Improving Pediatric Cardiac Arrest Survival and Neurologic Outcome

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，不仅要提高生存率， 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）-其中复苏滴定到有创血压（BP）-已在动物中显示出希望 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 BP目标未知。在最近发表的一项大型（n=164）多中心前瞻性观察性试验中， 研究小组证明，≥1岁儿童CPR期间平均DBP ≥30 mmHg， 与较低的DBP相比，与更大的出院存活可能性相关（54%对35%， 分别）。作为回应，本提案的主要目的是评估两种不同血液的效果 压力目标（HD-CPRSD与HD-CPRHP）对生存率的影响。此外，由于大多数 存活的儿童在心脏骤停后有神经损伤，研究人员将确定是否 不同的血压策略对脑血流量有影响。同时，因为不是所有的病人 如果在逮捕时有侵入性监测，调查人员将进一步开发新的适应症， 对于一种新的设备，可以非侵入性地量化血液流动和氧合在大脑中，奠定了 在CPR之前、期间和之后监测和治疗儿童的范式转变的基础 事件，由于感知/实际风险，很少使用侵入性神经监测。最后，因为改善 CPR期间的脑血流不能完全逆转/介导心脏引起的神经损伤 逮捕，这项应用还将调查线粒体的作用-我们身体的细胞引擎， 细胞生/死的关键调节因子--在心脏骤停后脑损伤发展中的作用， 潜在的治疗靶点;并根据令人兴奋的初步数据，测试一种有前途的创新治疗方法， 它为线粒体提供了一种替代燃料来源，以保持细胞能量的产生， 心脏骤停后的损伤。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， 提出了儿科住院心脏骤停的治疗方案，其目的如下： ·比较靶向策略之间的存活率和停搏期间全身和脑血流动力学 阈值血压目标为HD-CPRSD，而阈值血压目标为更高的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、脑成像和神经病理学以及神经功能结局， HD-CPRSD和HD-CPRHP治疗组之间的24小时和7天。 ·评估细胞可渗透的琥珀酸酯前药的有效性-一种新的靶向药物， 治疗-改善氧化磷酸化和减弱生物能量危机。

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.