Nutrition Support in Acute Pancreatitis: A Systematic Review of the Literature 
From the * Department of Medicine, University of
Louisville School of Medicine, Louisville, Kentucky; Correspondence: Stephen A. McClave, MD, Professor of Medicine, Division of Gastroenterology/Hepatology, University of Louisville School of Medicine, Louisville, KY 40202. Electronic mail may be sent to Stephen.McClave{at}louisville.edu.
Background: Failure to use the gastrointestinal (GI) tract in
patients with acute pancreatitis may exacerbate the stress response and
disease severity, leading to greater incidence of complications and prolonged
hospitalization. The objectives of this study were to determine the optimum
route for nutrition support, whether nutrition therapy is better than no
artificial nutrition support, whether specific additives to enteral or
parenteral therapy can further enhance their efficacy, and whether
methodologic differences in delivery of enteral nutrition (EN) influence
tolerance. Methods: A computerized search was performed of MEDLINE,
Cochrane database, EMBASE, and reference lists of pertinent review articles
for prospective randomized trials in adult patients with acute pancreatitis
that evaluated interventions with nutrition therapy. Primary outcome data and
surrogate endpoint parameters (for nutrition indices, stress markers, and
measures of the inflammatory/immune response) were extracted in duplicate
independently. Where appropriate, meta-analysis was performed by
random-effects model. Results: From 119 articles screened, 27
randomized controlled trials were included and analyzed. In patients admitted
for acute pancreatitis, meta-analysis of 7 trials showed that use of EN was
associated with a significant reduction in infectious morbidity (risk ratio
[RR] = 0.46; 95% confidence interval [CI], 0.29 – 0.74; p =
.001) and hospital length of stay (LOS; weighted mean difference [WMD] =
–3.94; 95% CI, –5.86 to –2.02; p < .0001), a
trend toward reduced organ failure (RR = 0.59; 95% CI, 0.28–1.27;
p = .18), with no effect on mortality (RR = 0.88; 95% CI,
0.43–1.79; p = .72) when compared with use of parenteral
nutrition (PN). Results from individual studies suggest that EN in comparison
to PN reduces oxidative stress, hastens resolution of the disease process, and
costs less. Insufficient data exist to determine whether EN improves outcome
over standard therapy (no artificial nutrition support) in patients admitted
for acute pancreatitis. However, in those patients requiring surgery for
complications of acute pancreatitis, meta-analysis of 2 trials indicates that
provision of EN postoperatively may reduce mortality (RR = 0.26; 95% CI, 0.06
– 1.09; p = .06) compared with standard therapy. PN provided
early within 24 hours of admission was shown to worsen outcome, whereas PN
provided later after full-volume resuscitation appeared to improve outcome
when compared with standard therapy. In early individual studies, specific
supplements added to EN, such as arginine, glutamine, Although <15%–20% of all patients admitted to the hospital for acute pancreatitis are found to have severe disease with pancreatic necrosis, the burden of disease for these patients is considerable.1–3 In these patients, mean hospital length of stay is approximately 1 month, multiple-organ failure will complicate their course of disease in 16%–33% of cases, and infection will develop in 30%–50%.1–3 The mortality rate for severe pancreatitis alone is 19%–30%.4 However, mortality approaches 50% if necrosis involves >50% of the gland,5 may exceed 54% if organ failure develops,4 or may increase up to 80% if sepsis occurs.6 Nutrition therapy in the form of enteral feeding has been shown to favorably affect this burden of disease in patients with severe acute pancreatitis (not mild to moderate pancreatitis), providing the opportunity to change the course of illness, reduce complications, attenuate oxidative stress, and promote faster recovery and resolution of the disease process.7–10
Parenteral nutrition (PN) in the past has always appeared ideally suited as
the preferred route for nutrition support over enteral nutrition (EN) in
patients with acute pancreatitis. The pathophysiology of the disease process
involves a catabolic stress state with elevated caloric requirements and
reduction in pancreatic stimulation appears to be needed to allow resolution
of inflammation within the gland. However, evidence has emerged that other
pathophysiologic processes outside the pancreas itself may contribute to the
stress state seen in these patients. Failure to use the gut may actually
exacerbate the stress response, prolong the duration and severity of disease,
increase the likelihood for
complications.7,8,10
and More recent clinical trials have suggested that EN in comparison to PN may
maintain gut integrity, reduce intestinal permeability, and down-regulate the
systemic immune response, thereby favorably affecting clinical outcome for the
patient with severe acute
pancreatitis.11
Further evidence suggests that not only is the route of feeding a factor in
outcome, but specific agents added to the EN or PN (immune-modulating agents)
