title: Glutamine, fish oil and antioxidants in critical illness: MetaPlus trial post hoc safety analysis.
abstract: 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.
  
  
  CONCLUSIONS
  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 ).
authors.affiliation: Nutricia Research, Utrecht, The Netherlands.
authors.forename: Zandrie
authors.initials: Z
authors.lastname: Hofman
authors.affiliation: Nutricia Research, Utrecht, The Netherlands.
authors.forename: Sophie
authors.initials: S
authors.lastname: Swinkels
authors.affiliation: Department of Intensive Care, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716 RP, Ede, The Netherlands. zantena@zgv.nl.
authors.forename: Arthur R H
authors.initials: ARH
authors.lastname: van Zanten
keywords: Antioxidants; Clinical outcome; Critically ill; Enteral nutrition; Fish oil; Glutamine; Immune-modulating nutrients; Mortality; Nutritional support