Chapter 37 Severe acute pancreatitis
Acute inflammation of the pancreas produces a spectrum of symptoms, which may be mild and self-limiting, or reflect severe disease that leads rapidly to multiple-organ failure and death. In a majority of patients a treatable underlying cause is identified. Although mild, interstitial, oedematous pancreatitis is more common, it is the more severe form, acute necrotising pancreatitis (ANP), that accounts for the associated mortality. Two decades ago the mortality was frequently quoted to be 25–35%, even in the best centres.1 However, more recently published series have suggested a lower mortality (15%).2 Management of patients with severe ANP is time-consuming, and labour- and resource-intensive. Long-term follow-up suggests that, although some survivors suffer permanent exocrine and endocrine insufficiency, most maintain a good quality of life.3
AETIOLOGY
Biliary disease and alcohol remain the two commonest causes of acute pancreatitis worldwide, accounting for 70% of cases. Although no discernible cause is found in many of the remaining cases, there are well-established associations with a number of infections, certain drugs, hyperlipidaemias and trauma. See Table 37.1 for a more exhaustive list.
| Excess alcohol ingestion |
| Biliary tract disease |
| Idiopathic |
| Metabolic |
| Hyperlipidaemia |
| Hyperparathyroidism |
| Diabetic ketoacidosis |
| End-stage renal failure |
| Pregnancy |
| Post renal transplant |
| Mechanical disorders |
| Posttraumatic, postoperative, post endoscopic retrograde cholangiopancreatography |
| Penetrating duodenal ulcer |
| Duodenal obstruction |
| Infections |
| Human immunodeficiency virus, mumps, Epstein–Barr virus, Mycoplasma, Legionella, Campylobacter, ascariasis |
| Vascular |
| Necrotising vasculitis – systemic lupus erythematosus, thrombotic thrombocytopenia |
| Atheroma |
| Shock |
| Drugs |
| Azathioprine, thiazides, furosemide, tetracyclines, oestrogens, valproic acid, metronidazole, pentamidine, nitrofurantoin, erythromycin, methyldopa, ranitidine |
| Toxins |
| Scorpion venom, organophosphates, methyl alcohol |
RANSON’S CRITERIA
Although the overall mortality rate for acute pancreatitis is approximately 10%, the vast majority of deaths occur in those with the severe form of the disease. Since 1974 the standard means of documenting the severity of disease and risk of mortality has been by Ranson’s criteria (Table 37.2).4 These factors were determined following the analysis of 100 patients with predominantly alcohol-induced pancreatitis using clinical and laboratory data obtained on admission and after 48 hours, and the number of positive criteria should predict outcome. A decade later these criteria were re-evaluated and the first eight were found to be most predictive – this is now known as the Glasgow criteria, or Imrie score.5
Table 37.2 Adverse prognostic factors in acute pancreatitis: Ranson’s score4
| On admission | Age > 55 years |
| White cell count > 16 000/mm3 | |
| Glucose 11 mmol/l | |
| Lactate dehydrogenase 400 IU/l | |
| Aspartate transaminase > 250 IU/l | |
| Within 48 hours of hospitalisation | Decrease in haematocrit > 10% |
| Increase in blood urea > 1.8 mmol/l | |
| Calcium < 2 mmol/l | |
| PaO2 < 8 kPa | |
| Base deficit > 4 mmol/l | |
| Fluid deficit > 6 litres | |
| Risk factors | Mortality rate |
| 0–2 | < 1% |
| 3–4 | ≅ 15% |
| 5–6 | ≅ 40% |
| > 6 | ≅ 100% |
Blamey et al.5 found only eight variables (not lactate dehydrogenase, base deficit and fluid deficit) were predictive and are often referred to as the Glasgow criteria or Imrie score.