such as probiotics or For these patients with acute severe pancreatitis at the height of the systemic inflammatory response syndrome (SIRS), the presence of abdominal pain, nausea, vomiting, and intermittent ileus jeopardizes the provision of EN. Adequacy of nutrition support with EN thus becomes tightly linked to the process of tolerance. Tolerance for any patient may be defined as "provision of adequate feeding without ill effect."14 Tolerance for the patient with acute pancreatitis is primarily determined by the balance between feeding into the gastrointestinal (GI) tract, which may be in a state of partial ileus and providing enteral nutrients while causing only minimal stimulation of pancreatic exocrine secretion. Additional factors, such as the severity of pancreatitis and the timing of nutrition support throughout the period of the acute phase response, contribute to the degree to which patients tolerate the EN. Several excellent recent reports3,15–18 the have reviewed specific aspects of nutrition therapy in patients admitted for acute pancreatitis. These papers have tended to focus primarily on the comparison of enteral vs parenteral routes of feeding in this disease process,3,16,17 with only limited discussion of means by which to modify efficacy of EN or PN.3 Little or no evaluation of tolerance is provided in these reviews. Uncertainty remains regarding other issues related to the nutrition management of the patient with pancreatitis. Does nutrition therapy by either route (EN or PN) improve outcome compared with "standard therapy" (STD), where no artificial nutrition support is provided? Can recommendations for nutrition therapy in the patient newly admitted for severe acute pancreatitis be extrapolated for use in the postoperative setting in the patient requiring surgical intervention for complications of pancreatitis? Do alterations in the composition of nutrition therapy influence outcome? Does the method of enteral delivery affect tolerance? These key issues serve as the focus of this systematic review. The overall purpose of this report is to critically appraise the literature, synthesize data where appropriate, and then ultimately offer clinical recommendations according to the evidence present.
A computerized bibliographic search for all relevant articles from 1966 to August 2005 was made of MEDLINE, Cochran database, and EMBASE. Terms used for the search included enteral nutrition, parenteral nutrition, gastrointestinal intubation, nutrition support, enteral tube feeding, total parenteral nutrition, clinical trials, comparative studies, placebo, randomized trial, and controlled trials. Reference lists from the articles were obtained and personal files were searched as well. The search was limited to prospective randomized controlled trials (PRCTs) in adult patients. Clinically important outcome parameters of significance were evaluated (such as morbidity, LOS, infection, organ failure, noninfectious complications, need for surgical intervention, resolution of the disease process, and mortality). Surrogate outcome parameters were also evaluated, such as nutrition markers (visceral protein level, nitrogen balance, amount of total calories infused, and change in weight), measures of the inflammatory/immune response (tumor necrosis factor, and various cytokines), and stress markers (epinephrine, norepinephrine, and C-reactive protein). Studies were selected that evaluated interventions involving EN, PN, or STD and studies that evaluated specific additives to nutrition therapy (such as probiotics, immune-stimulating agents, or antioxidants). All citations were reviewed by 2 authors (SAM and WKC). Data were extracted for primary endpoints and for surrogate outcome parameters by these 2 independent reviewers. Primary authors were contacted to obtain data that were either missing or unclear. The methodologic quality of the papers was assessed using a previously published scoring system.19 Eligible studies were scored independently by the two reviewers (Table I). Each paper was assessed in duplicate and evaluated on whether the randomization was concealed, results were blinded, and whether the analysis was done by intent to treat. The patient population was evaluated to determine whether consecutive eligible patients were included (or whether some selection process appeared to be in place), whether treatment groups were comparable at baseline, and whether or not follow-up was at 100%. Studies were further evaluated to determine whether treatment protocols were reproducibly described, current interventions were all equal and well described, and whether outcome parameters were objectively defined (Table I). Disagreement between the reviewers was resolved by consensus.
Where 2 or more similar studies were identified in a particular category, meta-analysis was performed. Data were combined from pertinent studies to determine common relative risk for a particular endpoint or outcome parameter, and associated 95% CI were calculated. The treatment effect was summarized using risk ratios (RR). The meta-analysis used maximum likelihood methods of combining RR across all trials, examining data for evidence of heterogeneity within groups. Mantel-Haenszel method was used to test the significance of treatment effect. Random-effects model was used to estimate overall RR. To test heterogeneity across subgroups, the t-test was used for the difference between subgroups. A p value < .05 was considered to be statistically significant; a p value < .20 was considered to be a statistical trend. Variance in the manner by which certain outcome parameters were defined, such as overall complications, organ failure, and need for surgical intervention, precluded meta-analysis of these endpoints (issues of variance which could not be resolved even after contacting the original investigators; Table II).
