Primary objective(s):To evaluate the effect of early haloperidol prophylaxis on the incidence, severity and duration of in-hospital delirium in at-risk patients aged 70 years and over who are acutely admitted to the hospital through the ED, for…
Source
Brief title
Condition
- Deliria (incl confusion)
Synonym
Research involving
Sponsors and support
Intervention
No registrations found.
Outcome measures
Primary outcome
An absolute reduction of delirium incidence of 10%.
An absolute reduction of delirium duration (according to the DOS score,
positive mean DOS score >3/24 uur indicated delirium).
Less severe delirium in haloperidol intervention group (according to the
gliding scale: DRS-R-98 score, >16 out of the total score of 39)
Secondary outcome
A reduction of mean hospital length of stay.
A reduction in 6-month mortality of 5%.
Background summary
Delirium is a serious and common consequence of (acute) illness mainly
occurring in the older patient. Hospital prevalence rates range approximately
from 8.6% to 52% in patients age 65 years and over. Delirium is associated with
poor medical outcome and increased health related costs, which in the future
will be a much more significant problem due to the percentage increase in
ageing population. Primary prevention strategies have shown to play an
important role in preventing delirium, though implementation can be complex due
to poor protocol-adherence. A potential role in delirium prevention is proposed
for haloperidol prophylaxis in patients at-risk for delirium. Little though
promising evidence comes from single-centre studies evaluating the role of
haloperidolprophylaxis in preventing post-operative delirium.
We propose a multicenter, randomised, 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 trough the emergency department (ED) for
internal medicine or surgical specialism, 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).
We hypothesize that this intervention will reduce the incidence of in-hospital
delirium as well as duration and severity of delirium.
Study objective
Primary objective(s):
To evaluate the effect of early haloperidol prophylaxis on the incidence,
severity and duration of in-hospital delirium in at-risk patients aged 70 years
and over who are acutely admitted to the hospital through the ED, for internal
medicine or surgical specialism, 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).
Secondary objective(s):
To determine:
- mean hospital length of stay (LOS) in days;
- in-hospital and 6-month mortality rates;
- (I)ADL and cognitive functionality at baseline, and at 3- and 6-months after
hospital discharge date;
- the need for additional (medical) care after hospital discharge,
institutionalization or (re)admissions;
- the cost-effectiveness;
And to additionally describe any differences in the abovementioned secondary
objectives between both intervention groups.
Study design
To address the aforementioned objectives, we propose a multicentre, randomized,
double-blind, placebo-controlled intervention trial.
Eligible patients or their proxies will be verbally informed by the executive
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 or their proxy is asked for informed consent.
Subjects are screened for eligibility according to the inclusion criteria and
the delirium-risk according to three delirium-risk questions, as recommended by
the Dutch VMS (veiligheidsmanagementsysteem) 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 an at-risk patient, who - if
eligible - 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 after written informed consent is obtained. 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. At two different times, 2 additional bloodsamples of 10ml each will be
drawn (once on admission/in the ED and once at admission day 4) and stored for
determination of plasma-haloperidol levels and future research. The
investigator will assess baseline cognitive- and physical functioning on
admission with different questionnaires and observational measures: index of
independence in activities of daily living (Katz ADL), instrumental activities
of daily living (Lawton IADL), cognitive functioning (6-item CIT), and
Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE-N). The
presence of delirium in the ED/on admission 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 (if possible) 8
for (extended) physical examination and 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) at the end of the 7-day study intervention period on
request of the investigator. An ECG will be repeated every 24 hours until a
steady state is reached, when patients are using QTc prolonging drugs in
addition to study medication, QTc >450ms (men) or >460ms (women) and * 500ms on
baseline ECG, or QTc prolongation > 25% from baseline. If QTc *500ms, the study
medication will be discontinued. A list of QTC prolonging drugs contraindicated
when using haloperidol is available and an 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 a geriatrician or psychiatrist.
In case of established delirium within the 7-day intervention period,
administration of the assigned intervention is stopped since one of the primary
endpoints (i.e. incidence) is reached. Unblinding will be performed immediately
according to protocol 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 the 7-day intervention period,
administration of the assigned intervention treatment is stopped after 7 days
(14 doses). Further admission course will be evaluated by retrospective
analysis of patients* charts.
In patients discharged home within the 7-day intervention period, the
intervention 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 independant 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.
In case of established delirium within the 7-day intervention period or when
clinically relevant side-effects (possibly) related to the intervention have
occured, unblinding procedures will be activated. Unblinding is possible 24
hours per day, 7 days a week through the contact information on the study
medication packing. Procedures and argumentation will be recorded by the person
performing the deblinding.
During the follow-up period, an executive 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 Katz ADL and
Lawton IADL, and cognitive function with the 6-item CIT. Also information on
hospital re-admission(s), the need for additional (health)care or (permanent)
institutionalization after hospital discharge and death are reported. Each
telephone conversation will take an estimated 20 minutes. If patients of their
proxy withdraw their informed consent during the study, they will be asked if
we can still contact them during the follow-up period.
Intervention
Both study arms will receive standard hospital care troughout the trial.
