|Year : 2015 | Volume
| Issue : 1 | Page : 1-10
Risk factors for post-ERCP pancreatitis: a prospective multicenter study in upper Egypt
Mohammed A Omar MD 1, Ahmed E Ahmed1, Omar A Said1, Hussein El-Amin2
1 Department of General Surgery, Faculty of Medicine, Sohag University, Sohag, Egypt
2 Department of Internal Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
|Date of Submission||27-May-2014|
|Date of Acceptance||02-Sep-2014|
|Date of Web Publication||17-Mar-2015|
Mohammed A Omar
Department of General Surgery, Faculty of Medicine, Sohag University, 82511 Sohag
Source of Support: None, Conflict of Interest: None
Background and study aims
Endoscopic retrograde cholangiopancreatography (ERCP) has become widely available for diagnosis and treatment of pancreatic and biliary diseases. Pancreatitis is the most common and serious complication to occur after ERCP resulting in substantial morbidity and occasional mortality. The aim of this study was to evaluate the potential patient and procedure-related risk factors for postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) in a prospective multicenter study.
Patients and methods
Consecutive ERCP procedures were prospectively studied at five centers (two universities, three private). Data were collected on patient characteristics and endoscopic techniques before the procedure, at the time of procedure, and 24-72 h after discharge. PEP was diagnosed and its severity graded according to consensus criteria.
Pancreatitis occurred after 104 (8.9%) of 1162 consecutive ERCP procedures and was graded mild in 66 (63.5%), moderate in 30 (28.8%), and severe in eight (7.7%) cases. On univariate analysis, 11 of 18 evaluated variables were found to be significantly associated with PEP. On multivariate analysis, significant risk factors with adjusted odds ratio (OR) were: difficult cannulation (OR: 10.2), previous PEP (OR: 8.1), previous pancreatitis (OR: 7.9), at least two pancreatic duct injections (OR: 3.1), pancreatic duct cannulation (OR: 2.7), difficult stone extraction (OR: 2.2), and precut sphincterotomy (OR: 1.2).
Technique-related risk factors are probably more numerous and potent than patient-related ones in determining high-risk predictors for PEP.
Keywords: endoscopic retrograde cholangiopancreatography, pancreatitis, risk factors
|How to cite this article:|
Omar MA, Ahmed AE, Said OA, El-Amin H. Risk factors for post-ERCP pancreatitis: a prospective multicenter study in upper Egypt. Egypt J Surg 2015;34:1-10
|How to cite this URL:|
Omar MA, Ahmed AE, Said OA, El-Amin H. Risk factors for post-ERCP pancreatitis: a prospective multicenter study in upper Egypt. Egypt J Surg [serial online] 2015 [cited 2018 Aug 21];34:1-10. Available from: http://www.ejs.eg.net/text.asp?2015/34/1/1/153364
| Introduction|| |
Endoscopic retrograde cholangiopancreatography (ERCP) is one of the most complex endoscopic procedures  . The reported incidence of ERCP-specific complications ranges from 5 to 40%, depending on the complexity of the procedure, the underlying diagnosis, and the patient comorbidities , .
Acute pancreatitis remains the most common and serious complication after ERCP with reported incidence ranging from 1.3 to 15.1% in most prospective series, resulting in substantial morbidity and occasional mortality ,,,,,, . Post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) is defined as acute pancreatitis that has developed de novo following ERCP , . The mechanisms that lead to PEP are complex and not fully understood. Rather than having a single pathogenesis, PEP is believed to be multifactorial, involving a combination of chemical, hydrostatic, enzymatic, mechanical, microbiologic, and thermal factors  .
Several technical and patient-related risk factors for PEP, which act independently or together, have been identified ,, . The most previous studies of PEP have focused primarily on procedural and technical factors. However, it is equally plausible that patient characteristics also account for susceptibility or resistance to PEP  . The reported risk factors vary widely from study to study and these discrepancies may be attributable to differences in criteria used for diagnosis, differences in patient populations, indications, endoscopic techniques, endoscopic expertise, methods of data collection, and the use of preventative techniques such as placement of pancreatic stents ,, . More important, the use of univariate analysis to identify risk factors for PEP may produce misleading results because of inability to sort out confounding variables ,,,, . Recent studies have used multivariate analysis as a tool to identify and quantify the effect of multiple potentially confounding risk factors ,,,,,,,, .
One of the most important steps to prevent PEP is to avoid the procedure altogether whenever possible, especially in patients who are thought to be at high-risk for this complication. Hence, awareness of the risk factors for PEP is essential for the recognition of high-risk cases in which ERCP should be avoided if possible or in which protective endoscopic or pharmacologic interventions should be considered  .
| Aim of the work|| |
The primary goal of this study was a comprehensive, prospective evaluation of risk factors for post-ERCP pancreatitis. To maximize the generalizability of the findings, groups in private practice as well as tertiary referral centers were included. This research attempted to evaluate the commonest postulated risk factors for PEP including patient and procedure-related variables, to generate a multivariate model that could identify the most important determinants of PEP for improving the safety of ERCP.
| Patients and methods|| |
This was a prospective, multicenter study conducted at five centers in Upper Egypt (three private practices, two universities-affiliated teaching hospitals). Of the 1162 consecutive patients scheduled to undergo ERCP, 712 (61.3%) were women and 450 (38.7%) were men, with a mean (± SD) age of 44.8 (± 13.9) years.
