Dexmedetomidine (Precedex®) for 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.
|Alcohol Withdrawal Delirium Alcohol Withdrawal Associated Autonomic Hyperactivity Alcohol Withdrawal Hallucinosis Alcohol Withdrawal-Induced Delirium Tremens||Drug: Dexmedetomidine Drug: Placebo||Phase 4|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator
Primary Purpose: Treatment
|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)|
- The length of ICU stay defined as the time between randomization and ICU transfer orders. [ Time Frame: up to 28 days in hours ]
- The number of delirium-free and ventilator-free days during the first 28 days of hospitalization [ Time Frame: up to 28 days ]
- The length in days of the hospital stay [ Time Frame: up to 28 days ]
- Scores at hospital discharge on the Mini Mental Exam, Beck Depression Inventory, Beck Anxiety Inventory and PTSD checklist. [ Time Frame: up to 28 days ]
- Resource utilization costs associated with this hospitalization. [ Time Frame: up to 28 Days ]
- Predefined adverse events [ Time Frame: up to 28 days ]
- average MINDS score [ Time Frame: up to 28 days ]
|Study Start Date:||March 2012|
|Estimated Study Completion Date:||September 2017|
|Primary Completion Date:||December 2015 (Final data collection date for primary outcome measure)|
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.
See arm details
Placebo Comparator: Placebo
Blinded placebo study drug administration in equal volume per hour as active study medication arm.
Sterile, clear saline 0.9%
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01362205
|United States, Colorado|
|Memorial Hospital Central|
|Colorado Springs, Colorado, United States, 80909|
|Memorial Hospital North|
|Colorado Springs, Colorado, United States, 80920|
|Denver Health Medical Center, Medical ICU|
|Denver, Colorado, United States, 80204|
|Porter Adventist Hospital|
|Denver, Colorado, United States, 80210|
|St. Anthony Hospital|
|Lakewood, Colorado, United States, 80228|
|United States, Louisiana|
|Louisiana State University|
|New Orleans, Louisiana, United States, 70112|
|United States, Texas|
|Ben Taub Hospital|
|Houston, Texas, United States, 77030|
|Principal Investigator:||Ivor S Douglas, MD, FRCP||Denver Health Medical Center|