What’s on Tap for the Treatment of Alcohol Withdrawal? Andrew Straznitskas, PharmD, BCPS Clinical...

What’s on Tap for the Treatment of Alcohol

Withdrawal?Andrew Straznitskas, PharmD, BCPS

Clinical Pharmacist, Medical Intensive Care UnitBellevue Hospital Center

NYSCHP 2015 Critical Care Program: Downstate October 2, 2015

Disclosure

• The presenter has no conflicts of interest to disclose

• UAN# 0134-0000-15-132-L01-P– Knowledge-based Activity– 1 contact hour (0.1 CEU)

Objectives

• Describe the pathogenesis and clinical progression of alcohol withdrawal syndrome.

• Evaluate commonly used monitoring tools for alcohol withdrawal syndrome and explain their limitations in a critically ill patient population.

• Compare treatment modalities for alcohol withdrawal syndrome and outline their benefits and drawbacks.

• Identify adjunctive treatments for alcohol withdrawal syndrome used in critical care and specify their appropriate place in therapy.

Incidence of Alcohol Use Disorders in Hospital Medicine and Critical Care

• Alcohol use disorders are present in more than 20% of US population – Heavy alcohol use: 6.3%

• Hospitalized Patients– 20-40%

• Intensive Care Unit– 10-30%

CHEST 2010;138:994-1003Crit Care Clin 2008;24:767-88

Alcohol Dependence and Development of Alcohol Withdrawal

• Estimated two million patients experience symptoms of alcohol withdrawal annually

• Mild Symptoms– > 80%– Anxiety, tremors, sleep disturbance, sweating, etc.

• Severe Symptoms– 15-30%– Delirium tremens, hallucinations, seizures

Am Fam Physician 2004;69:1443-50Alcohol Health Res World 1998;22:73-9

Complications of Alcohol Dependence and Withdrawal in Critically Ill

• Associated with worse outcomes– Increase sedative requirement– Increased incidence of sepsis– Increased need for and longer duration of

mechanical ventilation– Increased length of stay (ICU and hospital)– Increased mortality

CHEST 2010;138:994-1003Crit Care Clin 2008;24:767-88

Intensive Care Med 2013;39:16-30

Pathogenesis of Alcohol Withdrawal Syndrome (AWS)

• Neuromodulation associated with chronic alcohol use– GABA-A receptor down-regulation• Desensitization to GABA mediated stimulation• Impaired neuronal inhibition

– NMDA up-regulation• Hyper sensitization to glutamatergic stimulation• Increased neuronal excitability

J Clin Neurophysiol 2013;30:435-7

Pathogenesis of AWS

• Abrupt cessation of alcohol– Increase extracellular dopamine– Dopaminergic hyperexcitability– Excess catecholamines and hyperadrenergic state

• Repeated episodes of withdrawal amplify severity of AWS– Kindling effect

J Clin Neurophysiol 2013;30:435-7 Crit Care Med 2010;38[suppl.]:S494-501

Clinical Progression of AWSStage Clinical features Onset after last

drink Duration

Autonomic Hyperactivity

Tachycardia, diaphoresis, anxiety, agitation, tremulousness

6-8 hours 1-2 days

Alcoholic Hallucinosis

Visual, tactile, and, auditory hallucinations

8-48 hours 2-4 days

Withdrawal Seizures

Generalized tonic-clonic seizures 12-48 hours 2-3 days

Delirium Tremens

Severe sympathetic activity, hallucinations, delirium, agitation

48-96 hours 2-5 days

Aust Crit Care 2011;24:110-6Crit Care Med 2013;41:S57-68 Crit Care Clin 2008;24:767-88

Crit Care Med 2010;38[suppl.]:S494-501

Risk Factors for Severe Alcohol Withdrawal

• Previous withdrawal history• Family history• Race• Benzodiazepine dose• Liver disease (protective)• Inconsistent association with alcohol levels


