Enteral nutrition formulations for acute pancreatitis

Description of the condition

Acute pancreatitis (AP) is a potentially life‐threatening inflammatory disorder of the pancreatic gland, with an incidence in most Western and Asian countries ranging between 10 and 30 per 100,000 inhabitants, and accounting for more than 270,000 hospital admissions in the United States annually (Goldacre 2004; Imamura 2004; Lindkvist 2004; NIS 2012). An indicative increase in the incidence of AP has been reported and has been attributed to the use of more accurate diagnostic tests (i.e. computed tomography (CT) and endoscopic ultrasound) and to an increase in the incidence of gallstones and obesity (Frey 2006; Yadav 2006). In about 80% to 85% of cases, AP presents as a mild and self‐limiting disease, requiring only conservative treatment; the remaining 15% to 20% of cases represent severe forms of the disease characterised by the development of local and systemic complications (Sakorafas 2010; Tonsi 2009). Local complications consist of possible tissue destruction or necrosis; formation of a pseudocyst ‐ an abnormal collection of fluid or necrotic material for which walls are formed by the pancreas and other surrounding organs; and formation of an enclosed collection of liquefied, dead and infected tissue, called abscess. Systemic complications are caused by a systemic inflammatory response possibly leading to organ failure (most commonly, kidney failure, respiratory failure and shock). The most common causes of AP are gallstone disease and excessive alcohol consumption, which account for more than two‐thirds of cases (Munsell 2010). Less common causes include metabolic disorders such as hypertriglyceridaemia (abnormal elevation of serum triglycerides ‐ normal constituents of oil and fat) and hypercalcaemia (abnormal elevation of serum calcium), autoimmune pancreatitis, various bacterial or viral infections (i.e. mumps, Coxsackievirus, Mycoplasma pneumoniae), parasitic infestations of the biliary tract (e.g. Ascaris lumbricoides), abdominal abnormalities, trauma and drugs (e.g. steroids, sulphonamides, furosemide, thiazides).

Although the disease mechanisms of AP are still controversial, it is believed that a causative factor leads to uncontrolled activation of enzymes (chemical compounds that promote chemical reactions) within the pancreatic tissue and to self‐digestion of the gland, causing release of molecules that mediate the inflammatory response, tissue damage and possible necrosis. These local changes can trigger an intense inflammatory cascade leading to the development of systemic inflammatory response syndrome (SIRS) ‐ a generalised inflammatory response affecting different organs and whole organ systems, which can consequently cause organ failure and death (Frossard 2008; Kilciler 2008). The described events represent the first phase of the clinical course of severe acute pancreatitis (SAP), which can be followed in up to 40% of cases by a second phase marked by infection of the dead (necrotic) pancreatic tissue (Haney 2007). Infected pancreatic necrosis usually develops after the first week of disease and is associated with a significant increase in the prevalence of organ failure, with death occurring in about 30% of cases (Büchler 2000; Uhl 2002).

