CLINICAL LIVER, PANCREAS, AND BILIARY TRACT

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1 GASTROENTEROLOGY 2003;124: CLINICAL LIVER, PANCREAS, AND BILIARY TRACT Diclofenac Reduces the Incidence of Acute Pancreatitis After Endoscopic Retrograde Cholangiopancreatography BILL MURRAY, ROSS CARTER, CLEM IMRIE, SUSAN EVANS, and CRIOSTOIR O SUILLEABHAIN Lister Department of Surgery, Glasgow Royal Infirmary, Glasgow, Scotland See editorial on page Background & Aims: Acute pancreatitis following endoscopic retrograde cholangiopancreatography presents a unique opportunity for prophylaxis and early modification of the disease process because the initial triggering event is temporally well defined and takes place in the hospital. We report a prospective, single-center, randomized, double-blind controlled trial to determine if rectal diclofenac reduces the incidence of pancreatitis following cholangiopancreatography. Methods: Entry to the trial was restricted to patients who underwent endoscopic retrograde pancreatography or had manometrically verified sphincter of Oddi hypertension. Immediately after endoscopy, patients were given a suppository containing either 100 mg diclofenac or placebo. Estimation of serum amylase levels and clinical evaluation were performed in all patients. Results: A total of 220 patients entered the trial, and 110 received rectal diclofenac. Twenty-four patients developed pancreatitis (11%), of whom 7 received rectal diclofenac and 17 received placebo (P < 0.05). Conclusions: This trial shows that rectal diclofenac given immediately after endoscopic retrograde cholangiopancreatography can reduce the incidence of acute pancreatitis. Acute pancreatitis is the most frequent major complication of endoscopic retrograde cholangiopancreatography (ERCP); it occurs in 1% 10% of patients overall, with a higher incidence when only patients who have had imaging or instrumentation of the pancreatic duct are considered. 1 4 The incidence of post-ercp pancreatitis varies according to the indications for the procedure and intervention performed. Patient-related factors are also important, and mortality rates of between 0.2% and 0.6% have been reported. 5 7 Risk factors reported for ERCP-induced pancreatitis include a history of pancreatitis, 8 difficult cannulation, 6 repeated injection of the pancreatic duct, 8 pancreatic acinar opacification, 9 sphincter of Oddi hypertension (SOH), 7,10 and precut or needle-knife endoscopic sphincterotomy. 3,7 Although the pathogenesis of ERCP-induced pancreatitis is not clearly understood, it seems that the patient s inflammatory response to pancreatic duct imaging and/or instrumentation plays a critical role. 11 Initial intracellular events resulting in pancreatic acinar cell damage are followed by a local inflammatory response that in turn leads to the release of chemokines and proinflammatory cytokines into the general circulation. 12 The severity of the attack is determined by the magnitude of the resultant systemic inflammatory response. 13 The fact that the initial triggering event is temporally well defined makes post-ercp pancreatitis a unique model to study the potential benefit of early immunomodulation. 11 The results of several placebo-controlled, randomized trials using prophylactic agents such as glucagon, 14 calcitonin, 15 nifedipine, 16 octreotide, 17 and corticosteroids 18 have been disappointing. Somatostatin has been studied in several prospective trials. Although earlier studies failed to show a reduction in the incidence of post-ercp pancreatitis, recent studies have shown a beneficial effect. 19 Pretreatment with glyceryl trinitrate has been shown to reduce the incidence of post-ercp pancreatitis, 20,21 an effect that may be due to relaxation of pancreatic sphincter hypertension. In 2001, Devière et al. reported a study showing that a single intravenous prophylactic dose of interleukin 10, a major anti-inflammatory cytokine, given 30 minutes before therapeutic ERCP at a dose of either 4 or 20 g/kg can reduce the incidence of post-ercp pancreatitis. 22 Dumot et al., however, failed to show any reduction in the incidence of pancreatitis following ERCP when interleukin 10 was Abbreviations used in this paper: ERCP, endoscopic retrograde cholangiopancreatography; NSAID, nonsteroidal anti-inflammatory drug; PLA 2, phospholipase A 2 ; SOH, sphincter of Oddi hypertension by the American Gastroenterological Association /03/$30.00 doi: /s (03)

