Dexmedetomidine (Precedex®) for Severe Alcohol Withdrawal Syndrome (AWS) and Alcohol Withdrawal Delirium (AWD)

Conditions:Neurology, Psychiatric
Therapuetic Areas:Neurology, Psychiatry / Psychology
Age Range:18 - 89
Start Date:March 2012
End Date:September 2016

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A Randomized, Double-blind, Placebo-controlled, Parallel-group Study of Dexmedetomidine (Precedex®), With Lorazepam Rescue, for the Management of Severe Alcohol Withdrawal Syndrome (AWS) and Alcohol Withdrawal Delirium (AWD)

This is a prospective, randomized, double-blind, placebo-controlled, parallel-group study of
dexmedetomidine versus placebo, with lorazepam rescue, for the management of severe alcohol
withdrawal syndrome (AWS) and alcohol withdrawal delirium (AWD) in critically ill adults.

The investigators hypothesize that the integration of dexmedetomidine (Precedex®) with usual
therapy for the management of severe alcohol withdrawal syndrome (AWS) and alcohol withdrawal
delirium/delirium tremens (AWD) in critically ill adult patients will reduce the time to
resolution of AWS/AWD, increase the number of delirium-free and ventilator-free days in the
first 28 days of hospitalization, reduce the length of ICU and hospital stays, and improve
neurocognitive and quality of life scores on hospital discharge.

Severe alcohol withdrawal syndrome (AWS) and alcohol withdrawal delirium (AWD) are frequent
principal indication/s for admission to intensive care units. Additionally, unanticipated
alcohol withdrawal complicates other critical illnesses and peri-operative states. Alcohol
intoxication and withdrawal syndrome are characterized by classic symptoms of adrenergic
activation, psychiatric agitation including seizures, as well as metabolic and respiratory
dysfunction. The majority of patients with severe AWS are effectively managed with
combinations of benzodiazepine (BZD) sedatives (e.g. lorazepam) and butyrophenone
antipsychotics (e.g. haloperidol) and require intensive care admission for 2-3 days. However,
almost 25% of patients with SAWS have a prolonged critical care course, often complicated by
respiratory failure and associated with excessive sedation and risk for complications such as
ventilator-associated pneumonia (VAP). AWS is frequently difficult to manage with usual care
including benzodiazepines. Additionally, while intermittent bolus dose sedation is
recommended for AWS, high dose BZD alone is associated with excessive respiratory suppression
and metabolic acidosis. Such therapy increases the likelihood of respiratory failure with its
attendant complications of hospital acquired pneumonia and sepsis. Further, patients with
underlying chronic liver disease are at greater risk for prolonged sedative effects of BZD
and progression of hepatic encephalopathy. The requirement for mechanical ventilation
additionally prolongs the course of treatment for AWD because of the need for prolonged
sedation. Strategies to control AWS/AWD that control symptoms but avoid adverse effects of
excessive respiratory suppression are anticipated to improve the short and medium-term
outcomes of AWS.

BZD infusions have also been shown by several investigators to result in excessive and
prolonged sedation. However, reasonable alternatives for effective control of psychomotor and
adrenergic activation have until recently, been unavailable. The centrally acting alpha-2
receptor agonist, clonidine has been suggested as a useful adjunctive therapy to BZD.
However, clonidine is only a mild sedative and can result in significant hemodynamic
compromise. By contrast, dexmedetomidine (Precedex), a more potent alpha-2 receptor agonist,
is potentially a more effective adjunctive therapy. Precedex is currently marketed in the USA
for short-term use as a potent peri-operative sedative and analgesic. This agent has a short
circulating half-life and has significantly fewer hemodynamic side effects than clonidine. In
addition to its cardiovascular properties, dexmedetomidine possesses anxiolytic,
hypnotic/sedative, anesthetic-sparing and analgesic actions and is devoid of significant
respiratory depressant effects.

Precedex has been shown to be a safe and effective single agent sedative for critically ill
medical and surgical patients in prolonged infusions up to thirty days and is associated with
significantly lower incidence of delirium than sedation with the benzodiazepine, midazolam.
Preclinical experience and case reports suggest anecdotally Precedex may be of particular
benefit in patients with SAWS.

Measures of sedation and delirium will be assessed with the Minnesota Detoxification Scale
(MINDS) derived for use in critically ill adults from the validated Clinical Institute
Withdrawal Assessment (CIWA-r) scale.

Inclusion Criteria:

- Male or female patients, 18 years or older, with severe AWS or AWD per DSM-IV
definitions (below) requiring admission to the ICU for medical management

- Ability to provide informed consent (via a proxy decision maker or patient).

- Within 96 hours of ICU admission.

- Meets DSM-IV diagnostic criteria for 291.8 Alcohol Withdrawal Syndrome:

- Cessation of (or reduction in) alcohol use that has been heavy and prolonged.

- Two (or more) of the following, developing within several hours to a few days
after Criterion A:

1. autonomic hyperactivity (e.g., sweating or pulse rate greater than 100)

2. increased hand tremor

3. insomnia

4. nausea or vomiting

5. transient visual, tactile, or auditory hallucinations or illusions

6. psychomotor agitation

7. anxiety

8. grand mal seizures

- The symptoms are not due to a general medical condition and are not better accounted
for by another mental disorder.

AND Meets DSM-IV diagnostic criteria for 291.0 Alcohol Intoxication or Withdrawal Delirium

- Disturbance of consciousness

- A change in cognition

- The disturbance develops over a short time and can fluctuate

- Onset is temporal associated with Alcohol Withdrawal Syndrome

Exclusion Criteria:

- Age < 18 years

- Physician anticipates ICU transfer orders in less than 12 hours from time of consent.

- Recent traumatic brain injury

- Active status epilepticus

- Pregnancy or lactation

- Known allergy or adverse response to any of the study medications

- Requiring glucocorticoid therapy for treatment of acute hepatitis or Stage III
(advanced) decompensated liver failure and encephalopathy

- Trauma or burns as admitting diagnoses

- Neuromuscular blockade other than for intubation

- Epidural or spinal analgesia

- General anesthesia 24 hours prior to, or planned after, the start of study drug

- Serious central nervous system pathology (acute stroke, uncontrolled seizures, severe

- Unstable angina or acute myocardial infarction

- Left ventricular ejection fraction less than 30%

- Heart rate less than 50/min

- Second- or third degree heart block

- Systolic blood pressure less than 90 mm Hg despite continuous infusions of 2
vasopressors before the start of study drug infusion.

- Previous randomization into this study.
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