Harnessing the latent heat of saline evaporation for safe and effective endovascular therapeutic organ cooling

项目摘要 缺血性中风是全球第二大死亡原因，耗资约716亿美元。 大血管闭塞（LVO）患者不成比例地增加了这些成本。的最新进展 紧急血栓切除术改善了结局，但超过50%的患者未能达到良好的效果。 即使在最近的试验中也是如此。开发神经保护剂以减轻神经元损伤 在缺血事件期间和紧接在缺血事件之后，现在是该领域研究人员的主要焦点。之间 在众多被提出的神经保护剂策略中，低温仍然是最有希望的。以前很多 研究者已经提出了选择性脑冷却与血栓切除术相结合的方法， 进入颈动脉的导管已经就位，并且可以在凝块去除后立即使用。 这些选择性冷却方法使用冷盐水直接注入颅内血流， 冷盐水，以在流动的血液沿着留置导管壁沿着时冷却流动的血液。这两种方法都受到限制， 冷盐水在到达目标位置时的固有升温。此外，这些技术不能被 在血栓切除术结束之前实施，错过了最大化 血栓切除术过程中通过侧支血流对半影组织的保护性冷却作用。 这项研究和开发提案的长期目标是实现一种全新的方法， 使用生理盐水作为制冷剂的脑冷却，其在导管系统内的超低压下蒸发。 从液体到蒸汽的盐水相变充当比蒸发器大几个数量级的散热器。 仅盐水输注的简单对流/传导。此外，用于实现这种相变的真空 也可作为伴随微导管系统的理想绝缘体，用于将冷盐水输注到 颅内循环最后，冷却装置还可用作最先进的引导导管， 在血栓切除术开始时实施，从而优化冷却干预， 而不是像竞争器械那样等到凝块去除之后。 该R21提案的第一个目标涉及同轴输液导管的设计、构造和台架测试 其能够有效地蒸发环形空间内的盐水，所述环形空间与脉管系统和中央 血栓切除术的工作腔。Milestone将包括传热和机械设计 指标.在目标2期间，我们将进行体内试验，评估我们的主动冷却导管的有效性和安全性。 该研究计划将涉及制造和测试具有明确定义的MILLENT的多腔导管， 达到可接受的传热指标、扭结、刚度、扭矩和压力阈值，以最大限度地提高热量 同时最小化整个系统外径。该研究计划将包括将该设备放置在 猪的颈动脉和肾动脉，测量实质冷却的速度、深度和持续时间 与被动绝缘导管相比，并评估局部和全身不良反应。

PROJECT SUMMARY Ischemic stroke represents the second leading cause of death worldwide, costing approximately $71.6 billion. These costs are disproportionately driven by patients with large vessel occlusions (LVO). Recent advances in urgent thrombectomy have led to improved outcomes, yet more than 50% of patients fail to achieve good functional outcomes even in the most recent trials. Developing neuroprotectants to mitigate neuronal injury during and immediately following the ischemic event is now a primary focus for researchers in this area. Among numerous proposed neuroprotectant strategies, hypothermia remains the most promising. Numerous previous investigators have proposed selective brain cooling in conjunction with thrombectomy procedures since the access catheters to the carotid arteries are already in place and could be utilized immediately after clot removal. These selective cooling approaches use either infusion of cold saline directly into the intracranial blood flow or cold saline to cool flowing blood as it passes along an indwelling catheter wall. Both approaches are limited by the cold saline's inherent warming as it travels to the target location. Further, these techniques cannot be implemented until the thrombectomy procedure has concluded, missing an opportunity to maximize the protective cooling effect of penumbral tissue via collateral flow during the thrombectomy procedure itself. The long-term goal of this research and development proposal is to enable an entirely new approach to selective brain cooling using saline as a refrigerant, which is evaporated at ultra-low pressure within the catheter system. The saline phase change from liquid to vapor acts as a heat sink that is orders of magnitude larger than the simple convection/conduction of saline infusion alone. Further, the vacuum used to enable this phase change also acts as an ideal insulator for a concomitant microcatheter system for infusion of cold saline into the intracranial circulation. Last, the cooling device also serves as a state-of-the-art guide catheter that allows cooling to be implemented at the beginning of the thrombectomy procedure, thus optimizing the cooling intervention, rather than waiting until after clot removal as with competitive devices. The first Aim of this R21 proposal involves design, construction, and bench-testing of a coaxial infusioncatheter capable of efficiently vaporizing saline within an annular space, separated from the vasculature and central working lumen for the thrombectomy procedure. Milestones will include heat transfer and mechanical design metrics. During Aim 2, we will carry out in vivo tests assessing the efficacy and safety of our active coolingcatheter. The research plan will involve fabrication and testing of multi-lumen catheters with clearly defined Milestones to achieve acceptable heat transfer metrics, kink, stiffness, torque, and pressure thresholds to maximize heat transfer while minimizing overall system outer diameter. The research plan will include placementof the device in the carotid and renal arteries in swine, measuring the speed, depth, and duration of parenchymal cooling compared to passively-insulated catheters, and assessment of local and systemic adverse reactions.