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Prevention of post-ERCP pancreatitis: pharmacologic solution or patient selection and pancreatic stents?

2003; Elsevier BV; Volume: 124; Issue: 7 Linguagem: Inglês

10.1016/s0016-5085(03)00553-5

1528-0012

Martin L. Freeman,

Esophageal and GI Pathology

Pancreatitis is a complication that has plagued endoscopic retrograde cholangiopancreatography (ERCP) since its inception. Pancreatitis occurs after ERCP in 1%–30% of cases, varying with case mix, patient susceptibility, the endoscopist, the definition of pancreatitis, and the thoroughness of follow-up. Pancreatitis can range in severity from mild, with a 1- or 2-day hospital stay and a full recovery, to severe and life threatening, with permanent disability or death. Several approaches have been taken toward avoiding this all-too-common complication. In this editorial, we will attempt to put into perspective the relative importance of each approach, including the study published in this issue of Gastroenterology by Murray et al.1Murray B. Carter C. Imrie C. Evans S. O'Suilleabhain C. Diclofenac reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography.Gastroenterology. 2003; 124: 1786-1791Abstract Full Text Full Text PDF PubMed Scopus (223) Google ScholarThe first approach is pharmacologic prevention of post-ERCP pancreatitis. Such a holy grail has been sought for many years.2Testoni P.A. Preventing post-ERCP pancreatitis where are we?.J Pancreas. 2003; 4: 22-32PubMed Google Scholar, 3Poon R.T.P. Fan S.T. Antisecretory agents for prevention of post-ERCP pancreatitis rationale for use and clinical results.J Pancreas. 2003; 4: 33-40PubMed Google Scholar, 4Cavallini G. Frulloni L. Antiproteasic agents in the prevention of post-ERCP pancreatitis rationale for use and clinical results.J Pancreas. 2003; 4: 75-82PubMed Google Scholar, 5Andriulli A. Caruso N. Quitadamo M. Forlano R. Leandro G. Spirito F. De Maio G. Antisecretory vs. antiproteasic drugs in the prevention of post-ERCP pancreatitis the evidence-based medicine derived from a meta-analysis study.J Pancreas. 2003; 4: 41-48PubMed Google Scholar, 6Demols A. Deviere J. New frontiers in the pharmacological prevention of post-ERCP pancreatitis the cytokines.J Pancreas. 2003; 4: 49-57PubMed Google Scholar, 7Mariani A. Pharmacological prevention of post-ERCP pancreatitis which therapy is best?.J Pancreas. 2003; 4: 68-74PubMed Google Scholar Rationale has centered on interrupting various postulated mechanisms of injury. Some are unique to pancreatitis resulting from ERCP, including instrumental trauma to the pancreatic sphincter with obstruction to flow of pancreatic juice and hydrostatic injury, introduced infection, and acinar toxicity resulting from contrast exposure. Others are inherent to all forms of acute pancreatitis, including premature intracellular activation of proteolytic enzymes, and the inflammatory cascade, including chemokines and proinflammatory cytokines that lead to local and systemic inflammatory response. Although appealing in theory, the history of attempts to find the ideal drug is familiar: First 1 agent, then another, appears promising in animal studies and then in preliminary human studies. Initial single-center randomized trials suggest efficacy, followed by conflicting results from other centers. Disappointment ultimately ensues once larger, multicenter studies are conducted. The list of agents that have gone through this sequence is long (Table 1), including the latest contenders of platelet-activating factor inhibitors and interleukin 10. Meta-analyses suggest that 2 agents are effective in preventing post-ERCP pancreatitis.5Andriulli A. Caruso N. Quitadamo M. Forlano R. Leandro G. Spirito F. De Maio G. Antisecretory vs. antiproteasic drugs in the prevention of post-ERCP pancreatitis the evidence-based medicine derived from a meta-analysis study.J Pancreas. 2003; 4: 41-48PubMed Google Scholar One, somatostatin, is an antisecretory agent, whereas the other, gabexate, is a protease inhibitor. The caveats are that both drugs are not available in North America and, to be effective, both agents must be administered before ERCP and continued for a 12-hour infusion afterward. When administered as a single dose, neither agent has been consistently effective.5Andriulli A. Caruso N. Quitadamo M. Forlano R. Leandro G. Spirito F. De Maio G. Antisecretory vs. antiproteasic drugs in the prevention of post-ERCP pancreatitis the evidence-based medicine derived from a meta-analysis study.J Pancreas. 