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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

基本信息

批准号：
10614382
负责人：
Todd Justen Kilbaugh
金额：
$ 86万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614382
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 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 Titrations Translations United States 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 survival outcome targeted treatment therapeutic target tissue oxygenation

项目摘要

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，需要新的方法不仅要提高存活率，而且要保护心脏骤停儿童的大脑功能。血液动力学指导的心肺复苏 (HD-CPR)--复苏滴定到有创血压(BP)--在动物身上显示出希望模型，但它的使用在临床实践中并不常见。翻译的关键限制可能是最优的 BP的目标尚不清楚。在最近发表的一项大型(n=164)多中心前瞻性观察试验中，调查小组证明，在心肺复苏期间，≥≥1岁儿童的平均舒张压为30毫米汞柱与较低的DBP相比，出院后存活的可能性更大(54%比35%， )。作为回应，这项建议的主要目标是评估两种不同血液的效果生存压力目标(HD-CPRSD与HD-CPRHP)，利用这些阈值。此外，因为大多数幸存下来的儿童在心脏骤停后出现神经损伤，调查人员将确定不同的降压策略对脑血流量有影响。同时，因为不是所有的患者在逮捕时实施侵入性监测，调查人员将进一步开发一种新的适应症对于一种可以非侵入性量化大脑中的血流量和氧合的新型设备来说，奠定了为在心肺复苏术前、中和后监测和治疗儿童的范式转变奠定基础事件，由于感知/实际风险，很少使用侵入性神经监测。最后，因为改进心肺复苏期间脑血流不能逆转/介导心脏引起的神经损伤这个应用程序还将调查线粒体--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生发展中的作用潜在的治疗靶点；并基于令人兴奋的初步数据，测试一种有希望的创新治疗方法这为线粒体提供了一种替代燃料来源，以保护细胞能量生产，缓解大脑心脏骤停后的损伤。为了实现这些目标，在猪模型上进行了一项大型动物随机试验提出了儿科院内心脏骤停的治疗方案，目的如下： ·比较靶向策略的存活率和心内直视手术期间的全身和脑血流动力学阈值血压目标为HD-CPRSD，目标为更高目标的HD-CPRHP。 ·在IHCA术后24小时存活的动物中，比较脑线粒体功能障碍和反应性氧物种、脑代谢、脑成像、神经病理学和神经功能结果 HD-CPRSD组和HD-CPRHP组治疗后24小时和7天。 ·评估一种细胞透性琥珀酸酯前药--一种以线粒体为靶标的新型药物的有效性治疗-改善氧化磷酸化，减轻生物能量危机。