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Dexmedetomidine for Alcohol Withdrawal Syndrome: Should we add it to the tab?

Lauren Hernandez, Pharm.D. PGY2 Critical Care Pharmacy Resident

University Health System, San Antonio, TX Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center, University of Texas Health Science Center at San Antonio

September 20, 2013

Learning Objectives

1. Describe the pathophysiology and neurotransmitters involved with alcohol withdrawal

2. Identify characteristics, timing, and severity of clinical manifestations

3. Define the current pharmacologic options and strategies for treatment

4. Evaluate the role of dexmedetomidine to treat alcohol withdrawal

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Alcohol-Related Epidemiology

I. More than 50% of Americans (>12 years old) drink alcohol1,2

A. Binge drinking > 4 to 5 drinks on one occasion: 23%

B. Heavy drinking > 1 to 2 drinks per day on average: 6.5%

C. Alcohol use disorders3

i. Abuse: drinking pattern leading to physical and psychological harm

ii. Dependence: cravings, alcohol withdrawal after cessation, and tolerance

II. Alcohol-related morbidity and mortality3,4,5

A. 1.2 million emergency room visits a year

B. 40% of intensive care unit (ICU) admissions related to alcohol abuse

C. 80,000 deaths per year

D. Estimated economic cost $200 billion per year

III. Alcohol withdrawal syndrome (AWS) morbidity and mortality1,4

A. Develops in 8% of hospital admissions

i. One-third require ICU admission

ii. Higher prevalence in trauma patients

B. ICU complications6

i. 30% require mechanical ventilation

ii. Infections

iii. Increased ICU length of stay

C. Mortality

i. Increases three-fold in post-surgical and trauma patients

ii. Decreased from 50% to 10% since first recognition of syndrome

Alcohol Withdrawal Syndrome (AWS)

I. Pathophysiology A. Main central nervous system (CNS) neurotransmitters (NT) affected

1,3,7

i. Inhibitory NT: gamma-aminobutyric acid (GABA) binds to GABAA receptor ii. Excitatory NT: glutamate binds to N-methyl-d-aspartate (NMDA) receptor

De

B. Sympathetic nervous system4,8,9

i. Norepinephrine (NE) levels increased

1. Desensitization of alpha-2 receptor

2. Increased corticotropin-releasing hormone

ii. Resulting autonomic hyperactivity

Acute exposure ↑ GABA activation

↓ glutamate activation

Chronic exposure↓GABA levels

↓ GABAA receptors & sensitivity↑ NMDA receptors

Abrupt cessation↑Glutamate binding to

NMDA receptors↓GABA binding to GABAA receptors

↓ Level of consciousness ↓ Cognition

Tolerance ↑Alcohol required for same effects

Brain hyperexcitability Results in AWS

Figure 1. Pathophysiology of alcohol withdrawal

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C. Dopaminergic activity4,10

i. Increased dopamine levels

ii. Possible role in hallucinations and delirium tremens (DT)

D. Electrolyte disturbances4

i. Magnesium blocks NMDA receptors

ii. Hypomagnesemia linked to risk of seizures and cardiac arrhythmias

E. Kindling hypothesis8,11

i. Each period of alcohol cessation causes an intense excitatory CNS process

ii. Altered transmission of GABA, glutamate and NE in neurons

iii. Withdrawal symptoms become more severe with repeated occurrences of withdrawal

iv. Continual alterations in NTs increase risk for seizures and DTs

II. Diagnosis and clinical manifestations A. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

12

Table 1. Criteria for alcohol withdrawal

A. Cessation of (or reduction in) alcohol use that has been heavy and prolonged B. Two (or more) of the following, developing within several hours to a few days after criterion A

1. Autonomic hyperactivity (e.g. sweating or pulse rate >100 beats/min) 2. Increased hand tremor 3. Insomnia 4. Nausea or vomiting 5. Transient visual, tactile, or auditory hallucinations or illusions 6. Psychomotor agitation 7. Anxiety 8. Grand tonic-clonic seizures

C. The signs or symptoms in criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning

D. The signs or symptoms are not attributable to another medical condition and are not better explained by another mental disorder, including intoxication or withdrawal from another substance

B. Clinical manifestation timeline1

Autonomic Hyperactivity Diaphoresis Nausea Vomiting Anxiety Tremor Agitation Tachycardia

Hallucinations Visual Tactile Less common: Auditory Lasts: 1-6 days 30% of patients

Withdrawal Seizures Generalized tonic-clonic May occur as early as 2 hours 10% of patients

Delirium Tremens or Alcohol Withdrawal Delirium Disorientation (delirium) Agitation Hallucinations Tachycardia Hypertension Fever Lasts up to 7 days 5% of patients

Figure 2. Alcohol withdrawal symptoms timeline1

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III. Screening and assessment severity tools

A. Screening for unhealthy alcohol use3,13

i. CAGE questionnaire13

1. Four questions to assess cut down, annoyance, guilt, eye opener

2. Validated tool in non-ICUs to detect alcoholism and risk of AWS

3. ICU data limited and does not predict severity or outcome13

ii. Single screening questions determining quantity and frequency of heavy drinking days

iii. Prior episodes of alcohol withdrawal

B. Assessment severity tools used in AWS4,6,13,14

i. Scoring symptoms assess severity, progression and assist in management

ii. Clinical Institute of Withdrawal Assessment for Alcohol (CIWA-Ar) (Appendix A.)14

