The MIND Study: Modifying the INcidence of Delirium

This investigation will be the first placebo controlled trial of delirium
prevention/treatment, in or out of the ICU. As mentioned above, clinical practice guidelines
for medical management of pain, anxiety, and delirium (major determinants of patient
comfort) are endorsed by the major critical care societies. These guidelines will form the
template for this investigation. Pain management is prioritized as a clinicians' first
concern. The assessment and treatment algorithm in the guidelines then places anxiety and
delirium, respectively, as sequential tiers of priority. While delirium monitoring is now
available, recent data indicate that less than 5% of practicing ICU healthcare professionals
use a specific delirium monitoring instrument. Thus, as outlined here, most delirium is not
recognized or treated, which serves as the rationale for this placebo-controlled
investigation. Anxiety is currently treated with drugs such as benzodiazepines. Such
anxiety, however, may be due to delirium, in which case treatment with anxiolytics such as
benzodiazepines might exacerbate this form of brain dysfunction. On the other hand, it is
possible that treatment with antipsychotics will reduce the duration and severity of
delirium, result in less breakthrough sedatives (due to the sedating effects of the
antipsychotics), and improve clinical outcomes. Alternatively, treatment with antipsychotics
may not alter or worsen clinical outcomes.

The specific aims of this study are as follows:

Aim 1: To determine whether antipsychotics reduce the incidence and duration of delirium in
high risk mechanically ventilated patients.

Aim 2: To determine whether antipsychotics reduce the severity of neuropsychological
dysfunction at hospital discharge in high risk mechanically ventilated patients.

Hypothesis 1: Our primary hypothesis is that in mechanically ventilated patients, the
duration of delirium and the days alive and free of delirium - as measured using the
Confusion Assessment Method for the ICU (CAM-ICU)- will be significantly improved by early
treatment with antipsychotics (haloperidol or ziprasidone) as compared to placebo.
Furthermore, we hypothesize that delirium duration will be comparable between the two
intervention groups (haloperidol and ziprasidone). To test the primary hypothesis, we
propose to perform a randomized, double-blind, placebo-controlled trial of the
prevention/treatment of delirium in ICU patients using oral liquid formulations of
haloperidol versus ziprasidone versus placebo. This study is powered to show a 50%
improvement in the duration of delirium (CAM-ICU positive days) and will enroll 102 patients
(34 in each group) over a two-year period. In addition, we will compare between groups the
overall incidence of delirium and the number of delirium free days (DFDs) - defined as days
alive and free of coma and delirium to day 21.

Hypothesis 2: We hypothesize that scores on a neuropsychological testing battery
administered at the time of hospital discharge will be better in patients treated with
antipsychotics (either haloperidol or ziprasidone) than those treated with placebo.
Furthermore, we hypothesize that neuropsychological test scores will be comparable between
the two intervention groups (haloperidol and ziprasidone).

Inclusion Criteria:

- Medical or surgical ICU patients on mechanical ventilation who are receiving
sedatives or analgesics or displaying an abnormal level of consciousness (delirium or
coma).

Exclusion Criteria:

- Subjects expected to have a short time on mechanical ventilation. That is, those in
whom the likelihood for the need for mechanical ventilation is less than 24 hours.

- Subjects who have been on mechanical ventilation for more than 72 hours.

- Subjects in whom gastric access is not available (i.e., no enteral feeding tube or
NG/OG tube)and is not anticipated to be available for 48 hours.

- Subjects younger than 18 years old.

- Subjects who are pregnant (a pregnancy test will be performed on all women of child
bearing age) or breastfeeding.

- Inability to obtain informed consent from the subject or the subject's authorized
representative.

- Documented history of allergic reaction to ziprasidone or haloperidol.

- Subjects admitted to the ICU for drug/alcohol overdose, suicide attempts, alcohol
withdrawal/delirium tremens.

- Subjects with active seizures or cerebrovascular accident within the last 2 weeks.

- Subjects who are benzodiazepine dependent at the time of index hospitalization (i.e.,
patients on benzodiazepines as outpatient and whose attending judges it unsafe to
withhold these medications due to risk for withdrawal syndrome).

- Subjects with chronic pain syndromes or who are on maintenance narcotics.

- Subjects with a history of torsades de pointes, known history of QT prolongation
(e.g., congenital long QT syndrome), a QTc at baseline of 500 ms or over in the
absence of bundle branch block, documented myocardial infarction within the previous
2 weeks, or uncompensated NYHA IV heart failure (dyspnea or anginal syndrome present
at rest due to CHF). [NOTE: ICU patients who have an incidental rise in troponin in
the absence of definitive ischemic ECG changes remain eligible]

- Subjects who are on neuroleptic therapy as an outpatient maintenance drug (e.g.,
haloperidol, mesoridazine, thorazine, chlorpromazine, trifluoperazine, droperidol,
risperidone, quetiapine, olanzapine, or ziprasidone).

- Subjects who are receiving and will continue to receive other drugs that prolong the
QT interval such as sotalol, quinidine, other Class Ia or III anti-arrhythmics,
dofetilide (Tikosyn for arrhythmias), pimozide (for Tourette's), gatifloxacin,
moxifloxacin (levofloxacin permissible), pentamidine, tacrolimus (Prograf),
dolasetron (Anzemet). Azithromycin is an acceptable medication for study patients,
and anyone slated to receive (or receiving) either clarithromycin or erythromycin can
be switched to azithromycin by their primary team and be enrolled into the study the
following day. Patients receiving clindamycin or clotrimazole will be excluded from
the study.

- Subjects who have a history of neuroleptic malignant syndrome.

- Subjects with potassium levels below 3.0 mg/dl or magnesium levels below 1.8 mg/dl.
NOTE: If the patient is receiving replacement of K+ or Mg+, then he/she would be
eligible unless there is reason to suspect that these electrolyte abnormalities will
be refractory.

- Subjects with moderate/severe dementia (e.g., Alzheimer's type, vascular origin, or
HIV-related) as documented by medical history or modified Blessed dementia rating
scale (mBDRS) 4 or more or Informant Questionnaire of Cognitive Dysfunction in the
Elderly (IQCODE) over 3.6.

- Subjects who have suspected anoxic brain injury or documented cerebral edema at the
time of screening.

- Subjects who are moribund and not expected to survive 24 hours from the time of study
enrollment, or who have a "Do Not Resuscitate" order, or whose family or medical team
have not committed to aggressive support (e.g., not going to use vasopressors or
mechanical ventilation or likely to have withdrawal of support within 24 hours).