Alcohol Withdrawal: Pearls and Pitfalls

Authors: Drew Long, BS (Vanderbilt University School of Medicine, US Army) and Brit Long, MD (@long_brit) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Justin Bright, MD (@JBright2021)

Case

A 33 y/o man is brought in by EMS after a witnessed tonic-clonic seizure.  His vitals are notable for a HR of 124 and BP of 178/86.  The patient states he is trying to cut down on his alcohol consumption due to pressure from his wife and hasn’t had a drink in over 24 hours.  He is a social drinker and normally consumes “somewhere around 3-4 beers” each day in addition to “a little bit of vodka every now and then.”  He appears anxious, has a severe tremor, and is unable to hold a glass of water without spilling its contents.  The rest of the physical exam is unremarkable.  What is the initial workup and management of this patient?  Is he in alcohol withdrawal?  What other conditions must be ruled out?

Epidemiology

Alcohol use is extremely widespread throughout developed countries.  It is estimated that 8 million people in the US are alcohol dependent.1 Approximately 20% of men and 10% of women will at some point in their lives have an alcohol-use disorder.2 About half of people with alcohol-use disorders will have symptoms of withdrawal when they cut down or stop their alcohol consumption.3 Extreme complications, including seizures and/or delirium tremens, will occur in 3-5% of these people.3

Pathophysiology

Alcohol is a CNS depressant: it potentiates GABA receptors to enhance inhibitory tone in the brain and antagonizes the NMDA receptor to inhibit excitatory tone.1,4 Chronic alcohol exposure leads to brain adaptation to the effects of alcohol through changes in receptors.  Chronic ethanol use leads to down-regulation and conformational changes of the GABA receptor.  Additionally, in chronic alcoholics, NMDA receptors undergo conformational changes and up-regulation.  These changes lead to an increased tolerance to ethanol, requiring higher blood alcohol levels to achieve the similar effects of intoxication.1,5-7

The underlying pathophysiology of acute alcohol withdrawal is CNS hyperexcitation.6 After the chronic alcoholic ceases alcohol consumption, they lose the GABA inhibitory effect and have a potentiation of NMDA excitatory effects.  These effects lead to CNS hyperstimulation.

Differential Diagnosis and Evaluation

First and foremost, alcohol withdrawal syndrome (AWS) is a clinical diagnosis (cannot be confirmed by any laboratory tests) and a diagnosis of exclusion.  Even in the withdrawing chronic alcoholic, the Emergency Physician must evaluate for an underlying process resulting in the patient’s presentation.  It is vital to consider and rule out other pathologies that can mimic alcohol withdrawal syndrome (Table 1), while keeping in mind that chronic alcoholics are prone to malnutrition, trauma, and electrolyte abnormalities.  At the same time, the Emergency Physician must strive to recognize AWS early to prevent progression of minor symptoms to life-threatening complications.

Table 1.  Differential Diagnosis of Alcohol Withdrawal Syndrome6

 

 

 

Toxicologic

 

 

 

Alcohol intoxication

Sympathomimetic intoxication

Anticholinergic syndrome

Sedative-hypnotic withdrawal

Serotonin syndrome

Neuroleptic malignant syndrome

 

 

 

 

 

 

Medical

 

 

Thyrotoxicosis

Myocardial ischemia

PE

Meningitis/encephalitis

Acute psychosis

Hypoglycemia

Head trauma

Hepatic failure

GI bleed

Sepsis and septic shock

 

 

The diagnosis of AWS is driven by the history and physical.  The patient’s history of alcohol abuse, including amount of alcohol consumed per day in addition to number of years of alcohol use, must be quantified.  The Emergency Physician should keep in mind that patients with alcohol use disorder commonly minimize their alcohol consumption.  Furthermore, it is very important to recognize that a patient can have alcohol in their system and still be withdrawing.  For example, if a patient typically has a basal alcohol level of 0.30 g/dL, then a serum level of 0.15 g/dL would be a significant reduction for this patient.  The patient should also be asked why they decided to cease consumption of alcoholA quick and easy method of screening a patient with a positive history of alcohol use is the CAGE questionnaire (http://www.mdcalc.com/cage-questions-for-alcohol-use/).  The Emergency Physician should also inquire about illicit drug use.

In approaching the patient with alcohol withdrawal, the Emergency Physician should additionally consider underlying pathologies, such as pancreatitis or severe gastritis.  In tachycardic patients, further evaluation for PE, MI, sepsis, or dehydration may be warranted.6

Testing in patients with suspected alcohol withdrawal syndrome should be driven by the differential diagnosis, in which the Emergency Physician should rule out mimicking or potential coexisting conditions.  Helpful laboratory and imaging evaluations are shown in Table 2.

