A55-55 Hypoinflammatory ARDS Is Associated With Increased Mortality After Antioxidant and N-3 Fatty Acid Supplementation

Rationale

Preclinical studies and pilot clinical trials support anti-inflammatory and protective effects of omega-3 fatty acid supplementation in acute respiratory distress syndrome (ARDS). However, the largest randomized clinical trial, OMEGA, was stopped early due to futility and possible harm for ARDS patients receiving antioxidants, gamma-linoleic acid, and n-3 fatty acids. Host response subphenotypes are increasingly recognized as a potential source of heterogeneity in ARDS studies. We investigated whether host response subphenotypes impacted differential outcomes in the OMEGA study.

Methods

We performed a secondary analysis of the OMEGA trial (enrollment: January 2, 2008, through February 21, 2009), which randomized adults with ARDS to receive enteral n-3 fatty acids, gamma-linoleic acid, and antioxidant supplementation or an isocaloric control twice daily. We included data from 198 OMEGA participants with available pre-intervention biospecimens and measured plasma inflammatory biomarkers by Luminex assay (Bio-Rad, Hercules, CA). We used a previously published parsimonious model using angiopoetin-2, soluble tumor necrosis factor receptor-1, procalcitonin, and bicarbonate to determine hypoinflammatory and hyperinflammatory sub-phenotypes and investigated differences in 60-day mortality by Fisher’s exact and interaction testing.

Results

The OMEGA subset included 110 participants classified as hypoinflammatory (56%) and 88 as hyperinflammatory (44%). Consistent with prior studies, hypoinflammatory participants had lower severity of illness (median acute physiology and chronic health evaluation [APACHE] III score 78 [interquartile range 64-98] versus 104 [86-122], p < 0.001) compared to hyperinflammatory participants. Hypoinflammatory participants had increased mortality from the OMEGA intervention (28% versus 11% for placebo, p = 0.033) but mortality did not appear to be impacted by the intervention in the hyperinflammatory subphenotype (23% versus 26%, p = 0.807). Interaction testing did not reach statistical significance (p = 0.194).

Conclusions

Hypoinflammatory ARDS patients had higher mortality with antioxidants, n-3 fatty acids, and gamma linolenic acid in the OMEGA study, whereas no significant difference was observed in hyperinflammatory patients. While some results may be limited by sample size, our findings suggest that a majority of patients in the OMEGA study may indeed have experienced harm from the intervention. Future studies are needed to better understand the mechanisms by which omega-3 fatty acid and antioxidant interventions worsened outcomes in hypoinflammatory ARDS, and to determine whether differential responses exist to other fatty acid interventions in ARDS.

This abstract is funded by: NIH