Original articleGlutamine dipeptide-supplemented parenteral nutrition improves the clinical outcomes of critically ill patients: A systematic evaluation of randomised controlled trials
Introduction
Apart from its role as building block for the endogenous protein synthesis, the amino acid glutamine (Gln) is the transporter nitrogen between organs, regulates amino acid metabolism, serves as metabolic fuel for rapidly proliferating cells, and is a precursor of bioactive metabolites [1], [2], [3], [4]. Since Gln can be endogenously synthesized de novo and released by protein hydrolysis, it is classified as a dispensable nutrient for healthy humans. However, in severe disease states (e.g., trauma, abdominal major surgery, and burns), the stress-mediated hormonal changes that develop alter Gln metabolism in the whole body [5], [6], [7], [8], [9]: as a result, various organs (e.g., gut, liver, and kidneys) and cells (e.g., enterocytes and immunocompetent cells) need more Gln for the necessary synthesis of acute-phase proteins and radical-scavenging metabolites such as glutathione. Since the endogenous capacity of the body to release Gln generally cannot adapt to meet these increased needs, the metabolically stressed body becomes depleted of Gln, as indicated by marked decreases of intracellular Gln in the muscle tissue and, to a lower extent, in plasma [10]. This depletion in turn associates with metabolic impairment such as insufficient protein synthesis; most importantly, it worsens the clinical outcomes of severely ill patients [9], [10], [11], [12], [13]. Consequently, Gln is considered to be an indispensable substrate in the hypermetabolic situations that characterize critical illness [4], [11], [12], [13]. Because of galenic reasons, however, the so-called “standard” amino acid solutions for parenteral nutrition (PN) therapy are free of Gln. Consequently, a total PN regimen administrating even high doses of such a standard amino acid preparation (>1.5 g/kg BW/d) cannot prevent Gln depletion [13].
Beginning in the 1980s, randomised controlled trials (RCTs) were performed to evaluate whether parenteral supplementation with nutritive amounts of a Gln source (about 10–12 g/day) would prevent or reduce the Gln depletion in various PN-requiring patient groups and improve their outcomes. These RCTs were mainly single centre trials and the supplemented Gln source was either free Gln (bed-side preparation due to its limited chemical stability) or stable Gln dipeptides in ready-to-use solutions [14], [15], [16]. Consistent with the working hypotheses of these early RCTs, Gln supplementation ameliorated the disease-specific Gln depletion compared to standard treatment. This in turn improved various functions (e.g., maintenance of gut barrier function and gut-associated lymphoid tissue) and strengthened the biochemical pathways needed to fight the disease-associated metabolic stress (e.g., the cellular synthesis of short-life proteins). Most importantly, it reduced mortality and morbidity rates and the length of hospital stay (LOS) [17], [18], [19]. These RCTs led to changes in international guidelines, which then started to recommend that parenteral delivery of Gln dipeptides should be part of the nutritional care in critical illness [20], [21].
Within the last decade, several single and multi-centre RCTs that tested the usefulness of Gln-supplemented PN in various patient groups and following various designs have been performed. Recently, three meta-analyses have been initiated with obviously lacking consistency and only partly supporting the earlier recommendation for Gln use in critically ill patients [22], [23], [24]. These discrepancies may reflect some weaknesses in the meta-analysis criteria that determined study inclusion. Most importantly, these meta-analyses included the RCTs that used free Gln. This is problematic because most of these studies did not indicate the “true” Gln content in the solutions before administration. Moreover, free Gln and Gln dipeptides may differ in terms of their kinetics, which in turn may influence the degree of Gln uptake by the target sites. Thus, studies that used free Gln may not be equivalent to those that employed Gln dipeptide; meta-analyses should consider these RCTs separately. In addition, two of the three recent meta-analyses, namely, those by Bollhalder et al. [23] and Tao [24], included both critically ill and post-surgery patients in their cohorts. However, these patient groups vary markedly in terms of clinical outcomes, especially mortality and morbidity rates, and thus may not be directly comparable. This suggests that RCTs that employed mixtures of these patient groups to evaluate the effect of Gln supplementation on these outcome variables may suffer from bias.
These shortcomings encouraged us to perform the present meta-analysis which focused specifically and stringently on only those RCTs that examined the outcomes of critically ill adult patients without hepatic and/or renal failure who were haemodynamically and metabolically stabilised and who were administered glutamine dipeptide strictly according to current clinical guidelines (i.e., via the parenteral route at 0.3–0.5 g/kg/day; max. 30% of the prescribed nitrogen supply) in combination with adequate nutrition. The control group received isoenergetic and isonitrogenous supplements without Gln dipeptide supplementation.
Section snippets
Methods
This meta-analysis was performed and reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guideline [25].
Study identification and selection
As outlined in Fig. 1, 2035 publications were retrieved by the literature search. After removing duplicates, 1422 publications were screened. Of these, 192 articles were identified as potentially eligible for inclusion. After careful examination, 176 publications were excluded because they were not original research articles (n = 75), they lacked information regarding predefined endpoints (n = 26), the article was not in English or German (n = 15), the prescribed energy and N intake of the
Discussion
In our meta-analysis, we included all eligible RCTs that had been published up until 2015 and that had compared critically ill patients who received Gln dipeptides as part of a prescribed PN therapy to those whose isonitrogenous and isoenergetic therapy did not include glutamine. The aim was to rigorously examine previous claims, namely, that Gln (dipeptide) administration in critically ill patients reduces their infectious complication rates, length of hospital stay, need for mechanical
Conclusions
Our meta-analysis clearly indicated that when critically ill patients received Gln dipeptide supplementation as part of a balanced PN, it reduced the rate of infectious complications, the length of ICU and hospital stay, the number of days on mechanical ventilation, and the hospital mortality rate. Most importantly, in all of the clinical trials that were included in our study, the administration of Gln dipeptides was entirely consistent with the clinical guidelines [20], namely, via the
Conflicts of interest statement and funding
PS is a consultant of Fresenius Kabi Germany. AF, CS, JS, DS, and MW are employees of Fresenius Kabi Germany. The study was funded by an unrestricted educational grant from Fresenius Kabi Deutschland.
Authorship statement
PS, AF, and CS contributed equally to the conception and design of the study and drafted the manuscript. BE and DK contributed to the interpretation of the data. JS, DS, and WM revised the manuscript for important intellectual content. All authors have read and approved the final manuscript.
Acknowledgments
We thank M.A.R.C.O. GmbH & Co. KG (Duesseldorf, Germany) for the statistical analysis of the meta-analysis.
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