INTRODUCTION — An elevation in the serum amylase concentration is common after ERCP, occurring in up to 75 percent of patients; in comparison, acute clinical pancreatitis (defined as a clinical syndrome of abdominal pain and hyperamylasemia requiring hospitalization) occurs much less commonly [1]. Nevertheless, acute pancreatitis is the most common serious complication of ERCP [2]. It accounted for more than one-half of complications of endoscopic sphincterotomy in two large series [3,4], and for 23 out of 39 malpractice claims for compensation due to post-ERCP complications, including seven of nine that were fatal, in a Danish report [5]. Similarly, in an analysis of 59 ERCP lawsuits in North America, 30 cases and 6 of 15 deaths involved pancreatitis [6].

PATHOGENESIS — Several factors may act independently or in combination to induce post-ERCP pancreatitis [7]:

• Mechanical injury from instrumentation of the pancreatic duct — Prolonged manipulation around the papillary orifice, repeated instrumentation of the pancreatic duct and multiple pancreatic duct injections are common when selective bile duct cannulation is difficult [8].
• Hydrostatic injury from overinjection — Hydrostatic injury from overinjection of the pancreatic duct is probably a main determinant of pancreatitis after diagnostic ERCP and sphincter of Oddi manometry [9]. Overinjection has probably occurred when gland acinarization is apparent during pancreatography.
• Chemical or allergic injury from contrast medium — The role of ionic contrast agents and the relative safety of nonionic low osmolarity contrast agents is controversial. A meta-analysis of controlled trials found no significant difference [10].
• Enzymatic injury from intestinal content — Intraluminal activation of proteolytic enzymes has been suggested in laboratory studies and clinical trials.
• Infection — Bacterial injury from a contaminated endoscope and accessories can occur, but probably does not have a major role [7].
• Thermal injury — Thermal injury from electrocautery current may produce edema of the pancreatic orifice and obstruction of pancreatic juice flow [11].

GRADING AND INCIDENCE — Post-ERCP acute pancreatitis can be graded as mild, moderate, or severe based upon a consensus definition (table 1) [2]:

• Mild — Serum amylase at least three times normal at more than 24 hours after the procedure, requiring admission or prolongation of planned admission to two to three days
• Moderate — Hospitalization of 4 to 10 days
• Severe — Hospitalization of more than 10 days, or hemorrhagic pancreatitis, phlegmon or pseudocyst, or required intervention (percutaneous drainage or surgery)

Incidence — The incidence of post-ERCP pancreatitis has been estimated in several large clinical trials (table 2) [3,12-16]. In a series from North America, for example, acute pancreatitis occurred in 127 of 2347 cases (5.4 percent) [3]. Most cases were mild (n = 53) or moderate (n = 65); only nine patients (0.4 percent) developed severe pancreatitis including one death, three who required surgical treatment, and one who needed percutaneous drainage of a pseudocyst. Similar results were noted in another study in which acute pancreatitis developed in 4.7 percent of patients undergoing sphincterotomy, with severe disease occurring in 0.6 percent [13,14].

RISK FACTORS FOR POST ERCP PANCREATITIS — A number of risk factors for post-ERCP pancreatitis have been identified from a multitude of studies which had different study designs, examined different candidate predictor variables, and took place in a variety of settings (table 3) [3,12-33]. The strength of some of these associations has been supported by large, multicenter prospective trials, while others have been suggested in smaller series and from clinical experience.

As a general rule, most reports have found that the risk of pancreatitis is increased after therapeutic compared to diagnostic ERCP. In three series, for example, the incidence of pancreatitis was more than doubled in patients who underwent therapeutic ERCP [15,34,35]. However, severe and even fatal pancreatitis can occur after diagnostic ERCP [5].

The following operator, patient, and method-related factors were independent predictors of post-ERCP pancreatitis in at least one large prospective study [3,12-16,30-33,36,37]:

• Operator-related factors — Low case volume (sphincterotomy frequency less than 40 per year)
• Patient-related factors — Younger age, female sex, normal serum bilirubin, preexisting pancreatitis, prior ERCP-induced pancreatitis, absence of chronic pancreatitis, sphincter of Oddi dysfunction, small bile duct [15], dilated bile duct [31], pancreas divisum, previous laparoscopic cholecystectomy
• Method-related factors — Difficulty of cannulation, biliary sphincterotomy, deep wire pass in the pancreas, pancreatic opacification, number of pancreatic contrast injections, sphincter of Oddi manometry, precut sphincterotomy, failed clearing of biliary stones, pancreatic endoscopic sphincterotomy, minor papilla sphincterotomy, pain during the procedure, placement of a stent, pancreatic brush cytology, and biliary balloon sphincteroplasty. (See "Endoscopic balloon dilatation for removal of bile duct stones".)

