Development and Validation of a Clinically Relevant Swine Model of Neurologic Injury After Cardiac Arrest to Translate Neuroprotective Therapies

心脏骤停后临床相关猪神经损伤模型的开发和验证，以转化神经保护疗法

• 批准号: 10433506
• 负责人: Cindy Hsing-Liang Hsu
• 金额: $ 39.77万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433506
• 关键词: Address; Affect; Animal Disease Models; Animal Model; Animals; Axon; Base of the Brain; Behavior assessment; Biological; Biological Markers; Blinded; Blood; Blood Circulation; Brain; Brain Injuries; Canis familiaris; Caring; Cause of Death; Cessation of life; Clinical; Clinical Data; Clinical Trials; Confidence Intervals; Development; Disease model; Dose; Effectiveness; Electric Countershock; Electrophysiology (science); Face; Family suidae; Female; Glial Fibrillary Acidic Protein; Heart; Heart Arrest; Hospitalization; Hospitals; Hour; Human; Impaired cognition; Impairment; Individual; Injury; Ischemia; Life; Light; Measures; Mediating; Modeling; Molecular; Monitor; Nerve Degeneration; Nervous System Trauma; Neurocognitive Deficit; Neurologic; Outcome; Outcome Assessment; Pathway interactions; Patients; Pharmacodynamics; Phase; Phylogenetic Analysis; Physiologic Monitoring; Randomized; Recovery; Rodent; Severities; Somatosensory Evoked Potentials; Survivors; Techniques; Temperature; Testing; Therapeutic; Translating; Translations; United States; Validation; Variant; Ventricular Fibrillation; Weaning; Work; behavioral outcome; blood-based biomarker; clinical implementation; clinically relevant; cost; cost effective; digital; efficacy testing; functional outcomes; human data; human model; indexing; male; mortality; motor function recovery; nervous system disorder; neurofilament; neuropathology; novel; novel therapeutics; operation; out-of-hospital cardiac arrest; pharmacodynamic biomarker; phase III trial; porcine model; pre-clinical; preclinical study; randomized controlled study; translation to humans; translational barrier; treatment effect

PROJECT SUMMARY/ABSTRACT Sudden cardiac arrest is a leading cause of death in the United States, with an overall mortality rate of 90%. Brain injury accounts for 67% of deaths for patients who have their heart restarted after out-of-hospital cardiac arrest, and up to 50% of survivors have cognitive dysfunction. Historically, large animal cardiac arrest models (i.e., canines) were instrumental in the successful translation of hypothermic targeted temperature management, which is the only therapy clinically proven to reduce brain injury after cardiac arrest other than early CPR and defibrillations. However, currently available large animal models (i.e., swine) lack face validity because their mild injury severity, largely used to enable behavioral outcome assessment, does not model the neurocognitive deficits of human cardiac arrest victims. Large animal models are also cost prohibitive when their outcomes are quantified with clinical endpoints measured over multiple days during and after receiving ICU-level care. This limits the ability to adequately power studies that use these models. Given these issues, almost every neuroprotective therapy that demonstrated efficacy in these models has failed in human clinical trials. The lack of a validated, feasible large animal model of cardiac arrest is hindering the translation of the neuroprotective therapies that cardiac arrest patients desperately need. We will overcome the translational barrier and limitations of existing long-term models by developing a valid, clinically relevant, and cost-effective short-term cardiac arrest swine model of severe primary brain injury. Supported by emerging clinical data, we expect that quantitative endpoints of brain injury measured at 24 hours after return of spontaneous circulation will reflect the severity of primary brain injury and thereby enable reliable efficacy testing of neuroprotective therapies. In the R61 phase (Years 1 and 2), we will develop and validate a short-term swine model of severe primary brain injury following cardiac arrest. We will demonstrate the internal, face, and construct validities of clinically available blood-based brain injury biomarkers, brain electrophysiology, and neuropathology in our swine cardiac arrest model. Upon successful completion of the quantitative R61 milestones we have defined, we will confirm the predictive validity of these quantitative endpoints by confirming their treatment effects after hypothermic targeted temperature management in the R31 phase. Through this study, we will establish a feasible, lower-cost, and clinically relevant swine cardiac arrest model with quantitative pharmacodynamic biomarkers of post-cardiac arrest primary brain injury that can be used to validate neuroprotective therapies, which will catalyze translation to clinical trials.

项目总结/摘要 在美国，心脏骤停是导致死亡的主要原因，总体死亡率为90%。 脑损伤占院外心脏移植后心脏重新启动患者死亡的67% 死亡，多达50%的幸存者有认知功能障碍。历史上，大型动物心脏骤停模型 (i.e.,犬）在低温目标温度的成功翻译中起着重要作用 管理，这是唯一的治疗临床证明，以减少脑损伤后心脏骤停以外的其他 早期心肺复苏和除颤然而，目前可用的大型动物模型（即，猪）缺乏表面效度 因为他们的轻度损伤严重程度，主要用于使行为结果评估，不模拟 心脏骤停患者的神经认知缺陷。大型动物模型也是成本高昂的， 他们的结果是量化的临床终点测量了多天期间和之后， ICU级护理。这限制了使用这些模型进行充分把握度研究的能力。鉴于这些问题， 几乎每一种在这些模型中证明有效的神经保护疗法在人类临床试验中都失败了。 审判缺乏有效的、可行的心脏骤停的大型动物模型阻碍了 心脏骤停患者迫切需要的神经保护疗法。我们将克服 通过开发一种有效的、临床相关的、具有成本效益的 短期心脏骤停猪严重原发性脑损伤模型。在新出现的临床数据的支持下，我们 预期在自主循环恢复后24小时测量的脑损伤的定量终点 将反映原发性脑损伤的严重程度，从而能够进行可靠的神经保护剂的功效测试。 治疗在R61阶段（第1年和第2年），我们将开发和验证一个短期的猪模型， 心脏骤停后的原发性脑损伤我们将展示的内部，面对，和结构效度 临床上可用的基于血液的脑损伤生物标志物，脑电生理学和神经病理学在我们的研究中， 猪心脏骤停模型。在成功完成我们定义的定量R61里程碑后， 我们将通过确认这些定量终点的治疗效果来确认这些定量终点的预测有效性， R31阶段的低温目标温度管理。通过这项研究，我们将建立一个 具有定量药效学的可行、低成本和临床相关的猪心脏骤停模型 心脏骤停后原发性脑损伤的生物标志物可用于验证神经保护疗法， 这将催化转化为临床试验。