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. ? ? ?
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