1. Developed for non-ICU patients and not validated in ICU patients

2. Includes 10 items requiring patient participation

3. CIWA-Ar > 10 warrants management and reassessment a. Score 10 -18 correlates with moderate to severe

b. Score >20 consistent with severe

iii. CIWA-Ar studied in ICU setting 13

1. CIWA-Ar >20 used as trigger for therapy and reflected severe AWS

2. Mechanically-ventilated patients often excluded

3. Variable target CIWA-Ar scores and assessment intervals

iv. Validated ICU sedation scales used in AWS studies (Appendix A.)13

1. Included mechanically ventilated patients

2. Riker Sedation-Agitation Scale (SAS)

a. Score >5 triggered pharmacologic therapy with target goal 3 to 4

b. Assessment intervals varied from every hour to every 4 hours

3. Richmond Agitation-Sedation Scale (RASS)

a. Used to titrate pharmacologic therapy to goal 0 to -1

v. Confusion Assessment Method-ICU (CAM-ICU) (Appendix A.)

1. Validated tool to detect delirium but not used solely to manage AWS

IV. Risk factors3,13

Figure 3. Risk factors for severe course of AWS

Severe Course of AWS

Prior Alcohol -Related Seizures

Alcohol Dependence

Prior AWSSeizures

and/or DTs

CIWA >20

Comorbid Medical Conditions

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Management of AWS

I. Goals of therapy1

A. Alleviate symptoms B. Prevent progression of symptoms C. Treat underlying comorbidities D. Minimize sedation and respiratory suppression

II. Supportive care1,4

A. Fluid resuscitation

i. Fluid losses and intravascular volume depletion commonly observed B. Nutritional supplementation

6

i. Patients have inadequate nutritional intake and severe malnutrition ii. Thiamine

iii. Folic acid iv. Multi-vitamin

III. Benzodiazepines1,6

A. First-line therapy1,15

B. Mechanism of action (MOA)1

i. GABAA receptor agonist and glycine-mimetic effects

ii. Pharmacologic properties

1. Sedative

2. Anticonvulsant

3. Anxiolytic

4. Muscle relaxant

iii. Unfavorable adverse effects

1. Respiratory depression

2. Cardiovascular instability

C. Efficacy 15,16,17

i. Reduce development of alcohol withdrawal delirium

ii. Decrease seizure incidence and recurrent seizures

iii. No evidence to support one benzodiazepine over another

Table 2. Available benzodiazepine pharmacokinetics4,18

Generic (Brand) Equivalent Dose (mg)

Routes of Administration

Onset of Action (min)

Half-life (hours)

Hepatic Metabolism/ Active Metabolite

Chlordiazepoxide (Librium®)

25 Oral 30-120 7-28 CYP enzymes Active metabolite

Lorazepam (Ativan®)

1 Oral, IM, IV, continuous infusion

15-20 8-15 Conjugation

Midazolam (Versed®)

2 Oral, IM, IV, continuous infusion

2-5 3-11 CYP enzymes Active metabolite

Diazepam (Valium®)

5 Oral, IM, IV 2-5 20-120 CYP enzymes Active metabolite

IM: intramuscular, IV: intravenous

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D. Symptom-triggered vs fixed-schedule doses1,6

i. Benzodiazepines originally administered in fixed-scheduled doses

1. Predetermined dosing taper for 3 to 5 days for all patients

ii. Symptom-triggered directed by CIWA-Ar protocol allows for individualized therapy1,19

iii. Daeppen et al. randomized 117 alcohol dependent patients in a treatment facility19

1. Symptom-triggered (CIWA>8: administer dose; target score <8) vs fixed-dose

2. Results: 39% symptom-triggered received medications vs 100%, ↓treatment

duration, and six- fold less oxazepam use

iv. Spies et al. randomized 44 patients with AWS after ICU admission20

1. Continuous infusion therapy group (ITG) vs bolus therapy group (BTG) targeting

CIWA-Ar (CIWA-Ar >20 trigger for therapy)

2. BTG ↓ benzodiazepine amount used

3. ITG ↑ AWS duration, mechanical ventilation, pneumonia, ICU stay

v. Symptom-triggered benefits in non-ICU patients are similar to ICU; limitations on

severity scale validity may make it difficult to implement20,21

IV. Anticonvulsants1,10

A. Carbamazepine

i. MOA: Limit influx of sodium ions and other unknown mechanisms

ii. Better than placebo and equally effective to lorazepam for mild to moderate AWS

B. Valproic acid

i. MOA: Increase availability of GABA or enhance GABA action

ii. Compared to placebo decreased benzodiazepine use for symptom control in mild AWS

V. Antipsychotics1,6

A. Haloperidol, phenothiazines (i.e. chlorpromazine)

B. MOA: Dopamine antagonists

C. Adjunctive to benzodiazepines for symptom control; limited comparative studies

D. Undesirable effects

i. Decrease seizure threshold

ii. Increased risk of delirium with haloperidol

iii. QT prolongation

VI. Ethanol1,6

A. Use dates back to pre-benzodiazepine management

B. Primarily used in surgical services and as a prophylaxis measure

C. Controversial issues

i. Efficacy

ii. Dosing and administration

iii. Complications

VII. Adrenergic agents1,4

A. Control autonomic hyperactivity

B. Beta-blockers1,4

i. Can help to reduce tachycardia and hypertension

ii. Delirium found to be potential side effect of use

C. Alpha-2 agonist: clonidine8

i. MOA: Inhibits NE release from presynaptic neurons

ii. Clonidine comparative studies8,22-25

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Table 3. Clonidine for AWS22-25

Author (N) Patients Intervention Results

Baumgartner et al.

