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