INTRODUCTION — Alcohol use disorder is a global health concern, ranking seventh among the leading causes of death and disability [1]. As such, most clinicians are forced to confront its complications in some of their patients. There are an estimated eight million alcohol-dependent people in the United States alone, and approximately 500,000 episodes of withdrawal severe enough to require pharmacologic treatment occur each year [2]. Expressed another way, between 2 and 7 percent of patients with heavy alcohol use admitted for general medical care will develop severe alcohol withdrawal [3].
The inpatient 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 separately. (See "Ambulatory management of alcohol withdrawal" and "Approach to treating alcohol use disorder" and "Clinical manifestations and diagnosis of alcohol-associated fatty liver disease and cirrhosis" and "Hematologic complications of alcohol use" and "Screening for unhealthy use of alcohol and other drugs in primary care".)
PATHOPHYSIOLOGY
Overview — It is not entirely clear why some individuals suffer from more severe withdrawal symptoms than others, but some evidence suggests that genetic predisposition may play a role [4,5]. Experiments in 1955 demonstrated that alcohol-naïve volunteers given continual alcohol for longer periods developed more severe withdrawal than those who drank for shorter periods [6]. 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 [GABA] activity) and inhibits excitatory tone (via modulation of excitatory amino acid activity). In the patient with alcohol dependence, 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 — GABA is the major inhibitory neurotransmitter in the brain. Highly specific binding sites for ethanol are found on the GABA receptor complex [7]. Chronic ethanol use induces an insensitivity to GABA such that more inhibitor is required to maintain a constant inhibitory tone [8]. As alcohol tolerance develops, the individual retains arousal at alcohol concentrations that would normally produce lethargy or even coma in relatively alcohol-naïve individuals. Cessation of alcohol or a reduction from chronically elevated concentrations results in decreased inhibitory tone.
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 by binding to the glycine receptor on the NMDA complex. Ethanol inhibits glutamate-induced excitation [9,10]. Adaption occurs by increasing the number of glutamate receptors in an attempt to maintain a normal state of arousal. Cessation of alcohol or a reduction from chronically elevated concentrations results in unregulated excess excitation. Dopamine, too, appears to be involved in both alcohol dependence and the manifestations of withdrawal. Increases in dopamine during withdrawal likely contributes to hyperarousal [11].
COMPLICATIONS OF ALCOHOL WITHDRAWAL
Minor withdrawal symptoms — Minor withdrawal symptoms are due to central nervous system hyperactivity and include:
●Insomnia
●Tremulousness
●Mild anxiety
●Gastrointestinal upset, anorexia
●Headache
●Diaphoresis
●Palpitations
Symptoms are usually present within six hours of the cessation of drinking and often develop while patients still have a significant blood alcohol concentration (table 1) [12]. 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 outpatient management, is discussed separately. (See "Ambulatory management of alcohol withdrawal".)
Withdrawal seizures — Withdrawal-associated seizures are generalized tonic-clonic convulsions that usually occur within 12 to 48 hours after the last alcoholic drink but reportedly sometimes occur after as few as two hours of abstinence (table 1) [13]. The seizures occur predominantly in patients with a long history of alcohol use disorder, as evidenced by their typical onset during the fourth and fifth decades of life.
Withdrawal seizures are usually singular or occur as a brief flurry of seizures over a short period. Recurrent or prolonged seizures or status epilepticus are not consistent with withdrawal-associated seizures and should prompt an investigation into possible structural or infectious etiologies, generally guided by the findings of cranial computed tomography (CT) and/or lumbar puncture. Benzodiazepines, phenobarbital, and propofol are recommended in that order 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 [14-16]. (See "Evaluation and management of the first seizure in adults".)
While some authors use other anticonvulsants such as carbamazepine, valproate, and levetiracetam in the therapy of alcohol use disorder and withdrawal, the role of these medications in alcohol withdrawal-related seizures is incompletely evaluated and therefore cannot be recommended.
Although seemingly benign, alcohol withdrawal seizures left untreated progress to delirium tremens (DT) in nearly one-third of patients [13]. (See 'Delirium tremens' below.)
Alcoholic hallucinosis — Despite a tendency to equate alcoholic hallucinosis with DT, the two terms are not synonymous. Alcoholic hallucinosis refers to hallucinations that develop within 12 to 24 hours of abstinence and typically resolve within 24 to 48 hours (which is the earliest point at which DT typically develops) (table 1) [17]. Hallucinations are usually visual, although auditory and tactile phenomena are also described. Patients are aware that they are hallucinating and often very distressed. However, in contrast to DT, alcoholic hallucinosis is not associated with global clouding of the sensorium, but only with specific hallucinations, and vital signs are usually normal. (See "Approach to the patient with visual hallucinations", section on 'Alcohol and drug use or withdrawal'.)