Patients were excluded for any of the following reasons:
- Age less than 18 years,
- Mental disability,
- Patients with contraindication to ERCP (coagulopathy, history of contrast dye anaphylaxis, severe cardiopulmonary disease, recent myocardial infarction),
- Acute pancreatitis, cholangitis, or hyperamylasemia at the time of the procedure,
- Certain structural abnormalities of the upper gastrointestinal tract, which increase the risk of the procedure or renders it technically difficult or impossible, for example esophageal stricture,
- Planned biliary stent removal or exchange without planned ductal cannulation,
- Need for emergent ERCP within 12 h, or
- Prophylactic antibiotics. Ethical committee approval and informed written consent were taken before conducting the study at all participating centers.
All ERCP procedures were performed by high-volume endoscopists (who perform more than two sphincterotomies per week  . The data were collected during and after the procedure by the resident doctors who are not involved in the direct patient care and from the hospital reference sheets. All patients were admitted to the hospital at least for 24 h following the procedure to detect early complications. All patients were monitored at least for 6 h in the postoperative recovery room after the procedure to detect early symptoms and signs of pancreatitis then transferred to the inpatient department where they continue to be looked after by the resident for the rest of the 24 h until they can be discharged. Measurement of serum amylase was performed by sampling of blood at 4 h post-ERCP; if the 4 h amylase level was normal or less than three-fold increase, we repeat it on the next day before discharge. Abdominal ultrasonography was routinely performed in all patients suffering from pancreatic-like pain lasting at least 24 h for early detection of PEP. In cases of doubt of developing PEP, abdominal CT scan was performed. If complications arose, patients stayed in the hospital until they recovered.
Bile duct diameter was the measured maximal duct diameter within 2 cm of the papilla adjusted for X-ray magnification. If any stricture was present, bile duct diameter was measured proximal to the stricture , . Cannulation time was measured between the time when the papillotome was advanced out of the endoscope channel, in front of the papilla, and the time when successful deep cannulation was evidenced by injection of contrast  . Total procedure time was measured between the time when the endoscope was advanced in the mouth and the time when the endoscope was advanced out from the mouth  . The number of pancreatic duct contrast injections was the total number of times when any volume of contrast was injected into the pancreatic duct  . Pancreatic cannulation was defined as deep cannulation of the pancreatic duct with any device  . Successful cannulation was defined as free and deep instrumentation of the biliary tree. A cannulation attempt was defined as sustained contact between the cannulating device and the papilla for at least 5 s  . Difficulty of cannulation was determined on the basis of the number of attempts on the major papilla with a cannulation instrument before final: easy (one to five attempts); moderate (six to 15 attempts); and difficult (>15 attempts)  . Difficulty of stone extraction was classified into three degrees: easy (Grade 0), stone extraction with no resistance; moderate (Grade 1), stone extraction with some resistance; difficult (Grade 2), stone extraction after lithotripsy or failed stone extraction.
The generally accepted criteria for the diagnosis of PEP were proposed in 1991 during a consensus workshop  . These criteria include the new onset of pancreatic-type abdominal pain associated with at least a three-fold increase in serum amylase or lipase occurring within 24 h after an ERCP, and the pain symptoms need to be severe enough to require admission to the hospital or to extend the length of stay of patients who are already hospitalized  . Amylase values have been found to peak between 90 min and 4 h post-ERCP  . The serum amylase level measured 4 h after the procedure is the most reliable predictor of PEP , . We therefore used the 4 h amylase level as the most accurate amylase value for predicting subsequent pancreatitis. The severity of pancreatitis was classified on the basis of the length of hospital stay (2-3 days = mild; 4-10 days = moderate; >10 days or complications as hemorrhagic pancreatitis, pancreatic necrosis, pancreatic pseudocyst, or a need for percutaneous drainage or surgery = severe) , . Hyperamylasemia was defined as an increase of serum amylase to greater than the upper limit of normal  .
The primary outcome analyzed was development of PEP. Analysis of risk factors was performed as follows: 18 potentially relevant risk factors were assessed by univariate analysis with the χ2 -test for categorical variables and simple logistic regression for continuous variables. A two-tailed P value of less than 0.05 was considered significant. Significant univariate predictors were then included in a forward stepwise multiple logistic regression model to identify the most important risk factors for pancreatitis. Goodness-of-fit for the final multivariate model was assessed by the two-log likelihood criterion.
| Results|| |
This was a descriptive single-arm prospective study that included 1162 patients subjected for ERCP between June 2009 and June 2013 ([Table 1]). ERCP was carried out to all patients (1162); cannulation of the papilla of Vater was successful in 1124 patients (96.7%) and failed in 38 patients (3.3%), 20 cases after trials of standard cannulation and 18 cases after precut sphincterotomy ([Table 2]).
The patient-related risk factors that were evaluated for PEP are: age, sex, previous pancreatitis, previous PEP, previous cholecystectomy, previous sphincterotomy, total serum bilirubin, common bile duct (CBD) diameter, and nature of the disease. The technique-related risk factors that were evaluated for PEP are: total procedure time, cannulation time, degree of difficulty of cannulation, number of pancreatic duct cannulation, number of pancreatic duct injection, biliary sphincterotomy, precut sphincterotomy, balloon dilatation, and degree of difficulty of stone extraction.
Serum amylase level was estimated 4 h after ERCP, and accordingly patients were divided into three groups:
- Patients with no hyperamylasemia (normal serum amylase level),
- Patients with hyperamylasemia (serum amylase level less than three times the upper limit of normal=asymptomatic hyperamylasemia), and
- Patients with hyperamylasemia (serum amylase level equal to or greater than three times the upper limit of normal = acute pancreatitis).
