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...

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Published in:	Intensive care medicine Vol. 40; no. 6; pp. 830 - 838
Main Authors:	Karnad, Dilip R., Bhadade, Rakesh, Verma, Pradeep K., Moulick, Nivedita D., Daga, Mradul K., Chafekar, Neelima D., Iyer, Shivakumar
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-06-2014 Springer Springer Nature B.V
Subjects:	Adult Analysis Anesthesiology Bacterial infections Clinical trials Critical Care Medicine Cytokines Double-Blind Method Emergency Medicine Failure Female Glycoproteins - administration & dosage Health aspects Humans Infection Infections Infusions, Intravenous Intensive Intensive care Male Medical schools Medicine Medicine & Public Health Mortality Neutrophils Original Pain Medicine Pathogens Pediatrics Pilot Projects Pneumology/Respiratory System Pneumonia Prospective Studies Protease inhibitors Sepsis Sepsis - drug therapy Thrombin Trypsin Trypsin Inhibitors - administration & dosage Ventilators India Mumbai India Bacterial infection Abdominal sepsis Septic shock Pneumonia Inflammatory mediators Serine protease inhibitor
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Summary:	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.
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ISSN:	0342-4642 1432-1238
DOI:	10.1007/s00134-014-3278-8