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

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1 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 Hernandez 1

2 Alcohol-Related Epidemiology I. More than 50% of Americans (>12 years old) drink alcohol 1,2 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 disorders 3 i. Abuse: drinking pattern leading to physical and psychological harm ii. Dependence: cravings, alcohol withdrawal after cessation, and tolerance II. Alcohol-related morbidity and mortality 3,4,5 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 mortality 1,4 A. Develops in 8% of hospital admissions i. One-third require ICU admission ii. Higher prevalence in trauma patients B. ICU complications 6 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 GABA A receptor ii. Excitatory NT: glutamate binds to N-methyl-d-aspartate (NMDA) receptor Acute exposure GABA activation glutamate activation Chronic exposure GABA levels GABA A receptors & sensitivity NMDA receptors Abrupt cessation Glutamate binding to NMDA receptors GABA binding to GABA A receptors De Level of consciousness Cognition Tolerance Alcohol required for same effects Brain hyperexcitability Results in AWS Figure 1. Pathophysiology of alcohol withdrawal B. Sympathetic nervous system 4,8,9 i. Norepinephrine (NE) levels increased 1. Desensitization of alpha-2 receptor 2. Increased corticotropin-releasing hormone ii. Resulting autonomic hyperactivity Hernandez 2

3 C. Dopaminergic activity 4,10 i. Increased dopamine levels ii. Possible role in hallucinations and delirium tremens (DT) D. Electrolyte disturbances 4 i. Magnesium blocks NMDA receptors ii. Hypomagnesemia linked to risk of seizures and cardiac arrhythmias E. Kindling hypothesis 8,11 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 timeline 1 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 timeline 1 Hernandez 3

4 III. Screening and assessment severity tools A. Screening for unhealthy alcohol use 3,13 i. CAGE questionnaire 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 outcome 13 ii. Single screening questions determining quantity and frequency of heavy drinking days iii. Prior episodes of alcohol withdrawal B. Assessment severity tools used in AWS 4,6,13,14 i. Scoring symptoms assess severity, progression and assist in management ii. Clinical Institute of Withdrawal Assessment for Alcohol (CIWA-Ar) (Appendix A.) 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 correlates with moderate to severe b. Score >20 consistent with severe iii. CIWA-Ar studied in ICU setting 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.) 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 factors 3,13 Prior AWS Seizures and/or DTs Alcohol Dependence CIWA >20 Prior Alcohol - Related Seizures Severe Course of AWS Comorbid Medical Conditions Figure 3. Risk factors for severe course of AWS Hernandez 4

5 Management of AWS I. Goals of therapy 1 A. Alleviate symptoms B. Prevent progression of symptoms C. Treat underlying comorbidities D. Minimize sedation and respiratory suppression II. Supportive care 1,4 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. Benzodiazepines 1,6 A. First-line therapy 1,15 B. Mechanism of action (MOA) 1 i. GABA A 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 pharmacokinetics 4,18 Generic (Brand) Equivalent Dose (mg) Routes of Administration Onset of Action (min) Half-life (hours) Hepatic Metabolism/ Active Metabolite Chlordiazepoxide (Librium ) 25 Oral CYP enzymes Active metabolite Lorazepam 1 Oral, IM, IV, Conjugation (Ativan ) continuous infusion Midazolam (Versed ) 2 Oral, IM, IV, continuous infusion CYP enzymes Active metabolite Diazepam (Valium ) 5 Oral, IM, IV CYP enzymes Active metabolite IM: intramuscular, IV: intravenous Hernandez 5

6 D. Symptom-triggered vs fixed-schedule doses 1,6 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 therapy 1,19 iii. Daeppen et al. randomized 117 alcohol dependent patients in a treatment facility 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 admission 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 implement 20,21 IV. Anticonvulsants 1,10 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. Antipsychotics 1,6 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. Ethanol 1,6 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 agents 1,4 A. Control autonomic hyperactivity B. Beta-blockers 1,4 i. Can help to reduce tachycardia and hypertension ii. Delirium found to be potential side effect of use C. Alpha-2 agonist: clonidine 8 i. MOA: Inhibits NE release from presynaptic neurons ii. Clonidine comparative studies 8,22-25 Hernandez 6

