lipid composition and level of antioxidant vitamins (Table 1). The study diet used in the trial by Gadek et al¹¹ was changed to increase the amount of -3 lipids in the formula. This formula had an -6:-3 ratio of 3.8:1.

Sample size varied from 100 to 165 patients (a total of 411 patients out of which 296 were evaluable due to exclusion criteria defined by each study: 98 patients in Gadek et al,¹¹ 95 patients in Singer et al,¹² and 103 patients in Pontes-Arruda et al¹³). Details of randomization were mentioned in all 3 studies, and appropriate methods of allocation concealment were followed by each of the 3 selected studies.

Effect on Mortality
For the 296 evaluable patients from the 3 studies, the use of EPA + GLA was associated with a 60% reduction in the risk of 28-day in-hospital all-cause mortality (OR = 0.40; 95% confidence interval [CI] = 0.24–0.68; P = .001; Figure 1). In the EPA + GLA group (n = 152), 115 patients survived after 28 days, whereas in the control group (n = 144), only 82 patients survived. The ² test for heterogeneity was nonsignificant (0.91; P = .63); the I² measure was 0.0%. The funnel plot analysis for mortality results is shown in Figure 2.

View larger version (11K): [in this window] [in a new window]   Figure 1. Effect of the EPA + GLA diet when compared with the control diet on 28-day in-hospital all-cause mortality. Data are presented as odds ratio for each study (boxes), 95% confidence intervals (horizontal lines), and summary as odds ratio with 95% confidence interval (diamond).

View larger version (9K): [in this window] [in a new window]   Figure 2. Funnel plot of the mortality outcome data using odds ratio in the studies included for the evaluable patients.

28-Day Ventilator-Free Days
The combined 28-day ventilator-free days was 17.0 ± 9.7 days (mean ± standard deviation) for patients given the EPA + GLA diet and 12.1 ± 9.9 days for patient given the control diet. This represents a mean increase of 4.9 ventilator-free days within a 28-day observation period for the ALI/ARDS patients randomized to the EPA + GLA diet. The combined result for this outcome was statistically significant (SMD = 0.56 ± 0.12, mean ± SE; 95% CI = 0.32–0.79; P < .0001; Figure 3). The test for homogeneity was ² = 5.67, P = .06; the I² value was 64.7%. For this outcome, results based on the random-effects model were not different from the results based on the fixed-effects model. Note that ² and I² can give discordant results at times. The Z value for the overall effect was 4.67 (P < .0001).

View larger version (10K): [in this window] [in a new window]   Figure 3. Effect of the EPA + GLA diet when compared with the control diet on 28-day ventilator-free days. Data are presented as standardized mean differences for each study (boxes), 95% confidence intervals (horizontal lines), and summary as standardized mean differences with 95% confidence interval (diamond).

View larger version (10K): [in this window] [in a new window]   Figure 4. Effect of the EPA + GLA diet when compared with the control diet on 28-day ICU-free days. Data are presented as standardized mean differences for each study (boxes), 95% confidence intervals (horizontal lines), and summary as standardized mean differences with 95% confidence interval (diamond).

View larger version (9K): [in this window] [in a new window]   Figure 5. Effect of the EPA + GLA diet when compared with the control diet on the development of new organ dysfunction. Data are presented as odds ratio for each study (boxes), 95% confidence intervals (horizontal lines), and summary as odds ratio with 95% confidence interval (diamonds). The results of the study by Singer et al12 were not combined in this analysis because this outcome was neither primarily accessed nor retrospectively available.

