Proteomic Analysis of Postoperative Delirium from a randomized trial in Older Patients undergoing Cardiac Surgery exposed to Intraoperative Normoxia versus Hyperoxia: A Nested Case-Control Study

摘要 心脏手术后精神错乱影响大约30%-50%的患者，总计20万人 仅在这个国家，每年就有70岁以上的患者 接受心脏手术的患者中有50%。老年心脏手术患者围手术期的精神障碍 患者给出了严重的病态负担，功能和认知结果不良，增加 住院时间延长和死亡率增加。精神错乱对公众健康的影响 人口可能只会随着时间的推移而增加，这使得开发有效的方法来 预防和治疗更加势在必行。此外，有越来越多的数据表明 体外循环期间的氧化损伤和炎症反应 到术后器官功能障碍。此外，结束器官功能障碍、发病率和死亡率 与高氧对缺血再灌注损伤的有害影响有关 在其他几个疾病州。在目前的提案中，我们的目标是利用存储的血浆 作为前瞻性随机对照试验的一部分收集的样本被随机分配到 两种术中呼吸机管理策略之一，其中激发的部分 用相应的血液将氧气滴定到高氧(100%)或常氧(35%)条件下 氧气水平，以便进行嵌套的病例对照研究。在这个阶乘设计中，我们将 建立四个匹配队列：妄想阳性、妄想阴性、高氧暴露和 常氧暴露的患者样本，并将应用最先进的方法，包括 先进的蛋白质组学，评估循环蛋白质，以期发现生物标记物。 具体地说，我们的目标是定量评估血浆炎症之间的关系 使用先进的蛋白质组学分析，生物标记物负载与妄想和术中高氧， 65岁高龄患者体外循环前后两个时间点的采样 接受冠脉搭桥手术。利用这个模型，我们将寻求进一步阐明 与精神错乱和高氧症相关的病理生理模型，希望识别新的 可以预测、相互作用或定义精神错乱征兆的血清生物标志物。结果 建议的分析将为进一步的机制研究提供基础，以便 心脏手术后妄想的防治策略进展 并用来减轻老年人精神错乱的有害影响。

Abstract Delirium following cardiac surgery affects approximately 30-50% of patients, totaling 200,000 patients per year in this country alone, with patients over 70 years of age representing roughly 50% of those undergoing cardiac surgery. Perioperative delirium in the elderly cardiac surgical patient confers a significant morbid burden of poor functional and cognitive outcome, increased hospital length of stay and increased mortality. The public health impact of delirium in this population will likely only increase over time, making the development of effective approaches to prevention and treatment even more imperative. Further, there are accumulating data that oxidative damage and inflammatory response during cardiopulmonary bypass (CPB) contributes to postoperative organ dysfunction. Additionally, end organ dysfunction, morbidity and mortality have been linked to the deleterious effects of hyperoxia following ischemia-reperfusion injuries in several other disease states. In the current proposal we aim to leverage stored plasma samples collected as part of a prospective randomized controlled trial of patients randomized to one of two intraoperative ventilator management strategies in which the fraction of inspired oxygen is titrated to hyperoxia (100%) or normoxia (35%) conditions with corresponding blood oxygen levels, in order to undertake a nested, case control study. In this factorial design we will establish four matched cohorts of delirium positive, delirium negative, hyperoxia exposed and normoxia exposed patient samples and will apply state-of-the-art approaches, including advanced proteomics, to assess circulating proteins with a view towards biomarker discovery. Specifically, we aim to quantitatively assess the relationship between plasma inflammatory biomarker load with delirium and intraoperative hyperoxia, using advanced proteomic analysis, sampled at two intraoperative time points before and after CPB among patients 65 years old and over undergoing CABG surgery. Using this model we will seek to further elucidate the pathophysiological model related to delirium and hyperoxia, with the hope of identifying novel serum biomarkers that may be predictive of, interact with, or define delirium signatures. Results of the proposed analyses will provide the basis for further mechanistic studies to inform the development of prevention and treatment strategies for postoperative delirium in cardiac surgery and used to lessen the harmful impact of delirium in aging adults.