title: Intravenous administration of ulinastatin (human urinary trypsin inhibitor) in severe sepsis: a multicenter randomized controlled study.
abstract: OBJECTIVE
  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.
authors.affiliation: Critical Care, Jupiter Hospital, Thane, India, drkarnad@rediffmail.com.
authors.forename: Dilip R
authors.initials: DR
authors.lastname: Karnad
authors.forename: Rakesh
authors.initials: R
authors.lastname: Bhadade
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Verma
authors.forename: Nivedita D
authors.initials: ND
authors.lastname: Moulick
authors.forename: Mradul K
authors.initials: MK
authors.lastname: Daga
authors.forename: Neelima D
authors.initials: ND
authors.lastname: Chafekar
authors.forename: Shivakumar
authors.initials: S
authors.lastname: Iyer
mesh_terms: D000328:Adult; D004311:Double-Blind Method; D005260:Female; D006023:Glycoproteins / Q000008:administration & dosage*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010865:Pilot Projects; D011446:Prospective Studies; D018805:Sepsis / Q000188:drug therapy*; D014361:Trypsin Inhibitors / Q000008:administration & dosage*
chemical_list: D006023:Glycoproteins; D014361:Trypsin Inhibitors; C028665:urinastatin
references.citation: Mol Pharmacol. 2005 Mar;67(3):673-80
references.pmid: 15576631
references.citation: Nat Med. 2010 Aug;16(8):887-96
references.pmid: 20676107
references.citation: Chin Med J (Engl). 2009 Apr 20;122(8):883-8
references.pmid: 19493408
references.citation: J Infect Dis. 2008 Sep 1;198(5):723-30
references.pmid: 18613793
references.citation: J Clin Biochem Nutr. 2008 Nov;43(3):139-42
references.pmid: 19015747
references.citation: J Mol Med (Berl). 2011 Jan;89(1):23-8
references.pmid: 20809089
references.citation: Crit Care Med. 2005 Jun;33(6):1272-5
references.pmid: 15942343
references.citation: Inflamm Res. 2011 Jun;60(6):569-75
references.pmid: 21246393
references.citation: Nat Rev Immunol. 2008 Oct;8(10):776-87
references.pmid: 18802444
references.citation: Clin Chem Lab Med. 2005;43(1):1-16
references.pmid: 15653436
references.citation: Inflamm Res. 2010 Aug;59(8):597-606
references.pmid: 20148283
references.citation: J Infect Dis. 2005 Mar 15;191(6):930-8
references.pmid: 15717269
references.citation: Shock. 2011 Jan;35(1):42-4
references.pmid: 20523269
references.citation: Indian J Crit Care Med. 2011 Jul;15(3):147-56
references.pmid: 22013306
references.citation: J Biosci Bioeng. 2007 Oct;104(4):315-20
references.pmid: 18023806
references.citation: Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2005 Apr;17(4):228-30
references.pmid: 15836828
references.citation: J Infect Dis. 2003 Sep 15;188(6):919-26
references.pmid: 12964125
references.citation: Crit Care Med. 2001 Jul;29(7):1303-10
references.pmid: 11445675
references.citation: Inflamm Res. 2010 Sep;59(9):679-87
references.pmid: 20454830
references.citation: BMJ. 2012 Feb 09;344:e420
references.pmid: 22323509
references.citation: N Engl J Med. 2001 Mar 8;344(10):699-709
references.pmid: 11236773
references.citation: Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2013 Apr;25(4):219-23
references.pmid: 23660098
references.citation: Inflammation. 2012 Feb;35(1):176-82
references.pmid: 21318392
references.citation: Exp Toxicol Pathol. 2012 Sep;64(6):543-7
references.pmid: 21159497
references.citation: J Surg Res. 2013 Jun 15;182(2):296-302
references.pmid: 23158408
references.citation: Intensive Care Med. 2013 Oct;39(10):1839-42
references.pmid: 23925547
references.citation: Crit Care Med. 1985 Oct;13(10):818-29
references.pmid: 3928249
references.citation: N Engl J Med. 2013 Aug 29;369(9):840-51
references.pmid: 23984731
references.citation: JAMA. 2009 Dec 2;302(21):2323-9
references.pmid: 19952319
references.citation: Clin Ther. 1990 Jul-Aug;12(4):323-6
references.pmid: 2224946
references.citation: J Inflamm (Lond). 2010 Aug 30;7:45
references.pmid: 20804552
references.citation: J Intensive Care Med. 2009 Jan-Feb;24(1):47-53
references.pmid: 19033321
references.citation: Nihon Kyobu Shikkan Gakkai Zasshi. 1990 Jun;28(6):843-51
references.pmid: 2214425
references.citation: Chest. 2009 May;135(5):1150-1156
references.pmid: 19420193
references.citation: J Leukoc Biol. 2001 Feb;69(2):241-7
references.pmid: 11272274
references.citation: Crit Care Med. 1993 Jun;21(6):925-30
references.pmid: 8389269
references.citation: Lancet Infect Dis. 2008 Jan;8(1):32-43
references.pmid: 18063412
references.citation: Crit Care Med. 1997 Mar;25(3):430-4
references.pmid: 9118658
references.citation: Immunotherapy. 2011 Jan;3(1):117-28
references.pmid: 21174562