Membrane-controlled release of carbon monoxide in extracorporeal life support protects from neurological injury after hypoxic cardiac arrest

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Cardiac arrest with consecutive organ damage presents a major challenge to modern intensive care medicine. Despite cardiopulmonary resuscitation, only 10 % of patients with cardiac arrest survive until discharge, frequently showing severe neurological impairment. Extracorporeal life support uses temporary cardiopulmonary bypass to bridge heart and lung function thus restoring brain perfusion until return-of-spontaneous-circulation or until definitive treatment occurs. Pharmacological protection presents a promising concept to reduce cellular and organ damage. As one auspicious substance, the gaseous molecule carbon monoxide (CO) has been shown to potently protect from ischemic injury and organ damage in various models. However, applicability of this potentially toxic substance remains unsolved. Carbon monoxide releasing molecules (CORMs) contain harmful transition metals, which limit clinical utility. Recently we were able to decrease toxic effects of CORMs and were able to show excellent applicability in protecting transplanted organs using a novel membrane-controlled release of CO. A membrane, impervious to toxic CORM-related transition metals separates a releasing chamber from an effector chamber. Here, a modification to an extracorporeal CO releasing system (“ECCORS”) is suggested to use as an adjunct to extracorporeal based cardiopulmonary resuscitation. Thus, CO’s protective effects can be used quickly and effectively in a life-threatening condition. In a porcine model of hypoxic cardiac arrest ECCORS enables CO application into an extracorporeal circulation by separating a CORM circuit from blood flow by a CO-permeable membrane. In our proposed study, ECCORS’ effectiveness is tested in a clinically highly relevant scenario. Based on these facts, the following hypotheses are postulated:Hypothesis 1: CO release by the novel “extracorporeal CO releasing system” (ECCORS) is as effective as traditional (inhalative) CO application and is not associated with traceability of carbon monoxide releasing molecule (CORM)-related toxic transition metals.Hypothesis 2: Membrane-controlled release of CO from carbon monoxide releasing molecule (CORM) is effective to add a stable and controllable amount of CO into an extracorporeal circulation by ECCORS.Hypothesis 3: Carbon monoxide therapy by ECCORS a) protects from neurological injury after hypoxic cardiac arrest, andb) mediates its effects by induction of the heat-shock response and mitogen-activated protein kinase.Hypothesis 4: Carbon monoxide from ECCORS protects from extracorporeal circulation induced systemic inflammatory response.