22

61 Alcohol dependent Excluded- seizure history

Clonidine 0.2-0.6mg/day vs Chlordiazepoxide 50-150mg/day X 4 days Adjunct meds: APAP

Clonidine favored ↓ Alcohol withdrawal scale (p<0.02) ↓Mean SBP, HR (p<0.01, p<0.001) No differences HARS, RR, diaphoresis, restlessness

Robinson et al.

23

32 Detox unit Excluded- major AWS, seizure history

Clonidine 0.3-0.9mg/day vs chlormethiazole 1000-3000mg/day X 4 days Adjunct meds: None

8 study withdrawals: clonidine group (p=0.002) Reasons: seizures, hallucinations, orthostatic hypotension

Adinoff B.24

25 Alcohol dependent Excluded- seizure history

Clonidine 0.1mg, diazepam 10mg, alprazolam 1mg, or placebo for CIWA-Ar >10, every hour until CIWA-Ar <5 or 8 doses

Alprazolam favored Fewer doses vs clonidine (p<0.04) ↓CIWA-Ar vs clonidine (p<0.03)

Spies et al.25

159 Trauma ICU Alcohol dependent

IV bolus, then infusion to target CIWA-Ar<10 Flunitrazepam/clonidine (FC) vs chlormethiazole/haloperidol (CH) vs flunitrazepam/haloperidol (FH)

CH group ↑ MV duration (p=0.03) FC group ↓PNA (p=0.040) ↑bradycardia, 1

st-degree AV block,

hypotension (p=0.005) *p<0.05 Abbreviations: APAP: acetaminophen; SBP: systolic blood pressure; HR: heart rate; HARS: Hamilton anxiety rating scale; RR: respiratory rate; ICU: intensive care unit; IV: intravenous; MV: mechanical ventilation; PNA: pneumonia. Alcohol withdrawal scale = BP, HR, RR, tremor, diaphoresis, restlessness.

iii. Summary of trials8

1. Study design included randomized, double-blind or rater-blind

2. ↓ BP and HR were benefits from clonidine on alcohol withdrawal symptoms

3. Clonidine monotherapy associated with significant seizure occurrence

4. Severe bradycardia complication with IV clonidine therapy

iv. Place in therapy8

1. Adjunct to benzodiazepine therapy for control of sympathetic symptoms

2. Higher doses to achieve control resulted in greater risk for adverse effects

D. Barbiturates1,6

i. MOA: GABA-A agonist, weak NMDA inhibitor

ii. Adjunctive agent to benzodiazepine

1. Gold et al.26

studied a strategy for patients resistant to benzodiazepines

a. Persistent agitation for 1 hour after ↑ diazepam doses to 100-150mg

b. Phenobarbital added in ↑ doses (65, 130, 260mg) to control agitation

c. Need for mechanical ventilation ↓ compared to pre-strategy group

iii. Adverse effects

1. Respiratory depression

2. Hypotension

E. Propofol1,6

i. MOA: GABAA agonist and NMDA antagonist

ii. Adjunctive agent to benzodiazepine

1. Gold et al.26

gave bolus or continuous infusion if agitation persisted with

escalating doses of diazepam and phenobarbital

2. McCowan et al.27

reported successful treatment with propofol continuous

infusion in four DTs cases with limited response to high dose benzodiazepines

3. Both studies with continuous infusion required mechanical ventilation

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iii. Adverse effects

1. Respiratory depression

2. Hypotension

3. Hypertriglyceridemia

4. Propofol infusion syndrome with prolonged high doses

F. Benzodiazepine resistant alcohol withdrawal (RAW)1,28

i. Large doses of benzodiazepines needed for withdrawal symptoms or DTs

ii. Hack et al.28

defined diazepam doses >50 mg in 1 hour or >200mg in 3 hours as

suggestive criteria for RAW

iii. Mechanism for resistance

1. Downregulation and decreased function of GABAA receptors

2. Level of resistance dependent on individual’s receptor dysregulation

iv. Complications26

1. 47% require intubation due to need for alternative sedatives

2. Increased length of stay

3. Increased risk for infections

v. Alternative sedative options26,27

1. Phenobarbital

2. Propofol

Dexmedetomidine (Precedex®)

I. MOA29,30

A. Selective central alpha-2 receptor agonist

B. Binds to pre- and post-synaptic adrenergic neurons in the central nervous system (CNS)

i. Pre-synaptic: prevents release of norepinephrine from synaptic vesicles

ii. Post-synaptic: inhibits sympathetic activation

C. Dose-dependent alpha-2 selectivity

II. Pharmacological effects29,30

A. CNS

i. Sedation

1. High density of alpha-2 receptors in locus coeruleus

a. Predominant noradrenergic nucleus in brain

b. Modulator of alertness

2. Cooperative sedation

a. Allows for easy awakening

b. Facilitates routine patient assessment

ii. Analgesia

1. Mechanism not fully understood

2. Activation at supraspinal and spinal sites reduces nociceptive transmission

B. Cardiovascular

i. Initial transient increase in blood pressure resulting in reduced heart rate

1. Occurs within first 10 minutes of infusion

2. Associated with loading dose

ii. Subsequently, blood pressure decreases 10-20% from baseline and heart rate stabilizes