Improvement in Oxygenation Status and Ventilatory Variables
When the 3 trials were combined, significant improvements in a number of ventilation parameters were observed. A significant reduction in FiO₂ was found in the population nourished with the EPA + GLA diet at study day 4 (–0.39 ± 0.12; 95% CI = –0.63 to –0.16; P = .001), which was maintained through study day 7 (–0.40 ± 0.14; 95% CI = –0.69 to –0.11; P = .007). Also, a trend toward reduction in PEEP was found on study day 4 (–0.24 ± 0.12; 95% CI = –0.48 to 0.00; P = .053). A significant reduction in minute ventilation was observed on study day 4 (0.43 ± 0.13; 95% CI = 0.17–0.68; P = .001), but this reduction lost statistical significance on study day 7 (–0.14 ± 0.15; 95% CI = –0.44 to 0.15; P = .334). The most significant results among the individual ventilatory variables for the patients given the EPA + GLA diet were observed in terms of tidal volume and oxygenation status (defined by the PaO₂/FiO₂ ratio). Tidal volume significantly increased by study day 4 (0.44 ± 0.12; 95% CI = 0.20–0.69; P < .0001) and continued to increase by study day 7 (0.61 ± 0.16; 95% CI = 0.31–0.92; P < .0001). Significant improvements in oxygenation status was also observed on study day 4 (1.49 ± 0.14; 95% CI = 1.21–1.78; P < .0001), which was maintained on study day 7 (0.98 ± 0.17; 95% CI = 0.65–1.31; P < .0001). No significant improvements in PIP levels were observed on either study day 4 or study day 7 for patients receiving the EPA + GLA diet or the control diet (Table 4).

	Discussion

Top Materials and Methods Results Discussion

 
A meta-analysis of the clinical evidence from 3 independently conducted, randomized controlled trials showed significant improvements in oxygenation and clinical outcomes in critically ill, mechanically ventilated patients with ALI/ARDS given the EPA + GLA diet vs a control standard diet. All 3 studies were performed in a different critically ill patient population suffering from acute respiratory diseases in need of mechanical ventilation. Though the small number of available studies for this meta-analysis could be viewed as a limitation, the available data show a significant reduction in the risk of mortality (evaluable and ITT analyses), with significant reductions in the risk of developing new organ failures and time on mechanical ventilation and ICU stay.

The most consistent findings in this meta-analysis with the EPA + GLA diet are the significant improvements in gas exchange and the resultant improvements in ventilatory and oxygenation variables. Patients fed the EPA + GLA diet were able to significantly increase their PaO₂/FiO₂ ratio throughout the 7-day feeding period when compared with patients receiving the standard control diet. The increase in this ratio was accompanied by a decrease in PEEP, minute ventilation with improvements in tidal volume. In contrast, the control patients did not have the same changes in ventilatory variables, suggesting persistent pulmonary inflammation. One of the primary goals in treating an ALI/ARDS patient is to increase oxygenation by decreasing pulmonary inflammation and permeability. It is hypothesized that one of the mechanisms of action behind these physiologic benefits stems from the combined anti-inflammatory and vasodilatory properties of the EPA + GLA diet.^28-30 This formulation was derived from a number of studies using pig and rodent models of sepsis-induced ARDS.^6-9 The hypothesis was that EPA and GLA could reduce the severity of inflammatory injury by altering the availability of arachidonic acid (AA) in tissue and immune cell phospholipids. EPA can favorably modulate proinflammatory eicosanoid production from AA. GLA is rapidly elongated to dihomo-GLA and is incorporated into tissue and immune cell phospholipids. Dihomo-GLA can suppress leukotriene biosynthesis and is further metabolized to prostaglandin E₁, a potent vasodilator of pulmonary and systemic circulation. Thus, this combination of fatty acids can favorably reduce an elevated inflammatory response while promoting vasodilatation and oxygen delivery.

It is well recognized that ALI and ARDS are characterized by a persistent and uncontrolled production of oxygen free radicals and AA-derived inflammatory mediators, which have been shown to cause lung inflammation, edema, and alveolar tissue damage. The EPA + GLA diet has been supplemented with elevated levels of antioxidants to compensate for the increased antioxidant requirements in these patients.

