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

Intensive Care Medicine

Volumn 40, Issue 6, 2014, Pages 830-838

  Karnad, Dilip R ^a   Bhadade, Rakesh ^b   Verma, Pradeep K ^c   Moulick, Nivedita D ^d   Daga, Mradul K ^e   Chafekar, Neelima D ^f   Iyer, Shivakumar ^g  

^a Jupiter Hospital   (India)

^b BYL NAIR CHARITABLE HOSPITAL   (India)

^c SAFDARJUNG HOSPITAL   (India)

^d Department of Medicine Lokmanya Tilak Muncipal General Hospital Medical College ^*  (India)

^e MAULANA AZAD MEDICAL COLLEGE   (India)

^f Department of Medicine   (India)

^g Jehangir Clinical Development Centre   (India)

Author keywords

Abdominal sepsis; Bacterial infection; Inflammatory mediators; Pneumonia; Septic shock; Serine protease inhibitor

Indexed keywords

ANTIBIOTIC AGENT; HYPERTENSIVE FACTOR; PLACEBO; ULINASTATIN; GLYCOPROTEIN; TRYPSIN INHIBITOR;

ACUTE KIDNEY FAILURE; ADULT; ADULT RESPIRATORY DISTRESS SYNDROME; ANTIBIOTIC THERAPY; APACHE; ARTICLE; ARTIFICIAL VENTILATION; CAUSE OF DEATH; CONTROLLED STUDY; DISEASE SEVERITY; DOUBLE BLIND PROCEDURE; DRUG EFFECT; DRUG EFFICACY; FEMALE; HOSPITALIZATION; HUMAN; INFUSION RELATED REACTION; INTENTION TO TREAT ANALYSIS; MAJOR CLINICAL STUDY; MALE; MULTICENTER STUDY; MULTIPLE ORGAN FAILURE; PILOT STUDY; RANDOMIZED CONTROLLED TRIAL; SEPSIS; SHOCK; CLINICAL TRIAL; INTRAVENOUS DRUG ADMINISTRATION; PROSPECTIVE STUDY;

ADULT; DOUBLE-BLIND METHOD; FEMALE; GLYCOPROTEINS; HUMANS; INFUSIONS, INTRAVENOUS; MALE; PILOT PROJECTS; PROSPECTIVE STUDIES; SEPSIS; TRYPSIN INHIBITORS;

EID: 84901476727     PISSN: 03424642     EISSN: 14321238     Source Type: Journal    
DOI: 10.1007/s00134-014-3278-8     Document Type: Article

References (45)

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 (Pubitemid 32641789)
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
3. Rittirsch D, Flierl MA, Ward PA (2008) Harmful molecular mechanisms in sepsis. Nat Rev Immunol 8:776-787
4. Van der Poll T, Opal SM (2008) Hostpathogen interaction in sepsis. Lancet Infect Dis 8:32-43
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
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-amodernperspective/ urinary-trypsininhibitor- an-alternative-therapeuticoption- 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
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
10. Pugia MJ, Lott JA (2005) Pathophysiology and diagnostic value of urinary trypsin inhibitors. Clin Chem Lab Med 43:1-16 (Pubitemid 40287494)
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
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 (Pubitemid 37176040)
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-a and interleukin-1b in macrophages. J Infect Dis 191:930-938 (Pubitemid 40349809)
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 (Pubitemid 350102407)
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
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
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-a and IL-6 and augmentation of IL-10 and IL-13. Exp Toxicol Pathol 64:543-547
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
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
21. Antonopoulou A, Giamarellos- Bourboulis EJ (2011) Immunomodulation in sepsis: state of the art and future perspective. Immunotherapy 3:117-128
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 (Pubitemid 32204987)
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
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 a1: a prospective, randomized, controlled pilot study. Chin Med J 122:883-888
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
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 (Pubitemid 32163436)
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 (Pubitemid 40365315)
30. Bae HB, Jeong CW, Li M, Kim HS, Kwak SH (2012) Effects of urinary trypsin inhibitor on lipopolysaccharideinduced acute lung injury in rabbits. Inflammation 35:176-182
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 (Pubitemid 23173033)
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
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
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
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 (Pubitemid 20287914)
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 (Pubitemid 20268157)
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 (Pubitemid 27152736)
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
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 (Pubitemid 40827377)
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
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
43. Todi S, Chatterjee S, Sahu S, Bhattacharyya M (2010) Epidemiology of severe sepsis in India: an update. Crit Care 14(Suppl 1):382
44. Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13:818-829 (Pubitemid 15250137)
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