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INTRODUCTION — Alcoholism is such a common condition that virtually every clinician is confronted with its complications. There are an estimated 8 million alcohol dependent people in the United States. Approximately 500,000 episodes of withdrawal severe enough to require pharmacologic treatment occur each year .
The in-patient management of syndromes associated with moderate and severe alcohol withdrawal is reviewed here. The ambulatory management of mild alcohol withdrawal, the initial diagnosis and treatment of alcohol dependence, and specific conditions due to alcohol-related organ damage (eg, cirrhosis, pancreatitis) are discussed elsewhere. (See "Ambulatory alcohol detoxification" and "Psychosocial treatment of alcohol use disorder" and "Pharmacotherapy for alcohol use disorder" and "Clinical manifestations and diagnosis of alcoholic fatty liver disease and alcoholic cirrhosis" and "Etiology and pathogenesis of chronic pancreatitis in adults" and "Alcohol abuse and hematologic disorders" and "Screening for unhealthy use of alcohol and other drugs" and "Brief intervention for unhealthy alcohol and other drug use".)
Overview — It is not entirely clear why some individuals suffer from more severe withdrawal symptoms than others, but genetic predisposition may play a role . Experiments in 1955 demonstrated that alcohol-naive volunteers given continual alcohol for longer periods developed more severe withdrawal than those who drank for shorter periods . These results imply that most people are vulnerable to the effects of the abrupt cessation of prolonged, sustained ethanol intake. However, withdrawal usually does not occur in the general population because most people drink in an episodic fashion that does not lead to the sustained high blood concentrations of alcohol necessary to develop tolerance and withdrawal.
Symptoms of alcohol withdrawal occur because alcohol is a central nervous system depressant. Alcohol simultaneously enhances inhibitory tone (via modulation of gamma-aminobutyric acid activity) and inhibits excitatory tone (via modulation of excitatory amino acid activity). Only the constant presence of ethanol preserves homeostasis. Abrupt cessation unmasks the adaptive responses to chronic ethanol use resulting in overactivity of the central nervous system.
Gamma-aminobutyric acid — Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. Highly specific binding sites for ethanol are found on the GABA receptor complex . Chronic ethanol use induces an insensitivity to GABA such that more inhibitor is required to maintain a constant inhibitory tone . As alcohol tolerance develops, the individual retains arousal at concentrations which would normally produce lethargy or even coma.
Excitatory amino acids — 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. Ethanol inhibits glutamate induced excitation [6,7]. Adaption occurs by increasing sensitivity to glutamate in an attempt to maintain a normal state of arousal.
MINOR WITHDRAWAL SYMPTOMS — Minor withdrawal symptoms are due to central nervous system hyperactivity, and can include:
Symptoms are usually present within six hours of the cessation of drinking and may develop while patients still have a significant blood alcohol concentration (table 1) . If withdrawal does not progress, these findings resolve within 24 to 48 hours. The specific minor withdrawal symptoms in a given patient typically are consistent from one episode to the next. The ambulatory management of mild alcohol withdrawal, including criteria to determine which patients are suitable for out-patient management, is discussed elsewhere. (See "Ambulatory alcohol detoxification".)
WITHDRAWAL SEIZURES — Withdrawal-associated seizures are generalized tonic-clonic convulsions that usually occur within 12 to 48 hours after the last drink, but may occur after only two hours of abstinence (table 1) . The seizures occur predominantly in patients with a long history of chronic alcoholism.
Withdrawal seizures are usually singular or occur as a brief flurry over a short period. Recurrent or prolonged seizures or status epilepticus should prompt an investigation into possible structural or infectious etiologies, generally guided by the findings of cranial computed tomography (CT) or lumbar puncture. Benzodiazepines and phenobarbital can be used to treat status epilepticus while investigations proceed. Several studies have demonstrated that phenytoin is ineffective in the treatment of alcohol withdrawal seizures and the drug should not be used for this purpose [10-12]. (See "Evaluation of the first seizure in adults".)
