Post-ERCP Pancreatitis: New Insights, Evolving Therapies, and the Road Ahead

Post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) is the most common and clinically relevant complication of ERCP. While mechanical, hydrostatic, and chemical injury have been classically implicated in its pathogenesis, recent studies highlight additional mechanisms, including microvascular dysfunction, pancreatic steatosis, and calcium-calcineurin-driven acinar injury. Recent advances have reshaped our understanding of risk factors, optimal cannulation techniques, pharmacologic prophylaxis, and early diagnostic approaches.

This review combines established knowledge with current evidence for the prevention and early recognition of PEP. The number of pancreatic duct wire passages has been identified as a strong, objective predictor of PEP, beyond the traditional definitions of difficult cannulation. The DIPPP randomized trial confirms that rectal indomethacin and diclofenac offer equivalent prophylactic efficacy. Somatostatin analogs reduce overall and moderate PEP but show limited impact on mild or severe disease. Pancreatic steatosis has emerged as a significant risk phenotype. Perfusion CT provides a promising physiologic biomarker for early detection of PEP. These data support the development of a prevention algorithm integrating NSAIDs, evidence-based cannulation strategy, selective pancreatic duct stenting, lactated Ringer's hydration, and early post-procedure risk assessment.

Established interventions supported by high-quality RCTs: (1) Rectal NSAIDs remain the cornerstone of PEP prophylaxis and should be given to all the eligible patients. (2) Prophylactic pancreatic duct stenting provides additional benefit in high-risk cases. (3) Minimizing papillary trauma through guidewire-first cannulation and early adoption of advanced rescue techniques is a critical modifiable determinant of PEP risk. Adjunctive or investigational strategies: (1) Aggressive hydration should be individualized as trials do not show consistent incremental benefit over NSAIDs alone. (2) Combination regimens (NSAIDs + hydration or stenting) appear promising in indirect analyses, but definitive superiority over optimized NSAID-based prophylaxis remains unproven. (3) Emerging approaches including calcineurin inhibition, cryoprevention, and AI-based risk prediction are mechanistically compelling but remain investigational pending prospective validation.