7 Table 3. Clonidine for AWS Author (N) Patients Intervention Results Baumgartner et al Alcohol dependent Excludedseizure history Clonidine mg/day vs Chlordiazepoxide mg/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 Detox unit Excludedmajor AWS, seizure history Adinoff B Alcohol dependent Excludedseizure history Spies et al Trauma ICU Alcohol dependent Clonidine mg/day vs chlormethiazole mg/day X 4 days Adjunct meds: None Clonidine 0.1mg, diazepam 10mg, alprazolam 1mg, or placebo for CIWA-Ar >10, every hour until CIWA-Ar <5 or 8 doses IV bolus, then infusion to target CIWA-Ar<10 Flunitrazepam/clonidine (FC) vs chlormethiazole/haloperidol (CH) vs flunitrazepam/haloperidol (FH) 8 study withdrawals: clonidine group (p=0.002) Reasons: seizures, hallucinations, orthostatic hypotension Alprazolam favored Fewer doses vs clonidine (p<0.04) CIWA-Ar vs clonidine (p<0.03) 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 trials 8 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 therapy 8 1. Adjunct to benzodiazepine therapy for control of sympathetic symptoms 2. Higher doses to achieve control resulted in greater risk for adverse effects D. Barbiturates 1,6 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 mg 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. Propofol 1,6 i. MOA: GABA A 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 Hernandez 7

8 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 GABA A receptors 2. Level of resistance dependent on individual s receptor dysregulation iv. Complications % require intubation due to need for alternative sedatives 2. Increased length of stay 3. Increased risk for infections v. Alternative sedative options 26,27 1. Phenobarbital 2. Propofol Dexmedetomidine (Precedex ) I. MOA 29,30 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 effects 29,30 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 Hernandez 8

9 C. Respiratory i. No inhibition of respiratory drive ii. Additive effects on respiratory function in combination with anesthetics, sedatives, hypnotics, and opioids III. Pharmacokinetics 29,30 A. Onset: 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. Indications 29 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 clonidine 6,29,30 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 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 control 1 III. IV. A. Patient specific factors B. Resistant alcohol withdrawal i. Complications 1. Mechanical ventilation 2. Increase ICU stay 3. Increase infection Drawbacks to alternative sedative therapy A. Risk for respiratory depression requiring mechanical ventilation B. Hemodynamic instability Dexmedetomidine A. Provides sedation and decreases autonomic activity B. No effect on respiratory function Hernandez 9

10 Role of Dexmedetomidine in AWS I. Case reports for treatment of alcohol withdrawal 32,33 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 DEX initiation/dose First 48 hours: Diazepam 360mg, Haloperidol 12.5mg Thiamine 200mg On admission to ICU Load: 0.5mcg/kg; CI mcg/kg/hour Oxazepam 30mg twice daily, Thiamine 100mg IV daily, Phenytoin ICU: BZD dose, midazolam CI 31 hours after hospital admission CI mcg/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 Table 5. Abstracts evaluating safety and efficacy of DEX for AWS Jacob S et al Dailey RW et al 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 Diazepam 13mg/hour Pt 3 & 4 lorazepam 2-4mg every 1-2 hours DEX initiation Imminent intubation, facilitate extubation Not mentioned DEX dose mcg/kg/hour Mean 0.7mcg/kg/hour (range ) DEX duration hours Median 50 hours (range 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) CIWA-Ar to 13* diazepam to 3mg/hour* No intubation needed No additional benzodiazepine, no seizures 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 Hernandez 10

11 III. Review of published retrospective and prospective studies 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 o Additionally, if standard benzodiazepine-based treatment failed or 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 (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 DEX can be safe and effective for severe AWD refractory or intolerant to conventional therapy Conclusion 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 Hernandez 11

12 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: 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 mcg/kg/hour); mean duration 92.7 hours (range 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 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 Hernandez 12

13 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 Single-center retrospective analysis of a 23-bed mixed medical-surgical-neuroscience ICU Design Alcohol withdrawal protocol o o Standard physician orders (i.e. vitamin, electrolyte, and IV fluid therapy) 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* (21.1) Benzodiazepine dose (mg)* (61.5) Haloperidol dose (mg)* (46.7) HR (mmhg)* (22.8) SBP (mmhg)* (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 Authors Conclusion o DEX discontinued in one patient due to two 9-second asystolic pauses o Non-significant increases in bradycardia and systolic hypotension 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 Hernandez 13

14 Summary of evidence 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 mcg/kg/hour C. Duration ranged from 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 stability 29,39 A. Most reported side effects: hypotension and bradycardia i. ICU controlled trial compared to midazolam for sedation >24 hours duration 60% DEX (n=244) 50% 40% 30% 20% 10% 0% Hypotension Hypotension Bradycardia* Intervention Figure 4. Hypotension and bradycardia occurrence Bradycardia Intervention Midazolam(n=122) *p<0.05 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 Hernandez 14

