<< Alcohol Withdrawal Syndrome: Improving Outcomes Through Early Identification And Aggressive Treatment Strategies (Critical Care Issue)


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Evidence-based medicine requires a critical ap;praisal of the literature based upon study methodol;ogy and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study will be included in bold type following the reference, where available. In addition, the most informative references cited in this paper, as determined by the authors, will be noted by an asterisk (*) next to the number of the reference.

  1. Bard MR, Goettler CE, Toschlog EA, et al. Alcohol withdrawal syndrome: Turning minor injuries into a major problem. J Trauma . 2006;61(6):1441-1445. (Retrospective; 6431 patients)
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  3. Genther DJ, Gourin CG. The effect of alcohol abuse and alcohol withdrawal on short-term outcomes and cost of care after head and neck cancer surgery. Laryngoscope . 2012;122(8):1739-1747. (Retrospective cross-sectional; 92,312 patients)
  4. Picciotto MR. Common aspects of the action of nicotine and other drugs of abuse. Drug Alcohol Depend . 1998;51(1-2):165- 172. (Review)
  5. Moore M, Gray MG. Delirium tremens: a study of cases at the Boston City Hospital, 1915–1936. New Engl J Med . 1939;220(23):953-956. (Observational; 2375 patients)
  6. Caetano R, Clark CL, Greenfield TK. Prevalence, trends, and incidence of alcohol withdrawal symptoms: analysis of general population and clinical samples. Alcohol Health Res World . 1998;22(1):73-79. (Review)
  7. Marik P, Mohedin B. Alcohol-related admissions to an in;ner city hospital intensive care unit. Alcohol and Alcoholism . 1996;31(4):393-396. (Prospective; 200 patients)
  8. American Psychiatric Association. DSM-5 Task Force. Diagnostic and Statistical Manual of Mental Disorders: DSM-5 . 5th ed. Washington, D.C.: American Psychiatric Association; 2013. (Medical reference text)
  9. Nelson L, Goldfrank LR. Goldfrank’s Toxicologic Emergencies. 9th ed. New York: McGraw-Hill Medical; 2011. (Textbook)
  10. Brent J. Critical Care Toxicology: Diagnosis And Management Of The Critically Poisoned Patient . 1st ed. St. Louis, MO: Mosby; 2005. (Textbook)
  11. Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of the alcohol withdrawal syndrome. Cochrane Database Syst Rev . 2011(6):CD008537. (Systematic review)
  12. * Amato L, Minozzi S, Vecchi S, et al. Benzodiazepines for alcohol withdrawal. Cochrane Database Syst Rev . 2010(3):CD005063. (Systematic review)
  13. Asplund CA, Aaronson JW, Aaronson HE. 3 regimens for alcohol withdrawal and detoxification. J Fam Pract . 2004;53(7):545-554. (Review)
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  16. * Mayo-Smith MF, Beecher LH, Fischer TL, et al. Management of alcohol withdrawal delirium - an evidence-based practice guideline. Arch Internal Med . 2004;164(13):1405-1412. (Systematic review)
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  24. Kraemer KL, Mayo-Smith MF, Calkins DR. Independent clinical correlates of severe alcohol withdrawal. Subst Abuse. 2003;24(4):197-209. (Retrospective cohort; 284 patients)
  25. Wetterling T, Kanitz RD, Veltrup C, et al. Clinical predictors of alcohol-withdrawal delirium. Alcohol Clin Exp Res. 1994;18(5):1100-1102.
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  27. Tsuang JW, Irwin MR, Smith TL, et al. Characteristics of men with alcoholic hallucinosis. Addiction. 1994;89(1):73-78. (Descriptive; 532 patients)
  28. Kaim SC, Klett CJ, Rothfeld B. Treatment of the acute alcohol withdrawal state: a comparison of four drugs. Am J Psychiatry. 1969;125(12):1640-1646. (Prospective randomized double-blind placebo-controlled trial; 537 patients)
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  33. Hung OR, Dyck JB, Varvel J, et al. Comparative absorption kinetics of intramuscular midazolam and diazepam. Can J Anaesth. 1996;43(5 Pt 1):450-455. (Kinetics study; 11 patients)
  34. Wermeling DP, Miller JL, Archer SM, et al. Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous, and intramuscular administration. J Clin Pharmacol. 2001;41(11):1225-1231. (Randomized crossover study; 11 patients)
  35. Greenblatt DJ, Joyce TH, Comer WH, et al. Clinical pharmacokinetics of lorazepam. II. Intramuscular injection. Clin Pharmacol Ther. 1977;21(2):222-230. (Kinetics study; 6 patients)
  36. Elliott HW. Metabolism of lorazepam. Br J Anaesth. 1976;48(10):1017-1023. (Review)