According to clinical guidelines (Banks 2006; Forsmark 2007; UK Working Party on Acute Pancreatitis 2005), the diagnosis of AP is established by the presence of two of the following three features: a compatible clinical presentation, including abdominal pain, nausea and vomiting; a three‐fold or greater elevation in serum amylase or lipase concentrations (digestive enzymes essential in the breakdown of starch and fat, which are released to a greater extent from the inflamed pancreas into the blood); or evidence of AP on CT. No specific treatment is available for AP. Most patients respond well to conservative management, including fluid volume resuscitation, pain control, oxygen administration, use of anti‐vomiting drugs and introduction to and administration of regulated food intake. Severe cases require admission to an intensive care unit and continuous monitoring of vital signs. Severe acute pancreatitis precipitates metabolic distress, leading to increased total energy expenditure and enhanced protein consumption. Therefore, nutritional support is an essential part of disease treatment (Gianotti 2009; Meier 2006); several studies have suggested certain advantages of enteral nutrition (EN) versus total parenteral nutrition (TPN) (Al‐Omran 2010; Yi 2012). Enteral nutrition comprises nutritional preparations in liquid form, which are absorbed by the intestines. It usually involves the administration of nutrients directly into the stomach or small intestine in patients who have difficulty swallowing via specific tubes that can be placed throughout the oral or nasal cavity or can be surgically implanted through the abdominal wall directly into the specified gastrointestinal organ. Enteral nutrition can also be given orally, most often as a supplement to a specific diet in malnourished patients. Total parenteral nutrition is the intravenous administration of nutrients that a patient requires via a catheter inserted into a major central or smaller peripheral vein. Use of antibiotics to prevent infection of necrotic tissue is highly debated. A recent Cochrane systematic review showed no beneficial effects of antibiotic prophylaxis, except for imipenem, an antibiotic from the carbapenem group that has a broad antibacterial activity spectrum; its use has led to a significant decrease in the incidence of pancreatic infection (Villatoro 2010). Endoscopic procedures that facilitate visualisation of the common bile duct should be considered in the early stages of severe gallstone pancreatitis with co‐existing bile duct obstruction, infection of the biliary tract (cholangitis) or sepsis (bacterial infection of the blood) (Frossard 2008; Tse 2012). The most common procedure of this type is endoscopic retrograde cholangiopancreatography (ERCP), in which the biliary tract is visualised under X‐ray imaging when a contrast agent is injected from the initial part of the small bowel into the common bile duct. In these cases, cutting the sphincter of Oddi, a muscle that lies at the junction of the intestine with both the bile and the pancreatic ducts, could facilitate removal of bile duct stones or treatment of other causes of bile obstruction. Surgical removal of necrotic tissue, as well as fluid collections, pseudocysts or abscess drainage, is indicated only when infected tissue is present. Sterile necrosis should be treated conservatively (Isaji 2006; Werner 2005).

Description of the intervention

For decades, one of the main principles applied in the treatment of patients with AP has been 'nil‐by‐mouth' (no oral intake), with or without TPN, to achieve suppression of pancreatic enzyme secretion and bowel rest. However, experimental and clinical studies have demonstrated that this approach can lead to increased risk of infectious complications due to bacterial overgrowth and translocation in the gut, resulting in higher morbidity (disease state rate) and mortality (death rate) among patients with severe forms of the disease. Furthermore, SAP is marked by an increase in the amount of energy required to perform vital functions at complete rest, also called basal metabolism, with a potentially negative effect on nutritional status and disease progression (Meier 2006). Therefore, adequate nutritional support is essential, preferably provided by the enteral route. Administration should start as soon as possible, especially with pre‐existing malnutrition, usually within 48 hours of admission (McClave 2009). Nutritional support is preferably administered via a tube inserted through the nasal cavity and the upper gastrointestinal tract (oesophagus and stomach) into the middle part of the small intestine, called the jejunum. This nasojejunal tube should be placed distal to the duodenojejunal junction (the point at which the initial part of the small intestine ‐ the duodenum ‐ ends and the jejunum begins) blindly, endoscopically or through radiological procedures. It has been discussed that tube positioning offers several advantages: It avoids the problem of decreased or absent movement of the stomach wall (gastroparesis) and possible duodenal obstruction due to inflammation or pseudocyst formation; it also provides increased energy delivery to the small bowel and ensures better pancreatic rest than tubes placed closer to the stomach (Thomson 2008). However, studies show no significantly different effects between nasojejunal and nasogastric routes of administration, whereby nutrients are delivered into the stomach (Eatock 2005; Kumar 2006). A wide range of EN formulations are available for clinical use and for different indications. They can be divided into three groups: polymeric, oligomeric and specialised formulations. Polymeric formulations contain intact proteins, and carbohydrates are represented in the form of maltodextrins, or water‐soluble molecules containing three or more glucose molecules, and oligosaccharides, which are molecules that consist of two to six simple basic sugar molecules known as monosaccharides. Finally, lipids in polymeric formulations are present in the form of long‐chain fatty acids. Oligomeric, also known as elemental or semi‐elemental, formulations comprise maltodextrins and monosaccharides, medium‐chain fatty acids and free fatty acids; protein components consist of smaller molecules, such as free amino acids, dipeptides and tripeptides (two or three interconnected amino acids). Oligomeric formulations are preferred to polymeric formulations for the treatment of patients with AP because they are usually associated with better tolerance and absorption in the gut and improved achievement of pancreatic rest (Makola 2006; Tiengou 2006). However, they are several times more expensive than polymeric formulations. Specialised formulations represent a larger group of specifically designed formulas enriched with different supplements. These include immuno‐enhanced formulations, which are enhanced by substances potentially able to modify the immune response. They most often contain specific amino acids such as glutamine and arginine, omega‐3 fatty acids and nucleotides (chemical compounds composed of a base, a sugar molecule and a phosphate group, which are the main structural elements of nucleic acids such as deoxyribonucleic acid (DNA)). Other specialised formulations include fibre‐enhanced formulations that can have prebiotic activity, meaning that they can stimulate the growth of normal enteral micro‐organisms. Some formulations are supplemented with probiotics (substances containing live bacteria or yeasts that add to the normal gastrointestinal flora) and may contain probiotics and prebiotic fibres, which usually are called symbiotics; disease‐specific formulations are available (Petrov 2009). The cost of these specialised preparations is even higher, but evidence of their efficiency is not reliable. In addition, formulations enriched with certain strains of probiotics have been associated with increased mortality (Besselink 2008; Gianotti 2006).