1. Effect of inhibition of central sympathetic outflow

2. Decreased norephinephrine release

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C. Respiratory

i. No inhibition of respiratory drive

ii. Additive effects on respiratory function in combination with anesthetics, sedatives,

hypnotics, and opioids

III. Pharmacokinetics29,30

A. Onset: 15-30 minutes

B. Distribution: rapid, steady-state volume of distribution: 118 L

C. Metabolism

i. t ½ : 2 hours; severe hepatic impairment ↓ clearance

ii. Hepatic glucuronidation and CYP450 enzymes

D. Excretion: 95% urinary

IV. Indications29

A. Approved in 1999 by Food and Drug Administration (FDA)

i. ICU sedation

1. Intubated and mechanically ventilated patients in ICU; not to exceed 24 hours

2. Continuously infused prior to, during, and post extubation; not necessary to

discontinue prior to extubation

ii. Procedural sedation

1. Nonintubated patients prior to and/or during surgical or other procedures

V. Distinguishing features from clonidine6,29,30

A. More effective sedative and analgesic

B. Increased specificity for alpha-2 receptor

i. 8 times more potent

C. Shorter half-life (2-3 vs 12-24 hours)

D. Greater titratability

Understanding the Potential for Dexmedetomidine in AWS 1,6,31

I. Agitation and autonomic hyperactivity control is essential in severe AWS and DTs

II. Benzodiazepine monotherapy may be insufficient for control1

A. Patient specific factors

B. Resistant alcohol withdrawal

i. Complications

1. Mechanical ventilation

2. Increase ICU stay

3. Increase infection

III. Drawbacks to alternative sedative therapy

A. Risk for respiratory depression requiring mechanical ventilation

B. Hemodynamic instability

IV. Dexmedetomidine

A. Provides sedation and decreases autonomic activity

B. No effect on respiratory function

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Role of Dexmedetomidine in AWS

I. Case reports for treatment of alcohol withdrawal32,33

Table 4. DEX for treatment of alcohol withdrawal 32,33

Case 1 Case 2

Alcohol abuse history Severe alcohol dependence Previous AWS admissions, convulsions Last drink 3 days prior

Chronic alcohol abuse Previous AWS admissions Last drink 24 hour prior

Symptoms Convulsions, hallucinations, tremor, diaphoresis, delirium

Agitated, disoriented, combative, tremors, possible DTs,

Admission General ward ICU General ward ICU

Initial treatment First 48 hours: Diazepam 360mg, Haloperidol 12.5mg Thiamine 200mg

Oxazepam 30mg twice daily, Thiamine 100mg IV daily, Phenytoin ICU:↑ BZD dose, midazolam CI

DEX initiation/dose On admission to ICU Load: 0.5mcg/kg; CI 0.175 mcg/kg/hour

31 hours after hospital admission CI 0.2-0.7mcg/kg/hour

Adjunctive medications Diazepam 15mg/day, Haloperidol 5mg/day Midazolam CI

Symptom improvement Within 2 hours, ↓ symptoms, HR, restraints removed

Immediate, ↓ in tremor, confusion, agitation, ↓midazolam infusion rate

DEX duration 15.5 hours 39 hours (25 hours monotherapy)

DEX: dexmedetomidine; BZD: benzodiazepine; CI: continuous infusion

A. Take home points i. Significant alcohol history and possible DT presentations

ii. Dexmedetomidine initiated as symptoms worsened and benzodiazepine increased iii. Rapidly improved symptoms, restraint removal, HR, ↓ benzodiazepine dose

II. Abstracts 34-35

Table 5. Abstracts evaluating safety and efficacy of DEX for AWS34-35

Jacob S et al. 200834

Dailey RW et al. 201135

Study design Case series in ICU of 4 patients Case series in ICU of 10 patients

Airway intervention 2/4 prior to DEX None prior to DEX

Symptoms and severity Delirium, RASS 2 to 4, RAW, CIWA-Ar 20-30, Severe AWS or AWD, CIWA-Ar 26

Initial treatment Pt 1 & 2 CI midazolam 15-25mg/hour Pt 3 & 4 lorazepam 2-4mg every 1-2 hours

Diazepam 13mg/hour

DEX initiation Imminent intubation, facilitate extubation Not mentioned

DEX dose 0.2-0.7mcg/kg/hour Mean 0.7mcg/kg/hour (range 0.1-1.5)

DEX duration 24-29 hours Median 50 hours (range 7-206 hours)

Adjunctive meds No, benzodiazepine stopped Diazepam

Endpoints RASS score -1 to -2, CIWA-Ar <5 Extubation (2/2) 5 & 22 hours after drip Avoided intubation (2/2) No additional benzodiazepine, no seizures

↓ CIWA-Ar to 13* ↓diazepam to 3mg/hour* No intubation needed

Hemodynamics ↓BP, HR, no significant effects noted 5/10 SBP <100mmHg, 2/10 DEX held

*p <0.05; DEX: dexmedetomidine; AWD: alcohol withdrawal delirium; LOS: length of stay; PNA: pneumonia

A. Take home points

i. Severe AWS defined by CIWA-Ar, delirium, or RAW

ii. Dexmedetomidine ↓CIWA-Ar, RASS, HR, BP, benzodiazepine dosing, and possibly

facilitated extubation and prevented intubation

iii. Dexmedetomidine alone and adjunctive to benzodiazepines, no seizures reported

iv. Hypotension is a safety concern with dexmedetomidine

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III. Review of published retrospective and prospective studies36-38

Table 6. Tolonen J, Rossinen J, Alho H, Harjola VP. Dexmedetomidine in addition to benzodiazepine-based sedation in patients with alcohol withdrawal delirium. Eur J Emerg Med 2012;[Epub ahead of print].

