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div>Recently, Hagihara et al reported in a prospective observational propensity score analysis of data from 417,188 OHCA patients that use of prehospital adrenaline was associated with increased chance of ROSC before hospital arrival but also with decreased chance of survival and good functional outcomes 1 month after the event. This is in accordance with previous studies also questioning the beneficial effect of adrenaline administration in CA. Interestingly, several retrospective studies of trauma-, sepsis- and surgical patients have reported a paradoxical survival benefits for patients receiving β-blockers as part of their regular medication at the time of the injurious hit, despite these patients often being older and suffering from more co-morbidities compared to patients not receiving β-blockers. Randomized clinical studies comparing β-blockers with placebo in trauma, sepsis and patients suffering from acute ischemic heart disease have confirmed these findings. It is tempting to speculate that the beneficial effects of β-blockers observed in many acute critically ill patients may in part be due to protective effects on the endothelium in conditions with excessive catecholamine release. Glycocalyx damage is associated with pathophysiologic sequels like capillary leakage, accelerated inflammation, platelet activation and loss of vascular responsiveness. Previous studies investigating circulating syndecan-1 levels as a surrogate for endothelial glycocalyx damage have reported increased levels in trauma, sepsis, major vascular- and abdominal surgery, STEMI and OHCA patients, with the highest levels in 8-Hydroxy-2'-deoxyguanosine non-survivors and/or the most sick patients. In the present study, STEMI OHCA patients had several-fold higher syndecan-1 levels compared to patients with other causes of OHCA. It is not known if this is due to downstream effects of the STEMI, to iatrogenous factors such as the heparin IV injection given to these patients or to other factors. It is well described that heparin can destabilize the endothelial glycocalyx through induction of a rapid dose-dependent release of glycocalyx adsorbed heparan sulphate-bound proteins, and it is possible that this may contribute to accelerated glycocalyx damage following a “second hit”. However, shocked STEMI patients without cardiac arrest who receive a comparable IV injection of heparin display lower circulating syndecan-1 level compared to STEMI OHCA patients, indicating that other factors than heparin i.e., exogenous adrenaline administration, defibrillations, time from OHCA to ROSC, pH and lactate contribute to the glycocalyx damage. There is emerging evidence that the change from a normal quiescent endothelium to endothelial cell activation, glycocalyx damage, junctional disruption and ultimate endothelial cell injury reflects a progression from reversible to irreversible endothelial damage. In the present study, we investigated different endothelial derived molecules as surrogate markers for glycocalyx damage, endothelial cell activation, endothelial junction disruption and endothelial cell injury, to reveal the influence of progressive endothelial disruption on outcome in OHCA patients. Interestingly, we found that biomarkers reflecting endothelial damage were independently associated with shock degree whereas biomarkers reflecting endothelial activation and junctional disruption were independently associated with patient demography and/or other endothelial biomarkers. The finding that sE-selectin, sVE-cadherin and thrombomodulin were inter correlated supports the notion that endothelial activation, junctional disruption and cell injury are linked at the biologic level. Finally, we found that high circulating thrombomodulin was an independent predictor of increased mortality. In accordance with previous studies, higher age, male gender, high catecholamine levels and shock were all associated with high thrombomodulin levels. The strong predictive value of thrombomodulin supports the notion that patients with the most severe form of endothelial injury have the poorest outcome. The finding that post-CA therapeutic hypothermia may attenuate the anoxic brain injury and improve outcome, emphasizes that therapeutic interventions applied after ROSC can be beneficial. Given this, we infer that interventions aiming at protecting and/or restoring the endothelium, administered at