2003; 4: 41-48PubMed Google Scholar The economic and logistical viability of a 12-hour infusion of an expensive drug is highly questionable in today's environment, especially when 13–27 patients must be treated to prevent a single case of pancreatitis.5Andriulli A. Caruso N. Quitadamo M. Forlano R. Leandro G. Spirito F. De Maio G. Antisecretory vs. antiproteasic drugs in the prevention of post-ERCP pancreatitis the evidence-based medicine derived from a meta-analysis study.J Pancreas. 2003; 4: 41-48PubMed Google Scholar Thus, to date, a drug that is consistently effective in a single dose has not been found.Table 1Proposed Mechanisms of Post-ERCP Pancreatitis, Drugs Tested, and ResultsMechanismDrugOverall resultsaResults of large multicenter trials if performed.Sphincter spasmAnticholinergicsIneffectiveCalcium channel blockersIneffectiveGlucagonIneffectiveNitroglycerineMixedInfectionAntibioticsIneffectiveContrast toxicityNonionic contrastIneffectivePancreatic secretionOctreotideIneffectiveSomatostatinIneffective (≤2-hr infusion)Effective (12-hr infusion)Inflammatory cascadeCorticosteroidsIneffectiveAllopurinolIneffectivePAF InhibitorsIneffectiveIL-10IneffectiveHeparinIneffectiveGabexateIneffective (≤2-hr infusion)Effective (12-hr infusion)NSAID?IL, interleukin; PAF, platelet-activating factor; NSAID, nonsterodial anti-inflammatory drug.a Results of large multicenter trials if performed. Open table in a new tab The second approach to post-ERCP pancreatitis is the use of epidemiologic analyses to identify patient- and procedure-related risk factors so that ERCP can be avoided or technique modified in high-risk patients.8Freeman M.L. Adverse outcomes of ERCP.Gastrointest Endosc. 2002; 56: S273-S282Abstract Full Text Full Text PDF PubMed Google Scholar Recent prospective, large-scale multivariate analyses have taught us that risk of post-ERCP pancreatitis is determined as much by patient characteristics as by the procedure itself.9Freeman M.L. Nelson D.B. Sherman S. Haber G.B. Herman M.E. Dorsher P.J. Moore J.P. Fennerty M.D. Ryan M.E. Shaw M.J. Lande J.D. Pheley A.M. Complications of endoscopic biliary sphincterotomy.N Engl J Med. 1996; 335: 909-918Crossref PubMed Scopus (2146) Google Scholar, 10Freeman M.L. DiSario J.A. Nelson D.B. Fennerty M.B. Lee J.G. Bjorkman D.J. Overby C.S. Aas J. Ryan M.E. Bochna G.S. Shaw M.J. Snady H.W. Erickson R.V. Moore J.P. Roel J.P. Risk factors for post-ERCP pancreatitis a prospective, multicenter study.Gastrointest Endosc. 2001; 54: 425-434Abstract Full Text Full Text PDF PubMed Scopus (972) Google Scholar, 11Loperfido S. Angelini G. Benedetti G. Chilovi F. Costan F. De Berardinis F. DeBernardin M. Ederle A. Fina P. Fratton A. Major early complications from diagnostic and therapeutic ERCP a prospective multicenter study.Gastrointest Endosc. 1998; 48: 1-10Abstract Full Text Full Text PDF PubMed Scopus (1019) Google Scholar, 12Masci E. Toti G. Mariani A. Curioni S. Lomazzi A. Dinelli M. Minoli G. Crosta C. Comin U. Fertitta A. Prada A. Passoni G.R. Testoni P.A. Complications of diagnostic and therapeutic ERCP a prospective multicenter study.Am J Gastroenterol. 2001; 96: 417-423Crossref PubMed Google Scholar, 13Friedland S. Soetikno R.M. Vandervoort J. Montes H. Tham T. Carr-Locke D.L. Bedside scoring system to predict the risk of developing pancreatitis following ERCP.Endoscopy. 2002; 34: 483-488Crossref PubMed Scopus (60) Google Scholar The profile of the reactive pancreas patient includes recurrent abdominal pain (typically in women) in the absence of anatomic biliary obstruction (i.e., suspected stones or sphincter of Oddi dysfunction), younger age, or history of prior post-ERCP pancreatitis (Table 2); patients with multiple risk factors are at especially high risk.10Freeman M.L. DiSario J.A. Nelson D.B. Fennerty M.B. Lee J.G. Bjorkman D.J. Overby C.S. Aas J. Ryan M.E. Bochna G.S. Shaw M.J. Snady H.W. Erickson R.V. Moore J.P. Roel J.P. Risk factors for post-ERCP pancreatitis a prospective, multicenter study.Gastrointest Endosc. 2001; 54: 425-434Abstract Full Text Full Text PDF PubMed Scopus (972) Google Scholar Severe post-ERCP pancreatitis occurs almost exclusively in such patients, often after standard diagnostic or biliary therapeutic procedures.9Freeman M.L. Nelson D.B. Sherman S. Haber G.B. Herman M.E. Dorsher P.J. Moore J.P. Fennerty M.D. Ryan M.E. Shaw M.J. Lande J.D. Pheley A.M. Complications of endoscopic biliary sphincterotomy.N Engl J Med. 1996; 335: 909-918Crossref PubMed Scopus (2146) Google Scholar, 10Freeman M.L. DiSario J.A. Nelson D.B. Fennerty M.B. Lee J.G. Bjorkman D.J. Overby C.S. Aas J. Ryan M.E. Bochna G.S. Shaw M.J. Snady H.W. Erickson R.V. Moore J.P. Roel J.P. Risk factors for post-ERCP pancreatitis a prospective, multicenter study.Gastrointest Endosc. 