SCORING
The scoring of patients with acute pancreatitis is important for a number of reasons. Firstly, the clinician can be alerted to the presence of potentially severe disease. Secondly, comparisons of severity can be made both within and between patient series; and thirdly, rational selection of patients can be made for inclusion in trials of potential new treatments or interventions. Unfortunately the scoring systems used at present are often inadequate in patients with severe ANP, which is characterised by rapidly progressive multiple-system organ dysfunction. In this setting the Ranson criteria and APACHE score do not take account of the effects of treatment upon measured parameters. The way forward may be to use a combination of the Ranson score, the radiological scoring systems (see below) and a descriptive organ failure score such as the Sepsis-related Organ Failure Assessment.6
THE MANAGEMENT OF SEVERE PANCREATITIS
IMAGING
Dynamic contrast-enhanced computed tomography (CT) provides the best means of accurately visualising the pancreas and diagnosing pancreatitis and its local complications. It may also be used for guiding percutaneous catheter drainage. Guidelines have been suggested for the efficacious use of CT scanning and these are shown in Table 37.3.7
Table 37.3 Guidelines for efficacious use of computed tomography scanning in suspected acute pancreatitis6
| Patients in whom the clinical diagnosis is in doubt |
| Patients with hyperamylasaemia and severe clinical pancreatitis, abdominal distension, tenderness, high fever (> 39°C) and leukocytosis |
| Patients with Ranson score > 3 or APACHE II > 8 |
| Patients showing lack of improvement after 72 hours of initial conservative therapy |
| Acute deterioration following initial clinical improvement |
APACHE, Acute Physiology, Age and Chronic Health Evaluation.
In severe acute pancreatitis, there is lack of normal enhancement to contrast of the gland or a portion thereof. This is consistent with pancreatic necrosis, defined as diffuse or focal areas of non-viable parenchyma. Microscopically, there is evidence of damage to the parenchymal network, acinar cells and pancreatic ductal system and necrosis of perilobular fat. Areas of necrosis are often multifocal and rarely involve the whole gland, and may be confined to the periphery with preservation of the core. Necrosis develops early in the course of the disease and is usually established 96 hours after the onset of symptoms.8 The extent of pancreatic necrosis and the degree of peripancreatic inflammation have been used to determine outcome. A grading system combining the two CT prognostic indicators (the extent of necrosis and the grade of peripancreatic inflammation) has been developed to give the ‘CT severity index’. Most complications of acute pancreatitis occur in patients in whom the initial diagnosis is based upon peripancreatic fluid collections, and a strong correlation has been established between the CT depiction of necrosis and the development of complications and death.9 For patients with necrosis in the pancreatic head, the outcome is as severe as when the entire pancreas is affected. By contrast, for patients with necrosis in only the distal portion of the gland, the outcome is favourable, with few complications.10 The mechanism may be that necrosis in the pancreatic head causes obstruction of the pancreatic duct, and produces a rise in pressure in the acinar cells leading to damage and leakage of activated destructive proteases.
Ultrasonography in acute pancreatitis is less useful since visualisation of the gland may be obscured by ‘gas-filled’ bowel. Moreover, the degree of necrosis, which determines prognosis, cannot be assessed. However, there may be a role for this mode of imaging indemonstrating gallstones, or in the subsequent management when ultrasound-guided fine-needle aspiration (FNA) of the pancreas or surrounding tissue may help to establish the presence of infection.
SURGERY IN SEVERE PANCREATITIS
The role of surgery remains a controversial area in the management of severe ANP.11 During the 1980s, most patients with acute pancreatitis of even moderate severity underwent operative intervention. The results were poor, with mortality rates in excess of 50%, although this was without ICU facilities. In 1991, Bradley and Allen introduced the concept of a conservative, non-surgical approach to severe ANP.12 During the past decade, targeting surgical intervention according to infection status, based on Gram stain and culture of CT-guided FNA, has refined this conservative approach with beneficial results.13
A laparotomy for an acute abdomen is essential when the diagnosis of pancreatitis is in doubt. Surgery may increase the incidence of subsequent infection, but this risk is outweighed by the dangers of delaying the diagnosis and treatment of other serious intra-abdominal conditions. Accepted and controversial indications for surgery in severe ANP are summarised in Table 37.4. If severe acute pancreatitis is an unsuspected ‘chance’ finding at laparotomy, a T-tube should be inserted into the common bile duct, particularly if it has been explored and the opportunity taken for placement of a feeding jejunostomy tube. Some surgeons oppose this approach, as opening a hollow viscus risks peritonitis.
