Key points

Overview

Postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is defined as new or increased abdominal pain that is clinically consistent with a syndrome of acute pancreatitis and associated pancreatic enzyme elevation at least three times the upper limit of normal 24 hours after the procedure and resultant hospitalization (or prolongation of existing hospitalization) of at least 2 nights. Pancreatitis is still the most common complication of ERCP, occurring in 2% to 15% of cases, and accounting for substantial morbidity, occasional mortality, and health care expenditures in excess of $200 million annually in the United States. Despite significant advances over the last several decades in terms of patient selection, equipment, procedural technique, and prophylactic interventions, PEP remains a serious health problem and its prevention remains a major clinical and research priority. Strategies to prevent PEP are broadly divided into five areas: (1) appropriate patient selection, (2) risk stratification of patients undergoing ERCP and meaningful use of this information in clinical decision-making, (3) atraumatic and efficient procedural technique, (4) prophylactic pancreatic stent placement (PSP), and (5) pharmacoprevention. All five strategy areas should be considered in every case, and the latter two should be implemented when appropriate.

Overview

Postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is defined as new or increased abdominal pain that is clinically consistent with a syndrome of acute pancreatitis and associated pancreatic enzyme elevation at least three times the upper limit of normal 24 hours after the procedure and resultant hospitalization (or prolongation of existing hospitalization) of at least 2 nights. Pancreatitis is still the most common complication of ERCP, occurring in 2% to 15% of cases, and accounting for substantial morbidity, occasional mortality, and health care expenditures in excess of $200 million annually in the United States. Despite significant advances over the last several decades in terms of patient selection, equipment, procedural technique, and prophylactic interventions, PEP remains a serious health problem and its prevention remains a major clinical and research priority. Strategies to prevent PEP are broadly divided into five areas: (1) appropriate patient selection, (2) risk stratification of patients undergoing ERCP and meaningful use of this information in clinical decision-making, (3) atraumatic and efficient procedural technique, (4) prophylactic pancreatic stent placement (PSP), and (5) pharmacoprevention. All five strategy areas should be considered in every case, and the latter two should be implemented when appropriate.

Patient selection

Thoughtful patient selection before ERCP remains the most important strategy for reducing the incidence of PEP. Endoscopic ultrasound and magnetic resonance cholangiopancreatography allow highly accurate pancreaticobiliary imaging while avoiding the significant risks of ERCP. Two large meta-analyses have demonstrated that endoscopic ultrasound is highly sensitive and specific in the detection of bile duct stones (sensitivity, 89%–94%; specificity, 94%–95%). Similarly, magnetic resonance cholangiopancreatography has a sensitivity of 85% to 92% and a specificity of 93% to 97% for the same indication, although MRI seems less sensitive than endoscopic ultrasound for stones smaller than 6 mm. Additionally, endoscopic ultrasound, MRI, and other noninvasive modalities, such as radionucleotide-labeled scan and percutaneous drain fluid analysis, are very accurate in diagnosing a multitude of other pancreaticobiliary processes (eg, chronic pancreatitis, malignancy, and leaks), often obviating ERCP.

Indeed, the use of ERCP as a diagnostic procedure has steadily declined in favor of less invasive but equally accurate alternative tests, and ERCP has appropriately become a near-exclusively therapeutic procedure reserved for patients with a high pretest probability of intervention. This trend is consistent with recent clinical practice guidelines on the role of endoscopy in the evaluation of choledocholithiasis and the National Institutes of Health consensus statement on ERCP for diagnosis and therapy, both favoring less invasive tests over ERCP in the diagnosis of biliary disease.

An exception to the widespread practice of reserving ERCP for patients with a high likelihood of therapeutic intervention has been the evaluation of patients with suspected sphincter of Oddi dysfunction (SOD), for which an accurate, less-invasive alternative to ERCP-guided sphincter of Oddi manometry (SOM) remains elusive. Even when considering patients for SOM, however, thoughtful clinical judgment is necessary to select those who are most likely to benefit from the procedure. A recent multicenter randomized trial (the EPISOD study) has demonstrated that there seems to be no role for ERCP in patients with suspected SOD but no laboratory or radiographic abnormalities (previously known as type 3 SOD). Additional studies are necessary to determine whether diagnostic ERCP with SOM is truly beneficial in cases of suspected type 2 biliary SOD or recurrent unexplained pancreatitis. Pending such studies, many experts believe ERCP remains reasonable in these scenarios after careful assessment of the risk-benefit ratio and detailed informed consent. Another possible exception to the therapeutic ERCP trend may be the evaluation of biliary complications in liver transplant recipients, for whom a recent retrospective study suggested that diagnostic ERCP is a reasonable and efficient clinical approach in this patient population based on a high likelihood of therapeutic intervention and a very low rate of complications, in particular PEP.

