Ketamine vs. Placebo as Adjunctive Therapies for Severe Alcohol Withdrawal

Phase 4

Withdrawn

• Conditions: Alcohol Withdrawal
• Interventions: Drug: Ketamine; Drug: Dexmedetomidine; Drug: Normal saline

• Registration Number: NCT02823977
• Lead Sponsor: University of Colorado, Denver

Brief Summary

This study is designed to evaluate the addition of ketamine to dexmedetomidine as adjunctive therapies of severe alcohol withdrawal in medical ICU patients. Specifically, this study will assess whether the combination of ketamine and dexmedetomidine reduces the doses of conventional agents used for alcohol withdrawal while maintaining patient comfort and safety and will explore if the combination alters the expression of catecholamines in the serum over time.

Detailed Description

The combination of ketamine and dexmedetomidine for alcohol withdrawal is pharmacologically rationale and may provide additive benzodiazepine-sparing effects. All subjects will receive benzodiazepine therapy as standard of care.

The objectives of this randomized, double-blind pilot study of 20 subjects with severe alcohol withdrawal are to a) determine if adding ketamine 0.5 mg/kg per hour to dexmedetomidine 0.6 µg/kg per hour (both agents administered for up to 72 hours) as adjunctive therapies to a symptom-triggered benzodiazepine protocol reduces the dose requirements of conventional sedatives while maintaining patient comfort and safety; and to b) explore whether epinephrine, a marker of autonomic activity, is expressed differently when ketamine is added to dexmedetomidine as adjunctive therapies.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2016-07-01
• Study First Submitted QC: 2016-07-01
• Study First Posted: 2016-07-06
• Status Verified: 2018-01
• Last Update Submitted: 2018-01-17
• Last Update Posted: 2018-01-19
• Study Start: 2018-02
• Primary Completion: 2018-12
• Study Completion: 2018-12

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

1. Severe alcohol withdrawal defined by a CIWA score ≥ 15 and the need for at least 16 mg of lorazepam equivalents over a four-hour period. All benzodiazepine and barbiturate doses, whether oral or intravenous, will contribute to the cumulative amount using the following conversion: 1 mg lorazepam = 2 mg midazolam = 7.5 mg clorazepate = 15 mg phenobarbital.
2. Patients receiving standard therapy for severe alcohol withdrawal according to the UCH-specific, symptom-triggered alcohol withdrawal protocol in the ICU (or admission to the ICU is anticipated). Lorazepam is the preferred benzodiazepine agent for patients requiring ICU admission due to alcohol withdrawal.
3. Informed consent within 36 hours of qualifying for the study.

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Exclusion Criteria

1. Patients < 18 years of age or > 85 years of age.
2. Patients receiving benzodiazepine therapy for purposes other than alcohol withdrawal (e.g. sedation, seizure control other than alcohol withdrawal).
3. Patients with alcohol withdrawal not requiring ICU admission.
4. Patients receiving epidural administration of medication(s).
5. Comatose patients by metabolic or neurologic affectation.
6. Patients with active myocardial ischemia or second- or third-degree heart block.
7. Patients with Child-Pugh score of C.
8. Moribund state with planned withdrawal of life support.
9. Patient pending transfer to another facility.
10. Patients with known or suspected severe adverse reactions to dexmedetomidine (or clonidine) or ketamine.
11. Pregnant females or females suspected of being pregnant.
12. Prisoners or active parolees.
13. Previous study participation.
14. Patients already receiving ketamine for alcohol withdrawal. Patients receiving dexmedetomidine will be excluded if the infusion exceeds 1 µg/kg per hour for more than two hours or any rate for a cumulative duration of 12 hours.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ketamine / Dexmedetomidine	Ketamine	Ketamine 0.25 mg/kg bolus followed by 0.5 mg/kg per hour AND Dexmedetomidine by continuous infusion at a fixed rate of 0.6 µg/kg per hour, both administered for up to 72 hours
Ketamine / Dexmedetomidine	Dexmedetomidine	Ketamine 0.25 mg/kg bolus followed by 0.5 mg/kg per hour AND Dexmedetomidine by continuous infusion at a fixed rate of 0.6 µg/kg per hour, both administered for up to 72 hours
Placebo / Dexmedetomidine	Dexmedetomidine	Normal saline, as a 500 mL infusion bag, to represent placebo AND Dexmedetomidine by continuous infusion at a fixed rate of 0.6 µg/kg per hour, both administered for up to 72 hours
Placebo / Dexmedetomidine	Normal saline	Normal saline, as a 500 mL infusion bag, to represent placebo AND Dexmedetomidine by continuous infusion at a fixed rate of 0.6 µg/kg per hour, both administered for up to 72 hours

