Reassessing Ulinastatin for PEP Prophylaxis: Where Does it Stand?

Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) continues to be a concern for endoscopists, especially in high-risk patients. Despite routine use of rectal nonsteroidal anti-inflammatory drugs (NSAIDs), intravenous hydration, and pancreatic duct stenting in selected cases, PEP still occurs in up to 10 to 14% of procedures involving high-risk patients.[1] [2] Despite advancements in preventive strategies, there remains an unmet need for adjunctive pharmacologic options that are not only effective but also safe and practically deployable in routine clinical settings.

Ulinastatin, a urinary-derived serine protease inhibitor, has previously been investigated for the prevention of PEP, with variable outcomes. A notable multicenter randomized controlled trial demonstrated a significant reduction in PEP incidence among average-risk patients when Ulinastatin was administered as a single intravenous dose prior to ERCP.[3] In contrast, another in high-risk patients, using a lower dose administered after the procedure, did not show a statistically significant benefit.[4] Subsequent meta-analyses have suggested a potential role for Ulinastatin, particularly when used in higher doses and administered preprocedurally.[5] However, the data remain heterogeneous, and evidence in high-risk cohorts is still limited and inconclusive.

In this context, the prospective cohort study by Pal et al, published in this issue of Journal of Digestive Endoscopy, adds new data to the ongoing discussion.[6] The authors focused exclusively on high-risk patients—defined by clinical and procedural factors such as suspected sphincter of Oddi dysfunction (SOD), female gender under 40, and difficult cannulation—and administered 100,000 IU of Ulinastatin either before or immediately after the procedure. They report a significantly lower incidence of PEP in the Ulinastatin group (2.7%) compared to controls (11.6%), along with reductions in postprocedure pain scores, hospital stay, and cost of care. Notably, there were no significant adverse effects.

While the findings are encouraging, a few caveats merit discussion. The control group consisted of average-risk patients, which makes direct comparison challenging. The design also leaves some room for selection bias and confounding, particularly since all patients received standard prophylaxis—including NSAIDs and hydration—which could dilute or obscure the actual effect of Ulinastatin. Furthermore, most cases were biliary ERCPs; only a small number involved pancreatic interventions, limiting generalizability. Lastly, the dose of Ulinastatin used was lower than in some previous trials.

The timing of Ulinastatin administration—particularly when given prior to the procedure—may have contributed to the favorable outcomes observed in this study. This approach is consistent with the current understanding of PEP pathophysiology, where pancreatic injury is believed to begin early during cannulation. A single bolus dose, if effective, also offers logistical advantages over prolonged infusions. Cost, however, remains a limiting factor. Ulinastatin is significantly more expensive than established agents such as rectal NSAIDs, which are already supported by strong guideline recommendations. For widespread use, any new agent must demonstrate clear and consistent benefit beyond existing strategies. Nonetheless, in patients where NSAIDs or aggressive fluid therapy are contraindicated—such as those with renal or cardiac comorbidities—Ulinastatin may represent a feasible adjunctive option.

While Ulinastatin may not yet be ready for routine use, the findings from this study support its continued evaluation. Well-designed randomized trials focusing on high-risk populations, with standardized comparators and optimized dosing strategies, are needed to clarify its clinical utility. Until such evidence emerges, Ulinastatin may be considered selectively in patients for whom standard prophylactic measures are contraindicated or inadequate.

 

MissingLinkText

Conflict of Interest

None declared.

• References

• 1 Dumonceau JM, Kapral C, Aabakken L. et al. ERCP-related adverse events: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 2020; 52 (02) 127-149
• 2 Buxbaum JL, Freeman M, Amateau SK. , et al; ( ASGE Standards of Practice Committee Chair. American Society for Gastrointestinal Endoscopy guideline on post-ERCP pancreatitis prevention strategies: summary and recommendations. Gastrointest Endosc 2023; 97 (02) 153-162
• 3 Tsujino T, Komatsu Y, Isayama H. et al. Ulinastatin for pancreatitis after endoscopic retrograde cholangiopancreatography: a randomized, controlled trial. Clin Gastroenterol Hepatol 2005; 3 (04) 376-383
• 4 Yoo JW, Ryu JK, Lee SH. et al. Preventive effects of ulinastatin on post-endoscopic retrograde cholangiopancreatography pancreatitis in high-risk patients: a prospective, randomized, placebo-controlled trial. Pancreas 2008; 37 (04) 366-370
• 5 Zhu K, Wang JP, Su JG. Prophylactic ulinastatin administration for preventing post-endoscopic retrograde cholangiopancreatography pancreatitis: a meta-analysis. Exp Ther Med 2017; 14 (04) 3036-3056
• 6 Pal S, Bhaduri G, Mohta S, Panja S, Mahankali S, Bohidar NP. Efficacy of Ulinastatin in preventing post-ERCP pancreatitis in high risk patients: a prospective cohort study. J Dig Endosc 2025;

Publication History

Article published online:
08 July 2025