It is difficult to ascertain whether the elevated antioxidants in EPA + GLA contributed toward the described clinical benefits of the EPA + GLA. A study by Nelson et al³¹ attempted to provide some insight into this question. The authors assessed whether EPA + GLA could restore circulating antioxidant levels and therefore decrease plasma lipid peroxides (LPOs) and total radical antioxidant potential (TRAP) in ARDS patients enrolled in the study by Gadek et al.¹¹ Results showed that patients randomized to EPA + GLA were able to restore plasma -tocopherol and β-carotene levels when compared with controls; however, there were no subsequent improvements in LPO and TRAP during the study. These results suggest that any significant improvement in antioxidant status occurs only after lung inflammation and permeability are decreased, and lung tissue is in a process of healing and repair. Thus, a longer feeding period may be required to normalize these antioxidant parameters. More studies are required to elucidate the physiological benefits of enterally delivered antioxidants in critically ill patients.

Additional mechanistic evidence for EPA + GLA was provided by Pacht et al,¹⁰ who showed a significant negative relationship between bronchoalveolar lavage fluid (BALF) neutrophil counts and PaO₂/FiO₂, suggesting that when pulmonary inflammation (BALF neutrophil counts) was lowered, oxygenation was increased. These investigators also showed significant positive correlations between BALF neutrophil counts and IL-8 and LTB₄, suggesting that when a reduction in lung inflammation was observed, BALF levels of IL-8 and LTB₄ were decreased as well.

Although speculative, the observed findings of a reduction in the risk of developing new organ failures and the risk of mortality may be explained in part from EPA + GLA's ability to modulate an exaggerated and persistent inflammatory response while inducing vasodilatory effects to optimize the improvements in protein permeability and oxygenation. Strong evidence exists to demonstrate that additional EPA and docosahexaenoic acid (DHA) are inhibiting the nuclear translocation of nuclear factor (NFB) and the transcription of genes such as interleukin (IL)-2.³² Calder³³ suggested that the potentially beneficial anti-inflammatory effects of EPA against endotoxin could explain the effect of the addition of EPA to the enteral formula. More recently, another important role of EPA and DHA has been described because these lipids are the substrates of a new class of inflammatory agents called resolvins,^34,35 which are involved in activating the resolution from the inflammatory process.

There has always been considerable debate as to what is the most appropriate control formula to use when assessing novel formulations in the intensive care setting. The data from the studies by Singer et al¹² and Pontes-Arruda et al¹³ provide some answers to the previous criticism that the control formula used in the study by Gadek et al¹¹ exacerbated the inflammatory response in ARDS patients. The differences between the 2 groups were not due to the EPA + GLA group doing better as much as they were to the control group doing worse. The criticism stems from the belief that the control formula provided fatty acids (linoleic acid [LA]; 18:2n6) that are precursors to arachidonic acid (AA; 20:4n6) and thus would further stimulate the production of proinflammatory eicosanoids during critical illness. The formation of AA from LA involves 3 key enzymatic steps: a -6-desaturation to form 18:3n6 (GLA), followed by an elongation to 20:3n6 (dihomo-GLA), and finally a -5-desaturation to form 20:4n6. Both the -6 and -5 desaturase enzymes are rate limiting and their activity is further inhibited by catabolic hormone release. Thus, critically ill patients have a limited ability to form AA despite provision of LA. Extensive studies by Palombo et al,³⁶ using a well-established enteral feeding model in normal and endotoxic rats, showed that short-term (3 or 6 days), continuous or cyclic, enteral feeding of a diet enriched with LA (same diet as the control formula used in the study by Gadek et al¹¹) under normal or endotoxemic conditions did not increase the production of 18:3n6, 20:3n6, or 20:4n6 in lung and liver immune cell membrane phospholipids. Furthermore, no increase in the production of proinflammatory eicosanoids by these immune cells was observed in the LA group when compared with rats not given the control diet. Therefore, feeding a diet containing LA does not exacerbate a preexisting inflammatory condition.

