Acute Alcohol Withdrawal
Conditions
Brief summary
This study is designed to evaluate dexmedetomidine as adjunctive therapy of severe alcohol withdrawal of medical ICU patients. Specifically, this study will assess whether adjunctive dexmedetomidine reduces the doses of conventional agents used for alcohol withdrawal while maintaining patient comfort and safety and will explore if dexmedetomidine exhibits a dose-dependent profile of action when it is used for this indication. In addition, this study will assess the relationships between alcohol withdrawal, therapy with dexmedetomidine, and potential serum biomarkers of alcohol withdrawal.
Detailed description
The objectives of this randomized, double-blind, placebo controlled, dose escalation study are a) to determine if adding dexmedetomidine to symptom-triggered, standard therapy of severe alcohol withdrawal reduces the dose requirements of conventional sedatives, analgesics, and neuroleptics; maintains patient comfort and safety; and prevents and shortens tracheal intubation; b) to explore whether dexmedetomidine acts in a dose-dependent manner to reduce the dose requirements of conventional sedatives, analgesics, and neuroleptics while maintaining patient comfort; and c) determine the association between alcohol withdrawal and potential serum biomarkers of alcohol withdrawal and assess whether these are expressed differently when dexmedetomidine is used as adjunctive therapy. Dexmedetomidine will be added to existing sedative therapies in an effort to decrease the use of these agents while maintaining patient comfort. The study will randomize twenty-four patients in a double-blind manner to receive placebo or dexmedetomidine at doses of 0.4 or 1.2 µg/kg per hour for a maximum duration of five days. All patients will be managed using an existing institution-specific, symptom-triggered alcohol withdrawal protocol.
Interventions
DRUGDexmedetomidine
Dexmedetomidine at 0.4 or 1.2 µg/kg per hour is administered for a maximum duration of five days
OTHERPlacebo
Normal saline for five days.
Sponsors
Hospira, now a wholly owned subsidiary of Pfizer
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Severe alcohol withdrawal defined by a CIWA score ≥ 15 and the need for at least 16 mg of lorazepam over a four-hour period. All lorazepam doses, whether oral or intravenous, will contribute to the cumulative amount. 2. Patients receiving standard therapy for severe alcohol withdrawal according to a symptom-triggered alcohol withdrawal protocol. 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.
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). 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. Moribund state with planned withdrawal of life support. 8. Patients with known or suspected severe adverse reactions to dexmedetomidine (or clonidine). 9. Pregnant females or females suspected of being pregnant
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Cumulative Lorazepam Dose Over the First Seven Days of Alcohol Withdrawal | Seven days |
| 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 |
| 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Study Drug Administration | The duration of study drug in hours as measured when the subject was discharged from the ICU, for up to 24 weeks | — |
| The Degree of Alcohol Withdrawal Assessed by Clinical Institute Withdrawal Assessment (CIWA) Scores | Every 2-4 hours for 24 hours after starting study drug | Proportion of clinical institute withdrawal assessment (CIWA) Scores listed as severe or moderate 24 Hours after Starting Study Drug. All subjects had at least four CIWA assessments.The CIWA is a ten item scale with each item on the scale scored independently on a 0-7 or 0-4 scale, and the summation of the scores yielding an aggregate value that correlates to the severity of alcohol withdrawal. Ranges of scores are from 0 to 67. Mild alcohol withdrawal is defined with a score less than or equal to 15, moderate with scores of 16 to 20, and severe with any score greater than 20. The ten items evaluated include nausea and vomiting, tremor, sweats, anxiety, agitation, tactile disturbances, auditory disturbances, visual disturbances, headache, and orientation. |
| ICU Length of Stay | The duration of ICU stay in days as measured at time of hospital discharge, for up to 24 weeks | — |
| The Occurrence of Adverse Events. | Seven days | Occurrence of hypotension or bradycardia while on study drug |
| Plasma Epinephrine Concentrations Across Groups Over Time | Four days with samples measured prior to study drug and 48 and 96 hours after starting study drug | Plasma epinephrine concentrations |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dexmedetomidine, Low Dose Dexmedetomidine 0.4 µg/kg per hour administered for a maximum duration of five days
