Pyruvate-enhanced cardiopulmonary resuscitation

丙酮酸增强心肺复苏

• 批准号: 6559786
• 负责人: ROBERT T MALLET
• 金额: $ 35.5万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6559786
• 关键词: artificial respiration; bioenergetics; brain electrical activity; cardiopulmonary resuscitation; cytoprotection; dogs; dosage; heart arrest; heart contraction; implantable defibrillators; nonhuman therapy evaluation; pyruvates

DESCRIPTION (provided by applicant): Cardiac arrest is almost always fatal. Despite marked improvements in emergency medical care in the United States, the prognosis for victims of cardiac arrest remains bleak. Cardiac arrest interrupts nutritive perfusion of the heart and brain, leading to tissue energy depletion, intracellular calcium accumulation, and massive production of cytotoxic oxygen-centered free radicals upon reperfusion, culminating in failure of these vital organs. Interventions that both supply metabolic energy and neutralize oxyradicals would be particularly effective at mitigating cellular injury and preserving physiological function of myocardium and cerebral cortex following cardiac arrest and resuscitation. Recent work in our laboratory indicates that the natural carbohydrate pyruvate may be the first such pluripotent treatment identified. In post-ischemic myocardium, exogenous pyruvate markedly increases energy reserves and bolsters antioxidant redox potential in parallel with its enhancement of contractile performance. Pyruvate is nontoxic and readily traverses plasma membranes and the blood-brain barrier, so it could be an effective means of protecting the brain from ischemic injury, too. The overall objective of this application is to determine the therapeutic efficacy of pyruvate to protect myocardium and cerebral cortex during cardiac arrest and closed chest cardiopulmonary resuscitation (CPR). Experiments will be conducted in dogs chronically instrumented to measure left ventricular contractile function and cerebrocortical electrophysiological activity. After 5 min cardiac arrest, CPR will be administered by precordial chest compressions for 20 min, then hearts will be defibrillated to restore spontaneous circulation, while cardiac and cerebral function are monitored. Pyruvate will be infused intravenously at defined intervals and dosages during CPR and/or after defibrillation. Energy and antioxidant reserves, regional perfusion and tissue injury will be determined in biopsies of myocardium and cerebral cortex. Pyruvate's long-term impact on cardiac and cerebral function will be studied for 3 d post-arrest. By systematically determining the effective dosages, therapeutic window and cellular mechanisms of pyruvate's salutary effects, this investigation will establish the foundation for clinical development of pyruvate to treat cardiac arrest.

描述（由申请人提供）： 心脏骤停几乎总是致命的。 尽管在美国的紧急医疗护理方面有明显改善，但心脏骤停受害者的预后仍然黯淡。 心脏骤停会中断心脏和大脑的营养灌注，导致组织能量消耗，细胞内钙的积累以及再灌注后，以细胞毒性为中心的自由基产生，最终导致这些重要器官的失败。 供应代谢能量和中和草皮的干预措施在减轻细胞损伤并保留心脏骤停和复苏后心肌和脑皮质的生理功能方面特别有效。 我们实验室的最新工作表明，天然碳水化合物丙酮酸可能是第一次确定的多能治疗方法。 在缺血后心肌中，外源丙酮酸明显增加了能量储量，并与抗氧化剂氧化还原潜力相比，与收缩性能的增强相同。 丙酮酸是无毒的，很容易遍历质膜和血脑屏障，因此它也可能是保护大脑免受缺血性损伤的有效手段。 该应用的总体目的是确定丙酮酸在心脏骤停过程中保护心肌和脑皮质的治疗功效，并闭合胸部心肺复苏（CPR）。 实验将以长期仪器进行的狗进行，以测量左心室收缩功能和脑皮层电生理活性。 心脏骤停5分钟后，CPR将通过前胸部压缩持续20分钟，然后将心脏除颤以恢复自发循环，同时监测心脏和大脑功能。 丙酮酸将在CPR和/或除颤后以定义的间隔和剂量静脉注入。 能量和抗氧化剂储量，区域灌注和组织损伤将在心肌和脑皮质活检中确定。 丙酮酸对心脏和脑功能的长期影响将在逮捕后进行3 d研究。 通过系统地确定丙酮酸有益作用的有效剂量，治疗窗口和细胞机制，这项研究将为丙酮酸的临床发育建立基础以治疗心脏骤停。