Title: Parenteral glutamine should not be routinely used in adult critically ill patients
Abstract: We like to comment on the recent meta-analysis published in Clinical Nutrition by Stehle and coworkers on parenteral glutamine supplementation when combined with parenteral nutrition in adult critically ill patients [ [1] Stehle P. Ellger B. Kojic D. Feuersenger A. Schneid C. Stover J. et al. Glutamine dipeptide-supplemented parenteral nutrition improves the clinical outcomes of critically ill patients: a systematic evaluation of randomised controlled trials. Clin Nutr ESPEN. 2016; https://doi.org/10.1016/j.clnesp.2016.09.007 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar ]. 1.Although all authors have acknowledged their conflict of interest in the paper, the major conflict of interest with this topic of the authors being either a consultant or employee of the manufacturer of parenteral glutamine dipeptide should caution the interpretation of this work. 2.It is suggested by the authors that guidelines recommend supplementing parenteral glutamine (Gln) when parenteral nutrition (PN) is prescribed. Here only older guidelines are quoted [ [2] Singer P. Berger M.M. van den Berghe B.G. Biolo G. Calder P. Forbes A. et al. ESPEN guidelines on parenteral nutrition: intensive care. Clin Nutr. 2009; 28: 387e400 Abstract Full Text Full Text PDF Scopus (955) Google Scholar ]. In the recent ASPEN guidelines published in 2016 glutamine is no longer recommended: “Recommendation H6: We recommend that parenteral glutamine supplementation not be used routinely in the critical care setting” [ [3] McClave S.A. Taylor B.E. Martindale R.G. Warren M.M. Johnson D.R. Braunschweig C. et al. Society of Critical Care Medicine; American Society for Parenteral and Enteral NutritionGuidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine (SCCM) and american society for parenteral and enteral nutrition (A.S.P.E.N.). J Parenter Enter Nutr. 2016 Feb; 40: 159-211https://doi.org/10.1177/0148607115621863 Crossref PubMed Scopus (1651) Google Scholar ]. In the recent SCCM/ASPEN surviving sepsis campaign 2016 guidelines on nutrition in sepsis patients, a similar negative recommendation for glutamine administration can be found [ [4] Rhodes A. Evans L.E. Alhazzani W. Levy M.M. Antonelli M. Ferrer R. et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017 Jan 18; ([Epub ahead of print])https://doi.org/10.1007/s00134-017-4683-6 Crossref Scopus (3671) Google Scholar ]. 3.An analysis of multicenter versus single center studies is lacking. In the meta-analysis by Wischmeyer and coworkers on parenteral Gln administration it has been clearly demonstrated that the positive findings are due to older and smaller single center studies and no benefits in multicenter trials were found [ [5] Wischmeyer P.E. Dhaliwal R. McCall M. Ziegler T.R. Heyland D.K. Parenteral glutamine supplementation in critical illness: a systematic review. Crit Care. 2014 Apr 18; 18: R76https://doi.org/10.1186/cc13836 Crossref PubMed Scopus (137) Google Scholar ]. Furthermore Pasin and coworkers showed that when multicenter studies (including both enteral and parenteral glutamine supplementation studies) were combined even increased mortality by Gln supplementation could be demonstrated [ [6] Pasin L. Landoni G. Zangrillo A. Glutamine and antioxidants in critically ill patients. N Engl J Med. 2013 Aug 1; 369: 482-484https://doi.org/10.1056/NEJMc1306658#SA3 Crossref PubMed Scopus (0) Google Scholar ]. 4.The average number of patients per included study in the current meta-analysis by Stehle and coworkers is 52 [ [1] Stehle P. Ellger B. Kojic D. Feuersenger A. Schneid C. Stover J. et al. Glutamine dipeptide-supplemented parenteral nutrition improves the clinical outcomes of critically ill patients: a systematic evaluation of randomised controlled trials. Clin Nutr ESPEN. 2016; https://doi.org/10.1016/j.clnesp.2016.09.007 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar ]. Thus data is provided on mortality reduction by the intervention comparing 26 versus 26 patients in the underlying studies, a sample size essentially to small to infer any reasonable effect size. Furthermore only those studies were included in the meta-analysis where Gln dipeptide supplementation (dose range 0.3–0.5 g/kg per day) was part of a balanced PN solution in combination with adequate nutrition and in haemodynamically and metabolically stable patients [ [1] Stehle P. Ellger B. Kojic D. Feuersenger A. Schneid C. Stover J. et al. Glutamine dipeptide-supplemented parenteral nutrition improves the clinical outcomes of critically ill patients: a systematic evaluation of randomised controlled trials. Clin Nutr ESPEN. 