The MIND Study: Modifying the INcidence of Delirium
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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
|Official Title:||Delirium in the ICU: a Prospective, Randomized, Trial of Placebo vs. Haloperidol vs. Ziprasidone|
- Days alive and free of delirium and coma (delirium and coma free days) [ Time Frame: enrollment to day 21 ] [ Designated as safety issue: No ]
- Severity of neuropsychological dysfunction at hospital discharge [ Time Frame: 48-72 following d/c of study drug ] [ Designated as safety issue: No ]
- alive and free of delirium (delirium free days) [ Time Frame: enrollment to day 21 ] [ Designated as safety issue: No ]
- Length of stay on mechanical ventilation [ Time Frame: enrollment to day 21 ] [ Designated as safety issue: No ]
- Mechanical ventilation free days [ Time Frame: enrollment to day 21 ] [ Designated as safety issue: No ]
- length of stay in the ICU [ Time Frame: enrollment to day 21 ] [ Designated as safety issue: No ]
- Length of stay in the hospital [ Time Frame: enrollment to day 21 ] [ Designated as safety issue: No ]
- hospital mortality [ Time Frame: enrollment to day 21 ] [ Designated as safety issue: No ]
- mortality at 1 year [ Time Frame: enrollment to 12 months post discharge ] [ Designated as safety issue: No ]
|Study Start Date:||December 2004|
|Study Completion Date:||July 2007|
|Primary Completion Date:||July 2007 (Final data collection date for primary outcome measure)|
Placebo Comparator: A - placebo
per oral pill
Other Name: per oral pill
Active Comparator: B
Active Comparator: C
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).
|United States, Iowa|
|University of Iowa|
|Iowa City, Iowa, United States, 52242|
|United States, North Carolina|
|University of North Carolina - Chapel Hill|
|Chapel Hill, North Carolina, United States, 27599|
|Greensboro, North Carolina, United States, 27401|
|United States, Tennessee|
|Vanderbilt University Medical Center|
|Nashville, Tennessee, United States, 37232|
|Saint Thomas Hospital|
|Nashville, Tennessee, United States, 37205|
|Principal Investigator:||E Wesley Ely, MD, MPH||Vanderbilt University|