Omega-3 not a cure in Acute Lung Injury

Patients with acute lung injury did not benefit from daily supplementation with antioxidants and omega-3 (n-3) fatty acids, which might have done more harm than good, investigators reported.

Supplementation was associated with increased use of ventilator support, more ICU days, and a higher rate of nonpulmonary organ failure.

The 60-day mortality was 43% higher among patients who received supplements, although the difference from the control group did not achieve statistical significance, as reported online in JAMA. 

"Twice-daily enteral supplementation of n-3 fatty acids, gamma-linolenic acid, and antioxidants did not improve the primary endpoint of ventilator-free days or other clinical outcomes in patients with acute lung injury and may be harmful," Todd W. Rice, MD, of Vanderbilt University in Nashville, Tenn., and co-authors wrote in conclusion.

Neutrophilic inflammation drives the pathogenesis of acute lung injury and is mediated by pro-inflammatory and prothrombotic eicosanoid derivatives of cyclooxygenase and 5-lipoxygenase enzymes.

Eicosanoids liberated as a result of inflammation vary in type and activity according to the membrane phospholipid composition -- some are highly reactive and pro-inflammatory and others less active and anti-inflammatory, the authors noted in the introduction.

Patients at risk of acute lung injury have omega-3 levels about 25% of normal and those with established lung injury may have levels <10% of normal, the authors continued.

Several previous clinical trials demonstrated improved oxygenation and respiration in patients with acute lung injury given an enteral formula enriched with omega-3 fatty acids, gamma-linolenic acid, and antioxidants. However, the generalizability of these studies was limited by small sample size and analyses limited to patients who could tolerate treatment, the authors wrote.

To address the shortcomings of previous trials, Rice and colleagues conducted a phase III trial of twice-daily bolus-administration of omega 3-supplemented enteral nutrition versus a standard nutrition formula weighted toward carbohydrates. The trial design included intention-to-treat analysis and inclusion of patients unable to tolerate continuous feeding.

Investigators at 44 centers enrolled adults within 48 hours of development of acute lung injury that required ventilator support and whose treating physicians intended to initiate enteral nutrition. Patients were randomized to twice-daily enteral supplementation with omega-3 fatty acids, gamma-linolenic acid, and antioxidants or an isocaloric control formula.

Protocol-administered enteral nutrition was administered separately from the supplement.

The primary endpoint was ventilator-free days to study day 28.

At a planned interim analysis, the trial ended prematurely because of futility. At that point 272 patients had been enrolled.

Patients randomized to omega-3 supplementation had an eight-fold increase in plasma eicosapentaenoic acid levels, but had significantly fewer ventilator-free days (14 versus 17.2, P=0.02). The analysis also showed that the study group had:

    Significantly fewer ICU-free days (14 versus 16.7, P=0.04)
    Significantly fewer nonpulmonary organ failure-free days (12.3 versus 15.5, P=0.02)
    60-day hospital mortality of 26.6% versus 16.3% in the control group (P=0.054)
    60-day adjusted mortality of 25.1% versus 17.6% (P=0.11)
    Significantly more days with diarrhea (29% versus 21%, P=0.001)

Omega-3 supplementation also did not afford protection against nosocomial infection or improve nonpulmonary organ function, the authors wrote in their discussion.

"Despite significant increases in plasma n-3 levels, we did not demonstrate a reduction in levels of inflammatory biomarkers," Rice and co-authors wrote. "The reason why twice-daily supplementation failed to alter plasma biological marker levels is unclear."

"Although incorporation of n-3 fatty acids into cell membranes was not directly measured, data suggest that plasma levels correlate well with phospholipid membrane content, suggesting that our administration of n-3 fatty acids should have had a biological effect," they added.

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