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Negative Pressure Ventilation - A New Frontier for Ex Vivo Lung Perfusion
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- Author / Creator
- Aboelnazar, Nader Saber
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Lung transplantation is a life-saving therapy for patients suffering from end-stage lung disease; however, there exists a discrepancy between suitable donor grafts and utilization rates. At most, only 40% of offered donor lungs are utilized for transplantation. The majority are deemed unsuitable due to injury encountered during retrieval or cold preservation/transportation. To help mitigate the challenges facing lung transplantation, Ex Vivo Lung Perfusion (EVLP) was developed by a Swedish team in 2001. Since its inception, the platform’s preservation, evaluation, and reconditioning capabilities has been extensively researched worldwide. EVLP preserves donor lungs under normothermic protective strategies. Over the years, lung grafts have tolerated at least 4-6-hours of EVLP preservation, in clinical settings, and up to 12-hours in preclinical settings. As such, EVLP could be an influential device in the field of lung transplantation – injured/unsuitable donor lungs objectively evaluated for their transplant suitability and a platform for precision repair medicine. However, further research is needed to continue refining EVLP as a preservation and evaluative platform. Hence, this thesis aims to further elucidate potential enhancement strategies in perfusate and ventilation modalities during EVLP. In the first project, we sought to investigate an answer to a 10-year old conundrum – what is the optimal perfusate during conventional, positive pressure ventilation (PPV)-EVLP? Our institution is faced with a unique geographical isolation where our patient catchment encompasses a 6 million km2 area. Patients suffering from end-stage lung disease face odds of ~33% utilization rates of all donated grafts and waitlist mortality rates reported as high as 40%, in 2014. Therefore, our lab sought out to alleviate this burden by developing a portable custom-designed PPV-EVLP. Our platform captures in real-time various lung functional parameters; and as a portable platform it will ensure safer retrieval of suitable lung allografts. Normothermic preservation reduces the damage insulted to donated organs, compared to limited conventional cold preservation. As such, we began the journey to resolve the aforementioned conundrum with investigations on twenty-four porcine lungs. We assessed the physiological and functional effects of either an acellular or cellular (autologous blood and red blood concentrate) perfusate strategy, on our open left atrium PPV-EVLP platform. We demonstrated that the utilization of a physiologic perfusate (red blood concentrate or autologous blood) during extended (12-Hours) PPV-EVLP preserves lung compliance and maintains overall lung integrity. An acellular PPV-EVLP strategy significantly injured the organ, resulting in >50% in global edema formation, compared to either cellular based strategy. Moreover, compliance was found to be reduced with acellular treated lungs; but interestingly, compliance was only found to positively correlate with oxygenation and negatively correlate with edema formation, with a cellular based perfusate. Having explored the optimal perfusate strategy during extended EVLP, in 2015 we theorized that a more physiologic ventilation modality (negative pressure ventilation - NPV) would further optimize our EVLP protocol. To-date, all clinically accepted EVLP platforms differ with regards to their protocol strategies (perfusion and ventilation strategies); however, they unanimously utilize the same ventilation modality, positive pressure ventilation. Despite extensive research demonstrating that positive pressure ventilation can result in ventilator induced lung injury. Our first project elucidated that the greater the mimicry of physiologic conditions in an ex vivo setting, the more we optimize reconditioning during EVLP; hence, preventing further injury to fragile/injured donor lungs. As such, we developed another portable, custom-designed NPV-EVLP platform. For the first time, the effect of ventilation and perfusate were concurrently under investigation, during extended EVLP. Our second project included thirty-two porcine lungs, allocated randomly and equally into four treatment groups – mode of ventilation (PPV-EVLP versus NPV-EVLP) and perfusate composition (acellular versus red blood concentrate). Additionally, the impact of ventilation strategy was investigated on six unsuitable/injured human donor lungs, using only a cellular based perfusate. Irrespective of perfusate, the utility of NPV-EVLP compared to PPV-EVLP resulted in significantly attenuated barotrauma and volutrauma, inflammation and edema/lung injury. Additionally, the use of an acellular perfusate demonstrated significant edema formation (irrespective of ventilation strategy). Intriguingly, for the first time, we report human lungs subjected to extended NPV-EVLP demonstrating a “drying” effect – reduction in lung weight form baseline. Overall, this thesis lays the foundation for future research to come, by establishing our own unique University of Alberta protocol with our innovative NPV-EVLP platform. -
- Graduation date
- Spring 2019
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- Type of Item
- Thesis
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- Degree
- Master of Science
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- License
- Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.