2 June 2003 DICLOFENAC CAN PREVENT POST ERCP PANCREATITIS 1787 given 15 minutes before the procedure at an intravenous dose of 8 g/kg. 23 A German study has shown that patients receiving heparin for various reasons before ERCP had a significantly lower incidence of post-ercp pancreatitis without an increased risk of hemorrhage after endoscopic sphincterotomy. 24 This effect could not be attributed to other known or suspected confounders and may have been due to the anti-inflammatory effects of heparin. Phospholipase A 2 (PLA 2 ) is believed to play a key role in the initial inflammatory cascade of acute pancreatitis by regulating a number of proinflammatory mediators, including prostaglandins, leukotrienes, and platelet-activating factor. 25 Inhibition of PLA 2 has been the target of several agents used to treat non-ercp induced human acute pancreatitis with largely disappointing results. The role of these agents in the prevention of post-ercp acute pancreatitis is more promising. Gabexate mesilate, a protease inhibitor, with activity that includes inhibition of PLA 2, has been shown to prevent pancreatic damage related to ERCP and reduces the incidence of post-ercp pancreatitis. 26 It has been shown that nonsteroidal anti-inflammatory drugs (NSAIDs) are potent inhibitors of PLA 2 activity in the serum from patients with severe acute pancreatitis, with diclofenac second only in potency to indomethacin. 27 NSAIDs have also been shown to have beneficial effects in experimental acute pancreatitis. 28 We conducted a prospective, single-center, randomized, double-blind controlled trial to determine if a single diclofenac suppository given immediately after ERCP can reduce the incidence of post-ercp pancreatitis. Patients and Methods The study described in this report was approved by the ethics committee of Glasgow Royal Infirmary University National Health Service Hospitals Trust. Adult patients without clinical or biochemical evidence of acute or severe chronic pancreatitis due to undergo ERCP under the care of 3 experienced endoscopists (B.M., R.C., and C.I.) were asked to give informed consent to participate in the study. Patients were excluded if they had any contraindications to receiving diclofenac or had taken an NSAID during the preceding week. Entry to the study was restricted to patients who underwent endoscopic retrograde pancreatography cholangiography or who had either endoscopic retrograde pancreatography or cholangiography in the presence of manometrically verified SOH (basal pressure 40 mm Hg in the common sphincter, biliary sphincter, or pancreatic sphincter). These criteria were designed to create a study group of patients with an increased risk of developing post-ercp pancreatitis with a estimated incidence of 12% 18%. At the end of each procedure, the endoscopist recorded the details of the maneuvers performed, particularly the ease or difficulty of cannulation; number of cannulations; number of pancreatic duct injections; presence, if any, of pancreatic acinar filling on radiography; whether a needle-knife sphincterotomy was performed; the diameter of the pancreatic duct and bile duct; the presence of choledocholithiasis; and the anatomy of the duct of Wirsung. Between May 1999 and December 2002, 558 patients were assessed for eligibility to enter the study (Figure 1). A total of 220 of these patients fulfilled the entry criteria. Immediately on entering the recovery area after endoscopy, study patients were given a trial suppository containing either diclofenac (100 mg) or an inert placebo. The trial suppositories were prepared, sealed, and randomly numbered in batches of 20 in the pharmacy department. The content of each suppository remained unknown until the code was broken after 200 and then 220 patients entered the study. The study patients were allowed ice or water orally until estimation of serum amylase level 2 hours after the procedure. If the 2-hour serum amylase level was 600 IU/L and there was no clinical evidence of acute pancreatitis at that time, study patients were allowed free oral fluids and diet. If the 2-hour serum amylase level was 600 IU/L or if a study patient exhibited epigastric pain with guarding, back pain, or nausea/vomiting, then the patient was Figure 1. Patient flow diagram.