Upon studying patients after ERCP, 290 patients (25%) had no hyperamylasemia, 768 patients (66.1%) had asymptomatic hyperamylasemia, and 104 patients (8.9%) had acute pancreatitis [Assiut University Hospital 54 patients (9.1%), Sohag University Hospital 22 patients (8.2%), and the private centers: 10 (8.5%), 9 (8.7%), 9 (11%)]. All patients with an increase of serum amylase of three folds or more had epigastric pain radiating to the back persistent for 24 h (acute pancreatitis).
Upon studying patients with PEP according to the length of hospital stay, PEP was mild in 66 patients (63.5%), moderate in 30 patients (28.8%), and severe in eight patients (7.7%). Pancreatitis-related median hospital stay was 2.9, 9.5, and 17.5 days for mild, moderate, and severe disease, respectively. The PEP-related mortality rate was 1.9% (two cases) due to severe acute pancreatitis. No deaths were reported for mild or moderate pancreatitis.
Of 18 evaluated risk factors for PEP, 11 risk factors were found to be significantly associated with PEP: four patient-related risk factors (age, female sex, previous pancreatitis, and previous PEP) and seven procedure-related risk factors (difficult stone extraction, difficult cannulation, pancreatic duct cannulation, ≥2 pancreatic duct contrast injections, precut sphincterotomy, cannulation time, and total procedure time) ([Table 3] and [Table 4]).
|Table 3 Univariate analysis of risk factors for postendoscopic retrograde cholangiopancreatography pancreatitis|
Click here to view
|Table 4 Pancreatitis rates in with respect to the number of attempts at cannulation with and without precutting|
Click here to view
The variables found to be significant in univariate analyses were taken as candidate explanatory variables in a multivariate logistic regression analysis to identify those risk factors associated with an increased risk for PEP in a multivariate setting and to estimate their independent contributions adjusted for the effects of each of the other factors. Seven risk factors were identified to be independently associated with pancreatitis; two were patient-related risk factors and five were procedure-related risk factors ([Table 5]).
|Table 5 Multivariate logistic regression analysis of factors that predict postendoscopic retrograde cholangiopancreatography pancreatitis|
Click here to view
| Discussion|| |
Acute pancreatitis remains the most common and serious complication after ERCP. Awareness of the risk factors for PEP is essential for the recognition of high-risk cases in which ERCP should be avoided if possible or in which protective endoscopic or pharmacologic interventions should be considered. Risk factors for developing PEP have been assessed in various studies and include patient and procedure-related risk factors  .
Both PEP and asymptomatic hyperamylasemia occur because of injury to the pancreatic tissue induced by ERCP techniques, but the reason why some patients eventually develop pancreatitis and other asymptomatic hyperamylasemia remains unknown. The underlying mechanisms of the two vastly different clinical courses may include two respects: one may be attributable to the difference in the severity of the injury to the pancreas and the other to the difference in the magnitude of inflammatory response to the injury to pancreas. Asymptomatic hyperamylasemia is associated with mild injury to pancreas, perhaps without inflammatory response to pancreas. Pancreatitis may be associated with more severe injury to pancreas, meanwhile with inflammatory response to pancreas  .
Post-ERCP hyperamylasemia was reported by many authors to be extremely common reaching up to 70% ,,,, . The finding of post-ERCP hyperamylasemia is attributed to maneuvers used during ERCP as manipulation of the papilla during difficult cannulation, pancreatic duct cannulation or injection, precut sphincterotomy, balloon dilatation, and extraction of large stones. The mechanical trauma to the papilla or pancreatic sphincter during instrumentation may cause transient obstruction of outflow of pancreatic juice. In addition, subjecting the pancreatic duct to a sudden increase in pressure may be the cause of post-ERCP hyperamylasemia. Passage of common bile duct stones is also known to cause hyperamylasemia  .
All patients who had increase in serum amylase at least three times the upper normal limit developed clinical symptoms of acute pancreatitis lasting at least 24 h. None of patients developing increase in amylase level less than three times the upper normal limit had clinically relevant acute pancreatitis. These results are in agreement with the previous authors who found out that increased amylase level at least three times the upper normal limit is predictive of acute pancreatitis ,, .
The incidence of PEP ranged from 1.3 to 15.1% in most prospective series  . Higher rates reach up to 40% reported in certain series ,, . In our study, the incidences of PEP are still largely in agreement and comparable with the previous reports and agreed with the internationally acceptable norms; it was 8.9% of the cases (mild = 63.5%, moderate = 28.8%, and severe = 7.7%).
Younger age was associated with a high risk for pancreatitis only in the univariate analysis. This result is consistent with multiple studies showing that younger age was found to be a significant risk factor by univariate analysis but not by multivariate model ,, . There was an inverse relationship between the age and the occurrence of PEP (the younger the patient, the higher the percentage of pancreatitis). Younger age was first identified as an independent risk factor for PEP in a multicenter study in 1996  , and subsequently confirmed in four other multivariate analyses ,,, . The higher risk may be explained by the progressive decline in pancreatic exocrine function with aging that may protect older patients from pancreatic injury  . In contrast, one recent study revealed that age of 60 years or less is not associated with any clinically significant risk for PEP  . Another study reported that age less than 25 years was a high risk factor for PEP  . In addition, Nishino et al.'s  study concluded that one of the patient-related risk factors was age more than 65 years.
Female sex was a significant risk factor for PEP in univariate but not in multivariate analysis, and this result is in agreement with a large multicenter study  . Our study disagrees with the studies reporting that female individuals appear to be at higher risk for developing postprocedural pancreatitis compared with male individuals in both univariate and multivariate analysis ,,,,, . However, most previous studies have demonstrated a higher risk in patients with Sphincter of Oddi More Details dysfunction (SOD) ,, , a condition that occurs primarily in women  . In contrast, Testoni et al.  revealed that female sex was not associated with any clinically significant risk for PEP.