How the intervention might work

Intestinal barrier dysfunction has a pivotal role in the course of AP. It is known that micro‐organisms responsible for pancreatic infection and septic complications are generally common enteric bacteria normally present in the gut (Beger 1986; MacFie 1999). Disruption and overgrowth of these bacterial populations that form the normal intestinal flora in a metabolically deprived and immobile bowel could lead to bacterial and endotoxin translocation, meaning that bacteria and their toxic products could move through the intestinal membrane to emerge in the lymphatic or internal organ circulation. This mechanism is further supported by increased permeability of the intestinal membrane and local ischaemia (insufficient blood supply) of the gut due to dynamic changes in blood flow regulation in AP. The intense inflammatory state and the above mentioned processes cause impairment of the patient's immunological system (Xu 2006). Direct delivery of nutrients to the gut and stimulation of metabolic activity help maintaining the structural and functional integrity of the intestinal mucosa, thereby possibly reducing septic complications and morbidity (Buchman 1995). Data suggest that EN reduces the acute phase response by preserving protein metabolism of internal organs and down‐regulating the cytokine response (proteins acting as mediators between cells, as in the generation of an immune response) (Windsor 1998). The use of immuno‐enhanced formulas is supposed to intensify this effect. Glutamine released from muscle tissue acts as a gene promotor for cellular protection and immune responsiveness by activating the peroxisome proliferator‐activated receptor gamma, an intracellular receptor that regulates glucose metabolism and fatty acid storage. In addition, glutamine is a potent antioxidant through its metabolite glutathione, which is a tripeptide important for the protection of various cellular structures and the detoxification of harmful compounds. Furthermore, glutamine stimulates production of arginine ‐ another supplement that has demonstrated potential effects by influencing the production of nitric oxide (a naturally occurring gas in the body that stimulates blood vessel dilation and improves blood flow). Nucleotides act as prebiotics ‐ substances that stimulate the growth of beneficial enteric bacteria. Fish oils containing omega‐3 fatty acids have a suppressive effect on endothelial cells and pro‐inflammatory mediators. Their effects are believed to result from inhibition of nuclear factor kappa B (a protein that controls gene expression), displacement of arachidonic acid from cellular membranes and stimulation of leukotriene B4 and prostaglandin E2 production (Santora 2010). Arachidonic acid is an essential fatty acid that is the precursor to leukotrienes and prostaglandins, which are classes of molecules produced by cells to mediate allergic and inflammatory reactions.

Why it is important to do this review

Acute pancreatitis represents a global burden of morbidity and mortality with an increasing incidence. As the result of differences among the studies conducted to date and a variety of accessible preparations for enteral feeding, a systematic review of specific formulations is needed to try to determine the most efficient and cost‐effective use of enteral nutrition in these patients.

Criteria for considering studies for this review

Search methods for identification of studies

Data collection and analysis

Description of studies

See Characteristics of included studies and Characteristics of excluded studies.

Risk of bias in included studies

Risk of bias was assessed according to seven domains: allocation sequence generation, allocation concealment, blinding of participants and study personnel, blinding of outcome assessors, management of incomplete outcome data, selective outcome reporting and other potential sources of bias. All included trials were judged as having high risk of bias. Our risk of bias assessment is summarised in Figure 2 and Figure 3.