Table 37.4 Indications for surgery in severe acute pancreatitis
| Accepted | Controversial |
|---|---|
| Differential diagnosis | Stable but persistent necrosis |
| Persistent biliary pancreatitis | Deterioration in clinical course |
| INFECTED PANCREATIC NECROSIS | Organ system failure |
| Pancreatic abscess | Abdominal compartment syndrome |
STERILE PANCREATIC NECROSIS
The observation that some patients with severe ANP survive without becoming infected and avoid surgery is well documented. Moreover, operating upon such patients may hypothetically increase the risk of subsequent infection and its associated mortality. This is the basis of the critical decision as to whether patients with sterile ANP should undergo operative intervention. Currently a conservative approach is recommended, but with regular surveillance looking for evidence of pancreatic infection.14
PANCREATIC ABSCESSES
Pancreatic abscesses are circumscribed collections of pus containing little or no pancreatic necrosis, which arise as a later consequence of acute pancreatitis or pancreatic trauma. They commonly occur about 3–4 weeks after the onset of severe pancreatitis, and CT scan most accurately makes the diagnosis. If the appropriate expertise is available, percutaneous catheter drainage may be successful. Some series report effective drainage of intra-abdominal collections with a single treatment in 70% of patients, increasing to 82% with a second attempt, although proceeding to open surgical drainage is more frequently required in pancreatic abscess, especially if complicated by yeast infection.15
ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY (ERCP)
ERCP represents an alternative approach, particularly for patients with severe biliary pancreatitis. A number of prospective randomised studies have been carried out to compare early ERCP with conservative treatment in acute biliary pancreatitis. Although the studies are not entirely consistent, ERCP and papillotomy seem to be beneficial in confirmed or suspected severe biliary pancreatitis if undertaken by a skilled operator, whereas in mild pancreatitis the risks of intervention probably outweigh the benefits. This observation is confirmed by both a systematic review of the four ERCP trials,16 and by the recommendations of the 2004 International Consensus Conference on the management of severe acute pancreatitis in the critically ill.17
TREATMENT WITH PHARMACOLOGICAL AGENTS
Theories regarding the pathogenesis of acute pancreatitis have promoted the concept that autodigestion of the gland and peripancreatic tissue by activated pancreatic enzymes is a central component. This has led to the suggestion that the reduction of pancreatic exocrine secretion, thereby ‘resting the pancreas’, might improve outcome. The problem is that the secretory status of the pancreas in severe ANP is not known. Consequently, it is not clear whether inhibition of secretion actually occurs or whether this is beneficial. Therapies designed to inhibit pancreatic secretion, such as H2-blockers, atropine, calcitonin, glucagon and fluorouracil, do not alter the course of the disease. However, other pharmacological therapies, such as aprotonin and gabexate mesilate, both protease inhibitors, and somatostatin and octreotide, are in widespread use in the hope of improving the outcome.
SOMATOSTATIN AND OCTREOTIDE
Somatostatin and its long-acting analogue octreotide are potent inhibitors of pancreatic secretion. They also stimulate activity of the reticuloendothelial system and play a regulatory role, mostly inhibitory, in the modulation of the immune response via autocrine and neuroendocrine pathways. Both are cytoprotective with respect to the pancreas.18 Other effects include:
These actions may be important in the modulation of the pathogenesis of acute respiratory distress syndrome (ARDS) and septic shock, both of which can complicate severe ANP. Both agents are effective in experimental pancreatitis, and in the prevention of complications in patients undergoing surgery for chronic pancreatitis.19 Potential difficulties include:
Consequently, these agents have both beneficial and detrimental effects.
