title: Glutamine and antioxidants in the critically ill patient: a post hoc analysis of a large-scale randomized trial.
abstract: BACKGROUND
  The recent large randomized controlled trial of glutamine and antioxidant supplementation suggested that high-dose glutamine is associated with increased mortality in critically ill patients with multiorgan failure. The objectives of the present analyses were to reevaluate the effect of supplementation after controlling for baseline covariates and to identify potentially important subgroup effects.
  
  
  METHODS
  This study was a post hoc analysis of a prospective factorial 2 × 2 randomized trial conducted in 40 intensive care units in North America and Europe. In total, 1223 mechanically ventilated adult patients with multiorgan failure were randomized to receive glutamine, antioxidants, both glutamine and antioxidants, or placebo administered separate from artificial nutrition. We compared each of the 3 active treatment arms (glutamine alone, antioxidants alone, and glutamine + antioxidants) with placebo on 28-day mortality. Post hoc, treatment effects were examined within subgroups defined by baseline patient characteristics. Logistic regression was used to estimate treatment effects within subgroups after adjustment for baseline covariates and to identify treatment-by-subgroup interactions (effect modification).
  
  
  RESULTS
  The 28-day mortality rates in the placebo, glutamine, antioxidant, and combination arms were 25%, 32%, 29%, and 33%, respectively. After adjusting for prespecified baseline covariates, the adjusted odds ratio of 28-day mortality vs placebo was 1.5 (95% confidence interval, 1.0-2.1, P = .05), 1.2 (0.8-1.8, P = .40), and 1.4 (0.9-2.0, P = .09) for glutamine, antioxidant, and glutamine plus antioxidant arms, respectively. In the post hoc subgroup analysis, both glutamine and antioxidants appeared most harmful in patients with baseline renal dysfunction. No subgroups suggested reduced mortality with supplements.
  
  
  CONCLUSIONS
  After adjustment for baseline covariates, early provision of high-dose glutamine administered separately from artificial nutrition was not beneficial and may be associated with increased mortality in critically ill patients with multiorgan failure. For both glutamine and antioxidants, the greatest potential for harm was observed in patients with multiorgan failure that included renal dysfunction upon study enrollment.
authors.affiliation: Kingston General Hospital, Kingston, Ontario, Canada dkh2@queensu.ca.
authors.forename: Daren K
authors.initials: DK
authors.lastname: Heyland
authors.affiliation: University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Elke
authors.affiliation: St Joseph's Healthcare, Hamilton, Ontario, Canada.
authors.forename: Deborah
authors.initials: D
authors.lastname: Cook
authors.affiliation: University Hospital CHUV, Lausanne, Switzerland.
authors.forename: Mette M
authors.initials: MM
authors.lastname: Berger
authors.affiliation: University of Colorado School of Medicine, Aurora.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Wischmeyer
authors.affiliation: Hôpital du Sacré-Coeur de Montreal, Quebec, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Albert
authors.affiliation: Kingston General Hospital, Kingston, Ontario, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Muscedere
authors.affiliation: Ottawa Hospital, General Campus, Ottawa, Ontario, Canada.
authors.forename: Gwynne
authors.initials: G
authors.lastname: Jones
authors.affiliation: Kingston General Hospital, Kingston, Ontario, Canada.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Day
mesh_terms: D000368:Aged; D000975:Antioxidants / Q000009:adverse effects* / Q000627:therapeutic use; D016638:Critical Illness / Q000401:mortality / Q000628:therapy*; D019587:Dietary Supplements / Q000009:adverse effects*; D005973:Glutamine / Q000009:adverse effects* / Q000627:therapeutic use; D017052:Hospital Mortality; D006801:Humans; D007668:Kidney; D016015:Logistic Models; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000401:mortality / Q000628:therapy*; D016017:Odds Ratio; D011446:Prospective Studies
chemical_list: D000975:Antioxidants; D005973:Glutamine
keywords: antioxidants; critical care; glutamine; post hoc analysis; randomized clinical trials