The role of genomics in postoperative delirium and sedation

术后不良神经系统症状是老年患者术后常见的主要并发症， 手术这些包括谵妄，亚综合征谵妄和阿片类药物毒性。心理上的急剧变化 状态，沿着注意力不集中通常是一种较大老年综合征的标志，通常称为术后 谵妄和相关实体，亚综合征谵妄可被认为是亚临床谵妄。的患者 发生术后谵妄通常在医院停留更长时间，并有增加的风险， 出院后功能和认知状态下降，甚至增加长期死亡率。患者 阿片类药物毒性，如过度镇静，也可能有相关的呼吸抑制，如果不是临床上 如果抑郁是深刻和长期的，可能会发展到完全呼吸停止。 术后谵妄、亚综合征性谵妄和阿片类药物毒性的症状常见于 被认为与静脉内阿片类药物的给药有关， 减轻术后疼痛。对于有这些不良神经症状的患者， 战略是停止给予阿片类药物，以期扭转这些变化。但随着 停止阿片类药物给药，患者可能会反弹，术后疼痛严重， 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，静脉内阿片类药物的滴定在治疗 术后疼痛主要是经验性的。生物标志物是否可以解释或预测 术后认知功能的改变以前没有被系统地评价过。 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、亚综合征性谵妄和 阿片类药物毒性本调查中使用的合并数据库包括2000多个旧的 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。所有 评估患者是否存在住院术后谵妄、亚综合征谵妄， 阿片类药物毒性使用验证和结构化的协议。因为三个不同的病人群体 将被纳入发现队列，加上第4个前瞻性招募队列作为验证队列，我们的 这项研究有独特的机会来确定我们的研究结果的内部和外部有效性。我们的中央 有一种假设认为，具有某种遗传特征的个体术后并发症的发生率较高， 谵妄、亚综合征谵妄和阿片类药物毒性。 我们的研究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减少 老年高危人群术后谵妄、亚综合征性谵妄和阿片类药物毒性。

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.