Past history of pancreatitis was a highly significant risk factor for PEP, and these findings are consistent with several recent multivariate risk factor studies ,,, . Our analysis showed that the risk in such patients was increased eight-fold [odds ratio (OR): 7.9]. In contrast, our results are inconsistent with the studies by Freeman et al.  , Freeman et al.  , Friedland et al.  , and Testoni et al.  , which revealed that history of previous pancreatitis is only a significant risk factor by univariate analysis. In addition, history of previous PEP was found to be a highly significant factor for PEP with eight-fold risk (OR: 8.1), and these findings are consistent with several multivariate risk factors studies ,,,,,, . In contrast, a recent multivariate study revealed that history of PEP was not a significant risk factor for PEP  . The previous two findings suggest that certain individuals have a 'reactive' pancreas that places them at particular risk beyond that conferred by other definable risk factors  .
History of previous cholecystectomy was found to be insignificant risk factor for PEP. This result is in agreement with a recent multivariate study  . In contrast, the results obtained by Freeman et al.  and Cheng et al.  showed that prior cholecystectomy is a significant risk factor for PEP in univariate but not in multivariate analysis. In addition, history of previous sphincterotomy was found to be insignificant risk factor for PEP. This result is in agreement with two multivariate studies , .
No relationship was found between total serum bilirubin level and the rate of occurrence of pancreatitis after ERCP. Similarly, most studies agreed that hyperbilirubinemia is not a risk factor for pancreatitis  . Some studies showed that normal bilirubin level at the time of ERCP would independently increase the risk for PEP ,,, ; another one showed that normal bilirubin was not associated with any clinically significant risk for PEP  . None of the patients included in our study had normal serum bilirubin level at the time of the procedure.
Common bile duct diameter was insignificant risk factor for PEP. This result is in agreement with most studies that have found no independent influence of duct size on the risk for PEP ,,,,,,,,, . In contrast, many early studies suggested small CBD diameter as a risk factor for pancreatitis ,,, . The original descriptions of small CBD diameter as a risk factor came from centers with a preponderance of patients with sphincter dysfunction, most of whom also had nondilated bile ducts. Perhaps, small bile duct diameter has appeared to be important because it was a surrogate marker for absence of elevated serum bilirubin, presence of SOD, or female sex  .
No significant difference was found between benign and malignant nature of the disease with respect to PEP. This result is in agreement with the only study comparing the relationship of nature of the disease and PEP  . The higher incidence of pancreatitis in patients with benign obstructive jaundice in comparison with patients with malignant obstructive jaundice may be attributed to gallstones (the commonest indication in patients with benign obstructive jaundice), which increases the risk for pancreatitis. Proposed mechanisms include reflux of noxious bile into the pancreatic duct from transient obstruction of the ampulla during gallstone passage and pancreatic ductal hypertension from either a stone impacted at the ampulla or ampullary trauma caused by stone passage  . In addition, patients with pancreatic malignancy appear to be at decreased risk for PEP, likely because of chronic obstruction of the pancreatic duct along with atrophy of the upstream pancreatic parenchyma  .
Standard sphincterotomy was insignificant risk factor for PEP. This result is consistent with the previous data confirming that the performance of biliary sphincterotomy does not appear to add significant independent risk for pancreatitis after ERCP ,,,, . In certain circumstances, biliary sphincterotomy may be protective; pancreatitis occurred in four of 24 patients (17%) who had plastic biliary stents placed for hilar strictures without a sphincterotomy versus none (0%) of 59 in whom a sphincterotomy was performed, suggesting that a fulcrum effect of the proximal stricture on the large-caliber biliary stent, pushing it against the pancreatic duct orifice in the intact papilla, led to the increase in frequency of pancreatitis and that this could be precluded by biliary sphincterotomy  .
Precut sphincterotomy was a barely significant (OR: 1.2) risk factor for PEP. There is controversy in the literature regarding the relationship of precut sphincterotomy with the occurrence of pancreatitis and other complications ,,,, . Many authors reported that precut sphincterotomy was an independent risk factor for PEP ,,,,,, . It has been controversial whether higher rates of complications and pancreatitis after precut sphincterotomy are because of the precut itself, the antecedent repeated cannulation attempts, the indication for the procedure (most risky with SOD in the absence of pancreatic stenting), other anatomic factors such as small papillas, or the thermal injury to the pancreatic sphincter causing edema and duct obstruction , .
Our study also confirmed that early precut was safer than either delayed precut or multiple attempts at cannulating the papilla (6.9 vs. 25.6 and 28.6%), supporting the concept that, in expert hands, precut might be preferable to repeated cannulation attempts, especially in patients at high risk for postprocedure pancreatitis. This result is compatible with two recent meta-analyses; the first showed that PEP developed in 2.5% of patients randomized to early needle-knife sphincterotomy compared with 5.3% of patients who underwent persistent cannulation attempts before needle-knife sphincterotomy  and the second concluded that early needle-knife sphincterotomy significantly reduced the rate of PEP from 5.4 to 2.5%  . In addition, a recent retrospective study demonstrated that the rate of PEP was lower when this technique was performed with less than 10 cannulation attempts compared with 10 or more cannulation attempts without precutting  .
In contrast, in many series from tertiary referral centers, the complication rate for precut sphincterotomy was no different than that for standard sphincterotomy ,,,,,,, , suggesting that risk for precut sphincterotomy is highly operator-dependent. In addition, this result disagree with the result of Freeman et al.  who concluded that precut access was associated with higher univariate but no independent risk for pancreatitis; however, most of these procedures were performed by a few highly experienced endoscopists and often included placement of a pancreatic stent.
