Ketamine vs. Placebo as Adjunctive Therapies for Severe Alcohol Withdrawal

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.

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.

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.