2001; 54: 425-434Abstract Full Text Full Text PDF PubMed Scopus (972) Google Scholar, 14Trap P. Adamsen S. Hart-Hansen O. Henriksen M. Severe and fatal complications after therapeutic ERCP a prospective series of claims to insurance covering public hospitals.Endoscopy. 1999; 31: 125-130Crossref PubMed Scopus (98) Google Scholar Thus, paradoxically, patients who need ERCP the least are the most likely to suffer a complication. Procedural risk factors are also very important but widely misunderstood: diagnostic ERCP is not necessarily safer than therapeutic ERCP, and adept cannulation technique alone is not sufficient to prevent post-ERCP pancreatitis in high-risk patients.5Andriulli A. Caruso N. Quitadamo M. Forlano R. Leandro G. Spirito F. De Maio G. Antisecretory vs. antiproteasic drugs in the prevention of post-ERCP pancreatitis the evidence-based medicine derived from a meta-analysis study.J Pancreas. 2003; 4: 41-48PubMed Google Scholar The limitation of risk-factor stratification as a strategy is that prediction is not protection.Table 2Risk Factors for Post-ERCP Pancreatitis in Prospective Multivariate AnalysesDefiniteaSignificant by multivariate analysis in most studies.MaybebSignificant by univariate analysis in most studies.NocNot significant by multivariate analysis in any study.Suspected SODFemale sexSmall CBD diameterYounger ageAcinarizationSO manometryNormal bilirubinAbsent CBD stoneBiliary sphincterotomyPrior post-ERCP pancreatitisLower ERCP volumeDifficult cannulationPancreatic duct injectionPancreatic sphincterotomyPrecut sphincterotomy (by endoscopists of mixed experience)Balloon dilation of biliary sphincterCBD, common bileduct; SO, sphincter of Oddi; SOD, sphincter of Oddi dysfunction.a Significant by multivariate analysis in most studies.b Significant by univariate analysis in most studies.c Not significant by multivariate analysis in any study. Open table in a new tab The third approach to preventing post-ERCP pancreatitis is the placement of transsphincteric pancreatic stents. Theoretically, stents serve to mitigate instrumental papillary trauma, to preserve flow of pancreatic juice, and/or to empty the gland of reactive enzyme substrate. According to the plumbing concept, drainage of manipulated pancreatic ducts should prevent pancreatitis just as drainage of obstructed bile ducts prevents cholangitis. Prospective randomized trials have shown that post-ERCP pancreatitis rates of 20%–30% in high-risk control groups are reduced to 5%–10% with pancreatic stenting15Tarnasky P. Palesch Y. Cunningham J. Maulsin P. Cotton P. Hawes R.H. Pancreatic stenting prevents pancreatitis after biliary sphincterotomy in patients with sphincter of Oddi dysfunction.Gastroenterology. 1998; 115: 1518-1524Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar, 16Fazel A. Quadri A. Catalano M.F. Meyerson S.M. Geenen J.E. Does a pancreatic duct stent prevent post-ERCP pancreatitis? A prospective randomized study.Gastrointest Endosc. 2003; 57: 291-294Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, 17Tarnasky P. Mechanical prevention of post-ERCP pancreatitis by pancreatic stents results, techniques, and indications.J Pancreas. 2003; 4: 58-67PubMed Google Scholar (Table 3). Most strikingly, risk of severe or necrotizing pancreatitis is virtually eliminated by a properly positioned pancreatic stent, a finding corroborated by accumulating experience at advanced centers.15Tarnasky P. Palesch Y. Cunningham J. Maulsin P. Cotton P. Hawes R.H. Pancreatic stenting prevents pancreatitis after biliary sphincterotomy in patients with sphincter of Oddi dysfunction.Gastroenterology. 1998; 115: 1518-1524Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar, 16Fazel A. Quadri A. Catalano M.F. Meyerson S.M. Geenen J.E. Does a pancreatic duct stent prevent post-ERCP pancreatitis? A prospective randomized study.Gastrointest Endosc. 2003; 57: 291-294Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, 17Tarnasky P. Mechanical prevention of post-ERCP pancreatitis by pancreatic stents results, techniques, and indications.J Pancreas. 2003; 4: 58-67PubMed Google Scholar, 18Fogel E.L. Eversman D. Jamidar P. Sherman S. Lehman G.A. Sphincter of Oddi dysfunction pancreatobiliary sphincterotomy with pancreatic stent placement has a lower rate of pancreatitis rate than biliary sphincterotomy alone.Endoscopy. 