Effects of prophylactic use of haloperidol in critically ill patients with a high risk for delirium

Delirium is a neuropsychiatric disorder characterized by an acute onset of
confusion and consciousness alterations that fluctuate during the day. The
incidence of delirium in intensive care (ICU) patients is high, on average
30-50%, and its occurrence is associated with prolonged duration of mechanical
ventilation, increased ICU- and hospital length of stay unplanned removal of
tubes and catheters and an increased mortality. Therefore, preventive treatment
for delirium may be beneficial.
Apart from treatment of the underlying disease, haloperidol is the most common
and recommended anti-psychotic drug in delirium treatment. Recently, this drug
is also used to prevent delirium. In non-ICU patients beneficial effects of
prophylactic haloperidol in older and surgical patients have been reported.
For critically ill patients, data concerning preventive treatment with
anti-psychotic drugs is scarce, and inconsistent.
In one retrospective cohort study ICU patients treated with haloperidol a lower
mortality rate was found compared to non-treated ICU patients. Another recent
study showed that haloperidol prophylaxis in non-cardiac surgical ICU patients
had beneficial effects on delirium incidence and delirium free days.
Note worthily, in this study no delirium risk stratification was performed,
suggesting that the beneficial effects might be diluted in the whole group of
ICU patients (as also patients with a low risk to develop delirium were
included) and that more pronounced preventive effects may be present in
patients with a high risk to develop delirium. Recently, a delirium prediction
model for ICU patients was developed and validated. With this model the extent
of the preventive efficacy in different groups of delirium-risk can be
determined. In view of the high incidence of delirium, the impact of delirium
on outcome, and the availability of a delirium prediction model to identify
high risk ICU patients a delirium prevention protocol was implemented in
clinical practice using a low dosage of haloperidol. Subsequently the effect of
this prophylactic treatment in patients with a high risk was evaluated on
several relevant delirium outcome parameters. In this study were found: In
patients with a predicted risk to develop delirium >50%, delirium incidence was
(haloperidol vs control) 65 versus 75%, delirium-free and coma free days in 28
days 20 versus 13 and also complications related to delirium (e.g. unintended
removal of catheters and tubes) was significantly lower in the patients that
received haloperidol. Based on these results, these effects of prophylactic
treatment with haloperidol need to be confirmed in a randomized controlled
double-blind trial. Since no relevant side-effects were reported in
prophylactic studies with a low dosage of haloperidol and the described
moderate positive results (e.g. incidence from 75 to 65%) it is conceivable
that a somewhat higher dose of haloperidol may exert more pronounced beneficial
effects.

In this study we aim to examine the effects of a low dosage of prophylactic
haloperidol in patients with an expected ICU length of stay of >1 day. We use
two different dosages of haloperidol in this study to compare with placebo. A
dosage of 1mg, or 2mg three times a day in a double blinded fashion resulting
in a three-armed multicentre randomized double blinded controlled trial. The
PREDELIRIC-model will be used to determine the a priori chance to develop
delirium, enabling us to determine the preventive efficacy of haloperidol in
patient groups based on their risk to develop delirium. Patients that are
included in the study, but leave the ICU within 24 hours will be discarded for
further analysis. Since it is recognized that the onset of delirium is median
on day 2, low dosage and a short treatment duration with haloperidol has no
relevant side-effects, randomization will be started immediately prior to the
informed consent procedure. This procedure will be started as soon as possible,
and if no informed consent will be obtained patients are then still excluded
for this study and replaced until group size is achieved.

A prospective multicentre three armed block-randomized double-blind
placebo-controlled prophylactic intervention study in critically ill patients
with a high risk for delirium.

Number of centers: In total 19 centers in the Netherlands with a level 2 or 3
Intensive Care Unit will participate in this study.

Estimated study duration: Follow-up of included patients is till discharge of
the ICU or in case delirium occurred till the delirium has resolved (defined by
three consecutive days of negative delirium screenings). Total duration for the
conduct of the study: 1.5 year.

In this study we have two prophylactic haloperidol groups and one placebo
group. Patients allocated to the treatment group will receive either 3x1mg or
3x2mg prophylactic haloperidol until discharge from the ICU or when delirium
occurs. In the latter case study drug will be stopped and patients are
subsequently treated according to the delirium protocol with open-label
haloperidol. To avoid unnecessary risk for side-effects the dose will be halved
in patients:
- aged >= 80 years
- weight <= 50 kg
- liver failure (serum bilirubin level > 50 µmol/L)
Patients with an adjusted dosage of study drug remain allocated to their
original group.
In case of occurrence of QTc-time prolongation of over 500msec. the study drug
will be stopped immediately.

Based on historical data we know that the median predicted delirium risk is 35%
in patients with an expected stay on the ICU of over one day. This is
considered a high risk for delirium.
To assess patients for delirium using the CAM-ICU by ICU-nurses is part of
daily practice in all participating centres. Also, patients receive three times
a day a study drug of which two groups receive a low dose of haloperidol and a
third arm receive placebo. Concerning haloperidol, this drug is worldwide first
choice of drug in delirious patients. When delirium is diagnosed, patients are
treated according to delirium protocol, using a higher dosage than in the
prophylactic treatment period as described in this study protocol. It is
recognized that early treatment of delirium has beneficial effects compared
with delayed treatment, and also there is some evidence that delirium
prevention in ICU patients has beneficial effects, but study design was not
optimal.
Potential side-effects of haloperidol include, extrapyramidal symptoms,
drowsiness, agitation, and ventricular arrhythmias. The latter are extremely
rare (only case-reports are published and related to a higher dosage of
haloperidol. With the dosage that will be used in the present study (3x1 or
3x2mg daily) no relevant side-effects are anticipated. Nevertheless, and given
the preventive nature of this study, extra attention is being paid on
recognition of possible side-effects of haloperidol in the protocol.
Importantly, in three recent prophylactic haloperidol studies no relevant
side-effects and in particular no ventricular arrhythmias were reported using a
similar low dosage of haloperidol as described in the present protocol.