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Subsections
Ethanol Withdrawal

Toxicology

Ethanol Withdrawal

Background

  1. Definition
    • Chemical Abstracts Service (CAS):
      • 64-17-5
    • Ethanol withdrawal is a life-threatening condition
      • Approximately 500,000 cases of withdrawal are severe enough to require medical therapy each year
      • About 50% of alcohol-dependent patients will develop withdrawal symptoms
  2. Synopsis
    • About 3-5% will develop delirium tremens (DTs)
      • Usually starts 6-8 hrs post-cessation with peak withdrawal symptoms at 72 hrs
        • However, the duration of abstinence required to produce withdrawal and the serum ethanol level at which withdrawal symptoms occur vary greatly between patients
      • Caused by abrupt decrease of CNS ethanol concentration and unmasking of compensatory excitatory neurotransmitters hyperactivity
      • Important neurotransmitters involved in withdrawal
        • Gamma-aminobutyric acid (GABA)
          • Inhibitory neurotransmitter
          • Ethanol agonizes the GABA receptor
          • With chronic ethanol use, receptor is downregulated (more alcohol needed to achieve same effects)
        • Glutamate
          • Excitatory neurotransmitter acting on NMDA receptor
          • Inhibited by ethanol
          • Upregulation of glutamate receptors with chronic ethanol use
    • Stages of withdrawal (most commonly used)

Mild Withdrawal (CIWA-Ar < 8)

  1. Pathophysiology
    • Hypersympathetic state
      • Withdrawal of anticonvulsant properties of EtOH (loss of GABA agonism)
      • Hyperactivity of CNS
    • Kindling
      • The intensification of withdrawal symptoms with each subsequent withdrawal
      • Repeat withdrawal may lead to increased relapse, brain damage, and likelihood of future life-threatening withdrawal
  2. Diagnostics
    • Signs/Symptoms
      • Typical onset 2-8 hrs after last drink; duration 1-3 days
      • Symptoms can begin even with elevated ethanol levels
      • Diaphoresis, headache, hypertension, tachycardia, palpitations, fine tremor
      • Nausea/vomiting, anxiety, anorexia, emotional lability, insomnia, irritability
    • Labs/Tests
      • Electrolytes, BUN/Cr, glucose, Magnesium, Phosphate
      • Coags: decreased platelet count/function with EtOH
      • Liver enzymes/LFTs
      • Urinalysis, hCG in women, urine drug screen if concern for another substance
  3. Treatment
    • Benzodiazepines
      • Mainstay of treatment of withdrawal symptoms
        • Prevent progression of minor withdrawal symptoms to major (prevent "kindling")
        • Long-acting agents preferred
        • Route of administration depends on clinical setting (fixed dosing vs symptom-based dosing)
          • Fixed dosing is more commonly used
          • Evidence of symptom-based therapy benefit
            • Patients need less medication and have a shorter treatment time
            • Should only be considered for patients without major withdrawal symptoms
      • Psychomotor agitation
        • Chlordiazepoxide: 50-100 mg PO only
        • Diazepam: 2-10 mg IV/PO/IM/PR repeat as needed for objective withdrawal symptoms
        • Lorazepam: 1-2 mg IV/PO/IM
          • Dose required for control is highly variable
    • Adjuvant therapy
      • Recommended but literature basis is not strong
      • Intravenous fluids: normal saline
      • Dextrose
      • Thiamine (100 mg), Magnesium sulfate (2000 mg), multivitamins are commonly added to IV fluid
      • Correct electrolyte abnormalities
  4. Disposition
    • If reliable, discharge home with 3-6 days of medication in a tapering dose
    • Most can be discharged
    • Possible discharge medication protocols
      • Chlordiazepoxide (avoid if hepatic disease)
        • Day 1: 100 mg QID
        • Day 2: 75 mg QID
        • Day 3: 50 mg QID
        • Day 4: 25 mg QID
      • Lorazepam
        • Day 1: 1 mg QID
        • Day 2: 1 mg TID
        • Day 3: 1 mg BID
        • Day 4: 1 mg qD
      • Phenobarbital
        • 30 mg qD tapered over 6 days to 5 mg

Moderate Withdrawal (CIWA-Ar 8-15)

