Trial Comparing Haloperidol, Quetiapine and Placebo in the Pharmacological Treatment of Delirium
Trial Comparing Haloperidol, Quetiapine and Placebo in the Pharmacological Treatment of Delirium
Background:

 Delirium is an important problem in critical care. Its prevalence often reaches 75% in
 intensive care patients. Its occurrence is associated with numerous complications and
 deleterious consequences such as death, longer stay, higher cost, and long-term cognitive
 impairment. Delirium treatment entails correcting its underlying causes and usually
 initiating a pharmacological intervention with an antipsychotic. Typical antipsychotics,
 particularly haloperidol, are commonly used to treat delirium although few placebo-controlled
 trials of pharmacological treatments for delirium have been conducted. Furthermore,
 appropriate doses for delirium treatment have yet to be established. In critical care, two
 pilot studies provided the first randomized, placebo-controlled evidence for the
 pharmacologic treatment of ICU delirium. One found that neither haloperidol nor ziprasidone
 significantly reduced the incidence or duration of delirium compared with placebo whereas the
 other one found that quetiapine added to as-needed haloperidol resulted in faster delirium
 resolution.

 Objective:

 The goal of this study is to determine the effectiveness of antipsychotics in regular dosage
 regimen (quetiapine group and haloperidol group) compared to as-needed haloperidol (placebo
 group) in the pharmacological treatment of delirium. We will conduct a three-arm randomized
 controlled trial to achieve this goal.

 Materials and Methods:

 During one year, 45 delirious patients from three intensive care units will be recruited and
 randomized into one of three groups. Randomization will be performed in blocks of 9 by the
 pharmacy department, using a random numbers table.

 Patients will be continuously screened for delirium using the Intensive Care Delirium
 Screening Checklist (ICDSC) as part of routine care. A positive screening score (≥4) will
 warrant confirmation of delirium diagnosis by the treating physician. Treatment will begin
 according to randomization group, provided that informed consent has been obtained. Delirium
 status will be monitored during the episode using the Nursing Delirium Screening Scale
 (Nu-DESC). When the Nu-DESC monitoring will become negative for delirium (total score below
 2), the resolution of the episode will be confirmed by the treating physician. A clinical
 evaluation by a psychiatrist will be performed within 24-48 hours of each of the two
 evaluations made by the treating physician (beginning and end of the delirium episode).

 The treating physician will initiate twice-daily treatment at the first of five levels for
 each of the three groups: 1) 1 mg of intravenous (IV) haloperidol + oral (PO) placebo, 2) 50
 mg of PO quetiapine + IV placebo, or 3) IV + PO placebo. Therapy will be titrated upwards on
 a daily basis by increments of 1) 1 mg of IV haloperidol or 2) 50 mg of PO quetiapine, or 3)
 IV + PO placebo every 12 hrs, respectively, if the subject received at least two doses of
 as-needed haloperidol in the previous 24 hrs. As-needed (PRN) doses of 2 mg of IV haloperidol
 q 30 minutes will be available to patients from all three groups and administered by nurses
 until symptoms associated with delirium resolve. In case of unsuccessful as-needed treatment,
 rescue (STAT) doses of 5 mg of IV haloperidol q 30 minutes will be available to patients from
 all three groups and will be administered by nurses if agreement is reached with the treating
 physician that the situation indeed calls for it. The treatment level of patients requiring a
 STAT dose will immediately be raised to the above level. The treatment will stop when one of
 the following occurs: (1) the subject is deemed by the treating physicians, based on their
 clinical judgment, to no longer demonstrate signs of delirium and, therefore, to no longer
 require scheduled therapy with an antipsychotic agent; (2) 21 days of therapy has elapsed;
 (3) ICU discharge occurred; or (4) a life-threatening adverse event potentially attributable
 to the study drug occurred that warranted discontinuation of the study drug.

 Adverse effects will be closely monitored: extrapyramidal reactions, neuroleptic malignant
 syndrome, drowsiness, hypotension, QTc prolongation. The treatment level of patients
 presenting a non life-threatening adverse event will immediately be lowered to the level
 directly below.

 The sample size was calculated for a 2-tailed test with an alpha of .05 and a power of .80.

 The primary statistical analysis will involve Cox proportional time to event analysis
 comparing the three groups. Secondary analysis will use T-test comparisons for continuous
 variables and chi square for proportional analysis.
Primary Outcome Measures:

 •Time to first resolution of delirium.

 Secondary Outcome Measures:

 -  Days in delirium during the study

 -  Duration of delirium

 -  Severity of delirium (highest Nu-DESC score, mean episode Nu-DESC score)

 -  ICU and hospital mortality

 -  ICU and hospital length of stay

 -  Length of mechanical ventilation

 -  Time spent deeply sedated (RASS <3)

 -  Episodes of subject-initiated device removal

 -  Use of haloperidol therapy (including total dose in haloperidol equivalents during the
 study, number of doses, number of days of therapy, use of rescue IV haloperidol)

 -  Average daily and maximum total antipsychotic drug dose in haloperidol equivalents

 -  Duration of study drug administration

 -  Use of benzodiazepines (converted to lorazepam equivalents)

 -  Use of opioids (converted to morphine equivalents)

 -  QTc prolongation

 -  Extrapyramidal symptoms

 -  Neuroleptic malignant syndrome
Inclusion Criteria:

 -  Patients aged 18 years or older.

 -  Patients with a diagnosis of delirium made by a psychiatrist.

 Exclusion Criteria:

 -  Patients with active schizophrenia or bipolar disorder.

 -  Patients with Parkinson disease.

 -  Patients with severe liver failure.

 -  Patients with alcohol or sedative/hypnotics dependence.

 -  Patients with QTc interval above 500 msec.

 -  Pregnant patients.