Mechanical Ventilation Management, New or Progressive MODS, and Post-ICU Morbidity in Pediatric ARDS

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PROJECT SUMMARY Rationale: Most children with pediatric acute respiratory distress syndrome (PARDS), a severe form of lung injury, require mechanical ventilation. In adults with ARDS, injurious mechanical ventilation practices increase mortality, primarily attributed to the development of new or progressive multiple organ dysfunction syndrome (NPMODS). Pediatric studies have not found similar consistent associations between mechanical ventilation practices and mortality. NPMODS is a feasible alternative outcome to mortality, which is low in PARDS, that has strong biological plausibility for association with injurious mechanical ventilation and may improve identification of mechanical ventilation associated harm in children. Before adoption of the intermediary outcome NPMODS, as most children survive PARDS, it is crucial to characterize the association between NPMODS and post-ICU morbidity. Research: Through this career development award, Dr. Anoopindar Bhalla, a pediatric intensivist, seeks to understand the associations between ventilator management, NPMODS, and post-ICU morbidity in children with PARDS. The research will leverage the infrastructure and resources of a Phase II randomized controlled trial on a lung-protective ventilation strategy enrolling 276 children with PARDS and led by Dr. Bhalla’s co-mentor (PI: Khemani, NHLBI R01 HL134666, REDvent). The central hypothesis is that injurious mechanical ventilation leads to NPMODS and, in turn, NPMODS is associated with post-ICU morbidity in children with PARDS. These hypotheses will be tested through the following Specific Aims: 1) Determine whether a lung-protective ventilation strategy prevents NPMODS in PARDS; 2) Identify physiologic mechanisms of injurious ventilation which are associated with NPMODS in PARDS (including assessment of transpulmonary pressures); 3) Characterize the association between NPMODS and post-ICU morbidity (health-related quality of life, functional status, and pulmonary status) in PARDS. Career Development: Through completion of the proposed research, additional career development training activities, and multidisciplinary mentorship, Dr. Bhalla will learn key skills in 1) the principles of pediatric clinical trials; 2) advanced study design and biostatistics; 3) the assessment of post-ICU outcomes in children. Acquiring these skills is critical for Dr. Bhalla’s long-term career goal to lead well-designed clinical trials in critically ill children. The assembled mentorship team with world-class experts in respiratory physiology, biostatistics, and long-term outcomes as well as clinical trials, will support her in these endeavors. Impact: This research will provide crucial information on the associations between injurious mechanical ventilation, NPMODS, and post-ICU morbidity to guide future PARDS clinical trials. Furthermore, through the career development training and generated data, Dr. Bhalla will be well-positioned to successfully compete for R01 funding and become an independent investigator leading pediatric mechanical ventilation clinical trials.