3 1788 MURRAY ET AL. GASTROENTEROLOGY Vol. 124, No. 7 Table 1. Patient Details Diclofenac Control Gallbladder stones Postcholecystectomy Bile duct stones Normal pancreatic duct ERCP Endoscopic retrograde pancreatography only Endoscopic retrograde cholangiography only SOH 8 12 NOTE. There were no statistically significant differences. fasted and intravenous crystalloid fluids with appropriate analgesia were prescribed. 2,29 The following morning, study patients had their blood tests repeated and were interviewed and examined for clinical evidence of acute pancreatitis by the clinicians responsible for their care. A diagnosis of acute pancreatitis was made on the basis of a serum amylase level 4 times the upper level of normal for the reference laboratory ( 800 IU/L) in conjunction with epigastric pain, back pain, and epigastric rebound tenderness. Patients whose symptoms and signs did not settle within 48 hours underwent contrastenhanced computed tomography scanning. After 200 patients had entered the trial, the suppository content code was broken and the incidence of acute pancreatitis in the 2 study groups was compared. This initial data suggested a protective effect of diclofenac (P 0.07), and 20 additional subjects were then enrolled. This report discusses the findings for the full series of 220 patients. Statistical Analysis The difference in incidence of post-ercp pancreatitis between the 2 study groups was subjected to statistical analysis using Fisher exact test (2-tailed), with P 0.05 indicating a significant difference. Serum amylase values were compared using Student t test, and patient demographic and clinical factors were compared using Fisher exact test or 2 test as appropriate. Table 2. Results A total of 220 patients entered the study; 110 received 100 mg diclofenac per rectum (diclofenac group), and 110 received an inert suppository (control group). There were 69 women in the diclofenac group and 74 women in the control group. The patients were well matched in regard to age (mean SDM; diclofenac group, years; control group, years). Tables 1 and 2 show that the 2 groups were well matched for diagnoses, procedures performed, and factors that might increase the risk of post-ercp acute pancreatitis, particularly a history of acute pancreatitis, SOH, pancreatic acinar opacification, pancreatic duct instrumentation, and needle-knife sphincterotomy. The control group contained a larger number of patients with gallbladder stones, and this was reflected in a larger number of extrahepatic bile duct stones and a larger number of endoscopic sphincterotomies in this group. However, the differences observed between the 2 groups for these factors do not reach statistical significance. The time between pancreatic duct imaging/instrumentation and suppository administration was variable but did not exceed 50 minutes in either group. Two hours after the endoscopic procedure, the mean serum amylase level was (SEM) IU/L in the control group and IU/L in the diclofenac group. The morning after the endoscopic procedure, the mean serum amylase level was IU/L in the control group but only IU/L in the diclofenac group. The difference in mean serum amylase value between the 2 groups at 24 hours is statistically significant (P 0.01). Between 2 and 24 hours after ERCP, 24 study patients developed acute pancreatitis (11%) with a serum amylase level 1000 IU/L in each patient plus appropriate clinical findings. The 24 patients who developed post-ercp pancreatitis had a mean 2-hour serum amylase level of 1190 IU/L and a mean 24-hour serum amylase level of 2107 IU/L (both values significantly greater than those for the 196 patients without pancreatitis; P 0.001). Seven of the patients who developed pancreatitis were in the diclofenac group and 17 in the control group (Table 3). This difference is statistically significant (P 0.05; Table 3). Fourteen of 116 patients who underwent endoscopic sphincterotomy Table 3. Incidence of Post-ERCP Pancreatitis Diclofenac Group Control Group All patients 7/110 17/ a Sphincterotomized patients 2/53 12/ a Non-SOH patients 4/84 13/ a SOH patients 3/26 4/27 NS a Fisher exact test. Risk Factors for Post-ERCP Pancreatitis Diclofenac Control Previous acute pancreatitis SOH Needle sphincterotomy Pancreatic duct instrumentation Pancreatic acinar opacification 8 8 Prolonged cannulation Pancreatic duct stent NOTE. There were no statistically significant differences. P