Primary Outcome Measures

Name	Time	Method
Cumulative Lorazepam Dose Over the First 12 Hours of Alcohol Withdrawal	12 hours	As part of routine care, the bedside nurse will record the administration of all sedative agents. The hourly, daily and cumulative doses of agents will be determined by the sum of as needed doses, scheduled intermittent doses, and hourly infusion rates. All conventional therapies will be guided by the institution-specific, symptom-triggered alcohol withdrawal protocol to maintain CIWA scores ≤ 7. Intravenous lorazepam is the preferred benzodiazepine for management of alcohol withdrawal in the medical ICU. Phenobarbital and propofol are infrequently used and they are not included in the protocol. All benzodiazepine and barbiturate doses, whether oral or intravenous, will be converted to lorazepam equivalents using the following conversion: 1 mg lorazepam = 2 mg midazolam = 7.5 mg clorazepate = 15 mg phenobarbital.
Cumulative Lorazepam Dose Over the First 24 Hours of Alcohol Withdrawal	24 hours	As part of routine care, the bedside nurse will record the administration of all sedative agents. The hourly, daily and cumulative doses of agents will be determined by the sum of as needed doses, scheduled intermittent doses, and hourly infusion rates. All conventional therapies will be guided by the institution-specific, symptom-triggered alcohol withdrawal protocol to maintain CIWA scores ≤ 7. Intravenous lorazepam is the preferred benzodiazepine for management of alcohol withdrawal in the medical ICU. Phenobarbital and propofol are infrequently used and they are not included in the protocol. All benzodiazepine and barbiturate doses, whether oral or intravenous, will be converted to lorazepam equivalents using the following conversion: 1 mg lorazepam = 2 mg midazolam = 7.5 mg clorazepate = 15 mg phenobarbital.
Cumulative Lorazepam Dose Over the 72 Hours of Alcohol Withdrawal	72 hours	As part of routine care, the bedside nurse will record the administration of all sedative agents. The hourly, daily and cumulative doses of agents will be determined by the sum of as needed doses, scheduled intermittent doses, and hourly infusion rates. All conventional therapies will be guided by the institution-specific, symptom-triggered alcohol withdrawal protocol to maintain CIWA scores ≤ 7. Intravenous lorazepam is the preferred benzodiazepine for management of alcohol withdrawal in the medical ICU. Phenobarbital and propofol are infrequently used and they are not included in the protocol. All benzodiazepine and barbiturate doses, whether oral or intravenous, will be converted to lorazepam equivalents using the following conversion: 1 mg lorazepam = 2 mg midazolam = 7.5 mg clorazepate = 15 mg phenobarbital.

Secondary Outcome Measures

Name	Time	Method
Plasma Epinephrine Concentrations Across Groups Over Time	96 hours	Plasma epinephrine concentrations will be assessed prior to study drug and at times 24, 48, 72 and 96 hours after initiating study drug
Change in 12-Hour Lorazepam Requirement Pre- and Post-Treatment	12 hours before treatment, 12 hours after treatment on first day of starting study drug	As part of routine care, the bedside nurse will record the administration of all sedative agents. The hourly, daily and cumulative doses of agents will be determined by the sum of as needed doses, scheduled intermittent doses, and hourly infusion rates. All conventional therapies will be guided by the institution-specific, symptom-triggered alcohol withdrawal protocol to maintain CIWA scores ≤ 7. Intravenous lorazepam is the preferred benzodiazepine for management of alcohol withdrawal in the medical ICU. Phenobarbital and propofol are infrequently used and they are not included in the protocol. All benzodiazepine and barbiturate doses, whether oral or intravenous, will be converted to lorazepam equivalents using the following conversion: 1 mg lorazepam = 2 mg midazolam = 7.5 mg clorazepate = 15 mg phenobarbital.
Change in 24-Hour Lorazepam Requirement Pre- and Post-Treatment	24 hours before treatment, 24 hours after treatment on first day of starting study drug	As part of routine care, the bedside nurse will record the administration of all sedative agents. The hourly, daily and cumulative doses of agents will be determined by the sum of as needed doses, scheduled intermittent doses, and hourly infusion rates. All conventional therapies will be guided by the institution-specific, symptom-triggered alcohol withdrawal protocol to maintain CIWA scores ≤ 7. Intravenous lorazepam is the preferred benzodiazepine for management of alcohol withdrawal in the medical ICU. Phenobarbital and propofol are infrequently used and they are not included in the protocol. All benzodiazepine and barbiturate doses, whether oral or intravenous, will be converted to lorazepam equivalents using the following conversion: 1 mg lorazepam = 2 mg midazolam = 7.5 mg clorazepate = 15 mg phenobarbital.
The Degree of Alcohol Withdrawal Assessed by Clinical Institute Withdrawal Assessment (CIWA) Scores	72 hours	CIWA scores will be assessed hourly by the bedside nurse. The proportion of CIWA scores ≥ 15 (severe withdrawal symptoms), 8 - 14 (moderate withdrawal symptoms), and ≤ 7 (minimal withdrawal symptoms) will be determined.
The Occurrence of Adverse Events: hypotension, hypertension, bradycardia, tachycardia	72 hours	Blood pressure and heart rate will be assessed hourly by the bedside nurse. Hypotension will be defined as a systolic blood pressure ≤ 90 mmHg or a decrease of systolic blood pressure of 40 mmHg, hypertension will be defined as a systolic blood pressure ≥ 180 mmHg or an increase of systolic blood pressure of 40 mmHg, bradycardia will be defined as a heart rate ≤ 55 beats/minute or a decrease of 20 beats/minutes, and tachycardia will be defined as a heart rate ≥ 120 beats/minute or an increase of 20 beats/minutes. Highest and lowest daily measurements of each will also be collected.

Trial Locations

Locations (1)

University of Colorado Hospital; 🇺🇸 Aurora, Colorado, United States