Objective Report safety and efficacy of DEX in patients classified with alcohol withdrawal delirium (AWD)

Study Design

Multi-center prospective study CAM-ICU and RASS performed daily Medications: diazepam, lorazepam, and/or haloperidol orally and/or IV to target RASS of zero;

thiamine 100mg daily for 3 days Delirium was defined as resolved when both RASS and CAM-ICU returned to normal DEX initiated at discretion of physician based on hospital sedation protocol

o Additionally, if standard benzodiazepine-based treatment failed or o Directly if it was obvious at admission that large amounts of benzodiazepines or

haloperidol were not tolerated

Patients Inclusion o Adult patients with AWD defined by CAM-ICU

Exclusion o Pregnancy, invasive ventilator support at admission

Statistics Data expressed as mean and standard deviation

Results Baseline characteristics o 18 patients were enrolled (male = 15, female =3), mean age 53.9 years o PMH and current diagnosis included CVD, ICH, RA, asthma, epilepsy, pancreatitis,

depression, bipolar, alcohol dementia, delirium Alcohol withdrawal treatment

o DEX initiation from admission ranged from day 1 to day 3 (majority day 1) o DEX mean max rate 1.5 mcg/kg/hour (SD 1.2); mean duration 23.9 hours (SD 18.4) o Mean cumulative dose (mg): diazepam 193.6 (SD 165.8), lorazepam 9.3 (SD 8.6),

haloperidol 26.5 (SD 25) AWS symptoms

o Mean (SD) admission RASS 1.1 (1.8), DEX start 1.4 (1.5), 24 hours from DEX start 0.3 (1.4) o Time to delirium resolution mean (SD): 3.8 (1.3) days

No patients were intubated Mean (SD) length of stay in ICU 7.1 (2.7) days, in hospital 12.1 (4.5) days Two patients required subsequent rehabilitation One patient died due to acute pancreatitis not related to DEX therapy

Authors Conclusion

DEX can be safe and effective for severe AWD refractory or intolerant to conventional therapy Escalation of therapy to anesthesia and intubation is avoided

Critique Retrospective study with no comparison or control group AWD diagnosed by CAM-ICU solely, with no mention of patients’ alcohol use history Refractory/intolerant to therapy not quantified and decided by physician RASS not validated for AWS and significance of improvement prior to and after DEX not reported Hemodynamic parameters to measure efficacy and safety not collected or reported

DEX: dexmedetomidine; CVD: cardiovascular disease; ICH: intracranial hemorrhage; RA: rheumatoid arthritis

A. Take home points

i. Patients with delirium defined by CAM-ICU but no clear distinction between delirium

caused by alcohol withdrawal or other factors (i.e. ICU)

ii. Adjunctive dexmedetomidine improved sedation and possibly avoided intubation

iii. Delirium resolution due to correction of underlying cause or environmental factors

iv. Safety of dexmedetomidine cannot be determined

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Table 7. DeMuro JP, Botros DG, Wirkowski E, Hanna AF. Use of dexmedetomidine for the treatment of alcohol withdrawal syndrome in critically ill patients: a retrospective case series. J Anesth 2012;26:601-605.

Objective Report on the use of DEX in patients for AWS

Study Design

Retrospective case series of a 55-adult bed ICU at a single center Institution protocol

o DEX initiated for AWS starting at 0.1 mcg/kg/hour, titrating rapidly to target HR <100 bpm, Ramsay scale of 2, with maximum dose of 1.2 mcg/kg/hour

o Adjunctive medications: Lorazepam 2 mg IV every 6 hours, haloperidol if needed for agitation, and beta-blockers (metoprolol 5 mg IV every 6 hours)

o If no response, extra dose of lorazepam followed by continuous infusion started o If above not adequate, patient intubated and DEX switched to propofol infusion

DEX and benzodiazepines were used at discretion of intensivist

Patients

Inclusion o Adult ICU patients receiving DEX in a 12-month period o Patients that received DEX for AWS diagnosed by DSM-IV

Statistics Hemodynamic parameters prior and 4 hours after DEX compared using Student’s t test

Results Baseline characteristics o 10 patients were identified (all male), mean age 53.6 years, mostly post-operative o Alcohol abuse (9 defined as heavy)and 60% were agitated within 48 hours of admission o Documented ICH in three patients; head trauma followed by seizure in 1 patient

Alcohol withdrawal treatment o DEX no loading dose; mean dose 0.63 mcg/kg/hour (range 0.2-1.2 mcg/kg/hour);

mean duration 92.7 hours (range 13-247 hours) o DEX alone (n=3); DEX plus intermittent benzodiazepine (n=7) o Antipsychotics: 70% of patients (haloperidol most common) o Beta-blockers: all patients

AWS symptoms improved in 1-2 hours o Mean duration of AWS 106.7 hours o No seizures or deaths reported

Failure of DEX to control severe agitation (n=3) o DEX discontinued, propofol in addition to lorazepam or midazolam started

No significant change in vital signs were observed 4 hours after DEX infusion started o HR decreased by 10.5%, MAP by 2.8%, RPP by 12.8% o No bradycardia requiring discontinuation of DEX

Mechanical ventilation required in 3 patients for mean of 5.3 days Average ICU LOS 9.3 days and hospital LOS 14.2 days

Authors Conclusion

DEX is effective and safe in combination with other agents to control AWS symptoms except in severe cases