Study Identification and Selection A total of 119 citations were identified through the computerized bibliographic search. Of these eligible studies, 277–10,12,13,20–40 met inclusion criteria as PRCTs and formed the basis of this review. Of these 27 studies, the mean quality score was 8.15, with a range from 6 to 11. Eleven of the studies compared different methods of feeding (EN, PN, and STD) in patients consecutively admitted for acute pancreatitis,7–10,20–24,38,39 whereas 4 studies evaluated these same feeding strategies provided postoperatively in patients requiring surgical intervention for complications of acute pancreatitis.25–28 Nine studies evaluated specific modifications of either EN or PN,12,13,29–34,40 whereas 3 other studies examined issues related to tolerance.35–37 There was 100% agreement on which articles cited should be included in this review. Reasons for excluding potentially relevant articles included studies that were retrospective, prospective trials that failed to properly randomize patients, reviews in which the data were duplicated in other papers, or reports in which there was contamination by patients with a disease process other than pancreatitis.
Studies Evaluating Route of Nutrition Support in Patients Admitted for Acute Pancreatitis
Overall complications were reported in 2 studies,7,8 including pancreatitis-related complications, nutrition-related complications, and metabolic abnormalities. In the study by Abou-Assi et al,7 overall complications were twice as common (36 vs 15), as were the number of overall complications per patient (1.33 per patient vs 0.58 per patient) in those patients placed receiving PN compared with those given EN, respectively, but these differences did not reach statistical significance.7 On the other hand, results from the Kalfarentzos et al8 study did show a significant reduction in overall complications. Use of EN was associated with 10 complications involving 8 patients (0.55 complications per patient), which was significantly less than the 27 complications seen in 15 patients for whom PN was used (1.35 complications per patient, p < .05).8 Need for surgical intervention was less with use of EN compared with PN in each of 4 studies8–10,22 that reported this parameter. Out of these 4 studies, use of PN was associated with need for surgical intervention in 21 patients, whereas use of EN was associated with need for an operative procedure in only 10 patients.8–10,22 None of the individual differences in these studies reached statistical significance.
Several studies reported the effect of route of nutrition support on markers of the stress response.10,21,22 A study by Windsor showed that over a week of nutrition therapy, patients randomized to PN showed no change in mean C-reactive protein levels (125–124 mg/L).10 Antioxidant defenses in these patients (as measured by total antioxidant capacity) were diminished by a mean 27.7%.10 In contrast, those patients randomized to EN showed a significant drop in C-reactive protein levels (156 – 84 mg/L, p < .005).10 Total antioxidant capacity in this latter group was actually fortified or increased by a mean of 32.6% (p < .05 for changes with EN vs PN).10 Similarly, the study by Louie et al21 showed that the time duration for C-reactive protein levels to drop by 50% was shorter in the group randomized to EN when compared with the group of patients randomized to PN (mean 6.0 vs 11.0 days respectively, p = .09).21 Markers for lipid peroxidation in the Gupta et al22 study showed no significant differences between the groups randomized to EN and PN.
Four studies showed differences between routes of feeding in the degree of stress-induced hyperglycemia.7,8,20,21 These studies showed evidence of better glycemic control in those patients randomized to EN compared with those randomized to PN,7,8,20,21 with significant differences seen in 2 of these studies.7,20 Abou-Assi et al7 showed significantly lower maximal glucose levels (200 vs 325 mg/dL, p = .03) and lower median glucose levels (138 vs 180 mg/dL, p = .03) in those patients randomized to EN compared with those given PN, respectively. McClave et al20 showed a statistically significant increase in serum glucose levels over the first 6 days of nutrition therapy in those patients randomized to PN (p < .05), a change that was not seen in those patients randomized to EN. By the sixth day of hospitalization, the mean difference in serum glucose levels was lower in the group randomized to EN compared with those receiving PN (151 vs 206 mg/dL, p = .07).20 In only 1 study could the differences in serum glucose levels or degree of glycemic control be explained by a significantly lower number of calories provided to the group receiving EN.7
Resolution of the disease process in acute pancreatitis is usually
indicated by absence of abdominal pain, successful advancement to oral diet,
and continued decreases in serum amylase and lipase levels toward normal (but
not necessarily to within normal limits). Three different parameters were
reported in these studies that indirectly related to resolution of the disease
process as an important clinical
outcome.10 The
Windsor et al study evaluated resolution of SIRS. Over 1 week of nutrition