Screening and Monitoring for AWS

• Assist in early identification• Indicate when medication is needed• Recognize worsening of symptoms and need

to escalate care• Aid in de-escalation of treatment • Easy to administer and high inter-evaluator

reliability

Alcohol Alcohol 2001;36:104-8

Screening and Monitoring Tools for AWS

• Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar)

• Clinical Institute Withdrawal Assessment for Alcohol revised to DSM

• Alcohol Withdrawal Symptom Checklist• Glasgow Modified Alcohol Withdrawal Scale

Alcohol Clin Exp Res 2007;31:612-8 Am J Addict 2006;15:85-93Q J Med 2012;105:649-56

CIWA-Ar


CIWA-Ar• 10 item scale– Assessing various symptoms– 7 items require patient participation

• Can be used as frequently as every 30 minutes– Most commonly every 1-2 hours

• Score range from 0-67– Score ≥ 10 prompts treatment– Score ≥ 20 signifies increased AWS severity

Crit Care Med 2013;41:S57-68 Aust Crit Care 2011;24:110-6

Br J Addict 1989;84:1353-7

Limitations of AWS Assessment Tools

• Lack validation in critically ill patients

• Many items require active patient interaction

• Alternatives– Richmond Analgesia and Sedation Score (RASS)– Sedation-Agitation Scale (SAS)

Crit Care Med 2013;41:S57-68 Aust Crit Care 2011;24:110-6

AWS Treatment Goals

• Decrease symptom severity

• Mitigate AWS progression and complications– Withdrawal seizures– Delirium tremens

• Minimize adverse treatment effects– Over-sedation– Need for mechanical ventilation

Crit Care Clin 2008;24:767-88

Treatment of AWS: Benzodiazepines

• Gold standard for treatment of AWS

• Compared to placebo–Decreased AWS severity –Withdrawal seizures• 0.5% vs. 8% (p < 0.001)• Number Needed to Treat: 13

–Delirium• 1.7% vs. 5.9% (p = 0.04)• Number Needed to Treat: 24 Crit Care Clin 2008;24:767-88

JAMA 1997;278:144-51 Cochrane Database Syst Rev 2010;3:CD005063

Treatment of AWS: Benzodiazepines vs. Non-Benzodiazepines

• Compared with other medication classes – No proven benefit of benzodiazepines

• Direct comparison trials limited– Small patient population– Low AWS severity – Heterogeneous interventions

Crit Care Clin 2008;24:767-88 JAMA 1997;278:144-51

Cochrane Database Syst Rev 2010;3:CD005063





Pharmacokinetic Comparison of Commonly Used Benzodiazepines in AWS

Benzodiazepine Routes of Administration

Equivalent Dosage Half-life (hours) Metabolism

Chlordiazepoxide PO 25 mg Parent: 6-24Metabolite: 24-96

Hepatic Active metabolite

Diazepam PO, IM, IV, PR 5 mg Parent: 24-48 Metabolite: 72-96

HepaticActive metabolite

Lorazepam PO, IM, IV 1 mg ~12 GlucuronidationInactive metabolite

Oxazepam PO 15 mg 8-12 GlucuronidationInactive metabolite

Midazolam IM, IV 2 mg 2-6 HepaticActive metabolite

Chapter 17. Hypnotics and SedativesChlordiazepoxide. In: Lexicomp Online

Diazepam. In: Lexicomp OnlineLorazepam. In: Lexicomp OnlineOxazepam. In: Lexicomp Online

Midazolam. In: Lexicomp Online

Selection of Benzodiazepine

• Comparative data demonstrates similar efficacy among benzodiazepines– Long-acting agents suggested to have improved

efficacy in prevention of withdrawal seizures and delirium tremens

Cochrane Database Syst Rev 2010;3:CD005063 JAMA 1997;278:144-51

Crit Care Clin 2008;24:767-88 Crit Care Med 2013;41:S57-68






• Route of administration– Intravenous generally preferred for critically ill

patients

• Pharmacokinetic differences– Agents with long half-lives and active metabolites

may accumulate in patients with hepatic failure

• Dosage form considerations– Lorazepam and diazepam injection formulations

contain propylene glycol diluentCrit Care Clin 2008;24:767-88 Crit Care Med 2013;41:S57-68

