Log in | Register

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

Dilip R. Karnad| Rakesh Bhadade| Pradeep K. Verma| Nivedita D. Moulick| Mradul K. Daga| Neelima D. Chafekar| Shivakumar Iyer
Original
Volume 40, Issue 6 / June , 2014

Pages 830 - 838

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.

Keywords

References

  1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303–1310
    • View reference on PubMed
    • View reference on publisher's website
  2. Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, Moreno R, Lipman J, Gomersall C, Sakr Y, Reinhart K (2009) International study of the prevalence of infection and outcomes of infections in intensive care units. JAMA 302:2323–2329
    • View reference on PubMed
    • View reference on publisher's website
  3. Rittirsch D, Flierl MA, Ward PA (2008) Harmful molecular mechanisms in sepsis. Nat Rev Immunol 8:776–787
    • View reference on PubMed
    • View reference on publisher's website
  4. Van der Poll T, Opal SM (2008) Host-pathogen interaction in sepsis. Lancet Infect Dis 8:32–43
    • View reference on PubMed
    • View reference on publisher's website
  5. Levi M, van der Poll T (2013) Endothelial injury in sepsis. Intensive Care Med 39:1839–1842
  6. Angus D, van der Poll T (2013) Severe sepsis and septic shock. N Engl J Med 369:840–851
    • View reference on PubMed
    • View reference on publisher's website
  7. 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
  8. 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
    • View reference on publisher's website
  9. Kessenbrock K, Dau T, Jenne DE (2011) Tailor-made inflammation: how neutrophil serine proteases modulate the inflammatory response. J Mol Med 89:23–28
    • View reference on PubMed
    • View reference on publisher's website
  10. Pugia MJ, Lott JA (2005) Pathophysiology and diagnostic value of urinary trypsin inhibitors. Clin Chem Lab Med 43:1–16
    • View reference on PubMed
    • View reference on publisher's website
  11. Shigetomi H, Onogi A, Kajiwara H, Yoshida S, Furukawa N, Haruta S, Tanase Y, Kanayama S, Noguchi T, Yamada Y, Oi H, Kobayashi H (2010) Anti-inflammatory actions of serine protease inhibitors containing the Kunitz domain. Inflamm Res 59:679–687
    • View reference on PubMed
    • View reference on publisher's website
  12. Lim YP, Bendelja K, Opal SM, Siryaporn E, Hixson DC, Palardy JE (2003) Correlation between mortality and the levels of inter-alpha inhibitors in the plasma of patients with severe sepsis. J Infect Dis 188:919–926
    • View reference on PubMed
    • View reference on publisher's website
  13. Wakahara K, Kobayashi H, Yagyu T, Matsuzaki H, Kondo T, Kurita N et al (2005) Bikunin suppresses lipopolysaccharide-induced lethality through down-regulation of tumor necrosis factor-α and interleukin-1β in macrophages. J Infect Dis 191:930–938
    • View reference on PubMed
    • View reference on publisher's website
  14. Ueki M, Taie S, Chujo K, Asaga T, Iwanaga Y, Ono J, Maekawa N (2007) Urinary trypsin inhibitor reduces inflammatory response in kidney induced by lipopolysaccharide. J Biosci Bioeng 104:315–320
    • View reference on PubMed
    • View reference on publisher's website
  15. Tanaka R, Fujita M, Tsuruta R, Fujimoto K, Aki HS, Kumagai K et al (2010) Urinary trypsin inhibitor suppresses excessive generation of superoxide anion radical, systemic inflammation, oxidative stress, and endothelial injury in endotoxemic rats. Inflamm Res 59:597–606
    • View reference on PubMed
    • View reference on publisher's website
  16. Huang N, Wang F, Wang Y, Hou J, Li J, Deng X (2013) Ulinastatin improves survival of septic mice by suppressing inflammatory response and lymphocyte apoptosis. J Surg Res 182:296–302
    • View reference on PubMed
    • View reference on publisher's website
  17. Cao YZ, Tu YY, Chen X, Wang BL, Zhong YX, Liu MH (2012) Protective effect of ulinastatin against murine models of sepsis: inhibition of TNF-α and IL-6 and augmentation of IL-10 and IL-13. Exp Toxicol Pathol 64:543–547
    • View reference on PubMed
    • View reference on publisher's website
  18. 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
  19. 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
    • View reference on PubMed
  20. Opal SM, Lim YP, Cristofaro P, Artenstein AW, Kessimian N, DelSesto D, Parejo N, Palardy JE, Siryaporn E (2011) Inter-alpha inhibitor proteins: a novel therapeutic strategy for experimental anthrax infection. Shock 35:42–44
    • View reference on PubMed
    • View reference on publisher's website
  21. Antonopoulou A, Giamarellos-Bourboulis EJ (2011) Immunomodulation in sepsis: state of the art and future perspective. Immunotherapy 3:117–128
