Acute pancreatitis is a major complication of endoscopic

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1 GASTROENTEROLOGY 2001;120: Interleukin 10 Reduces the Incidence of Pancreatitis After Therapeutic Endoscopic Retrograde Cholangiopancreatography JACQUES DEVIÈRE,* OLIVIER LE MOINE,* JEAN LUC VAN LAETHEM,* PIERRE EISENDRATH,* AXELLE GHILAIN,* NATHALIE SEVERS,* and MARIELLE COHARD *Department of Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium; and Schering-Plough Research Institute, Kenilworth, New Jersey Background & Aims: Prophylactic administration of interleukin (IL)-10 decreases the severity of experimental pancreatitis. Prevention of post endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis in humans is a unique model to study the potential role of IL-10 in this setting. Methods: In a single-center, doubleblind, randomized, placebo-controlled study, the effect of a single injection of 4 g/kg (group 1) or 20 g/kg (group 2) IL-10 was compared with that of placebo (group 0), all administered 30 minutes before therapeutic ERCP. The primary endpoint was the effect of IL-10 on serum levels of amylases and lipases measured 4, 24, and 48 hours after ERCP. The secondary objective was to evaluate changes in plasma cytokines (IL-6, IL-8, tumor necrosis factor) at the same time points and the incidence of acute pancreatitis in the 3 groups. Subjects undergoing a first therapeutic ERCP were eligible for inclusion. Results: A total of 144 patients were included. Seven were excluded based on intention to treat (n 1) or per protocol (n 6). Forty-five, 48, and 44 patients remained in groups 0, 1, and 2, respectively. The 3 groups were comparable for age, sex, underlying disease, indication for treatment, type of treatment, and plasma levels of C-reactive protein (CRP), cytokines, and hydrolases at baseline. No significant difference was observed in CRP, cytokine, and hydrolase plasma levels after ERCP. Forty-three patients developed hyperhydrolasemia (18 in group 0, 14 in group 1, and 11 in group 2; P 0.297), and 19 patients developed acute clinical pancreatitis (11 in group 0, 5 in group 1, 3 in group 2; P 0.038). Two severe cases were observed in the placebo group. No mortality related to ERCP was observed. Logistic regression identified 3 independent risk factors for post therapeutic ERCP pancreatitis: IL-10 administration (odds ratio [OR], 0.46; 95% confidence interval [95% CI ], ; P 0.039), pancreatic sphincterotomy (OR, 5.04; 95% CI, ; P 0.008), and acinarization (OR, 8.19; 95% CI, ; P 0.006). Conclusions: A single intravenous dose of IL-10, given 30 minutes before the start of the procedure, independently reduces the incidence of post therapeutic ERCP pancreatitis. Acute pancreatitis is a major complication of endoscopic retrograde cholangiopancreatography (ERCP). Unlike hemorrhage, duodenal perforation, or cholangitis, its incidence has not decreased with the technical improvements of recent years and expertise of the operators. 1,2 The risk of post-ercp pancreatitis varies greatly with the indications, being 5% for management of common bile duct (CBD) stones and reaching 20% or more in cases of suspected sphincter of Oddi dysfunction (SOD) and manipulation of small bile ducts or of a well-functioning pancreatic gland in young patients. 1,3 6 A silent increase in serum pancreatic enzyme levels is much more frequent than clinical pancreatitis after ERCP and may be encountered in up to 70% of the cases. 5,7 9 Among the numerous drugs that have been tested to prevent post-ercp pancreatitis, only gabexate mesylate, 9 a synthetic protease inhibitor, and native somatostatin, 7,8 an inhibitor of pancreatic enzymes secretion, have been proved effective. However, their short half-life makes necessary a continuous infusion lasting for 6 12 hours that further increases the cost of the procedure and renders outpatient endotherapy difficult. 10,11 Whatever the cause of pancreatitis, initial intracellular events are followed by an early local and systemic inflammatory reaction that is boosted by chemokines and proinflammatory cytokines 12,13 and plays a major role in the development of pancreatic necrosis and distant organ damage. Interleukin (IL)-10 is a major anti-inflammatory cytokine able to limit this proinflammatory cascade in vivo and in vitro. In animal models, endogenous IL-10 limits the severity of acute pancreatitis, 14,15 and its ad- Abbreviations used in this paper: 95% CI, 95% confidence interval; CBD, common bile duct; CRP, C-reactive protein; EPS, endoscopic pancreatic sphincterotomy; ERCP, endoscopic retrograde cholangiopancreatography; IL, interleukin; OR, odds ratio; TNF, tumor necrosis factor by the American Gastroenterological Association /01/$35.00 doi: /gast