The study by Pontes-Arruda et al¹³ used a similar isocaloric control formula but it was enriched with a balance of -3 (linolenic acid), monounsaturated, and -6 fatty acids. Similar to the other previously mentioned studies, the control formula had a neutral effect as there were no observations of a worsening of the preexisting inflammatory condition by a deterioration of physiologic and outcomes variables. Thus, similar physiologic and outcome benefits with the EPA + GLA diet were observed in the studies by Gadek et al,¹¹ Singer et al,¹² and Pontes-Arruda et al,¹³ regardless of the composition of the control diet.

Another important aspect to any new intervention in the critically ill patient population is to establish a strong safety profile, where the clinical benefits outweigh the risks to the patient. Each of the 3 studies discussed show that the early administration (within 6 hours¹³ or 24 hours^11,12 of study entry) of the EPA + GLA diet to a heterogeneous group of critically ill patients on mechanical ventilation was safe and well tolerated as evidenced by a low percentage of GI-related adverse events as well as no differences in the incidence of cardiac, hematologic, respiratory, and skin and appendage disorders when compared with the control group. In addition, the safety profile of the EPA + GLA diet has recently been confirmed in 2 separate pediatric studies: 1 in young, critically ill burned children with respiratory failure³⁷ and 1 in mechanically ventilated children with ALI/ARDS.^38,39

In a changing health care environment, outcome variables such as reduction of morbidity, ventilator days, and time in the ICU should receive increased attention in terms of pharmacoeconomics. The reduction in the risk of developing new organ failures, time on mechanical ventilation, and ICU stay would indicate significant cost savings in the overall treatment of the critically ill patient.^40,41 The development of multiple system organ failures is the common pathway that brings patients with ALI, ARDS, and sepsis from a systemic and uncontrolled inflammatory reaction to death. Thus, the huge impact observed in the reduction of the risk of developing a new organ failure associated with the use of EPA + GLA clearly points toward the necessity of a study to evaluate if this diet can play a role in the early stages of sepsis, preventing the development of severe sepsis or septic shock. Currently, more clinical studies assessing the effects of EPA + GLA in critically ill patients are ongoing. Therefore, we expect more evidence to be available in the coming years that can be added to this meta-analysis.

Top Materials and Methods Results Discussion

 
Financial disclosure: SJ DeMichele and A Seth are employees of Ross Products Division, Abbott Laboratories, Columbus, OH. A Pontes-Arruda received research grants from Ross Products Division, Abbott Laboratories and has participated in advisory board activities for Abbott Nutrition International. P Singer participates in the Abbott Laboratories Advisory Board and receives honoraria for lectures.

Received for publication January 28, 2008. Accepted for publication July 24, 2008.