Risk factors that were recognized as independent predictors in more than one study included: younger age, female sex, pancreas divisum, sphincter of Oddi dysfunction, prior ERCP-induced pancreatitis, difficulty of cannulation, pancreatic duct injection, and operator experience.

Other predictors identified on univariate analysis in the above studies were [3,12-15,30,36]:

• Patient-related factors — Any history of pancreatitis or allergy to contrast material increased the risk, while the presence of common bile duct stones decreased the risk [3,23,24]. One study suggested that the risk may be increased with the use of drugs that were potentially toxic to the pancreas (ie, estrogen, azathioprine, valproic acid, mesalazine, morphine derivatives and prednisone) [38].
• Method-related factors — Acinarization of the pancreas, guidewire used for cannulation, nasobiliary tube

Independent predictors are additive, as demonstrated in several studies [3,12]. As examples, young age, female sex, suspected sphincter of Oddi dysfunction, normal bilirubin, a difficult cannulation, and the absence of bile duct stones involve a risk of pancreatitis over 40 percent.

Several risk factors that have been thought to be associated with post-ERCP pancreatitis were not significant in some of the above studies. These include emergency procedures, a peripapillary diverticulum, Billroth II gastrectomy, the type of contrast medium (ionic versus nonionic), use of guidewire for cannulation, wire length of the sphincterotome, and the type of electrocautery current (blended versus pure cut). In addition, hypotension during ERCP [39] and obesity [40] were not significant.

Studies that have specifically addressed the issue of electrocautery have given disparate results. (See 'About electrocautery current for biliary sphincterotomy' below.)

Summary — Predictors for pancreatitis identified in the large prospective trials that incorporated multivariate analysis are probably the most robust, particularly variables identified in more than one study. These include younger age, female sex, pancreas divisum, sphincter of Oddi dysfunction, prior ERCP-induced pancreatitis, difficulty of cannulation, precut sphincterotomy, and pancreatic duct injection. In addition, sphincter of Oddi manometry and a small common bile duct (<5 mm) particularly in the setting of sphincter of Oddi dysfunction are widely considered to be risk factors, although not recognized as independent risk factors. These conditions should be considered "warning signs" that may deserve special care in preventing post-ERCP pancreatitis [41]. (See below and (see "Prophylactic pancreatic stents to prevent ERCP-induced pancreatitis: When do you use them?".

EARLY DIAGNOSIS — The diagnosis of pancreatitis is based upon clinical and laboratory features, which are discussed in detail separately. (See "Clinical manifestations and diagnosis of acute pancreatitis".) In the setting of ERCP, it is desirable to establish the diagnosis as early as possible, particularly since the procedure is now increasingly being performed on an outpatient basis.

Although the serum amylase and lipase concentrations are commonly elevated following ERCP in patients without clinical pancreatitis, the degree and rapidity of their elevation may be a way to identify patients with incipient pancreatitis. This hypothesis was supported in a study involving 231 patients in whom serum amylase and lipase determinations were obtained serially following ERCP [42]. Values of amylase and lipase below 276 U/L (4.6 nkat/L) and 1000 U/L (166.7 kat/liter), respectively, two hours after terminating the procedure were highly predictive of the absence of pancreatitis, even in patients who had abdominal pain (negative predictive value of 97 and 98 percent, respectively). In a similarly designed study involving 409 patients who underwent endoscopic sphincterotomy, determination of serum amylase four hours after the procedure was useful for predicting subsequent clinical pancreatitis; two-thirds of patients who developed pancreatitis had a serum amylase concentration higher than five times the upper limit of normal [43]. Another study concluded that the presence of pancreatic-type pain at 24 hours in conjunction with an elevated serum amylase level (more than five times normal) was the most accurate predictor of pancreatitis [44].

Serum and urinary trypsinogen values have also been proposed as markers of early pancreatitis. A serum trypsinogen 2 concentration more than three times greater than the upper limit of normal six hours after ERCP has been an accurate indicator of pancreatitis (sensitivity 93 percent and specificity 91 percent) [45], while a negative urinary trypsinogen 2 test strip six hours after the procedure has been highly predictive of the absence of pancreatitis (negative predictive value 98 percent) [46]. Serum C-reactive protein and interleukin-6, serially determined at 12 to 24 hours and at 36 to 48 hours, were useful early markers for predicting the severity of ERCP-induced pancreatitis in a pilot study of 84 patients [47].

