Characterizing clinical and biologic features of persistent hypoxemic respiratory failure

项目总结/摘要 研究：需要机械通气的急性低氧性呼吸衰竭（AHRF）是一种常见的，昂贵的 死亡率高，但治疗仍然支持。确定有效的靶向治疗方法， 像AHRF这样的异质性疾病取决于患者的特征子集或亚表型， 疾病相关事件或治疗反应的可能性较高。该项目将描绘一个新的子- 机械通气AHRF中的持续性低氧性呼吸衰竭（PHRF）表型 患者，PHRF定义为ICU第3天持续机械通气和低氧血症。使用临床 在其他异质性综合征中定义亚表型的轨迹有助于描述 不同的预后和突出的生物学机制有助于轨迹。大型、独立 来自华盛顿大学和范德比尔特大学的预期ICU队列，Sathe博士将在 以下目的：（1）确定ICU第1天与PHRF相关的临床因素（2）确定生物学 通过分析ICU第1天和第3天肺损伤的循环生物标志物来评估PHRF的特征，以及（3）发展和 验证预测ICU第3天PHRF的多变量模型。了解PHRF的风险因素将有助于 研究肺损伤病理反应的早期重要机制。优势分- 在AHRF而不是ARDS（先前的努力集中）中进行表型分析包括扩大 我们治疗的目标患者，并提高研究定义的可靠性。此外，区分 将要和不会发展PHRF的患者将有助于临床诊断、资源分配和有针对性的治疗。 试验入组的患者不太可能通过现有治疗改善。结果将填补关键的知识空白 NHLBI优先考虑哪些因素决定了持续性低氧血症的风险，以及 这些因素在ARDS和AHRF的其他条件下重叠。 候选人/环境：在华盛顿大学的支持下，Mark Wurfel博士、Catherine博士 “Terri”Hough和生物统计学家Leila Zelnick博士，这个奖项将有助于建立Sathe博士的职业生涯， 从事肺部和重症监护的转化医学科学家。通过这项研究，她 将发展分析纵向队列数据的基本技能，当代机器学习 预测方法以及肺损伤生物标志物的高质量测量和分析。这项工作将 确定生物学途径，以便在前瞻性AHRF队列中进行更深入的研究，她将在 未来的K23她计划建立一个职业生涯，研究急性呼吸衰竭和其他疾病的异质性。 ICU综合征，以促进危重患者靶向治疗的发展。

PROJECT SUMMARY/ABSTRACT Research: Acute hypoxemic respiratory failure (AHRF) requiring mechanical ventilation is a common, costly condition with high mortality, yet treatment remains supportive. Identifying effective targeted therapeutics in heterogeneous conditions like AHRF depends on characterizing subsets, or sub-phenotypes, of patients with high likelihood of disease related events or response to therapy. This project will characterize a novel sub- phenotype called persistent hypoxemic respiratory failure (PHRF) among mechanically ventilated AHRF patients, with PHRF defined by ongoing mechanical ventilation and hypoxemia on ICU day 3. Using clinical trajectory to define sub-phenotypes in other heterogeneous syndromes has helped delineate patients with distinct prognosis and highlight biologic mechanisms contributing to trajectories. With large, independent prospective ICU cohorts from the University of Washington and Vanderbilt University, Dr. Sathe will address the following aims: (1) identify clinical factors on ICU day 1 associated with PHRF (2) determine biologic features of PHRF by analyzing ICU day 1 and day 3 circulating biomarkers of lung injury and (3) develop and validate a multivariable model that predicts PHRF on ICU day 3. Understanding risk factors for PHRF will help hone in on the early mechanisms important for pathologic responses to lung injury. Advantages to sub- phenotyping within AHRF rather than ARDS (where prior efforts were focused) include expanding the scope of patients we target for therapy and improving reliability of study definitions. In addition, discriminating between patients who will and will not develop PHRF will aid clinical prognostication, resource allocation, and targeted trial enrollment of patients unlikely to improve with existing treatment. The results will fill key knowledge gaps prioritized by the NHLBI regarding which factors determine risk for persistent hypoxemia, and the degree to which these factors overlap across ARDS and other conditions in AHRF. Candidate/Environment: With the support of the University of Washington, Dr. Mark Wurfel, Dr. Catherine “Terri” Hough, and biostatistician Leila Zelnick, PhD, this award will help establish Dr. Sathe’s career as a translational physician-scientist practicing Pulmonary and Critical Care. Through the proposed research, she will develop fundamental skills for analysis of longitudinal cohort data, contemporary machine learning methods for prediction, and high-quality measurement and analysis of lung injury biomarkers. This work will identify biologic pathways for more in-depth study in prospective AHRF cohorts, which she will pursue in a future K23. She plans to establish a career examining the heterogeneity of acute respiratory failure and other ICU syndromes, to advance the development of targeted therapeutics for critically ill patients.