From our facility to yours–wishing you Happy Holidays and a New Year free of aspiration, C.Diff and high gastric residuals!
We do not host training programs in December, but here at UVA there is never a danger that we will become too idle. In between stress-testing our gastric emptying at Thanksgiving and preparing for the next round of holiday festivities, we made time for journal club. We have been awaiting the full results of this month’s article, and moved it into the fast-track for journal club once it was available.
Rice TW, Wheeler AP, Thompson BT, et al; NHLBI ARDS Clinical Trials Network Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA. 2011;306(14):1574-81.
This study was part of the very large National Heart, Lung, and Blood Institute (NHLBI) ARDS Clinical Trial Network study – the EDEN-OMEGA trial. EDEN-OMEGA was a multi-center study that was designed to answer 2 questions by randomizing patients with acute lung injury (ALI)/ARDS to receive omega-3/gamma-linolenic fatty acids with antioxidants vs placebo and also trophic compared to full feeding in a 2X2 factorial design. In the OMEGA arm of the study, participants were randomized to receive a twice daily supplement of Omega-3 and gamma-linolenic fatty acids with vitamin C and E, b-carotene, zinc, selenium, L-carnitine and taurine in doses similar to 1600-1800 calories of the commercial formula designed for ALI/ARDS patients. The placebo supplement was isocaloric composed of carbohydrates and 16 gms more protein/day than the study supplement.
The primary outcome of this study was ventilator-free days (number of days alive and breathing without assistance from randomization until day 28). Secondary end points included 60-day mortality before hospital discharge with unassisted breathing, number of ICU- and organ failure–free days, frequency of gastrointestinal intolerance, plasma levels of IL-6 and IL-8 on days 3 and 6, urinary levels of series 4 and 5 leukotrienes on day 6, and development of new infections. Selected plasma fatty acid levels were also measured at baseline and on days 3, 6, and 12.
Inclusion and Exclusion Criteria were:
Patients with ALI (PaO2/FiO2 < 300) who required mechanical ventilation and whose physicians intended to start enteral nutrition.
There were more than 30 exclusion criteria (too many to list in full), but the most common reasons patients were excluded were previous severe chronic lung disease, greater than 48 hrs since ALI diagnosis or 72 hours since intubation, inability to obtain consent, likely fatal underlying disease, recent intracranial hemorrhage, severe liver disease, moribund, refractory shock, coagulopathy or refused consent
Major Results reported by authors:
This study was planned to have a maximum enrollment of 1000 patients, but the data and safety monitoring board stopped the study at the first interim analysis after examining data from 272 patients.
The n-3 supplement group had significantly fewer ventilator-free days to study day 28 compared with controls (14.0 vs 17.2, P=0.02) and significantly fewer ICU-free days (14.0 vs 16.7, P=0.04).
The n-3 supplement group also appeared to have greater 60-day mortality than the placebo group, with 38 of the 143 patients (26.6%) expired compared with 21 of the 129 (16.3%) in the control group (P=0.054). After the investigators adjusted for baseline variables that are associated with mortality in ALI, the 60-day mortality in n-3 group was 25.1% vs 17.6% in the control group (P=0.11).
Patients in both groups received an average of 85% of the planned twice-daily dosages of the study supplement. Patients receiving the n-3 supplement had significantly more instances of diarrhea, which occurred in 28.7% of the n-3 group and 20.9% of the control group (P=0.001).
Plasma EPA levels were increased 8-fold on days 3, 6, and 12 in the study group, but were unchanged in the control group. Plasma levels of the arachidonic acid, IL-6, IL-8, leukotriene E4, leukotriene E5 and urinary levels of F2-isoprostane were not significantly different between the study and control groups. Urinary levels of F3-isoprostanes (derived from n-3 fatty acids) were significantly higher in the n-3 group on day 6 compared with controls.
The authors concluded that: “..twice-daily enteral supplementation of n-3 fatty acids, GLA, and antioxidants change plasma levels of n-3 fatty acids, but do not improve clinical outcomes or biomarkers of systemic inflammation in patients with ALI and in fact may be harmful.”
This was a double-blind, randomized study that has the advantage over previous studies of EPA/GLA/antioxidants of being multi-centered, and importantly, does not use a high-fat control formula. The use of a supplement separate from enteral feedings allowed patients to receive the study formula without the delays that can arise from enteral feeding interruptions or intolerance.