Balloon dilatation of the CBD orifice for stone extraction was insignificant risk factor for PEP. This result was consistent with several studies that have demonstrated that balloon dilatation of the distal CBD and ampulla can be a well-tolerated and effective technique for the removal of biliary stones without increasing the rate of PEP ,,,,,, . In contrast, other studies showed that balloon dilatation has been associated with a markedly increased risk for PEP ,,, .
The duration of the whole procedure and the cannulation time were significant risk factors for pancreatitis in univariate but not in multivariate analysis, and this result is compatible with those obtained by two large studies , . Average ERCP and cannulation times were reported as 18 and 4 min by Penaloza-Ramirez et al.  , and similar average durations of 16.5 and 3 min were determined by Sabri et al.  . Our results revealed that average ERCP and cannulation times were 28 and 5 min, and this disagreement may be explained by trainees' participation.
Difficult cannulation was the highest significant independent risk factor for PEP. More than 15 attempts at cannulating the Vater's papilla increased the risk for pancreatitis about 10-folds (OR: 10.2); interestingly, the risk rate showed a linear progression either between five or less attempts and six to 15 attempts (OR: 3.1) or between six to 15 and greater than 15 attempts (OR: 10.2). PEP had inverse relationship with the difficulty of cannulation (the higher the difficulty of cannulation, the higher the incidence of pancreatitis). Pancreatitis occurred in 4.8% of cannulation rated as easy, 9.3% of those considered to be moderately difficult, and 25% of cases when cannulation was considered difficult. The high incidence of pancreatitis after repeated attempts at cannulating, independently of pancreatic duct contrast injection, confirms that papillary edema-related and sphincter hypertension-related impairment of pancreatic drainage resulting from the extent of manipulation and repeated trauma of the papilla using guide wires and cannulation devices, rather than hydrostatic ductal and contrast agent injury, is a major factor. The fact that difficult cannulation did not reach significance as a risk factor in a study where prophylactic pancreatic stents were frequently used further confirms this  . These data also suggest that alternative techniques, such as precut sphincterotomy, should be adopted in cases with difficult cannulation, rather than insisting with multiple attempts, and confirm the preventive role of early precut in reducing the risk for pancreatitis, as in another study  .
The difficulty of cannulation is not easily quantifiable and interactions with time for cannulation, method of cannulation, and number of pancreatic duct injections may occur  . Most studies came to similar results, namely difficulty in cannulation, which can produce papillary trauma, proved to be an independent risk factor for procedural complications and this risk should increase with the number of failed cannulations ,,,,, . Although the difficulty of cannulation was all judged by the number of cannulation attempts in previous studies, the cutoff numbers vary widely, with six attempts in two studies, eight attempts in one study, and 20 attempts in another study ,,, .
Pancreatic duct cannulation was a significant risk factor in both univariate and multivariate analyses (OR: 2.7). This is most probably due to manipulation of pancreatic duct and pancreatic sphincter leading to subsequent spasm of pancreatic duct and obstruction of the flow of pancreatic enzymes. In addition, injury to the pancreatic duct and pancreatic parenchyma may cause premature activation of pancreatic enzymes leading to autodigestion of the pancreas. This finding agrees with that reported by Freeman et al.  stating that pancreatic duct deep cannulation is significantly associated with the risk for PEP.
Pancreatic duct injection (≥2) was an independent risk factor for PEP with a three-fold increase in risk (OR: 3.1), and this result is compatible with most previous reports ,,,,,, . In contrast, Wang et al.  concluded that pancreatic duct injection was significant only by univariate but not by multivariate analysis. They explained their result by the frequent use of guide wires cannulation that minimizes the unintentional injections into the pancreatic duct  .
Difficult stone extraction was a significant risk factor by both univariate and multivariate analyses (OR: 2.6). PEP had inverse relationship with the degree of difficulty of stone extraction (the higher the difficulty of stone extraction, the higher the incidence of pancreatitis). In our study, pancreatitis occurred in 1.6% of extraction rated as easy, 6.1% of those considered to be moderately difficult, and 24.2% of cases when extraction was considered difficult. This result may be explained by repeated trauma during trial of extraction and prolonged cannulation and procedure time.
Trainee participation has been previously evaluated in three large multicenter studies, and the result showed that it was not a significant risk factor for PEP ,, . In another report, the complications of ERCP performed solely by attending physician were not significantly different from those performed by fellows under the supervision of attending endoscopists  . Similarly, in our series, trainee participation did not increase the risk for PEP in univariate or multivariate analysis.
Data from this study can be used by the clinician to decide whether or not to recommend ERCP for an individual patient. Intraoperative laparoscopic cholangiography, MRCP, and EUS all have accuracy rates rivaling that of ERCP and are becoming widely available. These techniques may be preferable to ERCP for patients with equivocal evidence of biliary obstruction, especially those at high risk for PEP. If pathologic obstruction such as a stone is definitely identified by one of these methods, then conventional ERCP is indicated. If no pathologic obstruction is found, then ERCP should be avoided altogether or direct referral to a center with extensive experience with manometric and pancreatic therapeutic ERCP should be considered. These data can be used by the endoscopist to decide how an ERCP will be performed. In high-risk patients, prolonged efforts at cannulation and the use of high-risk maneuvers such as precut sphincterotomy should be avoided. The current data may also be useful with respect to studies on the use of pharmacologic agents to reduce PEP. Until a cost-effective agent that prevents post-ERCP pancreatitis is found, the primary hope for reducing the burden of morbidity from ERCP lies in knowledge of the risk factors and the understanding that this knowledge will be used in deciding whether an ERCP is necessary, and, if so, how best to perform the procedure.
| Conclusion|| |
Multivariate analysis indicates that technique-related risk factors are probably more numerous and potent than patient-related ones in the risk for PEP. All patients should be followed by 4 h serum amylase after ERCP for early identification of patients with PEP for early and adequate management. The most important risk factors for PEP are difficult cannulation, previous history of pancreatitis and PEP, pancreatic duct cannulation and injections, difficult stone extraction, and precut sphincterotomy.
| Acknowledgements|| |
Conflicts of interest
| References|| |
Freeman ML, Guda NM ERCP cannulation, a review of reported techniques. Gastrointest Endosc 2005; 61: 112-125.