15 II. Hepatic impairment A % of people with alcoholism develop cirrhosis 41 B. Manufacturer recommendations for hepatic impairment 29 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 showed 42 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 dexmedetomidine 43 A. Average wholesale price per 400mcg/100ml vial: $ i. 24 hour infusion mcg/kg/hour for 70kg patient: $ $ B. Compared to midazolam = ~$40 per day II. Potential cost associated with AWS and ICU admission 44 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 seizures 1,16 i. RAW requires sedation and is associated with a ~40% mechanical ventilation rate 23 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 15

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 Not going to intubate and does not meet RAW: continue BZD trigger therapy Imminent Intubation Intubated 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 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 baseline, 72 hours later Rate, if SBP <90mmHg 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 Duration DEX up to 48 hours Hernandez 16

17 References 1. Sarff M, Gold JA. Alcohol withdrawal syndromes in the intensive care unit. Crit Care Med 2010;38:S494-S Kanny D, Liu Y, Brewer RD, Garvin WS, Balluz L. Vital signs: Binge drinking prevalence, frequency, and intensity among adults United States, MMWR 2012;61: Moss M, Burnham EL. Alcohol abuse in the critically ill patient. Lancet 2006;368: Carlson RW, Kumar N, Wong-Mckinstry ES, et al. Alcohol withdrawal syndrome. Crit Care Clin 2012;28: Bouchery EE, Harwood HJ, Sacks JJ, Simon CJ, Brewer RD. Economic costs of excessive alcohol consumption in the United States, Am J Prev Med 2011;41: Awissi DK, Lebrun G, Fagnan M, Skrobik Y. Alcohol, nicotine, and iatrogenic withdrawals in the ICU. Crit Care Med 2013;41:S57-S Stehman CR, Mycyk MB. A rational approach to the treatment of alcohol withdrawal in the ED. Am J Emerg Med 2013;31: Muzyk AJ, Fowler JA, Norwood DK, Chillpko A. Role of α2-agonists in the treatment of acute alcohol withdrawal. Ann Pharmacother 2011;45: Linnoila MA, Mefford IM, Nutt D, Adinoff B. Alcohol withdrawal and noradrenergic function. Ann Intern Med 1987;107: McKeon A, Frye M, Delanty N. The alcohol withdrawal syndrome. J Neurol Neurosurg Psychiatry 2008;79: Bayard M, Mcintyre J, Hill KR, Woodside J. Alcohol withdrawal syndrome. Am Fam Phyician 2004;16: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association, Web. [access date: 1 June 2013]. dsm.psychiatryonline.org 13. Awissi DK, Lebrun G, Coursin DB, Riker RR, Skrobik Y. Alcohol withdrawal and delirium tremens in the critically ill: a systematic review and commentary. Intensive Care Med 2013;39: 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: Kaim SC, Klett CJ, Rothfeld B. Treatment of acute alcohol withdrawal state: A comparison of four drugs. Amer J Psychiat 1969;125:L D Onofrio G, Rathlev NK, Ulrich AS, Fish S, Freedland ES. Lorazepam for the prevention of recurrent seizures related to alcohol. N Engl J Med 1999;340: Amato L, Minozzi S, Vecchi S, Davoli M. Benzodiazepines for alcohol withdrawal. Cochrane Database Syst Rev 2010;3:CD Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013;41: Daeppen JB, Gache P, Landry U, Sekera E, Schweizer V. Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal. A randomized treatment trial. Arch Intern Med 2002; 162: Spies CD, Otter HE, Huske B, et al. Alcohol withdrawal severity is decreased by symptom-orientated adjusted bolus therapy in the ICU Intensive Care Med 2003;29: DeCarolis D, Rice KL, Ho L, Willenbring ML, Cassaro S. Symptom-driven lorazepam protocol for treatment of severe alcohol withdrawal delirium in the intensive care unit Pharmacotherapy. 2007;27: Baumgartner GR, Rowen RC. Clonidine vs chlordiazepoxide in the management of acute alcohol withdrawal syndrome. Arch Intern Med 1987;147: Robinson BJ, Robinson GM, Maling TJ, Johnson RH. Is clonidine useful in the treatment of alcohol withdrawal? Alcohol Clin Exp Res 1989;13: Hernandez 17

