title: Glutamine supplementation for critically ill adults.
abstract: BACKGROUND
  Glutamine is a non-essential amino acid which is abundant in the healthy human body. There are studies reporting that plasma glutamine levels are reduced in patients with critical illness or following major surgery, suggesting that glutamine may be a conditionally essential amino acid in situations of extreme stress. In the past decade, several clinical trials examining the effects of glutamine supplementation in patients with critical illness or receiving surgery have been done, and the systematic review of this clinical evidence has suggested that glutamine supplementation may reduce infection and mortality rates in patients with critical illness. However, two recent large-scale randomized clinical trials did not find any beneficial effects of glutamine supplementation in patients with critical illness.
  
  
  OBJECTIVE
  The objective of this review was to:1. assess the effects of glutamine supplementation in critically ill adults and in adults after major surgery on infection rate, mortality and other clinically relevant outcomes;2. investigate potential heterogeneity across different patient groups and different routes for providing nutrition.
  
  
  METHODS
  We searched the Cochrane Anaesthesia Review Group (CARG) Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 5); MEDLINE (1950 to May 2013); EMBASE (1980 to May 2013) and Web of Science (1945 to May 2013).
  
  
  METHODS
  We included controlled clinical trials with random or quasi-random allocation that examined glutamine supplementation versus no supplementation or placebo in adults with a critical illness or undergoing elective major surgery. We excluded cross-over trials.
  
  
  METHODS
  Two authors independently extracted the relevant information from each included study using a standardized data extraction form. For infectious complications and mortality and morbidity outcomes we used risk ratio (RR) as the summary measure with the 95% confidence interval (CI). We calculated, where appropriate, the number needed to treat to benefit (NNTB) and the number needed to treat to harm (NNTH). We presented continuous data as the difference between means (MD) with the 95% CI.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anesthesiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Room 404, Building 3, Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, Shanghai, China, 200438.
authors.forename: Kun-Ming
authors.initials: KM
authors.lastname: Tao
authors.forename: Xiao-Qian
authors.initials: XQ
authors.lastname: Li
authors.forename: Li-Qun
authors.initials: LQ
authors.lastname: Yang
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Yu
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Lu
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Sun
authors.forename: Fei-Xiang
authors.initials: FX
authors.lastname: Wu
mesh_terms: D000328:Adult; D016638:Critical Illness / Q000401:mortality; D003428:Cross Infection / Q000401:mortality / Q000517:prevention & control*; D005973:Glutamine / Q000008:administration & dosage*; D017052:Hospital Mortality; D006801:Humans; D007362:Intensive Care Units / Q000706:statistics & numerical data; D007902:Length of Stay / Q000706:statistics & numerical data; D061366:Numbers Needed To Treat; D016032:Randomized Controlled Trials as Topic; D012121:Respiration, Artificial / Q000706:statistics & numerical data; D013514:Surgical Procedures, Operative / Q000401:mortality
chemical_list: D005973:Glutamine