Delirium Clinical Trial
Official title:
Early Pharmacological Intervention to Prevent Delirium: Haloperidol Prophylaxis in Older Emergency Department Patients
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.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
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