1. Alcohol Withdrawal Therapeutic Interventions
The University of New Mexico Health Science Center
Alcohol Withdrawal Therapeutic Interventions
Lenka Hřebíčková, Pharm.D.
ICU/ER Clinical Pharmacist III

2. The University of New Mexico Health Science Center
Therapeutic Goals
Over-treatment vs. under-treatment
Control agitation
Light somnolence
Amount of medication required vary from patient to patient
Taper to prevent the emergence of breakthrough symptoms and withdrawal seizures
Prevent complications

3. The University of New Mexico Health Science Center
Therapeutic Options
Benzodiazepines
Phenobarbital
Propofol
Dexmedetomidine
Crit Care Med 2010 Vol. 38, No.9

4. The University of New Mexico Health Science Center
Benzodiazepines
1st line agents
Better efficacy, good margin of safety, lower potential of abuse
No specific benzodiazepine is recommended for use
Selection of agent based on kinetic parameters, potential for abuse, cost
MCH:
GABA agonist
Increases the frequency of GABA chloride channel opening – alcohol replacement
Crit Care Med 2010 Vol. 38, No.9
CMAJ. 1999;160:

5. Benzodiazepines – Which One?
The University of New Mexico Health Science Center
Benzodiazepines – Which One?
Duration of activity
Long: prevent breakthrough
Short: elderly, hepatic or renal disease
Pharmacokinetics
Absorption:
Affects time to onset
Distribution
Lipophillicity
Metabolism
Oxidation (CYP P450 system) vs. conjugation, active metabolites
Elimination

6. Benzodiazepines Comparison
The University of New Mexico Health Science Center
Benzodiazepines Comparison
Medication (action)
Onset of action
Dose Equivalent (mg)
Average Half Life (Hr) in Healthy patient
Active Metabolite and Metabolism
Chlordiazepoxide (long)
Oral
1-2 hrs 25
6.6-25
Yes (Desmethyldiazepam)
CYP3A4
Diazepam (long)
Oral, IV, rectal
Almost immediate 5
20-50
Yes
(Desmethyldiazepam)
Lorazapam (short)
Oral, IV, IM
5-20 minutes
0.75-1
10.5 No
Glucuronide conjugation
Oxazepam (short) 15

7. Assessment Recommendation
The University of New Mexico Health Science Center
Assessment Recommendation
Intubated and non-responsive:
Sedation scale (Riker, etc.)
Delirium assessment (CAM-ICU, ICDSC)
Not intubated and responsive:
CIWA-Ar

8. Benzodiazepines: Optimal Regimen
The University of New Mexico Health Science Center
Benzodiazepines: Optimal Regimen
Dosing is variable (various protocols)
Symptom-triggered vs. fixed-schedule
Two studies in general population:
Daeppen JB, et al: Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: A randomized treatment trial. Arch Intern Med 2002;162:
Saitz R, et al: Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial. JAMA 1994; 272:
One study in ICU:
Spies CD, et al: Alcohol withdrawal severity is decreased by symptom-oriented adjusted bolus therapy in the ICU. Intensive Care Med 2003; 29:

9. Benzodiazepines: Symptom-Triggered Approach in Non-ICU Patients
The University of New Mexico Health Science Center
Benzodiazepines: Symptom-Triggered Approach in Non-ICU Patients
Daeppen JB, et al: Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: A randomized treatment trial. Arch Intern Med 2002;162:
Prospective, randomized, double-blinded controlled trial
117 patients admitted to alcohol treatment inpatient program at Lausanne and Geneva university hospitals in Switzerland
Fixed schedule: oxazepam 30 mg PO Q6H for 4 doses, then 15 mg PO Q6H for 8 doses and PRN oxazepam
Symptom triggered: placebo 30 mg PO Q6H x 4 doses, then placebo 15 mg PO Q6H for 8 doses, CIWA-Ar score > 8 – 15 received 15 mg of oxazepam, CIWA-Ar score > 15 received 30 mg oxazepam; Q30min
Results:
Similar demographics between groups
Only 22 (39%) patients in ST group were treated with oxazepam vs. 100% in FS group (p < 0.001)
Mean oxazepam dose: 37.5 mg ST vs mg FS (p < 0.001)
Mean duration of treatment: 20 hr ST vs hr FS (p < 0.001)

