Division of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.
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.
Crit Care. 2021 Mar 19;25(1):114. doi: 10.1186/s13054-021-03541-5.
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.
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.
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%]).
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.
最近的一项随机试验表明，重组血栓调节蛋白对合并凝血障碍和器官功能障碍的脓毒症患者没有益处。最近的几项研究表明，脓毒症患者存在临床表型，不同脓毒症表型的治疗效果存在异质性。我们检查了合并凝血障碍的脓毒症的潜在表型，以及血栓调节蛋白治疗与每个表型的 28 天和住院死亡率之间的关系。
这是对包含日本重症监护病房收治的严重脓毒症或感染性休克患者数据的三个多中心登记处的二次分析。三个多中心登记处分为推导（两个登记处）和验证（一个登记处）队列。使用凝血标志物、血小板计数、凝血酶原时间/国际标准化比值、纤维蛋白原、纤维蛋白原/纤维蛋白降解产物（FDP）、D-二聚体和抗凝血酶活性的 k-均值方法得出表型。使用广义估计方程评估推导聚类中血栓调节蛋白治疗与生存结局（28 天和住院死亡率）之间的关系。
从推导队列中的 3694 名患者中得出了四个脓毒症表型。簇 dA（n=323）有严重的凝血障碍，FDP 和 D-二聚体水平高，器官功能严重障碍，死亡率高。簇 dB 有严重的疾病，中等程度的凝血障碍。簇 dC 和 dD 有中度和轻度疾病，分别有和没有凝血障碍。只有在簇 dA 中，血栓调节蛋白治疗与较低的 28 天（调整后的风险差异[RD]：-17.8%[95%置信区间-28.7%至-6.9%]）和住院（调整后的 RD：-17.7%[95%置信区间-27.6%至-7.8%]）死亡率相关。验证队列中的脓毒症表型相似，血栓调节蛋白治疗也与较低的 28 天（RD：-24.9%[95%置信区间-49.1%至-0.7%]）和住院死亡率（RD：-30.9%[95%置信区间-55.3%至-6.6%]）相关。
我们确定了四个基于凝血标志物的脓毒症表型。血栓调节蛋白的治疗效果在不同的脓毒症表型之间存在差异。这一发现将有助于未来血栓调节蛋白的试验，其中可以针对 FDP 和 D-二聚体高的脓毒症表型进行治疗。
