Alcohol Withdrawal Syndrome: Identification and Management

Authors: Jack Yancey, MD (EM Resident Physician, University of Kentucky); Drew Micciche, MD (Medical Toxicologist/EM Attending Physician, University of Kentucky) // Reviewed by: Todd Phillips, MD (@ToddsToxTalks, EM Attending Physician/Medical Toxicologist, UTSW/Parkland); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case

A 47-year-old male presents to the emergency department with anxiety, insomnia, and new onset tremors most noticeable in his bilateral upper extremities.  His symptoms began less than a day ago, worsening over the last 6 hours.  The patient lives alone, and has been self-quarantining in his apartment since being diagnosed with COVID-19 six days ago.  Vital signs are notable for a HR of 127, BP 155/85, RR 25, T 37.4, SpO2 98% RA.  He has no past medical history, however admits to drinking alcohol daily for several years, typically one pint of whiskey.  His last drink was 24 hours ago, when he ran out of alcohol in his apartment.  On exam he is anxious appearing, diaphoretic, and visibly tremulous.  Bedside point of care glucose is 97.  The remainder of his physical exam is unremarkable.  How would you work up and manage this patient in the emergency department?  What are your differential diagnoses?  How do you make the diagnosis of alcohol withdrawal syndrome, and how would you determine the severity of his withdrawal?

Epidemiology

Alcohol use is extremely common in the United States and other developed countries.¹  Approximately 8 million people are alcohol dependent in the US; 20% of men and 10% of women will suffer from alcohol use disorder (AUD) within their lifetime with an overall prevalence of 14%.^1,2,3  Roughly half of those with AUD will experience withdrawal symptoms following decreased alcohol consumption or complete cessation.¹  Severe complications, including seizures and/or delirium tremens, will occur in 3-5% of these people.^2,15  Alcohol use is associated with 88,000-100,000 US deaths annually, making it the third leading preventable cause of death in the United States.^4,5  In 2011, there were approximately 4 million alcohol-related emergency department visits in the US, with a 47% increase in incidence occurring between 2006 and 2014.^6,7

Clinical Relevance

Generally speaking, most emergency medicine physicians treat at least one patient with an alcohol-related chief complaint per shift.  This can range from the intoxicated trauma patient to the patient in florid withdrawal.  Current studies show an increasing incidence of alcohol-related ED visits, therefore emergency medicine physicians must be comfortable recognizing and managing this patient population.  The focus of this writeup moving forward will be on the identification, management, and disposition of patients with alcohol withdrawal syndrome (AWS).

Pathophysiology

Ethanol acts as a central nervous system (CNS) depressant after consumption.  This is mainly due to its effects on the brain’s GABA_A and NMDA receptors.  The majority of the effect of ethanol is on the GABA_A receptor as an agonist. This increases inhibitory tone within the brain. An often-forgotten mechanism is that it is also an NMDA receptor antagonist that inhibits CNS excitatory tone.  Prolonged daily consumption of ethanol leads to conformational changes at these receptors, which include down-regulation of the GABA receptors and up-regulation of the NMDA receptors.  Due to this, patients with AUD require the constant presence of ethanol to achieve CNS homeostasis and prevent withdrawal symptoms.  Additionally, these patients often develop tolerance to ethanol, requiring higher blood alcohol levels to achieve clinical intoxication.^2,3  Abrupt reduction or cessation in ethanol consumption creates CNS hyperexcitation due to deficient GABA activity and excessive NMDA activity (Figure 1).¹³  This is the primary physiological abnormality associated with AWS.  CNS hyperexcitation releases catecholamines causing increased sympathetic tone, which manifests as the initial symptoms of AWS.^2,10

Differential Diagnosis and Evaluation

AWS is both a clinical diagnosis, and a diagnosis of exclusion.  When considering this, emergency physicians must first evaluate for, and subsequently rule out other pathologies or disease mimickers that could account for the patient’s presentation (Table 1).  Equally important, early recognition and treatment of AWS is crucial to prevent withdrawal progression into life-threatening complications, such as withdrawal seizures and delirium tremens.^2,15  The patient’s vital signs, history, and physical exam should guide your workup and differential diagnoses.^2,8

Initial evaluation should include an assessment of the patient’s ABC’s, vital signs, mental status, and a POC glucose.² Compared to the general population, patients with AUD are more prone to trauma, electrolyte abnormalities, and malnutrition.^13,15  Oftentimes these patients may have reduced their alcohol consumption due to underlying illnesses (pancreatitis, pneumonia, sepsis).  It is important to perform a screening physical exam, and then evaluate for any underlying pathologies when indicated.  All patients should be inspected for signs of head trauma or focal neurological deficits, as this population is more prone to falls and intracranial hemorrhage.^2,8

Several important questions to ask regarding their alcohol use are listed below.^12,19

• Daily alcohol intake?
• Number of years of alcohol use?
• When was their last drink?
• Why did they decide to quit or cut back?
• Have they ever had alcohol withdrawal seizures or delirium tremens?

