Risk factors and prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis

Abstract

Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most common and serious complication following ERCP, with incidence rates ranging from 3% to 15% and up to 40% in high-risk patients. Its multifactorial pathogenesis involves both patient-related and procedure-related factors. Established risk factors include female sex, younger age, sphincter of Oddi dysfunction, previous pancreatitis, difficult cannulation, and pancreatic duct injection. The combination of several risk factors markedly increases the likelihood of PEP, underscoring the need for individualized risk assessment. Preventive strategies have evolved from empirical approaches to evidence-based interventions. Rectal non-steroidal anti-inflammatory drugs and prophylactic pancreatic duct stenting are strongly supported by clinical evidence as effective measures, particularly in high-risk patients. Aggressive intravenous hydration and early precut sphincterotomy have also shown benefit. However, the efficacy of pharmacological agents such as somatostatin, gabexate, and nafamostat mesilate remains inconsistent. Recent advances include the development of risk prediction models and scoring systems that integrate patient and procedural variables, offering moderate predictive accuracy. Ongoing research explores the use of artificial intelligence to improve risk stratification and guide prophylactic strategies. Future efforts should focus on standardizing diagnostic criteria, validating predictive tools, and optimizing combined preventive protocols. Through integrated risk assessment and tailored prevention, the incidence and severity of PEP may be significantly reduced, improving safety and outcomes in ERCP practice.

Key Words: Post-endoscopic retrograde cholangiopancreatography pancreatitis; Risk factors; Prevention; Rectal non-steroidal anti-inflammatory drugs; Pancreatic duct stenting

Core Tip: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis remains the most frequent and severe complication of ERCP, arising from the interplay of patient and procedural risk factors. Key predictors include female sex, younger age, sphincter of Oddi dysfunction, difficult cannulation, and pancreatic duct manipulation. Evidence strongly supports rectal non-steroidal anti-inflammatory drugs, prophylactic pancreatic duct stenting, and aggressive intravenous hydration as effective preventive measures, particularly in high-risk patients. Recent advances in risk prediction models and artificial intelligence-driven analytics offer opportunities for individualized risk assessment and tailored prophylaxis, which may markedly reduce post-ERCP pancreatitis incidence and improve procedural safety.

INTRODUCTION

Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remains the most frequent and serious complication of ERCP, with reported incidence ranging from 3% to 15% and up to 40% in high-risk patients[1]. Its multifactorial pathogenesis involves a complex interplay of patient-related and procedure-related factors, including mechanical trauma, hydrostatic injury, and enzymatic activation within the pancreatic duct (PD)[2,3]. The widespread transition of ERCP from a diagnostic to a predominantly therapeutic procedure has increased procedural complexity and consequently elevated the risk of PEP[4,5]. Despite decades of research, variability in diagnostic definitions and inconsistent reporting continue to obscure precise risk estimates and impede the development of universally accepted preventive protocols.

EPIDEMIOLOGY AND INCIDENCE TRENDS

The overall incidence of PEP remains approximately 3.5%-10% in unselected populations, with rates approaching 30%-50% among high-risk groups such as those with sphincter of Oddi dysfunction (SOD) or difficult cannulation[6,7]. Meta-analyses report pooled rates around 8%-9%, reflecting heterogeneity in diagnostic thresholds and patient selection[8,9]. Nationwide studies indicate that PEP contributes to rising hospital admissions and mortality, despite improvements in procedural technique and pharmacologic prophylaxis[10,11]. While most cases are mild, severe PEP - requiring prolonged hospitalization or intensive care - occurs in 0.3%-0.6% of procedures[12].

PATIENT-RELATED RISK FACTORS

Multiple studies consistently identify female sex, younger age, and SOD as strong, independent predictors of PEP[7,13,14] (Table 1). A history of previous pancreatitis or prior PEP further increases susceptibility[2,15]. The higher risk in women and younger individuals may reflect hormonal influences on sphincter contractility and pancreatic enzyme activation[2]. Comorbidities such as low body mass index and normal bilirubin levels have also been implicated as risk modifiers[1,11]. Conversely, advanced age alone is not consistently associated with increased risk, suggesting the predominance of anatomical and functional rather than chronological factors[16]. A comprehensive summary of risk factors and prevention strategies for PEP is presented in Figure 1.