2002; 34: 280-285Crossref PubMed Scopus (175) Google Scholar Downsides of pancreatic stenting as a strategy are its unfamiliarity to many endoscopists, the decision about which cases warrant a stent, the difficulty of stent insertion in patients with small or tortuous ducts, the potential for ductal injury,19Kozarek R.A. Pancreatic stents can induce ductal changes consistent with chronic pancreatitis.Gastrointest Endosc. 1990; 36: 93-95Abstract Full Text PDF PubMed Scopus (295) Google Scholar and the follow-up required for stent removal.Table 3Prospective Randomized Trials Assessing Efficacy of Pancreatic Stents for Prevention of Post-ERCP Pancreatitis in High-Risk SettingsSettingBenefitBiliary sphincterotomy for SODYes (1 study)Pancreatic sphincterotomy for SODTrend (1 preliminary abstract)Biliary balloon dilation for stoneYes (1 study)Precut (access) biliary sphincterotomyYes (1 abstract)High risk, including difficult cannulationYes (1 study), no (1 study)SOD, sphincter of Oddi dysfunction. Open table in a new tab In this context, Murray et al.1Murray B. Carter C. Imrie C. Evans S. O'Suilleabhain C. Diclofenac reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography.Gastroenterology. 2003; 124: 1786-1791Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar bravely charge where others have fallen, with an attempt to test the efficacy of a single dose of a drug to interrupt the inflammatory cascade leading to post-ERCP pancreatitis. In their well-conceived and -executed study, 220 patients determined to be at high risk were randomized to receive either a rectal suppository of the NSAID agent, diclofenac, or a placebo. Appealing features of the treatment strategy include (1) the drug is relatively inexpensive; (2) it was administered as a single dose; (3) it was administered immediately after ERCP, so patient risk stratification could include intraprocedural events; and (4) any center can administer such a treatment, unlike techniqueoriented strategies such as pancreatic stent placement. The primary outcome was clinical pancreatitis, defined approximately by consensus criteria,20Cotton P.B. Lehman G. Vennes J.A. Geenen J.E. Russell R.C.G. Meyers W.C. Liguory C. Nickl N. Endoscopic sphincterotomy complications and their management an attempt at consensus.Gastrointest Endosc. 1991; 37: 383-391Abstract Full Text PDF PubMed Scopus (2373) Google Scholar which occurred in 6.4% of patients receiving diclofenac versus 15.5% of controls. Concerns with the study are the following. (1) Differences in outcome barely achieved statistical significance (P = 0.049). (2) No multivariate analysis was performed to assess the effect of the treatment versus other variables. (3) Inclusion criteria were rather broad, including merely the performance of pancreatography, thus lowering the background rate of pancreatitis in the intended high-risk control group. (4) The drug was not effective in the subgroup of patients with sphincter of Oddi dysfunction, the very group of patients that is usually the most problematic. (5) The occurrence of 2 cases of necrotizing pancreatitis in patients without sphincter of Oddi dysfunction is unusual, and one wonders whether these patients were among those receiving pancreatic stents—probably not, if the experience of others is borne out.Are we now to hope that a simple NSAID will significantly reduce risk of post-ERCP pancreatitis? Perhaps, as the authors suggest, NSAID's ability to inhibit steps early in the inflammatory cascade involving prostaglandins, phospholipase-A2 (PLA2), or endothelial-neutrophil attachment will be the magic key. One wonders why a simple NSAID would effectively interrupt the inflammatory cascade when all other agents administered as a single dose have failed. However, it will likely turn out that, with more and larger studies, history will repeat itself and the efficacy will disappear. Or perhaps potential adverse effects of NSAIDs on bleeding or renal function, not discussed in the article by Murray et al.,1Murray B. Carter C. Imrie C. Evans S. O'Suilleabhain C. Diclofenac reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography.Gastroenterology. 