PREVENTION — A number of measures have been studied in an effort to reduce the incidence of post-ERCP pancreatitis [48]. Of fundamental importance is attention to basic ERCP technique. The role of pharmacologic prophylaxis is unclear.

Endoscopic techniques — Considering the risk factors discussed above and basic principles of endoscopy, several recommendations to avoid or limit pancreatitis can be proposed:

• Proper training and expertise of endoscopist and assistants
• Adequate case volume for endoscopy unit and single endoscopists to acquire experience and maintain proficiency
• Correct disinfection of endoscope and sterilization of accessories
• Avoidance of diagnostic ERCP when alternative less invasive methods are available
• Enhancing selective cannulation and avoiding cannulation and injection of the pancreatic duct when not indicated
• Limiting cannulation time and the number of injections, and avoiding pancreatic acinarization
• Avoid any pancreatic injection if not necessary to the planned procedure
• Limit the extent of pancreatic injection to the minimal necessary
• Careful use of electrocautery current with standard or precut sphincterotomy (judicious use of precut, limiting coagulation current near the pancreatic orifice, and performing sphincterotomy in steps)
• Use of an aspirating catheter for sphincter of Oddi manometry of the pancreatic duct
• Considering referral to specialized ERCP centers

About cannulation — Instruments have been developed that facilitate cannulation (such as catheters with distal markings and a radio-opaque tip, hydrophilic coated guidewires, double-lumen sphincterotomes, and others) [49-52]. A meta-analysis of five randomized controlled trials found that wire-guided cannulation was superior to a standard cannulation technique. Primary cannulation rates were better for the wire-guided technique compared to the standard technique (85 versus 75 percent) and the risk of post-ERCP pancreatitis was lower (OR 0.23, 95% CI 0.13-0.41) [53].

About electrocautery current for biliary sphincterotomy — Studies that have specifically addressed the issue of electrocautery have given disparate results. In two series, the incidence of pancreatitis was reduced with pure cut electrocautery compared to blended current (3.5 versus 11.9 percent) [54] and with bipolar compared to monopolar electrocautery (0 versus 12 percent) [55]. However, a subsequent large, randomized prospective study found no significant difference in the rates of pancreatitis with pure-cut versus blended current (7.8 versus 6.1 percent) [56]. A meta-analysis of four trials (with a total of 804 patients) comparing pure current to mixed current in patients undergoing sphincterotomy found no significant difference in the rates of pancreatitis [57]. However, pure current was associated with more episodes of bleeding (mostly minor).

Some endoscopists start with pure cut and complete the sphincterotomy with blended current. The value of this approach is currently being tested in clinical trials [58-60]. In one study, no statistical difference was noted in the rates of overall pancreatitis [60], while another study concluded that this approach was associated with an increased rate of complications compared to using pure cutting current [59]. Endocut (another method of producing current using the Erbe, Inc, cautery device by automatically varying the intensity of current and current blend according to tissue resistance) did not reduce the rate of pancreatitis in a large retrospective study [61] and in a randomized trial [62]. (See "Standard sphincterotomy technique: The cutting edge".)

About pancreatic stenting — Placement of a pancreatic stent or nasopancreatic catheter may have a role in prophylaxis against ERCP-pancreatitis in some high risk settings. Examples include patients with known or suspected sphincter of Oddi dysfunction (particularly those with a common bile duct <5 mm), patients undergoing pancreatic sphincterotomy or pancreatic endotherapy, and patients undergoing precut sphincterotomy. The possible benefit is hypothesized to be related to a reduction in pancreatic intraductal pressure from stenting. However, pancreatic stenting has been associated with a number of complications (particularly stent-related ductal changes), and should only be attempted by highly experienced endoscopists, preferably in the setting of clinical trials (see "Prophylactic pancreatic stents to prevent ERCP-induced pancreatitis: When do you use them?" and "Overview of pancreatic stenting and its complications".

Pharmacologic prophylaxis — The search for a prophylactic agent that can reduce the incidence of post-ERCP pancreatitis began soon after the introduction of ERCP and still continues. Several agents have been tested experimentally and in clinical trials, but none is used routinely in clinical practice (table 4).