2 February 2001 IL 10 AND POST ERCP PANCREATITIS 499 ministration before 16,17 or early after 18 induction of pancreatitis dramatically decreases its severity. Because the initial noxious event is timely well defined, post-ercp pancreatitis is a unique model to study the potential role of prophylactic IL-10 administration in reducing the incidence and/or the severity of human pancreatitis. This study was primarily designed to study the safety of IL-10 pretreatment and its effect on increases in pancreatic serum enzymes after therapeutic ERCP, with the prevention of acute pancreatitis and the modulation of proinflammatory cytokines serum levels as secondary endpoints, on an a priori purpose. Patients and Methods Over a 14-month period, 144 patients with definite indication for therapeutic ERCP were included in the study. Over the same period, a total of 1389 ERCPs were performed in the department, of which 752 were follow-up ERCPs for stent exchange and/or additional treatment of severe chronic pancreatitis. Of the 637 remaining patients, 204 were eligible for the study and 144 agreed to participate and gave their written informed consent. Eligible patients were those undergoing a first therapeutic ERCP. Exclusion criteria included previous therapeutic ERCP, age 18 years, acute pancreatitis, hyperamylasemia or hyperlipasemia at baseline blood analysis, cholangitis (which might influence the cytokine plasma levels), chronic pancreatitis with calcifications and/or pancreatic duct dilation or marked parenchymal atrophy on computed tomographic scanning, known pancreatic cancer, ampulloma, metastatic tumors, severe systemic disease with possible pancreatic involvement, pain graded 2 on a 1 10 visual scale before the procedure, pregnancy or breast feeding in women as well as use of inadequate contraception, use of any immunomodulating therapy within 90 days of entry, and use of any experimental drug within 30 days of entry. All patients gave their written informed consent to participate in the study, which was approved by the local ethics committee. Study Design This single-center, double-blind, placebo-controlled randomized study compared 3 groups of patients who received a single intravenous (IV) injection of either placebo (group 0) or of 4 (group 1) or 20 g/kg (group 2) recombinant human IL minutes before the procedure. The choices of IL-10 doses were based on those known to be active in other indications. 19 Drugs and placebos were packaged by Schering- Plough Research Institute (Kenilworth, NJ) on the basis of a computer-generated random code (randomization by blocks of 6). None of the physicians or nurses caring for the patients, running the study, or performing the procedures were aware of the codes or of the medications received. The number of patients to be included in each group (at least 42) was calculated to meet the primary endpoint of the study (reduction of hyperhydrolasemia from 50% to 25%; error, 0.05; error, 0.2). All patients were questioned about their clinical history, underwent a physical examination, and were asked to grade their pain on a 1 10 scale before and after therapeutic ERCP. They agreed to give blood immediately before the procedure and 4, 24, and 48 hours after for hydrolases, C-reactive protein (CRP), IL-6, IL-8, and tumor necrosis factor (TNF) measurements (Figure 1). Only the patients with a decision of therapeutic ERCP made before the procedure were considered, and all patients stayed overnight after the examination as a policy of the institution. Patients undergoing therapeutic ERCP during hospitalization for another reason were not included in the study. After discharge, the subjects were monitored as outpatients for the Figure 1. Study design. E, Blood sampling; *, clinical evaluation.