AWS Treatment Modalities

• Fixed dose– Set, scheduled doses, tapered over several days– Additional treatment as needed

• Symptom triggered– Frequent, scheduled patient assessments using

standardized monitoring tool– Treatment as needed in response to symptoms – Treatment withheld if no or minimal symptoms

National Clinical Guideline Centre (UK) 2010;Clinical Guideline 100

What is the preferred AWS treatment modality at your institution?

a. Fixed dose benzodiazepine

b. Symptom triggered benzodiazepine

c. Provider specific; No preferred modality

d. Unsure; Do not know

“Individualized Treatment for Alcohol Withdrawal”

• Randomized, controlled trial at VA Medical Center– Included 101 patients in alcohol detoxification unit– Symptom triggered vs. fixed dose therapy

• Fixed dose – Chlordiazepoxide 50 mg Q6hr for 24 hours followed by

25 mg Q6hr for 48 hours– Additional chlordiazepoxide (25-100 mg) as needed for

CIWA-Ar ≥ 8

• Symptom triggered – Chlordiazepoxide Q1hr as needed for CIWA-Ar ≥ 8

JAMA 1994;272:519-23

• Primary outcome– Duration of treatment – 9 vs. 68 hr (p < 0.001)– Total benzodiazepine – 100 vs. 425 mg (p < 0.001)

• No significant difference in AWS severity or development of complications

JAMA 1994;272:519-23


• Low acuity patient population– Alcohol detoxification unit– Low withdrawal severity

• Staff training– Participating staff provided adequate training on

use of monitoring tools and treatment protocol

JAMA 1994;272:519-23


• Randomized, controlled trial of patients admitted to an inpatient alcohol detoxification program– Randomized 117 patients to symptom based vs. fixed

dose

• Fixed dose– Oxazepam 30 mg Q6hr for 24 hours followed by 15 mg

Q6hr for 38 hours– Additional medication as needed based on symptoms

• Symptom Triggered– Oxazepam as needed based on development of

symptomsArch Intern Med 2002;162:1117-21

Inpatient Management of AWS: Symptom Triggered vs. Fixed Dose

• Total benzodiazepine: 38 vs. 231 mg (p < 0.001)

• Treatment duration: 20 vs. 63 hr (p < 0.001)

• No difference in AWS severity or development of complications

• Subgroup analysis among patients with history of severe AWS– Total benzodiazepine: 94 mg vs. 240 mg (p = 0.07)– Treatment duration: 23 vs. 62 hr (p = 0.04)

Arch Intern Med 2002;162:1117-21


• Inpatient population– Low AWS severity

• Subgroup analysis suggestive that symptom triggered management may be beneficial in patients with more severe AWS

• Lack of controlled data in severe AWS or benzodiazepine resistant AWS– Is symptom-triggered management appropriate for

these patients?Arch Intern Med 2002;162:1117-21


• Retrospective study of 40 patients requiring ICU admission for severe AWS

• Pre-protocol management– Non-protocol based – Standard practice: continuous midazolam infusion

• Protocol based care– Frequent patient assessments using MINDS – As needed lorazepam boluses (2-8 mg)– Initiation of infusion if symptoms remain uncontrolled– Protocol based down-titration of infusion

Pharmacotherapy 2007;27:510-8

Symptom Triggered Management of AWS in Critical Care

• Mean time to symptom control– 19.4 vs. 7.7 hours (p = 0.002)

• Total benzodiazepine dose– 1677 mg vs. 1044 mg (p = 0.014)

• Time receiving continuous infusion– 122.1 vs. 52 hr (p = 0.001)

• No significant difference in length of stay outcomes



• Treatment-related complications (non-significant)– Pre-protocol: 44% (n = 7)• Three required intubation (19%)• Two aspiration pneumonia• Two diazepam extravasation

– Post-implementation: 25% (n = 6)• Two required intubation (8%)• One health-care associated pneumonia• One myocardial infarction• Two propylene glycol toxicities