Systematic evaluation suggests that there is insufficient evidence at present to support the use of octreotide or somatostatin in the treatment of patients with moderate to severe acute pancreatitis.21 Additionally, the therapeutic effect of octreotide, if present at all, is probably very small and therefore unlikely to have any significant impact on the management of ANP.
PROTEASE INHIBITORS
The only two prospective, randomised studies of the protease inhibitor gabexate mesilate in patients with moderate or severe pancreatitis, when combined, showed no significant reduction in mortality or the need for surgery.22
The reason why these agents, in clinical practice, do not have the expected beneficial effect on outcome may be the lag time between the onset of pancreatitis and administration. Additionally, derangement to the microvascular control of the pancreas combined with increased vascular permeability may contribute. Continuous regional arterial infusion or intraperitoneal administration may be more advantageous, but so far trials using these modes of administration have only involved small numbers of patients. At present, there is insufficient evidence to recommend protease inhibitors in ANP.23
ANTI-INFLAMMATORY THERAPY
Patients with ANP exhibit a generalised uncontrolled inflammatory response. Potentially there is a therapeutic window between the onset of symptoms and the development of organ failure during which anti-inflammatory therapy might be successful. Potential targets include tumour necrosis factor-α, interleukin (IL)-1β, IL-6, IL-8, IL-10, platelet-activating factor and intracellular adhesion molecules.24 Although many have been studied in animals, there are limited human data. Recombinant human activated protein C (rh-APC) has proven effectiveness in reducing mortality in severe sepsis.25 Sixty-two patients with pancreatitis were enrolled in the PROWESS trial; mortality was 24% in the placebo arm and 15% in those receiving rh-APC.17 All patients had a known or suspected source infection, which is not the case in many patients with ANP. There are currently no studies of rh-APC in patients without a documented source of infection, yet it seems that these patients demonstrate the same low levels of activity of protein C, antithrombin III, and higher concentrations of D-dimer and plasminogen activator inhibitor that are associated with poor outcome in patients with severe sepsis.26
It is also fascinating to observe that there is a constellation of changes in hypopituitary–adrenal axis hormone levels that strongly suggest that the existence of relative adrenocortical insufficiency in patients with ANP is very comparable to that of severe sepsis and multiple-organ failure.27 There are currently no published trials of corticosteroid therapy in patients with ANP.
PROPHYLACTIC ANTIBIOTICS
Bacterial infection of necrotic pancreatic tissue occurs in approximately 40–70% of patients with ANP, and infection is the major cause of morbidity and mortality.28 Early studies investigating the role of antibiotics in acute pancreatitis showed no benefit, but most included patients with mild disease and employed agents (e.g. ampicillin) with inefficient penetration of pancreatic tissue. Subsequent studies are more encouraging.
Carbapenems have exceptional penetration into pancreatic tissues and broad activity against most of the common pathogens encountered in this disease. One study compared imipenem with placebo in patients with early necrotising pancreatitis.29 The incidence of septic complications was significantly reduced in the treated group (12.2 versus 30.3%), although there was only a trend towards decreased mortality (7 versus 12%). In another study of ethanol-induced ANP, cefuroxime was compared to placebo.30 There were more infectious complications in the non-antibiotic group (mean per patient 1.8 versus 1.0; P < 0.01) and mortality was also higher (7 versus 1 death; P = 0.03). The most recent meta-analysis of the only three adequately controlled studies of prophylactic antibiotics in patients with contrast-enhanced CT proven ANP strongly suggests benefit, with a reduction in sepsis of 21%, and a reduced mortality of 12.3%.31
Patients with mild pancreatitis do not benefit from antibiotics.