3 500 DEVIÈRE ET AL. GASTROENTEROLOGY Vol. 120, No hour blood sampling and clinical examination. Patients were sedated or anesthetized as usual (midazolam or propofol), avoiding morphine-like analgesics. They received antibiotic prophylaxis when they had cholestasis at the pretherapeutic work-up, 20 and no other treatment possibly influencing the occurrence of post-ercp pancreatitis was given. No protective pancreatic stenting 21 in high-risk patients was performed. The diagnosis and the type of treatment applied (biliary and/or pancreatic sphincterotomy, dilation, and/or stenting) were recorded. The whole duration of the procedure was mentioned for each case, and the operator was asked to evaluate the difficulty of the procedure on a 1 6 scale. All the procedures were performed by experienced endoscopists performing more than 200 ERCPs/year. Radiographs were carefully analyzed for the presence of pancreatic acinarization. The occurrence of immediate complication was recorded, as well as the use of coagulation for mild, non clinically relevant bleeding occurring during the procedure. Pain was again graded on a 1 10 scale at 4, 24, and 48 hours. Patients who had clinical pancreatitis at day 1 were systematically kept one additional night in the hospital. On day 7, clinical evaluation was obtained by a telephone call, and the patient was seen in outpatient visit, if appropriate. The complications were graded as mild, moderate, or severe according to the method of Cotton et al. 22 The primary endpoint of the study was decrease in the incidence of hyperhydrolasemia. Secondary endpoints included incidence of clinical acute pancreatitis and evaluation of increases in IL-6, IL-8, and TNF serum levels in the whole group and among patients with hyperhydrolasemia. Cytokine Measurements Cytokine plasma levels were measured using a commercially available enzyme-linked immunoassay (Medgenix, Fleurus, Belgium). Detection limits of the tests were 13, 5, and 10 pg/ml for IL-6, IL-8, and TNF, respectively. Amylases (normal value, 200 IU) and lipases (normal value, 200 IU) were measured at 30 C with commercially available kits (Boehringer, Mannheim, Germany) based on methods recommended by the International Federation of Clinical Chemistry. Definitions Hyperhydrolasemia was defined as an increase in amylase and/or lipase levels more than 3 times the normal values occurring within 2 days after the ERCP. Clinical pancreatitis was defined as hyperhydrolasemia (amylase/lipase levels 3 normal) associated with new or worsened abdominal pain persisting more than 4 hours after ERCP ( 3 grades on a 0 10 scale). They were classified as mild when the length of stay was 3 nights, moderate when the hospital stay was 4 10 nights, and severe if more than 10 days of hospitalization, intensive care unit (ICU) admission, or surgery was needed. 22 Statistical Analysis Results are expressed as means SEM. Comparisons between groups were done using the Pearson 2 test for categorical variables (or the Fisher exact test if appropriate) and 1-way analysis of variance (ANOVA) for continuous variables with Bonferroni correction as a post hoc test. Potential risk factors for clinical pancreatitis or hyperhydrolasemia (as dependent variables) after therapeutic ERCP were included in a backward, stepwise multiple logistic regression to identify independent risk factors affecting the dependent variables (SPSS for windows, release 8.02, Chicago, IL). A P value of 0.05 was considered significant. Results One hundred forty-four patients were included in the study, 7 of whom were excluded (1 case of preexisting unrecognized acute pancreatitis, 1 case of ampulloma, and 5 cases of failure to reach the papilla requiring percutaneous transhepatic access [2 Billroth II with a long afferent loop, 1 total gastrectomy with roux-en-y anastomosis on 2 duodenal stenoses]). There were 45, 48, and 44 patients remaining in groups 0 (placebo), 1 (IL-10, 4 g/kg), and 2 (IL-10, 20 g/kg), respectively. The 3 groups were comparable for age and sex as well as indications for therapeutic ERCP (Table 1). Patients with suspected common bile duct stones are those with high clinical suspicion of stone migration for whom a decision of endoscopic sphincterotomy has been made. The early chronic pancreatitis group includes patients with acute relapsing pancreatitis in whom mild 23 changes of chronic pancreatitis have been shown at secretin magnetic resonance cholangiopancreatography. 24 The group with suspected pancreatic cancer includes patients without radiologic evidence of tumors in whom tissue sampling from the pancreas and/or the bile duct was indicated. Intraductal mucinous papillary tumors Table 1. Age, Sex, and Indications for Therapeutic ERCP Diagnosis before the procedure Group 0 (n 45) Group 1 (n 48) Group 2 (n 44) Sex (M/F) 17/28 24/24 18/26 Age (yr) a CBD stone (n) Suspected CBD stone (n) Biliary cancer (n) Early chronic pancreatitis (n) Pancreatic cyst (n) Suspected pancreatic cancer (n) Intraductal mucus-producing tumor (n) Benign CBD lesion (n) Choledococele (n) Suspected SOD (n) a Mean SEM.