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6

Summary of main results

This systematic review contains 15 trials with a total of 1376 participants investigating different types of enteral nutrition (EN) formulations for the treatment of patients with acute pancreatitis (AP). To address the diversity of available EN formulations, we constructed five separate analyses comparing a specific formulation versus control, consisting of another type of EN, placebo or no intervention. These five analyses refer to immunonutrition; EN supplemented with probiotics; formulations supplemented with immunonutrients, probiotics and fibres; semi‐elemental formulations; and fibre‐enriched EN. All trials were assessed as having high risk of bias.

Immunonutrition compared with control showed a reduction in all‐cause mortality, but no such improvement was confirmed for other outcomes, which were reported by fewer trials. When we stratified analyses on primary outcomes only for studies comparing immunonutrition versus other EN formulations, we could not confirm this effect. Therefore, benefit derived from the addition of immunomodulatory agents to any type of EN is questionable. These findings are based on low‐quality evidence, which was downgraded by one point for high risk of bias of included trials, and by one point for imprecision of results. Subgroup analysis stratified for patients with severe AP could not confirm a significant difference between immunonutrition and control regarding all‐cause mortality and occurrence of systemic inflammatory response syndrome (SIRS). Immunonutrition generally was well tolerated, with few mild adverse events reported. One isolated case of bowel ischaemia developed in the Hallay 2001 trial, affecting a participant in the control group who was receiving fibre‐enriched polymeric EN; this was judged by review authors as a serious adverse event. Sensitivity analyses performed according to 'worst‐best case' and 'best‐worst case' scenarios for primary outcomes yielded similar results, most likely because a fairly small number of participants were lost to follow‐up.

Evidence of an effect on primary outcomes when EN is supplemented with probiotics with or without fibres is inconclusive and has been graded as having low to very low quality based on high risk of bias, rather small numbers of participants and events included and inconsistency of results. We noted a reduction in other infections, but numbers of local septic complications were similar in both groups. The frequency of adverse events was similar in the two groups; however, we were not able to include data from Besselink 2008 because it was not clear whether one participant experienced more than one reported adverse event. The same participant could, for example, have had abdominal pain and diarrhoea due to bowel ischaemia, but all were reported separately. In this trial, 9/153 participants in the probiotic group developed bowel ischaemia, and seven died as a result of this. This number was significantly higher than that reported in the trial's control group, which received fibre‐enriched polymeric EN without probiotics, and in which none of the participants developed bowel ischaemia. As a consequence, trial investigators reported a significantly higher death rate in the group treated with probiotics, addressing a warning for use of probiotics in the treatment of patients with AP. However, the Besselink 2008 trial had been criticised for design issues and flaws, and we raise concern regarding the detected baseline imbalance between study groups, with a significantly higher number of patients with organ failure at baseline included in the probiotics group. Nevertheless, because of the rather small numbers of participants and adverse events reported in this comparison, and because significant heterogeneity was detected between studies included in assessment of all‐cause mortality, the review authors would like to emphasise that safety concerns regarding use of probiotics in patients with AP do exist, and that routine supplementation of EN with probiotics is not backed up by currently available evidence. We undertook analysis of serum C‐reactive protein (CRP) concentrations measured on the third day after admission, which is a generally accepted point in time by which CRP reaches its highest levels. These high values are not usually a consequence of infective complications but instead are due to a non‐septic inflammatory response typical among patients with AP. Infectious complications such as infected pancreatic necrosis are more common in later phases of the disease, usually during the second week, and are characterised by a secondary rise in CRP levels. C‐reactive protein levels were higher in the probiotics group, but this result should be interpreted with caution, as it is based on reports of only two trials. Furthermore, this finding could not be explained by the occurrence of SIRS, as this was not significantly different between groups. When analysing last available follow‐up values for CRP concentrations, we could not confirm a conclusive effect of probiotics on CRP values. Other analysed secondary outcomes were similar. Subgroup analysis of specific formulations of EN supplemented with probiotics compared with other specific EN formulas did not confirm any specific advantage or disadvantage of the intervention for primary outcomes.