Vandervoort J, Soetikno RM, Tham TC, et al.
Risk factors for complications after performance of ERCP. Gastrointest Endosc 2002; 56: 652-656.
Jaik NP, Hoey BA, Stawicki SP Evolving role of endoscopic retrograde cholangiopancreatography in management of extrahepatic ductal injuries due to blunt trauma: diagnostic and treatment algorithms. HPB Surg 2008; 2: 59-141.
Freeman ML, Nelson DB, Sherman S, et al.
Complications of endoscopic biliary sphincterotomy. N Engl J Med 1996; 335: 909-918.
Loperfido S, Angelini G, Benedetti G, et al.
Major early complications from diagnostic and therapeutic ERCP: a prospective multicenter study. Gastrointest Endosc 1998; 48: 1- 10.
Freeman ML, DiSario JA, Nelson DB, et al.
Risk factors for post-ERCP pancreatitis: a prospective, multicenter study. Gastrointest Endosc 2001; 54: 425-434.
Masci E, Toti G, Mariani A, et al.
Complications of diagnostic and therapeutic ERCP: a prospective multicenter study. Am J Gastroenterol 2001; 96: 417-423.
Vandervoort J, Tham TCK, Wong RCK, et al.
Prospective analysis of risk factors for pancreatitis after diagnostic and therapeutic ERCP [abstract]. Gastrointest Endosc 1996; 43: AB400.
Cheng CL, Sherman S, Watkins JL, et al.
Risk factors for post-ERCP pancreatitis: a prospective multicenter study. Am J Gastroenterol 2006; 101: 139-147.
Williams EJ, Taylor S, Fairclough P, et al.
Risk factors for complication following ERCP; results of a large-scale, prospective multicenter study. Endoscopy 2007; 39: 793 -801.
Wang P, Li ZS, Liu F, et al.
risk factors for ERCP-related complications: a prospective multicenter study. Am J Gastroenterol 2009; 104: 31-40.
Gottlieb K, Sherman S ERCP and biliary endoscopic sphincterotomy-induced pancreatitis. Gastrointest Endosc Clin N Am 1998; 8: 87-114.
Cotton PB, Lehman G, Vennes AJ, et al.
Endoscopic sphincterotomy complications and their management: an attempt at consensus. Gastrointest Endosc 1991; 37: 383-391.
Masci E, Mariani A, Curioni S, et al.
Risk factors for pancreatitis following endoscopic retrograde cholangiopancreatography: a meta-analysis. Endoscopy. 2003; 35: 830-834.
Testoni PA, Bagnolo F, Caporuscio S, et al.
Serum amylase measured four hours after endoscopic sphincterotomy is a reliable predictor of post-procedure pancreatitis. Am J Gastroenterol 1999; 94: 1235-1241.
Andriulli A, Leandro G, Federici T, et al.
Prophylactic administration of somatostatin or gabexate does not prevent pancreatitis after ERCP: an updated meta-analysis. Gastrointest Endosc 2007; 65: 624-632.
Cha SW, Leung WD, Lehman GA, et al.
Does leaving a main pancreatic duct stent in place reduce the incidence of precut biliary sphincterotomy-associated pancreatitis? A randomized, prospective study. Gastrointest Endosc 2013; 77: 209-216.
Sherman S, Lehman GA ERCP- and endoscopic sphincterotomy. Gastrointest Endosc 1991; 44: 339-342.
Wilson MS, Tweedle DE, Martin DF Common bile duct diameter and complications of endoscopic sphincterotomy. Br J Surg 1992; 79: 1346-1347.
Chen YK, Foliente RL, Santoro MJ, et al.
Endoscopic sphincterotomy-induced pancreatitis: Increased risk associated with non dilated bile ducts and sphincter of Oddi dysfunction. Am J Gastroenterol 1994; 89: 327-333.
Johnson GK, Geenen JE, Johanson JF, et al.
Evaluation of post-ERCP pancreatitis: potential causes noted during controlled study of differing contrast media. Gastrointest Endosc 1997; 46: 217-222.
Tarnasky P, Cunningham J, Cotton P, et al.
Pancreatic sphincter hypertension increases the risk of post-ERCP pancreatitis. Endoscopy 1997; 29: 252-257.
Mehta SN, Pavone E, Barkun JS, et al.
Predictors of post-ERCP complications in patients with suspected choledocholithiasis. Endoscopy 1998; 30: 457-463.
Maldonado ME, Brady PG, Mamel JJ, et al.
Incidence of pancreatitis in patients undergoing sphincter of Oddi manometry. Am J Gastroenterol 1999; 94: 387-390.
Rabenstein T, Schneider HT, Bulling D, et al.
Analysis of the risk factors associated with endoscopic sphincterotomy techniques: preliminary results of a prospective study, with emphasis on the reduced risk of acute pancreatitis with low-dose anticoagulation treatment. Endoscopy 2000; 32: 10-19.