PROPHYLACTIC ANTIFUNGAL THERAPY
The incidence of fungal infection correlates with the extent of pancreatic necrosis, as well as the severity of disease on admission. Antibiotic administration has been claimed to promote fungal infection; however, up to 25% of patients with ANP who do not receive antibiotics also develop fungal infection with an associated mortality rate of up to 84%.32 One small, randomised study suggested fluconazole reduced the rate of fungal infection, but had no effect on mortality. Advocates of prophylactic antifungal therapy argue that it may delay the need for surgery, which is associated with a better outcome.33
SELECTIVE DECONTAMINATION OF THE GUT
The original selective digestive decontamination (SDD) strategy contained three components: oropharyngeal and gastric decontamination with polymyxin E, tobramicin, and amphotericin B and intravenous cefotaxime for 4 days.34 There is ongoing debate as to the effectiveness of this strategy and results are conflicting regarding any reduction in mortality, particularly when applied to a general critically ill population. However, more promising results have been seen in specific patient populations.
Severe acute pancreatitis may be one clinical situation which supports the hypothesis that gut hypoperfusion promotes bacterial translocation, leading to infection of the inflamed pancreas and peripancreatic tissue.35 The only controlled trial of SDD in pancreatitis was performed in 102 patients,36 who were randomised to receive SDD: oral colistin, amphotericin and norfloxacin with addition of a daily dose of the three drugs given as a rectal enema and systemic cefotaxime until Gram-negative bacteria were successfully eliminated from the oral cavity and rectum. Surveillance samples were taken regularly to assess whether any subsequent infection was of exogenous or endogenous origin. There were 18 deaths (35%) in the control group, compared with 11 (22%) in the SDD group (P < 0.05). This difference was caused by a fall in late mortality due to significant reduction in the incidence of Gram-negative pancreatic infection. There was also a reduction in the mean number of laparotomies in the SDD patients. Since the SDD regimen used in this study incorporated intravenous cefotaxime it could be argued that the improvement in outcome was not due to the colistin, amphotericin or norfloxacin components, but merely due to a systemic antibiotic effect.
Meta-analyses of SDD suggest that there are clear trends towards a reduction in mortality in critically ill patients.37 However, the perhaps unfounded fear of the emergence of resistant Gram-positive cocci prevents widespread adoption of this strategy.
NUTRITIONAL SUPPORT IN ACUTE NECROTISING PANCREATITIS
The provision of nutritional support for the patient with ANP is an essential component of supportive therapy, especially since many patients with pancreatitis are nutritionally depleted prior to their illness and face increased metabolic demands throughout the course of their disorder. Failure to reverse or prevent malnutrition, and a prolonged negative nitrogen balance, increases mortality rates. The route by which nutrition is administered is, none the less, still debated. In the last two decades there has been a trend away from the use of total parenteral nutrition (TPN) in favour of enteral nutrition (EN) in supporting the critically ill. Studies suggest that early EN started within 24 hours of admission to ICU, compared with TPN, is associated with reduced infective complications and hospital length of stay.38
ENTERAL NUTRITION
Consequently, jejunal tube feeding as far distally as possible in the upper gastrointestinal tract conforms to the concept of ‘pancreatic rest’. A number of comparisons of EN with TPN have been made in mild and severe acute pancreatitis, all suggesting that EN is well tolerated without adverse effects on the course of the disease.39 Patients who received EN experienced fewer total complications and were at lower risk of developing septic complications than those receiving TPN.40 EN seems to modulate the inflammatory and sepsis response beneficially, and if tolerated, may be superior to TPN.41 In spite of the enthusiasm for EN of some clinicians, in ANP where there is often an ileus and slow bowel transit time, some patients will not tolerate it.42 It is not uncommon to be faced with the option of no nutrition or TPN; in this situation TPN enriched with glutamine should be used.43
A number of recommendations can be made:
1 Banerjee AK, Kaul A, Bache E, et al. An audit of fatal acute pancreatitis. Postgrad Med J. 1995;71:472-475.
2 Malangoni MA, Martin EL. Outcome of severe pancreatitis. Am J Surg. 2005;189:273-277.
3 Cinquepalmi L, Boni L, Dionigi G, et al. Long-term results and quality of life of patients undergoing sequential surgical treatment for severe acute pancreatitis complicated by infected pancreatic necrosis. Surg Infect. 2006;7:S113-116.
