Early Pharmacological Intervention to Prevent Delirium: Haloperidol Prophylaxis in Older Emergency Department Patients

To address the aforementioned objectives, we propose a multicenter, randomized, double-blind, placebo-controlled clinical trial.

Eligible patients and/or their proxies will be verbally informed by the investigator on the content of the study, benefits and risks, and will receive a patient information folder on the nature of the study (version number, see appendix). The time to consider participation to the trial will be 4 hours maximum. Subsequently, the patient and/or their proxy will be asked for informed consent.

Subjects are screened for delirium-risk by the executive investigator administrating three delirium-risk questions to the patients or their care-givers, as recommended by the Dutch Safety Management (VMS) program:

1. Do you have memory complaints?
2. Did you need any help with activities of daily living in the past 24 hours?
3. During previous illness or hospital admission(s), did you have periods of confusion? One or more positive answers will identify at-risk patients. Eligible patients will be assigned a daily intervention with either low-dose haloperidol (an oral dosage of 1mg, twice-daily at 12pm and 8pm) or placebo by stratified randomization. The maximum intervention duration is 7 days. Hospital admission course of non at-risk patients according to the three VMS delirium-risk questions will be retrospectively assessed by medical chart review. Different study measurements will be collected on admission. A baseline ECG and standard ED laboratory will be done. Two additional blood samples of 10ml each will be drawn (one on admission and one at admission day 4) to determine haloperidol plasma levels and stored for future research. The investigator will assess baseline cognitive- and physical functioning on admission with different questionnaires and observational measures: the 6-item cognitive impairment test (CIT), the 6-item Index of Independence in Activities of Daily Living (ADL), the 8-item Instrumental Activities of Daily Living scale (IADL) and Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE-N). The presence of delirium in the ED will be established according to the CAM-ICU and DSM-IV criterial. During admission, all subjects will receive the same 'high standard delirium care' based on effective non-pharmacological delirium intervention methods. Additionally to the standard ward rounds, the investigator will visit the patient at least on day 2, 4, and 8 for (extended) physical examination to evaluate any possible side-effects related to the intervention. According to protocol, an ECG is performed at least 24 hours (2 doses) and 72 hours (6 doses) after the first intervention dose, and if possible and the end of the study intervention period on request of the investigator. An ECG will be repeated at a 24-hour time-interval after every dose until a steady state is reached, when QTc >420ms-500ms on baseline ECG, or QTc prolongation >25% from baseline, of in case other QTc prolonging drugs are used. If QTc ≥ 500ms, the study medication will be discontinued. A list of QTC prolonging drugs contraindicated when using haloperidol (1st degree drug interactions, reason for action) is available and a warning system is implemented in the medication prescription system.

Development of delirium symptoms during the study will be evaluated by the Delirium Observation Screening (DOS) scale, administered 3 times per day. When delirium is suspected based on a mean DOS scale score >3/24 hours, the diagnosis is established according to the DSM-IV criteria by either the geriatrician or psychiatrist.