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

项目总结 缺血性中风是全球第二大死亡原因，造成约716亿美元的损失。 这些费用不成比例地由大血管闭塞(LVO)患者推动。的最新进展 紧急血栓切除术虽然改善了预后，但仍有超过50%的患者效果不佳 即使在最近的试验中，功能结果也是如此。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着发生的事件现在是这一领域的研究人员的主要关注焦点。其中 尽管提出了许多神经保护策略，但低温仍然是最有希望的。之前的众多 研究人员提出了选择性脑冷却与血栓切除手术相结合的建议，因为 进入颈动脉的导管已经到位，可以在血栓清除后立即使用。 这些选择性降温方法要么直接向颅内血流注入冷盐水，要么 冷生理盐水，用于冷却流经留置导管壁的血液。这两种方法都受到以下限制 冷盐水在到达目标位置时本身就会变暖。此外，这些技术不能 实施到血栓摘除程序结束，错过了最大化 血栓清除过程中侧支循环对半影区组织的保护性降温作用。 这项研究和开发提案的长期目标是实现一种全新的方法来选择 使用生理盐水作为冷冻剂来冷却大脑，在导管系统内以超低压蒸发。 盐相从液体到蒸汽的变化起到了散热器的作用，散热器的体积比 单纯盐水输注的简单对流/传导。此外，用于实现这种相变的真空度 也是配套的微导管系统的理想绝缘体，用于将冷盐水注入 颅内循环。最后，冷却装置也是一种最先进的导尿管，可以进行冷却 在血栓切除程序开始时实施，从而优化冷却干预， 而不是像竞争设备那样等到血栓清除之后。 R21提案的第一个目标涉及同轴输液导管的设计、建造和台架测试 能够有效地蒸发环状空间内的盐水，从血管系统和中央分离 血栓切除手术的工作管腔。里程碑将包括传热学和机械设计 指标。在AIM 2期间，我们将进行体内测试，评估我们的主动冷却导管的有效性和安全性。 研究计划将包括制造和测试具有明确定义的里程碑的多腔导管，以 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 转移时将整个系统外径降至最小。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 与被动绝缘导尿管相比，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.