    • View reference on PubMed
    • View reference on publisher's website
  22. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709
    • View reference on PubMed
    • View reference on publisher's website
  23. 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
    • View reference on PubMed
  24. Yang H, Zhen XF, Li HY (2006) Clinical observation of ulinastatin in the treatment of multiorgan dysfunction syndrome. J Guangdong Coll Pharm 6:036
  25. 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
    • View reference on PubMed
  26. 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
  27. Zhang Y, Chen H, Li YM, Zheng SS, Chen YG, Li LJ, Zhou L, Xie HY, Praseedom RK (2008) Thymosin alpha1- and ulinastatin-based immunomodulatory strategy for sepsis arising from intra-abdominal infection due to carbapenem-resistant bacteria. J Infect Dis 198:723–730
    • View reference on PubMed
    • View reference on publisher's website
  28. 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
    • View reference on PubMed
  29. Inoue K, Takano H, Shimada A, Yanagisawa R, Sakurai M, Yoshino S, Sato H, Yoshikawa T (2005) Urinary trypsin inhibitor protects against systemic inflammation induced by lipopolysaccharide. Mol Pharmacol 67:673–680
    • View reference on PubMed
    • View reference on publisher's website
  30. Bae HB, Jeong CW, Li M, Kim HS, Kwak SH (2012) Effects of urinary trypsin inhibitor on lipopolysaccharide-induced acute lung injury in rabbits. Inflammation 35:176–182
    • View reference on PubMed
    • View reference on publisher's website
  31. Tani T, Aoki H, Yoshioka T, Lin KJ, Kodama M (1993) Treatment of septic shock with a protease inhibitor in a canine model: a prospective, randomized, controlled trial. Crit Care Med 21:925–930
    • View reference on PubMed
    • View reference on publisher's website
  32. Inoue K, Takano H, Yanagisawa R, Yoshikawa T (2008) Protective effects of urinary trypsin inhibitor on systemic inflammatory response induced by lipopolysaccharide. J Clin Biochem Nutr 43:139–142
    • View reference on PubMed
    • View reference on publisher's website
  33. Zhang X, Liu F, Liu H, Cheng H, Wang W, Wen Q, Wang Y (2011) Urinary trypsin inhibitor attenuates lipopolysaccharide-induced acute lung injury by blocking the activation of p38 mitogen-activated protein kinase. Inflamm Res 60:569–575
    • View reference on PubMed
    • View reference on publisher's website
  34. 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
    • View reference on PubMed
    • View reference on publisher's website
  35. 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
    • View reference on PubMed
  36. 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
    • View reference on PubMed
  37. Aibiki M, Cook JA (1997) Ulinastatin, a human trypsin inhibitor, inhibits endotoxin-induced thromboxane B2 production in human monocytes. Crit Care Med 25:430–434
    • View reference on PubMed
    • View reference on publisher's website
  38. 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
    • View reference on publisher's website
  39. 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
  40. Kapadia F, Singh M, Divatia J, Vaidyanathan P, Udwadia FE, Raisinghaney SJ, Limaye HS, Karnad DR (2005) End of life limitation and withdrawal of intensive therapy at the end of life: practices in intensive care units in Mumbai, India. Crit Care Med 33:1272–1275
    • View reference on PubMed
    • View reference on publisher's website
  41. Kulkarni HS, Kulkarni KR, Mallampalli A, Parkar SR, Karnad DR, Guntupalli KK (2011) Comparison of anxiety, depression, and post-traumatic stress symptoms in relatives of ICU patients in an American and an Indian public hospital. Indian J Crit Care Med 15:147–156
    • View reference on PubMed
    • View reference on publisher's website
  42. Panchabhai TS, Dangayach NS, Krishnan A, Kothari VM, Karnad DR (2009) Oropharyngeal cleansing with 0.2% chlorhexidine for prevention of nosocomial pneumonia in critically ill patients: an open-label randomized trial with 0.01% potassium permanganate as control. Chest 135:1150–1156
    • View reference on PubMed
    • View reference on publisher's website
  43. Todi S, Chatterjee S, Sahu S, Bhattacharyya M (2010) Epidemiology of severe sepsis in India: an update. Crit Care 14(Suppl 1):382
    • View reference on publisher's website
  44. Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13:818–829
    • View reference on PubMed
    • View reference on publisher's website
  45. 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
    • View reference on publisher's website

Sign In

Connect with ICM

Top 5 Articles Editors Picks Supplement