How to understand the results of studies of glutamine supplementation

Critical Care, Nov 2015

The lack of understanding of the mechanisms behind possible beneficial and possible harmful effects of glutamine supplementation makes the design of interventional studies of glutamine supplementations difficult, perhaps even hazardous. What is the interventional target, and how might it relate to outcomes? Taking one step further and aggregating results from interventional studies into meta-analyses does not diminish the difficulties. Therefore, conducting basic research seems to be a better idea than groping in the dark and exposing patients to potential harm in this darkness.

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How to understand the results of studies of glutamine supplementation

Wernerman Critical Care How to understand the results of studies of glutamine supplementation 0 Karolinska University Hospital Huddinge & Karolinska Institutet , K32 14186 Stockholm , Sweden The lack of understanding of the mechanisms behind possible beneficial and possible harmful effects of glutamine supplementation makes the design of interventional studies of glutamine supplementations difficult, perhaps even hazardous. What is the interventional target, and how might it relate to outcomes? Taking one step further and aggregating results from interventional studies into meta-analyses does not diminish the difficulties. Therefore, conducting basic research seems to be a better idea than groping in the dark and exposing patients to potential harm in this darkness. - Introduction Meta-analyses do not bring much clarity over the possible beneficial effect of glutamine supplementation to critically ill patients. This is related to five issues: (a) The patients with hypoglutaminemia, who are the ones who have an association between a possible glutamine shortage and unfavorable outcomes, have never been properly investigated. (b) The mechanism that associated hypoglutaminemia with enhanced morbidity and mortality is not known. (c) The artificial separation according to route of administration has not been very helpful in interpreting the results. (d) The variable doses of glutamine and the combination with other nutrients have further blurred the interpretation of results. Finally, (e) the absence of characterization of nutritional status of the patients studied and the variable time course of critical illness at supplementation also contribute to the difficulty to digest the results presented. Hypoglutaminemia A situation in which mechanism of action is not understood makes the meta-analysis technique particularly hazardous. The impact of route of administration, dosing, combination with other nutrients, definition of shortage, and time course of treatment all call for subgroup analyses in which the individual studies in the end will stand quite alone with their specific treatment protocols. Meta-analyses may be a useful tool when the mechanism of action is known and the peculiarities of the individual studies can be evaluated in that context. When the mechanism is obscure, results become much more speculative, and the value of combining studies into a meta-analysis is discounted and may even become confusing. Until today, only one study provides plasma glutamine concentration at the time of study start [1]. It is unfortunate that the study protocol did not select the patients with hypoglutaminemia to randomization. Another unfortunate factor is that the intervention was not confined to glutamine supplementation but also included omega3 fatty acids, and therefore post hoc subgroup analyses of the hypoglutaminemic subject did not shed any light on the effect of glutamine supplementation in that particular group. So to summarize, the hypothesis that glutamine supplementation may be beneficial in critically ill patients with hypoglutaminemia is still not addressed. Mechanism of action The failure to understand the mechanism that associates hypoglutaminemia with an unfavorable outcome in critical illness is a crucial issue. Much more effort should be spent on exploring the pathophysiology of hypoglutaminemia in critically ill subjects. Extrapolation of results from animal studies has not been very helpful. Patients with hyperglutaminemia obviously do not need supplementation. This is a small group within the critically ill patients, often associated with hepatic failure [2, 3]. This is not confined to patients with acute fulminant liver failure but also applies to a large fraction of the patients © 2015 Wernerman. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. with chronic or acute-on-chronic liver failure. Hyperglutaminemia may also occur in other critically ill patients and is shown to be associated with an unfavorable outcome [3]. Also, a high, but normal, plasma glutamine concentration during glutamine supplementation is related to post-intensive care unit (post-ICU) mortality [4]. In this case, however, this was strongly related to discharge Sequential Organ Failure Assessment (SOFA) scoring, making interpretation difficult. Overall, the mechanism behind hypo- and hyperglutaminemia and the relation to outcome in critical illness need to be further explored before starting (...truncated)


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Jan Wernerman. How to understand the results of studies of glutamine supplementation, Critical Care, 2015, pp. 385, 19, DOI: 10.1186/s13054-015-1090-7