Aerosol Ventilation for Rapid Cooling of Transplant Donor Lungs

项目总结 在美国，每年有超过2700例肺移植手术，但严重缺乏 捐献肺意味着每年有成千上万的人在等待合适的捐赠者时死亡。 管风琴。尽管目前美国大多数捐赠者的肺都来自脑死亡的捐赠者，但只有 约20%的多器官脑死亡供者提供适合移植的肺。一个重要的 获得更多供体肺的机会在于心脏死亡(DCD)供体后的捐赠，但只有 美国极少数DCD捐赠者被用于肺移植，原因是 缺血性损伤。肺被认为是热缺血造成的严重损伤，如果没有 在灌流或氧合减弱后60-90分钟内冷却和充氧。此外, DCD供者的肺在采购前&gt；60分钟处于热缺血状态， 支气管愈合受损，移植物原发功能障碍或再灌注损伤的风险更大。AS 因此，开发了一种简单且非侵入性的肺降温和充氧方法 潜在的不受控制的DCD捐赠者将减轻热缺血的损害影响，而 捐赠者为采购做好了准备，并为此提供了无限的肺捐赠者 未开发的捐赠者池。 为了改善可用的供体肺池，无国界科学公司开发了一种双液 雾化通风(BAV)设备原型，快速有效地冷却肺部 死亡。BAV气雾化两种液体全氟化碳(LP)的混合物，介绍了 雾化的液滴通过呼吸机或口罩进入肺部，收集蒸发的LP蒸气 从肺部冷凝和氧化蒸汽，并将冷却的LP液体返回到 通过最初的雾化方法治疗肺部感染。LP的汽化热提供了快速的 在降温的同时，其携带氧气的能力可以防止缺氧性肺损伤。这款安全、易用、 便携式设备是可移动的，可用于ICU和急诊室，以非侵入性冷却和 在死后一小时内给移植肺充氧。 此阶段1提案的目标是提供概念证明，即肺可以有效 从37°C冷却到20°C(以减少肺部的代谢消耗，同时提供 氧气进入呼吸道)在&lt；30分钟内使用LP的组合。要实现高效冷却，请使用 BAV，我们认为我们需要纳入以下优化参数：液滴大小 以及它们的肺泡停留时间、LP混合物的沸点和换热流体。这将是 通过四个具体目标实现。目标1：创建最佳液滴大小和密度以 用雾化的全氟戊烷有效地渗透肺泡。目标2：构建和评估 呼气冷却系统，以回收汽化的液化石油气。目标3：确定最佳配方 LP和临床相关的冷却方法，使猪的肺可以冷却17°C(到 20°C)，使用优化的BAV参数可在30分钟内完成。目标4：修改呼吸机设置以 操纵LP液滴的肺泡停留时间。一旦获得概念证明，我们 将进入第二阶段，在那里我们将改进我们的原型设备，在活体动物身上测试它，并 进行组织健康测试，并寻求FDA的批准。

PROJECT SUMMARY Over 2,700 lung transplants are performed in the US each year, but a significant shortage of donor lungs means that thousands of people die each year while waiting for a suitable donor organ. Although most donor lungs in the US are currently taken from brain-dead donors, only ~20% of multiorgan brain dead donors provide suitable lungs for transplantation. A significant opportunity for more donor lungs lies with donation after cardiac death (DCD) donors, but only a tiny fraction of DCD donors in the US are used for lung transplantation due to concerns over ischemic damage. Lungs are considered significantly injured from warm ischemia if they are not cooled and oxygenated within 60–90 min of diminished perfusion or oxygenation. In addition, lungs from DCD donors subject to warm ischemia for >60 min prior to procurement have impaired bronchial healing and greater risk of primary graft dysfunction or reperfusion injury. As such, developing a simple and non-invasive method of cooling and oxygenating lungs in potential uncontrolled DCD donors would mitigate the damaging effects of warm ischemia while the donor is prepared for procurement and provide a boundless supply of lung donors from this untapped donor pool. To improve the pool of usable donor lungs, Boundless Science, LLC developed a bi-liquid aerosolized ventilation (BAV) device prototype that cools a lung quickly and efficiently following death. The BAV aerosolizes a mixture of two liquid perfluorocarbons (LP), introduces the atomized droplets into the lungs through a ventilator or mask, collects evaporated LP vapors from the lungs, condenses and oxygenates the vapor, and returns the cooled LP liquid to the lungs via the original aerosolization method. The LP’s enthalpy of vaporization provides rapid cooling while its ability to carry oxygen prevents hypoxic lung damage. This safe, easy-to-use, portable device is ambulatory and can be used in the ICU and the ER to non-invasively cool and oxygenate lungs for transplant well within an hour after death. The objective of this phase 1 proposal is to provide proof of concept that lungs can be efficiently cooled from 37°C to 20°C (to decrease metabolic consumption by the lungs while providing oxygen to the airways) in <30 min using a combination of LPs. To achieve efficient cooling with BAV, we believe that we need to incorporate the following optimized parameters: droplet size and their alveolar dwell time, boiling point of the LP mixture, and heat transfer fluid. This will be achieved using four Specific Aims. Aim 1: Create the optimal droplet size and density to effectively infiltrate alveoli with aerosolized Perfluoropentane. Aim 2: Build and evaluate an exhaled cooling system to recover the vaporized LP. Aim 3: Determine the optimized mixture of LPs and a clinically relevant cooling method such that pig lungs can be cooled by 17°C (to 20°C) in under 30 minutes using optimized BAV parameters. Aim 4: Modify ventilator settings to manipulate the alveolar dwell time of LP droplets. Once proof of concept has been obtained, we will progress to Phase II, where we will refine our prototype device, test it on live animals and test for tissue health, and pursue FDA approval.