Co-administration of iloprost and eptifibatide in septic shock (CO-ILEPSS)\u2014a randomised, controlled, double-blind investigator-initiated trial investigating safety and efficacy

Rasmus Ehrenfried Berthelsen,Morten Heiberg Bestle,Per Ingemar Johansson,Sisse Rye Ostrowski

doi:10.1186/s13054-019-2573-8

Abstract

BackgroundPart 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.MethodThe 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 μg/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.ResultsWe 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.ConclusionOur 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.Trial registrationClinicaltrials.com, NCT02204852 (July 30, 2014); EudraCT no. 2014-002440-41

Highlights

Septic shock is a leading cause of death in the intensive care unit (ICU) with mortality rates above 40% [1, 2]
The proinflammatory response induces widespread endothelial and microvascular injury resulting in disseminated intravascular coagulation with microvascular thrombosis, consumptive thrombocytopenia, coagulopathy, bleeding and a loss of endothelial integrity leading to capillary leakage, tissue oedema, tissue ischaemia and shock [5,6,7]
Alkaline phosphatase was significantly different between groups at baseline, and it is worth noting that the disease severity was considerable with Sequential Organ Failure Assessment (SOFA) scores of 8–10, SAPS Simplified Acute Physiology Score (II) scores of 46–48 and an observed 90-day mortality of 25–50%

Summary

Introduction

Septic shock is a leading cause of death in the intensive care unit (ICU) with mortality rates above 40% [1, 2]. The initial reaction to infection is a neurohumoral, generalised pro- and anti-inflammatory response [4, 5] resulting in mobilisation and/or “spill over” of plasma substances and excessive cellular, coagulation and endothelial activation. The proinflammatory response induces widespread endothelial and microvascular injury resulting in disseminated intravascular coagulation with microvascular thrombosis, consumptive thrombocytopenia, coagulopathy, bleeding and a loss of endothelial integrity leading to capillary leakage, tissue oedema, tissue ischaemia and shock [5,6,7]. 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

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Results

Discussion

Conclusion