4 February 2001 IL 10 AND POST ERCP PANCREATITIS 501 Table 2. Therapeutic Maneuvers and Observations During Treatment Group 0 (n 45) Group 1 (n 48) Group 2 (n 44) P Biliary sphincterotomy Pancreatic sphincterotomy Biliary dilation Pancreatic dilation Biliary stent Pancreatic stent Precut Acinarization Use of coagulation Duration of ERCP (min) a Ease (score) a a Mean SEM. were diagnosed by ERCP, pancreatoscopy, and/or tissue sampling into the main pancreatic duct. All the patients included in the analysis had at least an opacification of the CBD (n 127) or of the pancreatic duct (n 111). Six patients (2 in each group) had only an opacification for failure of deep cannulation (n 3) or decision of the operator, during the procedure, to cancel or postpone the indication for treatment (n 3). Therapeutic maneuvers are reported in Table 2. There were no significant differences between the 3 groups, although the number of endoscopic pancreatic sphincterotomies (EPSs) was slightly higher in group 0 than in groups 1 and 2, and the number of precuts was higher in groups 0 and 2 than in group 1. Other therapeutic observations that might influence the incidence of pancreatitis are also mentioned in Table 2. In addition to pancreatitis, 3 other complications occurred, including 2 mild bleeding episodes without the need for transfusion and 1 retroperitoneal perforation treated conservatively and requiring hospitalization for 7 days. No adverse events related to administration of the study drug were observed. No patient died, required surgery, or was admitted in the ICU because of complications of ERCP. Two cases of pancreatitis were classified as severe; both were observed in the placebo group. Computed tomographic scanning 3 and 4 days after ERCP in these 2 patients showed Balthazar grade D pancreatitis 25 in both cases (presence of a pancreatic collection that became infected in 1 case). Plasma Levels of Hydrolases, CRP, and Cytokines After ERCP No significant difference was observed in plasma levels of amylases, lipases, CRP, IL-6, IL-8, and TNF between the 3 groups (Table 3). Forty-three patients (31.4%) developed hyperhydrolasemia after ERCP, with no statistical difference in incidence between the 3 groups (Table 4). When only these patients were considered, TNF plasma levels were higher in group 0 than in groups 1 and 2 at 4 and 24 hours ( vs and pg/ml, P 0.038; and vs and pg/ml, P 0.016), respectively, and no difference was observed at baseline ( vs and pg/ml, P 0.41). Clinical Post-ERCP Pancreatitis Forty-one patients (29.9%) developed abdominal pain after the procedure. Among them, 19 patients (13.8%) had pain and hyperhydrolasemia and were hospitalized at least 1 additional night. The incidence was significantly higher in the placebo group than in groups 1and2(P 0.038). Two episodes of severe pancreatitis were observed in group 0 and none in groups 1 and 2 (Table 4). IL-6 serum levels measured 24 hours after ERCP, which are excellent markers of post-ercp pancreatitis, 5 were significantly higher in patients with acute pancreatitis (n 19) than in the control group (n 105), from which patients with acute cholangitis were excluded (90 27 vs pg/ml; P 0.02). Among patients with post-ercp acute pancreatitis, IL-6 serum levels at 24 hours increased with severity (53 13, 68 25, and pg/ml in mild, moderate, and severe cases, respectively; P 0.01). Independent Factors Affecting the Onset of Hyperhydrolasemia and Clinical Pancreatitis In univariate analysis, in addition to the dose of IL-10 (P 0.016), the following variables were identified as risk factors for acute clinical pancreatitis with a P value of 0.2: EPS (P 0.008), acinarization (P 0.027), suspected SOD (P 0.181), and age (P 0.049) (Table 5). Because the placebo group included more EPS than the 2 other groups, logistic regression analysis was performed with clinical pancreatitis as a dependent variable and the 5 risk factors identified above as independent variables to determine whether IL-10 pretreatment independently affected the occurrence of acute pancreatitis. Three variables were identified as independently influencing the occurrence of acute clinical pancreatitis (Table

