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Thromb Haemost 2015; 114(03): 537-545
DOI: 10.1160/TH15-01-0053
Coagulation and Fibrinolysis
Schattauer GmbH

Supplemental dose of antithrombin use in disseminated intravascular coagulation patients after abdominal sepsis

Takashi Tagami
1   Department of Clinical Epidemiology and Health Economics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
2   Department of Emergency and Critical Care Medicine, Nippon Medical School, Tokyo, Japan
,
Hiroki Matsui
1   Department of Clinical Epidemiology and Health Economics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
,
Kiyohide Fushimi
3   Department of Health Informatics and Policy, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo, Japan
,
Hideo Yasunaga
1   Department of Clinical Epidemiology and Health Economics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
› Author Affiliations Financial support: This work was supported by the Ministry of Health, Labour and Welfare of Japan (Research on Policy Planning and Evaluation, grant H26-Policy-011 to Prof. Fushimi and Prof. Yasunaga.). The funders had no role in the execution of this study or interpretation of the results.
Further Information

Publication History

Received: 19 January 2015

Accepted after minor revision: 25 March 2015

Publication Date:
21 November 2017 (online)

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Summary

The effectiveness of supplemental dose antithrombin administration (1,500 to 3,000 IU/ day) for patients with sepsis-associated disseminated intravascular coagulation (DIC), especially sepsis due to abdominal origin, remains uncertain. This was a retrospective cohort study of patients with mechanically ventilated septic shock and DIC after emergency surgery for perforation of the lower intestinal tract using a nationwide administrative database, Japanese Diagnosis Procedure Combination inpatient database. A total of 2,164 patients treated at 612 hospitals during the 33-month study period between 2010 and 2013 were divided into an antithrombin group (n=1,021) and a control group (n=1,143), from which 518 propensity score-matched pairs were generated. Although there was no significant 28-day mortality difference between the two groups in the unmatched groups (control vs antithrombin: 25.7 vs 22.9 %; difference, 2.8 %; 95 % confidence interval [CI], –0.8–6.4), a significant difference existed between the two groups in propensity-score weighted groups (26.3 vs 21.7 %; difference, 4.6 %; 95 % CI, 2.0–7.1) and propensity-score matched groups (27.6 vs 19.9 %; difference, 7.7 %; 95 % CI, 2.5–12.9). Logistic regression analyses showed a significant association between antithrombin use and lower 28-day mortality in propensity-matched groups (odds ratio, 0.65; 95 % CI, 0.49–0.87). Analysis using the hospital antithrombin-prescribing rate as an instrumental variable showed that receipt of antithrombin was associated with a 6.5 % (95 % CI, 0.05–13.0) reduction in 28-day mortality. Supplemental dose of antithrombin administration may be associated with reduced 28-day mortality in sepsis-associated DIC patients after emergency laparotomy for intestinal perforation.

