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

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.

Study Overview

• Status: Terminated
• Conditions: Alcohol Withdrawal Delirium; Alcohol Withdrawal Associated Autonomic Hyperactivity; Alcohol Withdrawal Hallucinosis; Alcohol Withdrawal-Induced Delirium Tremens
• Intervention / Treatment: Drug: Dexmedetomidine; Drug: Placebos

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.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Colorado Springs, Colorado, United States, 80920
      • Memorial Hospital North
    • Colorado Springs, Colorado, United States, 80909
      • Memorial Hospital Central
    • Denver, Colorado, United States, 80210
      • Porter Adventist Hospital
    • Denver, Colorado, United States, 80204
      • Denver Health Medical Center, Medical ICU
    • Lakewood, Colorado, United States, 80228
      • St. Anthony Hospital
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Louisiana State University
  • Texas
    • Houston, Texas, United States, 77030
      • Ben Taub Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 89 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dexmedetomidine; Dexmedetomidine titrated to achieve predefined goals on selected components of the MINDS score using the minimum amount of medication possible. Blinded study medication will be started at a rate determined by the MINDS score. The maximum infusion rate is 1.4 μg/kg per hour. Uncontrolled SAWS/D symptoms, will be treated with open label lorazepam according to the MINDS score algorithm. Persistent SAWS/D symptoms despite maximum infusion rate of study medication treatment limiting symptoms while receiving higher infusion rates of study medication, ancillary therapies will be administered according to the MINDS score algorithm, at the discretion of the treating physician.	Drug: Dexmedetomidine; Other Names: Precedex
Placebo Comparator: Placebo; Blinded placebo study drug administration in equal volume per hour as active study medication arm.	Drug: Placebos; Inactive placebo (normal saline)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The Length of ICU Stay Defined as the Time Between Randomization and ICU Transfer Orders.	up to 28 days in hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average MINDS Score	Minnesota Detoxification Scale (MINDS) min score 0, max score 46. The higher the score, the worse the symptoms of AWS/AWD.	up to 28 days
The Number of CAM-ICU Negative Days After Randomization.	The Confusion Assessment Method (CAM)-ICU is a validated instrument used to detect the presence or absence of delirium in the ICU. A delirium free day is counted for any day a patient is negative by the CAM-ICU. The higher the number of CAM-ICU negative days indicates the more days a patient was able to think clearly.	up to 28 days
Number of Ventilator Free Days After Randomization.	A ventilator day is counted for any use of invasive mechanical ventilation during a calendar day	up to 28 days
The Length in Days of the Hospital Stay	A hospital day is counted for any time on a calendar day the patient is admitted to the hospital. Hospital days are inclusive of ICU days.	up to 28 days
Scores at Hospital Discharge on the Mini Mental Exam.	The Mini Mental State Examination or Folstein test is a validated 30-point questionnaire used to measure cognitive impairment (min score 0, max score 30). A score of 24 points (out of a max of 30) indicates normal cognition, less than or equal to 9 points indicates severe impairment, 10-18 indicates moderate impairment and 19-23 mild impairment.	up to 28 days
Scores at Hospital Discharge on the Beck Depression Inventory.	The Beck Depression Inventory is a validated questionnaire used to measure severity of depression (min score 0, max score 63). The higher the score the greater the severity of depression. A score of 30-63 indicates severe depression, 19-29 moderate depression, 10-18 mild depression and 0-9 minimal depression.	Up to 28 days.
Scores at Hospital Discharge on the Beck Anxiety Inventory	The Beck Anxiety Inventory is a validated questionnaire used to measure severity of anxiety (min score 0, max score 63). The higher the score the greater the severity of anxiety. A score of 30-63 indicates severe anxiety, 17-29 moderate anxiety, 10-16 mild anxiety and 0-9 minimal anxiety.	Up to 28 days.
Scores at Hospital Discharge on the PTSD Civilian Checklist	PTSD checklist consists of 17 questions graded on a scale of 1 to 5. The PTSD score is comprised from the sum of the scores 17 questions. The PTSD score has possible values from to 17 to 85 with higher values indicating greater symptom severity.	Up to 28 days
Resource Utilization Costs Associated With This Hospitalization Billed by Physicians.		up to 28 Days
Resource Utilization Costs Associated With This Hospitalization Billed by Facility.		Up to 28 days

Collaborators and Investigators

• Sponsor: Denver Health and Hospital Authority
• Investigators: Principal Investigator: Ivor S Douglas, MD, FRCP, Denver Health Medical Center

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• Maccioli GA. Dexmedetomidine to facilitate drug withdrawal. Anesthesiology. 2003 Feb;98(2):575-7. doi: 10.1097/00000542-200302000-00041. No abstract available.

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): September 1, 2016

Study Registration Dates

• First Submitted: May 24, 2010
• First Submitted That Met QC Criteria: May 26, 2011
• First Posted (Estimate): May 30, 2011

Study Record Updates

• Last Update Posted (Actual): November 6, 2017
• Last Update Submitted That Met QC Criteria: October 4, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Severe Alcohol Withdrawal Delirium Tremens
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Nervous System Diseases; Alcohol-Related Disorders; Substance-Related Disorders; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Poisoning; Alcohol-Induced Disorders; Neurotoxicity Syndromes; Alcohol-Induced Disorders, Nervous System; Delirium; Substance Withdrawal Syndrome; Alcohol Withdrawal Delirium; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Hypnotics and Sedatives; Dexmedetomidine
• Other Study ID Numbers: COMIRB 09-0822

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No