4 June 2003 DICLOFENAC CAN PREVENT POST ERCP PANCREATITIS 1789 developed acute pancreatitis (12%). Two of these patients were in the diclofenac group (n 53) and 12 in the control group (n 63). This difference is statistically significant (P 0.021; Table 3). Fifty-three patients had manometrically verified SOH (24%), and 7 of these patients developed acute pancreatitis (13%). Three of these patients were in the diclofenac group and 4 in the control group, suggesting no benefit with respect to post- ERCP pancreatitis from administration of diclofenac in patients with SOH (Table 3). Twenty-two of the 24 patients who developed post- ERCP pancreatitis had mild attacks with no further complications. The 2 remaining patients developed sterile pancreatic necrosis that resolved without surgical intervention. Both of these patients were in the control group, and neither had SOH. All of the study patients survived their acute pancreatitis and were discharged from hospital alive. The mean inpatient stay for the 24 patients who developed acute pancreatitis was 3 days for the diclofenac group and 5 days for the control group. No adverse effects were noted from the single NSAID dose given to the patients in the diclofenac group. Discussion We have shown that a single inexpensive 100-mg diclofenac suppository given immediately after ERCP can reduce the incidence of post-ercp pancreatitis. The incidence of acute pancreatitis after ERCP varies according to the indications for the procedure, patient characteristics, and type of intervention performed. It is perhaps optimistically reported as 1% 2% for diagnostic ERCP, 1% 4% for endoscopic sphincterotomy, 4% 8% for pancreatic sphincterotomy, and 8% 11% for sphincterotomies in patients with SOH. 3,4,6 The 10-year audit of the principal investigator of this report (B.M.) shows an all-comers post-ercp pancreatitis rate of 3.8% (76 of 2004). The overall incidence of post-ercp pancreatitis in this study was 10.9%, with a control group incidence of 15.5%. These figures are high when compared with all-comers data but reflect the study design, which intentionally created a study population with a high incidence of post-ercp pancreatitis by restricting study entry to patients who had ERCP, pancreatic duct instrumentation, or manometrically verified SOH. This trend can be seen in several recent studies of post-ercp pancreatitis, with reported incidences of pancreatitis in the control group of 11.3%, 2 15%, 21 18%, 22 and 24%. 23 In this study, prophylaxis was not given until after a highrisk patient had been identified. Accepted risk factors for ERCP-induced acute pancreatitis were prospectively audited in this study, and no significant difference was found between the diclofenac and control groups. The incidence of acute pancreatitis in patients with SOH undergoing ERCP was 13%, which is comparable with reported results from other centers. 10,28 This study has shown that diclofenac protects against post-sphincterotomy pancreatitis but did not protect against post-ercp pancreatitis in patients with SOH. 30 This may be related to the fact that postmanipulation sphincter spasm or postsphincterotomy edema resulting in an increase in pressure in the pancreatic duct outlasts the protective effects of diclofenac in patients with SOH. However, this finding requires verification with a larger group of patients because the observation may be due to a lack of statistical power in the SOH subpopulation (n 53). The peak concentration of diclofenac administered by suppository occurs between 30 and 90 minutes after insertion, and bioavailability is complete. The elimination half-life from plasma is 2 hours, and 90% of the drug clearance has taken place 3 4 hours after administration. 31 All 220 study patients remained in the hospital at least until the day after their ERCP procedure, and acute pancreatitis was diagnosed or reconfirmed by clinical examination and measurement of serum amylase level the morning following ERCP. This was between 15 and 22 hours after the procedure and hence well beyond any possible analgesic masking effect from the 100-mg diclofenac suppository given to one half of the study patients. The mechanism of ERCP-induced pancreatic injury is not clearly understood, and a number of hypotheses exist. Trauma or thermal injury to the papilla can cause edema or spasm of the sphincter of Oddi and lead to temporary obstruction of the pancreatic duct. Contamination of the pancreatic duct by bacterial proteases during cannulation may activate pancreatic proenzymes intraductally. 