Clinical trial NCT01362205: Dexmedetomidine (Precedex®) for Severe Alcohol Withdrawal Syndrome (AWS) and Alcohol Withdrawal Delirium (AWD)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Alcohol Withdrawal Delirium
Alcohol Withdrawal Associated Autonomic Hyperactivity
Alcohol Withdrawal Hallucinosis
Alcohol Withdrawal-Induced Delirium Tremens
Keywords: Severe Alcohol Withdrawal Delirium Tremens
Lead sponsor: Denver Health and Hospital Authority
Sponsor class: OTHER
First posted: 2011-05-30
Enrollment: 49
Sex: ALL
Minimum age (years): 18
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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 infusion
* Serious central nervous system pathology (acute stroke, uncontrolled seizures, severe dementia),
* 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.

Primary outcomes:
measure: The Length of ICU Stay Defined as the Time Between Randomization and ICU Transfer Orders.
timeFrame: up to 28 days in hours
Secondary outcomes:
measure: Average MINDS Score
timeFrame: up to 28 days
measure: The Number of CAM-ICU Negative Days After Randomization.
timeFrame: up to 28 days
measure: Number of Ventilator Free Days After Randomization.
timeFrame: up to 28 days
measure: The Length in Days of the Hospital Stay
timeFrame: up to 28 days
measure: Scores at Hospital Discharge on the Mini Mental Exam.
timeFrame: up to 28 days
measure: Scores at Hospital Discharge on the Beck Depression Inventory.
timeFrame: Up to 28 days.
measure: Scores at Hospital Discharge on the Beck Anxiety Inventory
timeFrame: Up to 28 days.
measure: Scores at Hospital Discharge on the PTSD Civilian Checklist
timeFrame: Up to 28 days
measure: Resource Utilization Costs Associated With This Hospitalization Billed by Physicians.
timeFrame: up to 28 Days
measure: Resource Utilization Costs Associated With This Hospitalization Billed by Facility.
timeFrame: Up to 28 days
Other outcomes:
Locations:
city: Colorado Springs
country: United States
facility: Memorial Hospital Central
state: Colorado
city: Colorado Springs
country: United States
facility: Memorial Hospital North
state: Colorado
city: Denver
country: United States
facility: Denver Health Medical Center, Medical ICU
state: Colorado
city: Denver
country: United States
facility: Porter Adventist Hospital
state: Colorado
city: Lakewood
country: United States
facility: St. Anthony Hospital
state: Colorado
city: New Orleans
country: United States
facility: Louisiana State University
state: Louisiana
city: Houston
country: United States
facility: Ben Taub Hospital
state: Texas
Study officials:
affiliation: Denver Health Medical Center
name: Ivor S Douglas, MD, FRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, Whitten P, Margolis BD, Byrne DW, Ely EW, Rocha MG; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009 Feb 4;301(5):489-99. doi: 10.1001/jama.2009.56. Epub 2009 Feb 2.
citation: Darrouj J, Puri N, Prince E, Lomonaco A, Spevetz A, Gerber DR. Dexmedetomidine infusion as adjunctive therapy to benzodiazepines for acute alcohol withdrawal. Ann Pharmacother. 2008 Nov;42(11):1703-5. doi: 10.1345/aph.1K678. Epub 2008 Sep 9.
citation: Rovasalo A, Tohmo H, Aantaa R, Kettunen E, Palojoki R. Dexmedetomidine as an adjuvant in the treatment of alcohol withdrawal delirium: a case report. Gen Hosp Psychiatry. 2006 Jul-Aug;28(4):362-3. doi: 10.1016/j.genhosppsych.2006.03.002.
citation: Maccioli GA. Dexmedetomidine to facilitate drug withdrawal. Anesthesiology. 2003 Feb;98(2):575-7. doi: 10.1097/00000542-200302000-00041. No abstract available.