A 32-year-old male with anxiety and tremor

You are working an evening shift during your first year as an Emergency Medicine resident. A new patient shows up on the board. You briefly check his information, and you learn that he is a 32-year-old male with history of alcohol abuse coming into the Emergency Department for anxiety and tremors.

Triage note says in bold: “last drink 50 hours ago.” The patient is tachycardic, hypertensive, and mildly tachypneic. 

You go to see the patient and based on the information you got, you diagnose him with alcohol withdrawal syndrome complicated by withdrawal delirium (delirium tremens). Good! You have a clinical diagnosis, but what does this patient need for workup and management?

Figure 1. DSM-5 Criteria for Alcohol Withdrawal and Delirium. If the patient fulfills the criteria for both the diagnosis of alcohol withdrawal complicated by withdrawal delirium is made.

Pathophysiology

There are two different ethanol action in the central nervous system (CNS) that lead to symptoms of alcohol withdrawal. Overall, alcohol is a central nervous system depressant. It simultaneously increases inhibitory tone via modulation of GABA activity and decreases excitatory tone via modulation of excitatory amino acid activity. In a patient with alcohol abuse disorder, only a constant presence of alcohol keeps the necessary homeostasis. Sudden cessation unmasks the adaptive responses to chronic ethanol use, resulting in overactivity of the central nervous system.

Gamma-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. Highly specific binding sites for ethanol are found on the GABA receptor complex. Chronic ethanol use induces GABA receptor insensitivity to GABA resulting in a need for a stronger inhibitory stimulus to maintain a constant inhibitory tone. As alcohol tolerance develops, the individual retains arousal at alcohol concentrations that would normally produce lethargy or even coma in people who do not have alcohol use disorder. Sudden cessation of alcohol intake or a reduction from chronically elevated concentrations results in decreased inhibitory tone due to the lack of inhibitory effects of ethanol.

Glutamate is one of the major excitatory amino acids. When glutamate binds to the N-methyl-D-aspartate (NMDA) receptor, calcium influx leads to neuronal excitation by binding to the glycine receptor on the NMDA complex. Ethanol inhibits glutamate-induced excitation. Adaption occurs by increasing the number of glutamate receptors in an attempt to maintain a normal state of arousal.

Figure 2. Inhibitory and excitatory balance in a healthy individual.
Inhibitory and excitatory balance in an individual with chronic alcohol abuse.
Figure 3. Inhibitory and excitatory balance in an individual with chronic alcohol abuse. The constant presence of alcohol is needed to maintain inhibitory tone on insensitive GABA receptors and to inhibit excitatory tone on upregulated NMDA receptors.
Loss of the inhibitory and excitatory balance after alcohol cessation.
Figure 4. Loss of the inhibitory and excitatory balance after alcohol cessation. Upregulated NMDA receptors lead overexcitation, and insensitive GABA receptors are not enough to counteract that. Alcohol withdrawal symptoms ensue.

Differential Diagnosis

Alcohol withdrawal remains a clinical diagnosis. The severity of presentation can be assessed using a clinical assessment scale called Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) that can be found on MD Calc.

In some cases, several additional tests might be needed to rule out other conditions that mimic or coexist with alcohol withdrawal syndrome. This is especially true when the patient has altered mental status and fever. Conditions such as infection (e.g., meningitis), trauma (e.g., intracranial hemorrhage), metabolic abnormalities, drug overdose, hepatic failure, and gastrointestinal bleeding can mimic or coexist with alcohol withdrawal. Also, it is of marked importance to try to understand why the patient stopped consuming alcohol. If you establish that he wanted to get sober, that is great, you or the admitting team can help setting up rehab for him after the acute problems are controlled. However, you should get suspicious if there is not a clear cause for the abrupt cessation of alcohol intake since it could be an acute condition being masked by the withdrawal syndrome.

Initial workup might include:

  • Point of care glucose

  • CBC and platelets

  • Sodium, potassium, chloride, bicarbonate, BUN, creatinine

  • Calcium, magnesium, and phosphorus

  • Total protein, albumin, total bilirubin, AST, ALT, and alkaline phosphatase, and lipase

  • Creatine kinase

  • Chest x-ray to rule out simultaneous pneumonia

  • Consider head CT and lumbar puncture, if there are any findings concerning for trauma, intracranial hemorrhage, or CNS infections

  • Consider drug screen if concern for co-ingestion

Figure 5. The differential diagnosis for alcohol withdrawal. It is important to not anchor on this diagnosis and to look for mimics and conditions that might coexist with it.

