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Recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysisOpen access

Kazuma Yamakawa| Hiroshi Ogura| Satoshi Fujimi| Miki Morikawa| Yoshihito Ogawa| Tomoyoshi Mohri| Yasushi Nakamori| Yoshiaki Inoue| Yasuyuki Kuwagata| Hiroshi Tanaka| Toshimitsu Hamasaki| Takeshi Shimazu
Original
Volume 39, Issue 4 / April , 2013

Pages 644 - 652

Abstract

Purpose

Evidence of efficacy and safety of, and especially mortality related to, recombinant human thrombomodulin (rhTM) treatment for sepsis-induced disseminated intravascular coagulation (DIC) is limited. We hypothesized that patients with sepsis-induced DIC receiving treatment with rhTM would have improved mortality compared with those with similar acuity who did not.

Methods

This retrospective cohort study conducted in three tertiary referral hospitals in Japan between January 2006 and June 2011 included all patients with sepsis-induced DIC who required ventilator management. Primary endpoint was in-hospital mortality, with duration of intensive care unit treatment, changes in DIC scores and rate of bleeding complications as secondary endpoints. Regression technique was used to develop a propensity model adjusted for baseline imbalances between groups.

Results

Eligible were 162 patients with sepsis-induced DIC; 68 patients received rhTM and 94 did not. Patients receiving rhTM had higher severity of illness according to baseline characteristics. After adjusting for these imbalances by stratified propensity score analysis, treatment with rhTM was significantly associated with reduced in-hospital mortality (adjusted hazard ratio, 0.45; 95 % confidential interval, 0.26–0.77; p = 0.013). An association between rhTM treatment and higher numbers of intensive care unit-free days, ventilator-free days, and vasopressor-free days were observed. DIC scores were significantly decreased in the rhTM group compared with the control group in the early period after rhTM treatment, whereas the incidence of bleeding-related adverse events did not differ between the two groups.

Conclusions

Therapy with rhTM may be associated with reduced in-hospital mortality in adult mechanically ventilated patients with sepsis-induced DIC.