Keywords

Antithrombin - disseminated intravascular coagulation - sepsis - surgery
 

  • References

  • 1 Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med 2013; 369: 840-851.
    CrossrefPubMedSearch in Google Scholar
  • 2 Gando S, Iba T, Eguchi Y. et al. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria. Crit Care Med 2006; 34: 625-631.
    CrossrefPubMedSearch in Google Scholar
  • 3 Gando S, Saitoh D, Ogura H. et al. 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 2008; 36: 145-150.
    CrossrefPubMedSearch in Google Scholar
  • 4 Hunt BJ. Bleeding and coagulopathies in critical care. N Engl J Med 2014; 370: 847-859.
    CrossrefPubMedSearch in Google Scholar
  • 5 Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 341: 586-592.
    CrossrefPubMedSearch in Google Scholar
  • 6 Dhainaut JF, Shorr AF, Macias WL. et al. Dynamic evolution of coagulopathy in the first day of severe sepsis: relationship with mortality and organ failure. Crit Care Med 2005; 33: 341-348.
    CrossrefPubMedSearch in Google Scholar
  • 7 Fourrier F. Severe sepsis, coagulation, and fibrinolysis: dead end or one way?. Crit Care Med 2012; 40: 2704-2708.
    CrossrefPubMedSearch in Google Scholar
  • 8 Wiedermann CJ. Clinical review: molecular mechanisms underlying the role of antithrombin in sepsis. Crit Care 2006; 10: 209.
    CrossrefPubMedSearch in Google Scholar
  • 9 Iba T, Gando S, Thachil J. Anticoagulant therapy for sepsis-associated disseminated intravascular coagulation: the view from Japan. J Thromb Haemost 2014; 12: 1010-1019.
    CrossrefPubMedSearch in Google Scholar
  • 10 Fourrier F, Chopin C, Huart JJ. et al. Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Chest 1993; 104: 882-888.
    CrossrefPubMedSearch in Google Scholar
  • 11 Warren BL, Eid A, Singer P. et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. J Am Med Assoc 2001; 286: 1869-1878.
    CrossrefPubMedSearch in Google Scholar
  • 12 Afshari A, Wetterslev J, Brok J. et al. Antithrombin III in critically ill patients: systematic review with meta-analysis and trial sequential analysis. Br Med J 2007; 335: 1248-1251.
    CrossrefPubMedSearch in Google Scholar
  • 13 Eid A, Wiedermann CJ, Kinasewitz GT. Early administration of high-dose anti-thrombin in severe sepsis: single center results from the KyberSept-trial. Anesth Analg 2008; 107: 1633-1638.
    CrossrefPubMedSearch in Google Scholar
  • 14 Rublee D, Opal SM, Schramm W. et al. Quality of life effects of antithrombin III in sepsis survivors: results from the KyberSept trial [ISRCTN22931023]. Crit Care 2002; 06: 349-356.
    CrossrefPubMedSearch in Google Scholar
  • 15 Wiedermann CJ, Hoffmann JN, Juers M. et al. High-dose antithrombin III in the treatment of severe sepsis in patients with a high risk of death: efficacy and safety. Crit Care Med 2006; 34: 285-292.
    CrossrefPubMedSearch in Google Scholar
  • 16 Wiedermann CJ, Kaneider NC. A systematic review of antithrombin concentrate use in patients with disseminated intravascular coagulation of severe sepsis. Blood Coagul Fibrinolysis 2006; 17: 521-526.
    CrossrefPubMedSearch in Google Scholar
  • 17 Oda S, Aibiki M, Ikeda T. et al. The Japanese Guidelines for the Management of Sepsis. J Intensive Care 2014; 02: 55.
    CrossrefPubMedSearch in Google Scholar
  • 18 Iba T, Saito D, Wada H. et al. Efficacy and bleeding risk of antithrombin supplementation in septic disseminated intravascular coagulation: A prospective multicenter survey. Thromb Res 2012; 130: e129-e133.
    CrossrefPubMedSearch in Google Scholar
  • 19 Iba T, Saitoh D, Wada H. et al. Efficacy and bleeding risk of antithrombin supplementation in septic disseminated intravascular coagulation: a secondary survey. Crit Care 2014; 18: 497.
    CrossrefPubMedSearch in Google Scholar
  • 20 Gando S, Saitoh D, Ishikura H. et al. A randomized, controlled, multicenter trial of the effects of antithrombin on disseminated intravascular coagulation in patients with sepsis. Crit Care 2013; 17: R297.
    CrossrefPubMedSearch in Google Scholar
  • 21 Angus DC, Linde-Zwirble WT, Lidicker J. et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29: 1303-1310.
    CrossrefPubMedSearch in Google Scholar
  • 22 Tagami T, Matsui H, Horiguchi H. et al. Antithrombin and mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: an observational nationwide study. J Thromb Haemost 2014; 12: 1470-1479.
    CrossrefPubMedSearch in Google Scholar
  • 23 Tagami T, Matsui H, Horiguchi H. et al. Low-dose corticosteroid use and mortality in severe community-acquired pneumonia patients. Eur Respir J 2015; 45: 463-472.
    CrossrefPubMedSearch in Google Scholar
  • 24 Tagami T, Matsui H, Horiguchi H. et al. Recombinant human soluble thrombomodulinand mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: an observational nationwide study. J Thromb Haemost 2015; 13: 31-40.
    CrossrefPubMedSearch in Google Scholar
  • 25 Schoenfeld DA, Bernard GR. Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome. Crit Care Med 2002; 30: 1772-1777.
    CrossrefPubMedSearch in Google Scholar