Lack of early response at max doses of DEX signals failure of the drug to control AWS DEX allowed lower doses of other agents to be used Not using a bolus dose, hypotension and bradycardia avoided

Critique Retrospective study No alcohol withdrawal scale to quantify severity DEX initiation at physician discretion using hospital protocol applicable to all patients with AWS No record of benzodiazepine requirements prior and after starting Variety of patients including ICH which could have an effect on agitation and hemodynamics

DEX: dexmedetomidine; RPP: rate-pressure product=SBP X HR; ICH: intracranial hemorrhage; LOS: length of stay

B. Take home points

i. Patients had alcohol abuse history with AWS ranging in severity requiring ICU care

ii. Adjunctive dexmedetomdine ↓agitation within 1-2 hours, HR, BP, RPP

iii. May not be successful in all AWS patients especially severe

iv. HR and BP affected by combination dexmedetomidine and beta-blockers

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Table 8. Rayner SG, Weinert CR, Peng H, Jepsen S, Broccard AF, Study Institution. Dexmedetomidine as adjunct treatment for severe alcohol withdrawal in the ICU. Ann Intensive Care 2012;2:12.

Objective Report use of DEX for benzodiazepine-refractory AWS

Study Design

Single-center retrospective analysis of a 23-bed mixed medical-surgical-neuroscience ICU Alcohol withdrawal protocol

o Standard physician orders (i.e. vitamin, electrolyte, and IV fluid therapy) o Nursing-administered alcohol withdrawal severity assessment protocol

10 parameters consisting of vital signs, physical and behavioral findings Ranges of total points linked to dosing ranges of IV or oral lorazepam

o Standing order for IV haloperidol 2mg per hour for severe agitation or hallucinations DEX addition was intensivist driven and with no specific protocol

Patients

Inclusion o ICU patients with ICD9-code for alcohol withdrawal during hospitalization o DEX used solely for management of alcohol withdrawal

Exclusion o Severe comorbid disease: CNS trauma, CVA, end-stage metastatic cancer, severe sepsis

Statistics Compared group means 24 hours before to means for first 24hours of DEX therapy Two-tailed t test to compare group means with p<0.05 defined as significant

Results Baseline characteristics: 20 patients (male = 19, female = 1), mean age 44.9 years Mean DEX dose 0.53 mcg/kg/hour (5 patients received load ) Mean duration of DEX therapy 49.1 hours

Table 5a. 24 hours prior compared to first 24 hours of DEX therapy

Parameter 24 hours prior First 24 hours of DEX Difference (% Decrease)

Alcohol withdrawal scoring* 9 7.1 1.9 (21.1)

Benzodiazepine dose (mg)* 52.7 20.3 32.4 (61.5)

Haloperidol dose (mg)* 12 6.4 5.6 (46.7)

HR (mmHg)* 102.8 79.3 23.4 (22.8)

SBP (mmHg)* 140.2 126.7 13.5 (9.6)

*p<0.05; reported values as means

One required intubation (excluded from analysis) 13 hours after start of DEX Mean length of ICU 98.5 hours; all survived to hospital discharge Adverse effects

o DEX discontinued in one patient due to two 9-second asystolic pauses o Non-significant increases in bradycardia and systolic hypotension

Authors Conclusion

Adjunct therapy with DEX in severe alcohol withdrawal patients led to reductions in benzodiazepine dosing, alcohol withdrawal score, and HR and BP within a few hours of DEX initiation and sustained for 24 hours

Critique Retrospective study DEX initiation at physician discretion Validity of alcohol withdrawal scoring system and lack of defining severity of score Benzodiazepine-refractory not defined as inclusion criteria Oral and IV beta-blockers administered could affect hemodynamic parameters

DEX: dexmedetomidine

C. Take home points

i. AWS ICU patients with mean lorazepam dose 52.7mg in 24hours

ii. Adjunctive dexmedetomidine ↓ severity score, haloperidol and benzodiazepine dosing

within 4 hours

iii. HR and BP affected by combination of dexmedetomidine and adjunctive beta-blockers

iv. Dexmedetomidine discontinuation required in one patient due to asystolic pauses

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0%

10%

20%

30%

40%

50%

60% DEX (n=244)

Midazolam(n=122)

Summary of evidence32-38

I. Limited to case reports, case series, retrospective and prospective studies

A. Pre-and post-dexmedetomidine data

B. No studies were compared to a non-dexmedetomidine group

II. Patients studied

A. Majority non-intubated

B. AWS (severity not always quantified)

i. Severe alcohol withdrawal defined by CIWA >20

ii. AWD or DTs

iii. Benzodiazepine-refractory (lorazepam 52.7 mg/24 hours)

iv. RAW (lorazepam 4-40mg/2 hours)

III. Dexmedetomidine initiation, dosing and duration highly variable

A. Initiation varied, not defined and at physician discretion

B. Load was not common; continuous infusion ranged from 0.1-1.5mcg/kg/hour

C. Duration ranged from 15.5-206 hours

IV. Additional medications for AWS included benzodiazepines, antipyschotics, and beta-blockers

V. Efficacy and safety outcomes

A. Rapid decrease in symptoms, CIWA-Ar and RASS scores in most patients

B. No seizures reported

C. Significant reduction in benzodiazepines and haloperidol use

D. Possible avoidance of intubation and facilitation of extubation

E. Hypotension and bradycardia reported

Safety Concerns for Dexmedetomidine

I. Hemodynamic stability29,39

A. Most reported side effects: hypotension and bradycardia

i. ICU controlled trial compared to midazolam for sedation >24 hours duration

B. Tan et al.40

meta-analysis compared dexmedetomidine to other sedatives and analgesics in ICU

i. No significant difference in risk of hypotension

ii. Significant increase in risk of bradycardia requiring intervention

1. Loading dose

2. Maintenance doses >0.7mcg/kg/h

Hypotension Hypotension Intervention

Bradycardia* Bradycardia Intervention

Figure 4. Hypotension and bradycardia occurrence

*p<0.05

Hernandez 15

II. Hepatic impairment

A. 10-15% of people with alcoholism develop cirrhosis41

B. Manufacturer recommendations for hepatic impairment29

i. May be necessary to consider dose reduction

ii. Severe impairment: mean clearance value is half that observed in healthy people