therapy, almost all of the patients randomized to EN (9 of 11) resolved SIRS
compared with only 2 of 12 in the group randomized to PN (p <
.05).10 Days to
oral diet were hastened in 3
studies20–22
with use of EN compared to that with PN, with differences reaching statistical
significance in one of the studies (mean of 2 [0–3] vs mean of
3 [2–9] days, respectively, p =
.02).22 Duration of
nutrition therapy was shorter in 4
studies7,8,21,22
that addressed this parameter, reaching statistical significance in 2 of the
studies.7,22
Abou-Assi et al7
showed that use of EN reduced the mean duration of nutrition therapy from 10.8
± 1.7 days in the PN group to 6.7 ± 1.1 day in the EN group
(p = .03). In this same study, when data on patients with severe
pancreatitis (defined by
True cost of raw materials, cost to third-party payers, and direct cost to the patient for delivery of nutrition therapy are difficult, if not impossible, to determine. Of the 5 studies that evaluated cost of nutrition therapy as a clinical endpoint, 4 referred nonspecifically to "cost," "direct cost," or "mean cost."7,8,21,22; only 1 study defined cost according to charges to the patient.20 Nonetheless, cost reductions, ranging from 2-fold to 7-fold in degree, were found to be associated with use of EN compared with PN (as reported in the 5 studies).7,8,20–22 These differences reached statistical significance in 2 studies7,20 and fell short of conventional levels of statistical significance a third study.21 Abou-Assi et al7 in showed a 7-fold reduction in cost of nutrition therapy, from a mean of $2756 per patient in those randomized to PN to $394 per patient in those randomized to EN (p = .004). McClave et al20 showed a 5-fold reduction in cost of nutrition therapy, from $3294 ± 552 per patient in those randomized to PN to $761 ± 50 per patient for those patients randomized to EN (p < .005). Louie et al21 showed that cost of nutrition therapy was reduced by half with use of EN compared with PN ($1375 per patient vs $2208 per patient, respectively), but results just missed statistical significance (p = .08). Recommendations: In patients with severe acute pancreatitis, the use of EN compared with PN favorably affects patient outcome by reducing hospital LOS, infectious morbidity, and possibly organ failure.7–10,20–22 In comparison to PN, use of EN may hasten resolution of the disease process, as evidenced by shorter duration of nutrition therapy, faster recovery from SIRS (systemic inflammatory response system) and fewer days to advancement to oral diet.7,8,10,20–22 Cost of nutrition therapy is reduced with use of EN compared with PN.7,8,20–22 Therefore, when initiating specialized nutrition therapy, EN is clearly the preferred route over PN for patients admitted with acute severe pancreatitis. Neither EN nor PN may be necessary in mild to moderate acute pancreatitis, as patients have a >80% chance of advancing successfully to an oral diet within 7 days.23 EN/PN vs STD. Only 1 small study24 attempted to address potentially the most important question in nutrition therapy in acute pancreatitis, which is whether nutrition therapy provided by the optimal route (EN) has a more favorable impact on patient outcome than STD, in which no artificial nutrition support is provided. Unfortunately, limits in the design of this project probably resulted in a negative study.24 Although consecutive patients admitted for acute pancreatitis were appropriately randomized to EN or STD, the overall quality score was 7, only 21% of caloric requirements were infused in the group receiving EN, the study duration was only 4 days in length, and small numbers of patients were recruited (total of 27).24 No significant differences were seen between the 2 groups with respect to overall complications, hospital LOS, or time to advancement to oral diet (Table III). Although markers of inflammation (tumor necrosis factor, interleukin-6, and C-reactive protein levels) appeared to be lower in the group receiving EN compared with those randomized to STD, none of the differences were statistically significant over the 4 days of the study. Abnormalities in intestinal permeability occurred more often in the group receiving EN than those randomized to STD (p = .03), a difference that could not be explained by the authors.24
Two studies23,38 compared PN with STD (no artifical nutrition support) (Table III). Surprisingly, results of the first study by Sax et al23 suggested net harm from use of early PN. Consecutive patients admitted for acute pancreatitis were randomized to receive PN early in the course of hospitalization (within 24 hours of admission) vs STD with analgesia and IV fluid resuscitation only.23 Patients in general had mild pancreatitis, as evidenced by mean albumin levels that were within normal limits and a mean Ranson criterion for the entire group of 1.1.23 Those patients receiving PN had a significantly longer hospital LOS compared with those randomized to STD (16 ± 3 days vs 10 ± 2 days, p < .04).23 Days to successful advancement to clear liquid diet were longer in the PN group at 10 ± 2 days compared with those randomized to STD at 6 ± 1 days, but the differences just missed statistical significance (p = .08)23 (Table III). In