2003; 124: 1786-1791Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar will counterbalance any protective effect against pancreatitis.In the big picture, it is this author's opinion that the primary way to reduce post-ERCP pancreatitis remains to educate endoscopists to avoid many of the diagnostic and empirical therapeutic ERCPs still performed in practice for marginal indications such as "possible" bile duct stones or "suspected" sphincter of Oddi dysfunction. Magnetic resonance cholangiopancreatography, intraoperative laparoscopic cholangiography, and endoscopic ultrasound are safe and increasingly available diagnostic alternatives to find real obstructive biliary and pancreatic pathology. Patients without anatomic biliary pathology, determined by using these techniques, are probably best served either by avoiding ERCP altogether or by referral of such patients, along with technically difficult cases, to specialized centers capable of advanced endoscopic techniques for diagnosis and therapy, including endoscopic ultrasound, sphincter of Oddi manometry, and pancreatic therapeutic ERCP. At specialized centers, and also increasingly in diverse practice settings, avoidance of post-ERCP pancreatitis will probably continue to pivot on improved technique including judicious use of pancreatic stents. Until such time as a simple and effective pharmacologic panacea is found, the tools for avoidance of post-ERCP pancreatitis will remain in endoscopists' head and hands. Pancreatitis is a complication that has plagued endoscopic retrograde cholangiopancreatography (ERCP) since its inception. Pancreatitis occurs after ERCP in 1%–30% of cases, varying with case mix, patient susceptibility, the endoscopist, the definition of pancreatitis, and the thoroughness of follow-up. Pancreatitis can range in severity from mild, with a 1- or 2-day hospital stay and a full recovery, to severe and life threatening, with permanent disability or death. Several approaches have been taken toward avoiding this all-too-common complication. In this editorial, we will attempt to put into perspective the relative importance of each approach, including the study published in this issue of Gastroenterology by Murray et al.1Murray B. Carter C. Imrie C. Evans S. O'Suilleabhain C. Diclofenac reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography.Gastroenterology. 2003; 124: 1786-1791Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar The first approach is pharmacologic prevention of post-ERCP pancreatitis. Such a holy grail has been sought for many years.2Testoni P.A. Preventing post-ERCP pancreatitis where are we?.J Pancreas. 2003; 4: 22-32PubMed Google Scholar, 3Poon R.T.P. Fan S.T. Antisecretory agents for prevention of post-ERCP pancreatitis rationale for use and clinical results.J Pancreas. 2003; 4: 33-40PubMed Google Scholar, 4Cavallini G. Frulloni L. Antiproteasic agents in the prevention of post-ERCP pancreatitis rationale for use and clinical results.J Pancreas. 2003; 4: 75-82PubMed Google Scholar, 5Andriulli A. Caruso N. Quitadamo M. Forlano R. Leandro G. Spirito F. De Maio G. Antisecretory vs. antiproteasic drugs in the prevention of post-ERCP pancreatitis the evidence-based medicine derived from a meta-analysis study.J Pancreas. 2003; 4: 41-48PubMed Google Scholar, 6Demols A. Deviere J. New frontiers in the pharmacological prevention of post-ERCP pancreatitis the cytokines.J Pancreas. 2003; 4: 49-57PubMed Google Scholar, 7Mariani A. Pharmacological prevention of post-ERCP pancreatitis which therapy is best?.J Pancreas. 2003; 4: 68-74PubMed Google Scholar Rationale has centered on interrupting various postulated mechanisms of injury. Some are unique to pancreatitis resulting from ERCP, including instrumental trauma to the pancreatic sphincter with obstruction to flow of pancreatic juice and hydrostatic injury, introduced infection, and acinar toxicity resulting from contrast exposure. Others are inherent to all forms of acute pancreatitis, including premature intracellular activation of proteolytic enzymes, and the inflammatory cascade, including chemokines and proinflammatory cytokines that lead to local and systemic inflammatory response. Although appealing in theory, the history of attempts to find the ideal drug is familiar: First 1 agent, then another, appears promising in animal studies and then in preliminary human studies. Initial single-center randomized trials suggest efficacy, followed by conflicting results from other centers. Disappointment ultimately ensues once larger, multicenter studies are conducted. The list of agents that have gone through this sequence is long (Table 1), including the latest contenders of platelet-activating factor inhibitors and interleukin 10. Meta-analyses suggest that 2 agents are effective in preventing post-ERCP pancreatitis.5Andriulli A. Caruso N. Quitadamo M. Forlano R. Leandro G. Spirito F. De Maio G. Antisecretory vs. antiproteasic drugs in the prevention of post-ERCP pancreatitis the evidence-based medicine derived from a meta-analysis study.J Pancreas. 