Table 2.  Tests in AWS6
CBC
Serum pH and osmolality
CMP (evaluate for alcoholic hepatitis)
ECG
Serum salicylate and APAP levels
Ethanol level (controversial)
CXR
Head CT
Coagulation panel (PT/INR, PTT)

 

A CBC may show pernicious anemia from vitamin B12 deficiency.  The CMP may show hypokalemia, hypomagnesemia, hyponatremia, and/or elevated liver enzymes.  Chronic alcoholics are prone to electrolyte abnormalities due to malnutrition and dehydration.  In regards to LFTs, remember that in alcoholic hepatitis, AST is elevated to a greater degree than ALT. Especially if the patient is altered, a rapid glucose is necessary to evaluate for and if necessary correct hypoglycemia.  If concerned with another ingestion, it is helpful to order serum salicylate and APAP levels.  An ECG can assist in evaluating for ischemia or other toxic ingestions. If fever or hypoxia is present, a CXR is useful in ruling out pulmonary pathologies (most likely pneumonia).  A head CT is warranted if there is a concern for any type of trauma or the patient is altered.  Coagulation studies may reveal elevated INR.5,6

Stages of Withdrawal

Reductions in the concentration of alcohol in the blood lead to symptoms that are generally the opposite of the acute effects of alcohol intoxication.  Symptoms from alcohol withdrawal usually start within 6-8 hours (after the blood alcohol level decreases), peak at 72 hours, and diminish by days 5 to 7 of abstinence.1,7 Broad withdrawal symptoms from alcohol include insomnia, anxiety, GI upset (nausea/vomiting), tremulousness, headache, diaphoresis, palpitations, increased body temperature, heart rate, and blood pressure.1,3  Of note, patients taking beta blockers or alpha-2 agonists may have blunted autonomic hyperactivity.5  If the patient’s withdrawal does not progress, these withdrawal symptoms will often resolve within 24 to 48 hours.8

Alcohol hallucinations generally occur 12-24 hours after the patient’s last drink.9 Alcoholic hallucinations occur in 7-8% of patients with AWS.10 These hallucinations are most commonly tactile but may also be visual.  Importantly, alcoholic hallucinations can be differentiated from delirium tremens in that patients with alcoholic hallucinations will have an otherwise normal sensorium.

Withdrawal seizures generally occur 12-48 hours after the patient’s last drink.11 These seizures, while generalized tonic-clonic, are typically minor (isolated, short in duration, little post-ictal period).  In the seizing alcoholic patient, alternative causes of seizures must be considered (i.e. infection, subdural hematoma, or metabolic abnormalities).6 Of note, AWS patients who have withdrawal seizures have a higher likelihood of progressing to delirium tremens, as 1/3 of patients with withdrawal seizures progress to DT.11

Delirium tremens (DT) is a rapid-onset, fluctuating disturbance of attention and cognition (sometimes with hallucinations) plus alcohol withdrawal symptoms and autonomic instability.5 DT occur in 3-5% of patients who are hospitalized for alcohol withdrawal.7,12,13 DT usually begins 3 days after the appearance of withdrawal symptoms and lasts for 1 to 8 days.7,14,15 The mortality of hospitalized patients with DT is currently estimated to be 1-4%.7,13-15 DT can be predicted by the following factors:16-18

  • History of previous DT
  • History of sustained drinking
  • CIWA scores > 15
  • Patients with SBP > 150, or patients with HR greater than 100
  • Recent withdrawal seizures
  • Prior withdrawal delirium or seizures
  • Older age
  • Recent misuse of other depressants
  • Concomitant medical problems

Treatment

Like every patient presenting to the ED, the initial management for any patient with suspected alcohol withdrawal is the ABCs (airway, breathing, circulation).  The mainstay of treatment of mild, moderate, and severe alcohol withdrawal is benzodiazepines.7,14,19 Benzodiazepines act as central GABAA agonists, addressing the underlying problem being alcohol withdrawal (CNS hyperexcitation).  Benzodiazepines treat the psychomotor agitation experienced by withdrawing alcoholics in addition to preventing progression to more serious withdrawal symptoms.   While benzodiazepines are the optimal treatment for AWS, there is debate regarding which benzodiazepine is best.  No single benzodiazepine has been shown to be superior. 