Key Point: AWS is both a clinical diagnosis, and a diagnosis of exclusion that is driven by the history and physical exam.  Early recognition and treatment are crucial to prevent progression of withdrawal symptoms into life-threatening complications.

Evaluation

The workup of AWS in the emergency department is largely dependent on the patient presentation.  Common labs and imaging studies to consider are listed in Table 2.  We recommend a comprehensive metabolic panel to assess electrolytes and liver functioning.  Always address any nutritional deficiencies.³  If there is concern for cardiac stress or ischemia given their hyperadrenergic state, an EKG can be considered.  Hypomagnesemia and hypokalemia are common electrolyte abnormalities in this population.¹⁰  Screen patients for pancreatitis with an abdominal exam and a lipase level.  A complete blood count can evaluate for an occult GI bleed, or deficiencies in B12/folate.^3,15

Ethanol levels are controversial, however we recommend obtaining one in patients being considered for AWS for several reasons.  First, they can be helpful when there is uncertainty or inconsistent history.  A negative ethanol level suggests that the last drink was many hours before.  Detectable ethanol levels, generally those less than 200 mg/dL, should not be used to rule out AWS, as patients with AUD have developed tolerance with higher basal ethanol levels. Conversely, a patient stating that he is in acute withdrawal with an ethanol level of 300 mg/dL is acutely intoxicated.^3,14 While it is true that people can withdrawal at any level, a moderately elevated ethanol level more likely points to intoxication over withdrawal. Overall, a patient’s clinical presentation and daily alcohol consumption need to be factored into determining the presence of withdrawal when an ethanol level is elevated.

A urine drug screen rarely changes management acutely, however the presence of a sympathomimetic may help elucidate the etiology of a patient’s encephalopathy or autonomic instability.³  A beta-hydroxybutyrate (BHB) level can be helpful in differentiating patients with elevated anion gap metabolic acidosis (AGMA) in whom you suspect alcohol ketoacidosis.  Markedly elevated BHB levels suggest alcohol ketoacidosis verses other causes of AGMA, such as toxic alcohols.  Serum osmolality and toxic alcohol levels should be considered when there is concern for toxic alcohol ingestion or unexplainable metabolic derangements.²⁵  Acetaminophen and salicylate levels are dependent on patient presentation.¹⁵  Chest XR should be ordered for any patient with chest pain, hypoxia, or fever.  Any patient with evidence of head trauma, focal neurological deficits, or first-time seizures should have head imaging with a non-contrasted CT scan.^3,14

Key Point:  The workup of AWS is largely dependent on the patient’s presentation and overall clinical picture.  It is important to remember that certain patients can be in withdrawal with mild to modestly elevated blood alcohol levels.  However, this should always be taken into context with their physical exam, clinical presentation, and daily alcohol consumption to differentiate true withdrawal from intoxication.

Stages of Withdrawal

Symptoms of alcohol withdrawal typically begin 6-8 hours after cessation or reduction in alcohol consumption.  Common symptoms include nausea/vomiting, insomnia, tremulousness, anxiety, and diaphoresis.  Tachycardia, hypertension, and hyperthermia are the most common vital sign abnormalities associated with AWS.^3,12  Occasionally withdrawal does not progress, and symptoms resolve within 24-48 hours.  However, if the withdrawal syndrome continues, peak symptom intensity occurs at 72 hours, and then diminishes after 5-7 days of abstinence.²

A quick visual assessment or “eye-balling” patients in passing or from afar, prior to introducing yourself as their physician can provide a great amount of information.  Comfortable appearing, resting patients are unlikely to be in acute withdrawal.  Conversely, patients with signs/symptoms of autonomic hyperactivity and visible distress need your attention quickly.  Patients in withdrawal often have an intention tremor, which is a fine motor tremor that is absent at rest, but occurs with purposeful movement.¹⁴  A good test to see if the tremor is real is to have them drink a glass of water.  Lastly, patients taking beta blockers or alpha-2 agonists may have blunted autonomic hyperactivity that can mask their withdrawal symptoms.¹⁵

Pearl: Patients presenting with symptoms of alcohol withdrawal that have been sober for at least 5-7 days are unlikely to be in acute withdrawal.  Evaluate for other etiologies that could account for their presentation first, however consider secondary gain or other motives if the timeline does not match up with their presenting symptoms.

