Characterizing clinical and biologic features of persistent hypoxemic respiratory failure

项目总结/文摘

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.