C. Pharmacokinetic population study showed42

i. Correlation between high levels of AST and bilirubin and decreased clearance

ii. Changes in hepatic blood flow and cardiac output more likely to affect clearance due to

high extraction ratio of dexmedetomidine

Cost Considerations of Dexmedetomidine: Who’s picking up the tab?

I. Cost of dexmedetomidine43

A. Average wholesale price per 400mcg/100ml vial: $190.00

i. 24 hour infusion 0.2-1.2mcg/kg/hour for 70kg patient: $190.00-$957.60

B. Compared to midazolam = ~$40 per day

II. Potential cost associated with AWS and ICU admission44

A. Trauma patients with AWS compared to those without AWS

i. ICU LOS differed significantly: 7.58 days (AWS) vs 3.30 days (no AWS)

ii. Reported mean ventilator days for AWS patients was 6.79 days

B. Gold et al.23

compared intubated vs non-intubated patients with severe AWS and DTs

i. 47% required intubation after ICU admission

ii. ICU LOS: intubated patients (5.6 days) vs non-intubated patients (3.4 days)

iii. Pneumonia rates significantly differed: intubated (42%) vs non-intubated (21%)

C. ICU cost room and board only per day: $2480

D. Mechanical ventilation: initial intubation $1295, followed by $952 per day

III. No current cost comparison for dexmedetomidine for the treatment of AWS

Summary and Recommendations

I. Management in the critically ill setting A. Severe alcohol withdrawal characterized by

1

i. Profound agitation

ii. Autonomic hyperactivity

iii. Alcohol withdrawal seizures and delirium

B. Lack of validated measurement tool for ICU patients especially mechanically ventilated

i. Options studied in ICU patients CIWA-Ar, SAS, RASS

C. Benzodiazepines standard of care to prevent delirium and seizures1,16

i. RAW requires ↑ sedation and is associated with a ~40% mechanical ventilation rate23

ii. Alternative sedation options: phenobarbital, propofol, dexmedetomidine

Table 9. Pharmacologic properties of agents used for severe AWS

Medication Sedative Anxiolytic Anticonvulsant Respiratory Depression

Hemodynamic Effects

Benzodiazepine X X X X X

Propofol X X X X X

Phenobarbital X X X X X

Dexmedetomidine X X X

Hernandez 16

II. Review of dexmedetomidine for severe alcohol withdrawal

A. Clinical outcomes and efficacy

i. Limited data on clinical outcomes (i.e. mechanical ventilation, ICU length of stay)

ii. Case series comparing pre- and post-dexmedetomidine show rapid response

1. Improved CIWA-Ar score or institution derived AWS score

2. Decrease in blood pressure and heart rate

3. Reduction in benzodiazepines and haloperidol usage

iii. Proposed benefits: Avoid mechanical ventilation and facilitate extubation

B. Safety

i. No anticonvulsant properties and seizure protection not established

ii. Hypotension and bradycardia most common adverse effects

iii. Safe dosing and adverse effects in severe hepatic impairment not studied

C. Cost

i. Substantially more costly compared to alternatives

ii. Difficult to assess cost-effectiveness for this indication with no outcomes data

III. Algorithm to identify patients that may benefit with dexmedetomidine

1. Obtain baseline severity score (i.e. CIWA-Ar preferred, RASS, SAS)

2. Assess symptom control with BZD-trigger therapy RAW: Persistent symptom severity after cumulative doses

of diazepam >200mg over first 3-4 hours Persistent symptoms assessed by CIWA-Ar >20, RASS, SASS worsening, vital sign abnormalities

Continue BZD-trigger therapy Consider DEX (consider ↑BP ↑HR) or

Phenobarbital

DEX dosing guide No load. Start: 0.2mcg/kg/hour, then titrate

CIWA-Ar <10, RASS 0 to -1, SAS 3 to 4, normal vitals Max 1.2mcg/kg/hour

Monitoring Efficacy: CIWA-Ar, RASS, SAS, vitals, BZD dose

At 24 hours from DEX, if above increased = DC DEX and initiate CI BZD and/or propofol

Safety: DC DEX if HR <50bpm, SBP <90 mmHg

Intubated

Duration DEX up to 48 hours

Continue BZD therapy Consider adding

Propofol continuous infusion start 5mcg/kg/min Titrate to 50mcg/kg/min; target RASS 0 to -1, SAS 3 to 4

Monitoring: RASS, SAS, vitals TG levels @ baseline, 72 hours later

↓Rate, if SBP <90mmHg

Not going to intubate and does not meet RAW: continue BZD trigger therapy

Imminent Intubation

Hernandez 17

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Appendix A. Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) Patient____________________________________ Date___________________________Time_______

Pulse or heart rate taken for one minute_________________________Blood pressure_______________