The different stages of alcohol withdrawal syndrome are summarized in Table 3.  Alcohol hallucinosis (12-24 hours after last drink) often occurs first.  The hallucinations are most commonly visual, however auditory/tactile phenomena may occur.  Patients should have normal vital signs or mild autonomic reactivity with a clear sensorium, which differentiates it from delirium tremens (DT).^3,12  Without treatment, some patients will progress to develop severe AWS that includes withdrawal seizures and DT.  Patients with a prior history of withdrawal seizures or delirium tremens are at increased risk of progression to severe AWS.^3,13  Withdrawal seizures (12-48 hours after last drink) are most often generalized tonic-clonic seizures with shorter durations and post-ictal periods.  Multiple seizures and status epilepticus are decidedly less common.⁸  The overall prevalence of withdrawal seizures in AWS is roughly 10-30%.^2,3

Up to one third of patients with untreated alcohol withdrawal seizures will progress to the most severe manifestation of AWS, known as delirium tremens (DT).²   Historically, mortality rates were as high as 35%, however now with appropriate treatment and management rates are between 1-4%.^3,17  DT typically begins 3-5 days after the appearance of withdrawal symptoms, and can last up to 8 days.²  It is characterized by rapid-onset fluctuations in attention and cognition, sometimes with hallucinations, in the presence of alcohol withdrawal.  Severe DT patients often have agitation and extreme autonomic hyperactivity; including fever, tachycardia, hypertension, and profuse diaphoresis.^2,3  Hyperthermia and persistent tachycardia are associated with higher mortality rates.¹¹  Predictive risk factors for DT are listed below.^2,3

• Prior delirium tremens
• Development of withdrawal with a positive blood alcohol level
• History of sustained drinking
• CIWA score > 15
• SBP > 150 or HR > 100
• Recent withdrawal seizures, specifically if left untreated
• Last alcohol intake > 2 days
• Older age
• Recent misuse of other depressants
• Concurrent illness, such as respiratory, cardiac, or GI disease

Treatment

Benzodiazepines are recommended as the first line treatment option for AWS.  They act as central GABA_A agonists, increasing the frequency of GABA receptor channel opening.  This causes CNS depression, which addresses the underlying physiological abnormality of AWS, CNS hyperexcitation.^15,20  There is no clear evidence suggesting superiority of one benzodiazepine over another for AWS treatment.⁶  However, several of the more commonly used benzodiazepines include diazepam, lorazepam, midazolam, and chlordiazepoxide (Table 4).^2,6  For acute symptom control, IV diazepam is a great option.  It has a quick onset of action (1-5 minutes) compared to lorazepam (5-20 minutes), with less risk of dose stacking.  This fast onset of action makes it easily titratable, and active metabolites create a natural tapering effect that can be beneficial for patients being discharged.  Diazepam is contraindicated in patients with demonstrated liver failure due to extensive hepatic metabolism.  Patients with mild to moderate hepatic dysfunction can tolerate diazepam given the metabolism is based off of global liver function. In the true liver failure population, lorazepam is the preferred drug choice as it has a shorter half-life with less hepatic metabolism.^13,15  Chlordiazepoxide is an oral medication with a gradual onset and prolonged half-life that may be used in patients in mild withdrawal who are able to tolerate PO. Chlordiazepoxide, and diazepam when given orally, are good potential options for patients being discharged from the ED or an inpatient unit to complete home tapers. Patients without IV access who need emergent medication can be given intramuscular midazolam (2-5 minute onset of action) or lorazepam (less ideal with 15-30 minute onset of action) until IV access is obtained.^13,15

Symptom-triggered therapy is validated to be superior to fixed dosing in regards to total medication given and length of treatment periods.^21,23  CIWA-Ar can provide assistance in determining withdrawal severity, however it is a nursing driven protocol with questionable utility in the ED setting.  Briefly, CIWA scores of 15 or less represent mild withdrawal, 16-20 is moderate, and scores greater than 20 are recognized as severe withdrawal.²³  Instead, ED physicians should guide treatment based off of adequate symptom control, which requires re-evaluating the patient after intervention.^15,20

