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Meta-Analysis
. 2014 Sep 9;2014(9):CD010050.
doi: 10.1002/14651858.CD010050.pub2.

Glutamine supplementation for critically ill adults

Kun-Ming Tao  1 , Xiao-Qian Li, Li-Qun Yang, Wei-Feng Yu, Zhi-Jie Lu, Yu-Ming Sun, Fei-Xiang Wu
Affiliations
Meta-Analysis

Glutamine supplementation for critically ill adults

Kun-Ming Tao et al. Cochrane Database Syst Rev. .

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.

Objectives: 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.

Search 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).

Selection criteria: 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.

Data collection and analysis: 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.

Main 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.

Authors' 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.

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Conflict of interest statement

Kun‐Ming Tao: none known

Xiao‐Qian Li: none known

Li‐Qun Yang: none known

Wei‐Feng Yu: none known

Zhi‐Jie Lu: none known

Yu‐Ming Sun: none known

Fei‐Xiang Wu: none known

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition, Outcome 1 Infectious complications.
1.2
1.2. Analysis
Comparison 1 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition, Outcome 2 Short‐term mortality (within hospital stay or ≤1 month).
1.3
1.3. Analysis
Comparison 1 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition, Outcome 3 Long‐term mortality (≥6 month).
1.4
1.4. Analysis
Comparison 1 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition, Outcome 4 Length of hospital stay (days).
1.5
1.5. Analysis
Comparison 1 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition, Outcome 5 Length of ICU stay (days).
1.6
1.6. Analysis
Comparison 1 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition, Outcome 6 Days on mechanical ventilation.
1.7
1.7. Analysis
Comparison 1 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition, Outcome 7 Serious adverse events.
1.8
1.8. Analysis
Comparison 1 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition, Outcome 8 Side effects (ALT (U/L)).
1.9
1.9. Analysis
Comparison 1 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition, Outcome 9 Side effects (AST (U/L)).
1.10
1.10. Analysis
Comparison 1 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition, Outcome 10 Side effects (creatinine (mg/dl)).
2.1
2.1. Analysis
Comparison 2 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition (elective surgical patients versus critically ill patients), Outcome 1 Infectious complications.
2.2
2.2. Analysis
Comparison 2 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition (elective surgical patients versus critically ill patients), Outcome 2 Short‐term mortality (within hospital stay or ≤1 month).
2.3
2.3. Analysis
Comparison 2 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition (elective surgical patients versus critically ill patients), Outcome 3 Long‐term mortality (≥6 month).
3.1
3.1. Analysis
Comparison 3 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition (parenteral glutamine versus enteral glutamine supplementation), Outcome 1 Infectious complications.
3.2
3.2. Analysis
Comparison 3 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition (parenteral glutamine versus enteral glutamine supplementation), Outcome 2 Short‐term mortality (within hospital stay or ≤1 month).
3.3
3.3. Analysis
Comparison 3 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition (parenteral glutamine versus enteral glutamine supplementation), Outcome 3 Long‐term mortality (≥6 month).
4.1
4.1. Analysis
Comparison 4 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition (patients with malignant disease versus non‐malignant disease), Outcome 1 Infectious complications.
4.2
4.2. Analysis
Comparison 4 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition (patients with malignant disease versus non‐malignant disease), Outcome 2 Short‐term mortality (within hospital stay or ≤1 month).
4.3
4.3. Analysis
Comparison 4 Glutamine‐supplemented nutrition compared to non‐supplemented nutrition (patients with malignant disease versus non‐malignant disease), Outcome 3 Long‐term mortality (≥6 month).
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References

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References to studies excluded from this review