Miscellaneous agents

• Antibiotics [63], calcitonin [64,65], glucagon [66] and nifedipine [67,68] failed to show a reduction in the levels of pancreatic enzymes or in the complication rate. Studies evaluating allopurinol have produced discordant results, which might at least in part be explained by the varying doses used [69-73]. Pentoxifylline did not protect against post-ERCP pancreatitis or hyperamylasemia in a randomized study [74].
• Infusion of C1-inhibitor (the major inhibitor of the first component of the complement system and an inactivator of kallikrein and factor XII) prevented hyperamylasemia induced by endoscopic biliary sphincterotomy in a placebo controlled trial involving 40 patients [75].
• Secretin had a protective effect in a preliminary retrospective study [76]. However, no benefit was observed on ERCP-induced hyperamylasemia in a randomized trial [77].
• Low dose anticoagulation (unfractionated heparin or low molecular weight heparin) prior to ERCP combined with sphincterotomy appeared to reduce the risk of post-procedure pancreatitis in a prospective study involving 815 patients [78]. In contrast, no benefit from low molecular weight heparin was observed in a subsequent placebo controlled trial involving 458 patients [79].
• Intravenous glucocorticoids were suggested as promising therapy in initial reports [80,81]. However, no benefit was detected in at least three subsequent controlled trials [82-84]. Oral corticosteroids proved equally ineffective in two prospective, controlled trials involving a total of 1415 patients [69,85]. A meta-analysis of six randomized controlled trials of intravenous or oral corticosteroids found that prophylactic corticosteroids did not reduce the incidence of post-ERCP pancreatitis [86].
• Ulinastatin, a protease inhibitor, reduced hyperamylasemia and post-ERCP pancreatitis in a Japanese randomized, double-blind, placebo-controlled trial [87]. By contrast, in a randomized controlled trial of prophylactic low dose of ulinastatin in high-risk patients did not detect a benefit [88].
• A possible role of oxidant stress in the pathogenesis of post-ERCP pancreatitis has led to clinical trials of several antioxidant drugs. N-acetylcysteine [89] and sodium selenite [90] were not beneficial in randomized controlled trials. Another trial compared a single dose of natural beta-carotene 12 hour prior to the procedure versus placebo [91]. Although the incidence of pancreatitis was similar in the two groups (10 and 9.4 percent), the authors suggested that beta-carotene might reduce the severity of disease since four patients in the placebo group had severe pancreatitis compared with none in the beta-carotene group.
• 5-fluorouracil added to contrast medium appeared to reduce hyperamylasemia and post-ERCP pancreatitis in a randomized study [92].

The following discussion will focus on strategies that continue to be the subjects of clinical trials. These include drugs that suppress pancreatic exocrine secretion such as somatostatin [93-96] and its long-acting analogue octreotide [97-103], have antiproteolytic activity such as gabexate mesilate [104,105], have anti-inflammatory activity such as IL-10 [106], or relax the sphincter of Oddi such as glyceryl trinitrate [107]. As a general rule, promising findings from initial trials of these agents have been followed by conflicting results from subsequent studies.

Gabexate mesilate — Gabexate mesilate is a protease inhibitor that has been studied for treatment of pancreatitis due to a variety of causes and in the prevention of post-ERCP pancreatitis. (See "Treatment of acute pancreatitis".) Multiple trials have been conducted in the latter setting, which have produced discordant results. A meta-analysis of five studies concluded that it was ineffective in reducing post-ERCP pancreatitis and pain [108].

Somatostatin — Several controlled trials have evaluated the efficacy of somatostatin given prophylactically using various dosing schedules. A meta-analysis of nine high-quality trials concluded that somatostatin was ineffective in preventing post-ERCP pancreatitis when given either short-term (<6 hours) or long-term (<12 hours) [108]. However, a modest benefit was observed in studies using bolus injections (pooled absolute risk reduction of 8 percent (95% CI 0.57-0.81)). The authors concluded that additional studies were needed. Two subsequent controlled trials using bolus strategies had mixed results [109,110]. Thus, the role of somatostatin is uncertain.

Octreotide — The long-acting somatostatin analogue octreotide may reduce the serum amylase elevation [97,100-102,111] but studies evaluating the incidence of acute pancreatitis have produced mixed results [84,98,99,103,111,112]. A meta-analysis found no clear evidence for a benefit [113].

Nonsteroidal antiinflammatory drugs — A growing number of studies have evaluated NSAIDs given orally or rectally but more data are needed. A meta-analysis of four randomized controlled trials of rectal NSAIDs found a significant reduction in the incidence of pancreatitis (RR 0.36, 95% CI .22-.60) [114]. One of the individual trials, for example, included 220 patients undergoing diagnostic or therapeutic ERCP; a single 100 mg rectal dose of diclofenac administered immediately after the procedure significantly reduced incidence of pancreatitis compared with placebo (6.4 versus 15.5 percent) [115]. Another trial involving 490 patients found that a single 100 mg rectal dose of indomethacin administered before the procedure reduced the incidence and severity of pancreatitis [116]. These results require confirmation [117,118]. By contrast diclofenac was not more effective than placebo in a randomized controlled trial involving 207 patients [119].