5 502 DEVIÈRE ET AL. GASTROENTEROLOGY Vol. 120, No. 2 Table 3. Hydrolases, CRP, IL-6, IL-8, and TNF Serum Levels Group 0 (n 45) Group 1 (n 48) Group 2 (n 44) P Amylases (IU/mL) Lipases (IU/mL) CRP (mg/dl) IL-6 (pg/ml) IL-8 (pg/ml) TNF (pg/ml) NOTE. Data represent means SEM. 5): EPS (odds ratio [OR], 5.04; 95% confidence interval [95% CI ], ; P 0.008), acinarization (OR, 8.19; 95% CI, ; P 0.006), and dose of IL-10 (OR, 0.46; 95% CI, ; P 0.039). The fact that IL-10 keeps its independent protective effect in the multivariate analysis is related to the decreased incidence of acute pancreatitis that is also observed in the subgroups of high-risk patients undergoing EPS or in whom acinarization was observed. Because of the small number of outcomes (n 19) and the number of independent variables (n 5), the results of the multivariate analysis should be taken with some reserve. When looking for risk factors for hyperhydrolasemia, only EPS (P 0.046) and acinarization (P 0.070) were identified in univariate analysis. In a logistic regression analysis with hyperhydrolasemia as dependent factors, there were also only 2 independent factors affecting the development of hyperhydrolasemia (EPS: OR, 2.36; 95% CI, ; P 0.062; acinarization: OR, 2.78; 95% CI, ; P 0.088). Table 4. Incidence of Hyperhydrolasemia, Postprocedural Abdominal Pain, and Clinical Pancreatitis in the 3 Groups Group 0 (n 45) Group 1 (n 48) Group 2 (n 44) P Pain (n) Hyperhydrolasemia (n) Pancreatitis All (n) 11 a Mild (n) Moderate (n) Severe (n) Duration of stay for pancreatitis (days/no. of patients treated) a P and P for group 0 vs. group 1 and group 0 vs. group 2, respectively (Fisher exact test).

6 February 2001 IL 10 AND POST ERCP PANCREATITIS 503 Table 5. Risk Factors for Clinical Pancreatitis After Therapeutic ERCP Risk factor Clinical pancreatitis (n 19) All (n 137) P (univariate) Adjusted OR (95% CI) P Significant in multivariate analysis Pancreatic sphincterotomy (n) 8 25 b ( ) Acinarization (n) 5 14 c ( ) Dose of IL-10 (no. of patients in groups 0/1/2) 11/5/3 45/48/ ( ) Significant in univariate analysis Age (yr) a Not significant Precut (n) Suspected SOD (n) Ease (score) a Duration (min) a Female sex (n) Biliary sphincterotomy (n) a Mean SEM. b Among the 25 patients who underwent pancreatic sphincterotomy, the incidence of clinical pancreatitis was 5/13, 2/7, and 1/5 in groups 0, 1, and 2, respectively. c Among the 14 patients in whom an acinarization was observed, the incidence of acute pancreatitis was 4/5, 1/4, and 0/5 in groups 0, 1, and 2, respectively. Discussion This study shows that IL-10, given as a single bolus injection 30 minutes before starting therapeutic ERCP, is able to decrease the incidence of post-ercp pancreatitis independently of other risk factors. This finding was not the primary endpoint of the study, which was initially designed and the number of patients calculated to evaluate the safety of IL-10 pretreatment and its effect on post-ercp hyperhydrolasemia. The blood cytokine levels and the incidence of acute clinical pancreatitis were considered as secondary endpoints. The fact that it has been possible to demonstrate an effect on post-ercp pancreatitis in this study discloses the effectiveness of the treatment in a selected group of patients at high risk for post-ercp pancreatitis. Indeed, the incidence of post-ercp pancreatitis in the present study was 24% in the placebo group, a figure much higher than that usually reported in unselected patients. 1,6 This is related to (1) the selection of patients for whom the indication for treatment is already taken before the procedure; (2) the tertiary center effect, with many patients referred after previous failure of ERCP or for difficult therapeutic procedures (particularly in relationship to treatment of pancreatic diseases); and (3) the exclusion, for this study, of patients with a lower risk of post-ercp pancreatitis such as those with advanced chronic pancreatitis and the inclusion of patients with a very high risk of pancreatitis such as those with early pancreatic changes treated by EPS 26 or those with suspicion of pancreatic malignancy necessitating brushings and/or biopsies in the pancreatic ducts. The effect of IL-10 on the incidence of pancreatitis observed presently was significant only when pancreatitis of all stages was included. A larger group would be clearly needed to evaluate whether IL-10 pretreatment can significantly decrease the incidence of moderate and severe acute