Pharmacologic Evaluation of Intravenous Haloperidol for the Treatment of Delirium in Critically Ill Adults

Delirium is a common form of organ failure in the Intensive Care Unit (ICU).
The incidence of delirium at the ICU has been reported to be between 24- 82%,
especially in mechanically ventilated and sedated patients. Delirium is
associated with higher mortality, longer duration of mechanical ventilation and
post-ICU cognitive impairment. In addition, it is estimated that ICU delirium
is associated with health care costs ranging from $6 to $20 billion annually in
the United States only.

The Intensive Care Delirium Screening Checklist (ICDSC) is a validated
screening tool to identify delirium in the critically ill by non-psychiatrists,
e.g. trained ICU nurses. Recent evidence suggests that individual delirium
symptoms, when evaluated by the ICDSC, resolve differently over time.
Furthermore, Devlin et al found that quetiapine (atypical antipsychotic)
resolve several delirium symptoms faster than placebo in the Intensive Care
Unit. Despite the fact that no randomized, clinical trials exist that support
efficacy of antipsychotic drugs for the treatment of delirium in the critically
ill and the fact the recent *Clinical Practice for the management of pain,
agitation, and delirium in adult patients in the intensive care unit* (SCCM
PAD) guidelines do not advocate its use, haloperidol remains the preferred drug
among most ICU clinicians for the treatment of delirium. However the
pharmacologic response to IV haloperidol when used in critically ill patients
with delirium remains poorly characterized. This pertains to both
pharmacodynamics (PD) and pharmacokinetics (PK). The pharmacodynamics involve
efficacy, (i.e. the resolution of delirium symptoms) and safety (i.e. the
incidence of haloperidol-associated adverse effects such as extrapyramidal
effects, QTc-interval prolongation etc.). The pharmacokinetics involves
exposure to the drug, defined as area under the curve (AUC), maximum
concentration in serum (Cmax), half-life (t1/2) and clearance (Cl).
Characterization of the pharmacologic response of IV haloperidol will better
inform the clinicians on the optimal IV haloperidol dose that should be used to
resolve delirium (and the symptoms associated with it) and potentially help
reduce the safety concerns associated with its use. Furthermore, such knowledge
will help to define optimal dosing schedules for studies on efficacy of IV
haloperidol for the resolution of delirium symptoms in critically ill patients.
The aim of this study is to characterize the PK and PD of haloperidol in a
cohort of critically ill adults managed with a strict medical protocol.

The primary outcome of this study is to assess whether the maximum ICDSC score
achieved each day is related to PK parameters of haloperidol in ICU patients
with delirium.

Secondary outcomes:
- To characterize the association between daily haloperidol serum levels and
the resolution of individual delirium symptoms as measured by the daily ICDSC
score.
- To characterize the association between daily haloperidol serum levels and
the development of each of the following adverse events: a) any increase in the
QTc interval from baseline, b) development of akathisia or other extrapyramidal
symptoms and c) comedication.This association will be characterized over time.
- To investigate in-patient variability of daily serum levels of scheduled IV
haloperidol therapy and explore patient factors that might influence the
therapeutic levels achieved. Patients factors that will be evaluated: age, BMI,
gender, APACHE-IV score, co-medication and SOFA-score.
- To investigate the influence of CYP3A4 and CYP2D6 genotype on haloperidol
serum levels

Prospective observational cohort study.

Pharmacokinetics of haloperidol
Serum levels of haloperidol will be measured at day 2 at 1, 3, 5, and 7 hours
after the first dose of haloperidol. The levels from day 2 will be used to
calculate the exposure to haloperidol (by means of an AUC). Trough levels will
be measured at day 3, 4, 5, and 6 (end of study) or until haloperidol therapy
is stopped before day 6. Trough levels measured at day 3 to 6 will be
extrapolated to the AUC measured at day 2. Serum samples (1ml, purple tube)
will be drawn from an arterial line and will immediately be sent to the
laboratory of the hospital pharmacy and stored at -80 degrees C until analysis.
Serum level analysis will be performed by a validated Liquid Chromatography
Mass Spectometry Method (LC MS).

Haloperidol metabolism
CYP3A4 and CYP2D6 are the main enzymes involved in the metabolism of
haloperidol. Individuals are classified according to the number of active
enzyme alleles as: poor metabolizers (PM), intermediate metabolizers (IM),
extensive metabolizers (EM) and ultrarapid metabolizers (UM). CYP2D6 and CYP3A4
genotype will be measured at day 1 of study, the genotype will be used to
stratify metabolization rates. A validated method is available in the
Laboratory of Clinical Chemistry (AKC). For the analysis a blood sample will be
drawn (3 ml, purple tube).

Minimal risk is expected for collecting blood samples. Patients will be treated
according to standard protocol.