2016; https://doi.org/10.1016/j.clnesp.2016.09.007 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar ]. The question arises to what extent these study settings are in line with the average critical care setting. The three largest randomized controlled (Signet, Scandinavian Glutamine and REDOXS) trials to date show either no or adverse effects on the clinical outcome of typical critically ill patients with a Gln dose range of 0.2–0.78 g/kg per day [ 7 Andrews P.J. Avenell A. Noble D.W. Campbell M.K. Croal B.L. Simpson W.G. et al. Scottish Intensive care Glutamine or seleNium Evaluative Trial Trials GroupRandomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients. BMJ. 2011 Mar 17; 342: d1542https://doi.org/10.1136/bmj.d1542 Crossref PubMed Scopus (269) Google Scholar , 8 Wernerman J. Kirketeig T. Andersson B. Berthelson H. Ersson A. Friberg H. et al. Scandinavian Critical Care Trials GroupScandinavian glutamine trial: a pragmatic multi-centre randomised clinical trial of intensive care unit patients. Acta Anaesthesiol Scand. 2011 Aug; 55: 812-818https://doi.org/10.1111/j.1399-6576.2011.02453.x Crossref PubMed Scopus (117) Google Scholar , 9 Heyland D. Muscedere J. Wischmeyer P.E. Cook D. Jones G. Albert M. et al. Canadian Critical Care Trials GroupA randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013 Apr 18; 368 (Erratum in: N Engl J Med. 2013 May 9;368(19):1853. Dosage error in article text): 1489-1497https://doi.org/10.1056/NEJMoa1212722 Crossref PubMed Scopus (635) Google Scholar ]. These studies did not fulfill the highly selective study entry criteria of the meta-analysis by Stehle et al. Moreover, a large recent multicenter randomized-controlled trial by Ziegler et al. was not included [ [10] Ziegler T.R. May A.K. Hebbar G. Easley K.A. Griffith D.P. Dave N. et al. Efficacy and safety of glutamine-supplemented parenteral nutrition in surgical ICU patients: an American multicenter randomized controlled trial. Ann Surg. 2016 Apr; 263: 646-655https://doi.org/10.1097/SLA.0000000000001487 Crossref PubMed Scopus (47) Google Scholar ]. In this trial supplementation of alanyl-GLN dipeptide 0.5 g/kg per day as part of an isonitrogenous, isocaloric PN solution in combination with adequate nutrition (the “ideal and right” regimen as suggested by Stehle and coworkers) was compared with standard PN and did not affect infectious morbidity and all-cause mortality in 150 surgical critically ill patients requiring PN [ [10] Ziegler T.R. May A.K. Hebbar G. Easley K.A. Griffith D.P. Dave N. et al. Efficacy and safety of glutamine-supplemented parenteral nutrition in surgical ICU patients: an American multicenter randomized controlled trial. Ann Surg. 2016 Apr; 263: 646-655https://doi.org/10.1097/SLA.0000000000001487 Crossref PubMed Scopus (47) Google Scholar ]. 5.The hypothesis that glutamine plasma levels are low due to a conditional deficiency has been challenged [ 11 Smedberg M. Wernerman J. Is the glutamine story over?. Crit Care. 2016 Nov 10; 20: 361 Crossref PubMed Scopus (22) Google Scholar , 12 Van Zanten A.R. Glutamine and antioxidants: status of their use in critical illness. Curr Opin Clin Nutr Metab Care. 2015 Mar; 18: 179-186https://doi.org/10.1097/MCO.0000000000000152 Crossref PubMed Scopus (24) Google Scholar ]. Furthermore, high baseline Gln levels have been associated with increased mortality [ 13 Rodas P.C. Rooyackers O. Hebert C. Norberg Å. Wernerman J. Glutamine and glutathione at ICU admission in relation to outcome. Clin Sci (Lond). 2012 Jun; 122: 591-597https://doi.org/10.1042/CS20110520 Crossref PubMed Scopus (142) Google Scholar , 14 Hirose T. Shimizu K. Ogura H. Tasaki O. Hamasaki T. Yamano S. et al. Altered balance of the aminogram in patients with sepsis – the relation to mortality. Clin Nutr. 2014 Feb; 33: 179-182https://doi.org/10.1016/j.clnu.2013.11.017 Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar ]. Moreover, it may be that low levels actually reflect an adaptive response [ [15] Van den Berghe G. Low glutamine levels during critical illness–adaptive or maladaptive?. N Engl J Med. 2013 Apr 18; 368: 1549-1550https://doi.org/10.1056/NEJMe1302301 Crossref PubMed Scopus (28) Google Scholar ]. Therefore, it has become apparent that there is no strong clinical rationale to support Gln supplementation. Reply-Letter to the Editor-Glutamine dipeptide-supplemented parenteral nutrition improves the clinical outcomes of critically ill patients: A systematic evaluation of randomised controlled trialsClinical NutritionVol. 36Issue 4PreviewThank you very much for giving us the opportunity to respond to the Letter to the Editor written by van Zanten and Elke commenting on our recently published systematic review on the use of parenteral glutamine dipeptide supplementation as part of a balanced nutrition concept in critical illness [1]. Full-Text PDF
Publication Year: 2017
Publication Date: 2017-08-01
Language: en
Type: letter
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 5
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