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

项目总结 急性呼吸窘迫综合征(ARDS)的特征是严重的低氧血症和肺水肿 完全可以用心脏功能障碍或液体过多来解释。这种综合征每年影响美国4.5万名儿童。 美国的死亡率为20%，全球为30%。儿童ARDS发病率和 死亡主要通过心血管功能障碍和随后的器官衰竭来调节，而不是 肺损伤本身。目前还没有针对成人或儿童ARDS的特效药物疗法，尽管有许多 主要针对改善氧合作用的试验。小儿急性呼吸窘迫综合征的病理生理特点及治疗 如高呼气末正压和允许性高碳酸血症有助于 肺血管功能障碍(导致肺动脉高压)和右室收缩功能障碍 (右室功能障碍)。肺动脉高压是RV功能障碍的危险因素和RV功能障碍的原因 损害全身心输出量，因此，加重多器官功能障碍。因此，研究要定义 肺动脉高压和右室功能障碍在ARDS预后中的作用是必要的。二维图 斑点跟踪超声心动图(或应变回声)是右室功能障碍的敏感指标。最近的证据 提示右室功能障碍(通过应变回声测量)和肺动脉高压与 儿科ARDS的患者预后更差。此外，RV功能障碍和RV的血浆生物标记物 肺内皮细胞损伤可能有助于发现和预测这些心血管异常。建议数 这项研究利用了费城儿童医院和宾夕法尼亚大学的现有基础设施 应用系列超声心动图和血浆生物标志物进行前瞻性纵向队列研究 儿童急性呼吸窘迫综合征发病后第一周的评估。多样化和经验丰富的指导和 在翻译和临床研究方面具有专业知识的合作团队已经组建。他们将提供 通过严格的培训计划为候选人提供指导，包括高级研究行为、教学方法 流行病学分析、超声心动图方法培训和强化指导。建议数 研究将确定右室功能障碍和肺动脉高压的临床影响，并调查 250例儿童ARDS患者肺内皮细胞损伤的新生物标志物。鉴于这一重要性 对于儿童ARDS预后中的心血管功能障碍，将使用聚类分析对患者进行分类 转化为心血管亚型，将在未来的风险分层研究中使用，并测试有针对性的 改善患者预后的治疗方法。最后，应聘者将接受必要的临床培训 研究、超声心动图和生物标志物成熟为独立的临床医生-科学家 改善危重和受伤儿童的结局。

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.