Pharmaconutrition
The increasing recognition of food additives as pharmacologically active agents, rather than nutritional supplements, has been reflected by the changing terminology for this field from immunonutrition to pharmaconutrition. Although pharmaconutrients such as glutamine and selenium have been widely investigated across the critical care spectrum, fatty acids have been specifically used to reduce the production of proinflammatory arachidonic acid metabolites during ALI. In particular, flax oil- or fish oil-derived omega-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), plus the vegetable oil-derived omega-6 fatty acid gamma-linolenic acid (GLA), have been investigated in several clinical studies of ALI.
Early small clinical studies were promising. A double-blind, randomized, controlled trial in 146 enterally fed patients with acute respiratory distress syndrome (ARDS) compared diet containing EPA, DHA, and GLA with an isonitrogenous, isocaloric standard diet at a minimum caloric delivery of 75% of basal energy expenditure, multiplied by 1.3, for at least 4 to 7 days. The intervention was associated with numerous positive effects, including reduced pulmonary neutrophil recruitment, improved oxygenation, reduced durations of ventilation and intensive care unit (ICU) stay, and reduced organ failure. Additionally, this diet was not associated with any major complications. Using similar methodology, the same group performed a follow-up double blind, randomized, controlled trial in 43 ARDS patients, seeking to determine the mechanisms by which this formula induced these changes. Using bronchoalveolar lavage (BAL), they found decreased levels of pulmonary neutrophils and inflammatory markers, with associated reduced alveolar protein levels, and interpreted this as reduced alveolar barrier permeability in the setting of less severe pulmonary inflammation. A third double-blind, randomized, controlled study, using similar formulae and dosing as before, evaluated the effects of this intervention in 165 mechanically ventilated septic patients. Again, several outcome measures were improved, including oxygenation, duration of both ventilation and ICU stay, plus less new organ dysfunction. Also, mortality was significantly reduced (33% vs 52%; absolute risk reduction 19.4%, 95% CI, 0.3 to 36.7). A further randomized, controlled, unblinded study in 100 patients with ALI reported significant improvements in oxygenation, respiratory compliance, and duration of ventilation, but no effect on survival. A systematic review of 24 studies in mixed groups of critically ill burns and trauma patients identified a benefit in the subgroup of studies utilizing fish oils in critically ill patients with sepsis or ARDS, with decreases in mortality (odds ratio 0.42, 95% CI, 0.26 to 0.68; p < 0.001), secondary infections, and length of hospital stay.
To specifically test pharmaconutrients, the recent OMEGA study attempted to disconnect their effects from that of enteral feed, and to protect their delivery in those with feed intolerance. This was a phase 3 prospective, randomized, controlled trial investigating a combination of enterally delivered omega-3 (EPA and DHA) and -6 (GLA) fatty acids and antioxidants in ALI. The intervention was administered separately, twice daily, in enteral boluses. Despite an eightfold increase in plasma EPA levels, the administration of these fatty acids and antioxidants was associated with decreases in both ventilator-free days (14.0 vs 17.2; p = 0.02) and ICU-free days (14.0 vs 16.7; p = 0.04). Consistent with this, these additives were associated with fewer nonpulmonary organ failure-free days (12.3 vs 15.5; p = 0.02), and increased days with diarrhea (29% vs 21%; p = 0.001). Sixty-day hospital mortality was 26.6% in the intervention group and 16.3% in the control group (p = 0.054).
In a further attempt to isolate the effects of omega-3 fatty acids from commercial enteral feeds containing these additives, a prospective, double-blind, randomized, controlled phase 2 study in 90 patients with ALI was undertaken. Congruous with the OMEGA trial, despite increased serum EPA levels, no beneficial effects were observed for either the primary end point of BAL fluid IL-8 level, or secondary outcomes including inflammatory markers, both pulmonary and systemic, durations of organ failures, ventilation, ICU stay, hospital stay, and both in-hospital and 60-day mortality.
Several reasons may explain the failure of these recent studies, including (1) the choice of a different control feed than used previously; (2) a possible inability of bolus delivery of the intervention, in contrast to continuous administration, to reduce inflammation; and for the OMEGA study, (3) a lower mortality (21.7%) than previously reported in similar studies, making it more difficult to demonstrate efficacy; and (4) the factorial nature of the study, where subjects were also randomized to receive trophic or full feed for the first 5 days, potentially causing fatty acids to be consumed for calories in catabolic patients.