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.

项目摘要/摘要 心脏骤停是美国的主要死亡原因，总死亡率为90％。 脑损伤占院外心脏后心脏重新启动的患者死亡的67％ 逮捕，多达50％的幸存者患有认知功能障碍。从历史上看，大型动物心脏骤停模型 （即犬）在成功翻译体温过低的靶向温度中发挥了作用 管理，这是唯一在临床上证明的疗法，可减少心脏骤停后的脑损伤 早期CPR和除颤。但是，目前可用的大型动物模型（即猪）缺乏面部有效性 由于它们的轻度伤害严重程度（主要用于实现行为结果评估），因此不会对 人类心脏骤停受害者的神经认知缺陷。当大型动物模型的成本也很高 他们的结果在收到的临床终点上进行了量化 ICU级护理。这限制了充分使用这些模型的充分动力研究的能力。考虑到这些问题， 在这些模型中证明有效性的几乎所有神经保护疗法在人类临床中都失败了 试验。缺乏经过验证的，可行的大型心脏骤停动物模型正在阻碍翻译 心脏骤停患者迫切需要的神经保护疗法。我们将克服翻译 通过开发有效的，临床相关且具有成本效益的现有长期模型的障碍和局限性 严重原发性脑损伤的短期心脏骤停猪模型。在新兴临床数据的支持下，我们 期望自发循环后24小时测量的脑损伤的定量终点 将反映主要脑损伤的严重程度，从而实现神经保护的可靠疗效测试 疗法。在R61阶段（第1和2年），我们将开发并验证一个严重的短期猪模型 心脏骤停后脑损伤。我们将展示内部，面部和构造的有效性 我们 猪心脏骤停模型。成功完成定量R61里程碑后，我们已经定义了 我们将通过确认其治疗效果后，确认这些定量终点的预测有效性 R31阶段的低温靶向温度管理。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 后心脏骤停的生物标志物可用于证明神经保护疗法的脑损伤， 这将催化翻译为临床试验。