18 24. Adinoff B. Double-blind study of alprazolam, diazepam, clonidine, and placebo in the alcohol withdrawal syndrome: preliminary findings. Alcohol Clin Exp Res 1994;18: Spies CD, Dubisz N, Neumann T, et al. Therapy of alcohol withdrawal syndrome in the intensive care unit patients following trauma: results of a prospective randomized trial. Crit Care Med 1996;24: Gold JA, Rimal B, Nolan A et al. A strategy of escalating doses of benzodiazepines and Phenobarbital administration reduces the need for mechanical ventilation in delirium tremens. Crit Care Med 2007;35: McCowan C, Marik P. Refractory delirium tremens treated with propofol: A case series. Crit Care Med 2000;28: Hack JB, Hoffmann RS, Nelson LS. Resistant alcohol withdrawal: does an unexpectedly large sedative requirement identify these patients early? J Med Toxicol 2006;2: Dexmedetomidine (Precedex ) Package Insert. Hospira, Inc Gertler R, Brown HC, Mitchell DH, Silvius EN. Dexmedetomidine: a novel sedative-analgesic agent. Proc (Bayl Univ Med Cent). 2001;14: MacLaren R, Krisl JC, Cochrane RE, Mueller SW. A case-based approach to the practical application of dexmedetomidine in critically ill adults. Pharmacotherapy 2013;33: Rovasalo A, Tohmo H, Aantaa R, Kettunen E, Palojoki R. Dexmedetomidine as an adjuvant in the treatment of alcohol withdrawal delirium: a case report. Gen Hosp Psychiatry 2006; 28: Darrouj J, Puri N, Prince E, Lomonaco A, Spevetz A, Gerber DR. Dexmedetomidine infusion as adjunctive therapy to benzodiazepines for acute alcohol withdrawal. Ann Pharmacother 2008;42: Jacob S, Karczewski, Smith H, Khan A, Nanchal R. Novel use of dexmedetomidine in 4 adults with resistant alcohol withdrawal in the ICU. Crit Care Med 2008;36:A Dailey RW, Leatherman JW, Sprenkle MD. Dexmedetomidine in the management of alcohol withdrawal and alcohol withdrawal delirium. Am J Respir Crit Care Med 2011;183:A 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]. 37. 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: 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: Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009; Tan JA, Ho KM. Use of dexmedetomidine as a sedative and analgesic agent in critically ill adult patients: a meta-analysis. Intensive Care Med 2010;36: Mann RE, Smart RG, Govoni R. Epidemiology of alcoholic liver disease. National Institute on Alcoholism Abuse and Alcoholism. Accessed 14 Sept Valitalo PA, Ahtola-Satila T, Wighton A, Sarapohja T, Pohjanjousi P, Garratt C. Population pharmacokinetics of dexmedetomidine in critically ill patients. Clin Drug Investig 2013;33: Guinter JR, Kristeller JL. Prolonged infusions of dexmedetomidine in critically ill patients. Am J Health-Syst Pharm 2010;67: Bard MR, Goettler CE, Toschlog EA, et al. Alcohol withdrawal syndrome: turning minor injuries into a major problem. J Trauma 2006;61: Hernandez 18

19 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 TACTILE DISTURBANCES Ask Have you any itching, pins, and needles sensations, any you vomited? Observation. burning, any numbness, or do you feel bugs crawling on your skin? Observation. 0 No nausea and no vomiting 0 none 1 mild nausea with no vomiting 1 very mild itching, pins and needles, burning or numbness 2 2 mild itching, pins and needles, burning or numbness 3 3 moderate itching, pins and needles, burning or numbness 4 intermiitent nausea with dry heaves 4 moderately severe hallucinations 5 5 severe hallucinations 6 6 extremely severe hallucinations 7 constant nausea, frequent dry heaves and vomiting 7 continuous hallucinations TREMOR Arms extended and fingers spread apart. Observation. 0 no tremor 1 not visible, but can be felt fingertip to fingertip moderate, with patient s arm extended severe, even with arms not extended PAROXYSMAL SWEATS Observation. 0 no sweat visible 1 barely perceptible sweating, palms most beads of sweat obvious on forehead drenching sweats ANXIETY Ask Do you feel nervous? Observation. 0 no anxiety, at ease 1 mild anxious moderately anxious, or guarded, so anxiety is inferred equivalent to acute panic states as seen in severe delirium or acute schizophrenic reactions AGITATION Observation. 0 normal activity 1 somewhat more than normal activity moderately fidgety and restless paces back and forth during most of the interview, or constantly thrashes about 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 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 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 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: Hernandez 19

20 Richmond Agitation Sedation Scale (RASS) +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 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 Riker Sedation Agitation Scale 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 Hernandez 20