16 Hydrostatic pressure from overfilling of the pancreatic duct may cause acinar damage and initiate pancreatitis. 9 Whatever the mechanism of injury, the host inflammatory response to endoscopic instrumentation seems to play an important role in the pathophysiology of acute pancreatitis. 11 A time delay of several hours (median of 4.5 hours) exists between pancreatic injury during ERCP and the onset of symptoms. 11 This therapeutic window invites the use of anti-inflammatory strategies to modulate the premature intracellular activation of proteolytic enzymes and acinar cell damage followed by a local inflammatory response that in turn leads to the release of

5 1790 MURRAY ET AL. GASTROENTEROLOGY Vol. 124, No. 7 chemokines and proinflammatory cytokines into the general circulation. 12 It has been widely accepted that the mechanism of action of NSAIDs is the inhibition of prostaglandin synthesis. However, the exact role of prostaglandins in acute pancreatitis is unclear and studies of NSAID administration in animal models of acute pancreatitis have shown conflicting results. NSAIDs have anti-inflammatory mechanisms of action other than inhibition of prostaglandin synthesis. 32 NSAIDs have been shown to be potent inhibitors of PLA 2 activity in the serum of patients with acute pancreatitis when tested in vitro. 27 Mäkelä et al. 27 showed that diclofenac was second only to indomethacin in its PLA 2 inhibitory activity. PLA 2 catalyzes the hydrolysis of cell membrane phospholipids, leading to the production of numerous inflammatory mediators, and is believed to play a critical role in the initial inflammatory cascade in acute pancreatitis by generating prostaglandins, leukotrienes, kinins, and platelet-activating factor, which in turn lead to tissue damage and autodigestion of the pancreas. 33 Because inhibition of PLA 2 results in suppression of several important classes of proinflammatory lipids (prostaglandins, leukotrienes, platelet-activating factor, and lysophospholipids), the use of PLA 2 inhibitors has been considered an attractive therapeutic strategy in the treatment of inflammation-related diseases and tissue injury. However, most studies concerning PLA 2 inhibitors in the prevention of tissue injury in experimental models of severe acute pancreatitis have been disappointing. This may be due to the fact that the stimulus used to induce acute pancreatitis in these animal models is too potent for a prophylactic or treatment benefit to be seen. However, the proteolytic enzyme inhibitor gabexate mesilate has been shown to have a beneficial role in the prevention of post-ercp acute pancreatitis. 26,34 It has been reported that several NSAIDs, including diclofenac, strongly inhibit neutrophil/endothelial cell attachment, thus preventing accumulation of neutrophils at the site of tissue damage, a key event in the inflammatory response. 31 NSAIDs have been shown in vitro to inhibit certain phenomena associated with neutrophil activation, such as synthesis of adenosine 3,5 -cyclic monophosphate, generation of superoxide anions, and the release of lysosomal enzymes. 35 Furthermore, NSAIDs can inhibit the expression of inducible nitric oxide synthase in vitro, an enzyme clearly associated with inflammation and cell damage. 36 This prospective, single-center, randomized, doubleblind clinical study has shown that the incidence of post-ercp acute pancreatitis can be reduced in patients without SOH by the administration of an inexpensive 100-mg diclofenac suppository immediately following the endoscopic procedure. It is theoretically possible that the observed benefit of rectal diclofenac is due to its ability to inhibit PLA 2 activity and hence down-regulate the inflammatory cascade that would otherwise lead to acute pancreatitis. This observation requires validation, more detailed biochemical investigation, and pharmacologic manipulation related to the choice of drug, route of delivery, and timing of administration. References 1. Nebel OT, Silvis SE, Rogers G, Sugawa C, Mandelstam P. Complications associated with endoscopic reteroscopic cholangiopancreatography: results of the 1974 ASGE survey. Gastrointest Endosc 1975;22: LaFerla G, Gordon S, Archibald M, Murray WR. Hyperamylasaemia and acute pancreatitis following retrograde cholangiography. Pancreas 1985;1: De Palma GD, Catanzano C. Use of corticosteroids in the prevention of post-ercp pancreatitis: results of a controlled prospective study. Am J Gastroenterol 1999;94: Rabenstein T, Hahn EG. Post-ERCP pancreatitis: new momentum. 