10. Benzodiazepines: Symptom-Triggered Approach in Non-ICU Patients
The University of New Mexico Health Science Center
Benzodiazepines: Symptom-Triggered Approach in Non-ICU Patients
Saitz R, et al: Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial. JAMA 1994; 272:
Chlordiazepoxide QID with PRN medications (FS; Fixed-Schedule) vs. chlordiazepoxide PRN (ST; Symptom-Triggered)
Randomized double-blind, controlled trial
Inpatient detoxification unit in a Veterans Affairs
111 eligible patients
Results:
Similar demographics
Total chlordiazepoxide doses: 100 mg ST vs. 425 mg FS (p < 0.001)
Mean duration of treatment: 9 hr ST vs. 68 hr FS (p < 0.001)

11. Benzodiazepines: Symptom-Triggered Approach in ICU
The University of New Mexico Health Science Center
Benzodiazepines: Symptom-Triggered Approach in ICU
Spies CD, et al. Intensive Care Med 2003:29;
Flunitrazepam (infusion) + clonidine + haloperidol vs. flunitrazepam (PRN) + clonidine (PRN) + haloperidol (PRN)
Prospective, randomized, controlled trial
Surgical ICU patients
Inclusion: non-intubated, CIWA-Ar > 20
Notable exclusion: concurrent acute medical illness (hypoxia, infection)
Both groups titrated to CIWA-Ar score

12. Benzodiazepines: Symptom-Triggered Approach in ICU
The University of New Mexico Health Science Center
Benzodiazepines: Symptom-Triggered Approach in ICU
Sample
44 patients
No differences at baseline
Mechanical Ventilation
34 of 44 patients (65%)
ICU stays
Bolus: 8 (5-10) days
Infusion: 14 (7-24) days, p < 0.01
Pneumonia
Bolus: 9/23 (39%)
Infusion: 15/21 (71%), p < 0.01
Spies CD, et al. Intensive Care Med 2003;29:

13. The University of New Mexico Health Science Center
Phenobarbital
Used if benzodiazepine-resistance
Doses of diazepam > 40 mg/1hr
Down-regulation of GABA receptors
Higher rates of intubation, longer ICU stay
Phenobarbital augment benzodiazepines at GABA and inhibits stimulatory glutamate receptors
Gold JA, et al: Crit Care Med 2007;35:724-30
Retrospective cohort study
Subjects admitted to the medical ICU with severe alcohol withdrawal
Symptom-triggered treatment: diazepam 10 mg IV up to mg, then phenobarbital mg IV + diazepam IV, then propofol
Results:
Need for mechanical ventilation: Pre 47% and Post 22%
Among patients requiring MV, less DZP administered in first 24 hrs 120 mg vs. 280 mg, p = 0.01
High doses of benzodiazepines in some subjects is necessary

14. The University of New Mexico Health Science Center
Propofol
Recommended in patients uncontrolled with larger benzodiazepine doses
Activates GABAa receptor and blocks stimulatory NMDA receptor
Case reports and series
Concerns: hypertriglyceridemia, pancreatitis, propofol-related infusion syndrome

15. The University of New Mexico Health Science Center
Dexmedetomidine
Centrally acting alpha-2 receptor agonist
Mediate hyper-adrenergic response
Only patient case reports
Predominately severe alcohol withdrawal
No phenobarbital or propofol used
Alleviates ethanol withdrawal in rats (rigidity, tremor, and irritability)
Adjunct therapy to benzodiazepines
Neuroprotective?
Role?
Expensive
Rovasalo A, et al. General Hospital Psychiatry 28 (2006)
Darrouj J, et al: Ann Pharmacother 2008; 42:

16. UNMH Alcohol Withdrawal Protocol
The University of New Mexico Health Science Center
UNMH Alcohol Withdrawal Protocol
Based on and adapted from alcohol withdrawal protocol at Bayfront Medical Center
CriticalCareNurse Vol 30, No. 3, June 2010