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

项目摘要/摘要 心脏骤停是美国主要的死亡原因，总体死亡率为90%。 在出院心脏手术后心脏重启的患者中，脑损伤占死亡的67% 被逮捕，高达50%的幸存者有认知功能障碍。从历史上看，大型动物心脏骤停模型 (即，犬类)在低温目标温度的成功转化中起到了重要作用 管理，这是唯一一种临床证明可以减少心脏骤停后脑损伤的疗法，而不是 早期的心肺复苏和除颤。然而，目前可用的大型动物模型(即猪)缺乏表面有效性 因为它们轻微的损伤严重程度，主要用于实现行为结果评估，不能对 人类心脏骤停患者的神经认知缺陷。大型动物模型的成本也令人望而却步 他们的结果是通过在接受治疗期间和之后的多天临床终点来量化的 ICU级别的护理。这限制了充分支持使用这些模型的研究的能力。鉴于这些问题， 几乎所有在这些模型中证明有效的神经保护疗法在人类临床上都失败了。 审判。缺乏有效的、可行的心脏骤停大动物模型阻碍了对 心脏骤停患者迫切需要的神经保护性治疗。我们将克服翻译中的 通过开发一种有效的、临床相关的、成本效益高的长期模型来阻碍和限制现有的长期模型 猪重度原发性脑损伤短期心脏骤停模型的建立。在新兴临床数据的支持下，我们 除脑损伤的定量终点在自主循环恢复后24小时内测量外 将反映原发脑损伤的严重程度，从而能够可靠地测试神经保护的有效性 治疗。在R61阶段(第1年和第2年)，我们将开发和验证重症猪的短期模型 心脏骤停后的原发脑损伤。我们将演示的内部、面向和构造的有效性 临床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 猪心脏骤停模型。在成功完成我们定义的定量R61里程碑之后， 我们将通过确认它们的治疗效果来确认这些量化终点的预测有效性 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 应用定量药效学建立可行、低成本、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记物，可用于验证神经保护治疗， 这将催化转化为临床试验。

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.