pancreatitis, which represents the major problem related to therapeutic ERCP. IL-10 pretreatment was also associated with a trend toward a decrease in the length of hospitalization required for treatment of acute pancreatitis. IL-10 also remains effective for 24 hours after a single IV injection 19 and does not require a prolonged stay for patients undergoing therapeutic ERCP on an ambulatory basis. These 2 factors might render this treatment not only useful but also costeffective compared with other medications currently recommended in this indication, 8,9,27 gabexate mesylate and somatostatin, which must be administered by continuous perfusion for 4 12 hours, 8,9 resulting in increased cost and relatively limited applicability. 2,27,28 It might also complete or be associated with other measures of post therapeutic ERCP pancreatitis prevention such as prophylactic pancreatic stenting for patients known to have a higher risk of pancreatitis. 21 Because IL-10 pretreatment independently affects the onset of pancreatitis in the higher-risk groups of patients with EPS or pancreatic acinarization, it might be particularly cost-effective in these patients. As a parallel with animal studies, 18 IL-10 might even keep its effectiveness if it is administered immediately after ERCP, when all the risk factors are identified. This possibility deserves further investigation.

7 504 DEVIÈRE ET AL. GASTROENTEROLOGY Vol. 120, No. 2 Pretreatment with IL-10 did not significantly affect the incidence of post-ercp hyperhydrolasemia. This condition occurred more frequently in patients undergoing pancreatic sphincterotomy and in those with acinarization during the procedure. These are the same independent factors associated with IL-10 for predicting the occurrence of posttherapeutic clinical pancreatitis in the multivariate analysis. This lack of effect of IL-10 on hyperhydrolasemia may be related to the known pathophysiologic process of acute pancreatitis and the experimental models of IL-10 immunomodulation currently described. Indeed, whatever the cause of pancreatitis, the initial event is the premature intracellular activation of proteolytic enzymes resulting in cell injury and autodigestive process. 12 Very early, acinar cells produce chemokines 13,29 that recruit immunocompetent cells into the pancreas and induce a multisystemic production of proinflammatory and anti-inflammatory cytokines. 14,15 The immune cells infiltrating the pancreas will secrete proinflammatory mediators and cytokines such as TNF- that may further worsen the pancreatitis process and induce the development of necrosis. This triggering of the proinflammatory cascade occurs not only in the pancreas but also in other organs, including liver and lungs. 14,15,30 When the disease becomes severe, there is a clear multisystemic imbalance between the production of proinflammatory factors and the anti-inflammatory regulation, of which IL-10 is a major factor. Although substances such as gabexate mesylate (a protease inhibitor) or native somatostatin (an inhibitor of pancreatic enzymes secretion) are supposed to act at the very early event of pancreatitis, IL-10 exerts its effect later (starting 2 8 hours after induction of acute pancreatitis in experimental models) and acts mainly on the proinflammatory cascade triggered by the immune cells infiltrating the pancreas. In these experimental models, IL-10 mainly reduces the development of pancreatic necrosis, inflammatory infiltrates, TNF production, and the systemic complications of acute pancreatitis, and serum hydrolase levels may be only marginally affected. 14 Interestingly, although no significant effect on the cytokine profile was observed in the whole population, IL-10 pretreatment was able to limit the increase in TNF plasma levels in the group of patients with hyperhydrolasemia. This is another observation suggesting that IL-10 might limit the local injury and increase the proportion of potential candidates for pancreatitis who will have an uneventful recovery by limiting the production of proinflammatory mediators, both locally and systemically. The questions to be answered about IL-10 and post therapeutic ERCP pancreatitis include its ability to specifically decrease the incidence of moderate and severe pancreatitis, a feature suggested but not proven by the present study. The major advantage in relation to this indication for prophylactic treatment is the knowledge of the events that will induce pancreatitis. Indeed, it became clear from other attempts at immunomodulating pancreatitis that an early treatment is mandatory and that the therapeutic window is limited to hours. 