Delirium Clinical Trial
Official title:
Delirium in the ICU: a Prospective, Randomized, Trial of Placebo vs. Haloperidol vs. Ziprasidone
Delirium is associated with increased risk of death, prolonged stay, higher cost of care, and likely long-term brain deficits in survivors. This form of brain dysfunction occurs in intensive care unit (ICU) patients in epidemic proportions, and the scope of this problem is likely to worsen in upcoming years due to the aging of our population and increased utilization of the ICU. Currently, delirium goes unrecognized and untreated in the vast majority of circumstances in the ICU unless the patient presents with hyperactive delirium and agitation. In the latter circumstance, a commonly used typical antipsychotic called haloperidol is considered the principal agent for treating delirium based largely on anecdotal evidence to support its usefulness, though no placebo controlled trials exist. There are no FDA approved medications for delirium. The atypical antipsychotics provide a promising alternative for the treatment of delirium due to their enhanced beneficial effects on positive (agitated) and negative (quiet) symptoms proven in mania and schizophrenia, reduced risk for side effects common to haloperidol such as extrapyramidal symptomatology, and less potentially lethal heart rhythm disturbances. It is imperative that well-designed phase II studies to determine proof of principle be conducted. A pilot study of feasibility to begin assessing the role of antipsychotics in the management of ICU 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).
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
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