• Retrospective study of patients admitted to ICU for severe AWS

• Included 95 patients with severe AWS– Delirium tremens: 98%– Withdrawal seizures: 34%

• Evaluated impact of protocol implementation emphasizing escalating doses of diazepam– Doses escalated to 100-150 mg– Escalating doses of phenobarbital if refractory– Propofol infusion for rescue

Crit Care Med 2007;35:724-30

Protocol Based Dose Escalation for Benzodiazepine Resistant AWS

• Mechanical ventilation: 47% vs. 21% (p = 0.008)– Pre-protocol: Inadequate sedation with standard

benzodiazepine doses– Post-implementation: over-sedation (n = 1);

protocol non-compliance (n = 2)• Mean diazepam dose– Initial 24 hours: ~250 mg vs. ~500 mg (p = 0.001)– Maximum dose: ~30 mg vs. ~ 90 mg (p < 0.001)

• Phenobarbital use: 17% vs. 58% (p < 0.001)

Crit Care Med 2007;35:724-30

Protocol Based Dose Escalation for Benzodiazepine Resistant AWS

Which of the following has not been associated with protocol based,

symptom-triggered benzodiazepine use in the management of AWS?

a. Reduction in benzodiazepine requirement

b. Shortened duration of treatment

c. Decreased need for mechanical ventilation

d. Increased incidence of progression of AWS

Benefits of Individualized Standard AWS Treatment Protocols

• Reduction in benzodiazepine use

• Decreased treatment complications– Over-sedation– Need for mechanical ventilation

• Shortened duration of treatment and length of stay

• Reduction in need for ICU admission

• Decreased treatment costsIntensive Care Med 2013;39:16-30

Adjunctive Treatments for AWS

• Propofol

• α-adrenergic agonists– Dexmedetomidine– Clonidine

• Antipsychotics– Haloperidol

• Anticonvulsants– Valproic acid– Carbamazepine Crit Care Clin 2008;24:767-88

Crit Care Med 2013;41:S57-68 Intensive Care Med 2013;39:16-30

Aust Crit Care 2011;24:110-6

Symptom Oriented AWS Treatment

• Observational study of 38 surgical patients who developed AWS– Compared cohorts before and after

implementation of standard treatment protocol– Patient evaluation classified symptoms into three

types– Protocol emphasized treatment directed by AWS

symptom type

Arch Otolaryngol Head Neck Surg 2008;134:865-72





• Type A symptoms (CNS Excitation)– Lorazepam 1-2 mg IV Q1hr as needed

• Type B symptoms (Adrenergic Hyperactivity)– Clonidine 0.2 mg Q3hr x 2 as needed

• Type C symptoms (Delirium)– Haloperidol 2-5 mg IV Q2hr as needed



• No significant change in length of stay after protocol implementation

• Decreased rates of escalation in care– 29% vs. 4% (p = 0.03)

• Lower rates of delirium and violence– 79% vs. 29% (p=0.004)– 36% vs. 8 % (P=0.04)

• No significant difference in medication use

Impact of Symptom Oriented Bolus vs. Continuous Adjunctive Treatment


• Randomized, controlled trial of 48 surgical patients who developed AWS– Randomized to adjunctive medication via

symptom oriented bolus vs. continuous infusion– All patients received continuous infusion

benzodiazepines





• Increased medication with continuous infusion– Clonidine: 1,270 vs. 61,098 mcg (p < 0.001)– Haloperidol: 180 vs. 1,713 mg (p < 0.001) – Flunitrazepam: 69.7 vs. 162 mg (p < 0.001)



• Decreased need for mechanical ventilation with symptom oriented bolus treatment– Incidence: 90% vs. 65% (p = 0.05)– Duration: 12 vs. 6 days (p < 0.001)

• Decreased treatment duration with symptom oriented bolus treatment– 6 vs. 2 days (p < 0.001)



Use of Symptom Oriented Adjunctive Treatment for AWS

• Decrease in benzodiazepine requirement

• Decreased severity of withdrawal and need for care escalation

• May be due to symptom oriented treatment or timely management guided by protocol

