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Adverse Events of ERCP: Prediction, Prevention, and Management
Endoscopic retrograde cholangiopancreatography (ERCP) has evolved from a diagnostic modality to a primarily therapeutic procedure for pancreatic and biliary disorders. ERCP alone or with associated biliary and pancreatic instrumentation and therapy can cause a variety of short-term adverse events, including pancreatitis, hemorrhage, perforation, and cardiopulmonary events ( Box 8.1 ). These adverse events can range from minor, with one or two additional hospital days followed by full recovery, to severe and devastating, with permanent disability or death. Adverse events may cause not only significant morbidity to the patient but also significant anxiety and exposure to medical malpractice claims for the endoscopist.
Box 8.1
Adverse Events of ERCP
-
Pancreatitis
-
Hemorrhage
-
Perforation
-
Cholangitis
-
Cholecystitis
-
Stent-related adverse events
-
Cardiopulmonary adverse events
-
Endoscope-transmitted infection
-
Anesthesia-related adverse events
-
Miscellaneous adverse events
Major advances in the approach to adverse events of ERCP have occurred in several areas: standardized consensus-based definitions of adverse events, large-scale multicenter multivariate analyses that have allowed clearer identification of patient-related and technique-related risk factors for adverse events, and introduction of new devices and techniques to minimize the risks of ERCP-related adverse events.
Definitions of Complications, Adverse Events, Unplanned Events, and Other Negative Outcomes
In 1991, standardized consensus definitions for complications of sphincterotomy were introduced, and although they are widely used ( Table 8.1 ), a consensus definition of adverse events for all endoscopic procedures, including ERCP, has been more recently adopted. Severity is graded primarily on number of hospital days and type of intervention required to treat the complication. This classification allows uniform assessment of outcomes of ERCP and sphincterotomy in various settings. Beyond immediate complications, there is an increasing awareness of the entire spectrum of negative (as well as positive) outcomes, including technical failures, ineffectiveness of the procedure in resolving the presenting complaint, long-term sequelae, costs, extended hospitalization, and patient (dis)satisfaction. Accordingly, the terminology has evolved from complications to adverse events, and more recently to unplanned events. The term adverse event is used throughout this book. Adverse events must be viewed in the context of the entire clinical outcome: a successful procedure with a minor or even a moderate adverse event may sometimes be a preferable outcome to a failed procedure attempt without any obvious adverse event. Failure at ERCP usually leads to a repeated ERCP or to an alternative percutaneous or surgical procedure that may result in significant additional morbidity, hospitalization, and cost.
TABLE 8.1
Consensus Definitions for the Major Adverse Events of ERCP
| Mild | Moderate | Severe | |
|---|---|---|---|
| Pancreatitis | Clinical pancreastitis, amylase at least three times normal more than 24 hours after the procedure, requiring admission or prolongation of planned admission to 2 to 3 days | Pancreatitis requiring hospitalization of 4 to 10 days | Hospitalization for more than 10 days, pseudocyst, or intervention (percutaneous drainage or surgery) |
| Bleeding | Clinical (i.e., not just endoscopic) evidence of bleeding, hemoglobin drop <3 g, no transfusion | Transfusion (4 units or fewer), no angiographic intervention or surgery | Transfusion (5 units or more), or intervention (angiographic or surgical) |
| Perforation | Possible, or only very slight leak of fluid or contrast, treatable by fluids and suction for ≤3 days | Any definite perforation treated medically for 4 to 10 days | Medical treatment for more than 10 days, or intervention (percutaneous or surgical) |
| Infection (cholangitis) | >38°C for 24 to 48 hours | Febrile or septic illness requiring more than 3 days of hospital treatment or percutaneous intervention | Septic shock or surgery |
Any intensive care unit admission after a procedure grades the adverse event as severe. Other rarer adverse events can be graded by length of needed hospitalization.
Analyses of Adverse Event Rates
Reported adverse event rates vary widely, even between prospective studies. In two large prospective studies, pancreatitis rates ranged between 0.74% for diagnostic and 1.4% for therapeutic ERCP, in one study, compared with 5.1% (about 7 times higher) for diagnostic ERCP and 6.9% (5 times higher) for therapeutic ERCP in another prospective study. Reasons for such variation include (1) definitions used; (2) thoroughness of detection; (3) patient-related factors; and (4) procedural variables, such as extent of therapy or use of prophylactic pancreatic stents or nonsteroidal antiinflammatory drugs (NSAIDs). For all of these reasons, it should not be assumed that a lower adverse event rate at one center necessarily reflects better quality of practice.
