April 28, 2016

Benzodiazepine-Refractory Alcohol Withdrawal

Background: Severe alcohol withdrawal syndrome (AWS) accounts for only 10% of the roughly 500,000 annual cases of AWS episodes that require pharmacologic treatment. AWS is characterized by an imbalance between inhibitory GABA and excitatory NMDA receptor stimulation secondary to chronic ethanol intake. Treatment is typically centered around supportive care and symptom-triggered benzodiazepines. However, some patients are refractory to benzodiazepines, defined as > 10 mg lorazepam equivalents in 1 hour or > 40 mg lorazepam equivalents in 4 hours. Doses exceeding this threshold provide little benefit and put patients at risk for increase morbidity and mortality, over sedation, ICU delirium, respiratory depression and hyperosmolar metabolic acidosis. 

What are Some Other Options for Benzodiazepine-Refractory Alcohol Withdrawal?

 

 

What is the Evidence for Each of These Medications?

Phenobarbital

  • 296 Patients
  • 1 Prospective Trial [1]
    • One prospective RCT with phenobarbital 10mg/kg vs placebo (+symptom-triggered lorazepam for both groups) showed significant decrease in both ICU admission rate and continuous lorazepam infusion use (1 single center trial, results have not been duplicated)
  • 1 Retrospective Trial [2]

Propofol

  • 225 Patients
  • 5 Retrospective Trials [3 – 7]
  • 1 Case Series [8]
  • 3 Case Reports [9 – 11]

Dexmedetomidine

  • 6 Retrospective Trials [6 – 7; 12 – 15]
  • 4 Case Reports/Case Series [16 – 19]
  • 1 Prospective Trial [20]
  • Dexemedetomidine does not protect against withdrawal seizures and should not be used as monotherapy

Ketamine

  • 1 Retrospective Review [21]

Clinical Bottom Line

  • Phenobarbital, propofol, and dexmedetomidine have been shown to reduce benzodiazepine requirements in AWS
  • Nothing has proven to shorten AWS duration or ICU LOS
  • Dexmedetomidine does not protect against withdrawal seizures and should not be used as monotherapy

References:

  1. Rosenson J et al. Phenobarbital for acute alcohol withdrawal: a prospective randomized double-blind placebo-controlled study. J Emerg Med. 2013;44:592-598.e2. PMID: 22999778
  2. Michaelsen IH et al. Phenobarbital versus diazepam for delirium tremens: a retrospective study. Dan Med Bull. 2010; 57 (8) A4169. PMID: 20682133
  3. Sohraby R et al. Use of propofol-containing versus benzodiazepine regimens for alcohol withdrawal requiring mechanical ventilation. Ann Pharmacother. 2014;48:456-461. PMID: 24436457
  4. Lorentzen K et al. Use of propofol infusion in alcohol withdrawal-induced refractory delirium tremens. Dan Med J. 2014;61:A4807. PMID: 24814732
  5. Wong A et al. Management of benzodiazepine-resistant alcohol withdrawal across a healthcare system: benzodiazepine dose escalation with or without propofol. Drug Alcohol Depend. 2015;154:296-299. PMID: 2605315
  6. Lizotte RJ et al. Evaluating the effects of dexmedetomidine compared to propofol as adjunctive therapy in patients with alcohol withdrawal. Clin Pharmacol. 2014;6:171-177. PMID: 25382987
  7. Ludtke K et al. Retrospective review of critically ill patients experiencing alcohol withdrawal: dexmedetomidine versus propofol and/or lorazepam continuous infusions. Hosp Pharm. 2015;50:208-213. PMID: 26405310
  8. McCowan C, Marik P. Refractory delirium tremens treatedwith propofol: a case series. Crit Care Med. 2000;28:1781-1784. PMID: 10890619
  9. Hughes DW et al. Propofol for benzodiazepine-refractory alcohol withdrawal in a non-mechanically ventilated patient. Am J Emerg Med. 2014;32:112.e3-112.e4. PMID: 24075805
  10. Coomes TR, Smith SW. Successful use of propofol in refractory delirium tremens. Ann Emerg Med. 1997;30:825-828. PMID: 9398785
  11. Mahajan R et al. Use of propofol as adjuvant therapy in refractory delirium tremens. Ind Psychiatry J. 2010;19:58-59. PMCID: PMC3105562
  12. Crispo AL et al. Comparison of clinical outcomes in nonintubated patients with severe alcohol withdrawal syndrome treated with continuous-infusion sedatives: dexmedetomidine versus benzodiazepines. Pharmacotherapy. 2014;34:910-917. PMID: 24898418
  13. Frazee EN et al. Influence of dexmedetomidine therapy on the management of severe alcohol withdrawal syndrome in critically ill patients. J Crit Care. 2014;29:298-302. PMID: 24360597
  14. Rayner SG et al. Dexmedetomidine as adjunct treatment for severe alcohol withdrawal in the ICU. Ann Intensive Care. 2012;2:12. PMID: 22620986
  15. VanderWeide LA 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 2016; 31(3): 198 – 204). PMID: 25326428
  16. Baddigam K et al. Dexmedetomidine in the treatment of withdrawal syndromes in cardiothoracic surgery patients. J Intensive Care Med. 2005;20:118-123. PMID: 15855224
  17. Darrouj J et al. Dexmedetomidine infusion as adjunctive therapy to benzodiazepines for acute alcohol withdrawal. Ann Pharmacother. 2008;42:1703-1705. PMID: 18780809
  18. Muzyk AJ et al. The use of dexmedetomidine in alcohol withdrawal. J Neuropsychiatry Clin Neurosci. 2012; 24: E45-E46. PMID: 23037682
  19. Rovasalo A et al. Dexmedetomidine as an adjuvant in the treatment of alcohol withdrawal delirium: a case report. Gen Hosp Psychiatry. 2006;28:362-363. PMID: 16814639
  20. Mueller SW et al. A randomized, double-blind, placebo-controlled dose range study of dexmedetomidine as adjunctive therapy for alcohol withdrawal. Crit Care Med. 2014;42:1131-1139. PMID: 24351375
  21. Wong A et al. Evaluation of adjunctive ketamine to benzodiazepines for management of alcohol withdrawal syndrome. Ann Pharmacother. 2015;49:14-19. PMID: 25325907

