Dexmedetomidine For Treatment of Alcohol Withdrawal Syndrome

Introduction:

• Alcohol causes an imbalance in the inhibitory GABA and excitatory NMDA receptors
  
• Benzodiazepines (benzos) have been shown effective in the prevention and treatment of AWS (alcohol withdrawal syndrome)
  
• Higher doses of benzos place patients at risk for respiratory depression, aspiration, and intubation
  
• Benzo monotherapy may not be effective enough to control symptoms and may worsen delirium
  
• Multiple studies have shown benzodiazepine use is associated with longer ventilator times, longer ICU/hospital stays, and higher ICU delirium rates
  
• Dexmedetomidine (Dex) is a sedation medication and recently has been proposed as an alternative to using benzos for treatment of AWS
  
• Dex is unique in that it does not depress respiratory drive at therapeutic doses and causes arousable sedation
  
• Dex was recently approved for use in non-intubated patients
  
• Dex decreases sympathetic activity; which may help in the treatment of AWS
  

Structure:
C13H17CIN2

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Pharmacology/Pharmacokinetics: Comparing Alpha2 Agonists

Dexmedetomidine
∗ Selectivity: α2:α1  1600:1
∗ t1/2 2.5hrs
∗ Only available IV
∗ Sedative-analgesic
∗ Primary sedative

Clonidine
∗ Selectivity: α2:α1 200:1
∗ t1/2 12 – 24 hrs
∗ PO, patch, epidural
∗ Antihypertensive
∗ Analgesic adjunct
∗ IV formulation rarely used in US; epidural solution available

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Dosing:

• Dex is a selective alpha-2-adrenergic agonist (at high doses may also select alpha-1)
  
• Sedation (non-intubated): loading dose (0.5 to 1.mcg/kg IV over 10 minutes) and maintenance dose (0.2 to 1.0 mcg/kg/hr)
  
• Intubated patients:  same dosing as above
  
• Dose adjustments: geriatric patients and hepatic impairment -> use a reduced dose
  
• Not indicated for use over 24 hours
  
• Loading dose is not indicated in most patients and is associated with increased hypo- and hypertension
  

Absorption/Distribution/Metabolism/Excretion:

• Absorption: only available in IV formulation
  
• Distribution: 94% protein bound. Vd 118 to 152L
  
• Metabolism: liver via direct glucuronidation and P450 (no active metabolites)
  
• Excretion: 95% renal excreted
  
• Elimination: 2 to 2.5 hrs half life (initial half life 0.1hrs)
  

Significant Drug/Drug Interactions:

• Increases CNS depression with other sedation drugs, otherwise no significant drug interactions 
  

Toxicity/Mechanism of Toxicity:

• Bradycardia/hypotension and tachycardia/hypertension have been reported (see images below)
  
• Dysrhythmias and cardiac arrest have occurred (with extremely high doses)
  
• Limited date on overdoses; Toxicity is similar to opioid overdose (including respiratory depression)
  
• Pregnancy category C
  
• Withdrawal symptoms (N/V, agitation, HTN, tachycardia) have been reported.  Increased chances if used over 48 hours.
  

Treatment/Management:

• Dexmedetomidine can be used for alcohol withdrawal
  
• Rayner showed 61% reduction in benzo dosing with adding Precedex and 20% reduction in AWS score
  
• However, Crispo studied 61 nonintubated patients with AWS and showed that Dex had more adverse drug affects and similar intubation rates/length of stay compared to benzos
  
• Mueller showed that Dex decreased benzo use in the short term, but not long term in tx of AWS
  
• Lizotte, VanderWeide, Savel, and Wong showed Dex is associated with lower benzo use in severe AWS
  
• More research is needed: No studies have used Dexmedetomidine to treat alcohol withdrawal without supplemental benzos

