AbstractVentilator-induced lung injury (VILI) can be associated with multiple organ dysfunction, yet the mechanisms underpinning it are unclear. It has been proposed that injurious mechanical ventilation can drive lung and distal organ injury through a process of biotrauma, and this was the focus of my research.
I assessed the pattern of lung injury in porcine and human lungs ventilated using injurious settings in an ex-vivo lung perfusion (EVLP) model, and I evaluated whether lung injury was transferrable from VILI to control lungs. Additionally, A549 cells were cultured in human EVLP perfusate and the effect on cellular metabolism between VILI and control lungs was measured. In patients recruited to the REST trial, I assessed the pattern of lung injury and inflammation between treatment arms using plasma samples. Separately, I evaluated whether average oxygen exposure was associated with outcomes in patients with acute respiratory distress syndrome. Finally, I studied the effect of diabetes on outcomes in a global cohort of patients with acute hypoxaemic respiratory failure (AHRF).
This work demonstrates that lung injury is characterised by increased lung weight in both porcine and human lungs ex-vivo, whilst there was transferrable injury demonstrated in porcine lungs. Perfusate from human lungs treated with injurious ventilation had an heterogenous effect on A549 cell metabolic activity. There was no difference in the pattern of lung injury or inflammation in patients recruited to the REST trial. In patients with ARDS, I identified that an average time-weighted PaO2 between 12.5 and 14kPa had the lowest predicted probability of ICU mortality. Finally, diabetes did not affect outcomes in patients with AHRF.
Together, these data suggest that biotrauma may contribute to VILI, however further mechanistic understanding is required. Although hyperoxaemia may contribute to lung injury, diabetes does not appear to modify outcomes in patients with AHRF.
Thesis embargoed until 31 December 2023.
|Date of Award||Dec 2021|
|Sponsors||Health and Social Care (Northern Ireland) Research and Development|
|Supervisor||Cecilia O'Kane (Supervisor), Danny McAuley (Supervisor) & James McNamee (Supervisor)|