Glutamine, fish oil and antioxidants in critical illness: MetaPlus trial post hoc safety analysis

BACKGROUND: The role of plasma glutamine, fish oil and antioxidants concentrations in the treatment effect of immune-modulating high-protein versus high-protein enteral nutrition on 6-month mortality in critically ill patients is explored, as unexpected negative outcomes of recent large randomized controlled trials on immune-modulating nutrients have raised questions about safety of these interventions. METHODS: Post hoc analysis of the MetaPlus randomized controlled trial which was performed in a total of 301 medical, surgical and trauma critically ill patients in fourteen European intensive care units. Patients received either immune-modulating (glutamine, fish oil and antioxidant enriched) high-protein (IMHP) or isocaloric high-protein (HP) enteral nutrition. Six-month mortality and baseline, day 4 and day 8 plasma concentrations of glutamine, (eicosapentaenoicacid + decosahexaenoicacid)/long-chain fatty acid plasma level ratio ((epa + dha)/lcf ratio), selenium, vitamin c, vitamin e and zinc were measured. RESULTS: The harmful treatment effect of the IMHP versus HP enteral nutrition on 6-month mortality was only demonstrated in the medical subgroup (HR 2.52, 95% CI 1.36–4.78, P = 0.004). Among medical patients, when corrected for age groups and APACHE-II scores, there were no statistically significant associations between baseline plasma levels and 6-month mortality, except for zinc (HR 1.06, 95% CI 1.00–1.12, P = 0.026). IMHP feeding resulted in statistically significant increase in plasma levels of glutamine, vitamin e, vitamin c and (epa + dha)/lcf ratio from baseline to day 4, while only the change from baseline to day 4 of (epa + dha)/lcf ratio was statistically significant associated with 6-month mortality (HR 1.18, 95% CI 1.02–1.35, P = 0.021) and identified as mediator for the harmful treatment effect of IMHP enteral nutrition among medical ICU patients. CONCLUSION: We hypothesize that the harmful effect of IMHP compared to HP enteral nutrition in a heterogeneous group of critically ill patients is limited to the medical critically ill patients and mediated by an early increase in (epa + dha)/lcf ratio. Trial Registration Dutch Trial Register 26 January 2010 (NTR2181 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2181). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13613-016-0220-y) contains supplementary material, which is available to authorized users.