Aerosol Ventilation to Reduce Ventilator Induced Lung Injury

项目总结

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.