Daisuke Kudo1, Tadahiro Goto2, Ryo Uchimido3, Mineji Hayakawa4, Kazuma Yamakawa5, Toshikazu Abe6,7, Atsushi Shiraishi8, Shigeki Kushimoto9. 1. Division of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan. kudodaisuke@med.tohoku.ac.jp. 2. Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. 3. Intensive Care Unit, Tokyo Medical and Dental University Medical Hospital, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. 4. Department of Emergency Medicine, Hokkaido University Hospital, Kita 14 Nishi-5, Kita-ku, Sapporo, 060-8648, Japan. 5. Division of Emergency Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, 569-8686, Japan. 6. Department of Emergency and Critical Care Medicine, Tsukuba Memorial Hospital, 1187-299 Kaname, Tsukuba, 300-2622, Japan. 7. Health Services Research and Development Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8577, Japan. 8. Emergency and Trauma Center, Kameda Medical Center, 929 Higashimachi, Kamogawa, 296-8602, Japan. 9. Division of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.
Abstract
BACKGROUND: A recent randomised trial showed that recombinant thrombomodulin did not benefit patients who had sepsis with coagulopathy and organ dysfunction. Several recent studies suggested presence of clinical phenotypes in patients with sepsis and heterogenous treatment effects across different sepsis phenotypes. We examined the latent phenotypes of sepsis with coagulopathy and the associations between thrombomodulin treatment and the 28-day and in-hospital mortality for each phenotype. METHODS: This was a secondary analysis of multicentre registries containing data on patients (aged ≥ 16 years) who were admitted to intensive care units for severe sepsis or septic shock in Japan. Three multicentre registries were divided into derivation (two registries) and validation (one registry) cohorts. Phenotypes were derived using k-means with coagulation markers, platelet counts, prothrombin time/international normalised ratios, fibrinogen, fibrinogen/fibrin-degradation-products (FDP), D-dimer, and antithrombin activities. Associations between thrombomodulin treatment and survival outcomes (28-day and in-hospital mortality) were assessed in the derived clusters using a generalised estimating equation. RESULTS: Four sepsis phenotypes were derived from 3694 patients in the derivation cohort. Cluster dA (n = 323) had severe coagulopathy with high FDP and D-dimer levels, severe organ dysfunction, and high mortality. Cluster dB had severe disease with moderate coagulopathy. Clusters dC and dD had moderate and mild disease with and without coagulopathy, respectively. Thrombomodulin was associated with a lower 28-day (adjusted risk difference [RD]: - 17.8% [95% CI - 28.7 to - 6.9%]) and in-hospital (adjusted RD: - 17.7% [95% CI - 27.6 to - 7.8%]) mortality only in cluster dA. Sepsis phenotypes were similar in the validation cohort, and thrombomodulin treatment was also associated with lower 28-day (RD: - 24.9% [95% CI - 49.1 to - 0.7%]) and in-hospital mortality (RD: - 30.9% [95% CI - 55.3 to - 6.6%]). CONCLUSIONS: We identified four coagulation marker-based sepsis phenotypes. The treatment effects of thrombomodulin varied across sepsis phenotypes. This finding will facilitate future trials of thrombomodulin, in which a sepsis phenotype with high FDP and D-dimer can be targeted.
BACKGROUND: A recent randomised trial showed that recombinant thrombomodulin did not benefit patients who had sepsis with coagulopathy and organ dysfunction. Several recent studies suggested presence of clinical phenotypes in patients with sepsis and heterogenous treatment effects across different sepsis phenotypes. We examined the latent phenotypes of sepsis with coagulopathy and the associations between thrombomodulin treatment and the 28-day and in-hospital mortality for each phenotype. METHODS: This was a secondary analysis of multicentre registries containing data on patients (aged ≥ 16 years) who were admitted to intensive care units for severe sepsis or septic shock in Japan. Three multicentre registries were divided into derivation (two registries) and validation (one registry) cohorts. Phenotypes were derived using k-means with coagulation markers, platelet counts, prothrombin time/international normalised ratios, fibrinogen, fibrinogen/fibrin-degradation-products (FDP), D-dimer, and antithrombin activities. Associations between thrombomodulin treatment and survival outcomes (28-day and in-hospital mortality) were assessed in the derived clusters using a generalised estimating equation. RESULTS: Four sepsis phenotypes were derived from 3694 patients in the derivation cohort. Cluster dA (n = 323) had severe coagulopathy with high FDP and D-dimer levels, severe organ dysfunction, and high mortality. Cluster dB had severe disease with moderate coagulopathy. Clusters dC and dD had moderate and mild disease with and without coagulopathy, respectively. Thrombomodulin was associated with a lower 28-day (adjusted risk difference [RD]: - 17.8% [95% CI - 28.7 to - 6.9%]) and in-hospital (adjusted RD: - 17.7% [95% CI - 27.6 to - 7.8%]) mortality only in cluster dA. Sepsis phenotypes were similar in the validation cohort, and thrombomodulin treatment was also associated with lower 28-day (RD: - 24.9% [95% CI - 49.1 to - 0.7%]) and in-hospital mortality (RD: - 30.9% [95% CI - 55.3 to - 6.6%]). CONCLUSIONS: We identified four coagulation marker-based sepsis phenotypes. The treatment effects of thrombomodulin varied across sepsis phenotypes. This finding will facilitate future trials of thrombomodulin, in which a sepsis phenotype with high FDP and D-dimer can be targeted.
Authors: Han Li; Asena Markal; Jeremy A Balch; Tyler J Loftus; Philip A Efron; Tezcan Ozrazgat-Baslanti; Azra Bihorac Journal: Crit Care Explor Date: 2022-03-30