1. Weinacker AB, Vaszar LT. Acute respiratory distress syndrome: physiology and new management strategies. Ann Rev Med.2001; 52:221 -237.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
2. Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med.2005; 353:1685 -1693.[Abstract/Free Full Text]
3. Jain R, DalNogare A. Pharmacological therapy for acute respiratory distress syndrome. Mayo Clin Proc.2006; 81:205 -212.[Abstract/Free Full Text]
4. Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P; Canadian Critical Care Clinical Practice Guidelines Committee. Canadian clinical practice guidelines for nutrition support in mechanically ventilated patients, critically ill adult patients. JPEN J Parenter Enteral Nutr. 2003;27:355 -373.[Abstract/Free Full Text]
5. Heyland DK, Dhaliwal R. Immunonutrition in the critically ill: from old approaches to new paradigms. Intensive Care Med.2005; 31:501 -503.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
6. Mancuso P, Whelan J, DeMichele SJ, Snider CC, Guszcza JA, Karlstad MD. Dietary fish oil and borage oil suppress intrapulmonary proinflammatory eicosanoids biosynthesis and attenuate pulmonary neutrophil accumulation in endotoxemic rats. Crit Care Med.1997; 25:1198 -1206.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
7. Mancuso P, Whelan J, DeMichele SJ, et al. Effects of eicosapentaenoic acid on lung permeability and alveolar macrophage eicosanoids synthesis in endotoxic rats. Crit Care Med.1997; 25:523 -532.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8. Murray MJ, Kumar M, Gregory TJ, Banks PL, Tazelaar HD, DeMichele SJ. Select dietary fatty acids attenuate cardiopulmonary dysfunction during acute lung injury in pigs. Am J Physiol.1995; 269:H2090 -H2099.[Web of Science][Medline] [Order article via Infotrieve]
9. Palombo JD, DeMichele SJ, Boyce PJ, et al. Effect of short-term enteral feeding with eicosapentaenoic and gamma-linolenic acids on alveolar macrophage eicosanoid synthesis and bactericidal function in rats. Crit Care Med.1999; 27:1908 -1915.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. Pacht ER, DeMichele SJ, Nelson JL, Hart J, Wennberg AK, Gadek JE. Enteral nutrition with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants reduces alveolar inflammatory mediators and protein influx in patients with acute respiratory distress syndrome. Crit Care Med. 2003;31:491 -500.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Gadek J, DeMichele S, 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;27:1409 -1420.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
12. Singer P, Theilla M, Fisher H, Gibstein L, Grozovski E, Cohen J. Benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in ventilated patients with acute lung injury. Crit Care Med.2006; 34:1033 -1038.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
13. Pontes-Arruda A, Aragão AM, Albuquerque JD. Effects of enteral feeding with eicosapentaenoic acid (EPA), gamma-linolenic acid and antioxidants in mechanically ventilated patients with severe sepsis and septic shock. Crit Care Med.2006; 34:2325 -2333.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
14. Heyland DK, MacDonald S, Keefe L, Drover JW. Total parenteral nutrition in critically ill patients: a meta-analysis. JAMA. 1998;280:2013 -2019.[Abstract/Free Full Text]
15. Doig GS, Simpson F, Delaney A. A review of the true methodological quality of nutritional support trials conducted in the critically ill: time for improvement. Anesth Analg.2005; 100:527 -533.[Abstract/Free Full Text]
16. Schultz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA.1995; 273:408 -412.[Abstract/Free Full Text]
17. Huwiler-Muntener K, Juni P, Junker C, Egger M. Quality of reporting of randomized trials as a measure of methodologic quality. JAMA. 2002;287:2801 -2804.[Abstract/Free Full Text]
18. Egger M, Juni P, Bartlett C, Holenstein F, Sterne J. How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? Empirical study. Health Technol Assess. 2003;7:1 -76.[Medline] [Order article via Infotrieve]
19. Graf J, Doig GS, Cook DJ, Vincent JL, Sibbald WJ. Randomized, controlled clinical trials in sepsis: has methodological quality improved over time? Crit Care Med.2002; 30:461 -472.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
20. Lachin JM. Statistical considerations in the intent-to-treat principle. Control Clin Trials.2000; 21:167 -189.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