ALCOHOLIC HALLUCINOSIS — Despite a tendency to equate alcoholic hallucinosis with delirium tremens, the two terms are NOT synonymous. Alcoholic hallucinosis refers to hallucinations that develop within 12 to 24 hours of abstinence and resolve within 24 to 48 hours (which is the earliest point at which delirium tremens typically develops) (table 1) . Hallucinations are usually visual, although auditory and tactile phenomena may also occur. In contrast to delirium tremens, alcoholic hallucinosis is not associated with global clouding of the sensorium, but with specific hallucinations, and vital signs are usually normal. (See "Approach to the patient with visual hallucinations", section on 'Alcohol and drug use'.)
DELIRIUM TREMENS (DT)
Clinical manifestations of severe withdrawal and DT — Delirium tremens (DT) is defined by hallucinations, disorientation, tachycardia, hypertension, fever, agitation, and diaphoresis in the setting of acute reduction or abstinence from alcohol. In the absence of complications, symptoms of DT can persist for up to seven days.
Patients with DT have significantly elevated cardiac indices, oxygen delivery, and oxygen consumption . Arterial pH rises due to hyperventilation, which may be a rebound effect related to the respiratory depressant properties of alcohol. Hyperventilation and consequent respiratory alkalosis in this setting result in a significant decrease in cerebral blood flow . There is a correlation between the length of the preceding alcohol binge, the degree of clouding of the sensorium, and the size of the average decrease in cerebral hemispheric blood flow, although there is no association between blood flow parameters and hallucinations or tremors .
Severe alcohol withdrawal may have an important impact on fluid and electrolyte status. Almost all patients in acute withdrawal are hypovolemic as a result of diaphoresis, hyperthermia, vomiting, and tachypnea. Hypokalemia is common due to renal and extrarenal losses, alterations in aldosterone levels, and changes in potassium distribution across the cell membrane [16,17]. Hypomagnesemia is common in patients with DT and may predispose to dysrhythmia and seizures . Hypophosphatemia may occur due to malnutrition, may be symptomatic, and if severe, may contribute to cardiac failure and rhabdomyolysis.
Risk factors — Approximately 5 percent of patients who undergo withdrawal from alcohol suffer from DT. DT typically begins between 48 and 96 hours after the last drink and lasts one to five days (table 1). DT and alcoholic hallucinosis are NOT synonymous and symptoms that occur a few hours after the cessation of drinking, even if severe, are not manifestations of DT. (See 'Alcoholic hallucinosis' above.)
Risk factors for the development of DT include [19-21]:
Mortality — DT is associated with a mortality rate of up to 5 percent. This figure has diminished from a 37 percent mortality rate reported in the early twentieth century, probably as a result of earlier diagnosis, improvements in supportive and pharmacologic therapies, and improved treatment of comorbid illnesses [2,22-26]. Death usually is due to arrhythmia, complicating illnesses, such as pneumonia, or failure to identify an underlying problem that led to the cessation of alcohol use, such as pancreatitis, hepatitis, or central nervous system injury or infection. Older age, preexisting pulmonary disease, core body temperature greater than 40ºC (104ºF), and coexisting liver disease are associated with a greater risk of mortality .
Ruling out alternative diagnoses — Alcohol withdrawal remains a clinical diagnosis. It may be necessary to perform extensive testing, including lumbar puncture and cranial CT, to rule out other diagnostic considerations with confidence. This is particularly true when the presentation includes altered mental status and fever. Conditions, such as infection (eg, meningitis), trauma (eg, intracranial hemorrhage), metabolic derangements, drug overdose, hepatic failure, and gastrointestinal bleeding, can mimic or coexist with alcohol withdrawal . A premature diagnosis of alcohol withdrawal can lead to inappropriate use of sedatives, which can further delay accurate diagnosis .