Sensitivity analyses for missing data based on 'worst‐best case' and 'best‐worst case' scenarios suggest that the numbers of participants lost to follow‐up were quite large, and this could have potentially influenced outcomes. As the 'worst‐best case' scenario resulted in a higher incidence of mortality and SIRS with no difference in organ failure, while the 'best‐worst case' scenario resulted in a lower incidence of organ failure with no differences in mortality and SIRS between probiotics and control, results of these extreme case scenarios should be taken cautiously because they may not be realistic.

In the light of previously discussed inconsistencies among results and observed heterogeneity, as well as design issues regarding the Besselink 2008 trial, we performed a post hoc sensitivity analysis by excluding participants from Besselink 2008 for all respective outcomes. Results of these analyses show that probiotics decreased all‐cause mortality, occurrence of organ failure and local septic complications but had no impact on other local complications and length of hospitalisation. This analysis may provide justification for further investigation of probiotics as EN supplements for patients with AP to potentially determine their efficacy or potential harmfulness.

Only one study evaluated the use of a fibre‐enriched polymeric EN supplemented with both immunonutrients and probiotics compared with a fibre‐enriched and plain polymeric EN, reporting no deaths in all three groups, as well as shorter hospital stay. However, results from only one study with very wide confidence intervals represent very low quality of evidence with no possibility of a conclusion regarding the effect of the intervention. Two studies evaluated the use of semi‐elemental formulations compared with polymeric and no nutritional support and did not confirm any effect on all‐cause mortality nor on length of hospital stay. As the quality of evidence was very low, we cannot be confident that this intervention had any effect on assessed outcomes. Two trials were included in the comparison of fibre‐enriched EN versus polymeric EN, showing a reduction in length of hospital stay; one trial reported reduced numbers of other local complications. Other reported outcomes were similar in the two groups. These findings are also based on very small numbers of included participants and reported events, thus they should be understood as very imprecise and derived from trials with high risk of bias. In this way, we downgraded the quality of evidence from high to very low.

We performed a subgroup analysis on trials comparing EN versus no intervention with the intention of assessing whether use of any type of EN formulation has any beneficial or harmful effect compared with no nutritional support at all. Our results, which were based on a total of 511 participants, suggest that EN decreases all‐cause mortality compared with no nutritional support, thus supporting the use of EN in patients with AP. However, very few cases of all‐cause mortality were reported among the included participants, and only one trial reported on SIRS, resulting in low to very low quality of available evidence. Although clinical logic and experience may suggest the usefulness and benefit of EN over no nutritional intervention in patients with AP, such assertions and opinions cannot currently be backed up by solid evidence.

Overall completeness and applicability of evidence

Included studies could not be pooled in a unique analysis because this would not be consistent with the purpose of this review, and because different EN formulations were assessed by investigators. Most trials included patients with AP of any severity, although some trials examined only severe cases and one trial (Petrov 2013) assessed exclusively mild forms of AP. In most trials, disease severity and local and systemic complications were defined according to the previous version of the Atlanta criteria (Bradley 1993). Poropat 2012 used the new revised Atlanta criteria from 2012 (Banks 2012); Huang 2008 defined severity according to the Bangkok 2002 criteria (Toouli 2002), and Wang 2007 according to the Chinese acute pancreatitis treatment guidelines (draft) (CMA 2004), so these differences should be taken into account.

Regarding comparisons of immunonutrition versus control and probiotics versus control, most included trials had similar endpoints and reported on outcomes of interest. However, the remaining three comparisons involved only one or two trials, which reported on very few outcomes, so overall completeness and applicability of the evidence are very limited.

Quality of the evidence

The overall quality of the evidence is low or very low. One of the main limitations of this systematic review is the diversity of interventions studied across trials, which explains why specific analyses had to be divided to fulfil the clinical meaning and aspects of use of different EN formulations for AP, as well as to satisfy the purposes of this review. Therefore, specific analyses included few trials with rather limited numbers of participants. We explored statistical heterogeneity qualitatively and quantitatively by using Chi² tests and I² values, respectively (Higgins 2003). When a meta‐analysis included a small number of trials or trials with small sample sizes, the Chi² test was seen to have low power, meaning that a statistically significant result may indicate a problem with heterogeneity, but lack of a statistically significant result does not exclude heterogeneity. This is why we applied both fixed‐effect and random‐effects models, and determined statistical significance for heterogeneity at a P value of 0.10. All included trials are at high risk of bias; therefore results of these studies should be interpreted with caution.

