Alcohol Withdrawal Syndrome

Etiology

Alcohol is a central nervous system (CNS) depressant that works by stimulating GABA, the primary inhibitory neurotransmitter. In acute, episodic intoxication, GABA is produced in excess, resulting in clinical effects such as sedation. Chronic alcohol use changes the balance of inhibitory (GABA) signals and excitatory (glutamate) signals in the CNS, so glutamate is endogenously over-produced to balance the influx of GABA provided by alcohol. When a patient who chronically drinks alcohol stops drinking or reduces how much they are drinking, the GABA signal is suddenly diminished, resulting in an overrepresentation of glutamate. This excess glutamate causes the autonomic hyperactive state seen in alcohol withdrawal syndrome.[3]

Epidemiology

As alcohol use has increased nationally over the last decade, especially during the COVID-19 pandemic, so too has the prevalence of alcohol withdrawal syndrome and its related complications.[4][5] Those who exhibit unhealthy alcohol use, which includes both risky drinking as well as AUD, are at risk for alcohol withdrawal syndrome when the amount they normally drink is reduced.[1] Approximately half of those who suddenly stop or reduce their drinking will experience alcohol withdrawal syndrome. However, the severity varies.[6] Not only is alcohol withdrawal syndrome a common cause of hospitalization, but it is also commonly treated in patients hospitalized for another reason. A 2013 sample of over 450,000 veterans’ hospital admissions found that 1 in 17 admitted patients were treated for alcohol withdrawal syndrome.[7]

Pathophysiology

To maintain homeostasis in the CNS, inhibitory signals from the GABAergic system are balanced by excitatory neurotransmitters such as glutamate. Alcohol, a CNS depressant, stimulates the GABAergic system and, in acute intoxication, causes a range of clinical manifestations such as disinhibition, euphoria, and sedation. The effect of alcohol in the acute setting is dose-dependent, with lower doses having a stimulating effect and higher doses having a sedating effect.[8] Chronic alcohol use results in neuroadaptive changes to the balance of GABA-glutamate by causing an upregulation of glutamate to compensate for alcohol-related increase in GABA. At the same time, endogenous GABA is downregulated.[3] Thus, when alcohol is withdrawn, a relative deficit of GABA may occur and simultaneous excess in glutamate, resulting in the excitatory symptoms seen in alcohol withdrawal syndrome.

Alcohol withdrawal syndrome exhibits a phenomenon known as kindling or sensitization, meaning successive withdrawal episodes tend to increase in severity, specifically concerning epileptic potential.[9] Repeated episodes of alcohol withdrawal syndrome lower the seizure threshold, making it more likely a person in withdrawal will experience a seizure. For those who have previously had alcohol-withdrawal seizures, their likelihood of experiencing another is quite high.[10]

History and Physical

Alcohol withdrawal syndrome is a clinical diagnosis that relies heavily on the history and physical, which is also used to gauge disease severity. The signs and symptoms may present within hours of alcohol cessation and peak around 72 hours.[2] In general, these signs and symptoms reflect the heightened excitability that results in the absence of the GABAergic input of alcohol and may include tremulousness, insomnia, agitation, diaphoresis, hypertension, tachycardia, or seizures. When in doubt, clinicians can refer to the DMS-V criteria for diagnosis.

If auditory, visual, or tactile hallucinations in the setting of alcohol withdrawal are present, the patient is likely experiencing alcohol hallucinosis, which affects approximately 2%.[11] The altered mental status that accompanies this presentation is concerning for alcohol withdrawal delirium. When taking the history, it is essential to ask about a history of complicated withdrawal, defined as withdrawal from alcohol that includes either seizures or delirium.[9] A history of complicated withdrawal increases the likelihood of future complicated withdrawal, and these patients should be treated in a monitored setting.

Evaluation

When the diagnosis is established, a validated scale such as the CIWA-Ar can determine severity. The CIWA-Ar assesses the severity of common symptoms of alcohol withdrawal syndrome, including but not limited to tremors, sensory disturbances, and agitation. Generally, mild alcohol withdrawal is defined as a CIWA-Ar score of 8 or less. CIWA-Ar scores between 8 and 15 indicate moderate withdrawal, and scores above 15 imply severe withdrawal.[2] Those with mild withdrawal symptoms without risk factors for progression to severe withdrawal, such as a history of prior withdrawal seizures or alcohol withdrawal delirium, medical comorbidities, age over 65, or physiologic dependence on benzodiazepines, may be treated in the ambulatory setting. The success of ambulatory treatment of alcohol withdrawal syndrome depends on the involvement of a support person who can monitor the patient’s symptoms, manage medications, and communicate with the care team.[3]