• Most benefit observed when used as needed guided by symptom oriented protocol

Propofol in Refractory AWS

• Commonly used as a “rescue” medication

• GABA-A agonist and NMDA antagonist

• Short half-life and predictable metabolism

• Bolus and continuous infusion

• Adverse Effects– Respiratory suppression– Hemodynamic depression– Hypertriglyceridemia– Propofol-related infusion syndrome Crit Care Med 2010;38[suppl.]:S494-501

Crit Care Med 2013;41:S57-68 Am J Emerg Med 2013;31:734-42


• Several case reports describing use of propofol in benzodiazepine resistant AWS– Prevented further seizures and successfully

sedated patient refractory to > 150 mg diazepam

– Provided successful sedation in four patients refractory to > 1,000 mg lorazepam over 3-4 days

– Provided successful sedation in three patients refractory to lorazepam > 10 mg/hr

Ann Emerg Med 1997;30:825-8 Crit Care Med 2000;28:1781-4

Emerg Med J 2004;21:632-4


• Retrospective, single-cohort study of propofol in 15 patients with benzodiazepine resistant AWS– Persistent agitation and delirium after diazepam 1-2 g

• Propofol infusion titrated to deep sedation – Mean awakening time after discontinuation: 3.4 days

• 80% of patients symptom free after awakening– Three patients with persistent delirium for 5-11 days

• No progression of AWS after initiation of propofol

Dan Med J 2014;61:A4807

Propofol vs. Benzodiazepines in Benzodiazepine Resistant AWS

• Retrospective study of 64 patients with AWS requiring mechanical ventilation– Propofol: 72% • 83% with supplemental benzodiazepine

– Benzodiazepine monotherapy: 28%

Ann Pharmacother 2014;48:456-61


• No significant difference in outcomes– Duration of withdrawal: 8 vs. 7 days– Hospital length of stay: 9 vs.10 days– Duration of mechanical ventilation: 4 vs. 3 days

• Post-hoc analysis of propofol monotherapy demonstrated no difference in outcomes

Ann Pharmacother 2014;48:456-61


• Retrospective study of 66 patients in benzodiazepine resistant AWS – Comparison of benzodiazepine monotherapy vs.

propofol infusion

• Benzodiazepine requirement 7 days post-resistant AWS designation– 576.7 vs. 743.3 mg diazepam equivalents (NS)

• Incidence of mechanical ventilation– 42.4% vs. 100% (p < 0.001)

Drug Alcohol Depend 2015;154:296-9


• Length of stay– ICU: 4 vs. 10 days (p < 0.001)– Hospital: 6.7 vs. 16.2 days (p < 0.001)

• Duration of AWS– 5 vs. 7 days (p = 0.025)

• Nosocomial pneumonia– 3% vs. 36.4% (p = 0.001)

• No complications of AWS after initiation of propofol

Drug Alcohol Depend 2015;154:296-9

Which of the following is true regarding the use of propofol in patients with refractory AWS?

a. Successful treatment with propofol has been described in benzodiazepine refractory patients

b. In mechanically ventilated patients, propofol has not been shown to improve patient outcomes

c. The use of propofol may be limited by the need for mechanical ventilation

d. All of the above


• Propofol may provide alternative to benzodiazepines among patients requiring mechanical ventilation– No documented progression of AWS

• Propofol associated with worse outcomes when compared to benzodiazepines in non-mechanically ventilated patients– Selection bias for higher AWS severity?– Likely associated with need for mechanical

ventilation

Dexmedetomidine in Refractory AWS

• Several reports of use for adjunctive sedation

• Centrally acting α2 agonist– Sympatholytic– Anxiolytic– No respiratory depression– No GABA-A activity