Four benzodiazepines to be aware of in the management of AWS are Valium (diazepam), Ativan (lorazepam), Versed (midazolam), and Librium (chlordiazepoxide). For acute symptom control, most clinicians prefer diazepam or lorazepam.  Diazepam has a faster onset of action (1-5 minutes) compared to lorazepam (5-20 minutes), which may allow for easier titration and avoidance of dose stacking.20 Diazepam also has active metabolites, nordazepam and oxazepam, which extend the duration of sedating effects. On the other hand, lorazepam has a short half-life and no active metabolites, which may help prevent prolonged effects of oversedation.  Another benzodiazepine to consider is chlordiazepoxide, which is available in only oral format.  Chlordiazepoxide has a slow onset of action and relatively long half-life, making it ideal for an outpatient setting.  These properties also provide chlordiazepoxide with a lower potential for abuse. Table 3 compares various benzodiazepines in the treatment of AWS.

Table 3.  Benzodiazepines for AWS6

Drug Lipid solubility Time to onset Active metabolites? Initial Dose
Diazepam ++++ 1-5 min IV Yes 10-20 mg IV

10-20 mg PO

Lorazepam +++ 5-20 min IV No 2-4 mg IV

2-4 mg PO

Midazolam +++ 2-5 min IM/IV Yes 2-4 mg IM/IV
Chlordiazepoxide +++ 2-3 hrs PO Yes 50-100 mg PO

 

The decision to give benzodiazepines is often based on symptom-triggered therapy, as evaluated by the Clinical Institute Withdrawal Assessment for Alcohol (CIWA) scale.  Symptom-triggered therapy was validated by Saitz et al in 1994.  This study was a randomized double-blind controlled trial comparing patients receiving chlordiazepoxide for AWS with either a fixed schedule or symptom-triggered therapy.  This study found patients in the symptom-triggered therapy group required less medication (median 100 vs. 425 mg) and a shorter treatment period (median 9 vs. 68 hours).21 The maximum score of the CIWA scale is 67.  A mild score is 15 or less, moderate is 16-20, and severe withdrawal is a score greater than 20.  For CIWA monitoring, evaluations as frequent as every 10-15 minutes may be appropriate for patients with severe AWS receiving treatment with benzodiazepines.  Once symptoms are under control, hourly reassessment with CIWA is effective.22

For patients with severe AWS, repeating escalating doses of IV diazepam (20, 40, 80 mg) or lorazepam (2, 4, 8, 16 mg) are recommended.  An escalating dose of diazepam can be given every 10-15 minutes as required, while an escalating dose of lorazepam can be given every 15-20 minutes as required.  The clinician should utilize this regimen of escalating doses based on the patient’s vital signs and clinical appearanceFor severe withdrawal, titrating benzodiazepines to achieve a state of somnolence with arousal to minimal stimulation is a reasonable goal.   This method of escalating benzodiazepines dosing and front-loading has been shown to reduce seizures, DT, and the need for mechanical ventilation in patients with severe AWS.6,23,24

A pitfall to avoid in the management of AWS is attributing complications from AWS to another condition and administering the incorrect treatment.  For example, in alcoholic hallucinosis, the management is benzodiazepines, with limited data showing that antipsychotics are actually detrimental in acute AWS.25 For withdrawal seizures, there is no role for antiepileptic medications, and benzodiazepines are again the treatment of choice.26

A small subgroup of patients may have benzodiazepine-resistant alcohol withdrawal and DT.  Early aggressive treatment of these patients is warranted, including fast escalation of doses of benzodiazepines.24 A reasonable choice in these patients not responding to benzodiazepines is a barbiturate such as phenobarbital, which has been associated with a decrease in ICU admissions when utilized early in the course of management of AWS.27 Additionally, intubation should be at the forefront of patients with severe AWS not responding to benzodiazepines, with propofol being ideal as an induction agent due to its GABA agonist and NMDA antagonist effects.28,29  Some preliminary evidence also supports the use of dexmedetomidine in these patients

Other therapies to consider in patients with AWS include re-orienting the patient to time, place, and date.  The patient should be placed in a well-lit room, provided reassurance, receive frequent monitoring of vitals, and receive adequate volume resuscitation.  Severe alcohol withdrawal has an important impact on a patient’s fluid and electrolyte status, and almost all patients with AWS are hypovolemic.  In addition, thiamine and multivitamins should be given to the chronic alcoholic.  Any electrolyte abnormalities should be corrected.