NAUSEA AND VOMITING – Ask “Do you feel sick to your stomach? Have you vomited?” Observation. 0 No nausea and no vomiting 1 mild nausea with no vomiting 2 3 4 intermiitent nausea with dry heaves 5 6 7 constant nausea, frequent dry heaves and vomiting

TACTILE DISTURBANCES – Ask “Have you any itching, pins, and needles sensations, any burning, any numbness, or do you feel bugs crawling on your skin?” Observation. 0 none 1 very mild itching, pins and needles, burning or numbness 2 mild itching, pins and needles, burning or numbness 3 moderate itching, pins and needles, burning or numbness 4 moderately severe hallucinations 5 severe hallucinations 6 extremely severe hallucinations 7 continuous hallucinations

TREMOR – Arms extended and fingers spread apart. Observation. 0 no tremor 1 not visible, but can be felt fingertip to fingertip 2 3 4 moderate, with patient’s arm extended 5 6 7 severe, even with arms not extended

AUDITORY DISTURBANCES – Ask “Are you more aware of sounds around you? Are they harsh? Do they frighten you? Are you hearing anything that is disturbing to you? Are you hearing things you know are not there?” Observation. 0 not present 1 very mild harshness or ability to frighten 2 mild harshness or ability to frighten 3 moderate harshness or ability to frighten 4 moderately severe hallucinations 5 severe hallucinations 6 extremely severe hallucinations 7 continuous hallucinations

PAROXYSMAL SWEATS – Observation. 0 no sweat visible 1 barely perceptible sweating, palms most 2 3 4 beads of sweat obvious on forehead 5 6 7 drenching sweats

VISUAL DISTURBANCES – Ask “Does the light appear to be too bright? Is its color different? Does it hurt your eyes? Are you seeing anything that is disturbing to you? Are you seeing things you know are not there?” Observation. 0 Not present 1 very mild sensitivity 2 mild sensitivity 3 moderate sensitivity 4 moderately severe hallucinations 5 severe hallucinations 6 extremely severe hallucinations 7 continuous hallucinations

ANXIETY – Ask “Do you feel nervous?” Observation. 0 no anxiety, at ease 1 mild anxious 2 3 4 moderately anxious, or guarded, so anxiety is inferred 5 6 7 equivalent to acute panic states as seen in severe delirium or acute schizophrenic reactions

HEADACHE, FULLNESS IN HEAD – Ask “Does your head feel different? Does it feel like there is a band around your head?” do not rate for dizziness or lightheadedness. Otherwise, rate severity. 0 not present 1 very mild 2 mild 3 moderate 4 moderately severe 5 severe 6 very severe 7 extremely severe

AGITATION – Observation. 0 normal activity 1 somewhat more than normal activity 2 3 4 moderately fidgety and restless 5 6 7 paces back and forth during most of the interview, or constantly thrashes about

ORIENTATION AND CLOUDING OF SENSORIUM – Ask “What day is this? Where are you? Who am I?” 0 oriented and can do serial additions 1 cannot do serial additions or is uncertain about date 2 disoriented for date by no more than 2 calendar days 3 disoriented for date by more than 2 calendar days 4 disoriented for place/or person Patients scoring <10 do not usually need additional medication for withdrawal. TOTAL CIWA-Ar Score ___________________ Maximum possible score 67

Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol withdrawal: the revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar). Br J Addict 1989;84:1353-1357.

Hernandez 20

Richmond Agitation Sedation Scale (RASS) CAM-ICU

If RASS is > -3 proceed to CAM-ICU 1. Acute change or fluctuating course of mental status AND 2. Inattention (S A V E A H A A R T test: >2 errors) AND 3 or 4 3. Altered levels of consciousness (RAAS anything but zero CAM-ICU Poistive) 4. Disorganized thinking (I,e. Will a stone float on water? Etc.) if yes, CAM-ICU Positive http://www.mc.vanderbilt.edu/icudelirium/docs/CAM_ICU_flowsheet.pdf

Riker Sedation Agitation Scale

+4 Combative Combative, violent, immediate danger to staff

+3 Very agitated Pulls to remove tubes or catheters: aggressive

+2 Agitated Frequent non-purposeful movement, fights ventilator

+1 Restless Anxious, apprehensive, movements not aggressive

0 Alert & calm Spontaneously pays attention to caregiver

-1 Drowsy Not fully alert, but has sustained awakening to voice (eye opening & contact >10 sec)

-2 Light sedation Briefly awakens to voice (eyes open & contact <10 sec)

-3 Moderate sedation

Movement or eye opening to voice (no eye contact)

-4 Deep sedation No response to voice, but movement or eye opening (to physical stimulation)

-5 Unarousable No response to voice or physical stimulation

http://www.mc.vanderbilt.edu/icudelirium/docs/RASS.pdf

7 Dangerous agitation

Pulling ET tube, remove catheters, climbing over bedrail, striking at staff, thrashing side to side

6 Very agitated Requiring restraint and frequent verbal reminding of limits, biting ETT

5 Agitated Anxious or physically agitated, calms to verbal instruction

4 Calm & cooperative

Calm, easily arousable, follows commands

3 Sedated Difficult to arouse but awakens to verbal stimuli or gentle shaking, follows simple commands but drifts off again

2 Very sedated Aroused to physical stimuli but does not communicate or follow commands, may move spontaneously

1 Unarousable Minimal or no response to noxious stimuli, does not communicate or follow commands

http://www.mc.vanderbilt.edu/icudelirium/docs/SAS.pdf