The fact that the results of this study suggest that EPA/GLA/antioxidants may be harmful in ALI/ARDS was a surprise and has led to a number of theories about why the results may be so different from the previous studies. The most obvious thought would be that perhaps EPA/GLA/antioxidants only appear to have benefits when compared to potentially detrimental high-fat enteral feedings during ALI/ARDS. Of course, it is conceivable that continuous infusion of EPA/GLA/antioxidants in concert with providing the full spectrum of nutrients in enteral feedings has different physiologic effects than 2X/day bolus feedings. There is data that continuous enteral feeding with omega-3 fatty acids will affect the composition of cell membrane phospholipids within 7 days1, but it is unclear if a 2X/day bolus delivery would affect the composition of cell membranes quite so rapidly.
The other aspect of this study that is important to remember is that the patients in the OMEGA study were part of a larger trial with a 4X4 factorial design, meaning that approximately ½ of the patients in both groups would have been receiving only trophic feedings for the first 6-7 days of the study. The control patients did receive 16 gm more protein/day than the study supplement group – a difference that would not be expected to impact outcomes in fully fed patients. However, in those patients receiving minimal nutrition for 6+ days, the increased carbohydrate and protein provided to the control group of the OMEGA arm could theoretically have crossed a threshold and been enough extra nutrition to impact outcome. It is also unclear if receiving minimal nutrition during critical illness and using the additional EPA/GLA to meet energy needs could have altered the effects of the supplement.
Another possible explanation is that EPA/GLA/antioxidants simply may not offer any clinical advantage in ALI/ARDS when “modern” lung-protective ventilation, early antibiotic, adequate resuscitation, adequate glucose control, etc. strategies are used. It is also possible that the positive effects seen in previous studies were simply because those studies are far too small to reliably study outcome in a diverse population of critically ill patients. Even though the OMEGA study was stopped early, it was still nearly 3 times larger than the 2006 study of EPA/GLA/antioxidants (272 compared to 103 patients analyzed).2 In populations of critically ill adults, it required an “n” of 1696 total patients to be able to firmly establish that a therapy in septic patients did not have benefits, after an earlier study with smaller numbers of the sickest patients actually suggested a benefit in that subgroup (Xigris® study).3 There is no other facet of critical care in which it would be acceptable to make changes in clinical practice based on studies of only 103 patients, or even a meta analysis of 411 patients.4
Our Take Home Message
Twice-daily enteral supplementation of n-3 fatty acids, GLA, and antioxidants does not improve clinical outcomes in patients with ALI, and in fact, may be harmful.
There is a need for (much) larger multicenter trials of enteral formulas containing EPA/GLA/antioxidants compared to standard feedings before these formulas are routinely used in clinical practice
The nutrition support and medical community has learned too many times over the potential negative effects of using therapies before they are adequately tested – to repeat those mistakes, knowing what we do today, would be foolish in the extreme.
1. Adams S, Yeh YY, Jensen GL. Changes in plasma and erythrocyte fatty acids in patients fed enteral formulas containing different fats. JPEN J Parenter Enteral Nutr. 1993;17(1):30-34.
2. Pontes-Arruda A, Aragão 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(9):2325-33.
3. 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(10):699-709.
4. Pontes-Arruda A, Demichele S, Seth A, Singer P. 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(6):596-605.
Other News on the UVAHS GI Nutrition Website: (www.ginutrition.virginia.edu):
GI Focused Weekend Warrior Nutrition Support Program
March 10-11, 2012 in Charlottesville, VA
Upcoming Webinars for Spring 2012:
–Tuesday, February 21–Nutrition Support in Pancreatitis–Carol Rees Parrish, MS, RD
–Wednesday, March 21–Liver Disease, Part I: Hepatic Encephalopathy–Neeral Shah, MD
–April–Liver Disease, Part II: Nutrition Support in Liver Disease–Joe Krenitsky, MS, RD
–May–Enteral Nutrition–Carol Parrish, MS, RD
–June–Effectively Communicating with Physicians–Kate Willcutts, MS, RD, CNSC
Check out What’s New:
· “Nutrition Support Blog”
Latest Practical Gastroenterology article:
· Carol took December off 🙂
Joe Krenitsky MS, RD
Carol Rees Parrish MS, RD
PS – Please feel free to forward on to friends and colleagues.