Figure 1 Overview of risk factors and evidence-based prevention strategies for post-endoscopic retrograde cholangiopancreatography pancreatitis. BMI: Body mass index; SOD: Sphincter of Oddi dysfunction; PEP: Post-endoscopic retrograde cholangiopancreatography pancreatitis; NSAID: Non-steroidal anti-inflammatory drug; PD: Pancreatic duct.

Table 1 Risk factors for post-endoscopic retrograde cholangiopancreatography pancreatitis.

Risk factor	Category	Description
Female sex	Patient-related	Higher risk due to hormonal influences on sphincter contractility and pancreatic enzyme activation
Younger age	Patient-related	Increased susceptibility is possibly due to hormonal influences and pancreatic enzyme activation
Sphincter of Oddi dysfunction	Patient-related	Independent predictor of PEP
Previous pancreatitis	Patient-related	A history of pancreatitis or prior PEP increases the risk
Low body mass index	Patient-related	Associated with an increased risk of PEP
Difficult cannulation	Procedure-related	Prolonged or difficult cannulation increases risk due to trauma and pressure
Prolonged cannulation time	Procedure-related	Increased procedure time increases the risk of PEP
Pancreatic duct injection or guidewire cannulation	Procedure-related	These techniques increase hydrostatic pressure and injury to pancreatic tissue
Precut sphincterotomy	Procedure-related	Risk, depending on technique and timing -can elevate or reduce risk
Endoscopist experience	Procedure-related	Higher procedure volumes correlate with lower complication rates

PEP: Post-endoscopic retrograde cholangiopancreatography pancreatitis.

PROCEDURE-RELATED RISK FACTORS

Procedural determinants exert substantial influence on PEP development. Difficult cannulation, prolonged cannulation time, and PD injection or guidewire cannulation are among the strongest procedural risk factors[3] (Table 1). Precut sphincterotomy, while sometimes necessary, can either elevate or reduce risk depending on timing and technique[5,15]. Multiple PD cannulations increase hydrostatic pressure and acinar injury, exacerbating inflammatory cascades[17,18]. The endoscopist’s experience also modulates risk - higher procedure volumes correlate with reduced complication rates[2,19]. Small bile duct diameter and pancreaticobiliary anatomical variants have emerged as additional contributors in specialized cohorts[20].

SYNERGISTIC AND EMERGING FACTORS

The concurrence of multiple risk factors exerts a multiplicative, not additive, effect on PEP probability[3,21]. Novel determinants - including PD morphology, intraductal ultrasonography use, and microbial alterations - are being explored as potential mechanistic drivers[6]. Elevated cannulation pressure and local microvascular ischemia are hypothesized to initiate premature trypsin activation, linking mechanical and biochemical pathways in early inflammation[22].

PREVENTIVE STRATEGIES

Pharmacologic interventions

Rectal non-steroidal anti-inflammatory drugs (NSAIDs), particularly indomethacin and diclofenac, remain the most evidence-based pharmacologic prophylaxis. Multiple randomized trials and meta-analyses confirm their efficacy in reducing PEP incidence across risk strata[4,6]. NSAIDs inhibit phospholipase A₂ and neutrophil activation, mitigating early inflammatory cascades[22]. Somatostatin and gabexate mesilate have yielded inconsistent outcomes, while nafamostat mesilate offers limited benefit restricted to select populations[23]. Statin use has recently emerged as a potential protective factor, likely through anti-inflammatory and endothelial-stabilizing effects. In addition, emerging drug-discovery platforms - such as proteolysis-targeting chimera technologies and multi-omics-based target identification - may enable the development of next-generation prophylactic agents by elucidating previously unrecognized molecular drivers of PEP and clarifying drug-mechanism interactions[24]. Incorporating these advanced approaches could further refine pharmacologic strategies and expand the therapeutic landscape for PEP prevention[25,26].

Endoscopic and technical measures

Prophylactic PD stenting substantially lowers PEP risk, particularly in cases involving difficult cannulation or inadvertent duct manipulation[6]. Stents prevent ductal obstruction and reduce intraductal pressure; however, optimal stent size and duration remain debated. Early precut sphincterotomy - when performed by experienced endoscopists - reduces repeated cannulation trauma and overall risk[5,18]. Guidewire cannulation techniques also minimize contrast-induced injury and have become standard practice[1].

