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01.06.2014 | Original | Ausgabe 6/2014 Open Access

Intensive Care Medicine 6/2014

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

Zeitschrift:
Intensive Care Medicine > Ausgabe 6/2014
Autoren:
Dilip R. Karnad, Rakesh Bhadade, Pradeep K. Verma, Nivedita D. Moulick, Mradul K. Daga, Neelima D. Chafekar, Shivakumar Iyer
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s00134-014-3278-8) contains supplementary material, which is available to authorized users.
Take-home message: Ulinastatin, a protease inhibitor, inhibits several pro-inflammatory proteases and decreases inflammatory cytokine levels and mortality in experimental sepsis. In this pilot study, intravenous administration of ulinastatin (200,000 IU 12 hourly for 5 days) reduced mortality, new onset of organ dysfunction, duration of mechanical ventilation and hospital stay in patients with severe sepsis when started within 48 h of onset of failure of one or more organs.

Abstract

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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