Treatment with Antithrombin or Thrombomodulin and Mortality from Heatstroke-Induced Disseminated Intravascular Coagulation: A Nationwide Observational Study

Hiroyuki Ohbe; Shunsuke Isogai; Taisuke Jo; Hiroki Matsui; Kiyohide Fushimi; Hideo Yasunaga

doi:10.1055/s-0039-1700520

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2019; 45(08): 760-766
DOI: 10.1055/s-0039-1700520

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Treatment with Antithrombin or Thrombomodulin and Mortality from Heatstroke-Induced Disseminated Intravascular Coagulation: A Nationwide Observational Study

Hiroyuki Ohbe

¹Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

,

Shunsuke Isogai

¹Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

,

Taisuke Jo

¹Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

,

Hiroki Matsui

¹Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

,

Kiyohide Fushimi

²Department of Health Policy and Informatics, Tokyo Medical and Dental University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan

,

Hideo Yasunaga

¹Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

› Author Affiliations

Abstract

Heatstroke-induced disseminated intravascular coagulation represents potential targets for specific intensive treatments. However, the effect of antithrombin or thrombomodulin treatment remains uncertain. Using a large nationwide inpatient database in Japan, this study aimed to evaluate whether treatment with antithrombin or thrombomodulin could reduce mortality among patients with heatstroke-induced disseminated intravascular coagulation. Using the Japanese Diagnosis Procedure Combination inpatient database from April 2014 to March 2017, we identified heatstroke patients who developed disseminated intravascular coagulation. We allocated patients who started treatment with antithrombin or thrombomodulin within 2 days after admission to the treatment group and allocated others to the control group. A primary outcome was in-hospital mortality. We used a doubly robust analysis to ensure the robustness of our findings. We also conducted two sensitivity analyses for thrombomodulin versus others and antithrombin versus others. We identified 1,606 eligible patients during the 81-month study period. Of these, 556 (35%) received antithrombin or thrombomodulin. The doubly robust analysis demonstrated that in-hospital mortality was significantly lower among patients in the treatment group than among those in the control group (risk difference −6.5%; 95% confidence interval: −12 to −1.4%). In-hospital mortality was significantly lower in patients with thrombomodulin than in others (risk difference −5.5%; 95% confidence interval: −9.5 to −1.6%). There was no significant difference in in-hospital mortality between patients with antithrombin and others (risk difference −4.2%; 95% confidence interval: −9.3 to 0.9%). Treatment with recombinant human thrombomodulin may be associated with lower in-hospital mortality among patients with heatstroke-induced disseminated intravascular coagulation.

Keywords

heatstroke - disseminated intravascular coagulation - antithrombin - thrombomodulin

