Reactive Oxygen Species in Respiratory Failure, Delirium, and Post-ICU Cognitive Impairment

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PROJECT SUMMARY One million adults in the United States receive mechanical ventilation for acute respiratory failure (ARF) annually and up to 80% of them develop delirium during their intensive care unit (ICU) stay. Delirium is associated with post-ICU cognitive and physical impairments. Delirium has no effective treatment due to our limited understanding of the pathophysiology connecting ARF and delirium which share a proinflammatory cytokine state. The systemic release of cytokines, ongoing alveolar injury, and production of reactive oxygen species (ROS) may connect ARF and delirium. We hypothesize that increased biomarkers of ROS are associated with increased cognitive and physical function impairments in critically ill older adults. To test our hypothesis, we propose a preliminary, prospective study titled Reactive Oxygen Species in Respiratory Failure, Delirium and Post-ICU Cognitive Impairment. We will measure levels of ROS using samples obtained from 80 critically ill, mechanically ventilated older adults, and follow these patients for 24 months. Blood samples and cognition and physical function assessments will be conducted at multiple time-points to accomplish our study aims. The primary aim is to measure the relationship between biomarkers of ROS and post-ICU mild cognitive impairment (MCI) and Alzheimer’s Disease and Related Dementias (ADRD) in critically ill older adults with acute respiratory failure. The secondary aims are to measure the relationship among biomarkers of oxidative injury and delirium duration and severity in critically ill older adults with ARF; and to measure the relationship among post- ICU biomarkers of inflammation and oxidative stress and post-ICU MCI and ADRD. The proposed career development plan integrates coursework, experiential training and mentorship in aging, and the conduct of prospective clinical research. The candidate will also learn leadership skills, participate in national meetings, and benefit from a well-established and highly successful multidisciplinary mentorship panel with a track record of success in training junior investigators. The candidate’s academic environment includes the highly acclaimed resources and faculty of Indiana University School of Medicine, the distinguished Indiana University Center for Aging Research, Regenstrief Institute, and the NIH-funded Indiana Clinical and Translational Sciences Institute (CTSI). This career development award will guarantee protected time that will be necessary to advance the candidate’s career in studying outcomes for older adults. Knowledge gained during the award will improve scientific understanding of the nexus between ARF, delirium, and ICU-acquired cognitive and physical impairment, and prepare for R01 submissions to further study oxidative stress in aging.