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  38. Hendey GW, Dery RA, Barnes RL, et al. A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal. Am J Emerg Med. 2011;29(4):382- 385. (Prospective; randomized trial; 44 patients)
  39. Hjermo I, Anderson JE, Fink-Jensen A, et al. Phenobarbital versus diazepam for delirium tremens--a retrospective study. Dan Med Bull. 2010;57(8):A4169. (Retrospective; 194 patients)
  40. Rosenson J, Clements C, Simon B, et al. Phenobarbital for acute alcohol withdrawal: a prospective randomized double-blind placebo-controlled study. J Emerg Med. 2013;44(3):592- 598. (Prospective randomized double-blind placebo-controlled trial; 102 patients)
  41. Korpi ER, Mattila MJ, Wisden W, et al. GABA(A)-receptor subtypes: clinical efficacy and selectivity of benzodiazepine site ligands. Ann Med. 1997;29(4):275-282. (Review)
  42. Ives TJ, Mooney AJ 3rd, Gwyther RE. Pharmacokinetic dosing of phenobarbital in the treatment of alcohol withdrawal syndrome. South Med J. 1991;84(1):18-21. (Case reports; 2 patients)
  43. Craft PP, Foil MB, Cunningham PR, et al. Intravenous ethanol for alcohol detoxification in trauma patients. South Med J. 1994;87(1):47-54. (Retrospective; 37 patients)
  44. DiPaula B, Tommasello A, Solounias B, et al. An evaluation of intravenous ethanol in hospitalized patients. J Subst Abuse Treat. 1998;15(5):437-442. (Retrospective; 68 patients)
  45. Weinberg JA, Magnotti LJ, Fischer PE, et al. Comparison of intravenous ethanol versus diazepam for alcohol withdrawal prophylaxis in the trauma ICU: results of a randomized trial. J Trauma. 2008;64(1):99-104. (Prospective randomized trial; 50 patients)
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  47. Alldredge BK, Lowenstein DH, Simon RP. Placebo-controlled trial of intravenous diphenylhydantoin for short-term treatment of alcohol withdrawal seizures. Am J Med. 1989;87(6):645-648. (Prospective randomized double-blind placebo-controlled trial; 90 patients)
  48. Rathlev NK, D’Onofrio G, Fish SS, et al. The lack of efficacy of phenytoin in the prevention of recurrent alcohol-related seizures. Ann Emerg Med. 1994;23(3):513-518. (Prospective randomized double-blind trial; 147 patients)
  49. D’Onofrio G, Rathlev NK, Ulrich AS, et al. Lorazepam for the prevention of recurrent seizures related to alcohol. N Engl J Med. 1999;340(12):915-919. (Randomized double-blind trial; 229 patients)
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  51. Hans P, Bonhomme V, Collette J, et al. Propofol protects cultured rat hippocampal neurons against N-methyl-D-aspartate receptor-mediated glutamate toxicity. J Neurosurg Anesthesiol. 1994;6(4):249-253. (Basic science; rat tissue culture)
  52. Irifune M, Takarada T, Shimizu Y, et al. Propofol-induced anesthesia in mice is mediated by gamma-aminobutyric acid-A and excitatory amino acid receptors. Anesth Analg. 2003;97(2):424-429. (Basic science; mice)
  53. Coomes TR, Smith SW. Successful use of propofol in refractory delirium tremens. Ann Emerg Med. 1997;30(6):825-828. (Case report)
  54. McCowan C, Marik P. Refractory delirium tremens treated with propofol: a case series. Crit Care Med. 2000;28(6):1781- 1784. (Case series; 4 patients)
  55. Corbett SM, Montoya ID, Moore FA. Propofol-related infusion syndrome in intensive care patients. Pharmacotherapy. 2008;28(2):250-258. (Review)
  56. Hughes DW, Vanwert E, Lepori L, et al. Propofol for benzodiazepine-refractory alcohol withdrawal in a non-mechanically ventilated patient. Am J Emerg Med. 2014;32(1):112 e113-e114. (Case report)
  57. Barrientos-Vega R, Mar Sanchez-Soria M, Morales-Garcia C, et al. Prolonged sedation of critically ill patients with mid-azolam or propofol: impact on weaning and costs. Crit Care Med. 1997;25(1):33-40. (Prospective randomized open-label trial; 108 patients)
  58. Daeppen JB, Gache P, Landry U, et al. Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial. Arch Intern Med. 2002;162(10):1117-1121. (Prospective randomized double-blind controlled trial; 117 patients)
  59. Maldonado JR, Nguyen LH, Schader EM, et al. Benzodiazepine loading versus symptom-triggered treatment of alcohol withdrawal: a prospective, randomized clinical trial. Gen Hosp Psychiatry. 2012;34(6):611-617. (Prospective randomized controlled trial; 47 patients)
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  64. Kotlinska J. NMDA antagonists inhibit the development of ethanol dependence in rats. Pol J Pharmacol. 2001;53(1):47-50. (Basic science; rats)
