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

项目摘要 美国有一百万成年人因急性呼吸衰竭（ARF）接受机械通气 每年都会发生谵妄，其中高达80%的人在重症监护室（ICU）期间出现谵妄。谵妄是 与重症监护室后的认知和身体障碍有关。谵妄没有有效的治疗， 我们对ARF和谵妄的病理生理学的有限理解， 促炎细胞因子状态。细胞因子的全身释放，持续的肺泡损伤， 活性氧（ROS）的产生可能与ARF和谵妄有关。我们假设 ROS生物标志物的增加与认知和身体功能障碍的增加有关 老年重症患者中。为了验证我们的假设，我们提出了一项初步的前瞻性研究， 呼吸衰竭、谵妄和ICU后认知障碍中的活性氧我们将 使用从80名重症、机械通气的老年人获得的样本测量ROS水平， 并对这些患者进行为期24个月的随访。血液样本以及认知和身体功能评估 将在多个时间点进行，以实现我们的研究目标。主要目的是测量 ROS生物标志物与ICU后轻度认知功能障碍（MCI）和阿尔茨海默病的关系 疾病和相关痴呆（ADRD）在重症老年人急性呼吸衰竭。的 第二个目的是测量氧化损伤和谵妄的生物标志物之间的关系 持续时间和严重程度的危重老年人与ARF;并衡量后， 炎症和氧化应激的ICU生物标志物以及ICU后MCI和ADRD。 拟议的职业发展计划将课程、体验式培训和导师制结合在一起， 老龄化，并进行前瞻性临床研究。候选人还将学习领导技能， 参加国家会议，并受益于一个完善和非常成功的 多学科指导小组，在培训初级调查员方面有成功的记录。的 候选人的学术环境包括印第安纳州备受赞誉的资源和教师 大学医学院，著名的印第安纳州大学衰老研究中心， Regenstrief研究所和NIH资助的印第安纳州临床和转化科学研究所（CTSI）。 这个职业发展奖将保证保护的时间，这将是必要的，以促进 候选人在研究老年人结果方面的职业生涯。获奖期间获得的知识将 提高对ARF、谵妄和ICU获得性认知和 身体损伤，并准备R 01提交进一步研究衰老中的氧化应激。

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.