4 Ranson JHC, Rifkind KM, Roses DF, et al. Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynaecol Obstet. 1974;139:69-81.
5 Blamey SL, Imrie CW, O’Neill J, et al. Prognostic factors in acute pancreatitis. Gut. 1984;25:1340-1346.
6 Halonen KI, Pettila V, Leppaniemi AK, et al. Multiple organ dysfunction associated with severe acute pancreatitis. Crit Care Med. 2002;30:1274-1279.
7 Balthazar E, Freeny P, van Sonnenberg E. Imaging and intervention in acute pancreatitis. Radiology. 1994;193:297-306.
8 Isenmann R, Buchler M, Uhl W, et al. Pancreatic necrosis: an early finding in severe acute pancreatitis. Pancreas. 1993;8:358-361.
9 Casas JD, Diaz R, Valderas G, et al. Prognostic value of CT in the early assessment of patients with acute pancreatitis. Am J Roentgenol. 2004;182:569-574.
10 Kemppainen E, Sainio V, Haapianen L, et al. Early localization of necrosis by contrast-enhanced computed tomography can predict outcome in severe acute pancreatitis. Br J Surg. 1996;83:924-929.
11 Uhl W, Warshaw A, Imrie C, et al. IAP guidelines for the surgical management of acute pancreatitis. Pancreatology. 2002;2:565-573.
12 Bradley EL, Allen K. A prospective longitudinal study of observation versus surgical intervention in the management of necrotizing pancreatitis. Am J Surg. 1991;161:19-25.
13 Buchler MW, Gloor B, Muller CA, et al. Acute necrotizing pancreatitis: treatment strategy according to the status of infection. Ann Surg. 2000;232:619-626.
14 Hartwig W, Maksan SM, Foitzik T, et al. Reduction in mortality with delayed surgical therapy of severe pancreatitis. J Gastrointest Surg. 2002;6:481-487.
15 Cinat ME, Wilson SE, Din AM. Determinants for successful percutaneous image-guided drainage of intra-abdominal abscess. Arch Surg. 2002;137:845-849.
16 Sharma VK, Howden CW. Metaanalysis of randomised controlled trials of endoscopic retrograde cholangiography and endoscopic sphincterotomy for the treatment of acute biliary pancreatitis. Am J Gastroenterol. 1999;94:3211-3214.
17 Nathens AB, Curtis JR, Beale RJ, et al. Management of the critically ill patient with severe acute pancreatitis. Crit Care Med. 2004;32:2524-2536.
18 Van Hagen PM, Krenning EP, Kwekkeboom DJ, et al. Somatostatin and the immune and haematopoietic system: a review. Eur J Clin Invest. 1994;24:91-99.
19 Friess H, Beger HG, Sulkowski U, et al. Randomised controlled multicentre study of the prevention of complications by octreotide in patients undergoing surgery for chronic pancreatitis. Br J Surg. 1995;82:1270-1273.
20 Klar E, Rattner DW, Compton C, et al. Adverse effect of therapeutic vasoconstrictors in experimental acute pancreatitis. Ann Surg. 1991;214:168-174.
21 Cavallini G, Frulloni L. Somatostatin and octreotide in acute pancreatitis: the never-ending story. Dig Liver Dis. 2001;33:192-201.
22 Heinrich S, Schafer M, Rousson V, et al. Evidenced-based treatment of acute pancreatitis. A look at established paradigms. Ann Surg. 2006;243:154-168.
23 Seta T, Noguchi Y, Shimada T, et al. Treatment of acute pancreatitis with protease inhibitors: a meta-analysis. Eur J Gastroenterol Hepatol. 2004;16:1287-1293.
