The investigators propose a multicenter, randomized, double-blinded, placebo-controlled trial to study the effect of additive low-dose haloperidol prophylaxis on top of exciting care in a general population of older patients (age 70 years and over) acutely admitted to the hospital through the emergency department (ED) for general medicine and surgical specialties, and who are at-risk for developing in-hospital delirium on admission according to the VMS delirium risk questions (one or more positive answers out of three questions).

The investigators hypothesize that this intervention will reduce the incidence of in-hospital delirium as well as duration and severity of delirium.

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.

In case of established delirium within 7-day after initiation of the study intervention, administration of the assigned intervention is stopped since one of the primary endpoints (i.e. incidence) is reached. Unblinding will be performed immediately (24-hours a day, 7 days a week through the local hospital pharmacy at VUmc, procedures and argumentation will be recorded), and the treating physician will further decide on the treatment of the patients' delirium. Nursing staff will perform the DOS score 3-times daily to assess the duration of delirium, according to protocol. In addition, the investigator will assess delirium duration and severity with the DRS-R-98 once-daily. Both the DOS scale and DRS-R-98 are performed until delirium symptoms resolve or if participation in the study is no longer possible due to for example transfer to an other facility, ICU/CCU admission or death.

If no delirium symptoms develop within 7-days after initiation of the study intervention, administration of the assigned intervention treatment is stopped (after 14 doses). Further admission course will be evaluated by retrospective analysis of patients' charts. In patients discharged home within 7-days after initiation of the study intervention, study medication is aimed to be stopped the day before discharge since it takes approximately 12 - 38 hours to eliminate half of the originally administered oral haloperidol dose. These patients will be subjected to en extended physical examination on the day of discharge to evaluate any possible side-effects related to the intervention, if possible. The independent physician and researchers can be contacted for questions any time.

At the end of the study, all subjects' charts will be reviewed by one of the investigators.

During the follow-up period, an investigator will contact the subject and/or proxy by telephone, respectively at 3- and 6-months after hospital discharge, to evaluate physical function at that time with the ADL and IADL scale, and cognitive function with the 6-item CIT. Also, information on hospital re-admission(s), need for additional (health)care or (permanent) institutionalization after hospital discharge and death are reported. Each telephone conversation will take an estimated 20 minutes.

Inclusion Criteria:

• Patients aged 70 years or over;
• The patient is at increased risk for developing in-hospital delirium on admission according to one or more positive answers on the VMS delirium-risk questions;
• The patient and/or proxy is able to provide written informed consent;
• The patient and/or proxy speaks either Dutch or English;
• The patient is admitted to the hospital for a general medicine or surgical specialty.

Exclusion Criteria:

• Patients presenting in the ED with delirium according to the DSM-IV criteria;
• Patients with clinically significant (cardiac) disorders: QTc interval prolongation (QTc ≥500ms), recent acute myocardial infarction, uncompensated heart failure (working diagnosis), acute coronary syndrome (ACS), arrhythmias treated with class IA and III antiarrhythmic medicinal products, history of ventricular arrhythmia, history of torsades, clinically significant bradycardia, second or third degree heart block, uncorrected hypokalaemia (potassium level 3.0 or lower);
• Patients with vascular dementia;
• Patients with Lewy Body dementia;
• Patients with Parkinson dementia;
• Patients with (a history of) hypokinetic movement disorders;
• Patients with (a history of) malignant neuroleptic syndrome;
• Patients with (a history of) serotonergic syndrome;
• Patients with (a history of) central anticholinergic syndrome;
• Patients who will be admitted to the oncology ward;
• Patients previously enrolled in the HARPOON study, or in other medical- or drug studies;
• Patients using QT prolonging drugs and/or medications of which concomitant use with haloperidol is contraindicated (clinically relevant drug interactions, 1st degree, listed in the appendix of the study protocol);
• Epilepsy;
• Substance abuse and dependence (DSM-IV criteria)
• Patients who are not able to take the study medication according to protocol (amendment)