Elevation in serum amylase occurs in as many as 75% of patients after ERCP [11, 32] and reaches a peak at 24 hours after ERCP as shown by our results, whereas PEP, namely, acute clinical pancreatitis manifesting as abdominal pain and hyperamylasemia occurs in a relatively small portion of patients but varies among reports [13]. Haciahmetoglu et al. [33] proposed that this variation might result from differences in the definition of PEP, data collection method, and, especially, inclusion of patients with preexisting risk factors or not. The overall frequency of PEP was 12.6% in our patients, who had at least two risk factors, similar to those at a higher risk reported by Sofuni et al. [34]. It was noted that our patients were prospectively found to be at a relatively higher risk while the high-risk patient cohort reported by Sofuni et al. [34] identified. The fundamental pathogenesis underlying PEP is mechanical injury from endoscopic instrumentation [35] and hydrostatic injury from contrast medium injection [36] on the pancreatic duct. Independent and dependent predisposing factors for PEP are categorized into patient- and procedure-related factors [36]: the former category mainly includes age below 60 years, female, previous history of acute or chronic pancreatitis, and normal serum bilirubin level, and the latter ones primarily include ampullary manipulation, repeated cannulation, use of the precut technique, and operator's experience.

A major pathophysiological mechanism underlying PEP is insufficient pancreatic duct drain and/or increased pancreatic duct hydrostatic pressure after ERCP. Some retrospective studies and meta-analyses demonstrated that prophylactic placement of pancreatic stent could significantly reduce the risk of PEP in high-risk patients by approximately 70%–80% [37, 38]. Previous studies also suggested that use of a larger-caliber stent and a polyethylene stent was associated with a significantly lower risk of PEP than the use of a smaller-caliber stent and of metallic stent, respectively [39, 40]. As displacement and removal of a retained pancreatic duct confer a risk for PEP, current consensus regarding prophylactic pancreatic stenting after ERCP recommends that stenting should only be given in high-risk patients, such as those with iatrogenic ampullary injury, inadvertent pancreatic duct injection, and residual gallstones [41]. Our results showed that prophylactic use of a pancreatic stent could significantly reduce the occurrence of PEP from 17.7% to 7.7% in high-risk patients in a randomized controlled study setting. However, the two groups were similar in times of PEP resolution with respect to clinical symptoms and serum amylase level as well as other ERCP-associated morbidities. This finding suggested that pancreatic stenting has a short- rather than long-term effect and a prophylactic rather than a therapeutic effect on PEP, necessitating the requirement of early stenting in patients with preexisting risk factors.

Pathophysiologically PEP is an iatrogenic acute pancreatitis secondary to ERCP elicited by a series of locoregional and/or systemic inflammatory cascade reactions. Our results showed that blood leukocyte and neutrophil counts exhibited a similar transient increase in both groups, suggesting a nonspecific systemic inflammatory response to ERCP rather than pancreatic stenting. Moreover, the similar improvement in liver function measures, especially those indicative of biliary tract drain sufficiency, between the two groups indicated that additional placement of pancreatic stent had no adverse effect on post-ERCP bile drain. A possible extra benefit of pancreatic stenting was reduction in potential risk of biliary sepsis as shown by the lower percentage of bile microbial culture positivity in the experimental group, although the two groups were comparable in bile leukocyte positivity. A possible explanation is that sufficient pancreatic duct drainage also helps to improve bile duct drainage as the two ductal systems share a common opening to the duodenum. Placement of the pancreatic stent led to sufficient drainage of pancreatic juice through the pancreatic duct to the duodenum, which could reduce the digestive effect of pancreatic enzymes and bacterial colonization through the duodenal papilla. Combined with the inhibitive effect of somatostatin on the Oddi's sphincter, pancreatic stenting could restore the Oddi's sphincter and pancreatic duct drainage [42, 43], which would further inhibit bacterial colonization and invasion.

There were some limitations in this study. First, this study was not investigator-blinded due to the requirement of pancreatic stenting. However, all ERCP procedures were performed by a single endoscopic team in a randomized setting. Secondly, PEP occurrence was not stratified by the severity of pancreatitis, which might underestimate the therapeutic effect of stenting on PEP with respect to PEP resolution time. However, previous reports suggested that ERCP itself was associated with the odds rather than severity of PEP [36]. Lastly, our results demonstrate the mid- or long-term efficacy and safety data after ERCP with or without pancreatic stenting as the primary study objective focused on the prophylactic effect of pancreatic stenting in PEP.

In conclusion, PEP is a common morbidity after ERCP, especially in high-risk patients with complicating CBD disorders. However, use of pancreatic stenting can significantly reduce the PEP risk in these patients by improving pancreatic duct drainage, although it does not expedite recovery from PEP. The presence of a pancreatic stent has a beneficial rather than adverse effect on bile duct drain. Long-term follow-up studies are required to validate the long-term efficacy and safety of additional pancreatic stenting for high-risk patients with complicating CBD disorders regarding PEP and other ERCP-associated morbidities.