Co-administration of iloprost and eptifibatide in septic shock (CO-ILEPSS)-a randomised, controlled, double-blind investigator-initiated trial investigating safety and efficacy
Co-administration of iloprost and eptifibatide in septic shock (CO-ILEPSS)-a randomised, controlled, double-blind investigator-initiated trial investigating safety and efficacy
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DOI：
10.1186/s13054-019-2573-8
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发表时间：
2019-09-05
期刊：
影响因子：
15.1
通讯作者：
Johansson, Per Ingemar
中科院分区：
文献类型：
--
作者：
Berthelsen, Rasmus Ehrenfried;Ostrowski, Sisse Rye;Johansson, Per Ingemar
感染性休克的部分病理生理机制是内皮和血小板的进行性活化导致广泛的微血管损伤，包括毛细血管渗漏、微血栓和耗血性凝血病。调节内皮细胞和血小板的炎症反应可能会减轻这种恶性循环并改善预后。方法CO-ILEPSS试验为随机、安慰剂对照、双盲、先导试验。脓毒性休克入住重症监护病房的患者被随机分配，并以2:1的比例分配到积极治疗中，伊洛前列素1 ng/kg/min和依替巴肽0.5 mu g/kg/min的双重治疗，持续48小时或安慰剂。主要结果是反映内皮活化和破坏、血小板消耗和纤维蛋白溶解的生物标志物的变化。我们采用混合模型、事后Wilcoxon sign -rank检验和Mann-Whitney U检验进行组间比较。我们纳入了24例患者，其中18例（12例活跃，6例安慰剂）完成了完整的7天试验期，并纳入了主要结局的按方案分析。两组间的直接比较显示主要结果没有差异。组内δ值分析显示，内皮活化和破坏的生物标志物在两组之间变化不同，安慰剂组血栓调节素（p = 0.03）和核小体（p = 0.02）水平升高，而积极治疗组se -选择素（p = 0.007）和sVEGFR1 （p = 0.005）水平降低。血小板计数在安慰剂组前48小时下降（p = 0.049），而在积极治疗组从基线到第7天增加（p = 0.023）。积极治疗组的纤维蛋白单体水平在前48小时内（p = 0.048）及以后（p = 0.03）下降。此外，积极治疗组的SOFA评分从48小时开始显著降低（p = 0.024）。对所有纳入患者的意向治疗分析显示，包括出血、使用血液制品或死亡率在内的严重不良事件没有差异。结论我们的研究结果表明，实验性治疗可以减少内皮损伤，减少血小板消耗，随后降低纤维蛋白溶解生物标志物，并提高SOFA评分。CO-ILEPSS试验的结果是探索性的和假设生成的，值得在大规模试验中进一步调查。
Background Part of the pathophysiology in septic shock is a progressive activation of the endothelium and platelets leading to widespread microvascular injury with capillary leakage, microthrombi and consumption coagulopathy. Modulating the inflammatory response of endothelium and thrombocytes might attenuate this vicious cycle and improve outcome. Method The CO-ILEPSS trial was a randomised, placebo-controlled, double-blind, pilot trial. Patients admitted to the intensive care unit with septic shock were randomised and allocated in a 2:1 ratio to active treatment with dual therapy of iloprost 1 ng/kg/min and eptifibatide 0.5 mu g/kg/min for 48 h or placebo. The primary outcomes were changes in biomarkers reflecting endothelial activation and disruption, platelet consumption and fibrinolysis. We compared groups with mixed models, post hoc Wilcoxon signed-rank test and Mann-Whitney U test. Results We included 24 patients of which 18 (12 active, 6 placebo) completed the full 7-day trial period and were included in the per-protocol analyses of the primary outcomes. Direct comparison between groups showed no differences in the primary outcomes. Analyses of within-group delta values revealed that biomarkers of endothelial activation and disruption changed differently between groups with increasing levels of thrombomodulin (p = 0.03) and nucleosomes (p = 0.02) in the placebo group and decreasing levels of sE-Selectin (p = 0.007) and sVEGFR1 (p = 0.005) in the active treatment group. Platelet count decreased the first 48 h in the placebo group (p = 0.049) and increased from baseline to day 7 in the active treatment group (p = 0.023). Levels of fibrin monomers declined in the active treatment group within the first 48 h (p = 0.048) and onwards (p = 0.03). Furthermore, there was a significant reduction in SOFA score from 48 h (p = 0.024) and onwards in the active treatment group. Intention-to-treat analyses of all included patients showed no differences in serious adverse events including bleeding, use of blood products or mortality. Conclusion Our results could indicate benefit from the experimental treatment with reduced endothelial injury, reduced platelet consumption and ensuing reduction in fibrinolytic biomarkers along with improved SOFA score. The results of the CO-ILEPSS trial are exploratory and hypothesis generating and warrant further investigation in a large-scale trial.