Alcohol Withdrawal Syndrome Treated With Adjunctive Phenobarbital or Ketamine

Study Overview
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Brief Summary
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The goal of this study will aim to determine if adding phenobarbital or ketamine to a symptom-triggered benzodiazepine regimen decreases the rate of intensive care unit admissions during the treatment of alcohol withdrawal syndrome when compared to symptom-triggered benzodiazepine therapy alone.

Detailed Description
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The primary objective of this study is to compare phenobarbital and ketamine adjunctive therapies to lorazepam-based therapy in the treatment of acute alcohol withdrawal syndrome. It is hypothesized that the use of an alternative agent, either phenobarbital or ketamine, when used as an adjunct to symptom-triggered lorazepam therapy will significantly reduce the rate of intensive care unit admissions and thereby reduce the total cost associated with hospital admission for treatment of alcohol withdrawal syndrome. Enrolled patients will be admitted to Santa Barbara Cottage Hospital where they will be monitored with continuous pulse oximetry and cardiac telemetry. They will remain hospitalized while undergoing study-guided therapy in addition to supportive care for acute alcohol withdrawal syndrome. Patients will undergo standard of care therapy with lorazepam symptom-triggered therapy regardless of study participation.

Official Title
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A Randomized, Double-Blinded, Placebo-Controlled Study Evaluating Phenobarbital and Ketamine Adjunctive Therapies in the Treatment of Alcohol Withdrawal Syndrome

Conditions
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Alcohol Withdrawal Syndrome

Intervention / Treatment
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* Drug: Ketamine
* Drug: Phenobarbital
* Drug: Lorazepam
* Drug: Placebo A
* Drug: Placebo B


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary admitting diagnosis of acute alcohol withdrawal syndrome based on International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10), code F10.3, F10.4. Exclusion Criteria: Significant comorbid medical illness requiring Intensive Care Unit admission; Pregnancy; Inability to obtain intravenous access; Child Pugh Class C; and Allergy to study medications (phenobarbital, ketamine, lorazepam).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: prospective, randomized control trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lorazepam + Ketamine + Placebo A<br>Ketamine - infusion (0.15 - 0.4 mg/kg/hr) and placebo injections titrated by increases of 0.075 mg/kg/hr every 30 minutes for Clinical Institute Withdrawal Assessment for Alcohol (revised version) (CIWA-Ar) greater than or equal to 10 in addition to lorazepam symptom-triggered therapy Ketamine dosing will be based on ideal body weight Ketamine infusion will be discontinued once CIWA-Ar less than 10 for 4 hours | Drug: Ketamine<br>* Ketamine infusion<br>* Other names: Ketalar;Drug: Lorazepam<br>* Standard of Care<br>* Other names: Ativan;Drug: Placebo A<br>* Placebo injection<br>* Other names: Normal saline;|
| Active Comparator: Lorazepam + Phenobarbital + Placebo B<br>Phenobarbital - IV push (260 mg loading followed by 130 mg q1 hour) with placebo infusion until CIWA-Ar less than 10 with a maximum daily dose of 10mg/kg in addition to lorazepam symptom-triggered dosing for recurrent symptoms (Gold 2007) Maximum daily dose will be used in order to prevent over sedation as well as provide adequate storage in pharmacy monitored refrigerators for study drugs | Drug: Phenobarbital<br>* Phenobarbital intravenous injection<br>* Other names: Solfoton, Luminal;Drug: Lorazepam<br>* Standard of Care<br>* Other names: Ativan;Drug: Placebo B<br>* Placebo infusion<br>* Other names: Normal saline;|
| Placebo Comparator: Lorazepam + Placebo A + Placebo B<br>Lorazepam will be administered every 30 minutes as indicated based on CIWA-Ar protocol for Cottage Health in addition to placebo injections and placebo infusion | Drug: Lorazepam<br>* Standard of Care<br>* Other names: Ativan;Drug: Placebo A<br>* Placebo injection<br>* Other names: Normal saline;Drug: Placebo B<br>* Placebo infusion<br>* Other names: Normal saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intensive Care Unit admission rate | Number of admissions to the intensive care unit | Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of withdrawal seizures | Number of patients with documented seizures while treated for alcohol withdrawal syndrome | Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years | 
| Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) scores | CIWA-Ar scores (initial, maximum, discharge); Total score is cumulative of subscale measures: Minimum score is 0 (no evidence of alcohol withdrawal), Maximum score is 67 (severe alcohol withdrawal) Subscale measures: A) Nausea and vomiting (score 0-7); B) Tremor (score 0-7); C) Paroxysmal sweats (score 0-7); D) Anxiety (score 0-7); E) Tactile disturbances (score 0-7); F) Auditory disturbances (score 0-7); G) Visual disturbances (score 0-7); H) Headache, fullness in head (score 0-7); I) Agitation (score 0-7); J) Orientation and clouding of sensorium (score 0-4) | Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years | 
| Cumulative dose of medication/s administered | Cumulative dose of Lorazepam, Ketamine, and Phenobarbital | Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years | 
| Incidence of refractory alcohol withdrawal requiring alternative sedation with dexmedetomidine, propofol or midazolam infusions | Number of patients who require Dexmedetomidine, Propofol or Benzodiazepine continuous infusions and average dose while being treated for alcohol withdrawal syndrome | Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years | 
| Rate of mechanical ventilation | Rate of intubation | Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years | 
| Incidence of alcohol withdrawal hallucinations | Number of patients with documented auditory or visual hallucinations | Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lorazepam, Ketamine, Phenobarbital