Transcript Empirically Appropriate Antibiotic Therapy for

The University of New Mexico Health Science Center
Alcohol Withdrawal
Therapeutic Interventions
Lenka Hřebíčková, Pharm.D.
ICU/ER Clinical Pharmacist III
The University of New Mexico Health Science Center
Therapeutic Goals
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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
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Therapeutic Options
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Benzodiazepines
Phenobarbital
Propofol
Dexmedetomidine
Crit Care Med 2010 Vol. 38, No.9
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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;160:649-655
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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
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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
(Desmethyldiaz
epam)
CYP3A4
Diazepam (long)
Oral, IV, rectal
Almost
immediate
5
20-50
Yes
(Desmethyldiaz
epam)
CYP3A4
Lorazapam (short)
Oral, IV, IM
5-20 minutes
0.75-1
10.5
No
Glucuronide
conjugation
Oxazepam (short)
Oral
1-2 hrs
15
2.8-8.6
No
Glucuronide
conjugation
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Assessment Recommendation
Not intubated and
responsive:
• CIWA-Ar
Intubated and nonresponsive:
• Sedation scale (Riker,
etc.)
• Delirium assessment
(CAM-ICU, ICDSC)
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Benzodiazepines: Optimal Regimen
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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; 272:519523
– 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
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Benzodiazepines: Symptom-Triggered Approach
in Non-ICU Patients
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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
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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:
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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)
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Benzodiazepines: Symptom-Triggered
Approach in Non-ICU Patients
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Saitz R, et al: Individualized treatment for alcohol
withdrawal. A randomized double-blind controlled trial.
JAMA 1994; 272:519-523
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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:
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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)
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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)
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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
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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: 2230-38.
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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
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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
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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?
Rovasalo A, et al. General Hospital Psychiatry 28 (2006) 362-363
• Expensive
.
Darrouj J, et al: Ann Pharmacother 2008; 42:1703-1705
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UNMH Alcohol Withdrawal Protocol
Based on and adapted from alcohol withdrawal
protocol at Bayfront Medical Center
CriticalCareNurse Vol 30, No. 3, June 2010