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The role of genomics in postoperative delirium and sedation

基因组学在术后谵妄和镇静中的作用

基本信息

批准号：
10227180
负责人：
JACQUELINE M LEUNG
金额：
$ 69.97万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-24 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227180
关键词：
Academic Medical Centers Acute Address Adult Adverse effects Adverse event Age Attention Benchmarking Biological Markers Biometry CYP2D6 gene Care given by nurses Caring Case Study Cognitive Cohort Studies Confusion Data Databases Delirium Dose Elderly Enzymes Genetic Genetic Markers Genetic Polymorphism Genomics Gerontology Homeostasis Hospitals Incidence Individual Individual Differences Investigation Laboratories Medicine Mental Depression Modeling Multicenter Studies Neuraxis Neurobehavioral Manifestations Neurologic Symptoms Older Population Operative Surgical Procedures Opioid Opioid Analgesics Pain Pain management Patient Care Patient-Focused Outcomes Patients Perioperative Pharmaceutical Preparations Pharmacogenomics Phenotype Postoperative Care Postoperative Complications Postoperative Pain Postoperative Period Protocols documentation Publishing Race Reporting Research Risk Role Sedation procedure Structure Symptoms Syndrome Therapeutic Therapeutic Intervention Titrations Validation Ventilatory Depression adverse outcome biomarker discovery brain dysfunction clinical effect clinical practice cognitive change cohort conventional therapy critical care nursing evidence base experience genetic information genetic profiling genetic variant genome wide association study high risk human old age (65+)improved inattention intravenous administration mental state metabolomics mortality older patient opioid injection opioid overdose patient population postoperative delirium precision medicine prevent prospective recruit respiratory sedative sex symptom management symptom science targeted treatment

项目摘要

Postoperative adverse neurological symptoms are frequent occurrences in the older patients after major surgery. These involve delirium, subsyndromal delirium and opioid toxicities. An acute change in mental status, along with inattention are often hallmark of a larger geriatric syndrome commonly called postoperative delirium, and a related entity, subsyndromal delirium can be considered as subclinical delirium. Patients who develop postoperative delirium typically stay in the hospital longer and have an increased risk of post- discharge decline in functional and cognitive status, and even increased long-term mortality. Patients with opioids toxicities such as over-sedation may also have associated respiratory depression, and if not clinically recognized, may progress to full respiratory arrest if the depression is profound and prolonged. The symptoms of postoperative delirium, subsyndromal delirium, and opioid toxicities are commonly thought to be related to the administration of intravenous opioids, conventional therapy prescribed for the alleviation of postoperative pain. For patients who have these adverse neurological symptoms, the typical strategy is to stop the administration of opioids in the hope of reversing these changes. However, with the cessation of opioids administration, patients may rebound with substantial postoperative pain which may actually increase their symptoms of confusion since pain has been reported to be associated with postoperative delirium. In current clinical practice, the titration of intravenous opioids in the treatment postoperative pain is largely empirical. Whether biomarkers can explain, or predict the symptoms of postoperative cognitive changes has not been previously evaluated in a systematic fashion. The objective of this study is to leverage several existing large patient cohort databases to determine the relationship of genetic variants and the phenotypes of postoperative delirium, subsyndromal delirium and opioid toxicities. The combined databases to be used in this investigation consist of over two thousand older patients who have undergone major non-cardiac surgery at three separate university medical centers. All patients were assessed for the presence of in-hospital postoperative delirium, subsyndromal delirium, and opioid toxicities using validated and structured protocols. Because three heterogeneous patient populations will be included in the discovery cohort plus a 4th prospectively recruited cohort as the validation cohort, our study has the unique opportunity to determine both internal and external validity of our findings. Our central hypothesis is that individuals who have a certain genetic profile have a higher incidence of postoperative delirium, subsyndromal delirium, and opioid toxicities. Our results will have significant impact on precision medicine and our strategy of assessment of biomarkers to facilitate personalized postoperative pain and symptom management may result in a decrease of postoperative delirium, subsyndromal delirium, and opioid toxicities in the at risk older population.

术后不良神经症状在老年患者中经常出现。外科手术。这些涉及谵妄、亚综合征谵妄和阿片类药物毒性。精神上的急剧变化状态和注意力不集中通常是一种更大的老年综合症的标志，通常称为术后谵妄和相关实体亚综合征谵妄可以被视为亚临床谵妄。患者谁发生术后谵妄通常会在医院停留更长时间，并且术后发生谵妄的风险增加出院时功能和认知状态下降，甚至长期死亡率增加。患者患有阿片类药物的毒性（例如过度镇静）也可能与呼吸抑制有关，如果临床上没有发现的话如果抑郁严重且持续时间较长，则可能会发展为完全呼吸停止。术后谵妄、亚综合征谵妄和阿片类药物中毒的症状很常见被认为与静脉注射阿片类药物有关，这是针对该疾病的常规疗法减轻术后疼痛。对于出现这些不良神经系统症状的患者，典型的策略是停止使用阿片类药物，以期扭转这些变化。然而，随着停止阿片类药物给药后，患者可能会出现明显的术后疼痛反弹，这可能实际上增加了他们的混乱症状，因为据报道疼痛与术后谵妄。在目前的临床实践中，治疗中静脉阿片类药物的滴定术后疼痛很大程度上是经验性的。生物标志物是否可以解释或预测症状此前尚未以系统的方式评估术后认知变化。本研究的目的是利用几个现有的大型患者队列数据库来确定遗传变异与术后谵妄、亚综合征谵妄和术后谵妄表型的关系阿片类药物毒性。本次调查使用的综合数据库包含 2000 多个较早的数据库在三个不同的大学医疗中心接受过重大非心脏手术的患者。全部评估患者是否存在院内术后谵妄、亚综合征谵妄和使用经过验证和结构化的方案来检测阿片类药物的毒性。因为三个异质的患者群体将被纳入发现队列以及第四个前瞻性招募队列作为验证队列，我们的研究有独特的机会来确定我们研究结果的内部和外部有效性。我们的中央假设具有一定遗传特征的个体术后发生率较高谵妄、亚综合征谵妄和阿片类药物毒性。我们的结果将对精准医学和我们的评估策略产生重大影响促进个性化术后疼痛和症状管理的生物标志物可能会导致高危老年人群术后谵妄、亚综合征谵妄和阿片类药物毒性。