Dexmedetomidine: Dexmedetomidine at 0.4 or 1.2 µg/kg per hour is administered for a maximum duration of five days | 8 |
| Dexmedetomidine, High Dose Dexmedetomidine 1.2 µg/kg per hour administered for a maximum duration of five days
Dexmedetomidine: Dexmedetomidine at 0.4 or 1.2 µg/kg per hour is administered for a maximum duration of five days | 8 |
| Placebo Normal saline
Placebo: Normal saline for five days. | 8 |
| Total | 24 |
Baseline characteristics
| Characteristic | Dexmedetomidine, Low Dose | Total | Placebo | Dexmedetomidine, High Dose |
|---|---|---|---|---|
| Acute Physiologic And Chronic Health Evaluation (APACHE) III | 69.5 units on a scale | 58.5 units on a scale | 49.5 units on a scale | 56.5 units on a scale |
| Age, Continuous | 47 years | 49.3 years | 51 years | 50 years |
| Child-Pugh Score | 7 units on a scale | 6.3 units on a scale | 6 units on a scale | 6 units on a scale |
| Endotracheal Intubation at Study Entry Intubated | 5 participants | 13 participants | 5 participants | 3 participants |
| Endotracheal Intubation at Study Entry Not intubated | 3 participants | 11 participants | 3 participants | 5 participants |
| Lorazepam requirement 24 Hour Prior to Study Entry | 94 mg | 69.3 mg | 39 mg | 75 mg |
| Race/Ethnicity, Customized Caucasian | 5 participants | 16 participants | 4 participants | 7 participants |
| Race/Ethnicity, Customized Other | 3 participants | 8 participants | 4 participants | 1 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 8 Participants | 22 Participants | 7 Participants | 7 Participants |
| Time from Study Qualification to Study Drug Start | 17.1 hours | 14 hours | 10.4 hours | 13.5 hours |
| Weight | 87.1 kg | 84.4 kg | 81.5 kg | 84.5 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 8 | 3 / 8 | 2 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Change in 12-Hour Lorazepam Requirement Pre- and Post-Treatment
Time frame: 12 hours before treatment, 12 hours after treatment on first day of starting study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dexmedetomidine, Low Dose | Change in 12-Hour Lorazepam Requirement Pre- and Post-Treatment | -42.5 mg |
| Dexmedetomidine, High Dose | Change in 12-Hour Lorazepam Requirement Pre- and Post-Treatment | -34.3 mg |
| Placebo | Change in 12-Hour Lorazepam Requirement Pre- and Post-Treatment | -17.5 mg |
p-value: 0.05Wilcoxon (Mann-Whitney)
p-value: 0.05Wilcoxon (Mann-Whitney)
Primary
Change in 24-Hour Lorazepam Requirement Pre- and Post-Treatment
Time frame: 24 hours before treatment, 24 hours after treatment on first day of starting study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dexmedetomidine, Low Dose | Change in 24-Hour Lorazepam Requirement Pre- and Post-Treatment | -62.1 mg |
| Dexmedetomidine, High Dose | Change in 24-Hour Lorazepam Requirement Pre- and Post-Treatment | -45 mg |
| Placebo | Change in 24-Hour Lorazepam Requirement Pre- and Post-Treatment | -8 mg |
p-value: 0.066Wilcoxon (Mann-Whitney)
p-value: 0.27Wilcoxon (Mann-Whitney)
Primary
Cumulative Lorazepam Dose Over the First Seven Days of Alcohol Withdrawal
Time frame: Seven days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dexmedetomidine, Low Dose | Cumulative Lorazepam Dose Over the First Seven Days of Alcohol Withdrawal | 180.5 mg |
| Dexmedetomidine, High Dose | Cumulative Lorazepam Dose Over the First Seven Days of Alcohol Withdrawal | 112.5 mg |
| Placebo | Cumulative Lorazepam Dose Over the First Seven Days of Alcohol Withdrawal | 109.1 mg |
p-value: 0.64Wilcoxon (Mann-Whitney)
p-value: 0.27Wilcoxon (Mann-Whitney)
Secondary
Duration of Study Drug Administration
Time frame: The duration of study drug in hours as measured when the subject was discharged from the ICU, for up to 24 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dexmedetomidine, Low Dose | Duration of Study Drug Administration | 53.1 hours |
| Dexmedetomidine, High Dose | Duration of Study Drug Administration | 78 hours |
| Placebo | Duration of Study Drug Administration | 70.3 hours |
p-value: 0.5Wilcoxon (Mann-Whitney)
p-value: 0.95Wilcoxon (Mann-Whitney)
Secondary
ICU Length of Stay
Time frame: The duration of ICU stay in days as measured at time of hospital discharge, for up to 24 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dexmedetomidine, Low Dose | ICU Length of Stay | 5.5 days |
| Dexmedetomidine, High Dose | ICU Length of Stay | 3.8 days |
| Placebo | ICU Length of Stay | 4 days |
p-value: 0.43Wilcoxon (Mann-Whitney)
