A randomized trial of glutamine and antioxidants in critically ill patients.
This review may be edited
Posted By: Elizabeth Sweetman
Posted Date: 09/05/2013
Title: A randomized trial of glutamine and antioxidants in critically ill patients.
Authors: Heyland D, Muscedere J, Wischmeyer PE, Cook D, Jones G, Albert M, Elke G, Berger MM, Day AG; Canadian Critical Care Trials Group.
Reference: N Engl J Med. 2013 Apr 18;368(16):1489-97.
Link: Click here for a direct link to the paper. A password may be required for access to fulltext.
Abstract: BACKGROUND: Critically ill patients have considerable oxidative stress. Glutamine and antioxidant supplementation may offer therapeutic benefit, although current data are conflicting.
METHODS: In this blinded 2-by-2 factorial trial, we randomly assigned 1223 critically ill adults in 40 intensive care units (ICUs) in Canada, the United States, and Europe who had multiorgan failure and were receiving mechanical ventilation to receive supplements of glutamine, antioxidants, both, or placebo. Supplements were started within 24 hours after admission to the ICU and were provided both intravenously and enterally. The primary outcome was 28-day mortality. Because of the interim-analysis plan, a P value of less than 0.044 at the final analysis was considered to indicate statistical significance.
RESULTS: There was a trend toward increased mortality at 28 days among patients who received glutamine as compared with those who did not receive glutamine (32.4% vs. 27.2%; adjusted odds ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.64; P=0.05). In-hospital mortality and mortality at 6 months were significantly higher among those who received glutamine than among those who did not. Glutamine had no effect on rates of organ failure or infectious complications. Antioxidants had no effect on 28-day mortality (30.8%, vs. 28.8% with no antioxidants; adjusted odds ratio, 1.09; 95% CI, 0.86 to 1.40; P=0.48) or any other secondary end point. There were no differences among the groups with respect to serious adverse events (P=0.83).
CONCLUSIONS: Early provision of glutamine or antioxidants did not improve clinical outcomes, and glutamine was associated with an increase in mortality among critically ill patients with multiorgan failure. (Funded by the Canadian Institutes of Health Research; number, NCT00133978.).
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
Study Group assignments were concealed using permuted blocks of random size and a secure central web based system.
Ventilated ICU Patients with two or more organ failures relating to their acute illness were randomised to one of four groups;
1. Placebo (via IV and EN routes)
2. Glutamine Supplementation (via IV and EN routes)
3. Antioxidant Supplementation (via IV and EN routes)
4. Glutamine and Antioxidant Supplementation (via IV and EN routes)
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
Yes. All patients 1223 randomised patients were accounted for in Figure 1 p. 1491 and in the results section of the manuscript.
There were 5/1223 (0.4%) study patients were not included in the primary outcome analysis due to loss to follow-up. 1218 patients were included in the intention to treat analysis.
2b. Were patients analyzed in the groups to which they were randomized?
Yes. All patients randomised into this study were analysed in the groups to which they were randomised.
3. Were patients, health workers, and study personnel blind to treatment?
All study supplements were blinded. Supplements and placebo solutions were prepared by an unblinded study pharmacist and delivered as masked solutions to participating ICUs.
4. Were the groups similar at the start of the trial?
Yes all four groups were similar at the start of the trial (See Table 1, 1492 - 1493).
5. Aside from the experimental intervention, were the groups treated equally?
Difficult to establish.
There was no mention by the authors of differences in care aside from the experimental intervention nor a table in the manuscript or supplmentary appendix.
What are the Results?
1. How large was the treatment effect?
Note: There was no significant interaction between Glutamine and Antioxidants P = 0.48, Results, Primary Outcome Section.
Primary Outcome:
28 Day Mortality -
Glutamine : A trend toward increased mortality in the Glutamine Group compared to the No Glutamine Group
32.4% Glutamine Group vs 27.2% No Glutamine Group, adjusted OR 1.28, P = 0.05
Antioxidants : No difference in the Antioxidant Group vs the No Antioxidant Group
30.8% Antioxidant Group vs 28.8% No Antioxidant Group, adjusted OR 1.09, P = 0.48
Secondary Outcomes:
In Hospital Mortality -
Glutamine : Statistically increased mortality in in-hospital mortality in Glutamine vs No Glutamine Groups
37.2% Glutamine Group vs 31.0% No Glutamine Group (P = 0.02)

Antioxidants : No difference in in-hospital mortality in Antioxidant vs No Antioxidant Groups
35.0% Antioxidant Group vs 33.1% No Antioxidant Group (P = 0.51)
6 Month Mortality -
Glutamine : Statistically increased mortality in 6 month mortality in Glutamine vs No Glutamine Groups
43.7% Glutamine Group vs 40.4% No Glutamine Group (P = 0.02)
Antioxidants : No difference in 6 month mortality in Antioxidant vs No Antioxidant Groups
40.4% Antioxidant Group vs 40.6% No Antioxidant Group (P = 0.87)
2. How precise was the estimate of the treatment effect?
28 Day Mortality -
Glutamine vs No Glutamine
95% CI 1.00 - 1.64
Antioxidants vs No Antioxidants
95% CI 0.86 - 1.40
Will the Results Help Me In Caring For My Patients?
1. Can the results be applied to my patient care?
Yes. The patients within this trial can be identified in all intensive care units.
2. Were all clinically important outcomes considered?
Outcomes of physical function, quality of life and costs could have been explored in this trial.
3. Are the likely treatment benefits worth the potential harms and costs?
There were no significant benefits found for either Glutamine or Antioxidants. In terms of the primary outcome of 28 Day Mortality there was a trend toward harm with Glutamine (P = 0.05) and no difference with Antioxidants (P = 0.48).
Given the results of this trial it is unlikely that ICUs who do not already use Glutamine and /or Antioxidants in this patient population will start using them.

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A randomized trial of glutamine and antioxidants in critically ill patients.

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