Disposition

Disposition of the AWS patient depends on accurate identification of the patient’s degree of withdrawal.  Patients who have a very mild CIWA score and are not currently intoxicated may be considered for discharge.  On the other end of the spectrum, patients with severe AWS and/or medical comorbidities will need ICU admission.  Table 4 outlines aspects to consider in the disposition of patients with AWS.

Table 4.  Disposition for AWS6

 

 

 

 

Discharge with detoxification referral31

 

-CIWA Score <8

-Patient not currently intoxicated (alcohol or other drugs)

-No history of complicated AWS (seizures, hallucinosis, DT)

-No significant medical or psychiatric comorbidities

 

 

 

 

 

 

Inpatient detoxification or medical unit

 

-No underlying medical or surgical condition requiring ICU-level care

Normalization or near-normalization of vitals in ED

Clear sensorium

-Responsive to 10-20 mg diazepam

Tolerates 2-4 hours between benzodiazepine doses

-Presence of medical or psychiatric condition requiring inpatient admission

 

 

 

 

 

 

 

Intensive Care Unit

 

-Underlying medical or surgical condition requiring ICU-level care

-Patient requires >100-200 mg of diazepam to control symptoms in ED

-Requires benzodiazepines more frequently than every 2 hours

-Requires phenobarbital or other adjunctive therapy to control AWS

-Hyperthermia present

-Altered sensorium or recurrent seizures present

 

 

Case Resolution

After your encounter with this patient, you remember that while he is likely going through alcohol withdrawal, this is a diagnosis of exclusion.  You evaluate the patient for other etiologies of his seizure (including infection, subdural hemorrhage, and metabolic abnormalities).  While considering other conditions, you place this patient on the CIWA scale, for which he scores 23.  A head CT is negative for any abnormalities, and his laboratory analysis is remarkable for an AST of 92, ALT of 41, and Tbili of 5.  His UDS comes back positive for cocaine and methamphetamine.

Due to his severe withdrawal as graded by the CIWA score, requirement for frequent monitoring and administration of benzodiazepines, he is admitted to the ICU for further management of his alcohol withdrawal.

Summary

  • The underlying pathophysiology of AWS is CNS hyperexcitation.
  • AWS is a diagnosis of exclusion; it is vital to rule out other mimicking conditions (including other toxins, head trauma, and sepsis).
  • AWS must be recognized early based on the presentation and history of alcohol use and cessation of alcohol consumption.
  • Patients can withdraw from alcohol even if they still have alcohol in their system
  • Stages of withdrawal include withdrawal symptoms, hallucinations, seizures, and delirium tremens.
  • Delirium tremens is a rapid-onset fluctuating disturbance of attention and cognition (sometimes with hallucinations) plus alcohol withdrawal symptoms and often autonomic instability. It usually begins about 3 days after the appearance of symptoms and can last anywhere from 1-8 days.
  • The mainstay of treatment for all stages of AWS is benzodiazepines.
  • Symptom-triggered therapy is recommended for dosing and administration of benzodiazepines.

Pearls/Pitfalls

  • Even in AWS patients who develop DT, early symptoms may be mild.
  • In the tachycardic alcoholic patient, be sure to consider PE, myocardial infarction, sepsis, dehydration, and other potential diagnoses other than AWS.
  • Alcoholics commonly present with a range of metabolic abnormalities, some of which can be life-threatening. Be sure to check for these abnormalities and correct as appropriate.
  • The presence of confusion or altered mentation in a patient with AWS may be due to DT and warrants admission to a higher level of care such as an ICU.
  • AWS is a diagnosis of exclusion: consider structural CNS pathology, metabolic abnormalities, infection, other toxicologic causes, and other conditions before diagnosing AWS.
  • A seizure in a patient with AWS who has never had a previous seizure warrants a complete neurological work-up and cranial imaging.
  • Patients with alcohol use disorder commonly minimize their alcohol consumption, often understating the true degree of how much alcohol they consume on a daily basis.
  • Benzodiazepines are always your first line treatment for alcohol withdrawal syndromes.

