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% andeven those that survive typically require MV and suffer long-term adverse impacts on their lung function. Theaggressive ventilator settings used during MC apply strong mechanical forces during ventilation that can leadto ventilator-induced lung injury (VILI) via physical disruption of the tissues and cells and activation of cytotoxicand inflammatory responses. Alternatives to MV, such as ECMO (extracorporeal membrane oxygenation), canefficiently perform ventilation and oxygenation, is exorbitantly expensive, requires highly specialized teams andequipment 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 morerapid 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 amechanical ventilator to yield a BAT system (BATS) to introduce a fine perfluorocarbon mist thatsimultaneously cools the lungs to reduce inflammation while enhancing oxygen delivery to overcomepulmonary dysfunction. Our preliminary results indicate that BATS successfully and rapidly cooled isolated piglungs to 32ËC. We hypothesize that BATS will achieve low polydispersity of median aerosol droplet to obtainuniform pulmonary distribution and consistent efficacy while using an LP mixture that enhances CO2 exhalationand thus improve patient outcomes. At the same time, the evaporative cooling in the epithelium will furtherreduce inflammation beyond the inherent anti-inflammatory properties of the LPs, while LP recycling within astandard 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 pulmonaryoxygenation (PaO2/FiO2) by 50% without causing trauma. We will progress toward this objective using thefollowing Specific Aims. Aim 1) Determine the optimal mixture of LPs that has low level cytotoxicity andprovides the highest anti-inflammatory effects in vitro. Aim 2) Create the optimal droplet size and LP ratio toeffectively infiltrate and cool alveoli with aerosolized LP. Aim 3) Evaluate the optimized aerosolized LP mixtureand droplet size from Aims 1 and 2 in an in vivo porcine model of ARDS. Successful results will not only showthe potential of BATS but will importantly provide the necessary design guidelines to drive the development ofa clinically and commercially viable system.
Public Health Relevance Statement: PROJECT NARRATIVE
Mechanical ventilation is used in an ICU setting when respiratory failure occurs for a variety of reasons,
including acute respiratory distress syndrome (ARDS), but it frequently causes pulmonary dysfunction and
ventilator-induced lung injury (VILI). Current alternatives to MV, such as extracorporeal membrane oxygenation
are extremely expensive, only available at tertiary care settings, and carry a high risk of cannulation insertion,
stroke, bleeding, and thrombosis, and so there is still a significant unmet medical need. We are developing an
add-on aerosolization device for existing mechanical ventilator systems to improve pulmonary oxygenation for
patients with severe ARDS, creating a solution that avoids the aggressive ventilator settings that cause VILI at
a commercially and clinically viable cost.
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