The Roles of Pulmonary Hypertension and Right Ventricular Dysfunction in Pediatric Acute Respiratory Distress Syndrome

PROJECT SUMMARY Acute respiratory distress syndrome (ARDS) is characterized by severe hypoxemia and pulmonary edema not fully explained by cardiac dysfunction or fluid overload. This syndrome affects 45,000 children annually in the United States; the mortality rate is 20% in the United States and 30% worldwide. Pediatric ARDS morbidity and mortality are primarily mediated through cardiovascular dysfunction with subsequent organ failure rather than lung injury itself. There are no specific pharmacologic therapies for adult or pediatric ARDS despite numerous trials that have mainly targeted improving oxygenation. Pediatric ARDS pathophysiology itself and treatments such as high positive end-expiratory pressure and permissive hypercapnia contribute to the development of pulmonary vascular dysfunction (leading to pulmonary hypertension) and right ventricular systolic dysfunction (RV dysfunction). Pulmonary hypertension is a risk factor for RV dysfunction and RV dysfunction causes impaired systemic cardiac output and, therefore, exacerbates multi-organ dysfunction. Thus, studies to define the roles of pulmonary hypertension and RV dysfunction in ARDS outcomes are needed. Two-dimensional speckle tracking echocardiography (or strain echo) is a sensitive indicator of RV dysfunction. Recent evidence suggests that RV dysfunction (as measured by strain echo) and pulmonary hypertension are associated with worse patient outcomes in pediatric ARDS. In addition, plasma-based biomarkers of RV dysfunction and pulmonary endothelial injury may help to detect and predict these cardiovascular abnormalities. The proposed study leverages existing infrastructure at the Children’s Hospital of Philadelphia and University of Pennsylvania to conduct a prospective longitudinal cohort study using serial echocardiography and plasma biomarker assessments over the first week following pediatric ARDS onset. A diverse and experienced mentorship and collaborative team, with expertise in translational and clinical research, has been assembled. They will provide guidance for the candidate through a rigorous training plan involving research conduct, didactics in advanced epidemiological analyses, training in echocardiographic methods, and intensive mentorship. The proposed studies will define the clinical impact of RV dysfunction and pulmonary hypertension and investigate the role of a novel biomarker of pulmonary endothelial damage in 250 patients with pediatric ARDS. Given the importance of cardiovascular dysfunction in pediatric ARDS outcomes, cluster analyses will be used to classify patients into cardiovascular subphenotypes that will be used in future studies for risk stratification and to test targeted therapies to improve patient outcomes. Finally, the candidate will gain the necessary training in clinical research, echocardiography, and biomarkers to mature into an independent clinician-scientist working to improve outcomes for critically ill and injured children.