Pulmonary vascular hyperpermeability in the acute respiratory distress syndrome

This thesis is comprised of studies that investigated alveolar-capillary hyperpermeability in the acute respiratory distress syndrome (ARDS), using prospective and observational clinical data. The overarching aims of the studies were to threefold. First to investigate alveolar-capillary barrier protection as a potential treatment for COVID-19 ARDS. Second, to assess the performance of lung ultrasound (LUS) to quantify pulmonary edema in patients with COVID-19 ARDS. Third, to investigate the potential of clinical and radiological parameters, and plasma biomarkers to characterize the mechanisms driving pulmonary edema in invasively ventilated patients.
We demonstrated that the use of the intravenous tyrosine kinase inhibitor imatinib as alveolar-capillary barrier protection was safe in COVID-19 ARDS patients but did not decrease extravascular lung water (EVLW). Thus, the trial does not support the use of imatinib in this population. Clinically, patients with the highest levels of EVLW had significantly worse oxygenation parameters and a longer duration on mechanical ventilation, thus highlighting the value of evaluating EVLW in these patients. The assessment of several LUS scores to estimate EVLW showed that the limited 8-region anterolateral score performed as well as the more extensive 12-region scores. When aiming to assess severe pulmonary edema, taking into account pleural morphology increases discriminatory capacity. Investigating molecular drivers of pulmonary edema, we found that biomarkers of alveolar injury and acute phase response were most strongly associated with radiological scores of pulmonary edema (LUS and chest x-ray), as well as with an increase in EVLW, underscoring the centrality of alveolar injury and acute inflammatory processes in driving pulmonary edema.