Mild to moderate AWS treatment can begin with diazepam 10 mg IV/PO, or a similar benzodiazepine equivalent.  The goals of initial treatment should include adequate symptom control, improvement in autonomic hyperactivity, and prevention of withdrawal progression into more severe, life-threatening symptoms.  The appropriate level of sedation in these patients would be getting them to the point where they are resting with their eyes closed, but remain easily arousable.^8,15,20

Certain patients with severe AUD may require rapidly escalating doses of benzodiazepines to prevent withdrawal seizures, delirium tremens, and the need for mechanical ventilation.^2,24  We recommend starting with 20 mg IV diazepam, followed by an additional 20 mg IV diazepam if the patient fails to respond after 5-10 minutes.  Continue to alternate doubled and repeated doses as needed every 5-10 minutes until symptoms are controlled. For example, escalating diazepam doses would look like this: 20, 20, 40, 40, 80, 80, 100, 100, 100.  If you are using lorazepam, an escalating dose approach can also be used, however doses should be spaced out every 15-20 minutes to avoid dose stacking. Due to its favorable pharmacokinetics, diazepam is favored over lorazepam for initial management of alcohol withdrawal.  Again, the goal is to get the patient looking more comfortable (resting with eyes closed, but easily arousable).^2,13

A small subset of patients may show benzodiazepine-refractory alcohol withdrawal and require adjunctive therapy with phenobarbital.  Generally, any patient with inadequate symptom control after the following medication requirements should be considered for benzodiazepine-refractory AWS.

> 50 mg IV diazepam or 10 mg IV lorazepam within the 1^st hour

OR

> 200 mg IV diazepam or 40 mg IV lorazepam within the first 3 hours²

We recommend giving 130-260 mg IV phenobarbital pushes every 15-20 minutes or 10 mg/kg IV over 1 hour to initiate treatment for severe refractory AWS.  This is a true emergency; clinicians should consult with their local medical toxicologist or poison control center for assistance in this situation.  Phenobarbital, a barbiturate, acts similarly to benzodiazepines as a GABA agonist.^16,20  It has been postulated in prior clinical studies to have NMDA receptor antagonism, however further research is needed.  Phenobarbital has a fairly quick onset of action (5-10 minutes) with a prolonged half-life (3-4 days); peak effect occurs in 20-30 minutes.  Due to its prolonged half-life, it is contraindicated in patients with liver failure or hepatic encephalopathy as it can induce a persistent coma in this population.¹³  Clinicians should remain at bedside whenever large doses of benzodiazepines or barbiturates are being given as there is risk of apnea and hypotension.  Patients should be on the monitor, and airway equipment should be in the room.  Assess the patient’s response to treatment and vital signs after being medicated.  Remember to keep a working differential for other etiologies if their clinical appearance and vitals fail to improve.²

Recent evidence supports the use of ketamine as adjunctive therapy for severe AWS and DT.  One recent study demonstrated decreased ICU length of stay and need for intubation in patients who received adjunctive treatment with 0.3 mg/kg IV ketamine bolus followed by 0.15-0.3 mg/kg/hr IV drip for severe AWS.  Ketamine is an NMDA antagonist, therefore it is postulated to attenuate NMDA neuroexcitation associated with severe AWS, reducing the total GABA agonist medication requirements.  Its short half-life is favorable, with less risk of causing iatrogenic delirium.²²  We would recommend consideration of adjunctive ketamine for any patient with DT who is being managed in a location in which ketamine infusions can be utilized (confined to intensive care units in many hospitals).