Andriulli A, Clemente R, Solmi L, et al.
Gabexate or somatostatin administration before ERCP in patients at high risk for post-ERCP pancreatitis: a multicenter, placebo-controlled, randomized clinical trial. Gastrointest Endosc 2002; 56: 488-495.
Cohen S, Bacon BR, Berlin JA, et al.
National institutes of Health State-of-the-Science Conference Statement: ERCP for diagnosis and therapy, Gastrointest Endosc 2002; 56: 803-809.
Adam AB, Michael JB, Arthur JK, et al.
Needle-knife sphincterotomy: factors predicting its use and the relationship with post-ERCP pancreatitis. Gastrointest Endosc 2009; 71: 266-271.
Ito K, Fujita N, Noda Y, et al.
Relationship between post-ERCP pancreatitis and the change of serum amylase level after the procedure, World J Gastroenterol 2007;13: 3855-3860.
Thomas PR, Sengupta S Prediction of pancreatitis following endoscopic retrograde cholangiopancreatography by the 4-h post procedure amylase level. J Gastroenterol Hepatol 2001; 16: 923-926.
Sutton VR, Hong MKY, Thomas PR: Using the 4-hour post-ercp amylase level to predict post-ERCP pancreatitis. JOP 2011; 12: 372-376.
Testoni PA, Bagnolol F, Natale C, et al.
Incidence of post-endoscopic retrograde cholangiopancreatography/sphincterotomy pancreatitis depends upon definition criteria. Dig Liver Dis 2000; 32: 412-418.
Cooper ST, Slivka A Incidence, risk factors, and prevention of post-ERCP pancreatitis. Gastroenterol Clin North Am. 2007; 36: 259-276.
Chen YK, Pleskow DK Spy Glass single-operator peroral cholangiopancreatoscopy system for the diagnosis and therapy of bile-duct disorders: a clinical feasibility study (with video). Gastrointest Endosc 2007; 65: 832-841.
Freeman ML Adverse outcomes of ERCP. Gastrointest Endosc 2002; 56: S273-S282.
Testoni PA, Bagnolo F Pain at 24 h associated with amylase levels greater than 5 times the upper normal limit as the most reliable indicator of post-ERCP pancreatitis. Gastrointest Endosc 2001; 53: 33-39.
Testoni PA, Mariani A, Giussani A, et al.
Risk factors for post-ERCP pancreatitis in high- and low-volume centers and among expert and non-expert operators: a prospective multicenter study. Am J Gastroenterol 2010; 105: 1753-1761.
Sherman S, Lehman GA, Freeman ML, et al.
Risk factors for post-ERCP pancreatitis: a prospective multicenter study [abstract]. Am J Gastroenterol 1997; 92: 1639.
Cotton PB, Garrow DA, Gallagher J, et al.
Risk factors for complications after ERCP: a multivariate analysis of 11497 procedures over 12 years. Gastrointest Endosc 2009; 70: 80-88.
Dickinson RJ, Davies S Post-ERCP pancreatitis and hyperamylasemia: the role of operative and patient factors. Eur J Gastroenterol Hepatol 1998; 10: 423-428.
Laugier R, Bernard JP, Berthezene P, et al.
Changes in pancreatic exocrine secretion with age: Pancreatic exocrine secretion does decrease in the elderly. Digestion 1991; 50: 202-211.
Nishino T, Toki F, Oyama H, et al.
More accurate prediction of post-ERCP pancreatitis by 4-H serum lipase levels than amylase levels. Dig Endosc 2008; 9: 169-177.
Christoforidis E, Goulimaris I, Kanellos I, et al.
Post-ERCP pancreatitis and hyperamylasemia: patient-related and operative risk factors. Endoscopy 2002; 34: 286-292.
Moffatt DC, Cote´ GA, Avula H, et al.
Risk factors for ERCP-related complications in patients with pancreas divisum: a retrospective study. Gastrointest Endosc 2011; 73: 963-970.
Kozarek RA Biliary dyskinesia: are we any closer to defining the entity? Gastrointest Endosc Clin N Am 1993; 3: 167-178.
Debenedet AT, Raghunathan TE, Wing JJ, et al.
Alcohol use and cigarette smoking as risk factors for post endoscopic retrograde cholangiopancreatography pancreatitis. Clin Gastroenterol Hepatol 2009; 7: 353e4-358e4.
Friedland S, Soetikno RM, Vandervoort J, et al.
Bedside scoring system to predict the risk of developing pancreatitis following ERCP. Endoscopy 2002; 34: 483-488.
Freeman ML, Guda MN Prevention of post-ERCP pancreatitis: a comprehensive review. Gastrointest Endosc 2004; 7: 854-864.
Hiroyuki M, Akira F, Hideyuki K, et al.
Risk of pancreatitis after endoscopic retrograde cholangiopancreatography and endoscopic biliary drainage. HPB (Oxford) 2009; 11: 222-228.
Cappell MS Acute pancreatitis: etiology, clinical presentation, diagnosis, and therapy. Med Clin North Am 2008; 92: 889- 923.
Banerjee N, Hilden K, Baron TH, et al.
Endoscopic biliary sphincterotomy is not required for transpapillary SEMS placement for biliary obstruction. Dig Dis Sci 2011; 56: 591-595.
Tarnasky PR, Cunningham J, Hawes RH, et al.
Transpapillary stenting of proximal biliary strictures: does biliary sphincterotomy reduce the risk of post-procedure pancreatitis? Gastrointest Endosc 1997; 45: 46-51.
Cotton PB Precut papillotomy: a risky technique for experts only. Gastrointest Endosc 1989; 35: 578-579.