Kinase inhibitors — Interleukin 10 (IL-10) is an antiinflammatory cytokine that limited the severity of acute pancreatitis in animal models [120-123]. A study in humans undergoing therapeutic ERCP found that a single intravenous dose given 30 minutes prior to the procedure significantly reduced the incidence of pancreatitis (8 versus 24 percent) [106]. The positive results should be interpreted cautiously because of the high rate of pancreatitis in the placebo group. The incidence of pancreatitis in those who received active treatment was closer to the control rate of post-ERCP pancreatitis observed in other studies. Furthermore, no benefit was detected in a subsequent placebo-controlled trial [124].

Pre-ERCP infusion of semapimod, a mitogen-activated protein kinase inhibitor, lowered post-ERCP hyperamylasemia but not the incidence of pancreatitis [125].

Nitroglycerin — Glyceryl trinitrate (sublingual or transdermal) reduces sphincter of Oddi pressure, providing a rationale for evaluating its efficacy in preventing post-ERCP pancreatitis. Initial controlled trials suggested a potential benefit but rates of pancreatitis in the control arms were unexpectedly high [107,126]. No benefit was observed in a third controlled trial involving 318 patients [127]. In a multicenter, double-blind trial, intravenous nitroglycerin after therapeutic ERCP did not decrease the incidence of post-ERCP pancreatitis [128].

Botulinum toxin — The hypothesis that botulinum toxin (BTX) injection might reduce the rate of post-procedure pancreatitis by reducing the pancreatic sphincter hypertension in patients with sphincter of Oddi dysfunction (SOD) provided the rationale for a controlled trial comparing BTX versus sham saline injection in 26 patients with elevated baseline pressures [129]. There was a lower rate of pancreatitis in the BTX group (25 versus 43 percent) but the results did not achieve statistical significance. A concern related to this study is that the rate of pancreatitis was much higher than other studies of similar patients. Furthermore, BTX injection without preliminary insertion of a pancreatic prosthesis may increase the risk of pancreatitis due to temporary occlusion of the pancreatic orifice [130]. Thus, this technique may deserve evaluation in future trials, but cannot at present be recommended [131].

Topical lidocaine — Topical application of lidocaine reduces sphincter of Oddi spasm [132]. Despite this theoretical benefit, topical lidocaine did not reduce the rate of post-ERCP pancreatitis in a randomized trial involving 294 patients [133].

Conclusions — Conclusive evidence on the efficacy of protease inhibitors and antisecretory agents for the prevention of post-ERCP pancreatitis requires confirmation in large prospective randomized trials that are capable of controlling for important covariates. The importance of such control was underscored in a study in which small endoscopy centers experienced a higher rate of moderate to severe pancreatitis in comparison with large centers (2.6 versus 0.9 percent) despite much more frequent administration of octreotide or somatostatin [15].

In addition, the cost-effectiveness of these drugs needs to be better understood before they can be recommended for use outside of clinical trials. It is possible that drugs such as gabexate mesilate and somatostatin will have a role for patients at increased risk such as young patients with suspected sphincter of Oddi dysfunction and nondilated bile ducts [41,134,135]. However, it may not be possible to identify many of these patients since some of the high risk features are usually detected during the ERCP, while the drugs require administration before the procedure. At present, pharmacological prophylaxis of post-ERCP pancreatitis should be regarded as a potential adjuvant and in no case as a substitute for proper training, experience, and technique.

TREATMENT — Most episodes of post-ERCP pancreatitis are mild, and require only a short hospital stay for bowel rest and intravenous hydration [3]. Patients who develop severe pancreatitis may require prolonged hospitalization in the intensive care unit with total parenteral nutrition. The management of such patients is the same as for patients with severe pancreatitis from other causes. Endoscopic reintervention may be required in patients with a biliary cause of pancreatitis if the ERCP did not produce adequate biliary decompression. (See "Treatment of acute pancreatitis".)

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: ERCP (endoscopic retrograde cholangiopancreatography)" and "Patient information: Acute pancreatitis".) We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

ACKNOWLEDGMENT — The authors and UpToDate would like to thank Dr. Fabio Monica, who contributed to earlier versions of this topic review.