The effect of severe obesity on regional lung perfusion in acute hypoxemic respiratory failure

Massachusetts General Hospital, Boston MA

Investigators

Abstract

Severe obesity, a population of over 30 million adult Americans, increases rates of acute hypoxemic respiratory failure (AHRF) and leads to cardiopulmonary complications and premature death. Unfortunately, AHRF in severe obesity remains insufficiently characterized, and there are no targeted pharmacologic therapies for this population. The K23 award application aims to address critical knowledge gaps for the care of acutely hypoxemic patients with severe obesity and develop methodologic expertise in functional lung imaging and endothelial biology for the candidate. The mentored research has two aims. Aim 1 will define the association between severe obesity and regional lung perfusion in a novel multicenter AHRF cohort containing functional imaging and clinical data. Aim 2 will test the effect of severe obesity on the pulmonary vasoreactivity to inhaled nitric oxide in a prospective cohort of mechanically ventilated patients with AHRF. Contributions from diabetes and sex will be assessed for both aims. The proposal's central hypothesis is that severe obesity impairs regional lung perfusion and vasoreactivity in AHRF. The candidate's long-term goal is to be an independent patient- oriented translational researcher who develops and tests precision diagnostics and therapies for AHRF patients with severe obesity. The research aims directly inform the training goals to 1) develop advanced knowledge of functional lung imaging techniques, 2) gain methodologic expertise in endothelial biology, 3) acquire skills in clinical trials in critical care settings, and 4) obtain certification in obesity medicine. The training plan includes hands-on laboratory experience, selected graduate coursework, planned research manuscripts, weekly seminars, and frequent mentor meetings that build on a solid clinical epidemiology and biostatistics background. The research project, institutional environment, mentorship team, and content advisors are ideally suited to the candidate's career development. This formative work has the potential to result in a significant shift in the focus of care of AHRF patients with severe obesity by targeting vascular derangements as a guide to personalized therapy. The K23 award will support the candidate's transition to lead independent research aimed at 1) integrating perfusion imaging into the care of AHRF patients with severe obesity, 2) investigating the role of nitric oxide signaling dysfunction on AHRF progression in severe obesity, and 3) identifying pathways of perfusion dysregulation as possible targets for novel therapeutic approaches.