  • 26 Austin PC. The use of propensity score methods with survival or time-to-event outcomes: reporting measures of effect similar to those used in randomized experiments. Stat Med 2014; 33: 1242-1258.
    CrossrefPubMedSearch in Google Scholar
  • 27 Rosenbaum P, Rubin D. Constructing a control-group using multivariate matched sampling methods that incorporate the propensity score. Am Stat 1985; 39: 33-38.
    PubMedSearch in Google Scholar
  • 28 Curtis LH, Hammill BG, Eisenstein EL. et al. Using inverse probability-weighted estimators in comparative effectiveness analyses with observational databases. Med Care 2007; 45: S103-107.
    CrossrefPubMedSearch in Google Scholar
  • 29 Dellinger RP, Levy MM, Rhodes A. et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41: 580-637.
    CrossrefPubMedSearch in Google Scholar
  • 30 de Stoppelaar SF, van ’t Veer C, van der Poll T. The role of platelets in sepsis. Thromb Haemost 2014; 112: 666-677.
    Thieme ConnectPubMedSearch in Google Scholar
  • 31 Austin PC. Using the Standardized Difference to Compare the Prevalence of a Binary Variable Between Two Groups in Observational Research. Communications in Statistics – Simulation and Computation 2009; 38: 1228-1234.
    CrossrefPubMedSearch in Google Scholar
  • 32 Stukel TA, Fisher ES, Wennberg DE. et al. Analysis of observational studies in the presence of treatment selection bias: effects of invasive cardiac management on AMI survival using propensity score and instrumental variable methods. J Am Med Assoc 2007; 297: 278-285.
    CrossrefPubMedSearch in Google Scholar
  • 33 Staiger D, Stock JH. Instrumental Variables Regression with Weak Instruments. Econometrica 1994; 65: 557-586.
    PubMedSearch in Google Scholar
  • 34 Kawano S, Uchino S, Endo A. et al. Impact of withdrawing antithrombin III administration from management of septic patients with or without disseminated intravascular coagulation. Blood Coagul Fibrinolysis 2014; 25: 795-800.
    CrossrefPubMedSearch in Google Scholar
  • 35 Levi M, Toh CH, Thachil J. et al. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol 2009; 145: 24-33.
    CrossrefPubMedSearch in Google Scholar
  • 36 Di Nisio M, Baudo F, Cosmi B. et al. Diagnosis and treatment of disseminated intravascular coagulation: guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res 2012; 129: e177-184.
    CrossrefPubMedSearch in Google Scholar
  • 37 Wada H, Thachil J, Di Nisio M. et al. Guidance for diagnosis and treatment of DIC from harmonisation of the recommendations from three guidelines. J Thromb Haemost 2013; 11: 761-767.
    CrossrefPubMedSearch in Google Scholar
  • 38 Wada H, Asakura H, Okamoto K. et al. Expert consensus for the treatment of disseminated intravascular coagulation in Japan. Thromb Res 2010; 125: 6-11.
    CrossrefPubMedSearch in Google Scholar
  • 39 Zhang Z, Ni H, Xu X. Observational studies using propensity score analysis underestimated the effect sizes in critical care medicine. J Clin Epidemiol 2014; 67: 932-939.
    CrossrefPubMedSearch in Google Scholar
  • 40 Zhang Z, Ni H, Xu X. Do the observational studies using propensity score analysis agree with randomized controlled trials in the area of sepsis?. J Crit Care 2014; 29: 886e889-815.
    PubMedSearch in Google Scholar
  • 41 Dahabreh IJ, Sheldrick RC, Paulus JK. et al. Do observational studies using propensity score methods agree with randomized trials? A systematic comparison of studies on acute coronary syndromes. Eur Heart J 2012; 33: 1893-1901.
    CrossrefPubMedSearch in Google Scholar
  • 42 Vincent JL. We should abandon randomized controlled trials in the intensive care unit. Crit Care Med 2010; 38: S534-538.
    CrossrefPubMedSearch in Google Scholar
  • 43 Kushimoto S, Gando S, Saitoh D. et al. Clinical course and outcome of disseminated intravascular coagulation diagnosed by Japanese Association for Acute Medicine criteria. Comparison between sepsis and trauma. Thromb Haemost 2008; 100: 1099-1105.
    Thieme ConnectPubMedSearch in Google Scholar
  • 44 Seam N, Suffredini AF. Is antithrombin treatment of disseminated intravascular coagulation a quixotic goal?. Critical Care 2014; 18: 639.
    CrossrefPubMedSearch in Google Scholar
  • 45 Ranieri VM, Rubenfeld GD, Thompson BT. et al. Acute respiratory distress syndrome: the Berlin Definition. J Am Med Assoc 2012; 307: 2526-2533.
    PubMedSearch in Google Scholar
  • 46 Tagami T, Nakamura T, Kushimoto S. et al. Early-phase changes of extravascular lung water index as a prognostic indicator in acute respiratory distress syndrome patients. Ann Intens Care 2014; 04: 27.
    PubMedSearch in Google Scholar
  • 47 Egi M, Morimatsu H, Wiedermann CJ. et al. Non-overt disseminated intravascular coagulation scoring for critically ill patients: the impact of antithrombin levels. Thromb Haemost 2009; 101: 696-705.
    Thieme ConnectPubMedSearch in Google Scholar
  • 48 Aota T, Matsumoto T, Suzuki K. et al. Antithrombin and mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: an observational nationwide study: comment. J Thromb Haemost. 2014 Epub ahead of print.
    PubMedSearch in Google Scholar