A phase III, seven-day randomised, double-blind, placebo-controlled, parallel group study to assess efficacy of Donepezil for reducing the incidence and severity of Post-Operative Delirium after an elective total hip or knee replacement in patients over 65 years old

INTERVENTION: 5 mg of donepezil (DPZ) or matched placebo once daily for seven days. CONDITION: Post‐operative delirium ; Surgery ; Post‐operative problems PRIMARY OUTCOME: The primary endpoint of the study will be the incidence of post‐operative delirium. Patients will be considered as a case of delirium if at any point during the course of follow up (to Day seven) they develop an episode of delirium. A risk ratio will be calculated.; ; Delirium will be diagnosed using the Confusion Assessment Method (CAM) as the primary outcome variable. This is the most widely used instrument for the detection of delirium in the acute hospital setting. It has a sensitivity of 94‐100% and a specificity of 90‐95% and generates a Diagnostic and Statistical Manual of mental disorders ‐ Fourth Edition (DSM IV) diagnosis of delirium. SECONDARY OUTCOME: 1. The severity of delirium: severity of delirium will be measured by the Delirium Symptom Index (DSI) post‐ operatively twice a day (morning and afternoon) up to day six. The DSI is a seven item clinician rated scale which measures the severity of delirium and is sensitive to change. It has good internal consistency and inter‐rater reliability; 2. Length of delirium: this will be measured as the total number of days on which a patient achieves DSM IV ?caseness? for delirium using the CAM. It will be considered that the patient has had delirium that day if either of the two assessments in a 24‐hour period were positive for delirium; 3. Presence of subsyndromal delirium and behavioural symptoms: this will be measured using the CAM and be defined as any symptoms of new disorientation, disturbance of attention or perceptual or behavioural disturbance that do not meet the full criteria for delirium; 4. Changes in cognition: the Mini‐Mental State Examination (MMSE) will be used post‐ operatively once a day (morning up to day six). This is the most widely used screening test for cognitive impairment. It has a maximum score of 30 and assesses a range of cognitive skills. The MMSE has high inter‐rater reliability (0.8); 5. Length of hospital stay: this outcome will indicate whether delirium prophylaxis using DPZ may have health economic benefits. Length of hospital stay will be measured in days INCLUSION CRITERIA: 1. Awaiting elective total hip or knee replacement 2. 65 years old or over 3. Valid written informed consent