Impact of tocilizumab on endothelial function following out-of-hospital cardiac arrest: a substudy of the IMICA randomized controlled trial

Biomarkers of endothelial activation and damage are elevated after out-of-hospital cardiac arrest (OHCA). Elevated plasma concentrations of syndecan-1, soluble thrombomodulin (sTM), and platelet endothelial cell adhesion molecule 1 (PECAM-1) reflect glycocalyx degradation, endothelial cell injury, and endothelial junction disruption, respectively. Interleukin 6 (IL-6) plays an important role in the inflammatory mechanisms that cause endothelial damage, and inhibiting IL-6 with tocilizumab may attenuate endothelial damage. The present study examines the effect of tocilizumab on endothelial biomarkers and their prognostic value in comatose resuscitated OHCA patients.

The ‘IL-6 Inhibition for Modulating Inflammation after Cardiac Arrest’ (IMICA) trial included 80 comatose OHCA patients who were randomized to receive tocilizumab (8 mg/kg) or placebo. Blood samples were drawn sequentially at hospital admission (0 h) and after 24, 48, and 72 h for biomarker measurements. Syndecan-1 concentrations declined over time in both groups; however, the reduction was significantly less in the tocilizumab group (all P < 0.003). No significant between-group differences were observed for sTM or PECAM-1. In prognostic analyses, baseline PECAM-1 had an AUROC of 0.71 (95% CI 0.59–0.83) for prediction of 30-day mortality. Syndecan-1 and sTM had no predictive value (AUROC 0.61 and 0.53, respectively).

Plasma syndecan-1 decline was less pronounced in comatose OHCA patients treated with tocilizumab, without affecting sTM or PECAM-1. This contrasts with previous IMICA findings of reduced systemic inflammation, vasopressor use, and myocardial injury, suggesting a complex relationship between inflammation and endothelial injury. Finally, PECAM-1 levels already at hospital admission had a moderate predictive value for mortality.

The trial is registered at clinicaltrials.gov (NCT03863015).