Full Text

References

References
1 Misset B, De Jonghe B, Bastuji-Garin S. , et al. Mortality of patients with heatstroke admitted to intensive care units during the 2003 heat wave in France: a national multiple-center risk-factor study. Crit Care Med 2006; 34 (04) 1087-1092
2 Hajat S, Vardoulakis S, Heaviside C, Eggen B. Climate change effects on human health: projections of temperature-related mortality for the UK during the 2020s, 2050s and 2080s. J Epidemiol Community Health 2014; 68 (07) 641-648
3 Sohal RS, Sun SC, Colcolough HL, Burch GE. Heat stroke. An electron microscopic study of endothelial cell damage and disseminated intravascular coagulation. Arch Intern Med 1968; 122 (01) 43-47
4 Chao TC, Sinniah R, Pakiam JE. Acute heat stroke deaths. Pathology 1981; 13 (01) 145-156
5 Jilma B, Derhaschnig U. Disseminated intravascular coagulation in heat stroke: a hot topic. Crit Care Med 2012; 40 (04) 1370-1372
6 Mustafa KY, Omer O, Khogali M. , et al. Blood coagulation and fibrinolysis in heat stroke. Br J Haematol 1985; 61 (03) 517-523
7 Bouchama A, Al-Mohanna F, Assad L. , et al. Tissue factor/factor VIIa pathway mediates coagulation activation in induced-heat stroke in the baboon. Crit Care Med 2012; 40 (04) 1229-1236
8 Levi M. Hemostasis and thrombosis in extreme temperatures (hypo- and hyperthermia). Semin Thromb Hemost 2018; 44 (07) 651-655
9 Huisse M-G, Pease S, Hurtado-Nedelec M. , et al. Leukocyte activation: the link between inflammation and coagulation during heatstroke. A study of patients during the 2003 heat wave in Paris. Crit Care Med 2008; 36 (08) 2288-2295
10 Hifumi T, Kondo Y, Shimazaki J. , et al. Prognostic significance of disseminated intravascular coagulation in patients with heat stroke in a nationwide registry. J Crit Care 2018; 44: 306-311
11 Hagiwara S, Iwasaka H, Goto K. , et al. Recombinant thrombomodulin prevents heatstroke by inhibition of high-mobility group box 1 protein in sera of rats. Shock 2010; 34 (04) 402-406
12 Hagiwara S, Iwasaka H, Shingu C, Matsumoto S, Uchida T, Noguchi T. High-dose antithrombin III prevents heat stroke by attenuating systemic inflammation in rats. Inflamm Res 2010; 59 (07) 511-518
13 Pechlaner Ch, Kaneider NC, Djanani A, Sandhofer A, Schratzberger P, Patsch JR. Antithrombin and near-fatal exertional heat stroke. Acta Med Austriaca 2002; 29 (03) 107-111
14 Fushimi K, Hashimoto H, Imanaka Y. , et al. Functional mapping of hospitals by diagnosis-dominant case-mix analysis. BMC Health Serv Res 2007; 7: 50
15 Yamana H, Horiguchi H, Fushimi K, Yasunaga H. Comparison of procedure-based and diagnosis-based identifications of severe sepsis and disseminated intravascular coagulation in administrative data. J Epidemiol 2016; 26 (10) 530-537
16 Ministry of Health. Labour and Welfare, Japan. Annual Report on the Functions of Medical Institutions. Available at: https://www.mhlw.go.jp/file/06-Seisakujouhou-10800000-Iseikyoku/11_h29_byouin_kinyuuyouryou_1.pdf . Accessed September 14, 2018
17 Wilhelms SB, Huss FR, Granath G, Sjöberg F. Assessment of incidence of severe sepsis in Sweden using different ways of abstracting International Classification of Diseases codes: difficulties with methods and interpretation of results. Crit Care Med 2010; 38 (06) 1442-1449
18 Bouchama A, Knochel JP. Heat stroke. N Engl J Med 2002; 346 (25) 1978-1988
19 Shigematsu K, Nakano H, Watanabe Y. The eye response test alone is sufficient to predict stroke outcome—reintroduction of Japan Coma Scale: a cohort study. BMJ Open 2013; 3 (04) e002736
20 Quan H, Li B, Couris CM. , et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol 2011; 173 (06) 676-682
21 Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29 (07) 1303-1310
22 Lo Re III V, Carbonari DM, Forde KA. , et al. Validity of diagnostic codes and laboratory tests of liver dysfunction to identify acute liver failure events. Pharmacoepidemiol Drug Saf 2015; 24 (07) 676-683
23 Funk MJ, Westreich D, Wiesen C, Stürmer T, Brookhart MA, Davidian M. Doubly robust estimation of causal effects. Am J Epidemiol 2011; 173 (07) 761-767
24 Cole SR, Hernán MA. Constructing inverse probability weights for marginal structural models. Am J Epidemiol 2008; 168 (06) 656-664
25 Austin PC. Using the standardized difference to compare the prevalence of a binary variable between two groups in observational research. Commun Stat Simul Comput 2009; 38 (06) 1228-1234
26 Stuart EA. Matching methods for causal inference: a review and a look forward. Stat Sci 2010; 25 (01) 1-21
27 Rosenbaum PR, Rubin DB. Constructing a control group using multivariate matched sampling methods that incorporate the propensity score. Am Stat 1985; 39 (01) 33-38
28 Bouchama A, Kunzelmann C, Dehbi M. , et al. Recombinant activated protein C attenuates endothelial injury and inhibits procoagulant microparticles release in baboon heatstroke. Arterioscler Thromb Vasc Biol 2008; 28 (07) 1318-1325
29 Chen C-M, Hou CC, Cheng KC, Tian RL, Chang CP, Lin MT. Activated protein C therapy in a rat heat stroke model. Crit Care Med 2006; 34 (07) 1960-1966
30 Levi M, Van Der Poll T. Thrombomodulin in sepsis. Minerva Anestesiol 2013; 79 (03) 294-298
31 Abeyama K, Stern DM, Ito Y. , et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest 2005; 115 (05) 1267-1274
32 Hauptman JG, Hassouna HI, Bell TG, Penner JA, Emerson TE. Efficacy of antithrombin III in endotoxin-induced disseminated intravascular coagulation. Circ Shock 1988; 25 (02) 111-122
33 Emerson Jr TE, Fournel MA, Leach WJ, Redens TB. Protection against disseminated intravascular coagulation and death by antithrombin-III in the Escherichia coli endotoxemic rat. Circ Shock 1987; 21 (01) 1-13
34 Wiedermann CJ, Hoffmann JN, Juers M. , et al; KyberSept Investigators. 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 (02) 285-292
35 Yamakawa K, Aihara M, Ogura H, Yuhara H, Hamasaki T, Shimazu T. Recombinant human soluble thrombomodulin in severe sepsis: a systematic review and meta-analysis. J Thromb Haemost 2015; 13 (04) 508-519
36 Allingstrup M, Wetterslev J, Ravn FB, Møller AM, Afshari A. Antithrombin III for critically ill patients: a systematic review with meta-analysis and trial sequential analysis. Intensive Care Med 2016; 42 (04) 505-520

Supplementary Material

Supplementary Material