13,31,32 In this line, the effectiveness of prolonged IL-10 treatment in patients with signs of acute pancreatitis within 24 hours after ERCP should also be investigated. The doses of IL-10 that have been currently selected are in the range of those used for other clinical indications such as Crohn s disease. 19 Although it is not possible to conclude from our data which dosage is the most appropriate, it appears that a single injection of 20 g/kg was highly effective and had no side effects. In conclusion, a single IV injection of IL-10 is safe and able to decrease the incidence of acute pancreatitis after therapeutic ERCP independently of any other risk factors associated with the procedure. This reduction of incidence averages 50%; if it becomes commercially available, this treatment will have the major advantage of being applicable to outpatient therapy, at a limited cost. References 1. Freeman ML, Nelson DB, Sherman S, Haber GB, Herman ME, Dorscher PJ, Moore JP, Fennerty MB, Ryan ME, Shaw MJ, Lande JD, Pheley AM. Complications of endoscopic biliary sphincterotomy. N Engl J Med 1996;335: Huibregtse K. Complications of endoscopoic sphincterotomy and their prevention. N Engl J Med 1996;335: Sherman S, Ruffolo TA, Hawes RH, Lehman GA. Complications of endoscopic sphincterotomy: a prospective series with emphasis on the increased risk associated with sphincter of Oddi dysfunction and nondilated bile ducts. Gastroenterology 1991;101: Sherman S, Troiano FP, Hawes RH, Lehman GA. Sphincter of Oddi manometry: decreased risk of clinical pancreatitis with use of a modified aspirating catheter. Gastrointest Endosc 1990;36: Messmann H, Vogt W, Holstege A, Lock G, Heinisch A, von Furstenberg A, Leser HG, Zirngibl H, Scholmerich J. Post ERCP pancreatitis as a model for cytokine induced acute phase response in acute pancreatitis. Gut 1997;40: Loperfido S, Angelini G, Beneditti G, Chiloui F, Costan F, DeBerardinis F, DeBarnardin M, Ederle A, Fina P, Fratton A. Major early complications from diagnostic and therapeutic ERCP: a prospective multicenter study. 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8 February 2001 IL 10 AND POST ERCP PANCREATITIS 505 Medical treatment can diminish pancreatic damages after ERCP: a meta-analysis. Gastrointest Endosc 2000;51: Cavallini G, Tittobello A, Frulloni C, Masci E, Mariani A, Di Francesco V, Gabexate in Digestive Endoscopy Italian Group. Gabexate for the prevention of pancreatic damage related to endoscopic retrograde cholangiopancreatography. N Engl J Med 1996;335: Freeman ML, Nelson DB, Sherman S, Haber GB, Fennerty MB, Disario JA, Ryan ME, Fortan PP, Dorscher PJ, Shaw MJ, Herman ME, Cunningham JT, Moore JP, Silverman WB, Imperial JC, Mackie RD, Jamidar PA, Yakshe PN, Logan GM, Pheley AM. Same day discharge after endoscopic biliary sphincterotomy: observations from a prospective multicenter complication study. Gastrointest Endosc 1999;49: Ho KY, Montes H, Sossenheimer MJ, Tham TC, Ruymann F, Van Dam J, Carr-Locke DL. Features that may predict hospital admission following outpatient therapeutic ERCP. 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Br J Surg 1997;84: Received June 16, Accepted September 28, Address requests for reprints to: Jacques Devière, M.D., Service Médico-Chirurgical de Gastroentérologie et d Hépato-pancréatologie, Hôpital Erasme, 808 route de Lennik, 1070 Bruxelles, Belgique. jdeviere@ulb.ac.be; fax: (32) Supported in part by a research grant from Schering-Plough Research Institute, Kenilworth, NJ, as an investigator-initiated study. The authors thank the following colleagues who made this study possible: M. Baize, M.D.; G. Cabrera, M.D., M. Cremer, M.D., M. Delhaye, M.D., C. Descamps, M.D., J.-M. Dumonceau, M.D., R. Jagodzinski, M.D., H. Louis, M.D., H. Reynaert, M.D., Ph. Ros, M.D., S. Solana, M.D., D. Urbain, M.D., C. Fernando, R.N., S. Dugardeyn, R.N., M. Mahieu, R.N., and M. Minet, R.N., from the Gastroenterology Department, and C. Denis, M.S., from the Laboratory of Experimental Gastroenterology.