Critically ill patients are at risk for significant oxidative stress; however, several small analyses have proposed that supplementation with glutamine, with or without antioxidants, may improve survival. Heyland and colleagues from the Canadian Critical Care Trials Group conducted an international, multicenter study to test the hypothesis that 28-day mortality in critically ill adults would be reduced by supplementation with glutamine, with or without antioxidants. Results were published in a recent issue of The New England Journal of Medicine.

In a randomized factorial, double-blinded, multicenter trial, consecutive adults admitted to an intensive care unit (ICU) and receiving mechanical ventilation were enrolled. Additionally, patients were required to have two or more organ failures related to their critical illness. Subjects were randomized to one of four groups: placebo, glutamine, antioxidants (selenium, beta carotene, vitamins E and C), or antioxidants plus glutamine. The primary outcome was 28-day mortality; several secondary outcomes were also studied. 

There were 1,223 patients randomized to one of four groups. All were followed appropriately, and an intention-to-treat analysis was conducted. No statistically significant baseline differences were detected among the four groups. Overall 28-day mortality was 29.8%.  Patients who received glutamine had a trend towards worse mortality at 28 days compared to patients who did not receive glutamine (32.4% vs. 27.2%; adjusted odds ratio [AOR], 1.28; 95% confidence interval [CI], 1.00 to 1.64; P=0.05). The combination of glutamine with antioxidants made no significant difference in survival (AOR, 1.09; 95% CI, 0.86 to 1.40; P=0.48). In-hospital mortality and mortality at 6 months were significantly higher among patients who received glutamine; they also had increases in ICU length of stay, length of mechanical ventilation, and overall hospital length of stay. Antioxidant supplementation had no effect on secondary outcomes.

The findings from this large, robust randomized study are in opposition to those of previous smaller studies. In this study, a majority of patients received enteral nutrition support and were in multiple organ failure. Moreover, only 1.3% to 3.0 % of patients were not in some form of shock. Thus, it is possible that glutamine and antioxidants may not be as efficacious in a population of seriously ill patients. The lack of benefit with antioxidants may also be explained by the patient population; these agents may be more efficacious in areas with a higher prevalence of antioxidant deficiency (e.g., selenium). For critically ill ICU patients in multiple organ failure, this work suggests that glutamine administration, with or without antioxidants, does not confer a therapeutic benefit and may cause harm.

Concise Critical Appraisal is a regular feature authored by SCCM member Samuel M. Galvagno Jr., DO, PhD. Each installment highlights journal articles most relevant to the critical care practitioner.