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.
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.
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.
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).
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.
Supplementary material 1 (DOCX 22 kb)134_2014_3278_MOESM1_ESM.docx
Inoue K, Takano H (2011) Urinary trypsin inhibitor, an alternative therapeutic option for inflammatory disorders. In: Nagal A (ed) Inflammatory diseases—a modern perspective. InTech, Croatia. ISBN: 978-953-307-444-3. http://www.intechopen.com/books/inflammatory-diseases-a-modernperspective/urinary-trypsin-inhibitor-an-alternative-therapeutic-option-for-inflammatory-disorders. Accessed 1 June 2013
Sharony R, Yu PJ, Park J, Galloway AC, Mignatti P, Pintucci G (2010) Protein targets of inflammatory serine proteases and cardiovascular disease. J Inflamm (Lond) 7:45 CrossRef
Moon SW, Lee SW, Hong YS, Park DW, Jang IJ, Yoon YH, Lim SI (2009) The effects of urinary trypsin inhibitor on the outcomes of severe sepsis and septic shock patients. J Korean Soc Emerg Med 20:80–85
Shao Y, Zhang L, Deng L, Yao H (2005) Clinical study on effects of ulinastatin on patients with systemic inflammatory response syndrome. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 17:228–230 PubMed
Wu TJ, Zhang LN, Kang CC (2013) The effect of ulinastatin on disbalance of inflammation and immune status in patients with severe sepsis. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 25:219–223 PubMed
Yang H, Zhen XF, Li HY (2006) Clinical observation of ulinastatin in the treatment of multiorgan dysfunction syndrome. J Guangdong Coll Pharm 6:036
Chen H, He MY, Li YM (2009) Treatment of patients with severe sepsis using ulinastatin and thymosin α1: a prospective, randomized, controlled pilot study. Chin Med J 122:883–888 PubMed
Li YM, Chen H, Li X, Zhou W, He MY, Chiriva-Internati M, Wachtel MS, Frezza EE (2009) A new immunomodulatory therapy for severe sepsis: ulinastatin plus thymosin alpha 1. J Intensive Care Med 24:47–53
Nakatani K, Takeshita S, Tsujimoto H, Kawamura Y, Sekine I (2001) Inhibitory effect of serine protease inhibitors on neutrophil-mediated endothelial injury. J Leukoc Biol 69:241–247 PubMed
Massberg S, Grahl L, von Bruehl ML, Manukyan D, Pfeiler S, Goosmann C, Brinkmann V, Lorenz M, Bidzhekov K, Khandagale AB, Konrad I, Kennerknecht E, Reges K, Holdenrieder S, Braun S, Reinhardt C, Spannagl M, Preissner KT, Engelmann B (2010) Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 16:887–896 PubMedCrossRef
Endo S, Inada K, Taki K, Hoshi S, Yoshida M (1990) Inhibitory effects of ulinastatin on the production of cytokines: implications for the prevention of septicemic shock. Clin Ther 12:323–326 PubMed
Kawai S, Sakayori S, Watanabe H, Kobayashi H (1990) Usefulness of a protease inhibitor (urinastatin) in ARDS with infectious diseases. Nihon Kyobu Shikkan Gakkai Zasshi 28:843–851 PubMed
Abe M, Ishikawa M, Soga Y, Suga H, Nakagawa T, Suzuki T (2004) Acute and high dose therapy of urinary trypsin inhibitor could inhibit vascular endothelial cell disorders in critical illness. Crit Care 8(suppl 1):199 CrossRef
Luo PF, Ren Y, Liu Y-L, Xia Z-F (2001) Ulinastatin and thymosin as immune modulators for the treatment of sepsis. Cochrane Database Syst Rev (7):CD009940. doi: 10.1002/14651858.CD009940
Todi S, Chatterjee S, Sahu S, Bhattacharyya M (2010) Epidemiology of severe sepsis in India: an update. Crit Care 14(Suppl 1):382 CrossRef
van den Boogaard M, Pickkers P, Slooter AJ, Kuiper MA, Spronk PE, van der Voort PH, van der Hoeven JG, Donders R, van Achterberg T, Schoonhoven L (2012) Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study. Br Med J 344:e420 CrossRef
- Intravenous administration of ulinastatin (human urinary trypsin inhibitor) in severe sepsis: a multicenter randomized controlled study
Dilip R. Karnad
Pradeep K. Verma
Nivedita D. Moulick
Mradul K. Daga
Neelima D. Chafekar
- Springer Berlin Heidelberg
Neu im Fachgebiet AINS
Meistgelesene Bücher aus dem Fachgebiet AINS
Mail Icon II