Does IL-6 receptor blockage following out-of-hospital cardiac arrest have protective effects on the endothelium? - A substudy of the IMICA trial

Abstract Introduction Several endothelial markers, indicating endothelial activation and endothelial damage are increased following out-of-hospital cardiac arrest (OHCA). Blood-borne biomarkers reflecting endothelial glycocalyx damage (syndecan-1), endothelial cell damage (soluble thrombomodulin, sTM), and endothelial junction disruption (platelet endothelial cell adhesion molecule 1, PECAM-1) have been associated with poor outcomes. Among the pro-inflammatory cytokines released by activated endothelium, IL-6 plays a central role in systemic inflammation. IL-6 can directly activate the endothelial cells, which again release IL-6 leading to a cytokine storm. In the "IL-6 Ihibition for Modulating Inflammation After Cardiac Arrest" (IMICA) trial, comatose resuscitated OHCA patients were randomized to tocilizumab – an IL-6 receptor antagonist, or placebo. Systemic inflammation was reduced by tocilizumab treatment. Effects on the endothelium are unknown. Purpose To determine whether tocilizumab infusion protects the endothelium as indicated by syndecan-1, sTM and PECAM1, and to investigate the prognostic abilities of these markers in comatose resuscitated OHCA patients Method In the IMICA trial, a double-blinded single center randomized controlled trial, 80 comatose survivors from OHCA were assigned to either IL-6 receptor antagonist (tocilizumab 8mg/kg) infusion or placebo in addition to standard care. Syndecan-1, sTM, and PECAM-1 were measured using ELISA at admission (0 hours) and 48 hours. Results Admission values of the endothelial markers were similar in the tocilizumab and placebo groups. Syndecan-1 was significantly higher at 48 hours in the tocilizumab group (p<0.01), while there were no group differences for sTM and PECAM-1. Furthermore, at admission, PECAM-1 predicted 30 days mortality (AUC = 0.71 [0.60-0.83], while syndecan-1 and sTM did not (AUC=0.61 [0.48-0.74] and 0.53 [0.40-0.67]). Conclusion Tocilizumab infusion did not decrease levels of endothelial markers at 48 hours compared to placebo. Conversely, syndecan-1 was increased in the tocilizumab -group and the responsible mechanism as well as possible clinical implications are unknown. The prognostic assessment showed that at admission, PECAM-1 has potential for prediction of mortality after cardiac arrest.Figure 1:Boxplots