Each patient who signed informed consent will be randomized to either receive
twice-daily a 1mg tablet of haloperidol or placebo at 12am and 20pm for 7
consecutive days, starting on admission (<24 hours).
Study burden and risks
- Nature and extent of the burden
After patients are informed and informed consent is signed, patients will be
subjected to different (obervational) questionnaires during their stay in the
ED and during hospital admission. Two additional blood samples (10ml each) will
be drawn at baseline (either together with the standard lab investigations in
the ED, through the intravenouws acces or if that is not possible with a vena
punction). At the end of the study, all included patients or their proxy will
be contact twice by telephone in the 6 month follow-up period after hospital
discharge, duration of one telephone conversation: ± 20 minutes.
The maximum time investment per patient for the entire duration of the study
will be approximately 8 hours, comprised of:
- CAM * ICU/DSM-IV criteria: duration ± 5 minutes, when indicated, once on
admission.
- 6-item CIT: duration ± 2 minutes, once on admission, and during both
telephone calls respectively 3- and 6 months after hospital discharge date.
- IADL and ADL: ± 15 minutes, once on admission, and during both telephone
calls respectively 3- and 6 months after hospital discharge date.
- IQCODE-N: duration ± 5 minutes, once on admission.
- DOS score: ± 2 minutes per administration, according to local standard
hospital protocol in patients at-risk for delirium. In case of established
delirium, the DOS score will be performed 3 times a day during the 7 day
intervention period.
- DRS-R-98 score: ±15-20 minutes, once daily in case of established delirium
during the 7 day intervention period.
- Physical examination and ECG: ± 30 minutes, once daily during the 7 day
intervention period at least once after 24 hours (2 doses), 72 hours (6 doses),
and if possible after the last study administration dose/at the end of the
study intervention period, according to study protocol.
- Telephone conversation at respectively 3- and 6 months after hospital
dischage date: duration ± 20 minutes per conversation.
Performing the (observational) questionnaires will not be of an extended burden
for the participating patients due to the small time invested per questionnaire
and the fact that patients are phoned during the follow-up period. No
additional hospital visitis related with study participation are required.
- Known and potential risks
Haloperidol is associated with prolongation of the QTc interval and ventricular
arrhythmias, which rarely leads to torsade de pointes (TdP) and sudden cardiac
death. During the intervention period several safety measures are taken. The
investigator will at least visit the patient on day 2, 4, and 8 for (extended)
physical examination. Case-reports on TdP associated with haloperidol use have
been described, mainly after intravenous administration of exceptionally high
doses. Only one case-report reports on TdP after a low-dose (4mg) after oral
haloperidol, though this patient had received a high oral haloperidol dose (5mg
three-times daily) until two weeks before, without any side-effects.
Other reported side-effects of haloperidol include hypotension, extra-pyramidal
side-effects such as akathisia, mild liver function abnormalities, mild
gastro-intestinal problems, dry mouth, vision problems, constipation and
headache.
- Known and potential benefits
To date, there are no randomized, double-blind, placebo-controlled trials
available establishing the efficacy or safety of the typical antipsychotic
haloperidol in the treatment of delirium. Most of the information on
haloperidol efficacy in delirium management comes from case-reports. Several
reviews have addressed the efficacy of haloperidol versus benzodiazepines or
other antipsychotics.The efficacy of the antipsychotic agents chlorpromazine,
olanzapine, risperidone and quetiapine in the treatment of delirium has been
evaluated, but there is no evidence that these atypical antipsychotics are more
effective than low-dose haloperidol (*3.5mg per day) . Notwithstanding,
low-dose haloperidol is the drug of choice in the symptomatic treatment of
delirium as recommended by the American Psychiatric Association (APA)
.Haloperidol is shown to be effective in the management of delirium in
hospitalized adults, is overall well tolerated with few anticholinergic
side-effects, and can be administered orally, intramuscular as well as
intravenously.
The little evidence today on the beneficial role of haloperidol prophylaxis in
delirium prevention comes from merely three single centre studies on the
incidence of postoperative delirium. Study results disagree, mostly due to
dissimilarities between sample size, study design and type of surgery. No
multi-centre randomized controlled trials in a general older patient population
have been performed yet.
De Boelelaan 1117
Amsterdam 1007 MB
NL
De Boelelaan 1117
Amsterdam 1007 MB
NL
Listed location countries
Age
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 or proxy is able to provide written informed consent;
- The patient or proxy speaks either Dutch or English;
- The patient is admitted to the hospital for an internal 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 torsade de pointes, 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 who have been previously enrolled in the HARPOON study, or are currently enrolled in other medical- or drug (intervention) studies;
- Patients using co-medication of which concomitant use with haloperidol and/or during the 7-day intervention period according to protocol (SOP comedication) is contraindicated. Patients using QTc prolonging drugs at presentation with QTc *450ms (men) / QTc *460ms (women) on baseline ECG may be included in the study with repetitive ECG control according to protocol;
- Epilepsy
- Substance abuse and dependence (DSM-IV criteria)
- Patients who are not able to take study medication according to the protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
EudraCT | EUCTR2011-004762-15-NL |
CCMO | NL38027.029.12 |
Other | NTR TC = 3207 |