Symptom control and supportive care — Once comorbid illnesses have been excluded or adequately treated, the management of alcohol withdrawal is directed at alleviating symptoms and identifying and correcting metabolic derangements. Benzodiazepines are used to control psychomotor agitation and prevent progression to more severe withdrawal. Supportive care, including intravenous fluids, nutritional supplementation, and frequent clinical reassessment including vital signs, is important. Clinicians must avoid complacency when treating patients with alcohol withdrawal. (See 'Treatment of psychomotor agitation with benzodiazepines' below and 'Symptom-triggered therapy' below.)
Patients should be placed in a quiet, protective environment. Mechanical restraint may be necessary temporarily for patients suffering from delirium tremens (DT) in order to protect both the patient and caretakers. Clinicians should follow their facility's guidelines for documentation and implementation of physical restraints. Once adequate chemical sedation is achieved, physical restraints should be removed, as resistance against restraints can increase temperature, produce rhabdomyolysis, and cause physical injury.
Volume deficits can be calculated and replaced accordingly, or, if there are no contraindications, isotonic intravenous fluid can be infused rapidly until patients are clinically euvolemic. Thiamine and glucose should be administered in order to prevent or treat Wernicke's encephalopathy [30,31]. Multivitamins containing or supplemented with folate should be given routinely, and deficiencies of glucose, potassium, magnesium, and phosphate should be corrected as needed. Initially (first day or two), treatment should be intravenous as gastrointestinal absorption is impaired in many patients who abuse alcohol chronically. The details of these supportive treatments are discussed separately. (See "Wernicke's encephalopathy", section on 'Treatment' and "Overview of the chronic neurologic complications of alcohol" and "Clinical manifestations and treatment of hypokalemia" and "Evaluation and treatment of hypophosphatemia".)
Some clinicians treat alcohol withdrawal patients with an intravenous infusion of a combination of thiamine, folate, and a multivitamin in isotonic saline with 5 percent dextrose. The multivitamin makes the fluid appear yellow, and thus, this treatment combination is sometimes referred to as a “banana bag”. Use of this treatment has not been well studied, and it may not meet the requirements for fluid, glucose, and other substrates of many patients with alcohol withdrawal.
During the early phases of withdrawal alcoholic patients are often given nothing by mouth (ie, NPO) to prevent aspiration . However, nutritional support is essential as alcoholic patients are frequently malnourished and have high metabolic needs due to their excited autonomic state. Initially, glucose supplementation is sufficient, but additional nutrition may be needed for patients who remain unable to eat for more than a day or two. Patients considered at high risk for complications should be monitored in an intensive care unit (table 2). (See "Nutrition support in critically ill patients: An overview".)
Treatment of psychomotor agitation with benzodiazepines
Drug selection — Benzodiazepines are used to treat the psychomotor agitation most patients experience during withdrawal and to prevent progression from minor withdrawal symptoms to major ones [22-25,28,32-37]. Diazepam (Valium), lorazepam (Ativan), and chlordiazepoxide (Librium) are used most frequently to treat or prevent alcohol withdrawal, but other benzodiazepines may be used . In general, long-acting benzodiazepines with active metabolites (eg, diazepam) are preferred because they seem to result in a smoother course with less chance of recurrent withdrawal or seizures. We recommend a symptom-triggered approach to treatment with benzodiazepines. (See 'Symptom-triggered therapy' below.)
We prefer lorazepam (Ativan) or oxazepam (Serax) for the treatment of patients with advanced cirrhosis. The shorter half-life of lorazepam and the absence of active metabolites with oxazepam may prevent prolonged effects if oversedation occurs. In contrast, chlordiazepoxide has a relatively long half-life and may lead to oversedation in patients with severe liver disease. Treatment with agents available in parenteral form (eg, lorazepam, diazepam) may be necessary in patients who cannot receive oral medications.
Given the recent trend of drug shortages, preferred agents may not always be available. A treatment algorithm for clinicians managing moderate or severe alcohol withdrawal without access to diazepam is provided (algorithm 1).