Patients who continue to show signs of severe AWS and/or withdrawal seizures/DT despite receiving the medications listed above may require mechanical ventilation and sedation with propofol.  Propofol is both a GABA agonist and NMDA receptor antagonist that is highly efficacious for the treatment of refractory AWS.^14,20

Clonidine and dexmedetomidine (central alpha-2 agonists) should not be used as adjunctive treatment for AWS in the ED.  While they may improve autonomic symptoms and abnormal vital signs, they lack effect on GABA/NMDA receptors, and fail to address the underlying abnormal physiology of the withdrawal state.  Studies have shown no effect on decreased hospital LOS, ICU status, or intubation rates; however, they are associated with adverse effects such as hypotension and bradycardia.^8,20  Anti-epileptic drugs (AEDs), beta-blockers, and antipsychotics are not recommended for the initial treatment of AWS.^2,20  Ethanol is not recommended, but could be used in the rare circumstance where benzodiazepines or barbiturates are not available.  Ethanol is inferior to benzodiazepines, difficult to titrate, and has numerous adverse metabolic effects.²⁰

All patients being treated for alcohol withdrawal should undergo folic acid and thiamine repletion. Folic acid can be administered either orally or intravenously at a dose of 1mg daily. Thiamine can be repleted orally or intravenously at a minimum dose of 100mg daily. Consider higher doses (such as 500mg every 8 hours for the first 3 days) in patients in which Wernicke’s encephalopathy or delirium tremens is expected.⁸

Key Point: AWS treatment goals are directed towards rapid control of symptoms, and prevention of symptom progression into more life-threatening complications.

Pearl: Additional therapies to consider when treating patients with AWS include reorientation, fluid resuscitation, correction of electrolyte abnormalities, and multivitamin supplementation.¹⁵

Disposition

The decision to admit patients with AWS depends on their clinical picture, severity of alcohol withdrawal, coexisting medical comorbidities, and degree of social support at home.³  Generally patients who are only showing signs of mild withdrawal are considered safe for discharge.¹⁴  Ensure that patients are fully treated prior to discharge and provide resources and pathways to support patients trying to quit.¹⁴   We encourage providing patients interested in outpatient detoxification with a prescription for diazepam to reduce the risk of relapse.^11,20  Keep in mind that older patients are at greater risk for DT, and may not tolerate the systemic stress of significant withdrawal.²⁰  Some patients may be good candidates for ED observation units or clinical decision units whose length of stay is likely to be no longer than 24 hours.¹⁸  Indications for ICU admission are summarized below.^2,20

AWS ICU Admission Criteria:

• Benzodiazepine-resistant withdrawal, requiring 2^nd line therapy
• Patient requires > 100-200 mg diazepam for symptom control in the ED
• Severe AMS or altered sensorium
• Recurrent seizures
• Hemodynamic instability
• Hyperthermia
• Underlying medical or surgical condition requiring ICU-level care

Case Resolution

After your initial encounter with the patient, you have a high suspicion that he is in acute alcohol withdrawal.  However, you remember that this is a clinical diagnosis of exclusion.  Based on his presentation, you evaluate the patient for other etiologies that could account for his abnormal vital signs and clinical appearance (including acute coronary syndrome, pulmonary embolism, sepsis, thyroid storm).  You also remember that AWS is a time-sensitive diagnosis that can quickly progress without treatment.  You order 10 mg IV diazepam, however he remains symptomatic and ultimately requires 30 mg of IV diazepam within the first hour to achieve adequate symptom control.  His labs are remarkable for AST of 85 and ALT of 43.  His urine drug screen and ethanol level are both negative.  After receiving early medication, his vital signs have normalized and he is now resting comfortably in bed.  Given his benzodiazepine requirements and initial presentation, you have the patient admitted to a progressive care unit.

Summary

• CNS hyperexcitation is the primary physiological abnormality seen in AWS
• AWS is a clinical diagnosis, and a diagnosis of exclusion. Consider other disease mimickers and rule them out during your workup
• Early diagnosis and treatment of AWS prevents symptom progression into life-threatening complications (withdrawal seizures, delirium tremens)
• Stages of AWS: withdrawal symptoms, hallucinations, withdrawal seizures, delirium tremens
• Benzodiazepines are the mainstay of treatment
• Patients with signs of mild withdrawal can be considered for discharge after receiving treatment
• Treat severe AWS with rapidly escalating doses of benzodiazepines to reduce risk of withdrawal seizures, delirium tremens, and need for intubation. Appropriate level of sedation is drowsy yet arousable
• Use phenobarbital for benzodiazepine-refractory AWS

Pearls/Pitfalls

• CIWA scores have questionable utility in the ED setting. They are nursing driven, and are not diagnostic for AWS.
• Inspect all patients for signs of head trauma and neurological deficits. Have a low threshold for CT head imaging
• Certain patients may develop withdrawal with mild to modestly elevated ethanol levels, however their clinical presentation and daily alcohol consumption should always be factored into the equation when determining whether the patient is in acute withdrawal.

References

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