a more recent Chinese study, Xian-Li et al38 evaluated patients admitted for severe acute pancreatitis who were given 1 of 3 separate management strategies for nutrition therapy: PN, PN with parenteral glutamine, or STD. Forty-four patients were randomized to PN or STD. Unlike the Sax et al23 study, in which the PN had to be started within 24 hours of admission to the hospital, PN in the Xian-Li et al38 study was initiated within 24–48 hours of completion of "liquid resuscitation." This may have led to a differential delay of several days with regard to the timing of the PN between the 2 studies, with PN being provided later in the Xian-Li et al38 study possibly after the peak of the inflammatory response. Although the patients are described as having "severe" acute pancreatitis, degree of disease severity cannot be ascertained from the data provided (no Ranson criteria, APACHE scores, or details of computed tomography findings are given). Patients in the Sax et al23 study had mild to moderate pancreatitis. Nonetheless, use of PN was shown to significantly improve patient outcome.38 Compared with STD, use of PN was associated with significantly fewer overall complications (52.4% vs 91.3%, p < .01), shorter hospital LOS (28.6 ± 6.9 vs 39.1 ± 10.6 days, p < .05), and reduced mortality (14.3% vs 43.5%, p < .05)38 (Table III). Recommendations: Whether any nutrition therapy is better than STD (where no artifical nutrition support is provided) is difficult to answer according to the limited studies available. Whether EN has any differential effect on outcome compared with STD when provided early in acute pancreatitis cannot be determined according to insufficient data from 1 small, potentially flawed study.24 PN initiated early in the course of hospitalization within 24–48 hours of admission may have worse impact on patient outcome than STD, increasing hospital LOS and prolonging the duration of time for advancement to oral diet (especially in patients with only mild to moderate pancreatitis).23 Therefore, in patients with severe pancreatitis in whom EN is not available or feasible, we recommend delaying the initiation of PN for at least 5 days after admission to the hospital, after the peak of inflammation. Effect of Supplemental EN. Use of PN supplemented by EN (vs PN alone) was evaluated in a Chinese study by Sun et al,39 where 100 patients with severe acute pancreatitis were randomized to PN or "individually staged nutrition support (ISNS)." Overall study design, in which the ISNS group advanced from PN with parenteral albumin (average 9.1 ± 6.2 days), to PN supplemented with EN (average 6.2 ± 3.1 days), to EN alone (average 3.2 ± 2.1 days), and the fact that the timing of advancement was left up to the primary physician according to "dynamic pathologic status and GI function," precluded evaluation of the effects of supplemental EN alone.39 Results showed that use of the ISNS regimen significantly reduced the incidence of sepsis or "superinfection" (8% vs 30%), abdominal cavity infection (4% vs 12%), hepatic dysfunction (4% vs 12%), hospital LOS (24.5 vs 30.2 days), days to oral diet (18.5 vs 24.8 days), and cost of hospitalization (4.1 vs 5.8 10,000 yuan) compared with use of PN, respectively (all comparisons, p < .05).39 Recommendations: Insufficient data exist to determine whether use of supplemental EN enhances the efficacy of PN in patients admitted for acute severe pancreatitis.
Studies Evaluating Route of Nutrition Support Postoperatively in Patients With Acute Pancreatitis Requiring Surgical Intervention
EN vs STD Postoperatively. Two papers by the same group27,28 addressed the important issue of whether nutrition therapy provided postoperatively in patients requiring surgical intervention for complications of acute pancreatitis by the optimal route (EN) had better impact on patient outcome than STD with no artifical nutrition support (Table IV). The second paper28 included a group of patients operated on for secondary peritonitis. After contacting the authors, the data were provided for the second study, excluding those patients with peritonitis. The authors confirmed that the 2 groups of patients for each of the 2 studies were different. Both studies were of identical design, in which patients operated on for complications of acute pancreatitis were randomized to EN (by nasojejunal or surgically placed jejunostomy tube on the day after surgery) vs STD (in which only IV fluid resuscitation and analgesia was provided).27,28 When the data from the 2 studies (which together involved a total of 71 patients) were aggregated by meta-analysis, a trend toward a reduction in mortality was seen with use of EN compared with STD (RR = 0.26; 95% CI, 0.06–1.09; p = .06; Figure 5). The incidence of postoperative peritonitis requiring repeat laparotomy in the patients operated on originally for complications of acute pancreatitis was also reduced 3-fold from 28.2% in those patients randomized to STD to 9.3% in those patients receiving EN (p = .07).27,28 Overall complications were reduced by half, and multiple-organ failure was less in the group receiving EN compared with those randomized to STD, but these differences did not reach statistical significance27,28 (Table IV).
