Identification of risk factors for post-endoscopic retrograde cholangiopancreatography pancreatitis in a high volume center

Background/Objectives Pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Several patients´ or procedure related risk factors for post-ERCP pancreatitis (PEP) have been suggested. The aim of this study was to validate the risk factors for PEP in a high-volume center. Methods All patients undergoing first time ERCP at a tertiary referral center between December 2010 and October 2013 were retrospectively included. PEP was defined according to the Atlanta Classification. Results 404 patients were included in the final analysis. The risk to develop PEP was increased in patients after inadvertent cannulation of the pancreatic duct (odds ratio 7.468 (2.792–19.975); p<0.001), which occurred in 37.4% of the patients. Inadvertent cannulation occurred significantly more frequently in patients with difficult cannulation of the papilla duodeni major (odds ratio 7.3; p<0.001). Conclusion Inadvertent cannulation of the pancreatic duct is a procedure related risk factor for PEP. Measurements on preventing inadvertent cannulation of the pancreatic duct should be established and studies on prophylactic measurements should focus particularly on patients with inadvertent cannulation of the pancreatic duct.


Introduction
Endoscopic retrograde cholangiopancreatography (ERCP) is a well-established therapeutic procedure for benign and malignant diseases of the biliopancreatic system. However, post-ERCP pancreatitis (PEP) is the most frequent complication of this procedure with an incidence of about 3-4% in unselected patients and up to 15% in high-risk patients [1][2][3]. Although most of the cases take a mild or moderate course, about 10% of all patients with PEP develop severe pancreatitis with an estimated pancreatitis-related mortality rate of 3% [1].
Over the last decades, several risk factors for PEP have been suggested. Female sex, young age, non dilated common bile duct, sphincter oddi dysfunction and previous incidence of pancreatitis are considered to be patient related risk factors [4][5][6][7][8]. Furthermore, difficult cannulation of the papilla and procedures associated with cannulation of the pancreatic duct such as pre-cut papillotomy and injection of contrast agent into the pancreatic duct seem to be procedure related risk factors [5-7, 9, 10].
Generally, mechanical trauma of the papilla during ERCP can lead to an edema or spasm of the sphincter of oddi and subsequently restrain the outlet of pancreatic juice thereby causing an elevation of the intrapancreatic pressure. As a consequence, pancreatic secretion is forced to the surrounding pancreas parenchyma, causing autodigestion, a critical event in the pathophysiology of acute pancreatitis [11,12]. Moreover, cannulation of the pancreatic duct can lead to a damage of the epithelium [13]. In addition to the mechanical and hydrostatic damage, chemical, enzymatic, microbiological, allergic, and thermal factors can further favor PEP [14,15].
The aim of this study was to validate the supposed and to possibly identify new risk factors for PEP in a high volume tertiary referral center.

Patients and methods
All patients undergoing first time ERCP at the department of endoscopy between December 2010 and October 2013 were included in the study. The endoscopic database, medical charts and laboratory data were analyzed retrospectively.
First time ERCP was performed in 463 patients. 37 patients were excluded due to intended cannulation of the pancreatic duct for pancreatolithiasis, stenosis of the pancreatic duct, or suspected IPMN (intraductal papillary mucinous neoplasm). Further, 22 patients who suffered from acute pancreatitis at the time of ERCP were also excluded. This resulted in 404 patients which were included into the final analysis. The study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee (Ethikkommission der Medizinischen Fakultät der Technischen Universität München, project number 321/14). The ethics committee waived the need for written informed consent for this retrospective study. The number of ERCPs during the 35-month study period was 1425 in total which were performed by twelve endoscopists. Therefore, the average number of yearly ERCP per endoscopist was about 40.
Statistical analyses were performed using IBM SPSS Statistics 23 (SPSS Inc., Chicago, Illinois, USA). For descriptive data, mean ± standard deviation was used for normally distributed data and median (range; interquartile range, IQR) for not normally distributed data. For explorative data analysis, a chi-square test was used to calculate the odds ratio or spearman's correlation to evaluate a statistical relation of suspected risk factors and PEP, inadvertent cannulation of the pancreatic duct, and difficult cannulation of the papilla duodeni major, respectively. To calculate correlations between continuous risk factors and dichotomous outcome we used a point biserial correlation. P-values < 0.05 were considered to be statistically significant.
Levels of difficulty for cannulation of the papilla duodeni major were categorized as easy (1-5 attempts) and difficult (>5 attempts) cannulation. PEP was defined according to the Atlanta Classification [16].

