Intravenous administration of ulinastatin (human urinary trypsin inhibitor) in severe sepsis: a multicenter randomized controlled study.

PURPOSE: Ulinastatin, a serine protease inhibitor, inhibits several pro-inflammatory proteases and decreases inflammatory cytokine levels and mortality in experimental sepsis. We studied the effect of ulinastatin on 28-day all-cause mortality in a double-blind trial in patients with severe sepsis in seven Indian hospitals. METHODS: Patients with sepsis were randomized within 48 h of onset of one or more organ failures to receive intravenous administration of ulinastatin (200,000 IU) or placebo 12 hourly for 5 days. RESULTS: Of 122 randomized subjects, 114 completed the study (55 receiving ulinastatin, 59 receiving placebo). At baseline, the mean APACHE II score was 13.4 (SD = 4.4), 48 (42 %) patients were receiving mechanical ventilation, 58 (51 %) were on vasopressors, and 35 % had multiple organ failure. In the modified intention-to-treat analysis (patients receiving six or more doses of study drugs), 28-day all-cause mortality was 7.3 % with ulinastatin (4 deaths) versus 20.3 % (12 deaths) with placebo (p = 0.045). On multivariate analysis too, treatment with ulinastatin (odds ratio 0.26, 95 % CI 0.07-0.95; p = 0.042) independently decreased 28-day all-cause mortality. However, the mortality difference did not reach statistical significance in the intention-to-treat analysis [10.2 % (6/59 deaths) with ulinastatin versus 20.6 % (13/63 deaths) in the placebo group; p = 0.11]. The ulinastatin group had lower incidence of new-onset organ failure (10 vs. 26 patients, p = 0.003), more ventilator-free days (mean ± SD 19.4 ± 10.6 days vs. 10.2 ± 12.5 days, p = 0.019), and shorter hospital stay (11.8 ± 7.1 days vs. 24.2 ± 7.2 days, p < 0.001). CONCLUSIONS: In this pilot study, intravenous administration of ulinastatin reduced mortality in patients with severe sepsis in the modified intention-to-treat analysis, but not in the intention-to-treat analysis.

Efficacy and safety of intravenous ulinastatin versus placebo along with standard supportive care in subjects with mild or severe acute pancreatitis.

BACKGROUND: Ulinastatin is reported to inhibit pro-inflammatory markers and also inhibits coagulation and fibrinolysis. The drug is available in East Asia for the treatment of acute pancreatitis. AIM: To study the effect of addition of ulinastatin to standard care on mortality and morbidity in Indian subjects with acute pancreatitis. DESIGN: Randomized, double-blind, placebo-controlled, multi-centre trial across 15 centres in India. METHODS: Subjects, aged 18 to 70 years, with acute pancreatitis and elevated serum C-reactive protein (CRP) levels, were eligible for enrolment. Acute pancreatitis was diagnosed if the patient had at least two of the following criteria: suggestive abdominal pain, serum amylase and/or lipase > 3 times upper limit of normal, and imaging findings of acute pancreatitis. Subjects were classified as having mild or severe acute pancreatitis on the basis of the APACHE II score (< 8 mild, > or = 8 severe). Standard care was given to all subjects as per the treating physician's protocol. Eligible subjects were randomized to receive intravenous infusion of 200,000 IU ulinastatin or placebo in 100 mL of 0.9% saline given over one hour every 12 hours for 5 days. RESULTS: Of 135 randomized subjects, 129 completed the study (mild 62, severe 67). Pancreatitis was due to alcohol intake in a majority (81%) of subjects. Baseline characteristics were similar between the ulinastatin and placebo groups. Efficacy was evaluated in subjects who had received at least 3 days (6 doses) of ulinastatin/placebo. One subject with severe pancreatitis in the ulinastatin group versus six in the placebo group died (p = 0.048). New organ dysfunction developed in 5 ulinastatin vs 4 placebo group subjects (p = 0.744) with mild pancreatitis and 12 ulinastatin vs 29 placebo group subjects (p = 0.0026) with severe pancreatitis. Adverse events were significantly lower in subjects with severe pancreatitis in the ulinastatin group as compared to the placebo group (p = 0.00001). Reduction in serum CRP was not different between the groups. Median hospitalization was shorter by one day in the ulinastatin group; the difference was not significant. There was no infusion-related adverse event. CONCLUSIONS: Ulinastatin prevents new organ dysfunction and reduces mortality in subjects with severe pancreatitis.