Most recent studies have used multivariate analysis as a tool to identify and quantify the effect of multiple potentially confounding risk factors, but these are not infallible as many potentially key risk factors were not examined in most studies, and some are overfitted (too many predictor variables for too few outcomes). Only a limited number of studies have included more than 1000 patients. Tables 8.2, 8.3, and 8.4 show summaries of risk factors for adverse events of ERCP and sphincterotomy based on published multivariate analyses.
TABLE 8.2
Risk Factors for Overall Adverse Events of ERCP in Multivariate Analyses
| Definite * | Maybe † | No ‡ |
|---|---|---|
| Suspected sphincter of Oddi dysfunction Cirrhosis Difficult cannulation Precut sphincterotomy Percutaneous biliary access Lower ERCP case volume |
Young age Pancreatic contrast injection Failed biliary drainage Trainee involvement |
Comorbid illness burden Small CBD diameter Female sex Billroth II Periampullary diverticulum |
CBD, Common bile duct.
* Significant by multivariate analysis in most studies.
TABLE 8.3
Risk Factors for Post-ERCP Pancreatitis in Multivariate Analyses
| Definite * | Maybe † | No ‡ |
|---|---|---|
| Suspected sphincter of Oddi dysfunction Young age Normal bilirubin History of post-ERCP pancreatitis Difficult or failed cannulation Pancreatic duct wire passage Pancreatic sphincterotomy (especially minor papilla) Balloon dilation of intact biliary sphincter Precut sphincterotomy Metallic biliary stent |
Female sex Acinarization Absence of CBD stone Lower ERCP case volume Trainee involvement |
Small CBD diameter Sphincter of Oddi manometry Biliary sphincterotomy |
CBD, Common bile duct.
* Significant by multivariate analysis in most studies.
TABLE 8.4
Risk Factors for Hemorrhage After Endoscopic Sphincterotomy in Multivariate Analyses
| Definite * | Maybe † | No ‡ |
|---|---|---|
| Coagulopathy Anticoagulation <3 days after ES Cholangitis before ERCP Bleeding during ES Lower ERCP case volume |
Cirrhosis Dilated CBD CBD stone Periampullary diverticulum Precut sphincterotomy |
Aspirin or NSAID Ampullary tumor Longer length sphincterotomy Extension of prior ES |
CBD, Common bile duct; ES, endoscopic sphincterotomy; NSAID, nonsteroidal antiinflammatory drug.
* Significant by multivariate analysis in most studies.
Overall Adverse Events of ERCP and Sphincterotomy
Most prospective series report an overall short-term adverse event rate for ERCP and/or sphincterotomy of about 5% to 10%. Traditionally there has been a particularly high rate of adverse events for patients with known or suspected sphincter of Oddi dysfunction (up to 20% or more, primarily pancreatitis, with up to 4% severe adverse events) and a very low adverse event rate for routine bile duct stone extraction, especially in tandem with laparoscopic cholecystectomy (less than 5% in most series). Sphincterotomy bleeding occurs primarily in patients with bile duct stones, whereas cholangitis occurs mostly in patients with malignant biliary obstruction.
Summaries of multivariate analyses of risk factors for overall adverse events of ERCP and sphincterotomy are shown in Table 8.2 . Although relevant studies are heterogeneous and sometimes omit potentially key risk factors, several patterns emerge (see Table 8.2 ):
- 1.
Indication of suspected sphincter of Oddi dysfunction was a significant risk factor whenever examined.
- 2.
Technical factors, likely linked to the skill or experience of the endoscopist, were found to be significant risk factors for overall adverse events. These technical factors include difficult cannulation, use of precut or “access” papillotomy to gain bile duct entry, failure to achieve biliary drainage, and use of simultaneous or subsequent percutaneous biliary drainage for otherwise failed endoscopic cannulation. In turn, the ERCP case volume of endoscopists or medical centers, when examined, has almost always been a significant factor in adverse events by both univariate and multivariate analyses.
- 3.
Death from ERCP is rare (less than 0.5%) but has most often been related to cardiopulmonary adverse events, highlighting the need for the endoscopist to pay attention to issues of safety during sedation and monitoring (see Chapter 6 ).
Notably, risk factors found not to be significant are the following: (1) older age or increased number of coexisting medical conditions—on the contrary, younger age generally increases the risk by both univariate and multivariate analyses; (2) smaller bile duct diameter, in contrast to previous observations; and (3) anatomic obstacles such as periampullary diverticulum or Billroth II gastrectomy, although these do increase technical difficulty for the endoscopist.