24 Bhatia M. Novel therapeutic targets for acute pancreatitis and associated multiple organ dysfunction syndrome. Curr Drug Targets Inflamm Allergy. 2002;1:343-351.
25 Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699-709.
26 Radenkovic D, Bajec D, Karamarkovic A, et al. Disorders of hemostasis during the surgical management of severe necrotizing pancreatitis. Pancreas. 2004;29:152-156.
27 Muller CA, Vogeser M, Belyaev O, et al. Role of endogenous glucocorticoid metabolism in human acute pancreatitis. Crit Care Med. 2006;34:1060-1066.
28 Beger HG, Rau B, Mayer J, et al. Natural course of acute pancreatitis. World J Surg. 1997;21:130-135.
29 Pederzoli P, Bassi C, Vesentini S, et al. A randomised multicenter trial of antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. Surg Gynaecol Obstet. 1993;176:480-483.
30 Sainio V, Kemppainen E, Puolakkainen P, et al. Early antibiotic treatment in acute necrotizing pancreatitis. Lancet. 1995;346:663-667.
31 Sharma VK, Howden CW. Prophylactic antibiotic administration reduces sepsis and mortality in acute necrotizing pancreatitis: a meta-analysis. Pancreas. 2001;22:28-31.
32 Gotzinger P, Wamser P, Barlan M, et al. Candida infection of local necrosis in severe acute pancreatitis is associated with increased mortality. Shock. 2000;14:320-323.
33 Eggiman P, Jamdar S, Siriwardena AK. Pro/con debate: antifungal prophylaxis is important to prevent fungal infection in patients with acute necrotizing pancreatitis receiving broad-spectrum antibiotics. Crit Care. 2006;10:229.
34 Stoutenbeek C, van Saene H, Miranda D, et al. The effects of selective decontamination of the digestive tract on colonisation and infection rate in multiple trauma patients. Intens Care Med. 1984;10:185-192.
35 Lee TK, Medich DS, Melhem MF, et al. Pathogenesis of pancreatic sepsis. Am J Surg. 1993;165:46-50.
36 Luiten EJT, Hop WCJ, Lange JF, et al. Controlled clinical trial of selective decontamination for the treatment of severe acute pancreatitis. Ann Surg. 1995;222:57-65.
37 D’Amoco R, Pifferi S, Leonetti C, et al. Effectiveness of antibiotic prophylaxis in critically ill adult patients: systematic review of randomised controlled trials. Br Med J. 1998;316:1275-1285.
38 Peter JV, Moran JL, Phillips-Hughes J. A metaanalysis of treatment outcomes of early enteral versus early parenteral nutrition in hospitalised patients. Crit Care Med. 2005;33:213-220.
39 McClave SA, Chang W-K, Dhaliwal R, et al. Nutritional support in acute pancreatitis: a systematic review of the literature. JPEN. 2006;30:143-156.
40 Abou-assi S, Craig K, O’Keefe SJ. Hypocaloric jejunal feeding is better than total parenteral nutrition in acute pancreatitis: results of a randomised comparative study. Am J Gastroenterol. 2002;97:2255-2262.
41 Windsor AC, Kanwar S, Li AG, et al. Compared with parenteral nutrition, enteral feeding attenuates the acute phase response and improves disease severity in acute pancreatitis. Gut. 1998;42:431-435.
42 Wan X, Gong Z, Wu K, et al. Gastrointestinal dysmotility in patients with acute pancreatitis. J Gastroenterol Hepatol. 2003;18:57-62.
43 Dechelotte P, Hasselmann M, Cynober L, et al. l-alanyl-l-glutamine dipeptide-supplemented total parenteral nutrition reduces infectious complications and glucose intolerance in critically ill patients: the French controlled, randomized, double-blind, multicenter study. Crit Care Med. 2006;34:598-604.