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6 June 2003 DICLOFENAC CAN PREVENT POST ERCP PANCREATITIS Arcidiacono R, Gambitta P, Rossi A, Grosso C, Bini M, Zanasi G. The use of long-acting somatostatin analogue (octreotide) for prophylaxis of acute pancreatitis after endoscopic sphincterotomy. Endoscopy 1994;26: Dumot JA, Conwell DL, O Connor JB, Ferguson R, Vargo JJ, Barnes DS, Shay SS, Sterling MJ, Horth KS, Issa K, Ponsky JL, Zuccaro G. Pretreatment with methylprednisolone to prevent ERCP-induced pancreatitis: a randomised, multicenter, placebocontrolled clinical trial. Am J Gastroenterol 1998;93: Andriulli A, Leandro G, Niro G, Mangia A, Festa V, Gambassi G, Villani MR, Facciorusso D, Conoscitore P, Spirito F, DeMaio G. Medical treatment can diminish pancreatic damage after ERCP: a meta-analysis. Gastrointest Endosc 2000;51: Sudhindran S, Bromwich E, Edwards PR. Prospective randomized double-blind placebo-controlled trial of glyceryl trinitrate in endoscopic retrograde cholangiopancreatography-induced pancreatitis. Br J Surg 2001;88: Moretó M, Zaballa M, Casado I, Merino O, Rueda M, Ramirez Z, Urcelay R, Baranda A. Transdermal glyceryl trinitrate for prevention of post-ercp pancreatitis: a randomized double-blind trial. Gastrointest Endosc 2003;57: Devière J, Le Moine O, Van Laethem J-L, Eisendrath P, Ghilain A, Severs N, Cohard M. Interleukin-10 reduces the incidence of pancreatitis after therapeutic endoscopic retrograde cholangiopancreatography. Gastroenterology 2001;120: Dumot JA, Darwin CL, Zuccaro G, Vargo JJ, Shay SS, Kirk A, Easley MS, Ponsky JL. A randomized, double blind study of interleukin 10 for the prevention of ERCP-induced pancreatitis. Am J Gastroenterol 2001;96: Rabenstein T, Roggenbuck S, Framke B, Martus P, Fischer B, Nusko G, Muehidorfer S, Hochberger J, Ell C, Hahn EG, Schneider HT. Complications of endoscopic sphincterotomy: can heparin prevent acute pancreatitis after ERCP? Gastrointest Endosc 2002;55: Gross V, Leser HG, Heinisch A, Scholmerich J. Inflammatory mediators and cytokines: new aspects of the pathophysiology and assessment of severity of acute pancreatitis? Hepatogastroenterology 1993;40: Italian Digestive Endoscopy Group: Cavallini G, Tittobello A, Frulloni L, Masci E, Mariani A, Francesco V. Gabexate for the prevention of pancreatic damage related to endoscopic retrograde cholangiopancreatography. N Engl J Med 1996;335: Mäkelä A, Kuusi T, Schröder T. Inhibition of serum phospholipase-a2 in acute pancreatitis by pharmacological agents in vitro. Scand J Clin Lab Invest 1997;57: Wildenhain PM, Melhem MF, Birsic WI, Sell HW, Rao KN. Acute haemorrhagic pancreatitis in mice: improved survival after indomethacin administration. Digestion 1989;44: MacKay CK, Murray WR. Can a 2 hour post ERCP serum amylase estimation predict post ERCP acute pancreatitis? (abstr) Gut 1994;35:S Tarnasky PR, Palsech YY, Cunningham JT, Mauldin PD, Cotton PB, Hawes RH. Pancreatic stenting prevents pancreatitis after biliary sphincterotomy in patients with sphincter of Oddi dysfunction. Gastroenterology 1998;11: Davies NM, Anderson KE. Clinical pharmacokinetics of diclofenac. Therapeutic insights and pitfalls. Clin Pharmacokinet 1997; 33: Diaz-Gonzalez F, Sánchez-Madrid F. Inhibition of leukocyte adhesion: an alternative mechanism of action for the anti-inflammatory drugs. Immunol Today 1998;19: Niederau C, Schulz HU. Current conservative treatment of acute pancreatitis: evidence of animal and human studies. Hepatogastroenterology 1993;40: Matsunga E, Sato J, Nakashima H, Deguchi T, Kojima H, Sagara K. Effect of Foy on prevention of the occurrence of pancreatitis after ERCP. Gendai Iryo 1979;11: Simon LS. Actions and toxicity of nonsteroidal anti-inflammatory drugs. Curr Opin Rheumatol 1996;8: Zurier RB, Quagliata F. Effect of prostaglandin E1 on adjuvant arthritis. Nature 1971;234: Received January 9, Accepted February 20, Address requests for reprints to: Bill Murray, M.D., F.R.C.S.(Glas), Lister Department of Surgery, Glasgow Royal Infirmary, Glasgow G31 2ER, Scotland. Fax: (44) The data from this study after 200 patients had been entered was presented to the American Pancreatic Association in November 2001 and to the Association of Surgeons of Great Britain and Ireland on May 23, 2002.