• Short half-life and easily titratable

Crit Care Med 2013;41:S57-68


• Case report of control of agitation after persistent agitation with benzodiazepine infusion– Rapid discontinuation of benzodiazepine infusion after

dexmedetomidine started – Transferred out of ICU on day 3

• Case series of ten patients with refractory AWS– Three treatment failures– Three patients required mechanical ventilation– No patients with significant hemodynamic instability or

development of withdrawal seizuresAnn Pharmacother 2008;42:1703-5

J Anesth 2012;26:601-5


• Retrospective descriptive studies evaluating use of dexmedetomidine in severe AWS– Reduction in benzodiazepine requirement by 60-

70%– Reduction in AWS severity by ~20% – Normalization of hemodynamics• ~80% increase in time with HR < 100 • ~40% decrease in time with SBP < 140

– Mechanical ventilation required in four patients– Significant hemodynamic depression in ~10%

Ann Intensive Care 2012;2:12J Crit Care 2014;29:298-302


• Retrospective study of 61 non-intubated patients with severe AWS– Compared benzodiazepine infusion vs. dexmedetomidine

• Median cumulative dose of benzodiazepine – 105 vs. 3.5 mg (p < 0.01)

• No significant difference in outcomes– Development of withdrawal seizures– Need for mechanical ventilation– Length of stay

• Hemodynamic adverse effects– ~15% vs. ~45% (p < 0.01)



• Randomized, controlled of 24 patients with severe AWS– Assessed adjunct dexmedetomidine to symptom-

triggered treatment with benzodiazepines– Randomized to one of three groups:• Placebo• Low dose (0.4 mcg/kg/hr)• High dose (1.2 mcg/kg/hr)

Crit Care Med 2014;42:1131-9


• Reduction in benzodiazepine dose post-initiation– -8 vs. -56.4 mg (p = 0.037)

• Post-initiation total benzodiazepine requirement– 109.1 vs. 58.1 (NS)

• No dose-response relationship identified

• Adverse effects– Bradycardia: 0% vs. 25% (NS)– Hypotension: 0% vs. 19% (NS)

• No patients required mechanical ventilation after initiation of study drug

Crit Care Med 2014;42:1131-9

All of the following benefits have been seen with dexmedetomidine use in AWS except:

a. Decrease in benzodiazepine requirement

b. Decreased need for mechanical ventilation

c. Improvement in adrenergic symptoms of AWS

d. Reduction in AWS severity score


• Potential benefits for use as adjunct– Decreased benzodiazepine requirement– Improved hemodynamics among patients with

significant hyperadrenergic symptoms– No respiratory depression

• No data demonstrating improved outcomes compared with benzodiazepines– Impact on length of stay– Impact on need for mechanical ventilation


• On-going randomized controlled trial – Patients requiring ICU admission for severe AWS

• Dexmedetomidine vs. placebo

• Goal enrollment: 150 patients

• Primary outcome– ICU length of stay

• Anticipated completion: 2017

ClinicalTrials.gov. NCT01362205

Summary

• Benzodiazepines are the gold standard intervention for treatment of AWS– No single benzodiazepine has demonstrated

superiority over another

• Symptom-triggered benzodiazepines have shown significant improvements in outcomes– Decreased benzodiazepine requirement– Decreased treatment duration and length of stay

Summary

• Standard protocols, validated monitoring tools, and staff education are essential for symptom-triggered management

• Management of AWS in critical care is often complicated by benzodiazepine resistance

Summary

• Propofol may provide alternative in refractory patients – Primary limitation is requirement for mechanical

ventilation

• Dexmedetomidine shows promise as adjunct– No data showing improvements in important

clinical endpoints compared with benzodiazepines– Future studies may elucidate role in management

of AWS in critically ill

Questions?

What’s on Tap for the Treatment of Alcohol Withdrawal?

Andrew Straznitskas, PharmD, BCPSClinical Pharmacist,

Medical Intensive Care UnitBellevue Hospital Center

NYSCHP 2015 Critical Care Program: DownstateOctober 2, 2015

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• ClinicalTrials.gov. Dexmedetomidine (Precedex®) for severe alcohol withdrawal syndrome (AWS) and alcohol withdrawal delirium (AWD). Available at https://clinicaltrials.gov/ct2/show/study/NCT01362205. Accessed September 3, 2015

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