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

基本信息

  • 批准号:
    9278278
  • 负责人:
  • 金额:
    $ 44.06万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

 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(由申请人提供):不到50%的心脏骤停(CA)幸存者表现出“良好”的神经功能结局,强调除了精心管理体温外,还需要新的神经保护策略。我们的研究与犬模型的CA和复苏(ROSC)证明了神经保护与血氧指导的常氧复苏相比,以前的标准做法高氧复苏。这些结果促成了AHA/ACLS关于CA/ROSC指南的重大变化;即,最大限度地减少呼吸氧,维持血红蛋白氧饱和度> 94%。虽然这些程序可以安全地在医院用于CA/ROSC,但与快速降低吸入O2相关的缺氧风险使得这种模式在院前复苏中是危险的。鉴于这些局限性,我们的主要目的是确定在院前复苏后优化神经功能结局的医院环境中重症监护的前2小时内吸入的O2水平。我们假设,与早期复苏期间常氧的益处相反,在初始再灌注诱导的自由基激增后和炎症发作前维持中度高氧血症将改善临床结局。我们相关的,虽然是独立的次要目的是检验炎症,氧化应激和脑线粒体功能障碍在很大程度上有助于缺血后脑损伤的假设。将比较常氧、轻度高氧和重度高氧通气后的神经学、组织学和生化结果,以及是否存在萝卜硫素诱导的细胞保护基因表达,这些基因的产物可防止这些损伤机制。方法包括使用我们的高度临床相关的犬CA/ROSC模型的短期结果,和大鼠CA和复苏模型的长期结果。男性和女性之间的其他比较将提高临床翻译的潜力,并检测脑损伤的任何性二态机制和对不同O2水平或萝卜硫素治疗的反应。转化结果测量包括高级组织病理学和神经行为测试。机制结果包括线粒体生物能量学、13 C标记葡萄糖的脑代谢、能量代谢物水平的质子NMR、炎症性小胶质细胞活化和氧化应激标志物的测量。相关性:我们的研究结果将为医院环境中使用的吸入O2水平提供新的见解,从而在院外CA/ROSC后获得最佳神经学结局。这些实验还将确定复苏后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。 每年有数千人幸存下来。

项目成果

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GARY M FISKUM其他文献

GARY M FISKUM的其他文献

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{{ truncateString('GARY M FISKUM', 18)}}的其他基金

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:
    9146416
  • 财政年份:
    2015
  • 资助金额:
    $ 44.06万
  • 项目类别:
Neuroprotection After Cardiac Arrest
心脏骤停后的神经保护
  • 批准号:
    6915012
  • 财政年份:
    2004
  • 资助金额:
    $ 44.06万
  • 项目类别:
EXPERIMENTAL SWELLING OF ISOLATED NEURONAL MITOCHONDRIA
离体神经元线粒体的实验肿胀
  • 批准号:
    6976411
  • 财政年份:
    2004
  • 资助金额:
    $ 44.06万
  • 项目类别:
Neuroprotection After Cardiac Arrest
心脏骤停后的神经保护
  • 批准号:
    6946151
  • 财政年份:
    2004
  • 资助金额:
    $ 44.06万
  • 项目类别:
Neuroprotection After Cardiac Arrest
心脏骤停后的神经保护
  • 批准号:
    7119518
  • 财政年份:
    2004
  • 资助金额:
    $ 44.06万
  • 项目类别:
Mitochondrial Mechanisms of Hypoxic Ischemic Neonatal Brain injury
新生儿缺氧缺血性脑损伤的线粒体机制
  • 批准号:
    7013469
  • 财政年份:
    2004
  • 资助金额:
    $ 44.06万
  • 项目类别:
Neuroprotection After Cardiac Arrest
心脏骤停后的神经保护
  • 批准号:
    6817717
  • 财政年份:
    2004
  • 资助金额:
    $ 44.06万
  • 项目类别:
NOVEL MECHANISMS OF MITOCHONDRIAL FREE RADIAL GENERATION
线粒体自由基产生的新机制
  • 批准号:
    6480123
  • 财政年份:
    2002
  • 资助金额:
    $ 44.06万
  • 项目类别:
Novel delivery of Bcl-2 for neuroprotection
用于神经保护的 Bcl-2 新型递送
  • 批准号:
    6683609
  • 财政年份:
    2002
  • 资助金额:
    $ 44.06万
  • 项目类别:
NOVEL MECHANISMS OF MITOCHONDRIAL FREE RADIAL GENERATION
线粒体自由基产生的新机制
  • 批准号:
    6625924
  • 财政年份:
    2002
  • 资助金额:
    $ 44.06万
  • 项目类别:

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