2003; 4: 41-48PubMed Google Scholar One, somatostatin, is an antisecretory agent, whereas the other, gabexate, is a protease inhibitor. The caveats are that both drugs are not available in North America and, to be effective, both agents must be administered before ERCP and continued for a 12-hour infusion afterward. When administered as a single dose, neither agent has been consistently effective.5Andriulli A. Caruso N. Quitadamo M. Forlano R. Leandro G. Spirito F. De Maio G. Antisecretory vs. antiproteasic drugs in the prevention of post-ERCP pancreatitis the evidence-based medicine derived from a meta-analysis study.J Pancreas. 2003; 4: 41-48PubMed Google Scholar The economic and logistical viability of a 12-hour infusion of an expensive drug is highly questionable in today's environment, especially when 13–27 patients must be treated to prevent a single case of pancreatitis.5Andriulli A. Caruso N. Quitadamo M. Forlano R. Leandro G. Spirito F. De Maio G. Antisecretory vs. antiproteasic drugs in the prevention of post-ERCP pancreatitis the evidence-based medicine derived from a meta-analysis study.J Pancreas. 2003; 4: 41-48PubMed Google Scholar Thus, to date, a drug that is consistently effective in a single dose has not been found. IL, interleukin; PAF, platelet-activating factor; NSAID, nonsterodial anti-inflammatory drug. The second approach to post-ERCP pancreatitis is the use of epidemiologic analyses to identify patient- and procedure-related risk factors so that ERCP can be avoided or technique modified in high-risk patients.8Freeman M.L. Adverse outcomes of ERCP.Gastrointest Endosc. 2002; 56: S273-S282Abstract Full Text Full Text PDF PubMed Google Scholar Recent prospective, large-scale multivariate analyses have taught us that risk of post-ERCP pancreatitis is determined as much by patient characteristics as by the procedure itself.9Freeman M.L. Nelson D.B. Sherman S. Haber G.B. Herman M.E. Dorsher P.J. Moore J.P. Fennerty M.D. Ryan M.E. Shaw M.J. Lande J.D. Pheley A.M. Complications of endoscopic biliary sphincterotomy.N Engl J Med. 1996; 335: 909-918Crossref PubMed Scopus (2146) Google Scholar, 10Freeman M.L. DiSario J.A. Nelson D.B. Fennerty M.B. Lee J.G. Bjorkman D.J. Overby C.S. Aas J. Ryan M.E. Bochna G.S. Shaw M.J. Snady H.W. Erickson R.V. Moore J.P. Roel J.P. Risk factors for post-ERCP pancreatitis a prospective, multicenter study.Gastrointest Endosc. 2001; 54: 425-434Abstract Full Text Full Text PDF PubMed Scopus (972) Google Scholar, 11Loperfido S. Angelini G. Benedetti G. Chilovi F. Costan F. De Berardinis F. DeBernardin M. Ederle A. Fina P. Fratton A. Major early complications from diagnostic and therapeutic ERCP a prospective multicenter study.Gastrointest Endosc. 1998; 48: 1-10Abstract Full Text Full Text PDF PubMed Scopus (1019) Google Scholar, 12Masci E. Toti G. Mariani A. Curioni S. Lomazzi A. Dinelli M. Minoli G. Crosta C. Comin U. Fertitta A. Prada A. Passoni G.R. Testoni P.A. Complications of diagnostic and therapeutic ERCP a prospective multicenter study.Am J Gastroenterol. 2001; 96: 417-423Crossref PubMed Google Scholar, 13Friedland S. Soetikno R.M. Vandervoort J. Montes H. Tham T. Carr-Locke D.L. Bedside scoring system to predict the risk of developing pancreatitis following ERCP.Endoscopy. 2002; 34: 483-488Crossref PubMed Scopus (60) Google Scholar The profile of the reactive pancreas patient includes recurrent abdominal pain (typically in women) in the absence of anatomic biliary obstruction (i.e., suspected stones or sphincter of Oddi dysfunction), younger age, or history of prior post-ERCP pancreatitis (Table 2); patients with multiple risk factors are at especially high risk.10Freeman M.L. DiSario J.A. Nelson D.B. Fennerty M.B. Lee J.G. Bjorkman D.J. Overby C.S. Aas J. Ryan M.E. Bochna G.S. Shaw M.J. Snady H.W. Erickson R.V. Moore J.P. Roel J.P. Risk factors for post-ERCP pancreatitis a prospective, multicenter study.Gastrointest Endosc. 2001; 54: 425-434Abstract Full Text Full Text PDF PubMed Scopus (972) Google Scholar Severe post-ERCP pancreatitis occurs almost exclusively in such patients, often after standard diagnostic or biliary therapeutic procedures.9Freeman M.L. Nelson D.B. Sherman S. Haber G.B. Herman M.E. Dorsher P.J. Moore J.P. Fennerty M.D. Ryan M.E. Shaw M.J. Lande J.D. Pheley A.M. Complications of endoscopic biliary sphincterotomy.N Engl J Med. 1996; 335: 909-918Crossref PubMed Scopus (2146) Google Scholar, 10Freeman M.L. DiSario J.A. Nelson D.B. Fennerty M.B. Lee J.G. Bjorkman D.J. Overby C.S. Aas J. Ryan M.E. Bochna G.S. Shaw M.J. Snady H.W. Erickson R.V. Moore J.P. Roel J.P. Risk factors for post-ERCP pancreatitis a prospective, multicenter study.Gastrointest Endosc. 