Potential biases in the review process

This systematic review was performed according to the recommendations of The Cochrane Collaboration. We strongly believe that the search strategies developed, as well as the predefined inclusion and exclusion criteria used, ensured unbiased selection of studies of interest. We performed searches of literature until the end of August 2013 (i.e. around six months before review submission), and review authors are unaware of newly published trials of substantial power that would drastically and significantly affect outcome estimates. Besides trials that reported in English, two trials that reported exclusively in Chinese and one trial that reported in Czech were included in this review, and three trials published in Chinese were excluded on the basis of study selection criteria. We also included unpublished information from one trial (Poropat 2012). GP and VG independently extracted data, assessed risk of bias and graded evidence quality. VG as an author of this systematic review was not otherwise involved in the planning, conduct, data analysis or writing of the abstract, nor in any other aspect of the Poropat 2012 trial. We contacted primary and corresponding authors of all trials to request additional information. Authors of seven included trials replied, providing additional information on trial design and conduct, missing data and other information of interest. One study (Pearce 2006) did not address the extent of the sponsor's involvement in the trial. Another trial (Olah 2007) did not provide the standard deviation (SD) for length of hospital stay, so we imputed values as an average of other trials included in the analysis. Lu 2008 presented data on length of hospital stay as means with standard errors, which we converted to SDs. Petrov 2013 reported length of hospital stay as medians with interquartile ranges, which we did not include in the analysis because of the possibility of skewed data.

All of the 15 trials included in our systematic review had been judged to have high risk of bias, and such trials are known to influence intervention effect estimates in such a way as to overestimate intervention effects. Five trials (33%) reported adequate random sequence generation, three (20%) had adequate allocation concealment, blinding was assessed as adequate in only two trials (13%), ten trials had low risk of attrition bias (67%), nine trials (60%) adequately reported on all prespecified and expected outcomes and eleven trials (73%) were assessed as having low risk of other potential sources of bias. Therefore, results and estimations of the intervention effect should be interpreted cautiously because systematic error is possible. Moreover, publication bias could not be assessed because of the limited number of trials included in the specific analyses of the review.

As a result of the diversity of interventions investigated in the included trials, we performed a fairly large number of subgroup analyses. This approach can easily lead to increased random error and spuriously significant results. We have to acknowledge that certain subgroup analyses intended to compare exclusively specific types of EN were insufficiently powered to reliably detect treatment effects.

Agreements and disagreements with other studies or reviews

We were able to identify only one meta‐analysis addressing the issue of use of different EN formulations in patients with AP (Petrov 2009). It included 20 randomised controlled trials with a total of 1070 participants. The review consisted of four separate analyses comparing semi‐elemental versus polymeric formulations, fibre‐enriched EN supplemented with probiotics versus fibre‐enriched EN, fibre‐enriched EN supplemented with immunonutrition versus fibre‐enriched EN and other studies that were not included in the meta‐analysis. However, it has to be stated that most of these comparisons were based on indirect meta‐analyses of groups of participants included in trials comparing EN versus TPN, in which TPN was used as a reference treatment. Furthermore, the review included certain trials in which the same group of participants or at least some participants were treated with a combination of EN and PN. Results could not confirm significant differences in effect of a specific EN formulation over another regarding infectious complications and mortality, nor regarding tolerance and safety of enteral feeding. Results of this review regarding efficacy of specific EN formulations are basically in agreement with the results that we reported; however, our results represent a contemporary and comprehensive systematic review based on reliable tools for assessing risk of bias in each included study as recommended by The Cochrane Collaboration. Furthermore, on the basis of relatively recent findings, our systematic review raises important concerns regarding the safety of EN supplemented with probiotics in the treatment of patients with AP .

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of ongoing studies [ordered by study ID]

Internal sources

• The Cochrane Upper Gastrointestinal and Pancreatic Disease Group, McMaster University, Hamilton, Ontario, Canada.

• Department of Gastroenterology, University Hospital Rijeka, Rijeka, Croatia.

External sources

• No sources of support supplied