Dose-Dependent Efficacy of Ulinastatin in Improving 28-Day and 30-Day Survival Rates in Sepsis: A Systematic Review and Meta-Analysis

Background: Sepsis poses a major global challenge in critical care medicine. Whileguideline-recommended interventions fail to reverse the core pathophysiological processof sepsis: inflammation–immune imbalance. Ulinastatin mitigates inflammatory cytokinestorms. However, its impact on 28-day and 30-day survival rate in sepsis remains controversial,and dose-dependent efficacy has not been systematically clarified. Methods:This systematic review and meta-analysis adhered to the PRISMA guidelines. Randomizedcontrolled trials published from February 2016 to September 2025 were identified throughPubMed, Embase, Cochrane Library, and ClinicalTrials.gov. Adult patients (≥18 years)with sepsis (Sepsis-3 criteria: SOFA ≥ 2 + suspected infection) were included. Primary outcomeswere 28-day and 30-day survival rates; secondary outcomes included inflammatorymarkers and prognostic scores. Data were pooled using RevMan 5.4.1, with RR for binaryoutcomes and mean difference for continuous variables. Heterogeneity was quantifiedby the I2 statistic, and publication bias was assessed via funnel plots and Begg’s/Egger’stests. Results: In six included RCTs (n = 535), ulinastatin significantly improved survivalrates at both 28 days (RR = 1.14, 95% CI: 1.01–1.29) and 30 days (RR = 1.39, 95% CI:1.20–1.60), with a statistically significant interaction between time points (p = 0.04). Exploratorysubgroup analyses suggested a “diminishing trend” with increasing daily doses,with 400,000 units appearing optimal. Treatment for >5 days was associated with betteroutcomes. The intervention also significantly lowered key inflammatory markers. Safetyreporting was limited. Safety data were limited to one study (n = 96), reporting mild adverseevents (rash, hypotension). Conclusions: A benefit has been shown with ulinastatinat 400,000 units daily, but not with higher doses. Treatment beyond 5 days may improveoutcomes, though longer duration is not clearly better. Current evidence is limited by geographicbias, small samples, and insufficient safety data. More high-quality, multinationalRCTs are needed to confirm the dose–response and long-term safety.