By Dr. Patrick Jackson, MD

References:
∗ Albertson T, Chenoweth J, Ford J, et. al.  Is it prime time for alpha2-adrenocepter agonists in the treatment of withdrawal syndromes?  J Med Toxicol.  2014; 10(4):369-381.
∗ Bryczkowski S, Lopreiato M, Yonclas P, et. al.  Risk factors for delirium in older trauma patients admitted to the surgical intensive care unit.  J Trauma Acute Care Surg.  2014; 77(6):944-951.  
∗ Crispo A, Daley M, Pepin J, Harford P, Brown C.  Comparison of clinical outcome in nonintubated patients with severe alcohol withdrawal syndrome treated with continuous-infusion sedatives: Dexmedetomidine versus benzodiazepines.  Pharmacotherapy.  2014; 34(9):910-917.
∗ DeMuro J, Botros D, Wirkoski E, Hanna A.  Use of dexmedetomidine for the treatment of alcohol withdrawal syndrome in critically ill patients: A retrospective case series.  J Anesth.  2012; 26(4)601-605.
∗ Flower O, Hellings S.  Sedation in traumatic brain injury.  Emerg Med Int.  2012; e-published.
∗ Lizotte R, Kappes J, Barte B, et. al.  Evaluating the effects of dexmedetomidine compared to propofol as adjunctive therapy in patients with alcohol withdrawal.  Clin Pharmacol.  2014; 31(6):171-177.
∗ Lonardo N, Mone M, Nirula R, et. al.  Propofol is associated with favorable outcomes compared with benzodiazepines in ventilated intensive care unit patients.  American Journal of Respiratory and Critical Care Medicine.  2014; 189(11):1383-1394.
∗ Mancl E, Brophy G.  Time to wake up: A historical perspective on modernized sedation management.  Society of Critical Care Medicine.  2013; e-published.
∗ Mazanikov M, Udd M, Kylanpaa L, et. al.  Dexmedetomidine impairs success of patient-controlled sedation in alcoholics during ERCP: A randomized, double blind, placebo-controlled study.  Surg Endosc.  2013; 27(6):2163-2168.  
∗ Muller S, Preslaski C, Kiser T, et. al.  A randomized, double-blind, placebo-controlled dose range study of dexmedetomidine as adjunctive therapy for alcohol withdrawal.  Crit Care Med.  2014; 42(5):1131-1139.
∗ Muzyk A, Kerns S, Brudney S, Gagliardi J.  Dexmedetomidine for the treatment of alcohol withdrawal syndrome: Rationale and current status of research.  CNS Drugs.  2013; 27(11):913-920.
∗ Rayner S, Weinert C, Jepsen S, Broccard A.  Dexmedetomidine as adjunct treatment for severe alcohol withdrawal in the ICU.  Ann Intensive Care.  2012; 23(1):12.
∗ Riihioja P, Jaatinen P, Haapalinna A, et. al.  Effects of dexmedetomidine on rat locus coeruleus and ethanol withdrawal symptoms during intermittent ethanol exposure.  Alcohol Clin Exp Res.  1999; 23(3):432-438.
∗ Riihioja P, Jaatinen P, Oksanen H, et. al.  Dexmedetomidine, diazepam, and propranolol in the treatment of ethanol withdrawal symptoms in the rat.  Alcohol Clin Exp Res.  1997; 21:801-804.
∗ Roberts D, Hall R, Kramer A, et. al.  Sedation for critically ill adults with severe traumatic brain injury: A systematic review of randomized controlled trails.  Crit Care Med.  2011; 39(12)2743-2751.
∗ Tolonen J, Rossinen J, Alho H, Harjola V.  Dexmedetomidine in addition to benzodiazepine-based sedation in patients with alcohol withdrawal delirium.  Eur J Emerg Med.  2013; 20(6):425-427.
∗ Traeger J, Popa A, Makii J.  Dexmedetomidine for acute alcohol withdrawal.  Society of Critical Care Medicine.  2014, e-published.  
∗ Savel R, Kupfer Y.  Using dexmedetomidine as adjunctive therapy for patients with severe alcohol withdrawal syndrome: Another piece of the puzzle.  Crit Care Med.  2014; 42(5)1298-1299.
∗ VanderWeide L, Foster C, MacLaren R, et. al. Evaluation of early dexmedetomidine addition to the standard of care for severe alcohol withdrawal in the ICU: A retrospective controlled cohort study.  J Intensive Care Med.  2014; e-published.  
∗ Wong A, Benedict N, Kane S.  Multicenter evaluation of pharmacologic management and outcomes associated with severe resistant alcohol withdrawal.  J Crit Care.  2015; 30(2):405-409.