Improving Pediatric Cardiac Arrest Survival and Neurologic Outcome

改善小儿心脏骤停的生存率和神经系统结果

• 批准号: 10369719
• 负责人: Todd Justen Kilbaugh
• 金额: $ 86.62万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369719
• 关键词: 1 year old; Acute Brain Injuries; Affect; Animal Model; Animals; Applications Grants; Attenuated; Automobile Driving; Bioenergetics; Blood Pressure; Blood flow; Brain; Brain Injuries; Brain imaging; Bypass; Cardiopulmonary Resuscitation; Cells; Cerebrovascular Circulation; Cerebrum; Cessation of life; Characteristics; Child; Childhood; Clinical; Cognitive deficits; Complex; Data; Development; Devices; Diastolic blood pressure; Diffuse; Dose; Evaluation; Event; Foundations; Functional disorder; Future; Generations; Goals; Heart; Heart Arrest; Hospitalized Child; Hospitals; Hour; Hypertension; Intensive Care Units; Ischemia; Knowledge; Lasers; Lead; Life; Magnetic Resonance Imaging; Measures; Mediating; Metabolism; Microdialysis; Mitochondria; Modeling; Molecular; Monitor; Morbidity - disease rate; Nervous System Physiology; Nervous System Trauma; Neurologic; Neurological outcome; Optics; Organ; Outcome; Oxidative Phosphorylation; Patients; Perfusion; Permeability; Physiological; Play; Prodrugs; Production; Publishing; Reactive Oxygen Species; Reperfusion Therapy; Research Personnel; Resuscitation; Risk; Role; Source; Spectrum Analysis; Succinates; Survivors; Techniques; Testing; Therapeutic; Time; Translations; United States; base; brain tissue; cerebral hemodynamics; cerebral oxygenation; clinical practice; clinically relevant; effectiveness evaluation; hemodynamics; improved; innovation; magnetic resonance spectroscopic imaging; mitochondrial dysfunction; neuropathology; novel; novel strategies; oxidative damage; personalized approach; porcine model; preservation; pressure; prospective; randomized trial; response; specific biomarkers; spectroscopic imaging; survival outcome; targeted treatment; therapeutic target; tissue oxygenation

Project Abstract Thousands of hospitalized children in the United States die from cardiac arrests each year. Brain injury is common among survivors. Therefore, new approaches are needed to not only improve survival, but to preserve brain function of children who suffer a cardiac arrest. Hemodynamic-directed cardiopulmonary resuscitation (HD-CPR) – where resuscitation is titrated to invasive blood pressure (BP) – has shown promise in animal models, but its use is not common in clinical practice. Critical limitations for translation may be that optimal BP targets are unknown. In a recently published, large (n=164), multi-center prospective observational trial, the investigative team demonstrated that a mean DBP during CPR ≥30 mmHg in children ≥1 year-old was associated with greater likelihood of survival to hospital discharge compared to lower DBPs (54% vs. 35%, respectively). In response, the primary objective of this proposal is to evaluate the effect of two different blood pressure targets (HD-CPRSD vs. HD-CPRHP) on survival, utilizing these thresholds. In addition, because most children who survive have a neurologic injury following cardiac arrest, the investigators will determine if different blood pressure strategies have an effect on cerebral blood flow. Concurrently, because not all patients have invasive monitoring in place at the time of arrest, the investigators will further develop a new indication for a novel device that can noninvasively quantify blood flow and oxygenation in the brain, laying the foundation for a paradigm shift in the monitoring and treatment of children before, during, and after a CPR event, where invasive neuromonitoring is rarely used due to perceived/actual risk. Finally, because improving cerebral blood flow during CPR cannot completing reverse/mediate neurologic injury initiated by cardiac arrest, this application will also investigate the role that mitochondria – the cellular engines of our bodies and key regulators of cellular life/death – play in the development of brain injury post-cardiac arrest to elucidate potential therapeutic targets; and, based on exciting preliminary data, test a promising, innovative therapeutic that provides an alternative fuel source to mitochondria to preserve cellular energy production mitigating brain injury following cardiac arrest. To achieve these objectives, a large animal randomized trial in a porcine model of pediatric in-hospital cardiac arrest is proposed with the following aims: • Compare survival and intra-arrest systemic and cerebral hemodynamics between strategy of targeting threshold blood pressure targets HD-CPRSD to one targeting higher goals HD-CPRHP. • Among animals surviving 24 hours post-IHCA, compare cerebral mitochondrial dysfunction and reactive oxygen species, cerebral metabolism, brain imaging, and neuropathology, and neurofunctional outcomes at 24 hours and at 7 days between those treated with HD-CPRSD and HD-CPRHP. • Evaluate the effectiveness of a cell permeable succinate prodrug – a novel mitochondria-targeted therapeutic – to improve oxidative phosphorylation and attenuate bioenergetic crisis.

项目摘要 美国每年有数千名住院儿童死于心脏骤停。脑损伤是 在幸存者中很常见。因此，需要新的方法来不仅提高生存率，而且保护 心脏骤停儿童的大脑功能。血流动力学指导的心肺复苏 (HD-CPR) – 将复苏滴定至有创血压 (BP) – 已在动物身上显示出希望 模型，但其在临床实践中的使用并不常见。翻译的关键限制可能是最佳的 血压目标未知。在最近发表的一项大型（n=164）多中心前瞻性观察试验中， 研究小组证明，对于 1 岁以上的儿童，心肺复苏期间的平均 DBP ≥30 mmHg 与较低的 DBP 相比，出院后生存的可能性更大（54% vs. 35%， 分别）。对此，该提案的主要目的是评估两种不同血液的效果 利用这些阈值确定生存压力目标（HD-CPRSD 与 HD-CPRHP）。另外，由于大多数 幸存的儿童在心脏骤停后出现神经损伤，调查人员将确定是否 不同的降压策略对脑血流量有影响。同时，由于并非所有患者 在逮捕时进行侵入性监测，调查人员将进一步开发新的适应症 一种可以无创地量化大脑血流量和氧合的新型设备，奠定了 为心肺复苏之前、期间和之后儿童监测和治疗的范式转变奠定了基础 由于感知/实际风险，很少使用侵入性神经监测。最后，因为改进 CPR期间的脑血流无法完成逆转/介导心脏引起的神经损伤 逮捕，该应用程序还将研究线粒体（我们身体的细胞引擎）和 细胞生命/死亡的关键调节因子——在心脏骤停后脑损伤发展中的作用以阐明 潜在的治疗靶点；并基于令人兴奋的初步数据，测试一种有前途的创新疗法 为线粒体提供替代燃料来源，以保持细胞能量产生，减轻大脑损伤 心脏骤停后受伤。为了实现这些目标，在猪模型中进行了一项大型动物随机试验 提出儿科院内心脏骤停的预防措施的目的如下： • 比较靶向策略之间的生存率和逮捕时的全身和脑血流动力学 阈值血压将 HD-CPRSD 目标定为更高目标 HD-CPRHP。 • 在 IHCA 后存活 24 小时的动物中，比较脑线粒体功能障碍和反应性 氧种类、脑代谢、脑成像、神经病理学和神经功能结果 HD-CPRSD 和 HD-CPRHP 治疗之间的 24 小时和 7 天。 • 评估细胞渗透性琥珀酸前药的有效性——一种新型线粒体靶向药物 治疗——改善氧化磷酸化并减轻生物能危机。