Circadian Rhythm as a Novel Therapeutic Target in the Intensive Care Unit

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PROJECT SUMMARY Candidate: My long-term career goal is to be an independent patient-oriented researcher who will improve outcomes in the intensive care unit (ICU) by investigating questions and developing interventions at the intersection of sleep physiology, circadian biology, and critical illness. I have proposed career development activities that will prepare me to successfully conduct a series of investigations focused on understanding ICU circadian rhythm abnormalities and the associated effects on ICU sleep disruption, delirium, and broader critical illness outcomes. I have relevant clinical training in critical care and sleep medicine. I have gained initial patient-oriented research experience by conducting several studies related to sleep disruption in the ICU. In this K23 application, I am proposing specific training in circadian biology with a focus on (1) circadian rhythm measurement, (2) circadian entrainment interventions, and (3) longitudinal data analysis. Completion of these training activities will bridge current knowledge gaps and set up future success as an independent investigator. Mentors and Environment: I will be mentored by Drs. Henry Klar Yaggi, Margaret Pisani, and Nancy Redeker, a team of experienced, committed experts in the fields of sleep medicine, critical care medicine, circadian measurement, ICU delirium, and patient-oriented research. This team has demonstrated collaborative success, and each member brings unique expertise. I will also work with advisors Dr. Kenneth Wright (circadian biology expert) and Dr. Terrence Murphy (analytics expert). My department Chairperson (Dr. Gary Desir) and Section Chief (Dr. Naftali Kaminski) have provided assurance that I will dedicate at least 75% of my time to career development activities. We will recruit study subjects from the Yale-New Haven Hospital Medical ICU which is a high volume ICU with sufficient patients to make this project feasible. Our section's Translational Research Core and Medical ICU Biorepository will support this project. Mentored Research Project: Delirium affects 50-80% of medical ICU patients. Prevention and treatment strategies are limited, and delirium is associated with poor outcomes including increased mortality. Because ICU sleep disruption is likely to be a contributor to the development of ICU delirium, sleep promotion is recommended for delirium treatment and prevention. Currently, there is a lack of investigation regarding the potentially significant contribution of circadian abnormalities to the problem of ICU sleep disruption and consequent delirium. Circadian abnormalities are potentially modifiable, and thus constitute a novel therapeutic target for ICU delirium. This project will prospectively study ICU patients (N=100) with detailed circadian measures. We will examine the impact of ICU light levels on circadian abnormalities and examine the association between circadian abnormalities and days of delirium. In addition, we will conduct a pilot randomized controlled trial (N=50) to assess the feasibility of providing daytime bright light to ICU patients to promote circadian entrainment.