Boelens 2002 {published data only}
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Griffiths 2002 {published data only}
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Grigoryev 2010 {published data only}
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Gurnani 2012 {published data only}
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Heyland 2007 {published data only}
    1. Heyland DK, Dhaliwalm R, Day A, Drover J, Cote H, Wischmeyer P. Optimizing the dose of glutamine dipeptides and antioxidants in critically ill patients: a phase I dose‐finding study. Journal of Parenteral and Enteral Nutrition 2007;31(2):109‐18. [PUBMED: 17308251] - PubMed
Houdijk 1998 {published data only}
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Jiang 2007 {published data only}
    1. Jiang H, Li B, Yan LN, Lu SC, Wen TF, Zhao JC, et al. Effect of Intravenous glutamine‐dipeptide fortified enteral nutrition on clinical outcomes in patients after liver transplantation: A prospective randomized controlled study. Chinese Journal of Clinical Nutrition 2007;15(1):21‐5.
Jones 1999 {published data only}
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Juan 2012 {published data only}
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Koksal 2011 {published data only}
    1. Koksal G, Karaoren G, Akarcay H, Karabulut E, Tunali Y, Vehid S, et al. Comparison of the effects of intravenous, enteral and enteral + intravenous supply of glutamine on malnutrition in sepsis. 31st International Symposium on Intensive Care and Emergency Medicine; 2011; Brussels, Belgium. Critical Care 15. S137.
Liu 2012 {published data only}
    1. Liu H, Ling W, Shen ZY, Jin X, Cao H. Clinical application of immune‐enhanced enteral nutrition in patients with advanced gastric cancer after total gastrectomy. Journal of Digestive Diseases 2012;13(8):401‐6. [PUBMED: 22788925] - PubMed
Mangano 1993 {published data only}
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McQuiggan 2008 {published data only}
    1. McQuiggan M, Kozar R, Sailors RM, Ahn C, McKinley B, Moore F. Enteral glutamine during active shock resuscitation is safe and enhances tolerance of enteral feeding. Journal of Parenteral and Enteral Nutrition 2008;32(1):28‐35. [PUBMED: 18165444] - PubMed
Nitta 2001 {published data only}
    1. Nitta H, Ikeda K, Aoki K. Effects of perioperative great amount of glutamine supplementation by enteral route on amino acids metabolism. Journal of Parenteral and Enteral Nutrition 2001;25:S22. [http://pen.sagepub.com/content/25/1/S1.full.pdf+html]
Ozgultekin 2008 {published data only}
    1. Ozgultekin A, Turan G, Durmus Y, Dincer E, Akgun N. Comparison of the efficacy of parenteral glutamine and branched‐chain amino acid solutions given as extra supplements in parallel to the enteral nutrition in head trauma. e‐SPEN, the European e‐Journal of Clinical Nutrition and Metabolism 2008;3(5):e211‐6. [DOI: 10.1016/j.eclnm.2008.05.006] - DOI
Palmese 2006 {published data only}
    1. Palmese S, Odierna I, Scarano D, Scibili AC, Natale A, Pezza M. Early enteral nutrition enriched with FOS and intravenous glutamine supplementation in intensive care unit patients. Nutritional Therapy Metabolism 2006;24(3):140‐6. [DOI: 10.5301/NTM.2012.9433] - DOI
Schulman 2005 {published data only}
    1. Schulman AS, Willcutts KF, Claridge JA, Evans HL, Radigan AE, O'Donnell KB, et al. Does the addition of glutamine to enteral feeds affect patient mortality?. Critical Care Medicine 2005;33(11):2501‐6. [PUBMED: 16276173] - PubMed
Xiangdong 2012 {published data only}
    1. Xiangdong G, Xiaoyue L. The impact of glutamine on organ function and mortality of patients with severe sepsis. Intensive Care Medicine 2012;38:S31.
Xue 2008 {published data only}
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Ziegler 2004 {published data only}
    1. Ziegler TR, Fernandez‐Estivariz C, Griffith DP, Szeszycki EE, Bazargan N, Luo M, et al. Parenteral nutrition supplemented with alanyl glutamine dipeptide decreases infectious morbidity and improves organ function in critically ill post‐operative patients: results of a double‐blind,randomized,controlled pilot study. Journal of Parenteral and Enteral Nutrition 2004;28:S11‐2.
Ziegler 2012 {published data only}
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References to studies awaiting assessment

Hallay 2002 {published data only}
    1. Hallay J, Kovács G, Kiss Sz S, Farkas M, Lakos G, Sipka S, et al. Changes in the nutritional state and immune‐serological parameters of esophagectomized patients fed jejunaly with glutamine‐poor and glutamine‐rich nutriments. Hepatogastroenterology 2002;49(48):1555‐9. [PUBMED: 12397734] - PubMed

References to ongoing studies

Al Balushi 2010 {published data only}
    1. Effect of Intravenous GLutamine Supplementation IN Trauma Patients Receiving Enteral Nutrition Study Protocol (GLINT Study): A Prospective, Blinded, Randomized, Placebo‐controlled Clinical Trial. Ongoing study March 2011. - PMC - PubMed
Pérez‐Barcena 2010 {published data only}
    1. Effectiveness of Dipeptide N (2)‐L‐Alanyl‐L‐Glutamine in Trauma ICU Patients: Pilot, Prospective, Randomized and Double Blind Study. Ongoing study October 2010.
Rastmanesh 2010 {published data only}
    1. Iranian Intensive Care Unit (ICU) Glutamine Study. Ongoing study October 2010.
Talukdar 2012 {published data only}
    1. Efficacy of Enteral Glutamine Supplementation in Patients With Predicted Severe Acute Pancreatitis‐ A Double‐Blinded Randomized Controlled Trial. Ongoing study January 2012.
Wischmeyer 2010 {published data only}
    1. The RE‐ENERGIZE study: a RandomizEd trial of ENtERal Glutamine to minimIZE thermal injury. Ongoing study 01/06/2010. - PMC - PubMed
Ziegler 2013 {published data only}
    1. A Randomized Controlled Trial of Glutamine Dipeptide in Severe Trauma (GLND Trauma). Ongoing study February 2013.

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