  1. Pathophysiology
    • Same as mild (e.g., Hypersympathetic state, Kindling) with some agitation/anxiety, and tremulousness
  2. Diagnostics
    • Signs/Symptoms
      • Same as mild + agitation, coarse tremor
      • Hallucinations, status epilepticus (3% incidence)
    • Labs/Tests
  3. Treatment
    • Benzodiazepines (see dosing above)
    • Barbiturates
      • Used if refractory to benzodiazepines
      • Phenobarbital: 65 mg PO/IV/IM/PR
    • Haldol has been recommended by some for agitation refractory to benzodiazepines and barbiturates
      • Use with extreme caution due to risk of QTc prolongation, torsades and sudden death
      • Use of antipsychotics in ethanol withdrawal warrants cardiac monitoring
    • Thiamine should be strongly considered for any patient with major withdrawal symptoms to prevent development of Wernicke's encephalopathy
  4. Disposition
    • Admit, monitor closely
    • Other indications for admission
      • Age > 60 years old, first episode of ethanol withdrawal, fever, dehydration
      • Resting tachycardia, DBP > 100 mmHg, CHF, trauma with loss of consciousness
      • Cardiac disease, hemodynamic instability, severe acid-base abnormality
      • Severe electrolyte abnormalities, renal insufficiency
      • Respiratory insufficiency, serious infection, GI bleeding
      • Hyperthermia, rhabdomyolysis
      • History of prior alcohol withdrawal with DTs, need for high dose of sedatives to control symptoms

Severe Withdrawal (CIWA-Ar > 15)

  1. Pathophysiology
    • Most often seen in long history of heavy alcohol use
    • Estimated 3% of alcoholics have seizures
      • Alcohol is a contributing factor in 20-40% presenting to the emergency dept with seizures
      • EtOH is a powerful anticonvulsant (would be an excellent anti-seizure medication except for its side effects)
      • Acute cessation of EtOH is like acute anticonvulsant noncompliance
  2. Diagnostics
    • Signs/Symptoms
      • Moderate symptoms
      • Alcoholic hallucinosis
        • Visual and tactile (formication) much more common than auditory
        • Autonomic hyperactivity
        • Onset 7-48 hrs after last drink; duration 1-2 days
        • Occurs with clear sensorium, may be permanent
        • Separate entity from DTs
      • Seizures
        • Usually abrupt onset, generalized, tonic-clonic, no aura, short post-ictal, rarely tongue biting or incontinence, self-limited (very brief)
        • Approximately 40% single
        • About 90% ≤ 4 seizures in 6 hr period
        • About 4-8% status epilepticus: get CT scan and metabolite screen
        • Approximately 3-20% focal: get CT scan
      • Onset 7-48 hrs after last drink (95% first 12 hrs); duration 6-12 hrs
        • Can occur as early as 2 hrs after last drink
    • Labs/Tests
      • Fingerstick glucose
      • Electrolytes, BUN/Cr, glucose, Mg, Phos
      • Coags: decreased platelet count and function with EtOH
      • Liver enzymes/LFTs
      Imaging
      • Consider CT in all patients
        • About 3-6% incidence of unsuspected intracranial pathology (e.g., subdural hemorrhage)
    • Other Tests/Criteria
      • Any patient with seizure should be evaluated for alternative treatable causes
        • Metabolic (e.g., hypoglycemia, hypo/hypernatremia)
        • Trauma
        • Infection
        • CVA
        • Non-compliance with seizure meds
        • Drug use other than alcohol
        • Status epilepticus (warrants further work-up)
        • Mass lesions
  3. Treatment
    • ABCs, IV access, O2, monitor
    • Benzodiazepines (see dosing)
    • Status epilepticus
      • Aggressive benzodiazepines: dosing regimens vary
        • Diazepam: 5-10 mg IV every 5 min until agitation controlled
          • Quicker onset of action, shorter duration of seizure control than lorazepam
        • Lorazepam: 2-4 mg every 10 min
          • Less sedation in elderly or patients with liver disease
          • Longer seizure control because of slow redistribution
      • IVF, thiamine, folate, glucose
      • MgSO4: 2000 mg over 20 min
      • Phenobarbital (be ready to intubate): 65-260 mg IV every 15-30 min
      • Propofol: 0.25-2 mg/kg bolus + 0-5 mg/kg/hr infusion
      • Insufficient data for carbamazepine use
      • Phenytoin, levetiracetam, and valproic acid ineffective for withdrawal seizures
  4. Disposition
    • Admit to ICU

