Aerosol Ventilation to Reduce Ventilator Induced Lung Injury

项目摘要 当由于各种原因发生呼吸衰竭时，在ICU环境中使用机械通气（MV）， 包括急性呼吸窘迫综合征（ARDS）。严重ARDS的死亡率接近50%， 即使是那些存活下来的人，通常也需要MV，并且对他们的肺功能产生长期的不利影响。的 在MC期间使用的积极呼吸机设置在通气期间施加强机械力， 呼吸机诱导的肺损伤（VILI）通过物理破坏的组织和细胞，并激活细胞毒性 和炎症反应。MV的替代方案，如ECMO（体外膜肺氧合）， 有效地进行通气和充氧，是非常昂贵的，需要高度专业化的团队， 这些设备并不广泛使用，并且具有中风、出血和血栓形成的高风险。 我们建议在MV期间用吸入的空气雾化液体全氟化碳（LP）将实现更多 快速冷却和有效的气体交换，无需高呼吸机设置，从而降低VILI。 为了实现这一目标，Boundless Science正在开发一种双液体雾化疗法（BAT）， 机械通风机，以产生BAT系统（BATS），以引入细的全氟化碳雾， 同时冷却肺部以减少炎症，同时增强氧气输送以克服 肺功能障碍我们的初步结果表明，BATS成功地和快速冷却隔离猪 肺部温度升至32摄氏度我们假设BATS将实现中值气溶胶液滴的低多分散性，以获得 在使用LP混合气体时，肺部分布均匀，疗效一致，可增强CO2呼出 从而改善患者的治疗效果。同时，上皮中的蒸发冷却将进一步 减少炎症超过LP固有的抗炎特性，而LP在体内循环， 标准呼吸机将降低成本，并使其首次在商业上可行。 本提案的目的是提供概念证明，证明BAT与MV联合使用将增加肺动脉压。 氧合（PaO 2/FiO 2）降低50%，而不会造成创伤。我们将利用 遵循具体目标。目的1）确定具有低水平细胞毒性的LP的最佳混合物， 在体外提供最高的抗炎效果。目标2）创建最佳液滴尺寸和LP比， 有效地渗透和冷却肺泡与雾化LP。目的3）评估优化的雾化LP混合物 和来自目的1和2的液滴尺寸。成功的结果不仅表明 的潜力，但重要的是提供必要的设计准则，以推动发展 临床和商业上可行的系统。

PROJECT SUMMARY Mechanical ventilation (MV) is used in an ICU setting when respiratory failure occurs for a variety of reasons, including acute respiratory distress syndrome (ARDS). The mortality of severe ARDS approaches 50% and even those that survive typically require MV and suffer long-term adverse impacts on their lung function. The aggressive ventilator settings used during MC apply strong mechanical forces during ventilation that can lead to ventilator-induced lung injury (VILI) via physical disruption of the tissues and cells and activation of cytotoxic and inflammatory responses. Alternatives to MV, such as ECMO (extracorporeal membrane oxygenation), can efficiently perform ventilation and oxygenation, is exorbitantly expensive, requires highly specialized teams and equipment that is not widely available, and carries high risks of stroke, bleeding, and thrombosis. We propose that aerosolizing liquid perfluorocarbons (LPs) with the inspired air during MV will achieve more rapid cooling and efficient gas exchange, negating the need for high ventilator settings and thus reducing VILI. To achieve this, Boundless Science is developing a bi-liquid aerosolized therapy (BAT) coupled to a mechanical ventilator to yield a BAT system (BATS) to introduce a fine perfluorocarbon mist that simultaneously cools the lungs to reduce inflammation while enhancing oxygen delivery to overcome pulmonary dysfunction. Our preliminary results indicate that BATS successfully and rapidly cooled isolated pig lungs to 32˚C. We hypothesize that BATS will achieve low polydispersity of median aerosol droplet to obtain uniform pulmonary distribution and consistent efficacy while using an LP mixture that enhances CO2 exhalation and thus improve patient outcomes. At the same time, the evaporative cooling in the epithelium will further reduce inflammation beyond the inherent anti-inflammatory properties of the LPs, while LP recycling within a standard ventilator will reducing costs and making it commercially viable for the first time. The objective of this proposal is to provide proof of concept that BAT coupled with MV will increase pulmonary oxygenation (PaO2/FiO2) by 50% without causing trauma. We will progress toward this objective using the following Specific Aims. Aim 1) Determine the optimal mixture of LPs that has low level cytotoxicity and provides the highest anti-inflammatory effects in vitro. Aim 2) Create the optimal droplet size and LP ratio to effectively infiltrate and cool alveoli with aerosolized LP. Aim 3) Evaluate the optimized aerosolized LP mixture and droplet size from Aims 1 and 2 in an in vivo porcine model of ARDS. Successful results will not only show the potential of BATS but will importantly provide the necessary design guidelines to drive the development of a clinically and commercially viable system.