References/Further Reading

  1. Kosten TR, O’Connor PG. Management of drug and alcohol withdrawal.  N Engl J Med.  2003 May 1;348(18):1786-95.
  2. Schuckit MA. Alcohol-use disorders.  Lancet.  2009;373:492-501.
  3. American Psychiatric Association. Diagnostic and statistical manual of mental disorders.  5th  DSM-5.  Washington, DC:  American Psychiatric Publishing, 2013.
  4. Schuckit MA. Ethanol and methanol.  In:  Brunton LL, Chabner BA, Knollmann BC, eds.  Goodman and Gilman’s the pharmacologic basis of therapeutics.  12th  New York:  McGraw-Hill, 2011:629-47.
  5. Schuckit MA. Recognition and management of withdrawal delirium (delirium tremens).  N Engl J Med.  2014 November 371;22:2109-2113.
  6. Yanta JH, Swartzentruber GS, Pizon AF. Alcohol withdrawal syndrome:  Improving outcomes through early identification and aggressive treatment strategies.  EB Medicine.  2015 June 17;6:1-20.
  7. Mainerova B, Prasko J, Latalova K, et al. Alcohol withdrawal delirium—diagnosis, course and treatment.  Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2013;157:1-9.
  8. Etherington JM. Emergency management of acute alcohol problems.   Part 1:  Uncomplicated withdrawal.  Can Fam Physician. 1996;42:2186.
  9. Victor M, Adams RD. The effect of alcohol on the nervous system.  Res Publ Assoc Res Nerv Ment Dis.  1953;32:526.
  10. Tsuang JW, Irwin MR, Smith TL, et al. Characteristics of men with alcoholic hallucinosis.    1994;89(1):73-78.
  11. Victor M, Brausch C. The role of abstinence in the genesis of alcoholic epilepsy.    1967;8(1):1.
  12. Eyer F, Schuster T, Felgenhauer N, et al. Risk assessment of moderate to severe alcohol withdrawal—predictors for seizures and delirium tremens in the course of withdrawal.  Alcohol Alcohol.  201146:427-33.
  13. Berggren U, Fahlke C, Berglund KJ, Blennow K, Zetterberg H, Balldin J. Thrombocytopenia in early alcohol withdrawal is associated with development of delirium tremens or seizures.  Alcohol Alcohol.  2009;44:382-6.
  14. Mayo-Smith MF, Beecher LH, Fischer TL, et al. Management of alcohol withdrawal delirium:  an evidence-based practice guideline.  Arch Intern Med.  2004;164:1405-12.
  15. Hjermo I, Anderson JE, Fink-Jensen A, Allerup P, Ulrichsen J. Phenobarbital versus diazepam for delirium tremens—a retrospective study.  Dan Med Bull.  2010;57:A4169.
  16. Ferguson JA, Suelzer CJ, Eckert GJ, Zhou XH, Dittus RS. Risk factors for delirium tremens development.  J Gen Intern Med.  1996;11(7):410.
  17. Cushman P Jr. Delirium tremens.  Update on an old disorder.  Postgrad Med.  1987;82(5):117.
  18. Schuckit MA, Tipp JE, Reich T, Hesselbrock VM, Bucholz KK. The histories of withdrawal convulsions and delirium tremens in 1648 alcohol dependent subjects.    1995;90(10):1335.
  19. Amato L, Minozzi S, Vecchi S, Davoli M. Benzodiazepines for alcohol withdrawal.  Cochrane Database Syst Rev.  2010;3:CD005063.
  20. Stehman CR, Mycyk MB. A rational approach to the treatment of alcohol withdrawal in the ED.  Am J Emerg Med.  2013;31(4):734-742.
  21. Saitz R, Mayo-Smith MF, Roberts MS, Redmond HA, Bernard DR, Calkins DR. Individualized treatment for alcohol withdrawal.  A randomized double-blind controlled trial.  JAMA.  1994;272(7):519.
  22. Hoffman RS, Weinhouse GL. Management of moderate and severe alcohol withdrawal syndromes.  UpToDate.  12 November 2015.
  23. Muzyk AJ, Leung JG, Nelson S, et al. The role of diazepam loading for the treatment of alcohol withdrawal syndrome in hospitalized patients. Am J Addict. 2013 Mar-Apr;22(2):113-8.
  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(3):724-730.
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. Irifune M, Takarada T, Shumizu 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.
  30. 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.  2013 Dec;20(6):425-7.
  31. Asplund CA, Aaronson JW, Aaronson HE. 3 regimens for alcohol withdrawal and detoxification.  J Fam Pract.  2004;53(7):545-554.
  32. Arendt RM, Greenblatt DJ, deJong RH, et al. In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamics action and peripheral distribution.  J Pharmacol Exp Ther.  1983;227(1):98-106.

4 thoughts on “Alcohol Withdrawal: Pearls and Pitfalls”

Leave a Reply

Your email address will not be published.