Aerosol Ventilation to Reduce Ventilator Induced Lung Injury

项目总结 机械通风(MV)用于ICU环境中因各种原因发生呼吸衰竭时， 包括急性呼吸窘迫综合征(ARDS)。重症ARDS的死亡率接近50%， 即使那些存活下来的人通常也需要接受MV，并对其肺功能造成长期的不利影响。这个 MC期间使用的激进呼吸机设置在通风过程中施加强大的机械力，可能会导致 通过组织和细胞的物理破坏和细胞毒的激活而导致呼吸机诱导的肺损伤(VILI) 和炎症反应。MV的替代品，如ECMO(体外膜氧合)，可以 高效地进行通风和充氧，成本过高，需要高度专业化的团队和 设备不是广泛可用的，并且具有中风、出血和血栓形成的高风险。 我们认为，在MV中吸入空气雾化液体全氟碳化合物(LP)将取得更好的效果 快速冷却和高效的气体交换，消除了对高通气扇设置的需要，从而降低了VILI。 为了实现这一点，无国界科学公司正在开发一种双液雾化疗法(BAT)，该疗法与 机械通气机产生BAT系统(BATS)以引入细微的全氟化碳雾化 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成功地快速冷却了隔离猪 肺至32˚C。我们假设BATS将实现中位气溶胶液滴的低多分散性，以获得 使用可促进二氧化碳呼出的LP混合物时，肺部分布均匀，疗效一致 从而改善患者的预后。同时，上皮中的蒸发冷却将进一步 减少炎症，超越脂多糖固有的抗炎特性，同时在 标准通风器将降低成本，并首次使其在商业上可行。 这项建议的目的是提供BAT与MV相结合将增加肺功能的概念证据 氧合(PaO2/FiO2)降低50%，不会造成创伤。我们将通过使用 遵循特定的目标。目的1)确定低水平细胞毒性的最佳脂多糖混合物和 在体外提供最高的抗炎效果。目标2)创建最佳液滴大小和液滴比以 雾化LP能有效渗透和冷却肺泡。目的3)评价最佳喷雾液化液 在ARDS的活体猪模型中，目标1和2的液滴大小。成功的结果不仅表明 BATS的潜力，但重要的是将提供必要的设计指南，以推动 临床上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.