For More on This Topic Checkout:

Post Peer Reviewed By: Salim Rezaie (Twitter: @srrezaie)

Cite this article as: Darrel Hughes, "Benzodiazepine-Refractory Alcohol Withdrawal", REBEL EM blog, April 28, 2016. Available at: https://rebelem.com/benzodiazepine-refractory-alcohol-withdrawal/.
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Darrel Hughes

University Health System Clinical Specialist, Emergency Medicine at University of Texas Health Science Center at San Antonio (UTHSCSA)
REBEL EM Guest Contributor and Author
6 Comments
  • Global Intensive Care | Benzodiazepine-Refractory Alcohol Withdrawal
    Posted at 02:42h, 29 April Reply

    […] post Benzodiazepine-Refractory Alcohol Withdrawal appeared first on R.E.B.E.L. EM – Emergency Medicine […]

  • Alcohol Withdrawal and Delirium Tremens | EM Cases
    Posted at 13:05h, 25 October Reply

    […] Salim Rezaei reviews the literature on adjuntive medications […]

  • George Hughes
    Posted at 12:24h, 08 November Reply

    The phenobarbital study showed decreased ICU Admissions. Though it does not show a decreased ICU LOS it seems that it would argue against your bottom line; not wrong but disingenuous.

    • Salim Rezaie
      Posted at 12:49h, 08 November Reply

      Hello George,
      Appreciate you reading the bottom line from the phenobarbital study reads:

      “A single dose of i.v. phenobarbital combined with a symptom-guided lorazepam-based alcohol withdrawal protocol resulted in decreased ICU admission and did not cause increased adverse outcomes.”

      So yes you are correct…decreased ICU admissions with phenobarbital if all you do is read the abstract…however, if you look at the entirety of the article ICU length of stay is dramatically affected:

      Phenobarbital: 34hrs (Range: 30 – 276)
      Placebo: 94hrs (Range: 43 – 134)

      Hope this helps.

      Salim

  • George
    Posted at 11:41h, 11 November Reply

    But the bottom line in this blog piece reads

    – Nothing has proven to shorten AWS duration or ICU LOS

    Doesn’t your response disagree with that bottom line.

    • Salim Rezaie
      Posted at 12:27h, 14 November Reply

      Not necessarily…Clinical Significance vs Statistical Significance. My original response to you was because of your “disingenuous” statement…if you look at the study there was a statistical significance in the mean time…however if you look at the range, which I included there is huge overlap which questions clinical significance. So, although statistically significant, the large range questions the clinical significance.

      Salim

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