Recognizing patients at increased risk for postendoscopic retrograde cholangiopancreatography pancreatitis

A high index of suspicion for, and early identification of, post-ERCP pancreatitis are critically important in ensuring favorable clinical outcomes. The ability to risk-stratify patients based on well-established clinical characteristics can inform the decision-making process that surrounds (1) proceeding with ERCP, (2) referral to a tertiary center, (3) fluid resuscitation, (4) prophylactic stent placement, (5) pharmacoprevention, and (6) postprocedural hospital observation.

A substantial amount of research over the last two decades has contributed to the understanding of the independent risk factors for post-ERCP pancreatitis. These risk factors, listed in Table 1 , can be divided into patient-related and procedure-related characteristics. The definite and probable patient-related risk factors that predispose to PEP are a clinical suspicion of SOD (regardless of whether or not SOM is performed), a history of prior PEP, a history of recurrent pancreatitis, normal bilirubin, younger age, and female gender. The definite and probable procedure-related risk factors for PEP are difficult cannulation, precut (access) sphincterotomy (discussed later), pancreatic sphincterotomy, ampullectomy, repeated or aggressive pancreatography, and short-duration balloon dilation of an intact biliary sphincter. Two recent systematic reviews have affirmed the association of most of these factors with PEP. Additional risk factors that have been implicated, but are not concretely accepted, as independent predictors of PEP are biliary sphincterotomy, pancreatic duct wire passage (see later), pancreatic acinarization, self-expanding metal stent placement, nondilated bile duct, intraductal papillary mucinous neoplasm, intraductal ultrasound, and Billroth 2 anatomy.

Operator (endoscopist)-dependent characteristics have also been implicated in the risk of PEP. Endoscopist procedure volume is suggested to be a risk factor for PEP, although multicenter studies have not confirmed this observation, presumably because low-volume endoscopists tend to perform lower-risk cases. Nevertheless, potentially dangerous cases (based on either patient-related factors or anticipated high-risk interventions) are best referred to expert medical centers where a high-volume endoscopist with expertise in prophylactic PSP can perform the case, and where more experience with rescue from serious complications may improve clinical outcomes. Similarly, trainee involvement in ERCP is a possible independent risk factor for PEP, although results of existing multivariable analyses are conflicting. Inexperienced trainees may augment procedure-related risk factors, such as prolonging a difficult cannulation or delivering excess electrosurgical current during an inefficient pancreatic sphicterotomy. Therefore, additional research focused on improving the process of ERCP training is necessary to minimize the contribution of trainee involvement to the development of PEP.

Several additional points regarding clinical risk stratification are worth considering. First, predictors of PEP seem multiplicative in nature. For example, a widely referenced multicenter study by Freeman and colleagues predating prophylactic PSP showed that a young woman with a clinical suspicion of SOD, normal bilirubin, and a difficult cannulation has a risk of PEP in excess of 40%. Second, patients with a clinical suspicion of SOD, particularly women, are not only at increased risk for PEP in general, but are also more likely to develop severe pancreatitis and death. When considering the risk-benefit ratio of ERCP in this patient population, not only should the patient’s overall risk of PEP be assessed, but their probability of experiencing a more dramatic clinical course should also be considered and discussed. Additionally, several clinical characteristics are thought to significantly reduce the risk of PEP. First, biliary interventions in patients with a pre-existing biliary sphincterotomy probably confer a very low risk of PEP. Prior sphincterotomy generally separates the biliary and pancreatic orifices, allowing avoidance of the pancreas, and making pancreatic sphincter or duct trauma unlikely. Furthermore, patients with chronic pancreatitis, in particular those with calcific pancreatitis, are at lower risk for PEP because of gland atrophy, fibrosis, and consequent decrease in exocrine enzymatic activity. Similarly, the progressive decline in pancreatic exocrine function associated with aging may protect older patients from pancreatic injury. Lastly, perhaps because of postobstructive parenchymal atrophy, patients with pancreatic head malignancy seem to be relatively protected.

Procedure technique

Efficient and atraumatic technical practices during ERCP are central to minimizing the risk of pancreatitis. Many of the procedure-related risk factors listed previously, although predisposing to PEP, are mandatory elements of a successful case. Even though these high-risk interventions are unavoidable for execution of the clinical objective, certain strategies can be used to minimize procedure-related risk.

