Empirically Appropriate Antibiotic Therapy for Hospitalized Patients

Alcohol WithdrawalTherapeutic InterventionsLenka Hebkov, Pharm.D.ICU/ER Clinical Pharmacist IIIThe University of New Mexico Health Science Center

The University of New Mexico Health Science CenterTherapeutic GoalsOver-treatment vs. under-treatmentControl agitationLight somnolenceAmount of medication required vary from patient to patientTaper to prevent the emergence of breakthrough symptoms and withdrawal seizuresPrevent complications

2The University of New Mexico Health Science CenterTherapeutic OptionsBenzodiazepinesPhenobarbitalPropofolDexmedetomidineCrit Care Med 2010 Vol. 38, No.9

3The University of New Mexico Health Science CenterBenzodiazepines1st line agents Better efficacy, good margin of safety, lower potential of abuse No specific benzodiazepine is recommended for useSelection of agent based on kinetic parameters, potential for abuse, costMCH: GABA agonist Increases the frequency of GABA chloride channel opening alcohol replacement

Crit Care Med 2010 Vol. 38, No.9CMAJ. 1999;160:649-655

4The University of New Mexico Health Science CenterBenzodiazepines Which One?Duration of activityLong: prevent breakthroughShort: elderly, hepatic or renal diseasePharmacokineticsAbsorption:Affects time to onsetDistributionLipophillicityMetabolismOxidation (CYP P450 system) vs. conjugation, active metabolitesElimination

5The University of New Mexico Health Science CenterBenzodiazepines ComparisonMedication (action)Onset of actionDose Equivalent (mg)Average Half Life (Hr) in Healthy patient

Active Metabolite and MetabolismChlordiazepoxide (long)Oral1-2 hrs256.6-25Yes (Desmethyldiazepam)CYP3A4Diazepam (long)Oral, IV, rectalAlmost immediate520-50Yes(Desmethyldiazepam)CYP3A4Lorazapam (short)Oral, IV, IM5-20 minutes0.75-110.5NoGlucuronide conjugationOxazepam (short)Oral1-2 hrs152.8-8.6NoGlucuronide conjugation

6The University of New Mexico Health Science CenterAssessment RecommendationNot intubated and responsive:CIWA-ArIntubated and non-responsive:Sedation scale (Riker, etc.)Delirium assessment (CAM-ICU, ICDSC)

7The University of New Mexico Health Science CenterBenzodiazepines: Optimal RegimenDosing is variable (various protocols)Symptom-triggered vs. fixed-scheduleTwo 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; 272:519-523One 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

8The University of New Mexico Health Science CenterBenzodiazepines: Symptom-Triggered Approach in Non-ICU PatientsDaeppen JB, et al: Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: A randomized treatment trial. Arch Intern Med 2002;162:1117-1121Prospective, randomized, double-blinded controlled trial117 patients admitted to alcohol treatment inpatient program at Lausanne and Geneva university hospitals in SwitzerlandFixed schedule: oxazepam 30 mg PO Q6H for 4 doses, then 15 mg PO Q6H for 8 doses and PRN oxazepamSymptom 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; Q30minResults:Similar demographics between groupsOnly 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)

9The University of New Mexico Health Science CenterBenzodiazepines: Symptom-Triggered Approach in Non-ICU PatientsSaitz R, et al: Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial. JAMA 1994; 272:519-523Chlordiazepoxide QID with PRN medications (FS; Fixed-Schedule) vs. chlordiazepoxide PRN (ST; Symptom-Triggered)Randomized double-blind, controlled trialInpatient detoxification unit in a Veterans Affairs111 eligible patientsResults:Similar demographicsTotal 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)

10The University of New Mexico Health Science CenterBenzodiazepines: Symptom-Triggered Approach in ICUSpies CD, et al. Intensive Care Med 2003:29;2230-2238.Flunitrazepam (infusion) + clonidine + haloperidol vs. flunitrazepam (PRN) + clonidine (PRN) + haloperidol (PRN)Prospective, randomized, controlled trialSurgical ICU patientsInclusion: non-intubated, CIWA-Ar > 20Notable exclusion: concurrent acute medical illness (hypoxia, infection)Both groups titrated to CIWA-Ar score

11The University of New Mexico Health Science CenterBenzodiazepines: Symptom-Triggered Approach in ICUSample44 patientsNo differences at baselineMechanical Ventilation34 of 44 patients (65%)ICU staysBolus: 8 (5-10) daysInfusion: 14 (7-24) days, p < 0.01PneumoniaBolus: 9/23 (39%)Infusion: 15/21 (71%), p < 0.01Spies CD, et al. Intensive Care Med 2003;29: 2230-38.

12The University of New Mexico Health Science CenterPhenobarbitalUsed if benzodiazepine-resistanceDoses of diazepam > 40 mg/1hrDown-regulation of GABA receptorsHigher rates of intubation, longer ICU stayPhenobarbital augment benzodiazepines at GABA and inhibits stimulatory glutamate receptorsGold JA, et al: Crit Care Med 2007;35:724-30Retrospective cohort studySubjects admitted to the medical ICU with severe alcohol withdrawalSymptom-triggered treatment: diazepam 10 mg IV up to 100-150 mg, then phenobarbital 65-260 mg IV + diazepam IV, then propofolResults: 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 = 0.01High doses of benzodiazepines in some subjects is necessary

13The University of New Mexico Health Science CenterPropofolRecommended in patients uncontrolled with larger benzodiazepine dosesActivates GABAa receptor and blocks stimulatory NMDA receptorCase reports and seriesConcerns: hypertriglyceridemia, pancreatitis, propofol-related infusion syndrome

14The University of New Mexico Health Science CenterDexmedetomidineCentrally acting alpha-2 receptor agonistMediate hyper-adrenergic responseOnly patient case reports Predominately severe alcohol withdrawalNo phenobarbital or propofol usedAlleviates ethanol withdrawal in rats (rigidity, tremor, and irritability)Adjunct therapy to benzodiazepinesNeuroprotective?Role? Expensive

Rovasalo A, et al. General Hospital Psychiatry 28 (2006) 362-363Darrouj J, et al: Ann Pharmacother 2008; 42:1703-1705.

15The University of New Mexico Health Science CenterUNMH Alcohol Withdrawal Protocol

Based on and adapted from alcohol withdrawal protocol at Bayfront Medical CenterCriticalCareNurse Vol 30, No. 3, June 2010

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