Keywords

References

  1. Levi M, van der Poll T (2010) Inflammation and coagulation. Crit Care Med 38:S26–S34
    • View reference on PubMed
    • View reference on publisher's website
  2. Esmon CT (2005) The interactions between inflammation and coagulation. Br J Haematol 131:417–430
    • View reference on PubMed
    • View reference on publisher's website
  3. Levi M, Toh CH, Thachil J, Watson HG (2009) Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol 145:24–33
    • View reference on PubMed
    • View reference on publisher's website
  4. Wada H, Asakura H, Okamoto K et al (2010) Expert consensus for the treatment of disseminated intravascular coagulation in Japan. Thromb Res 125:6–11
    • View reference on PubMed
    • View reference on publisher's website
  5. Di Nisio M, Baudo F, Cosmi B, D’Angelo A, De Gasperi A, Malato A, Schiavoni M, Squizzato A, Italian Society for Thrombosis and Haemostasis (2012) Diagnosis and treatment of disseminated intravascular coagulation: guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res 129:e177–e184
    • View reference on PubMed
    • View reference on publisher's website
  6. Nagato M, Okamoto K, Abe Y, Higure A, Yamaguchi K (2009) Recombinant human soluble thrombomodulin decreases the plasma high-mobility group box-1 protein levels, whereas improving the acute liver injury and survival rates in experimental endotoxemia. Crit Care Med 37:2181–2186
    • View reference on PubMed
    • View reference on publisher's website
  7. Iba T, Nakarai E, Takayama T, Nakajima K, Sasaoka T, Ohno Y (2009) Combination effect of antithrombin and recombinant human soluble thrombomodulin in a lipopolysaccharide induced rat sepsis model. Crit Care 13:R203
    • View reference on PubMed
    • View reference on publisher's website
  8. Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R, Hirayama A, Matsuda T, Asakura H, Nakashima M, Aoki N (2007) Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 5:31–41
    • View reference on PubMed
    • View reference on publisher's website
  9. Aikawa N, Shimazaki S, Yamamoto Y, Saito H, Maruyama I, Ohno R, Hirayama A, Aoki Y, Aoki N (2011) Thrombomodulin alfa in the treatment of infectious patients complicated by disseminated intravascular coagulation: subanalysis from the phase 3 trial. Shock 35:349–354
    • View reference on PubMed
    • View reference on publisher's website
  10. Yamakawa K, Fujimi S, Mohri T, Matsuda H, Nakamori Y, Hirose T, Tasaki O, Ogura H, Kuwagata Y, Hamasaki T, Shimazu T (2011) Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study. Crit Care 15:R123
    • View reference on PubMed
    • View reference on publisher's website
  11. Ogawa Y, Yamakawa K, Ogura H, Kiguchi T, Mohri T, Nakamori Y, Kuwagata Y, Shimazu T, Hamasaki T, Fujimi S (2012) Recombinant human soluble thrombomodulin improves mortality and respiratory dysfunction in patients with severe sepsis. J Trauma Acute Care Surg 72:1150–1157
    • View reference on PubMed
  12. Gando S, Iba T, Eguchi Y et al (2006) A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria. Crit Care Med 34:625–631
    • View reference on PubMed
  13. Dellinger RP, Carlet JM, Masur H et al (2004) Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Intensiv Care Med 30:536–555
    • View reference on publisher's website
  14. Dellinger RP, Levy MM, Carlet JM et al (2008) Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensiv Care Med 34:17–60
    • View reference on publisher's website
  15. Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M, Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH) (2001) Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 86:1327–1330
    • View reference on PubMed
  16. Gando S, Saitoh D, Ogura H et al (2008) Natural history of disseminated intravascular coagulation diagnosed based on the newly established diagnostic criteria for critically ill patients: results of a multicenter, prospective survey. Crit Care Med 36:145–150
    • View reference on PubMed
    • View reference on publisher's website
  17. D’Agostino RB Jr, D’Agostino RB Sr (2007) Estimating treatment effects using observational data. JAMA 297:314–316
    • View reference on PubMed
    • View reference on publisher's website
  18. Gayat E, Pirracchio R, Resche-Rigon M, Mebazaa A, Mary JY, Porcher R (2010) Propensity scores in intensive care and anaesthesiology literature: a systematic review. Intensiv Care Med 36:1993–2003
    • View reference on publisher's website
  19. Kurth T, Walker AM, Glynn RJ, Chan KA, Gaziano JM, Berger K, Robins JM (2006) Results of multivariable logistic regression, propensity matching, propensity adjustment, and propensity-based weighting under conditions of nonuniform effect. Am J Epidemiol 163:262–270
    • View reference on PubMed
    • View reference on publisher's website
  20. Cheng B, Chow S (2003) Validity of LOCF. In: Chow S (ed) Encyclopedia of biopharmaceutical statistics, 2nd edn. Inf Healthc, London, pp 1023–1029
  21. Bernard GR, Vincent JL, Laterre PF 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
  22. Dhainaut JF, Yan SB, Joyce DE, Pettilä V, Basson B, Brandt JT, Sundin DP, Levi M (2004) Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost 2:1924–1933
    • View reference on PubMed
    • View reference on publisher's website
  23. Ranieri VM, Thompson BT, Barie PS et al (2012) Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 366:2055–2064
    • View reference on PubMed
    • View reference on publisher's website
  24. Angus DC (2012) Drotrecogin alfa (activated)…a sad final fizzle to a roller-coaster party. Crit Care 16:107
    • View reference on PubMed
    • View reference on publisher's website
  25. Warren BL, Eid A, Singer P et al (2001) Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 286:1869–1878
    • View reference on PubMed
    • View reference on publisher's website
  26. Finigan JH (2009) The coagulation system and pulmonary endothelial function in acute lung injury. Microvasc Res 77:35–38
    • View reference on PubMed
    • View reference on publisher's website
  27. Uchiba M, Okajima K, Murakami K, Johno M, Okabe H, Takatsuki K (1996) Recombinant thrombomodulin prevents endotoxin-induced lung injury in rats by inhibiting leukocyte activation. Am J Physiol 271:L470–L475
    • View reference on PubMed
  28. Martí-Carvajal AJ, Solà I, Lathyris D, Cardona AF (2012) Human recombinant activated protein C for severe sepsis. Cochrane Database Syst Rev 3:CD004388
    • View reference on PubMed

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