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%的谵妄（急性神志不清）风险相关。我们之前的研究表明，谵妄独立地预示着髋部骨折后较差的功能恢复，并且持续性谵妄比迅速消退的谵妄与较差的恢复相关。在美国国立卫生研究院的支持下，我们设计并严格测试了一个积极的多因素老年医学咨询模型，该模型将谵妄的发病率降低了三分之一以上，严重谵妄的发病率降低了一半。然而，一旦出现谵妄，我们的干预对谵妄的持续时间及其后遗症没有影响。这些结果表明，除了多因素协议之外，最佳谵妄管理可能需要额外的策略。加强谵妄管理的一个潜在途径是药物治疗。胆碱酯酶抑制剂现在常用来改善痴呆患者的认知功能，通过增强中枢胆碱能传递。谵妄与痴呆相似，因为胆碱能传递的急性缺乏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进行双盲随机试验。所有受试者都将接受主动的多因素老年病学咨询，我们的试验将测试多奈哌齐的加入是否能增强预防这一高危人群出现新的谵妄症状。我们提出以下具体目标：1)确定老年髋部骨折患者服用30天多奈哌齐（5mg /天）疗程的安全性和耐受性；2)获得受试者应计收益的估计值，并初步估计主要结局指标的效应大小。通过纪念谵妄评估量表测量新的谵妄症状，以便制定明确的III期试验计划；3)通过检查术前、术后第2天和治疗结束时生物测定血清抗胆碱能活性是否与谵妄症状的发生率和持续性相关，从而更好地了解谵妄的病理生理学；4)探讨术前血清抗胆碱能活性与谵妄症状之间的相互作用；多奈哌齐治疗和谵妄症状这项研究是PI的第一个长期目标，以更好地了解谵妄的病理生理机制，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.