Elsevier

Pancreatology

Volume 13, Issue 5, September–October 2013, Pages 468-474
Pancreatology

Original article
Glutamine supplementation in acute pancreatitis: A meta-analysis of randomized controlled trials

https://doi.org/10.1016/j.pan.2013.07.282Get rights and content

Abstract

Background

There is emerging evidence that glutamine supplementation should be considered in patients with acute and critical illness associated with a catabolic response. There are reports of glutamine supplementation in acute pancreatitis but the results of these studies are conflicting. The aim of this study was to systematically review the randomised controlled trials (RCT) of glutamine in patients with acute pancreatitis.

Methods

The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, SCOPUS and 3 major Chinese databases were searched. The outcomes studied were mortality, total infectious complications, and length of hospital stay. A random effects model was used for meta-analysis of the outcomes in the included trials. A number of pre-specified subgroup analyses were also conducted. The summary estimates were reported as risk ratio (RR) for categorical variables and mean difference (MD) for continuous variables together with the corresponding 95% confidence interval.

Results

Twelve RCT that enrolled 505 patients with acute pancreatitis were included in the final analysis. Overall, glutamine supplementation resulted in a significantly reduced risk of mortality (RR 0.30; 95% CI, 0.15 to 0.60; P < 0.001) and total infectious complications (RR 0.58; 95% CI, 0.39 to 0.87; P = 0.009) but not length of hospital stay (MD −1.35; 95% CI, −3.25 to 0.56, P = 0.17). In the subgroup analyses, only patients who received parenteral nutrition and those who received glutamine in combination with other immunonutrients demonstrated a statistically significant benefit in terms of all the studied outcomes.

Conclusions

This meta-analysis demonstrates a clear advantage for glutamine supplementation in patients with acute pancreatitis who receive total parenteral nutrition. Patients with acute pancreatitis who receive enteral nutrition do not require glutamine supplementation. Further studies are warranted to determine whether patients who receive combined enteral and parenteral nutrition need glutamine supplementation.

Introduction

Over decades, supportive treatment has been the cornerstone in the management of non-mild acute pancreatitis (AP). Fasting has been employed traditionally to reduce pancreatic exocrine function with subsequent remission of the inflammatory process [1], [2]. However, this approach may exacerbate the malnutrition state in AP leading to further catabolism. Catabolic stress in AP increases the basal metabolic rate and alters carbohydrate, protein and lipid metabolism. In addition, dietary restriction results in a negative nitrogen balance that is associated with a significant increase in mortality [3], [4]. Further, a meta-analysis of randomized controlled trials (RCT) demonstrated that the use of non-volitional nutrition, either enteral (EN) or parenteral (PN), in patients with AP is associated with significant mortality benefits in comparison with no nutrition [5].

The next question for investigation has been to study whether advanced nutrition offers any benefit in comparison with standard nutrition [6]. Recently, the concept of “pharmaconutrition” has been introduced [7], [8]. Its main tenet is that the impact of nutrients is not constrained to correction of a nutrient deficiency. It is argued that the quantity of the nutrients delivered is largely dependent on the provision of an adequate volume of nutrition, which can often be problematic in severely ill patients, such as those with severe and critical AP [9]. Further, PN has a rather limited utility in nutritional management of patients with AP nowadays. The concept of pharmaconutrition advocates that the administration of key nutrients should be dissociated from the provision of PN or EN so that their full dose can be delivered, either parenterally or enterally, and their therapeutic effects evaluated appropriately.

Of all the candidates for being a pharmaconutrient, glutamine has received particular attention as it is involved in a variety of metabolic processes and immune functions [10]. Glutamine is the most abundant amino acid in the intracellular pool and the preferred fuel for rapidly dividing cells such as enterocytes, lymphocytes, macrophages and neutrophils [4], [11], [12]. Although classified as a non-essential amino acid, it is thought that glutamine becomes ‘conditionally essential’ because of increased demands in catabolic states, including multiple trauma, burn injury and major surgery [13], [14], [15], [16]. Glutamine also contributes to anti-oxidant defenses, immune function, and nitrogen retention. A number of RCT studied the effect of glutamine supplementation in elective surgical and critically ill patients and the data from these have been aggregated in several meta-analyses [17], [18]. The results of individual RCT were conflicting. Overall, the meta-analyses have demonstrated no effect on mortality [17], [19]. However, a significant reduction in the risk of infectious complications and a shorter length of hospital stay has generally been observed [17], [18]. Acute pancreatitis has been shown to be associated with glutamine deficiency [20], immune compromise, gut barrier failure, increased intestinal permeability and bacterial translocation, all of which may contribute to the systemic inflammatory response and development of organ failure [14], [21], [22].

The aim of this study is to systematically review, critically appraise, and statistically aggregate the clinically meaningful outcomes of RCT that investigated the effect of glutamine-supplemented EN and PN for patients with AP.

Section snippets

Study identification

The search terms “pancreatitis” and “glutamine” and “nutritional”, “nutrient”, “nutrition” or “supplementation”, “supplementary”, “supplements” were used. Three authors (VA, WKC, ZD) performed the literature search on MEDLINE, EMBASE, SCOPUS, Cochrane Central Register of Controlled Trials, CBM (China Biological Medicine Database), CNKI (Chinese National Knowledge Infrastructure Database) and VIP (Database of Chinese Science and Technology Periodicals). No language restriction was applied and

Study characteristics

Fig. 1 summarizes the study selection process. A total of 560 publications were screened and 15 potentially eligible RCT were identified. However, three of them were excluded as no data on the required outcomes was available, leaving a total of 12 RCT included in the final analysis (Table 1) [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]. These 12 RCT comprised 505 patients, of whom 251 patients were randomised to glutamine supplementation and 254 patients to the

Discussion

A comprehensive systematic review and meta-analysis of the effect of glutamine supplementation on clinically-meaningful outcomes of patients with AP has not previously been performed. The striking finding of this study is the significant reduction in the risk of mortality and total infectious complications in patients with AP who received glutamine supplementation. This effect was not apparent for length of hospital stay. Subgroup analyses have demonstrated that these beneficial effects were

References (40)

  • M.S. Petrov et al.

    Comparison of complications attributable to enteral and parenteral nutrition in severe acute pancreatitis: a systematic review and meta-analysis

    Br J Nutr

    (2010)
  • M.S. Petrov et al.

    Systematic review and meta-analysis of enteral nutrition formulations in acute pancreatitis

    Br J Surg

    (2009)
  • M.S. Petrov et al.

    Enteral nutrition and the risk of mortality and infectious complications in patients with severe acute pancreatitis – a meta-analysis of randomized trials

    Arch Surg

    (2008)
  • R. Meier et al.

    ESPEN guidelines on nutrition in acute pancreatitis

    Cin Nutr

    (2002)
  • M.S. Petrov et al.

    Systematic review: nutritional support in acute pancreatitis

    Alim Pharmacol Ther

    (2008)
  • N.E. Jones et al.

    Pharmaconutrition: a new emerging paradigm

    Curr Opin Gastroenterol

    (2008)
  • E.P. Dellinger et al.

    Pancreatitis across Nations Clinical Research and Education Alliance (PANCREA). Determinant-based classification of acute pancreatitis severity: an international multidisciplinary consultation

    Ann Surg

    (2012)
  • P.C. Calder

    Immunonutrition in surgical and critically ill patients

    Br J Nutr

    (2007)
  • T.R. Ziegler et al.

    Glutamine: from basic science to clinical application

    Nutrition

    (1996)
  • J.C. Hall et al.

    Glutamine

    Br J Surg

    (1996)
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