Effect of Supplemental EN Postoperatively. In a small study in patients again requiring surgery for complications of acute pancreatis, Bodoky et al26 evaluated the effect of providing supplemental EN added to PN vs receipt of PN alone. Overall, no significant differences in outcome parameters were seen between the 2 groups. In the first 60 hours after surgery, all patients showed little output of pancreatic enzymes (obtained by duodenal aspiration).26 After 60 hours, both groups showed a significant increase in output to a similar degree, as recovery of the pancreatic secretory function (volume, bicarbonate, and enzyme output) occurred.26 Recommendations: Postoperatively, in patients requiring surgical intervention for complications of acute pancreatitis, insufficient data exist to determine whether EN is clearly more beneficial than PN. Although a plethora of data in other surgical settings, such as trauma and major elective operations, has shown EN to be superior to PN,41–43 only 1 small study exists in surgery for pancreatitis,25 which is insufficient to draw a conclusion. EN appears safe and well tolerated in this setting. Providing EN postoperatively in those patients requiring surgical intervention for complications of acute pancreatitis does benefit patient outcome and may be expected to reduce postoperative mortality when compared with use of STD.27,28
Modifications in Composition of Traditional Nutrient Delivery
Two studies evaluated use of immune-enhanced formulas for EN.29,40 In 16 patients consecutively admitted for acute pancreatitis, Hallay et al29 evaluated the effects of the immune-enhanced EN vs standard EN (Table V). The treatment group received an enteral formula fortified with glutamine at 13 g/L and arginine at 8 g/L (Stresson Multi-Fiber, Nutricia), whereas controls were given a standard enteral formula (Nutrison Fiber, Nutricia), infused through a nasojejunal tube, started within 24 hours of admission.29 Although results showed that use of the immune-enhanced formula was associated with lower incidence of pneumonia, multiple-organ failure, and bowel necrosis with bleeding compared with the group receiving standard EN, none of these differences reached statistical significance.29 Comparing standard EN to immune-enhanced EN, reductions in intensive care unit (ICU) LOS (from 34.8 days to 8.6 days, respectively) and overall hospital LOS (from 48.4 days down to 27.2 days, respectively) were shown, but none of these differences reached statistical significance. The mortality and incidence of ARDS (adult respiratory distress syndrome) was equal between the 2 groups (Table V). Higher levels of immunoglobulin and visceral proteins (prealbumin and retinol binding protein) were seen in the treatment group compared with controls (p = NS).29
In a second study, Pearce et
al40 evaluated a
proto-type immune-enhanced formula (containing glutamine; arginine;
In a separate study of 28 patients,
Lasztity13
evaluated whether provision of Modifications of PN. Glutamine provided IV has the potential to maintain gut integrity, support glutathione antioxidant defenses, reduce systemic endotoxemia, and diminish release of inflammatory cytokines in patients with acute pancreatitis. Four studies evaluated PN with or without supplemental parenteral glutamine.30–32,38 In 28 patients with moderate to severe pancreatitis, Ockenga et al30 found that those patients randomized to PN with supplemental parenteral glutamine showed a trend toward reduced mean hospital LOS (21 [14–32] vs 25 [19–40] days, p = .07) and significantly shorter duration of nutrition therapy (10 [6–16] vs 16 [10–18] days, p = .03) when compared respectively to controls receiving PN without supplementation (Table V). Although the daily cost of nutrition therapy was significantly higher in the group receiving glutamine supplementation compared with controls (78 ± 25.7 vs 55 ± 19.3 Euros, respectively, p < .01), the overall cost of nutrition therapy was slightly less in the treatment group due to shorter duration of nutrition therapy (929 ± 586 vs 981 ± 507 Euros per patient vs controls, respectively, p = NS).30 Visceral protein levels, including albumin, transferrin, and total protein, were all significantly higher in the glutamine supplementation group compared with the group receiving PN alone (p < .05).30
In a second study of similar design, de Beaux et al31 again evaluated PN with and without supplemental parenteral glutamine (Table V). In this latter study, however, only those patients receiving long-term PN who had "persistent failure" of the GI tract for >7 days after the onset of acute pancreatitis were included in the study. As a result, patients were randomized on an average of 10–18 days after the onset of the illness. There were no deaths in the study. The incidence of major pancreatic complications (pancreatic necrosis, pseudocysts, abscess) was no different between the 2 groups; 4/7 patients in the treatment group receiving glutamine supplementation vs 5/7 patients in the control group31 (Table V). Interleukin-8, an inflammatory cytokine released by mononuclear cells (which is capable of priming circulating neutrophils and is often implicated in acute lung injury), decreased in the glutamine group by 17.7 ng/mL, whereas the levels increased significantly in controls receiving PN alone by 43.3 ng/mL (p = .045).31 Phytohemagglutinin-stimulated T-cell responses, mononuclear cell release of tumor necrosis factor, and