Optimal Oxygenation and Gene Expression During Critical Care after Cardiac Arrest

 描述(由申请人提供)：只有不到50%的心脏骤停(CA)幸存者表现出“良好”的神经学结果，强调除了精心管理体温外，还需要新的神经保护策略。我们在犬CA和复苏(ROSC)模型上进行的研究表明，与以前的高氧复苏标准做法相比，血氧仪引导的常氧复苏具有神经保护作用。这些结果促成了AHA/ACLS对CA/ROSC指南的重大改变；即，最大限度地减少呼吸机氧气，保持血红蛋白氧饱和度&94%。虽然这些程序可以安全地在医院内用于CA/ROSC，但与迅速降低吸入O2相关的低氧风险使这种范例在院前复苏中变得危险。鉴于这些局限性，我们的主要目标是确定在院前复苏后优化神经结局的医院环境中，在危重护理的前2小时内激发的氧气水平。我们假设，与早期复苏期间常氧的益处相反，在最初的再灌流诱导的自由基激增之后和炎症发生之前，维持适度的高氧血症将改善临床结果。我们相关但独立的次要目标是检验炎症、氧化应激和脑线粒体功能障碍在脑缺血后损伤中的重要作用这一假说。将比较常氧、轻度高氧和重度高氧机械通气后的神经学、组织学和生化结果，以及在没有或存在萝卜硫素诱导的细胞保护基因表达的情况下，这些基因的产物可以保护这些损伤机制。方法包括使用我们临床上高度相关的CA/ROSC犬模型来获得短期结果，以及使用大鼠CA和复苏模型来获得长期结果。男性和女性之间的额外比较将增强临床翻译的潜力，并检测脑损伤的任何性二态机制，以及对不同氧气水平或萝卜硫素治疗的反应。转化性结果测量包括高级组织病理学和神经行为测试。机制结果包括测量线粒体生物能量学、13C标记葡萄糖的大脑代谢、能量代谢产物水平的质子核磁共振、炎性小胶质细胞激活和氧化应激标志物。相关性：我们的研究结果将为我们提供新的视角，了解在医院环境中使用的激励氧气水平，从而在出院CA/ROSC后产生最佳的神经学结果。这些实验还将确定复苏后使用萝卜硫素治疗是否进一步改善神经功能，这是基于抑制氧化应激、炎症和线粒体功能障碍的细胞保护基因产物的刺激表达。任何一种神经保护方法都可以安全地转化为临床试验，最终改善数百人的生活质量 每年数以千计的CA幸存者。

 DESCRIPTION (provided by applicant): Less than 50% of cardiac arrest (CA) survivors exhibit "good" neurologic outcome, emphasizing the need for new neuroprotective strategies in addition to meticulous management of temperature. Our research performed with a canine model of CA and resuscitation (ROSC) demonstrated neuroprotection with oximetry-guided normoxic resuscitation compared to the previously standard practice of hyperoxic resuscitation. These results contributed to a major change in AHA/ACLS guidelines for CA/ROSC; i.e., minimize ventilatory O2, maintaining hemoglobin oxygen saturation >94%. While these procedures can be safely used in-hospital for CA/ROSC, the risk of hypoxia associated with rapidly lowering inspired O2 makes this paradigm dangerous in pre-hospital resuscitation. In light of these limitations, our primary aim is to determine the level of O2 inspired during the firt 2 hr of critical care in a hospital setting that optimizes neurologic outcome following pre-hospita resuscitation. We hypothesize that in contrast to the benefit of normoxia during early resuscitation, maintenance of moderate hyperoxemia at the period following the initial reperfusion-induced free radical surge, and prior to the onset of inflammation, will improve clinical outcome. Our related, albeit independent secondary aim is to test the hypothesis that inflammation, oxidative stress, and brain mitochondrial dysfunction contribute substantially to post-ischemic brain injury. Comparisons will be made of neurologic, histologic and biochemical outcomes following normoxic, mildly hyperoxic, and severely hyperoxic ventilation and in the absence or presence of sulforaphane-induced expression of cytoprotective genes whose products protect against these injury mechanisms. Methods of approach include use of our highly clinically relevant canine model of CA/ROSC for short-term outcomes, and a rat CA and resuscitation model for long-term outcomes. Additional comparisons between males and females will enhance potential for clinical translation and detect any sexually dimorphic mechanisms of brain injury and responses to different O2 levels or sulforaphane treatment. Translational outcome measures include advanced histopathology and neurobehavioral tests. Mechanistic outcomes include measurements of mitochondrial bioenergetics, cerebral metabolism of 13C-labeled glucose, proton NMR of energy metabolite levels, inflammatory microglial activation, and markers of oxidative stress. Relevance: Results from our studies will provide fresh new insight into the levels of inspired O2 used in a hospital setting that result in best neurologic outcome after out-of-hospital CA/ROSC. These experiments will also determine if treatment with sulforaphane after resuscitation further improves neurologic function, based on stimulated expression of cytoprotective gene products that inhibit oxidative stress, inflammation, and mitochondrial dysfunction. Either approach toward neuroprotection could be safely translated to clinical trials, eventually improving the quality of life experienced by the hundreds of thousands who survive CA each year.