Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury

Abstract

Context: The omega-3 (n-3) fatty acids docosahexaenoic acid and eicosapentaenoic acid, along with γ-linolenic acid and antioxidants, may modulate systemic inflammatory response 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, and 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.

Results: 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 eicosapentaenoic acid 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.

Trial registration: clinicaltrials.gov Identifier: NCT00609180.

Figure 1

Patient Screening, Enrollment, and Follow-up All 272 enrolled patients had complete follow-up to the earlier of hospital discharge or day 60. The omega-3 (n-3) supplement comprised the n-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid, the omega-6 γ-linolenic acid, and antioxidants. ^aReasons for exclusion sum to more than 2506 because patients could be excluded for more than 1 reason.

Figure 2

Plasma Levels of Eicosapentaenoic Acid (EPA) and Plasma Ratio of EPA to Arachidonic Acid (AA) The omega-3 (n-3) supplement comprised the n-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid, the omega-6 γ-linolenic acid, and antioxidants. Plasma levels of EPA increased almost 8-fold in the n-3 group while remaining unchanged in the control group; AA levels did not change in either group, resulting in a similar increase in plasma EPA:AA ratio. Levels were measured in the first 60 patients. Because of unavailable samples, actual measurements are from 24 n-3 and 30 control patients at baseline (24 in each group at day 3, 17 in each group on day 6, and 8 n-3 and 9 control patients on day 12)

Figure 3

PEEP, Plateau Pressure, and PaO₂:FIO₂ Ratio During Study The omega-3 (n-3) supplement comprised the n-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid, the omega-6 γ-linolenic acid, and antioxidants. Error bars indicate 95% confidence intervals. Positive end-expiratory pressure (PEEP) was similar between groups during the study; plateau pressures were similar between groups except day 2 during the first week (P=.04). Oxygenation (ratio of partial pressure of arterial oxygen [PaO2] to fraction of inspired oxygen [FIO2]) did not differ between groups.

Figure 4

Minute Ventilation and PaCO₂ During Study The omega-3 (n-3) supplement comprised the n-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid, the omega-6 γ-linolenic acid, and antioxidants. Error bars indicate 95% confidence intervals. Minute ventilation was similar between groups except day 3 (P=.01); Partial pressure of arterial carbon dioxide [PaCO2] values were slightly higher in the control group at days 1 (P=.04), 2 (P=.08), and 4 (P=.07).

Figure 5

Proportion Curves of 60-Day Hospital Survival and Unassisted Breathing The omega-3 (n-3) supplement comprised the n-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid, the omega-6 γ-linolenic acid, and antioxidants. Percentages were calculated daily; all patients completed follow-up and the denominators were the complete cohorts (143 for the omega-3 [n-3] group and 129 for the control group). Solid lines are survival curves and represent proportion of patients surviving at each period; dashed lines represent the proportion of patients breathing without assistance at each period. The areas above the solid lines represent the proportion of patients who have died in each group at each period; the areas below the dashed lines represent the proportion of patients alive and free of mechanical ventilation in each group at each period. Areas between the solid and dashed lines indicate percentages alive and still receiving mechanical ventilation in each group at each period.