Abstract and Introduction
Abstract
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 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.
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.
Introduction
Septic shock is a leading cause of death in the intensive care unit (ICU) with mortality rates above 40%.[1,2] Treatment strategies consist of early recognition and diagnosis to facilitate timely initiation of antibiotic therapy and supportive care.[3] A series of pathogenic events are responsible for the transition from sepsis to septic shock. 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 ultimately leading to capillary leakage, tissue oedema, tissue ischaemia and shock.[5–7] In the later stages of sepsis, immunodeficiency is a critical component of the pathology that causes multiple organ failure and death.[8]
There are three major pathogenic pathways associated with the coagulopathy in sepsis: (1) tissue factor-mediated thrombin generation, (2) dysfunctional anticoagulant pathways and (3) blocked fibrinolysis.[9] Treatment strategies aimed at reducing coagulation activation with antithrombin,[10] tissue factor pathway inhibitor[11] and activated Protein C[12,13] have all failed to show improved survival in large clinical trials refuting this as a pathophysiological explanation.
The platelets and endothelium are interdependent in the vicious cycle of endothelial damage, microcirculatory failure, consumptive thrombocytopenia, coagulopathy, bleeding, immunodeficiency, tissue ischaemia, shock, organ failure and death, in patients with severe sepsis/septic shock. Selective targeting of either platelets or the endothelium may be sufficient to prevent the progressively more activated and damaged endothelium and activation of the platelets.[14]
Prostacyclin is an endogenously produced molecule with anti-platelet, vasodilatory and cytoprotective properties released from the healthy endothelium as part of the natural anticoagulation system.[15] Intravenous prostacyclin in doses of 0.5–2.0 ng/kg/min has been reported to be successful at achieving endothelial modulating/preserving effects in patients with traumatic brain injury, without significant haemodynamic or platelet aggregation complications.[16,17]
Eptifibatide is a platelet glycoprotein (GP) IIb/IIIa receptor inhibitor that prohibits clot development in a predictable and easy controllable way. Inhibition of the GPIIb/IIIa receptor does not alter the paracrine function of platelets, which is considered a crucial part of maintaining vascular integrity and preventing haemorrhage in conditions with inflammation.[18,19] Animal studies have reported that treatment with GPIIb/IIIa inhibitor protects against endothelial dysfunction in experimental endotoxemia.[20,21] Furthermore, casuistic findings have shown that GPIIb/IIIa inhibition leads to clinically relevant thrombolysis in patients with mechanical prosthetic mitral valve thrombosis.[22,23]
The objective of the CO-ILEPSS trial was to investigate safety and efficacy of a combined infusion of low-dose prostacyclin (iloprost) and GPIIb/IIIa inhibitor (eptifibatide) for 48 h in patients with septic shock. We hypothesised that this dual treatment with iloprost and eptifibatide would deactivate the endothelium and restore vascular integrity, reduce formation of microvascular thrombosis and dissolve existing thrombi in the microcirculation and maintain platelet counts leading to improved platelet-mediated immune function and reduced risk of bleeding. Compared to the standard treatment (placebo), this was expected to translate into reduced organ failure and improved outcome in patients with septic shock.
Crit Care. 2019;23(301) © 2019 BioMed Central, Ltd.
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