Vandervoort J, Carr-Locke DL Needle-knife access papillotomy: an unfairly maligned technique? Endoscopy 1996; 28: 365-366.
Baillie J Treatment of acute biliary pancreatitis [editorial]. N Engl J Med 1997; 336: 286-287.
Freeman ML Precut (access) sphincterotomy. Tech Gastrointest Endosc 1999; 1: 40-48.
Desilets DJ, Howell DA Precut sphincterotomy: another perspective on efficacy and complications. Up To Date [serial online] 2004; 11, 3.
Tzovaras G, Shukla P, Kow L, et al.
What are the risks of diagnostic and therapeutic endoscopic retrograde cholangiopancreatography? Aust N Z J Surg 2000; 70: 778-782.
Haber GB Prevention of post ERCP pancreatitis. Gastrointest Endosc 2000; 51: 100-103.
Sriram PVJ, Rao GV, Reddy DN The precut - when, where and how? A review. Endoscopy 2003; 35: 24-30.
Cennamo V, Fuccio L, Zagari RM, et al.
Can early precut implementation reduce endoscopic retrograde cholangiopancreatography-related complication risk? Meta-analysis of randomized controlled trials. Endoscopy 2010; 42: 381-388.
Gong B, Hao L, Bie L, et al.
Does precut technique improve selective bile duct cannulation or increase post-ERCP pancreatitis rate? A meta-analysis of randomized controlled trials. Surg Endosc 2010; 24: 2670-2680.
Testoni PA, Giussani A, Vailati C, et al.
Precut sphincterotomy, repeated cannulation and post-ERCP pancreatitis in patients with bile duct stone disease. Dig Liver Dis 2011; 43: 792-796.
Huibregtse K, Katon RM, Tytgat GN Precut papillotomy via fine needle-knife papillotome: a safe and effective technique. Gastrointest Endosc 1986; 32: 403-405.
Foutch PG A prospective assessment of results for needle-knife papillotomy and standard endoscopic sphincterotomy. Gastrointest Endosc 1995; 41: 25-32.
Binmoeller KF, Seifert H, Gerke H, et al.
Papillary roof incision using the Erlangen-type pre-cut papillotome to achieve bile duct cannulation. Gastrointest Endosc 1996; 44: 689-695.
Tang SJ, Haber GB, Kortan P, et al.
Precut papillotomy vs. persistence in difficult biliary cannulation: a prospective randomized trial. Endoscopy 2005; 37: 58-65.
MacMathuna PM, White P, Clarke E, et al.
Endoscopic balloon sphincteroplasty (papillary dilation) for bile duct stones: efficacy, safety, and follow-up in 100 patients. Gastrointest Endosc 1995; 42: 468-474.
Bergman JJ, Rauws EA, Fockens P, et al.
Randomized trial of endoscopic balloon dilation versus endoscopic sphincterotomy for removal of bile duct stones. Lancet 1997; 349: 1124-1129.
Ochi Y, Mukawa K, Kiyosawa K, et al.
Comparing the treatment outcomes of endoscopic papillary dilation and endoscopic sphincterotomy for removal of bile duct stones. J Gastroenterol Hepatol 1999; 14: 90-96.
Fujita N, Maguchi H, Komatsu Y, et al.
Endoscopic sphincterotomy and endoscopic papillary balloon dilatation for bile duct stones: a prospective randomized controlled multicenter trial. Gastrointest Endosc 2003; 57: 151-155.
Vlavianos P, Chopra K, Mandalia S, et al.
Endoscopic balloon dilatation versus endoscopic sphincterotomy for the removal of bile duct stones: a prospective randomized trial. Gut 2003; 52: 1165-1169.
Maydeo A, Bhandari S Balloon sphincteroplasty for removing difficult bile duct stones, Endoscopy 2007; 39: 958-961.
Watanabe H, Yoneda M, Tominaga K, et al.
Comparison between endoscopic papillary balloon dilatation and endoscopic sphincterotomy for the treatment of common bile duct stones. J Gastroenterol 2007; 42: 56-62.
DiSario JA, Freeman ML, Bjorkman DJ, et al.
Endoscopic balloon dilation compared to sphincterotomy (EDES) for extraction of bile duct stones: preliminary results. Gastrointest Endosc 1997; 45: AB129.
Baron TH, Harewood GC Endoscopic balloon dilation of the biliary sphincter compared to endoscopic biliary sphincterotomy for removal of common bile duct stones during ERCP: a meta analysis of randomized, controlled trials. Am J Gastroenterol 2004; 99: 1455-1460.
Disario JA, Freeman ML, Bjorkman DJ, et al.
Endoscopic balloon dilation compared with sphincterotomy for extraction of bile duct stones. Gastroenterology 2004; 127: 1291-1299.
Penaloza-Ramirez A, Leal-Buitrago C, Rodriguez-Hernandez A Adverse events of ERCP at San Jose Hospital of Bogota (Colombia). Rev Esp Enferm Dig 2009; 101: 837-849.
Sabri S, Mehmet I, Abdulmecit K Endoscopic retrograde cholangiopancreatography (ERCP): outcomes of 3136 cases over 10 years. Turk J Med Sci 2011; 41: 615-621.
Cennamo V, Fuccio L, Repici A et al.
Timing of precut procedure does not influence success rate and complications of ERCP procedure: a prospective randomized comparative study. Gastrointest Endosc 2009; 69: 473-479.
Aronson N, Flamm CR, Bohn RL, et al.
Evidence-based assessment: patient, procedure, or operator factors associated with ERCP complications. Gastrointest Endosc 2002; 56: S294-S302.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]