Donepezil-enhanced management of delirium in aged hip fracture patients

描述(由申请人提供)：髋部骨折与40%-60%的精神错乱(急性精神错乱)有关。我们以前已经证明，精神错乱独立地预示着髋部骨折后功能恢复差，而且持续性精神错乱与康复快的精神错乱相比，与恢复更差有关。在NIH的支持下，我们设计并严格测试了一种积极主动的多因素老年病咨询模型，该模型将精神错乱的发生率降低了三分之一以上，将严重精神错乱的发生率降低了一半。然而，一旦出现精神错乱，我们的干预对精神错乱的持续时间或其后遗症没有影响。这些结果表明，最佳的精神错乱管理可能需要多因素方案以外的其他策略。加强对精神错乱的管理的一个潜在的方法是药物治疗。胆碱酯酶抑制剂现在通常用于通过增强中枢胆碱能传递来改善痴呆症患者的认知功能。精神错乱与痴呆症的相似之处在于，急性胆碱能传递不足被认为是导致认知功能障碍的“最终共同途径”。因此，我们建议招募40名70岁及以上的髋部骨折患者参加先导性双掩蔽随机试验。所有受试者都将接受前瞻性的多因素老年病学咨询，我们的试验将测试加入多奈哌齐是否能在这一高危人群中加强预防新的精神错乱症状。我们提出以下具体目标：1)确定老年髋部骨折患者每天服用5 mg的多奈哌齐30天疗程的安全性和耐受性，2)获得受试者收益的估计，以及对我们的主要结果测量的影响大小的初步估计：由纪念妄想评估量表测量的新的妄想症状，以便计划确定的III期试验，3)通过检查术前、术后第2天和治疗结束时通过生物测定测定的血清抗胆碱能活性是否与妄想症状的发生率和持续性相关，更好地了解妄想的病理生理学，以及4)探索术前血清抗胆碱能活性、多奈哌齐治疗，以及精神错乱症状。这项研究是PI长期目标中的第一项，目的是更好地了解精神错乱的病理生理机制，并开发和测试针对这些机制的治疗方法。

DESCRIPTION (provided by applicant): Hip fracture has been associated with 40-60% risk of delirium (acute confusion). We have previously shown that delirium independently predicts poor functional recovery after hip fracture, and that persistent delirium is associated with worse recovery than delirium that resolves quickly. With NIH support, we designed and rigorously tested a model of proactive multifactorial geriatrics consultation that reduced the incidence of delirium by over one-third, and severe delirium by one-half. However, once delirium developed, our intervention had no impact on the duration of delirium or its sequelae. These results suggest that optimal delirium management may require additional strategies beyond multifactorial protocols. One potential approach to enhance the management of delirium is drug treatment. Cholinesterase inhibitors are now used commonly to improve cognitive function in patients with dementia by enhancing central cholinergic transmission. Delirium parallels dementia in that an acute deficiency in cholinergic transmission is felt to be the "final common pathway" leading to cognitive dysfunction. Therefore, we propose to enroll 40 hip fracture patients aged 70 and older in a pilot double-masked randomized trial. All subjects will receive proactive multifactorial geriatrics consultation and our trial will test whether the addition of donepezil results in enhanced prevention of new delirium symptoms in this high risk population. We propose the following Specific Aims: 1) To determine the safety and tolerability of a 30-day course of donepezil 5 mg daily in aged hip fracture patients, 2) To obtain estimates of subject accrual, and preliminary estimates of effect size on our primary outcome measure: new delirium symptoms measured by the Memorial Delirium Assessment Scale, to allow for planning of a definitive Phase III trial, 3) To better understand the pathophysiology of delirium by examining whether serum anticholinergic activity, measured by bioassay preoperatively, on postoperative day 2 and at the end of treatment, correlates with the incidence and persistence of delirium symptoms, and 4) To explore the interaction between preoperative serum anticholinergic activity, donepezil therapy, and delirium symptoms. This study is the first in the PI's long-term goal to better understand the pathophysiological mechanisms of delirium and to develop and test therapies targeted to address these mechanisms.