Neurocognitive Impairment in Acute Respiratory Failure and Shock: Understanding the Role of Neuronal Excitotoxicity

急性呼吸衰竭和休克中的神经认知损伤：了解神经元兴奋性毒性的作用

• 批准号: 10383666
• 负责人: Brian J. Anderson
• 金额: $ 17.61万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383666
• 关键词: Acute; Acute respiratory failure; Address; Admission activity; Advisory Committees; Animal Model; Animals; Area; Attention; Behavior; Benchmarking; Brain; Brain Injuries; Cardiopulmonary; Clinical; Clinical Trials; Cognition; Cohort Studies; Coma; Critical Care; Critical Illness; Data; Delirium; Dementia; Early treatment; Electroencephalography; Enrollment; Failure; Funding; Future; Glial Fibrillary Acidic Protein; Glutamates; Hippocampus (Brain); Homeostasis; Hospitalization; Hospitals; Human; Image; Impaired cognition; Injury; Intensive Care Units; Knowledge; Kynurenine; Laboratories; Lead; Link; Measures; Mechanical ventilation; Mentors; Metabolism; Methods; Molecular; Morbidity - disease rate; Neurocognitive; Neurocognitive Deficit; Neurologic; Neuron-Specific Enolase; Neuronal Injury; Neurons; Outcome; Oxygen; Pathogenesis; Pathway interactions; Patients; Pharmacological Treatment; Pharmacology; Phase; Phenotype; Plasma; Population; Positioning Attribute; Public Health; Recovery; Research; Research Design; Research Personnel; Research Training; Risk; Risk Factors; Role; Scientist; Sedation procedure; Sepsis; Services; Shock; Subgroup; Survivors; Syndrome; Techniques; Testing; Time; Training; Training Programs; Translations; Tryptophan; clinical risk; clinical trial enrollment; cognitive neuroscience; cognitive testing; cohort; confusion assessment method; design; excitotoxicity; frontal lobe; high risk; injury and repair; innovation; mortality; neuronal patterning; neuroprotection; new therapeutic target; patient oriented; patient stratification; predictive modeling; predictive tools; prevent; prospective; risk stratification; septic patients; statistics; systemic inflammatory response; targeted treatment; therapeutic target

Project Summary Cardiopulmonary failure due to acute respiratory failure or shock is the most common syndrome necessitating intensive care unit services. Patients with cardiopulmonary failure often develop burdensome neurocognitive sequelae that threaten both short and long-term outcomes. In the short-term, these patients frequently develop delirium, a severe alteration in attention and cognition that is associated with increased mortality as well as longer durations of mechanical ventilation and ICU stay. After recovering, 1 in 4 survivors suffer long-term cognitive impairment (LTCI) similar to dementia. Despite the impact delirium and LTCI have on these patients, there are currently no proven pharmacologic therapies aimed at preventing these neurocognitive sequelae. Sepsis accounts for over 1 million hospitalizations per year and is the most common cause of cardiopulmonary failure, making it an ideal population to investigate the underlying mechanisms of delirium and LTCI. Our group and others have shown that delirium and LTCI are characterized by injury to the hippocampus and frontal cortex. Animal models show a similar pattern of neuronal injury, and implicate alterations in glutamate homeostasis and kynurenine metabolism as key downstream pathways of neuronal injury that can be therapeutically targeted. However, a lack of data on these pathways in humans and an inability to identify which patients would most likely benefit from early therapy are key knowledge gaps limiting the translation of these findings to clinical trials. To address these knowledge gaps, this proposal will investigate the role of glutamate and kynurenine dysregulation in an ongoing cohort of septic patients with cardiopulmonary failure who are followed prospectively for delirium and subsequent cognitive impairment. In addition to the proposed research, the candidate will engage in a rigorous training program designed to support his transition into an independent scientist. The specific objectives of this proposal are to: 1) determine the association of glutamate and kynurenine dysregulation with delirium and cognitive impairment in septic patients with cardiopulmonary failure, 2) identify risk factors for cognitive impairment and develop a predictive tool that could be used to guide enrollment in future clinical trials, 3) train the candidate in cognitive neuroscience, mechanisms of neuronal injury and repair, cohort study design and conduct, molecular laboratory techniques and advanced statistics, and 4) provide the candidate with individualized mentoring to support his transition to independence. The candidate's attainment of specific research and training benchmarks will be regularly reviewed by his mentors and advisory committee. Through completion of this proposal, the candidate will enhance our understanding of the underlying mechanisms of delirium and LTCI in these patients, and position himself to successfully compete for R01 funding of future projects aimed at testing neuroprotective therapies.

项目摘要 由于急性呼吸衰竭或冲击而导致的心肺衰竭是最常见的综合症 重症监护病房服务。心肺衰竭的患者通常会发展出繁重的神经认知 后遗症威胁到短期和长期结局。在短期内，这些患者经常发展 ir妄，注意力和认知的严重改变与死亡率的增加以及 机械通气和ICU停留时间更长。恢复后，四分之一的幸存者长期遭受 认知障碍（LTCI）类似于痴呆症。尽管del妄和LTCI对这些患者有影响，但 目前尚无旨在防止这些神经认知后遗症的验证药理疗法。 败血症每年的住院时间超过100万，是心肺的最常见原因 失败，使其成为研究del妄和LTCI的基本机制的理想人群。我们的小组 其他人则表明，del妄和LTCI的特征是海马和额叶受伤 皮质。动物模型显示出类似的神经元损伤模式，并暗示谷氨酸的改变 稳态和kynurenine代谢是神经元损伤的关键下游途径，可以是 治疗目标。但是，缺乏有关人类这些途径的数据，无法识别 哪些患者很可能会从早期治疗中受益，这是关键知识差距限制了翻译 这些发现是临床试验的。为了解决这些知识差距，该提议将调查 谷氨酸和kynurenine功能障碍在正在进行的败血症患者的群体中 前瞻性地追随del妄和随后的认知障碍。除了提议 研究，候选人将参与严格的培训计划，旨在支持他的过渡到 独立科学家。该提案的具体目标是：1）确定谷氨酸的关联 心肺肺病患者的del妄和认知障碍的kynurenine失调 失败，2）确定认知障碍的危险因素，并开发可用于指导的预测工具 注册以后的临床试验，3）训练候选人认知神经科学，神经元的机制 伤害和修复，队列研究设计和行为，分子实验室技术和高级统计， 4）为候选人提供个性化的指导，以支持他向独立过渡。这 候选人将定期审查候选人的特定研究和培训基准 和咨询委员会。通过完成此提案，候选人将增强我们对 这些患者在这些患者中的基本机制和LTCI的基本机制，并将自己定位为成功 竞争旨在测试神经保护疗法的未来项目的R01资金。

项目成果

Clinical Impact of an Electronic Dashboard and Alert System for Sedation Minimization and Ventilator Liberation: A Before-After Study.

• DOI: 10.1097/cce.0000000000000057
• 发表时间: 2019-10-01
• 期刊: Critical care explorations
• 作者: Anderson, Brian J;Do, David;Fuchs, Barry D
• 通讯作者: Fuchs, Barry D

Self-reported poor quality of sleep in solid organ transplant: A systematic review.

• DOI: 10.1016/j.trre.2021.100650
• 发表时间: 2021-12
• 期刊: Transplantation reviews (Orlando, Fla.)
• 作者: Cordoza M;Koons B;Perlis ML;Anderson BJ;Diamond JM;Riegel B
• 通讯作者: Riegel B