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

项目总结 美国有100万成年人因急性呼吸衰竭(ARF)接受机械通气 每年，他们中高达80%的人在重症监护病房(ICU)逗留期间出现精神错乱。精神错乱是 与ICU后的认知和身体障碍有关。精神错乱没有有效的治疗方法，因为 我们对ARF和精神错乱的病理生理学了解有限，这两种疾病具有共同的 促炎细胞因子状态。全身细胞因子的释放，持续的肺泡损伤，以及 活性氧(ROS)的产生可能与ARF和精神错乱有关。我们假设 ROS生物标志物的增加与认知和身体功能损害的增加有关 在病危的老年人身上。为了检验我们的假设，我们提出了一项初步的前瞻性研究，名为 呼吸衰竭、妄想症和ICU后认知功能障碍中的活性氧。我们会 使用80名危重、机械通气的老年人的样本来测量ROS水平， 并对这些患者进行24个月的跟踪调查。血液样本、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。其主要目标是测量 ROS生物标志物与ICU后轻度认知障碍及阿尔茨海默病的关系 老年重症急性呼吸衰竭患者的疾病及相关痴呆(ADRD)。这个 第二个目标是测量氧化损伤和精神错乱的生物标志物之间的关系。 老年危重患者ARF的持续时间和严重程度；并衡量急性肾功能衰竭后与 ICU炎症和氧化应激以及ICU后MCI和ADRD的生物标志物。 拟议的职业发展计划将课程工作、体验式培训和 老龄化，以及前瞻性临床研究的进行。候选人还将学习领导技能， 参加国家会议，并受益于一个久负盛名、非常成功的 多学科指导小组，在培训初级调查人员方面有成功的记录。这个 候选人的学术环境包括印第安纳州备受赞誉的资源和教职员工 大学医学院，著名的印第安纳大学老龄研究中心， Regenstrief研究所，以及NIH资助的印第安纳州临床和转化科学研究所(CTSI)。 这一职业发展奖将保证受保护的时间，这是必要的，以推动 候选人在研究老年人成果方面的职业生涯。在颁奖过程中获得的知识将 提高对ARF、精神错乱和ICU获得性认知障碍之间关系的科学理解 身体损伤，并准备R01提交，以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.