Periprocedural hydration

Aggressive intravenous hydration with lactated Ringer’s solution, initiated before and maintained after ERCP, significantly reduces PEP risk by maintaining pancreatic microcirculation and preventing ischemic injury[6,27]. This simple, cost-effective measure complements pharmacologic prophylaxis and is endorsed by recent clinical guidelines.

RISK PREDICTION AND STRATIFICATION MODELS

Recent advances have produced predictive models integrating patient and procedural parameters. Notably, Fuccio et al[28] developed a multicenter scoring system with an area under the receiver operating characteristic curve of 0.79, while Zhao et al[13] validated a similar model with strong calibration[14]. More recently, Cao and Sun[29] developed a multidimensional prediction model for acute pancreatitis after ERCP, integrating clinical, laboratory, and procedural variables, further demonstrating the feasibility of individualized risk stratification in routine endoscopic practice. These tools enable pre-procedural identification of high-risk patients and guide prophylactic interventions. However, external validation remains limited, and methodological heterogeneity hampers clinical adoption. The incorporation of machine learning algorithms offers promise for improving predictive accuracy and dynamic risk assessment[6,30].

CLINICAL IMPLICATIONS

Effective PEP prevention depends on combining evidence-based interventions within individualized management frameworks. High-risk patients - identified through validated risk scores - should receive routine rectal NSAIDs, aggressive hydration, and PD stenting when indicated. Standardized procedural protocols emphasizing minimal cannulation attempts, early precut techniques, and real-time monitoring of intraductal pressure may further reduce complication rates. Centralization of ERCP in high-volume centers with trained endoscopists has been associated with superior safety outcomes[2,19].

Despite these established measures, important clinical controversies remain. First, the optimal prophylactic approach in high-risk patients is still debated, particularly regarding whether PD stenting should be routinely combined with rectal NSAIDs or reserved for extremely high-risk scenarios[31-33]. Second, cost-effectiveness analyses increasingly suggest that PD stenting, while effective, may impose a substantial procedural and financial burden compared with the low-cost universal use of NSAIDs, raising questions about resource allocation in different healthcare systems[34]. Third, real-world implementation of guidelines remains challenging. These uncertainties underscore the need for more pragmatic clinical studies and consensus-driven strategies that address feasibility in addition to efficacy.

FUTURE DIRECTIONS

Although preventive strategies for PEP have advanced substantially, several controversies and unresolved issues continue to challenge real-world practice[35,36]. Ongoing debate persists regarding optimal prophylaxis selection in high-risk patients, particularly the relative roles of rectal NSAIDs vs prophylactic PD stenting and the cost-effectiveness of combined approaches[37]. In addition, variability in guideline adherence across centers highlights the gap between evidence and implementation, underscoring the need for standardized protocols and improved risk-based decision making[38-40]. These uncertainties emphasize the importance of refining individualized prevention strategies and remain key areas for future investigation.

Several research priorities emerge: (1) Standardization of diagnostic and severity criteria to enhance inter-study comparability; (2) Large-scale, prospective validation of predictive models[28]; (3) Pediatric-specific studies addressing unique anatomical and procedural considerations[41,42]; and (4) Trials evaluating combination prophylaxis and novel agents such as protease inhibitors or statins[27]. Integration of artificial intelligence into endoscopy workflows may enable real-time risk stratification and decision support.

CONCLUSION

PEP is a multifactorial, preventable complication. Its risk arises from the convergence of patient predisposition and procedural trauma. The consistent identification of key risk factors - female sex, younger age, SOD, difficult cannulation, and PD manipulation - provides a foundation for individualized prevention. Evidence strongly supports rectal NSAIDs, PD stenting, and aggressive hydration as core prophylactic measures. Future efforts should focus on refining predictive tools, standardizing definitions, and integrating AI-based analytics to personalize risk assessment. Through evidence-driven, tailored prophylaxis, both the incidence and severity of PEP can be substantially reduced, improving safety and outcomes in ERCP practice.