This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This study proposes that empiric treatment with donepezil in critically ill patients with respiratory failure will decrease the prevalence and severity of delirium; empiric treatment with donepezil will result in less agitated behavior and decreased requirement of sedatives and narcotics; and empiric treatment with donepezil will result in lower serum anticholinergic levels. Computation of donepezil pharmacokinetics will also be performed. Critically ill patients consume a disproportionately large percentage of health care resources, approximately 1% of the U.S. gross domestic product. Intensive care unit expenses consume 28% of hospital charges but account for less than 8% of hospital beds. Despite the enormous cost, critically ill patients benefit from this intensive care, and the majority of survivors (89%) are home one year after their critical illness. To care for critically ill patients, physicians routinely employ sedatives and narcotics as treatment for physical and psychiatric discomfort. Agitated behavior in the critically ill patient with respiratory failure may result from pain, anxiety, dyspnea, patient-ventilator dyssynchrony and delirium. The treatment of agitation is especially problematic in critically ill patients with respiratory failure due to the presence of artificial airways which preclude verbal communication on patients' part. Clinicians caring for these patients are left with the daunting task of determining the etiology of agitation, often empirically treating them for a multitude of conditions which manifest as agitated behavior. Delirium, also known as 'sun-downing' and 'intensive care unit psychosis,' is one of the etiologies of agitated behavior and has been the subject of recent investigations. Delirium is a psychiatric disorder manifested by acute onset of altered mental status, inattention and disorganized thinking, and can be considered a form of 'acute brain failure.' Management of delirium involves identification and treatment of underlying causes. In many instances no identifying factors are elucidated and empiric treatment with a pharmacological agent is initiated. In other instances, underlying etiologies are known but agitation poses substantial risk to the patient, such as self-removal of vital tubes and lines, including removal of artificial airway. Haloperidol is the medication most frequently used and is considered standard of care. Given the exceedingly high prevalence of delirium in the critically ill patient, and its onset early in the course of illness [8] (within 48 hours of hospitalization), a study of empiric or 'prophylactic' treatment in critically ill patients with respiratory failure is needed. Effective therapy aimed at preventing and reducing the severity of delirium has the potential to decrease the need of sedative/hypnotics and narcotic medications. Critically ill, mechanically ventilated adult patients in the intensive care unit will be enrolled in this study. The subjects will remain in the ICU during the study. Study drug, donepezil, will be administered to the subjects and behavior will be observed. Blood samples will be taken to measure drug levels throughout the study.
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