2001; 54: 425-434Abstract Full Text Full Text PDF PubMed Scopus (972) Google Scholar, 14Trap P. Adamsen S. Hart-Hansen O. Henriksen M. Severe and fatal complications after therapeutic ERCP a prospective series of claims to insurance covering public hospitals.Endoscopy. 1999; 31: 125-130Crossref PubMed Scopus (98) Google Scholar Thus, paradoxically, patients who need ERCP the least are the most likely to suffer a complication. Procedural risk factors are also very important but widely misunderstood: diagnostic ERCP is not necessarily safer than therapeutic ERCP, and adept cannulation technique alone is not sufficient to prevent post-ERCP pancreatitis in high-risk patients.5Andriulli A. Caruso N. Quitadamo M. Forlano R. Leandro G. Spirito F. De Maio G. Antisecretory vs. antiproteasic drugs in the prevention of post-ERCP pancreatitis the evidence-based medicine derived from a meta-analysis study.J Pancreas. 2003; 4: 41-48PubMed Google Scholar The limitation of risk-factor stratification as a strategy is that prediction is not protection. CBD, common bileduct; SO, sphincter of Oddi; SOD, sphincter of Oddi dysfunction. The third approach to preventing post-ERCP pancreatitis is the placement of transsphincteric pancreatic stents. Theoretically, stents serve to mitigate instrumental papillary trauma, to preserve flow of pancreatic juice, and/or to empty the gland of reactive enzyme substrate. According to the plumbing concept, drainage of manipulated pancreatic ducts should prevent pancreatitis just as drainage of obstructed bile ducts prevents cholangitis. Prospective randomized trials have shown that post-ERCP pancreatitis rates of 20%–30% in high-risk control groups are reduced to 5%–10% with pancreatic stenting15Tarnasky P. Palesch Y. Cunningham J. Maulsin P. Cotton P. Hawes R.H. Pancreatic stenting prevents pancreatitis after biliary sphincterotomy in patients with sphincter of Oddi dysfunction.Gastroenterology. 1998; 115: 1518-1524Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar, 16Fazel A. Quadri A. Catalano M.F. Meyerson S.M. Geenen J.E. Does a pancreatic duct stent prevent post-ERCP pancreatitis? A prospective randomized study.Gastrointest Endosc. 2003; 57: 291-294Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, 17Tarnasky P. Mechanical prevention of post-ERCP pancreatitis by pancreatic stents results, techniques, and indications.J Pancreas. 2003; 4: 58-67PubMed Google Scholar (Table 3). Most strikingly, risk of severe or necrotizing pancreatitis is virtually eliminated by a properly positioned pancreatic stent, a finding corroborated by accumulating experience at advanced centers.15Tarnasky P. Palesch Y. Cunningham J. Maulsin P. Cotton P. Hawes R.H. Pancreatic stenting prevents pancreatitis after biliary sphincterotomy in patients with sphincter of Oddi dysfunction.Gastroenterology. 1998; 115: 1518-1524Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar, 16Fazel A. Quadri A. Catalano M.F. Meyerson S.M. Geenen J.E. Does a pancreatic duct stent prevent post-ERCP pancreatitis? A prospective randomized study.Gastrointest Endosc. 2003; 57: 291-294Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, 17Tarnasky P. Mechanical prevention of post-ERCP pancreatitis by pancreatic stents results, techniques, and indications.J Pancreas. 2003; 4: 58-67PubMed Google Scholar, 18Fogel E.L. Eversman D. Jamidar P. Sherman S. Lehman G.A. Sphincter of Oddi dysfunction pancreatobiliary sphincterotomy with pancreatic stent placement has a lower rate of pancreatitis rate than biliary sphincterotomy alone.Endoscopy. 2002; 34: 280-285Crossref PubMed Scopus (175) Google Scholar Downsides of pancreatic stenting as a strategy are its unfamiliarity to many endoscopists, the decision about which cases warrant a stent, the difficulty of stent insertion in patients with small or tortuous ducts, the potential for ductal injury,19Kozarek R.A. Pancreatic stents can induce ductal changes consistent with chronic pancreatitis.Gastrointest Endosc. 1990; 36: 93-95Abstract Full Text PDF PubMed Scopus (295) Google Scholar and the follow-up required for stent removal. SOD, sphincter of Oddi dysfunction. In this context, Murray et al.1Murray B. Carter C. Imrie C. Evans S. O'Suilleabhain C. Diclofenac reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography.Gastroenterology. 