Abstract: Our search identified 1999 titles, of which 53 trials (57 articles) fulfilled our inclusion criteria. The 53 included studies enrolled a total of 4671 participants with critical illness or undergoing elective major surgery. We analysed seven domains of potential risk of bias. In 10 studies the risk of bias was evaluated as low in all of the domains. Thirty-three trials (2303 patients) provided data on nosocomial infectious complications; pooling of these data suggested that glutamine supplementation reduced the infectious complications rate in adults with critical illness or undergoing elective major surgery (RR 0.79, 95% CI 0.71 to 0.87, P ＜ 0.00001, I² = 8%, moderate quality evidence). Thirty-six studies reported short-term (hospital or less than one month) mortality. The combined rate of mortality from these studies was not statistically different between the groups receiving glutamine supplement and those receiving no supplement (RR 0.89, 95% CI 0.78 to 1.02, P = 0.10, I² = 22%, low quality evidence). Eleven studies reported long-term (more than six months) mortality; meta-analysis of these studies (2277 participants) yielded a RR of 1.00 (95% CI 0.89 to 1.12, P = 0.94, I² = 30%, moderate quality evidence). Subgroup analysis of infectious complications and mortality outcomes did not find any statistically significant differences between the predefined groups. Hospital length of stay was reported in 36 studies. We found that the length of hospital stay was shorter in the intervention group than in the control group (MD -3.46 days, 95% CI -4.61 to -2.32, P < 0.0001, I² = 63%, low quality evidence). Slightly prolonged intensive care unit (ICU) stay was found in the glutamine supplemented group from 22 studies (2285 participants) (MD 0.18 days, 95% CI 0.07 to 0.29, P = 0.002, I² = 11%, moderate quality evidence). Days on mechanical ventilation (14 studies, 1297 participants) was found to be slightly shorter in the intervention group than in the control group (MD - 0.69 days, 95% CI -1.37 to -0.02, P = 0.04, I² = 18%, moderate quality evidence). There was no clear evidence of a difference between the groups for side effects and quality of life, however results were imprecise for serious adverse events and few studies reported on quality of life. Sensitivity analysis including only low risk of bias studies found that glutamine supplementation had beneficial effects in reducing the length of hospital stay (MD -2.9 days, 95% CI -5.3 to -0.5, P = 0.02, I² = 58%, eight studies) while there was no statistically significant difference between the groups for all of the other outcomes. This review found moderate evidence that glutamine supplementation reduced the infection rate and days on mechanical ventilation, and low quality evidence that glutamine supplementation reduced length of hospital stay in critically ill or surgical patients. It seems to have little or no effect on the risk of mortality and length of ICU stay, however. The effects on the risk of serious side effects were imprecise. The strength of evidence in this review was impaired by a high risk of overall bias, suspected publication bias, and moderate to substantial heterogeneity within the included studies.

Plain-language summary: Glutamine is a non-essential amino acid which is abundant in the healthy human body. There are studies reporting that muscle and plasma glutamine levels are reduced in patients with critical illness, or following major surgery, suggesting that the body's demand for glutamine is increased in these situations. In the past decade, several clinical trials have examined the effects of glutamine supplementation in patients with critical illness or receiving surgery, and a systematic review of this clinical evidence suggested that giving glutamine to these patients may reduce infection and mortality rates. However, two recent large-scale clinical trials, published in 2011 and 2013, did not find any beneficial effects of glutamine supplementation in patients with critical illness. In this review, we searched the available literature until May 2013 and included studies which compared the outcomes with glutamine supplementation and without in adults with a critical illness or undergoing elective major surgery. We included 57 articles from 53 randomized controlled studies in this review. These 53 studies enrolled a total of 4671 patients with critical illness or undergoing elective major surgery. The risk of mortality, length of intensive care unit stay and the incidence of side effects were not significantly different between those given glutamine and those who were not. However, our findings showed that the risk of infectious complications in patients who were given glutamine was 79% of the risk for those who were not. In other words, 12 patients need to be supplemented with glutamine to prevent one case of infection. This result needs to be interpreted cautiously as the quality of evidence for infectious complications was moderate. The funnel plot for this outcome suggested that smaller studies with outcomes favouring non-supplemented patients have not been published, and further research is likely to have an impact on the estimate of effect for this outcome. The findings from this review also suggested that the average length of hospital stay in critically ill or surgical patients supplemented with glutamine was 3.46 days shorter than for patients without glutamine supplementation. This result should also be treated with care as there was substantial heterogeneity between these studies. We found in this review that the mean number of days on mechanical ventilation was 0.69 days shorter in patients with glutamine supplementation than for patients without glutamine supplementation.