Rapid Review Alert October 7, 2011
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 In EPA & DHA Research

Context: The long-chain omega-3 (n-3) fatty acids, EPA and DHA, along with γ-linolenic acid and antioxidants, may modulate systemic inflammatory responses and improve oxygenation and outcomes in patients with acute lung injury.

Objective: To determine if dietary supplementation of these substances to patients with acute lung injury would increase ventilator-free days to study day 28.

Design, Setting, Participants: The OMEGA study, a randomized, double-blind, placebo-controlled, multicenter trial conducted from January 2, 2008, through February 21, 2009. Participants were 272 adults within 48 hours of developing acute lung injury requiring mechanical ventilation whose physicians intended to start enteral nutrition at 44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. All participants had complete follow-up.

Interventions: Twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants compared with an isocaloric control. Enteral nutrition, directed by a protocol, was delivered separately from the study supplement.

Main Outcome Measure: Ventilator-free days to study day 28. 

 The study was stopped early for futility after 143 and 129 patients were enrolled in the n-3 and control groups. Despite an 8-fold increase in plasma EPA levels, patients receiving the n-3 supplement had fewer ventilator-free days (14.0 vs 17.2; P = .02) (difference, −3.2 [95% CI, −5.8 to −0.7]) and intensive care unit–free days (14.0 vs 16.7; P = .04). Patients in the n-3 group also had fewer nonpulmonary organ failure–free days (12.3 vs 15.5;P = .02). Sixty-day hospital mortality was 26.6% in the n-3 group vs 16.3% in the control group (P = .054), and adjusted 60-day mortality was 25.1% and 17.6% in the n-3 and control groups, respectively (P = .11). Use of the n-3 supplement resulted in more days with diarrhea (29% vs 21%; P = .001).

Conclusions: Twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants did not improve the primary end point of ventilator-free days or other clinical outcomes in patients with acute lung injury and may be harmful.
Rapid Review Alert
Sudden cardiac death
Omega-3s Harmful?

Review of:
Rice TW Wheeler AP Thompson BT deBoisblanc BP Steingrub J Rock P for the NHLBI ARDS Clinical Trials Network (published ahead of print Oct 5, 2011). Enteral Omega-3 fatty acid, gamma–linolenic acid, and antioxidant supplementation in acute lung injury. JAMA doi: 10.1001/jama.2011.1435.

To Better Understand this Review

• ALI - acute lung injury
• ARDS - acute respiratory distress syndrome
• Bolus – delivery of large volume in short period of time
• Enteral nutrition – delivery via gastrointestinal tract 
• GLA – gamma linolenic acid
• Parenteral nutrition – delivery intravenously

Take-Home Message

Contrary to results from previous investigations, including a meta-analysis, the present results suggest that a high-fat (>80%) enteral formula supplement with the long-chain omega-3 fatty acids (25% of total fat), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), along with the n-6 fatty acid, GLA, and antioxidants does not benefit individuals with ALI. When the present results, along with the authors’ conclusion that the enteral formula may have been harmful, are compared to the totality of the scientific evidence, dismissal of EPA & DHA as part of a useful treatment option for ALI would be premature, not to mention irresponsible. Further research is warranted. 

What Else Should You Know? 

  • In the current investigation, the nutrient (i.e. macronutrient and micronutrient) compositions between the enteral formula supplements was very different. While the enteral formulas were isocaloric, the control group received additional protein and carbohydrate (~17g and ~48g respectively), not to mention a disproportionate level of other nutrients. Because the two formulas were not appropriately matched, the contribution of EPA & DHA, or any nutrient for that matter, was confounded by other nutrients. For example, it is well known that protein needs increase when the body is stressed. So, when interpreting the results, how do you factor in the fact that the experimental group received 17 fewer grams of protein compared to the control group? You can't! 
  • In previous investigations demonstrating a benefit of enteral formulas, the nutrition was delivered continuously as the sole source of nutrition, rather than in a bolus as a supplement to the standard non n-3-enriched enteral formula. Delivery via a bolus, like in the present study, may have blunted the modulation of the inflammatory response. Likewise, the use of what was likely a high n-6 enteral supplement for the experimental group may have resulted in proinflammation. 

What Does the Prior Literature Tell Us? 

  • Gadek et al., 1999: The results suggest that a 55% lipid (EPA + GLA) enteral nutrition formula would be a useful adjuvant therapy in the clinical management of patients with or at risk of developing ARDS.
  • Gupta et al., 2011: In ventilated patients with ARDS, omega-3 fatty acids alone do not improve ventilation, length of ICU stay, or survival.
  • Pontes-Arruda et al., 2008: 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.
  • Pontes-Arruda et al., 2011: The data suggest that EPA + GLA may play a beneficial role in the treatment of enterally fed patients in the early stages of sepsis without associated organ dysfunction by contributing to slowing the progression of sepsis-related organ dysfunction, especially with regard to cardiovascular and respiratory dysfunction.
  • Singer et al., 2006: In patients with ALI, a diet enriched with EPA + GLA may be beneficial for gas exchange, respiratory dynamics, and requirements for mechanical ventilation.
  • Stapleton et al., 2011: Fish oil alone did not reduce biomarkers of pulmonary or systemic inflammation in patients with acute lung injury. 

Suggested Citation

Global Organization for EPA and DHA Omega-3s (2011). Omega-3s Harmful? [Peer commentary on the paper “Enteral Omega-3 fatty acid, gamma–linolenic acid, and antioxidant supplementation in acute lung injury” by Rice TW Wheeler AP Thompson BT deBoisblanc BP Steingrub J Rock P for the NHLBI ARDS Clinical Trials Network (published ahead of print Oct 5, 2011). JAMA doi: 10.1001/jama.2011.1435.].


Gadek JE DeMichele SJ Karlstad MD Pacht ER Donahoe M Albertson TE Van Hoozen C Wennberg AK Nelson JL Noursalehi M (1999). Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Enteral Nutrition in ARDS Study Group. Crit Care Med 27:1409-1420.

Gupta A Govil D Bhatnagar S Gupta S Goyal J Patel S Baweja H (2011). Efficacy and safety of parenteral omega 3 fatty acids in ventilated patients with acute lung injury. Indian J Crit Care Med 15:108-113.

Pontes-Arruda A Demichele S Seth A Singer P (2008). 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 32:596-605.

Pontes-Arruda A Martins LF de Lima SM Isola AM Toledo D Rezende E Maia M Magnan GB; the Investigating Nutritional Therapy with EPA, GLA and Antioxidants Role in Sepsis Treatment (INTERSEPT) Study Group (2011). Enteral nutrition with eicosapentaenoic acid, γ-linolenic acid and antioxidants in the early treatment of sepsis: Results from a multicenter, prospective, randomized, double-blinded, controlled study: the INTERSEPT Study. Crit Care 15:R144.

Singer P Theilla M Fisher H Gibstein L Grozovski E Cohen J (2006). Benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in ventilated patients with acute lung injury. Crit Care Med 34:1033-1038.

Stapleton RD Martin TR Weiss NS Crowley JJ Gundel SJ Nathens AB Akhtar SR Ruzinski JT Caldwell E Curtis JR Heyland DK Watkins TR Parsons PE Martin JM Wurfel MM Hallstrand TS Sims KA Neff MJ (2011). A phase II randomized placebo-controlled trial of omega-3 fatty acids for the treatment of acute lung injury. Crit Care Med 39:1655-1662.

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