Delirium Tremens

  1. Pathophysiology
    • Overexcitation of central nervous system after alcohol abstinence
    • Serious medical emergency
    • Morbidity/Mortality
      • Mortality < 6% with aggressive therapy
    • Risk factors for developing DTs
      • History of sustained drinking
      • History of previous DTs or withdrawal seizures
      • Age > 30 years old
      • Concurrent illness
      • CIWA-Ar score > 15
  2. Diagnostics
    • Signs/Symptoms
      • Any alcohol withdrawal stage + delirium (i.e., decreased attention/awareness, disturbance in perception, memory)
      • Onset 48-96 hrs after appearance of withdrawal symptoms
        • Can begin 10 days after last drink
        • Duration 1-8 days (2-3 days is typical but may last up to 2 weeks)
      • Usually preceded by withdrawal seizures
      • Hyperthermia
      • Increased risk if prior DTs
      • Autonomic lability
      • Severe hypertension
      • Severe tachycardia and tachypnea
      • Hyperthermia can be > 101°F
    • Labs/Tests
      • Fingerstick glucose
      • Electrolytes including Mg, BUN/Cr, glucose
      • Toxicologic screen: rule out other co-ingestions if indicated
      • LFTs, CPK
      • Coags
    • Imaging
      • Consider head CT/LP if alternative diagnoses
  3. Treatment
  4. Disposition
    • DTs must be treated in ICU setting
    • "Impending DTs" may be treated on floor

ED Management Algorithm

  1. Recognition and Diagnostics
    • Patient presents with autonomic hyperactivity (e.g., agitation, tremor, delirium, seizures)
      • Send labs, consider head CT (evaluate for AMS etiology), give IVF, thiamine, glucose, folate, multivitamins PRN
      • Initiate loading dose of benzodiazepine
      • Re-evaluate in 15-30 min
      • Has patient's symptoms improved? (YES/NO)
    • Symptoms have not improved or worsened
      • Initiate escalating doses of benzodiazepine until sedation with improved vital signs or max dose reached (200 mg diazepam or 40 mg lorazepam)
      • Re-evaluate every 15-30 min
      • Has patient improved vital signs? (YES/NO)
    • Symptoms have not improved after escalating doses of benzodiazepine
      • Continue escalating doses of benzodiazepine and consider escalating doses of phenobarbital until sedation or max dose reached (260 mg phenobarbital)
      • Re-evaluate every 15-30 min
      • Has patient improved vital signs? (YES/NO)
    • Symptoms have not improved after addition of phenobarbital
      • Switch to propofol IV boluses (20-40 mg every 15-30 min PRN) or intubate and initiate infusion (titrate to effect)
      • Manage electrolytes, head CT if persistent AMS, manage pain
  2. Patient Improvement
    • Improved after initial loading dose of benzodiazepine
      • Additional benzodiazepine doses PRN
      • Re-evaluate every 15-30 min
      • If symptoms worsen, escalate benzodiazepine
    • Improved after escalating dose of benzodiazepine
      • Re-evaluate every 15-30 min
      • Administer additional benzodiazepine at last given dose PRN for symptoms
    • Improved after addition of phenobarbital
      • Re-evaluate every 15-30 min
      • Additional benzodiazepine at max dose for symptoms (+/- phenobarbital at max dose)
      • Manage electrolytes, head CT if persistent AMS, manage pain

References

  1. Stehman CR, Mycyk MB. A rational approach to the treatment of alcohol withdrawal in the ED. Am J Emerg Med. Apr 2013;31(4):734-742
  2. Gold JA, Nelson LS. Ethanol Withdrawal. In: Hoffman RS, Howland MA, Lewin NA, et al; (eds). Goldfrank's Toxicologic Emergencies, 10th ed. New York, NY:McGraw-Hill, 2015;Chapter 81
  3. Schuckit MA. Recognition and management of withdrawal delirium (delirium tremens). N Engl J Med. Nov 27, 2014;371(22):2109-2113
  4. 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. Aug 1994;272(7):519-523
  5. Gerlach M, Warnke A, Greenhill L. Psychiatric Drugs in Children and Adolescents: Basic Pharmacology and Practical Applications. Springer-Verlag Wien, 2014;Chapter 10
  6. Sirven JI, Waterhouse E. Management of Status Epilepticus. Am Fam Physician. Aug 1, 2003;68(3):469-476

Contributor(s)

  1. Anwar, Mehruba, MD
  2. Pomerleau, Adam, MD
  3. Singh, Ajaydeep, MD

Updated/Reviewed: November 2021