Supportive Care

As important as proving control of the patient’s withdrawal symptoms is to provide high-quality supportive care, which includes:

  • Placement in a quiet and protective environment

  • Preference for chemical sedation over physical restraints, which should be removed as soon as adequate chemical sedation is achieved because resistance against restraints can increase temperature, produce rhabdomyolysis, and cause physical injury

  • IV fluids

  • Thiamine and glucose should be administered in order to prevent or treat Wernicke encephalopathy

  • Multivitamins containing or supplemented with folate should be given routinely

  • Deficiencies of glucose, potassium, magnesium, and phosphate should be corrected as needed

  • Nothing by mouth in the early stages of treatment to prevent aspiration

  • Patients considered at high risk for complications should be monitored in an intensive care unit

  • Consider ICU admission and EtCO2 monitoring in those patients with severe alcohol withdrawal per CIWA-Ar

Symptomatic Treatment

The basis for the treatment of alcohol withdrawal is CNS depressants, such as benzodiazepines, with a treatment goal of Richmond Agitation and Sedation Scale (RASS) -1 and HR < 110. No single drug benzodiazepine is superior to another. A common treatment strategy is to use a benzodiazepine of choice and give escalating doses until symptomatic control or until you reach criteria for refractory alcohol withdrawal.

Figure 6. Two common initial treatment strategies for alcohol withdrawal.

Refractory Withdrawal Delirium

Some patients have refractory delirium tremens (DT) despite treatment with high-dose benzodiazepines. Refractory DT is not clearly defined. It may be present if symptoms of severe withdrawal are not controlled adequately after the IV administration of more than 50 mg of diazepam or 10 mg of lorazepam during the first hour of treatment, or 200 mg of diazepam or 40 mg of lorazepam during the initial three to four hours of treatment. In such cases, as with any dangerous toxicologic disorder, you should obtain assistance from a medical toxicologist or poison control center. In case you diagnose your patient with alcohol withdrawal refractory to benzodiazepine treatment, you should have a few other options in your treatment arsenal.

Summary of sedation strategy.
Figure 7. Summary of sedation strategy. Initial treatment with benzodiazepines in escalating doses. If good response, keep regimen titrated to treatment goals. If no response, consider refractory withdrawal delirium and other pharmacologic options. If no response after secondary treatment, consider intubation with propofol.

Phenobarbital

There are case reports of up to 2000 mg of Phenobarbital administered orally or intravenously on the first day in patients with alcohol withdrawal delirium. Consider giving phenobarbital 130 to 260 mg IV, repeated every 15 to 20 minutes, until symptoms are controlled. Also, you can consider administering Phenobarbital earlier in the disease course. A randomized trial of 102 patients presenting to the emergency department with acute alcohol withdrawal, those treated with lorazepam and a single dose of Phenobarbital had substantially lower ICU admission rates compared with those treated with lorazepam alone (8 versus 25 percent).

Dexmetomedine

Another adjunctive medication for alcohol withdrawal is dexmedetomidine, an α2-adrenergic agonist that is used to provoke a state in which the patient is sedated but arousable, with a decreased sympathetic tone. Doses up to 0.7 μg per kilogram per hour have been administered in patients who do not have a good response to benzodiazepines. Heart block is a contraindication to this drug since it can cause bradycardia. In case it is given, blood pressure and heart rate must be closely monitored.

Propofol and Intubation

In patients who do not have a response to high doses of benzodiazepines (especially patients who are intubated), propofol may be administered to reach symptomatic control.

Take home points.
Figure 8. Take home points.

Further Reading

  • Schuckit, MA. “Recognition and Management of Withdrawal Delirium (Delirium Tremens)”, N Engl J Med 2014; 371:2109-2113
  • Hoffman, RS and Weinhouse, GL. “Management of moderate and severe alcohol withdrawal syndromes”, UpToDate, Dec 18, 2018. Available at https://www.uptodate.com/contents/management-of-moderate-and-severe-alcohol-withdrawal-syndromes
  • Weingart, S. “EMCrit Podcast 11 – Delirium Tremens”, EMCrit RACC, Sep 29, 2009. Available at https://emcrit.org/emcrit/delirium-tremens/

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