Aerosol Ventilation to Reduce Ventilator Induced Lung Injury

气雾通气可减少呼吸机引起的肺损伤

• 批准号: 10383334
• 负责人: Andrew Jones
• 金额: $ 30万
• 依托单位: BOUNDLESS SCIENCE, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383334
• 关键词: Acute Respiratory Distress Syndrome; Aerosols; Air; Alveolar; Alveolus; Anti-Inflammatory Agents; Antiinflammatory Effect; Apoptosis; Automobile Driving; Biopsy; Cannulations; Carbon Dioxide; Carrying Capacities; Cell Line; Cells; Clinical; Couples Therapy; Development; Devices; Endothelium; Endotoxins; Epithelial; Epithelial Cells; Equipment; Excision; Exhalation; Extracorporeal Membrane Oxygenation; Family suidae; Fluorocarbons; Functional disorder; Gases; Goals; Guidelines; Hemorrhage; Human; Image; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Injury; Intervention; Intubation; Lead; Liquid substance; Lung; Magnetic Resonance Imaging; Measures; Mechanical Ventilators; Mechanical ventilation; Medical; Medical Device; Methods; Minor; Monitor; Morbidity - disease rate; Necrosis; Oxygen; Partial Liquid Ventilation; Patient-Focused Outcomes; Patients; Phase; Process; Property; Pulmonary Edema; Pulmonary Gas Exchange; Pulmonary Vascular Resistance; Recycling; Respiratory Failure; Risk; Safety; Science; Small Business Innovation Research Grant; Stroke; Structure of parenchyma of lung; Surface; System; Technology; Testing; Thrombosis; Tidal Volume; Time; Tissues; Trauma; Ventilator; Ventilator-induced lung injury; aerosolized; airway epithelium; base; biomaterial compatibility; cost; cytokine; cytotoxic; cytotoxicity; design; efficacy evaluation; high risk; improved; in vivo; in vivo evaluation; inflammatory marker; lung injury; lung volume; mechanical force; mortality; porcine model; pressure; prototype; pulmonary function; respiratory; response; stroke risk; tertiary care; vapor; ventilation

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.

项目摘要 当出于多种原因发生呼吸衰竭时，机械通气（MV）用于ICU环境中 包括急性呼吸窘迫综合征（ARDS）。严重ARD的死亡率接近50％，并且 即使是那些存活的人，通常也需要MV并对其肺功能产生长期不利影响。这 MC期间使用的积极通风设置在通风过程中施加强大的机械力，可以领导 通过组织和细胞的物理破坏和细胞毒性激活来呼吸机诱导的肺损伤（VILI） 和炎症反应。 MV的替代方法，例如ECMO（体外膜氧合），可以 有效地执行通风和氧合，昂贵，需要高度专业的团队， 不广泛可用的设备，并且具有较高的中风，出血和血栓形成的风险。 我们建议在MV期间使用灵感的空气雾化液体全氟化合物（LPS）将获得更多 快速冷却和有效的气体交换，消除了对高通风器设置的需求，从而减少了VILI。 为了实现这一目标，无限科学正在开发一种双液雾化疗法（BAT），耦合 机械通气以产生蝙蝠系统（蝙蝠），以引入精美的全氟碳雾 类似地冷却肺以减轻炎症，同时增强氧气递送以克服 肺功能障碍。我们的初步结果表明蝙蝠成功，快速冷却的孤立猪 肺部至32°C。我们假设蝙蝠将达到中位气溶胶液滴的低分散性以获得 使用LP混合物增强CO2呼气的同时，均匀的肺部分布和一致的效率 从而改善患者的预后。同时，上皮中的蒸发冷却将进一步 减少炎症超出LP的继承抗炎特性，而LP在A内回收 标准呼吸机将首次降低成本并使其在商业上可行。 该提议的目的是提供概念证明，即蝙蝠与MV结合将增加肺部 氧合（PAO2/FIO2）在不引起创伤的情况下增加50％。我们将使用 遵循特定目标。目标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作用。目标2）创建最佳液滴尺寸和LP比率 用雾化的LP有效浸润和冷却肺泡。 AIM 3）评估优化的雾化LP混合物 AIM 1和2的液滴尺寸在体内ARDS的体内猪模型中。成功的结果不仅会显示 蝙蝠的潜力，但重要的是提供必要的设计指南，以推动开发 临床和商业上可行的系统。