title: Optimizing the dose of glutamine dipeptides and antioxidants in critically ill patients: a phase I dose-finding study.
abstract: BACKGROUND
  Supplementation with glutamine and antioxidants may be associated with an improvement in clinical outcomes, but the optimal dose of these substrates is unknown. The purpose of this study was to determine the safety of high doses of glutamine combined with antioxidants in critically ill patients.
  
  
  METHODS
  We conducted a single-center, open-label, dose-escalating clinical trial. Mechanically ventilated adult patients with clinical evidence of hypoperfusion were sequentially enrolled to 1 of 5 groups. Group 1 (n = 30): no supplementation; group 2 (n = 7): 0.35 g/kg/d of glutamine IV; group 3 (n = 7): same as group 2 plus 15 g/d of glutamine and 150 microg of selenium enterally; group 4 (n = 7): same as group 2 plus 30 g/d of glutamine and 300 microg of selenium enterally; and group 5 (n = 7): same as group 4 plus an additional 500 microg of selenium IV. After enrollment, nutrients were started as soon as possible. All patients were fed enterally according to clinical practice guidelines.
  
  
  RESULTS
  The primary outcomes for this study were change in sequential organ function assessment (SOFA) score and safety parameters. Secondary outcomes included whole blood glutathione (GSH), thiobarbituric acid reactive substances (TBARS), and blood cells' mitochondrial DNA/nuclear DNA ratio (RATIO). There were no adverse events attributable to the study nutrients, and the maximum and Delta SOFA did not differ across groups. In group 2, a significant decrease in GSH levels was observed (p = .03). With subsequent groups, the slopes straighten out and the p values are no longer significant, suggesting a greater preservation of GSH levels with escalating doses. In group 2, the slope of the line representing TBARS was horizontal. With subsequent groups, the slopes decrease, and by group 5, this decrease reaches statistical significance (p = .03), suggesting a greater reduction in oxidative stress with the higher doses in group 5. The difference in slopes across all groups describing the mitochondrial RATIO is statistically significant (p = .001), again suggesting that, with higher doses, there is increased mitochondrial function.
  
  
  CONCLUSIONS
  The doses of glutamine and antioxidants tested in this study seem to be safe and may have positive effects on some mechanistic endpoints. A larger trial will be necessary to confirm their therapeutic effects.
authors.affiliation: Kingston General Hospital/Queen's University, Kingston, Ontario, Canada. dkh2@post.queensu.ca
authors.forename: Daren K
authors.initials: DK
authors.lastname: Heyland
authors.forename: Rupinder
authors.initials: R
authors.lastname: Dhaliwalm
authors.forename: Andrew
authors.initials: A
authors.lastname: Day
authors.forename: John
authors.initials: J
authors.lastname: Drover
authors.forename: Helene
authors.initials: H
authors.lastname: Cote
authors.forename: Paul
authors.initials: P
authors.lastname: Wischmeyer
mesh_terms: D018806:APACHE; D000368:Aged; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D016638:Critical Illness / Q000628:therapy*; D004272:DNA, Mitochondrial / Q000378:metabolism; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D005260:Female; D005973:Glutamine / Q000008:administration & dosage / Q000627:therapeutic use*; D005978:Glutathione / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D012643:Selenium / Q000008:administration & dosage / Q000627:therapeutic use*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000975:Antioxidants; D004272:DNA, Mitochondrial; D017392:Thiobarbituric Acid Reactive Substances; D005973:Glutamine; D005978:Glutathione; D012643:Selenium