Benzodiazepines exert their effect via stimulation of gamma-aminobutyric acid (GABA) receptors, causing a decrease in neuronal activity and relative sedation. (See 'Gamma-aminobutyric acid' above.)
Route — All patients with seizures or DT require intravenous (IV) therapy with benzodiazepines. IV therapy is appropriate for the initial management of most patients with tremulousness from alcohol withdrawal because of guaranteed absorption and rapidity of onset. It is important to have IV access in all patients at risk of severe withdrawal.
Intramuscular administration should be avoided because of variable drug absorption. Oral formulations are preferred in most outpatient settings and for the prevention of withdrawal in asymptomatic patients known to be at risk. (See 'Prophylaxis' below and "Ambulatory alcohol detoxification".)
Dosing — Titration of medications should be based upon a given patient's risk factors for and ability to tolerate DT. As an example, a patient younger than 45 years with no comorbid illnesses should be lightly sedated to a degree that insures safety and comfort but does not obscure the neurologic examination. In contrast, an older patient with preexisting cardiopulmonary disease may benefit from heavier sedation, but must be closely monitored due to the greater risk imposed by the high systemic stress of major withdrawal or oversedation. Explicit criteria for ICU admission are provided (table 2).
A variety of dosing schedules can be used. We generally give IV diazepam, 5 to 10 mg IV every 5 to 10 minutes, until the appropriate level of sedation is achieved. Lorazepam, 2 to 4 mg IV every 15 to 20 minutes, can also be used. In severe withdrawal, select patients may require massive doses (>500 mg diazepam) to achieve initial control of symptoms, and continued aggressive use of benzodiazepines thereafter (>2000 mg diazepam over 48 hours).
Fixed schedule therapy, in which a benzodiazepine is given at fixed intervals even if symptoms are absent, is often administered despite a lack of strong supporting evidence. This strategy is most useful for preventing withdrawal in patients at risk, but asymptomatic or minimally symptomatic. The only advantage of this strategy is for the provider, as frequent reassessment is not required.
Symptom-triggered therapy — We favor a symptom-triggered approach to the treatment of alcohol withdrawal that involves providing medication only when a patient has symptoms.
To use this approach, a regular systematic assessment should be made of the patient's status using a validated instrument, such as the Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWAS-Ar), a measure of withdrawal severity (table 3) . A calculator to determine the CIWAS-Ar score is provided (calculator 1). Evaluation intervals as frequent as every 10 to 15 minutes are appropriate for patients with more severe symptoms being treated with IV benzodiazepines. Once severe symptoms are controlled, hourly reassessment of such patients is reasonable. In contrast, an interval of four to six hours is reasonable for stable patients with mild symptoms receiving oral benzodiazepines.
When the score is elevated, additional medication is given. For acute withdrawal, we give diazepam 5 to 10 mg IV for any score of 8 or greater on the CIWAS-Ar.
In some patients with severe alcohol withdrawal, including those who require tracheal intubation and mechanical ventilation, assessment scales such as the CIWAS-Ar that rely upon patients being able to answer specific questions cannot be used effectively. In these patients, we suggest using a sedation scale more appropriate for the intensive care setting such as the Richmond Agitation-Sedation Scale (RASS) (table 4). We aim for a score of 0 to -2 when using the RASS to manage such patients. (See "Sedative-analgesic medications in critically ill patients: Selection, initiation, maintenance, and withdrawal", section on 'Monitoring'.)
Multiple randomized and observational studies support this simple concept of giving the patient what they need, when they need it [40-44]. Taken collectively, these studies demonstrate that symptom-triggered therapy achieves equivalent or superior clinical endpoints while requiring lower total doses of sedatives and shorter periods of hospitalization.
In the landmark study of this approach, 101 patients admitted to an inpatient alcohol detoxification unit were randomly assigned to treatment with chlordiazepoxide using a fixed schedule or a symptom-triggered therapy . Patients in the symptom-triggered group required less medication (median 100 versus 425 mg) and a shorter treatment period (median 9 versus 68 hours).