Results
In total, 404 patients were included in the final analysis. Patients´characteristics are shown in Table 1.

Incidence of PEP
PEP occurred in 9.7% (39/404) of all patients. One case was classified as severe pancreatitis, all others as mild pancreatitis.
Incidence of PEP in patients with intended cannulation of the pancreatic duct was 16.2% (6/37).

Risk factors for PEP
In univariate analyses, only inadvertent cannulation of the pancreatic duct was statistically significantly associated with PEP (odds ratio 4.373 (2.142-8.927); p<0.001). All data are presented in Table 2.
Multivariate binary logistic regression analysis including the factors age, chronic pancreatitis in the medical history, normal serum bilirubin, non-dilated extrahepatic bile duct, cannulation of the pancreatic duct, and difficult cannulation of the papilla confirmed inadvertent cannulation of the pancreatic duct (odds ratio 7.468 (2.792-19.975); p<0.001) as an independent risk factor for PEP [17,18]. All 12 patients diagnosed with chronic pancreatitis had an early stage of the disease. The median time period from first diagnosis of chronic pancreatitis to first time ERCP was 6.0 month (IQR, 0-60 month; range 0-102 month). 9 out of 12 patients (75%) had no exocrine or endocrine insufficiency. Difficult cannulation of the papilla duodeni major, which means more than 5 attempts to intubate the papilla, was statistically significantly associated with inadvertent cannulation of the pancreatic duct in univariate analysis (p<0.001). In contrast, diagnosis of bile duct stones (odds ratio 0.607 (0.401-0.919); p = 0.018) was associated with lower risk of inadvertent cannulation of the pancreatic duct. All data are shown in Table 3.

Risk factors for difficult cannulation
The rate of difficult cannulation was 49.0% (198/404). There were no statistically significant risk factors for difficult intubation of the papilla duodeni major. All data are presented in Table 4. 15.3% of the patients (62/404) underwent measurements for preventing PEP. In 54 patients, a stent (5 French, various length) was put into the pancreatic duct, 11 patients received diclofenac (100 mg rectally), and 3 of these patients received both. After exclusion of these patients, subgroup analyses showed only inadvertent cannulation of the pancreatic duct as a risk factor for PEP (odds ratio 4.824 (2.221-10.478); p<0.001; Table 5).

Discussion
This study on risk factors for PEP revealed inadvertent cannulation of the pancreatic duct as an independent risk factor. These date are mostly in line with current studies and guidelines [17,19]. There are contradicting data on a non-dilated common bile duct as a risk factor for PEP [17,20]. Our data are conclusive with a metaanalysis by Freeman et al. which did not show an increased risk by multivariate analysis. Sphincter oddi dysfunction, another previously described risk factor, was not examined in our patients [4].
Because most of the risk factors such as sex, age, bilirubin level, or bile duct diameter are not influenceable, efforts must be undertaken to minimize the procedure related risk factors and to optimize prophylactic measurements.
Inadvertent cannulation of the pancreatic duct was associated with an increased risk of PEP (odds ratio 7.468) in our study and others [17]. Procedures associated with cannulation of the pancreatic duct such as pre-cut papillotomy and injection of contrast agent into the pancreatic duct have also been confirmed as risk factors in other studies [5-7, 9, 10]. However, the reasons for inadvertent cannulation of the pancreatic duct are unclear. Our data show that difficult intubation of the papilla, which means more than 5 attempts, is a statistically significant risk factor for inadvertent cannulation. This seems to happen more frequently during ERCPs on call. Although the reasons for that can be manifold, it is conceivable that ERCPs on call are likely more challenging or performed under difficult conditions.

Conclusion
Inadvertent cannulation of the pancreatic duct is a procedure related risk factor for PEP. Measurements on preventing inadvertent cannulation of the pancreatic duct should be established and studies on prophylactic measurements should focus particularly on patients with inadvertent cannulation of the pancreatic duct.