Pancreatitis
Pancreatitis is the most common adverse event of ERCP, with reported rates ranging from 1% to 40%, with a rate of about 5% being most typical. In the consensus classification, pancreatitis is defined as a clinical syndrome consistent with pancreatitis (i.e., new or worsened abdominal pain) with an amylase at least three times normal more than 24 hours after the procedure, and requiring more than one night of hospitalization (see Table 8.1 ). Some events are difficult to classify in the consensus definitions. Examples include postprocedural abdominal pain and elevation of amylase to just under three times normal, serum lipase more than three times normal with less than three times elevation of amylase, and dramatic enzyme elevations with minimal symptoms that are not clearly suggestive of clinical pancreatitis. There are many potential mechanisms of injury to the pancreas during ERCP and endoscopic sphincterotomy (ES): mechanical, chemical, hydrostatic, enzymatic, microbiologic, and thermal. Although the relative contribution of these mechanisms to post-ERCP is not known, recent multivariate analyses have helped to identify the clinical patient-related and procedure-related factors that are independently associated with pancreatitis. Recent trials have concentrated more on determining the methods of preventing post-ERCP pancreatitis (PEP). Risks and interventions for PEP have been described as the four P's: patient-related factors, procedural techniques, pancreatic stents, and pharmacologic agents.
Patient-Related Risk Factors for Post-ERCP Pancreatitis
The risk of PEP is determined at least as much by the characteristics of the patient as by endoscopic techniques or maneuvers (see Table 8.3 ). Patient-related predictors found to be significant in one or more major studies include younger age, indication of suspected sphincter of Oddi dysfunction, history of previous PEP, and absence of elevated serum bilirubin. Women may have increased risk, but it is difficult to sort out the contribution of sphincter of Oddi dysfunction, a condition that occurs almost exclusively in women. In one meta-analysis, female gender was clearly a risk and accounted for a majority of cases of severe or fatal PEP.
Sphincter of Oddi dysfunction, most often suspected in women with postcholecystectomy abdominal pain (see Chapter 47 ), poses a formidable risk for pancreatitis after any kind of ERCP, whether diagnostic, manometric, or therapeutic. Suspicion of sphincter of Oddi dysfunction independently triples the risk of PEP to about 10% to 30%. The reason for heightened susceptibility in these patients remains unknown. Contrary to the widely held opinion that sphincter of Oddi manometry is the culprit, multivariate analyses show that empirical biliary sphincterotomy or even diagnostic ERCP has similarly high risk in this patient population. With the widespread use of aspiration instead of conventional perfusion manometry catheters (see Chapter 16 ), the risk of manometry has probably been reduced to that of cannulation with any other ERCP accessory. Most previous studies linking manometry with risk have been from tertiary centers in which manometry was always performed in patients with suspected sphincter of Oddi dysfunction, thus losing the ability to separate the contribution of procedural risk from that of patient risk. Two studies specifically compared risk of PEP in patients having ERCP for suspected sphincter of Oddi dysfunction with and without sphincter of Oddi manometry and found no detectable independent effect of manometry on risk. Absence of a stone in patients with suspected choledocholithiasis has been found to be a potent single risk factor for PEP in patients suspected of having stones, thus fitting into the category of possible sphincter of Oddi dysfunction. These observations point out the danger of performing diagnostic ERCP to look for bile duct stones in women with recurrent postcholecystectomy pain, as there is generally a low probability of finding stones in such patients and a high risk of causing pancreatitis. It is an erroneous and potentially dangerous assumption that merely avoiding sphincter of Oddi manometry will significantly reduce risk. These risk factors have been revealed to be additive, thus highlighting the importance of not only identifying risk factors but also abstaining from performing ERCP in cases with marginal indication (see Chapter 7 ). Ironically, people who have these procedures performed for least indicated reasons have higher chances of PEP.
History of previous PEP has been found to be a potential risk factor (odds ratio [OR] is 2.0 to 5.4) and warrants special caution. Advanced chronic pancreatitis, on the other hand, confers some immunity against PEP, perhaps because of atrophy and decreased enzymatic activity. Pancreas divisum is a risk factor only if minor papilla cannulation is attempted.
Despite many early studies suggesting small bile duct diameter to be a risk factor for pancreatitis, most recent studies have shown no independent influence of duct size on risk; small duct diameter may have been a surrogate marker for sphincter of Oddi dysfunction in the earlier studies using only univariate analysis. ERCP for removal of bile duct stones has been found to be relatively safe with respect to pancreatitis rates (<4%) in multicenter studies regardless of bile duct diameter. IPMN with a small pancreatic duct has also been found to be a risk factor for PEP. This is most likely related to the inability of mucus to drain well after instrumentation, despite placement of a prophylactic pancreatic duct stent. Neither the presence of periampullary diverticula nor Billroth II gastrectomy has been found to influence risk of pancreatitis.
A recent study has also shown current smoking and chronic liver disease to be protective against PEP.
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