Slide 2 Alcohol Withdrawal Therapeutic Interventions Lenka
Hebkov, Pharm.D. ICU/ER Clinical Pharmacist III The University of
New Mexico Health Science Center Slide 3 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 Slide 4 The University of
New Mexico Health Science Center Therapeutic Options
Benzodiazepines Phenobarbital Propofol Dexmedetomidine Crit Care
Med 2010 Vol. 38, No.9 Slide 5 The University of New Mexico Health
Science Center Benzodiazepines 1 st 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;160:649-655
Slide 6 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 Slide 7 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 hrs256.6-25Yes (Desmethyldiaz
epam) CYP3A4 Diazepam (long) Oral, IV, rectal Almost immediate
520-50Yes (Desmethyldiaz epam) CYP3A4 Lorazapam (short) Oral, IV,
IM 5-20 minutes0.75-110.5No Glucuronide conjugation Oxazepam
(short) Oral 1-2 hrs152.8-8.6No Glucuronide conjugation Slide 8 The
University of New Mexico Health Science Center Assessment
Recommendation Not intubated and responsive: CIWA-Ar Intubated and
non- responsive: Sedation scale (Riker, etc.) Delirium assessment
(CAM-ICU, ICDSC) Slide 9 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: 1.Daeppen JB, et al:
Symptom-triggered vs fixed-schedule doses of benzodiazepine for
alcohol withdrawal: A randomized treatment trial. Arch Intern Med
2002;162:1117-1121. 2.Saitz R, et al: Individualized treatment for
alcohol withdrawal. A randomized double-blind controlled trial.
JAMA 1994; 272:519- 523 One study in ICU: 1.Spies CD, et al:
Alcohol withdrawal severity is decreased by symptom-oriented
adjusted bolus therapy in the ICU. Intensive Care Med 2003;
29:2230-2238 Slide 10 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;162:1117-1121 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. 231.4 mg FS (p <
0.001) Mean duration of treatment: 20 hr ST vs. 62.7 hr FS (p <
0.001) Slide 11 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; 272:519-523
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) Slide 12 The University of New Mexico Health Science
Center Benzodiazepines: Symptom-Triggered Approach in ICU Spies CD,
et al. Intensive Care Med 2003:29;2230-2238. 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 Slide 13
The University of New Mexico Health Science Center Benzodiazepines:
Symptom-Triggered Approach in ICU Sample44 patients No differences
at baseline Mechanical Ventilation 34 of 44 patients (65%) ICU
staysBolus: 8 (5-10) days Infusion: 14 (7-24) days, p < 0.01
PneumoniaBolus: 9/23 (39%) Infusion: 15/21 (71%), p < 0.01 Spies
CD, et al. Intensive Care Med 2003;29: 2230-38. Slide 14 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 100-150 mg, then phenobarbital
65-260 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 Slide 15 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 Slide 16 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) 362-363 Darrouj J, et al: Ann
Pharmacother 2008; 42:1703-1705. Slide 17 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