Disposition and monitoring — Patients being treated for moderate or severe alcohol withdrawal must be closely monitored and many require admission to an intensive care unit (ICU). A table of ICU admission criteria is provided (table 2). Older patients are at greater risk for delirium tremens and may not tolerate the systemic stress of major withdrawal. Standard monitoring includes continual assessment of vital signs, pulse oximetry, fluid status, and neurological function. (See 'Delirium tremens (DT)' above.)
Refractory delirium tremens — Some patients have refractory delirium tremens despite treatment with high-dose benzodiazepines, possibly because of low endogenous GABA levels or acquired conformational changes in the GABA receptor [45,46]. Refractory delirium tremens is not clearly defined. It may be present if more than 50 mg of diazepam or 10 mg of lorazepam is required to control the symptoms of severe withdrawal during the first hour of treatment, or if doses greater than 200 mg of diazepam or 40 mg of lorazepam fail to adequately control symptoms during the initial three to four hours of treatment . As with any dangerous intoxication, we recommend obtaining assistance from a medical toxicologist or poison control center in such instances. (See 'Additional resources' below.)
In patients with refractory delirium tremens, barbiturates (specifically phenobarbital) can be very effective when given with benzodiazepines . We give phenobarbital 130 to 260 mg IV, repeated every 15 to 20 minutes, until symptoms are controlled.
Benzodiazepines, which increase the frequency of GABA chloride channel opening, and barbiturates, which increase the duration of channel opening, may work synergistically.
Another reasonable alternative is propofol, which can act to open chloride channels in the absence of GABA, and may also antagonize the excitatory amino acids that are upregulated during alcohol withdrawal [48,49]. Endotracheal intubation and mechanical ventilation are frequently necessary if phenobarbital or propofol are used.
Alternative and contraindicated agents — Drugs other than phenobarbital and propofol have been used with benzodiazepines or, rarely, alone to treat alcohol withdrawal. These agents are less well studied than benzodiazepines and may mask the hemodynamic signs of withdrawal, which can precede seizures. We believe they should not be used routinely in the treatment of moderate or severe alcohol withdrawal. Such drugs include:
All of these agents can reduce the frequency and intensity of minor withdrawal symptoms, but more data support the efficacy and safety of benzodiazepines in reducing the risk of seizures and delirium tremens.
PROPHYLAXIS — Patients with a history of seizures, delirium tremens, or prolonged, heavy alcohol consumption, who are minimally symptomatic or asymptomatic and are admitted to the hospital for other reasons, can be prophylactically treated with oral chlordiazepoxide. Should more severe symptoms develop, the patients are managed in standard fashion. (See 'Management' above.)
For prophylaxis, we give 50 to 100 mg every six hours for one day, followed by 25 to 50 mg every six hours for an additional two days. Monitoring is no different from patients in active withdrawal. Patients should be reassessed frequently and additional 25 to 50 mg doses of chlordiazepoxide administered each hour if a score of 8 or greater is achieved on the Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWAS-Ar) (table 3) .
Asymptomatic or minimally symptomatic patients at lower risk for seizures or delirium tremens who are being admitted to the hospital for other reasons should be closely monitored and may be treated with oral chlordiazepoxide 25 to 50 mg every hour as needed when a score of 8 or greater is achieved on the CIWAS.
After acute treatment, all patients should be screened for alcohol dependence and should be considered at risk for recurrent episodes of withdrawal. In-hospital evaluation and long-term follow-up are recommended. (See "Psychosocial treatment of alcohol use disorder".)
ADDITIONAL RESOURCES — Regional poison control centers in the United States are available at all times for consultation on patients who are critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have clinical and/or medical toxicologists available for bedside consultation and/or inpatient care. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. The World Health Organization provides a listing of international poison centers at its website: www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html
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SUMMARY AND RECOMMENDATIONS — A table summarizing the emergent management of alcohol withdrawal is provided (table 5).
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