p-value: 0.64Wilcoxon (Mann-Whitney)
Secondary
Plasma Epinephrine Concentrations Across Groups Over Time
Plasma epinephrine concentrations
Time frame: Four days with samples measured prior to study drug and 48 and 96 hours after starting study drug
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dexmedetomidine, Low Dose | Plasma Epinephrine Concentrations Across Groups Over Time | Baseline | 0.27 ng/mL | Standard Deviation 0.17 |
| Dexmedetomidine, Low Dose | Plasma Epinephrine Concentrations Across Groups Over Time | Time 96 hours | 0.26 ng/mL | Standard Deviation 0.33 |
| Dexmedetomidine, Low Dose | Plasma Epinephrine Concentrations Across Groups Over Time | Time 48 hours | 0.27 ng/mL | Standard Deviation 0.47 |
| Dexmedetomidine, High Dose | Plasma Epinephrine Concentrations Across Groups Over Time | Time 96 hours | 0.27 ng/mL | Standard Deviation 0.17 |
| Dexmedetomidine, High Dose | Plasma Epinephrine Concentrations Across Groups Over Time | Time 48 hours | 0.21 ng/mL | Standard Deviation 0.09 |
| Dexmedetomidine, High Dose | Plasma Epinephrine Concentrations Across Groups Over Time | Baseline | 0.29 ng/mL | Standard Deviation 0.1 |
| Placebo | Plasma Epinephrine Concentrations Across Groups Over Time | Time 96 hours | 0.3 ng/mL | Standard Deviation 0.04 |
| Placebo | Plasma Epinephrine Concentrations Across Groups Over Time | Baseline | 0.31 ng/mL | Standard Deviation 0.25 |
| Placebo | Plasma Epinephrine Concentrations Across Groups Over Time | Time 48 hours | 0.27 ng/mL | Standard Deviation 0.17 |
p-value: <0.05Repeated measures ANOVA
Secondary
The Degree of Alcohol Withdrawal Assessed by Clinical Institute Withdrawal Assessment (CIWA) Scores
Proportion of clinical institute withdrawal assessment (CIWA) Scores listed as severe or moderate 24 Hours after Starting Study Drug. All subjects had at least four CIWA assessments.The CIWA is a ten item scale with each item on the scale scored independently on a 0-7 or 0-4 scale, and the summation of the scores yielding an aggregate value that correlates to the severity of alcohol withdrawal. Ranges of scores are from 0 to 67. Mild alcohol withdrawal is defined with a score less than or equal to 15, moderate with scores of 16 to 20, and severe with any score greater than 20. The ten items evaluated include nausea and vomiting, tremor, sweats, anxiety, agitation, tactile disturbances, auditory disturbances, visual disturbances, headache, and orientation.
Time frame: Every 2-4 hours for 24 hours after starting study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dexmedetomidine, Low Dose | The Degree of Alcohol Withdrawal Assessed by Clinical Institute Withdrawal Assessment (CIWA) Scores | moderate | 31 percentage of ciwa assessment |
| Dexmedetomidine, Low Dose | The Degree of Alcohol Withdrawal Assessed by Clinical Institute Withdrawal Assessment (CIWA) Scores | severe | 11 percentage of ciwa assessment |
| Dexmedetomidine, High Dose | The Degree of Alcohol Withdrawal Assessed by Clinical Institute Withdrawal Assessment (CIWA) Scores | severe | 15 percentage of ciwa assessment |
| Dexmedetomidine, High Dose | The Degree of Alcohol Withdrawal Assessed by Clinical Institute Withdrawal Assessment (CIWA) Scores | moderate | 24 percentage of ciwa assessment |
| Placebo | The Degree of Alcohol Withdrawal Assessed by Clinical Institute Withdrawal Assessment (CIWA) Scores | severe | 25 percentage of ciwa assessment |
| Placebo | The Degree of Alcohol Withdrawal Assessed by Clinical Institute Withdrawal Assessment (CIWA) Scores | moderate | 22 percentage of ciwa assessment |
Comparison: Percentage of CIWA scores rates as severep-value: 0.18Chi-squared, Corrected
p-value: 0.35Chi-squared, Corrected
Secondary
The Occurrence of Adverse Events.
Occurrence of hypotension or bradycardia while on study drug
Time frame: Seven days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dexmedetomidine, Low Dose | The Occurrence of Adverse Events. | Hypotension | 1 participants |
| Dexmedetomidine, Low Dose | The Occurrence of Adverse Events. | Bradycardia | 1 participants |
| Dexmedetomidine, High Dose | The Occurrence of Adverse Events. | Hypotension | 2 participants |
| Dexmedetomidine, High Dose | The Occurrence of Adverse Events. | Bradycardia | 3 participants |
| Placebo | The Occurrence of Adverse Events. | Hypotension | 0 participants |
| Placebo | The Occurrence of Adverse Events. | Bradycardia | 0 participants |
Comparison: For hypotensionp-value: 1Fisher Exact
Comparison: For hypotensionp-value: 0.47Fisher Exact
Comparison: For bradycardiap-value: 1Fisher Exact
Comparison: For bradycardiap-value: 0.2Fisher Exact