interleukin-6 levels were no different between the 2 groups.31 The design of a third study, the Chinese paper by Xian-Li et al,38 allowed further evaluation of the effects of supplemental parenteral glutamine, as 41 patients with severe acute pancreatitis were randomized to receive either PN or PN with glutamine (Table V). In these patients, use of PN with parenteral glutamine was associated with significantly less pancreatic infection (0.0% vs 23.8%, p < .05) and fewer overall complications (20% vs 52.4%, p < .05) compared, respectively, to use of PN alone without supplemental glutamine38 (Table V). Similarities in the design of these 3 studies allowed for aggregation of the data and meta-analysis of the effect of supplemental parenteral glutamine to PN on patient outcome.30,31,38 Aggregating the data from all 3 studies, use of PN with parenteral glutamine was associated with a trend toward a reduction in overall complications (RR = 0.68; 95% CI, 0.42–1.09; p = .11) (Figure 6) compared with use of PN alone.30,31,38 Two of these studies showed shorter hospital LOS with PN/glutamine compared with PN alone, a nonsignificant reduction of 3 days in the Xian-Li et al,38 study (25.3 ± 7.6 vs 28.6 ± 6.9 days, respectively) and a statistically significant reduction of 4 days in the Ockenga et al30 study (21 days [14–32] vs 25 days [19–40], respectively). In a slight variation of this theme, a Chinese study by Zhao et al32 again compared a treatment group receiving PN with added parenteral glutamine to a control group receiving conventional PN alone without glutamine. Furthermore, the treatment group was transitioned to receive supplemental EN once "gut paralysis" was relieved. No outcome parameters were evaluated in the 96 patients randomized in this study. Inflammatory markers (including tumor necrosis factor, interleukin-6, and C-reactive protein levels) decreased faster and to a greater extent in the treatment group compared with controls at 4, 7, and 11 days (all differences reaching statistical significance).32 By the 15th day of the study, the levels of these stress markers were no different between the 2 groups. Over the 3 weeks of the study (at 7, 15, and 21 days), circulating systemic levels of endotoxin were significantly less in the treatment group compared with controls.32 Likewise, over the same time period, gut permeability was less (as indicated by reduced urinary lactose/mannitol ratios) in the treatment group compared with controls.32 Similarly, the ratio of CD4:CD8 T-cell lymphocyte subset populations was significantly higher in the treatment group compared with controls over the period of study.32 Modifying the glucose composition in PN to control stress-induced hyperglycemia was the focus of 2 small studies from China and Spain.33,34 In the Chinese study, Wu et al33 randomized 17 patients with acute necrotic pancreatitis to receive nutrition therapy over a 2-week period of time with either glucose-based PN (in which all nonprotein calories were given as dextrose) or glucose/lipid-based PN (in which nonprotein calories were evenly divided between dextrose and IV fat emulsion). Hyperglycemia was present in 64% of the patients on admission and was particularly difficult to control over the first 10 days of nutrition therapy. The hyperglycemia was easier to control in the group receiving the glucose/lipid-based PN compared with the glucose-based PN group, but it is not clear whether the differences reached statistical significance.33 In the group receiving the glucose/lipid-based PN, there was no evidence of hypertriglyceridemia, and no harmful effects on liver function were seen.33 In the Spanish study, Martinez et al34 randomized 47 patients to receive experimental PN in which dextrose was supplemented with nonglucose carbohydrates (fructose and xylitol) or traditional PN with carbohydrate in the form of dextrose alone. Both groups received standard amino acid and Intralipid preparations in the PN. The amount of insulin required after 10 days of nutrition therapy was significantly less in the treatment group receiving the nonglucose carbohydrate mixture (17 ± 15 vs 42 ± 16 IU/d, p = .05), and triglyceride levels were lower as well in the treatment group (167 ± 68 vs 294 ± 88, p = .05) when compared respectively to the control group receiving glucose-based PN.34 No significant differences were seen between the groups in overall glucose levels, serum cholesterol, or uric acid levels. No outcome parameters were evaluated in either study.33,34
Recommendations: The beneficial effect of EN on patient outcome in
acute pancreatis may be enhanced by providing certain supplements. Although
adding arginine, glutamine,