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  66. Ron D, Wang J. The NMDA receptor and alcohol addiction. In: VanDongen AM, ed. Biology of the NMDA Receptor. Boca Raton, FL: CRC Press; 2009. (Textbook)
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  68. Nagy J, Horvath C, Farkas S, et al. NR2B subunit selective NMDA antagonists inhibit neurotoxic effect of alcohol-withdrawal in primary cultures of rat cortical neurones. Neurochem Int. 2004;44(1):17-23. (Basic science; tissue culture)
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  70. Sass H, Soyka M, Mann K, et al. Relapse prevention by acamprosate. Results from a placebo-controlled study on alcohol dependence. Arch Gen Psychiatry. 1996;53(8):673-680. (Randomized double-blind placebo-controlled trial; 272 patients)
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  72. Bouza C, Angeles M, Munoz A, et al. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction. 2004;99(7):811-828. (Review)
  73. Staner L, Boeijinga P, Danel T, et al. Effects of acamprosate on sleep during alcohol withdrawal: a double-blind placebo-controlled polysomnographic study in alcohol-dependent subjects. Alcohol Clin Exp Res. 2006;30(9):1492-1499. (Double-blind placebo-controlled trial; 24 patients)
  74. Whitworth AB, Fischer F, Lesch OM, et al. Comparison of acamprosate and placebo in long-term treatment of alcohol dependence. Lancet. 1996;347(9013):1438-1442. (Double-blind placebo-controlled; 455 patients)
  75. Menke NB, King AM, Katz KD, et al. Adjunct ketamine use in the management of severe alcohol withdrawal: a case series (abstract). Clin Toxicol. 2012;50(7):611. (Case series abstract)
  76. Soto E, Stewart DR, Mannes AJ, et al. Oral ketamine in the palliative care setting: a review of the literature and case report of a patient with neurofibromatosis type 1 and glomus tumor-associated complex regional pain syndrome. Am J Hosp Palliat Care. 2012;29(4):308-317. (Case report and review)
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  79. Addolorato G, Balducci G, Capristo E, et al. Gamma-hy;droxybutyric acid (GHB) in the treatment of alcohol withdrawal syndrome: a randomized comparative study versus benzodiazepine. Alcohol Clin Exp Res . 1999;23(10):1596-1604. (Randomized controlled single-blind trial; 60 patients)
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  83. Muzyk AJ, Fowler JA, Norwood DK, et al. Role of alpha(2)- agonists in the treatment of acute alcohol withdrawal. Ann Pharmacother. 2011;45(5):649-657. (Review)
  84. Keaney F, Strang J, Gossop M, et al. A double-blind randomized placebo-controlled trial of lofexidine in alcohol withdrawal: lofexidine is not a useful adjunct to chlordiazepoxide. Alcohol Alcohol . 2001;36(5):426-430. (Prospective randomized double-blind placebo-controlled trial; 72 patients)
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  87. Koethe D, Juelicher A, Nolden BM, et al. Oxcarbazepine- -efficacy and tolerability during treatment of alcohol withdrawal: a double-blind, randomized, placebo-controlled multicenter pilot study. Alcohol Clin Exp Res. 2007;31(7):1188-1194. (Randomized double-blind placebo-controlled pilot; 50 patients)
  88. Aliyev ZN, Aliyev NA. Valproate treatment of acute alcohol hallucinosis: a double-blind, placebo-controlled study. Alcohol Alcohol. 2008;43(4):456-459. (Randomized double-blind placebo-controlled trial; 40 patients)
  89. Eyer F, Schreckenberg M, Hecht D, et al. Carbamazepine and valproate as adjuncts in the treatment of alcohol withdrawal syndrome: a retrospective cohort study. Alcohol Alcohol. 2011;46(2):177-184. (Retrospective cohort; 827 patients)
  90. Karst M, Passie T, Friedrich S, et al. Acupuncture in the treatment of alcohol withdrawal symptoms: a randomized, placebo-controlled inpatient study. Addict Biol. 2002;7(4):415- 419. (Prospective randomized placebo-controlled trial; 34 patients)
  91. Perry EC. Inpatient management of acute alcohol withdrawal syndrome. CNS Drugs. 2014;28(5):401-410. (Review)
Publication Information

Joseph H. Yanta, MD; Greg S. Swartzentruber, MD; Anthony F. Pizon, MD

Publication Date

June 1, 2015

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Current Guidelines For The Management Of Acute Alcohol Withdrawal In The Emergency Department (FREE) - EM Practice Guidelines Update - July 2010

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