2003; 124: 1786-1791Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar bravely charge where others have fallen, with an attempt to test the efficacy of a single dose of a drug to interrupt the inflammatory cascade leading to post-ERCP pancreatitis. In their well-conceived and -executed study, 220 patients determined to be at high risk were randomized to receive either a rectal suppository of the NSAID agent, diclofenac, or a placebo. Appealing features of the treatment strategy include (1) the drug is relatively inexpensive; (2) it was administered as a single dose; (3) it was administered immediately after ERCP, so patient risk stratification could include intraprocedural events; and (4) any center can administer such a treatment, unlike techniqueoriented strategies such as pancreatic stent placement. The primary outcome was clinical pancreatitis, defined approximately by consensus criteria,20Cotton P.B. Lehman G. Vennes J.A. Geenen J.E. Russell R.C.G. Meyers W.C. Liguory C. Nickl N. Endoscopic sphincterotomy complications and their management an attempt at consensus.Gastrointest Endosc. 1991; 37: 383-391Abstract Full Text PDF PubMed Scopus (2373) Google Scholar which occurred in 6.4% of patients receiving diclofenac versus 15.5% of controls. Concerns with the study are the following. (1) Differences in outcome barely achieved statistical significance (P = 0.049). (2) No multivariate analysis was performed to assess the effect of the treatment versus other variables. (3) Inclusion criteria were rather broad, including merely the performance of pancreatography, thus lowering the background rate of pancreatitis in the intended high-risk control group. (4) The drug was not effective in the subgroup of patients with sphincter of Oddi dysfunction, the very group of patients that is usually the most problematic. (5) The occurrence of 2 cases of necrotizing pancreatitis in patients without sphincter of Oddi dysfunction is unusual, and one wonders whether these patients were among those receiving pancreatic stents—probably not, if the experience of others is borne out. Are we now to hope that a simple NSAID will significantly reduce risk of post-ERCP pancreatitis? Perhaps, as the authors suggest, NSAID's ability to inhibit steps early in the inflammatory cascade involving prostaglandins, phospholipase-A2 (PLA2), or endothelial-neutrophil attachment will be the magic key. One wonders why a simple NSAID would effectively interrupt the inflammatory cascade when all other agents administered as a single dose have failed. However, it will likely turn out that, with more and larger studies, history will repeat itself and the efficacy will disappear. Or perhaps potential adverse effects of NSAIDs on bleeding or renal function, not discussed in the article by Murray et al.,1Murray B. Carter C. Imrie C. Evans S. O'Suilleabhain C. Diclofenac reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography.Gastroenterology. 2003; 124: 1786-1791Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar will counterbalance any protective effect against pancreatitis. In the big picture, it is this author's opinion that the primary way to reduce post-ERCP pancreatitis remains to educate endoscopists to avoid many of the diagnostic and empirical therapeutic ERCPs still performed in practice for marginal indications such as "possible" bile duct stones or "suspected" sphincter of Oddi dysfunction. Magnetic resonance cholangiopancreatography, intraoperative laparoscopic cholangiography, and endoscopic ultrasound are safe and increasingly available diagnostic alternatives to find real obstructive biliary and pancreatic pathology. Patients without anatomic biliary pathology, determined by using these techniques, are probably best served either by avoiding ERCP altogether or by referral of such patients, along with technically difficult cases, to specialized centers capable of advanced endoscopic techniques for diagnosis and therapy, including endoscopic ultrasound, sphincter of Oddi manometry, and pancreatic therapeutic ERCP. At specialized centers, and also increasingly in diverse practice settings, avoidance of post-ERCP pancreatitis will probably continue to pivot on improved technique including judicious use of pancreatic stents. Until such time as a simple and effective pharmacologic panacea is found, the tools for avoidance of post-ERCP pancreatitis will remain in endoscopists' head and hands.