Difficult cannulation and pancreatic duct injection are independent risk factors for PEP. As such, interventions that improve the efficiency of cannulation and limit injection of contrast into the pancreas are likely to decrease the risk of pancreatitis. Guidewire-assisted cannulation accomplishes both, representing a major paradigm shift in ERCP practice. In contrast to conventional contrast-assisted cannulation, which may lead to inadvertent injection of the pancreatic duct or contribute to papillary edema, guidewire-assisted cannulation uses a small-diameter wire with a hydrophilic tip that is initially advanced into the duct, subsequently guiding passage of the catheter. Because the wire is thinner and more maneuverable than the cannula, it is easier to advance across a potentially narrow and off-angle orifice. Moreover, this process limits the likelihood of an inadvertent pancreatic or intramural papillary injection. A recent Cochrane Collaboration meta-analysis, which included 12 randomized controlled trials (RCTs) involving 3450 subjects, indeed confirms that guidewire-assisted cannulation reduces the risk of PEP by approximately 50% (relative risk, 0.51; 95% confidence interval, 0.32–0.82). When wire cannulation is used for biliary access, it is important to advance the guidewire cautiously in the event it is actually in the pancreatic duct where forceful advancement may result in sidebranch perforation.

When initial cannulation attempts are unsuccessful, several alternative techniques are available to facilitate biliary access. The double-wire technique is a common second-line approach when initial cannulation attempts result in repeated unintentional passage of the wire into the pancreas. The wire can be left in the pancreatic duct, thereby straightening the common channel and partially occluding the pancreatic orifice, allowing subsequent biliary cannulation alongside the existing pancreatic wire. The double-wire technique has been shown to improve cannulation success compared with standard methods, although some data suggest a higher incidence of PEP with this technique or when a wire is passed into the pancreatic duct. Furthermore, a recent RCT of difficult cannulation cases requiring double-wire technique demonstrated that prophylactic PSP reduced the incidence of PEP in this patient population. Based on this, some experts believe that a prophylactic pancreatic stent should be placed in all patients requiring double-wire cannulation. Others, including the author, however, believe that placement of a wire in the pancreas does not independently predispose to PEP, and that pancreatitis in this context is generally related to the preceding difficult cannulation. If double-wire technique is used early (within two to three cannulation attempts) in a low-risk patient, and the wire advances seamlessly into the pancreatic duct in a typical pancreatic trajectory, PSP may not be necessary if rectal indomethacin is given.

Additional alternative cannulation techniques include wire cannulation alongside a pancreatic stent, precut sphincterotomy, septomotomy, and needle-knife fistulotomy. Although these techniques can be helpful in gaining biliary access during challenging cases, some have been implicated as procedure-related risk factors for PEP. In many cases, however, the risk of PEP is actually driven by the preceding prolonged cannulation time that leads to increasing papillary trauma and edema. Therefore, implementing alternate cannulation techniques early in the case and in rapid succession is an important aspect of reducing PEP. This principle is best demonstrated by a meta-analysis of six randomized trials that showed that early precut sphincterotomy significantly reduced the risk of PEP when compared with repeated standard cannulation attempts (2.5% vs 5.3%; odds ratio, 0.47). Importantly, however, the studies included in this meta-analysis were conducted in mostly low-risk patients, often with favorable anatomy for precut sphincterotomy. Additional observational and randomized data have also suggested that precut sphincterotomy, especially if successful, is not an independent risk factor for PEP. Further studies are needed to help define the exact point at which the risk-benefit ratio favors precut sphincterotomy over repeated cannulation attempts, although the natural tendency to continue standard cannulation attempts beyond 5 to 10 minutes should be controlled, and alternative strategies should be attempted early in a difficult case.

Other technical strategies that reduce the risk of PEP include minimizing the frequency and vigor of pancreatic duct injection, performing SOM using the aspiration technique, and avoiding balloon dilation of an intact sphincter, especially without prophylactic PSP. In coagulopathic patients with choledocholithiasis and native papillae, balloon dilation can be avoided by providing real-time decompression with a bile duct stent and repeating the ERCP with sphincterotomy and stone extraction when coagulation parameters have been restored. If this is not possible, and balloon dilation is mandatory, longer duration dilation (2–5 minutes) seems to result in lower rates of pancreatitis compared with 1-minute dilation. Of note, balloon dilation after biliary sphincterotomy to facilitate large stone extraction does not seem to increase the risk of PEP. All these factors are modifiable and should be considered during every ERCP.