Acute respiratory distress syndrome (ARDS) arising from trauma, sepsis, pneumonia or other diseases affects nearly 190,000 patients in the U.S. each year, and the mortality rate remains high at 35-40%. Currently, the last resort for treating ARDS, where mechanical ventilation has failed, is ECMO: a temporary, artificial, extracorporeal support of the respiratory system. Thrombosis and other significant safety complications are associated with extracorporeal membrane oxygenation (ECMO), and clinical trials of ECMO for the treatment of ARDS has shown limited efficacy. We propose to develop intraperitoneal membrane ventilation with oxygen microbubbles as a safe and effective alternative method for extra pulmonary oxygenation to treat these patients by providing essential systemic oxygen while allowing the lung injury to heal. Oxygen microbubbles are less expensive and have a higher oxygen carrier capacity than prior aqueous formulations of fluorocarbon emulsions and liposomal hemoglobin. Additionally, oxygen microbubbles provide an overall rate of oxygen transfer to the peritoneum that is at least three orders of magnitude higher than mechanical ventilation of the intraperitoneal cavity. Our preliminary data in a small animal model for ARDS shows that PMO is a promising therapy for severe hypoxemia. The proposed work will bring this technology closer to human translation by investigating its effectiveness for treating ARDS in large animals. The two specific aims of this proposal are to determine microbubble gas exchange transport properties in vitro, and to demonstrate microbubble peritoneal ventilation in vivo by use of an established ARDS animal model. The first working hypothesis is that circulating OMBs through the peritoneal cavity exchanges physiologically relevant levels of O2 for CO2. Therefore, the purpose of aim 1 is to determine the kinetics of gas exchange between OMBs and blood in a simple in vitro system. The second working hypothesis is that circulation of OMBs through the peritoneal cavity prevents hypoxia in a rat model of moderate to severe ARDS. Translation of our previously successful short-term use of this technology will require demonstration of successful oxygenation over a clinically relevant time period, therefore the activity for aim 2 is to evaluate oxygenation before, during, and after circulation of OMBs through the peritoneal cavity of the animal model. Relevance to Public Health: ARDS syndrome affects nearly 190,000 patients in the U.S. each year, and the mortality rate remains high at 40% owing to inadequate and injurious effects of mechanical ventilation. This project will develop and test peritoneal ventilation with oxygen microbubbles - an innovative extra pulmonary oxygenation technology - for the treatment of these patients.

Public Health Relevance

Our goal is to develop a safe and effective extra-pulmonary oxygenation strategy to treat hypoxemic patients suffering from acute respiratory distress syndrome (ARDS). The purpose of this project is to quantify this therapy's effectiveness in a clinically relevant animal lung injury model which, once it is translated to humans, could lead to a significant increase in the survivability of ARDS patients by creating an effective alternative therapy to extracorporeal membrane oxygenation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Harabin, Andrea L
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University of Nebraska Lincoln
Engineering (All Types)
Biomed Engr/Col Engr/Engr Sta
United States
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Fix, Samantha M; Papadopoulou, Virginie; Velds, Hunter et al. (2018) Oxygen microbubbles improve radiotherapy tumor control in a rat fibrosarcoma model - A preliminary study. PLoS One 13:e0195667
Legband, Nathan; Black, Arielle; Kreikemeier-Bower, Craig et al. (2018) Preliminary Evaluation of the Viability of Peritoneal Drainage Catheters Implanted in Rats for Extended Durations. J Invest Surg :1-10
Thomas, Alec N; Borden, Mark A (2017) Hydrostatic Pressurization of Lung Surfactant Microbubbles: Observation of a Strain-Rate Dependent Elasticity. Langmuir 33:13699-13707