21. Flather MD, Farkouth ME, Pogue JM, Yusuf S. Strengths and limitations of meta-analysis: larger studies may be more reliable. Control Clin Trials.1997; 18:568 -579.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
22. Haynes R, Wilczynski N, McKibbon A, Walker C, Sinclair J. Developing optimal search strategies for detecting clinically sound studies in MEDLINE. J Am Med Inform Assoc.1994; 1:447 -458.[Abstract/Free Full Text]
23. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699 -709.[Abstract/Free Full Text]
24. Borenstein M, Hedges L, Higgins J, Rothstein H. Introduction to Meta-Analysis. Chichester, UK: Wiley;2008 .
25. Mayer D. Meta-analysis and systematic reviews. In: Mayer D, ed. Essential Evidence-Based Medicine. Cambridge, UK: Cambridge University Press; 1994:321 -328.
26. Elamin M, Hughes LF, Drew D. Effect of enteral nutrition with eicosapentaenoic acid (EPA), gamma-linolenic acid (GLA), and antioxidants reduced alveolar inflammatory mediators and proteins influx in patients with acute respiratory distress syndrome (ARDS). Chest.2005; 128(suppl):225S .[Abstract]
27. Moran V, Grau T, García-de-Lorenzo A, et al. Effect of an enteral feeding with eicosapentaenoic and gamma-linolenic acids on the outcome of mechanically ventilated critically ill septic patients. Crit Care Med. 2006;34:A70 .
28. DeMichele SJ, Wood SM, Wennberg AK. A nutritional strategy to improve oxygenation and decrease morbidity in patients who have acute respiratory distress syndrome. Respir Care Clin N Am.2006; 12:547 -566.[Medline] [Order article via Infotrieve]
29. Mizock BA. Nutritional support in acute lung injury and acute respiratory distress syndrome. Nutr Clin Pract.2001; 16:319 -328.[Abstract/Free Full Text]
30. Mizock BA, DeMichele SJ. The acute respiratory distress syndrome: role of nutritional modulation through dietary lipids. Nutr Clin Pract. 2004;19:563 -574.[Abstract/Free Full Text]
31. Nelson JL, DeMichele SJ, Pacht E, Wennberg AK; Enteral Nutrition in ARDS Study Group. Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants on antioxidant status in patients with acute respiratory distress syndrome. JPEN J Parenter Enteral Nutr. 2003;27:98 -104.[Abstract/Free Full Text]
32. Denys A, Hichami A, Khan NA. n-3 PUFAs modulate T-cell activation via protein kinase C-alpha and -epsilon and the NF-kappaB signaling pathway. J Lipid Res.2005; 46:752 -758.[Abstract/Free Full Text]
33. Calder PC. N-3 polyunsaturated fatty acids and inflammation: from molecular biology to the clinic. Lipids.2003; 38:343 -352.[Web of Science][Medline] [Order article via Infotrieve]
34. Hasturk H, Kantarci A, Goguet-Surmenian E, et al. Resolvin E1 regulates inflammation on the cellular and tissue level and restores tissue homeostasis in vivo. J Immunol.2007; 179:7021 -7029.[Abstract/Free Full Text]
35. Bannenberg G, Arita M, Serhan CN. Endogenous receptor agonists: resolving inflammation. ScientificWorldJournal.2007; 7:1440 -1462.[CrossRef][Medline] [Order article via Infotrieve]
36. Palombo JD, DeMichele SJ, Boyce PJ, Noursalehi M, Forse RA, Bistrian BR. Metabolism of dietary alpha-linolenic acid vs eicosapentaenoic acid in rat immune cell phospholipids during endotoxemia. Lipids. 1998;33:1099 -1105.[Web of Science][Medline] [Order article via Infotrieve]
37. Mayes T, Gottschlich M, Kagan R. An evaluation of the safety and efficacy of an anti-inflammatory, pulmonary enteral formula in the treatment of pediatric burn patients with respiratory failure. J Burn Care Res. 2008;29:82 -88.[Web of Science][Medline] [Order article via Infotrieve]
38. Nadkarni V, DeMichele S, Goldstein B, Checchia P, Ayad O, Jacobs B; The Nutritional Immunomodulation in Children with Lung Injury (NICLI) Study Group. Safety of an enteral formula enriched with eicosapentaenoic and gamma-linolenic acids in critically ill children with acute lung injury. Crit Care Med.2005; 33:172M .
39. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303 -1310.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
40. Salipante DM. Developing a multidisciplinary weaning unit through collaboration. Crit Care Nurse.2002; 22:30 -39.[Free Full Text]
41. Teres D, Rapoport J, Lemeshow S, Kim S, Akhras. Cost of care associated with early sepsis (first 24 hours of ICU admission) in a United States medical center. Crit Care.2001; 5(suppl 1):P258 .

Journal of Parenteral and Enteral Nutrition, Vol. 32, No. 6, 596-605 (2008)
DOI: 10.1177/0148607108324203


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