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

项目摘要 候选人：我的长期职业目标是成为一名独立的、以病人为导向的研究人员， 通过调查问题和制定干预措施， 睡眠生理学、昼夜节律生物学和危重疾病的交叉点。我建议职业发展 这些活动将使我做好准备，成功地进行一系列调查，重点是了解ICU 昼夜节律异常及其对ICU睡眠中断、谵妄和更广泛的 重大疾病的结果。我接受过重症监护和睡眠医学的相关临床培训。我已经获得了 通过在ICU进行几项与睡眠中断相关的研究，获得了以患者为导向的研究经验。在 在K23的应用中，我建议进行生物节律方面的具体培训，重点是（1）生物节律 测量，（2）昼夜节律夹带干预，和（3）纵向数据分析。完成这些 培训活动将弥补目前的知识差距，并为今后作为独立调查员取得成功奠定基础。 导师和环境：我将由亨利克拉亚吉博士，玛格丽特皮萨尼和南希指导 Redeker是一个经验丰富的团队，致力于睡眠医学，重症监护医学， 昼夜节律测量、ICU谵妄和面向患者的研究。这个团队已经证明了 合作成功，每个成员都带来了独特的专业知识。我还将与顾问肯尼思博士 赖特（昼夜节律生物学专家）和特伦斯墨菲博士（分析专家）。主任医师（Dr. 加里德西尔）和科长（Naftali Kaminski博士）已经提供了保证，我将投入至少75% 我的职业发展活动的时间。我们将从耶鲁纽黑文医院招募研究对象 医疗ICU是一个高容量的ICU，有足够的病人使这个项目可行。我们的部门 转化研究核心和医学ICU生物储存库将支持该项目。 指导研究项目：谵妄影响50-80%的内科ICU患者。预防和治疗 治疗策略有限，谵妄与不良结局相关，包括死亡率增加。因为 ICU睡眠中断可能是ICU谵妄发生的一个因素，促进睡眠是 推荐用于治疗和预防谵妄。目前，缺乏关于 昼夜节律异常对ICU睡眠中断问题的潜在重要贡献， 随之而来的精神错乱昼夜节律异常可能是可改变的，因此构成了一种新的治疗方法。 目标是重症监护室精神错乱本项目将前瞻性研究ICU患者（N=100）， 措施我们将检查ICU光照水平对昼夜节律异常的影响，并检查 昼夜节律异常和谵妄天数之间的关系。此外，我们会进行一个试点， 一项随机对照试验（N=50），旨在评估为ICU患者提供日间强光的可行性， 促进昼夜节律的变化。

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.