Optimal Oxygenation and Gene Expression During Critical Care after Cardiac Arrest

心脏骤停后重症监护期间的最佳氧合和基因表达

• 批准号: 9278278
• 负责人: GARY M FISKUM
• 金额: $ 44.06万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9278278
• 关键词: Acute; Animals; Antioxidants; Biochemical; Biochemical Markers; Bioenergetics; Blood; Blood Circulation; Brain; Brain Injuries; Canis familiaris; Cell Death; Cerebrum; Clinical; Clinical Research; Clinical Trials; Critical Care; Dangerousness; Development; Encephalitis; Energy Metabolism; Environmental air flow; Exhibits; Female; Free Radicals; Gene Expression; Genes; Glucose; Goals; Guidelines; Heart Arrest; Hemoglobin; Histologic; Histopathology; Hospitals; Hour; Hyperoxia; Hypoxia; Impairment; Inflammation; Inflammatory; Injury; Intervention; Ischemic Brain Injury; Label; Level of Evidence; Life Experience; Light; Maintenance; Measurement; Measures; Metabolic; Metabolic stress; Metabolism; Methods; Mitochondria; Modeling; Molecular; Nervous System Physiology; Nervous System Trauma; Neurologic; Neurological outcome; Outcome; Outcome Measure; Oxidative Stress; Oxygen; Oxygen saturation measurement; Pre-hospital setting; Procedures; Protons; Quality of life; Rattus; Reperfusion Therapy; Research; Residual state; Resistance; Resuscitation; Risk; Sulforaphane; Survivors; Temperature; Testing; Translating; Treatment Efficacy; Work; base; brain cell; cell injury; clinical translation; clinically relevant; critical period; design; experimental study; gene product; improved; improved outcome; insight; knowledge translation; male; mitochondrial dysfunction; model design; neurobehavioral test; neuron loss; neuronal survival; neuroprotection; pre-clinical; prospective; public health relevance; response to brain injury; restoration; sex; survival outcome

 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.

 描述（由适用提供）：不到50％的心脏骤停（CA）冲浪者暴露了“良好”神经系统效果，强调除了对温度的细致管理外，还需要对新的神经保护策略。与先前标准的高氧复苏实践相比，我们使用CA和复苏的犬模型（ROSC）进行了神经保护作用。这些结果导致了CA/ROSC的AHA/ACLS指南的重大变化；即，最小化通风O2，保持血红蛋白氧气安全> 94％。虽然这些程序可以安全地用于CA/ROSC的院内使用，但与快速降低启发的O2相关的缺氧风险使该范式在院前复苏中危险。鉴于这些局限性，我们的主要目的是在医院环境中确定重症监护2小时的O2水平，以优化疗程前的神经系统效果。我们假设，与早期复苏期间正常氧的益处相反，在初始再灌注引起的自由基激增后以及感染发作之前，维持中等高氧的维持将改善临床结果。我们相关的，尽管独立的次要目的是检验以下假设：感染，氧化应激和脑线粒体功能障碍对缺血后脑损伤产生了重大贡献。在常氧，轻度高氧和严重的过度氧化通气后，在磺胺paphane诱导的细胞保护基因表达的情况下，将其比较与神经系统，组织学和生化结果进行比较，其产物可抵抗这些损伤机制。方法的方法包括使用我们高度临床相关的CA/ROSC犬模型作为短期结局，以及用于长期结局的大鼠CA和复苏模型。男性和女性之间的附加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O2水平或磺胺治疗的反应。翻译结果指标包括晚期组织病理学和神经行为测试。机械结局包括测量线粒体生物能学，13C标记葡萄糖的脑代谢，能量代谢物水平的质子NMR，炎性小胶质细胞激活以及氧化应激的标志物。相关性：我们的研究结果将为医院环境中使用的受启发的O2水平提供新的新见解，从而在院外CA/ROSC后最佳神经系统效果。这些实验还将基于抑制氧化应激，感染和线粒体功能障碍的细胞保护基因产物的刺激表达，从而确定复苏后用磺烷治疗进一步改善神经系统功能。两种方法都可以安全地转化为临床试验，最终改善了数百人的生活质量 每年有成千上万的CA。