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The University of New Mexico Health Science Center. Alcohol Withdrawal Therapeutic Interventions. Lenka H ř eb íč kov á , Pharm.D. ICU/ER Clinical Pharmacist III. The University of New Mexico Health Science Center. Therapeutic Goals. Over-treatment vs. under-treatment Control agitation

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Alcohol withdrawal therapeutic interventions

The University of New Mexico Health Science Center

Alcohol WithdrawalTherapeutic Interventions

Lenka Hřebíčková, Pharm.D.

ICU/ER Clinical Pharmacist III


Therapeutic goals

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


Therapeutic options

The University of New Mexico Health Science Center

Therapeutic Options

  • Benzodiazepines

  • Phenobarbital

  • Propofol

  • Dexmedetomidine

Crit Care Med 2010 Vol. 38, No.9


Benzodiazepines

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;160:649-655


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



Assessment recommendation

The University of New Mexico Health Science Center

Not intubated and responsive:

CIWA-Ar

Intubated and non-responsive:

Sedation scale (Riker, etc.)

Delirium assessment (CAM-ICU, ICDSC)

Assessment Recommendation


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;162:1117-1121.

      • Saitz R, et al: Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial. JAMA 1994; 272:519-523

    • 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; 29:2230-2238


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;162:1117-1121

    • 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)


Benzodiazepines symptom triggered approach in non icu patients1

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)


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;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


Benzodiazepines symptom triggered approach in icu1

The University of New Mexico Health Science Center

Benzodiazepines: Symptom-Triggered Approach in ICU

Spies CD, et al. Intensive Care Med 2003;29: 2230-38.


Phenobarbital

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


Propofol

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


Dexmedetomidine

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.


Alcohol withdrawal therapeutic interventions

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