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

心脏骤停伴连续器官损伤对现代重症监护医学提出了重大挑战。尽管进行了心肺复苏，但只有10%的心脏骤停患者能存活到出院，经常表现出严重的神经功能障碍。体外循环生命支持使用临时心肺转流来桥接心脏和肺功能，从而恢复脑灌注，直到自发循环恢复或直到最终治疗发生。药理学保护提出了一个有前途的概念，以减少细胞和器官损伤。作为一种吉祥物质，气体分子一氧化碳（CO）已被证明在各种模型中有效地保护缺血性损伤和器官损伤。然而，这种潜在有毒物质的适用性仍然没有解决。一氧化碳释放分子（CORM）含有有害的过渡金属，限制了临床应用。最近，我们能够减少CORM的毒性作用，并能够显示出良好的适用性，在保护移植器官使用一种新的膜控制释放的CO。膜，不受有毒的CORM相关的过渡金属分离释放室的效应室。在此，建议对体外CO释放系统（“ECCORS”）进行修改，以用作体外心肺复苏的辅助。因此，CO的保护作用可以在危及生命的情况下快速有效地使用。在缺氧性心脏骤停的猪模型中，ECCORS通过CO渗透膜将CORM回路与血流分离，使CO应用于体外循环。在我们提出的研究中，ECCORS的有效性在临床高度相关的情况下进行了测试。基于这些事实，提出了以下假设：假设1：新型“体外CO释放系统”（ECCORS）的CO释放与传统方法一样有效（吸入）CO应用，并且与一氧化碳释放分子（CORM）相关的有毒过渡金属的可追溯性无关。从一氧化碳释放分子（CORM）的CO的膜控制释放有效地通过ECCORS将稳定且可控量的CO添加到体外循环中。假设3：一氧化碳治疗（ECCORS）a） 保护缺氧性心脏骤停后的神经损伤，和b） 通过诱导热休克反应和丝裂原活化蛋白激酶介导其作用。假设4：ECCORS中的一氧化碳可保护体外循环诱导的全身炎症反应。

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.