Tolerance Tolerance specifically for advancement to oral diet was evaluated by Pandey et al35 in 28 patients admitted for acute pancreatitis. At the point at which abdominal pain had resolved and any ileus had subsided, patients were randomized to begin oral diet or refeeding by nasojejunal tube. Out of the 15 patients randomized to oral feedings (begun a median of 7 days after onset of symptoms), relapse of abdominal pain occurred in 4. No relapse of pain occurred in those patients randomized to jejunal tube feedings (begun a median of 5 days after onset of symptoms); the difference between groups just missing statistical significance, p = .06.35 Hospital LOS was 9 days shorter in the group randomized to jejunal feedings, compared with those receiving oral diet (12 vs 21 days, respectively, p = NS).35 Factors associated significantly with pain on refeeding were longer duration of initial pain and higher severity index score on computed tomography scan.35 Total hospital LOS was significantly longer in those patients who experienced relapse of pain on refeeding compared with those with no relapse (50.5 vs 9.5 days, respectively, p < .004).35 In a study by Eatock et al,36 patients with acute severe pancreatitis were randomized to nasogastric vs nasojejunal feedings, begun within 72 hours of onset of abdominal pain. The study was designed after these researchers noted that patients receiving nasojejunal tube feeding in the past appeared to tolerate nasogastric feeding on several occasions when the tube accidentally slipped back into the stomach. Both groups in this randomized study were advanced to full rate of feeding on an average of 36 hours after initiation of feedings. Several outcome parameters, including mortality, number of patients requiring placement in the ICU, hospital LOS, resolution of pain (according to decreasing scores), analgesic requirements, time to advancement to oral feedings, and decreasing C-reactive protein levels, were no different between the 2 groups.36 Only 2 patients in the group fed by the nasogastric route experienced abdominal pain compared with no patients in the nasojejunal group. Due to the surprising tolerance of the nasogastric feedings and its comparative simplicity (obviating the need for radiographic or endoscopic procedures and IV sedation), these authors recommended that nasogastric feeding could now be considered as a therapeutic option in the management of patients with severe acute pancreatitis.36 Harsanyi et al37 evaluated tolerance as it relates to the manner of infusion of EN in patients operated on for complications of acute pancreatitis. After surgery, 14 patients were fed by the enteral route for 6 days. On the seventh day postoperatively, after an overnight fast, patients were randomized to receive either bolus EN (100 mL immediate infusion) or continuous infusion of EN (100 mL over 60 minutes). Secretory output was measured via duodenal aspiration for 2 hours after the infusion. Volume, bicarbonate content, and enzyme output from the pancreas were significantly greater in the group randomized to bolus infusion compared with the group given continuous infusion (p < .05).37 With regard to reducing stimulation of the pancreas, continuous infusion appeared to be safer than bolus infusion of EN in this disease process.37 Recommendations: Placing a nasogastric tube and initiating enteral feeding may be considered even in patients with severe acute pancreatitis. Those patients with a prolonged period of pain and greater degrees of pancreatic necrosis on computed tomography scan may benefit from a trial of nasojejunal feedings before advancement to oral feedings, to assure tolerance and prevent prolongation of hospital LOS.35 Tolerance to enteral feeding may be enhanced by diverting the level of infusion of formula lower in the GI tract and switching to continuous infusion.
Review of all the current existing PRCTs in the nutrition therapy of the patient with severe acute pancreatitis emphasizes the changing concepts for which the clinician should be aware. Insufficient data do not allow a determination of whether either route of nutrition support (EN or PN) is superior to STD in the patient newly admitted for acute pancreatitis. When both routes of nutrition support are available, use of EN results in better patient outcome than use of PN for those patients with severe acute pancreatitis. When EN is not feasible in these patients, delaying the initiation of PN for 5 days after admission may improve its efficacy and result in better outcome than continuation of STD in that setting. Providing EN after surgery for complications of acute pancreatitis clearly has a better impact on outcome than STD. The role of PN provided postoperatively in pancreatitis patients cannot be determined from available data. Adding enteral supplements of arginine, glutamine,  -3 fatty acids, or probiotics to EN
may improve its efficacy compared with EN alone without supplementation.
Likewise, addition of parenteral glutamine to PN may improve outcome compared
with use of PN alone. With aggressive use of EN in this patient population,
wide variation in tolerance should be expected. Specific changes in content
and strategy of infusion of the enteral formula can improve overall
delivery. These emerging data emphasize the tremendous capability of nutrition support to modulate the stress response, set the tone for systemic immunity, and ultimately affect patient outcome in acute pancreatitis. In this sense, nutrition therapy has emerged from supportive adjunctive therapy to proactive primary therapy and has become one of the few management tools by which the clinician can favorably alter the course of this disease process.
Summary of Recommendations and Key Findings
Received for publication October 5, 2005. Accepted for publication December 14, 2005.
Journal of Parenteral and Enteral Nutrition, Vol. 30, No. 2,
143-156 (2006) This article has been cited by other articles:
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MATERIALS AND METHODS
RESULTS
3 Ranson criteria) were extracted out from the
rest, duration of feedings was reduced to a greater extent, from a mean of
12.8 ± 2.8 days in the PN group to 6.8 ± 1.6 days in the EN
group (p =
.03).
