Pharmaconutrition in acute lung injury.

DURING THE LAST DECADE, THERE HAS BEEN A MAJOR conceptual shift in thinking about artificial nutrition provided to critically ill patients. Because of its modulating effect on pathophysiology and emerging evidence about potential effects on clinical outcomes, nutrition is now considered “therapy” and not simply “supportive care. ” For example, arginine-supplemented diets are associated with reduced infections and lengths of hospital stay in patients undergoing elective operations, glutamine-supplemented parenteral nutrition is associated with reduced infection and mortality in critically ill patients, and antioxidant supplementation is associated with reduced mortality among critically ill patients with systemic inflammation. The new model of “pharmaconutrition” calls for trials examining the dose, route, timing, and duration of each intervention, focusing on whether the intervention is designed to restore an existing deficiency, reduce ongoing loss of an expended substrate, and/or provide supratherapeutic exposure. In this issue of JAMA, Rice and colleagues, writing for the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network, report the results from the OMEGA clinical trial involving patients with acute lung injury, who were randomized to receive either placebo or a supplement comprising the omega-3 fatty acids docosahexaenoic and eicosapentaenoic acid, -linolenic acid, and antioxidants. The hypothesis was that the pharmaconutrient supplement would increase ventilator-free days (the primary outcome), favorably influence inflammation, and have other salutary effects on clinical end points. Rigorous features of this trial are the concealed allocation, blinding, standardization of important cointerventions related to ventilation and other care management, high compliance, an a priori analysis plan, adherence to the intention-to-treat principle, and excellent follow-up. One potential challenge to delivering pharmaconutrients is that combining them with commercially available nutrition solutions renders their delivery dependent on patient tolerance of the baseline nutrition solution. In the setting of enteral nutrition, feeding intolerance can preclude contemporary delivery of supplemental pharmaconutrients, attenuating any treatment effect if one exists. Therefore, investigations in pharmaconutrition call for pharmaconutrients to be dissociated from the baseline nutrition. Rice and colleagues devised an innovative approach to this issue, removing key nutrients from a commercially available solution, then using small-volume bolus administration twice daily to maximize adherence. A comparable bolus of standard complete enteral nutrition was used in the control group, resulting in successful delivery of 85% of the intervention in both groups. Reports of trials testing similar pharmaconutrients have increased over time, and results have been propitious. To date, 5 trials enrolling 554 patients evaluated the effect of fish oils, borage oils, and supplemental antioxidants in a commercially available complete enteral solution, delivered continuously to critically ill patients who had established lung injury and organ failure. Meta-analysis suggested a reduction in 28-day mortality rates (risk ratio, 0.67 [95% CI, 0.51 to 0.87]; P=.003), reduced duration of mechanical ventilation (weighted mean difference, −4.83 days [95% CI, −7.96 to −1.70]; P=.002), and reduced intensive care unit (ICU) length of stay (weighted mean difference, −4.48 days [95% CI, −6.49 to −2.47]; P .001). In another recent trial enrolling patients with early sepsis and organ failure, prophylactic administration of these pharmaconutrients was associated with less severe sepsis and septic shock, less multiorgan failure, and shorter duration of mechanical ventilation, ICU stay, and hospital stay. It was therefore unexpected that, although faithful to the prespecified stopping guides, enrollment was suspended early in the OMEGA trial because of perceived futility. Analysis of 272 patients showed that patients receiving the pharma-