Ulinastatin, a broad‑spectrum serine protease inhibitor widely used in Asia, has gained interest in critical care. This review summarizes evidence in acute pancreatitis (AP), severe acute pancreatitis (SAP), sepsis, acute respiratory distress syndrome (ARDS), and perioperative cardiac surgery with cardiopulmonary bypass (CPB). Meta‑analyses suggest reduced mortality, shorter ICU and hospital stays, and attenuated inflammation, though most studies are Asian, small, heterogeneous, and inconsistently dosed. Safety appears favorable, but long‑term and multinational data are limited. International multicenter RCTs are needed.
Introduction
Ulinastatin is used mainly in Asia for AP and SAP, with off‑label use in sepsis, ARDS, and perioperative cardiac surgery. Evidence suggests anti‑inflammatory, immunomodulatory, and organ‑protective properties, but geographic bias, methodological inconsistencies, and limited high‑quality trials constrain conclusions.
Mechanism and Pharmacokinetics
Ulinastatin inhibits proteases (trypsin, elastase, α‑chymotrypsin, hyaluronidase, myeloperoxidase), reducing tissue injury. It suppresses pro‑inflammatory cytokines, enhances anti‑inflammatory cytokines, stabilizes lysosomal membranes, reduces apoptosis, protects endothelium via nitric oxide, and modulates immunity. It is renally excreted, with a half‑life of ~40 min and ~24% urinary excretion within 6 h.
AP and SAP
Meta‑analyses suggest ulinastatin plus standard treatment reduces mortality and shortens hospital stay, but evidence is mainly from China with low‑quality RCTs. It reduces C‑reactive protein, IL‑6, and TNF‑α in Asian patients. A 2024 meta‑analysis confirmed mortality reduction and faster pain resolution, but no benefit for hospital stay or APACHE II scores; evidence certainty was low. Combination with somatostatin or octreotide reduces ARDS, MODS, and acute kidney injury versus monotherapy, though studies are small and lack multinational validation. Overall, evidence quality remains low.
Perioperative Cardiac Surgery with CPB
Meta‑analyses show ulinastatin reduces pro‑inflammatory cytokines, enhances anti‑inflammatory cytokines, lowers myocardial injury markers, and shortens intubation and mechanical ventilation duration (MVD), without increasing spontaneous resuscitation. However, studies are predominantly East Asian, heterogeneous in dosing, and small. No significant differences were found in hemodynamics, cardiac function, ICU stay, or postoperative complications. Earlier meta‑analyses found reduced inflammatory markers and extubation time but no impact on ICU stay, mortality, or major complications. A meta‑analysis of 12 RCTs suggested reduced ICU stay and MVD, with possible renal protection, but heterogeneity and lack of standardized dosing limit conclusions.
Sepsis and Septic Shock
Meta‑analyses suggest ulinastatin reduces all‑cause mortality, APACHE II scores, and MODS incidence, while reducing IL‑6 and TNF‑α and increasing IL‑10. However, studies are mainly from China and India, small, and methodologically limited. A systematic review on septic shock reported reduced mortality, MODS, ICU/hospital stay, and improved APACHE II/SOFA scores, but evidence is limited by Chinese‑language trials and modest samples. A 2025 meta‑analysis of ulinastatin plus continuous blood purification (CBP) found reduced mortality and improved biomarkers, but studies were single‑center, heterogeneous, and rarely reported adverse events. An umbrella review found combination therapies reduced short‑term mortality, ICU stay, MVD, and inflammatory markers, but all studies were from China and quality was low. Independent effects of ulinastatin remain difficult to isolate.
ARDS
A meta‑analysis of 33 RCTs found ulinastatin reduced mortality, ventilator‑associated pneumonia, MVD, ICU stay, and hospitalization, and improved oxygenation index (OI), but studies were mainly Chinese and heterogeneous. A review of 29 trials found improved OI, reduced ICU mortality, and shorter ICU stay, but no difference in 28‑day mortality; trials were small, single‑center, and of low quality. Ulinastatin plus continuous renal replacement therapy (CRRT) reduced mortality, ICU stay, MVD, and improved APACHE II and oxygenation versus CRRT alone, but studies were small and single‑center. In pulmonary edema, ulinastatin reduced incidence, extravascular lung water index, MVD, and ICU stay, but evidence is limited and benefit is more plausible in permeability‑related edema (e.g., ARDS) than hydrostatic edema.
Safety
A real‑world study of 11,252 patients found low ADR/ADE incidence (<5%), including liver function abnormalities, thrombocytosis/thrombocytopenia, leukocytosis/leukopenia, and rash. Most events were mild and resolved after discontinuation. However, the study was conducted only in China, most use was off‑label, and concomitant medications increased ADR risk. Continued surveillance is needed.
Discussion
A 2023 Chinese expert consensus recommends ulinastatin for SAP, sepsis, shock, severe pneumonia, ARDS, severe burns, severe trauma, cardiac arrest, severe heatstroke, and acute poisonings. However, recommendations are based on heterogeneous studies with variable dosing and lack of high‑quality RCTs.
Limitations
Evidence is limited by geographic bias (mostly East and South Asia), substantial heterogeneity in outcomes (ICU stay, MVD, inflammatory markers), and reliance on small, single‑center trials. Improvements in inflammatory markers and oxygenation do not consistently translate into hard clinical outcomes such as mortality or long‑term recovery, reflecting the multifactorial nature of critical illness.
Future Directions
International multicenter RCTs are needed to standardize dosing and assess long‑term impact across diverse populations. Differences in ICU infrastructure and clinical practices may influence treatment effects, underscoring the need for global collaboration. Future studies should examine efficacy across ethnic and genetic groups, explore synergy with other anti‑inflammatory and organ‑supportive therapies, and integrate ulinastatin into precision medicine frameworks. Ongoing pharmacovigilance is essential.
Conclusions
Ulinastatin shows biological plausibility and consistent signals of benefit with a favorable safety profile. However, evidence is limited by heterogeneity, variable quality, and predominantly Asian populations. Well‑designed international multicenter RCTs are warranted.
Full text
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The study was recently published in the Journal of Translational Critical Care Medicine .
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