In contrast, those with moderate to severe alcohol withdrawal syndrome at initial assessment will need inpatient level care, where they will receive frequent reassessment to monitor their condition. Frequent reassessment of the patient’s condition is paramount to prevent progression to alcohol withdrawal, delirium, and seizures. Each reassessment will involve administration of the CIWA-Ar as well as checking the patient’s vital signs. The CIWA-Ar can only be used in awake and alert patients, which is not always the case in severe alcohol withdrawal syndrome. If the patient cannot participate in the CIWA-Ar assessment, the MINDS (Minnesota Detoxification Scale) score is utilized instead.[9]

Treatment / Management

In the outpatient setting, mild alcohol withdrawal syndrome can be treated using a tapering regimen of either benzodiazepines or gabapentin administered with the assistance of a support person. Proposed regiments include fixed dosing with as-needed doses available. Should symptoms worsen, patients and their support person should be instructed to present to the emergency department for evaluation and further treatment.

Inpatient treatment will typically necessitate benzodiazepines and/or phenobarbital. Benzodiazepines can be administered in a fixed-dose fashion with symptom-triggered doses for elevated CIWA-Ar scores or solely based on symptoms. Unless significant concern exists for underlying hepatic dysfunction, diazepam should be used first-line given its rapid onset of action and longer duration of action. When diazepam is not an option, lorazepam can be utilized instead. For those already in severe withdrawal or at the highest risk for progression to severe withdrawal, a “loading dose” of benzodiazepine or phenobarbital may be appropriate.[3][12] Phenobarbital, a barbiturate, can be used as monotherapy in place of benzodiazepines or as a rescue therapy.[13](A1)

Patients presenting with alcohol withdrawal syndrome should receive thiamine and folate supplementation as they are often nutritionally deficient. To treat Wernike and the progression of neuropsychiatric manifestations, it is prudent to administer high-dose, intravenous, or intramuscular thiamine, as oral thiamine is unpredictably absorbed.[14] Electrolytes, including magnesium and phosphorus, should also be checked and repleted. The propensity for patients with alcohol withdrawal syndrome to be hypophosphatemic puts them at risk of refeeding syndrome.[15] Patients who present with an anion-gap metabolic acidosis likely have alcohol-related ketoacidosis and require treatment with a glucose-containing fluid such as dextrose 5%-normal saline.

Finally, it is paramount to diagnose and address underlying AUD, which often involves starting a medication and ensuring appropriate outpatient follow-up. The 3 FDA-approved medications for AUD include naltrexone, acamprosate, and disulfiram. These can often be safely started before discharge and reduce 30-day readmission.[14]

Differential Diagnosis

When suspecting alcohol withdrawal syndrome, it is important to rule out concurrent withdrawal syndromes, particularly sedative-hypnotics such as benzodiazepines or barbiturates. If the patient is presenting with seizures or delirium, one must consider medical or neurologic causes other than alcohol.[9]

In the workup, it is important to consider clinical entities that exhibit signs and symptoms similar to alcohol withdrawal syndrome, such as thyrotoxicosis, hypoglycemia, diabetic ketoacidosis, stimulant substance use, status epilepticus, CNS infection, withdrawal from sedative-hypnotics, essential tremors, hepatic encephalopathy, intracranial hemorrhage, cerebrovascular accident, and psychosis.[16]

Prognosis

The prognosis of alcohol withdrawal syndrome depends both on the severity at presentation as well as how promptly treatment is initiated. Treatment with benzodiazepines reduces the risk of progression. For patients who experience a withdrawal seizure, they are at risk for recurrent seizures as well as alcohol withdrawal delirium. Historically, the mortality rate of alcohol withdrawal delirium has been as high as 20%, but with advances in critical care, prompt diagnosis, and treatment, the rate is now around 1%.[17]

Complications

The following are common complications of alcohol withdrawal syndrome:

• Wernicke encephalopathy: Untreated, severe thiamine deficiency can result in Wernicke encephalopathy, an acute neurological condition that can be fatal in its most severe form.[3] It is characterized by ocular changes, altered mental status, and ataxia.

• Withdrawal seizure: Alcohol-related seizures typically occur between 8 and 48 hours after alcohol cessation. Following a seizure, the patient should be treated with benzodiazepines and monitored closely for the next approximately 24 hours. Alcohol-related seizures can occur in the absence of other signs and symptoms of alcohol withdrawal.[9]

• Alcohol hallucinosis: An alcohol-induced psychotic disorder, alcohol hallucinosis consists primarily of auditory hallucinations and paranoia that resolve within 72 hours.[9]

• Alcohol withdrawal delirium (formerly delirium tremens): Alcohol withdrawal delirium can occur at any point up to 3 to 5 days after alcohol cessation or reduction. Delirium requires treatment and close monitoring, often in an intensive care setting, especially after a patient has received high doses of benzodiazepines or phenobarbital.[9]