Delirium tremens
Clinical manifestations of severe withdrawal and delirium tremens — Approximately 5 percent of patients who undergo withdrawal from alcohol suffer from DT. DT is defined by hallucinations, disorientation, tachycardia, hypertension, hyperthermia, agitation, and diaphoresis in the setting of acute reduction or abstinence from alcohol. 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 usually not manifestations of DT. Virtually all patients who develop DT experience some symptoms of minor alcohol withdrawal prior to the onset of DT. (See 'Alcoholic hallucinosis' above.)
Patients with DT have significantly elevated cardiac indices, oxygen delivery, and oxygen consumption [18]. 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 [19]. 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 [19].
Severe alcohol withdrawal is often associated with fluid and electrolyte abnormalities. Almost all patients in acute withdrawal are hypovolemic as a result of diaphoresis, hyperthermia, vomiting, tachypnea, and decreased oral intake. Hypokalemia is common due to renal and extrarenal potassium losses, alterations in aldosterone concentrations, and changes in potassium distribution across the cell membrane [20,21]. Hypomagnesemia is common in patients with DT and predisposes them to dysrhythmias and seizures [22]. Hypophosphatemia results from malnutrition, may be symptomatic, and, if severe, can contribute to cardiac failure and rhabdomyolysis.
Risk factors — Risk factors for the development of DT include [3,23-25]:
●A history of sustained drinking
●A history of alcohol withdrawal seizures
●A history of DT
●Age greater than 30
●The presence of a concurrent illness
●The presence of significant alcohol withdrawal in the presence of an elevated blood alcohol concentration
●A longer period since the last drink (ie, patients who present with alcohol withdrawal more than two days after their last drink are more likely to experience DT than those who present within two days)
The best predictor for clinically significant alcohol withdrawal is a Prediction of Alcohol Withdrawal Severity Scale (PAWSS) score (table 2) greater than or equal to 4 [3,26,27].
Mortality — With early identification and appropriate management, mortality from DT is less than 5 percent. This figure has diminished from the 37 percent mortality rate reported in the early 20th century, probably as a result of earlier diagnosis, improvements in supportive and pharmacologic therapies, and improved treatment of comorbid illnesses [4,28-32]. Death usually is due to dysrhythmia, 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 cardiopulmonary disease, core body temperature greater than 40ºC (104ºF), and coexisting liver disease are associated with a greater risk of mortality [33].
MANAGEMENT
Excluding alternative diagnoses — Alcohol withdrawal remains a clinical diagnosis. It may be necessary to perform extensive testing, including lumbar puncture and cranial computed tomography (CT), to exclude 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 [34]. A premature diagnosis of alcohol withdrawal can lead to inappropriate use of sedatives, which can further delay accurate diagnosis [35].
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 (IV) 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 temporarily necessary 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 IV fluid can be infused rapidly until patients are clinically euvolemic. Thiamine and glucose should be administered in order to prevent or treat Wernicke encephalopathy [36,37]. 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 IV as gastrointestinal absorption is impaired in many patients who abuse alcohol chronically. The details of these supportive treatments are discussed separately. (See "Wernicke encephalopathy", section on 'Treatment' and "Overview of the chronic neurologic complications of alcohol" and "Clinical manifestations and treatment of hypokalemia in adults" and "Hypophosphatemia: Evaluation and treatment".)
Some clinicians treat alcohol withdrawal patients with an IV 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 with regard to clinical outcomes, and it may not meet the specific requirements for fluid, glucose, and other substrates of many patients with alcohol withdrawal.
During the early phases of moderate to severe withdrawal, alcoholic patients are often given nothing by mouth (ie, kept "NPO") to prevent aspiration [38]. However, nutritional support is essential as alcoholic patients are frequently malnourished and have high metabolic needs due to their excited autonomic state. Initially, parenteral glucose supplementation is sufficient, but additional nutrition is 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 (ICU). The indications for ICU admission are summarized in the following table (table 3). (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 [29-31,34,38-42]. Diazepam (Valium), lorazepam (Ativan), and chlordiazepoxide (Librium) are used most frequently to treat or prevent alcohol withdrawal, but other benzodiazepines may be used [43]. In general, long-acting benzodiazepines with active metabolites (eg, diazepam or chlordiazepoxide) are preferred because they seem to result in a smoother clinical course with lower chance of recurrent withdrawal or seizures. For most patients, we recommend a symptom-triggered approach to treatment with benzodiazepines; patients at greater risk of complications may be appropriate for a front-loading approach. (See 'Symptom-triggered therapy' below and 'Front-loading therapy' below.)
We prefer lorazepam (Ativan) or oxazepam (Serax) for the treatment of patients with advanced cirrhosis or acute alcoholic hepatitis. The shorter half-life of lorazepam and the absence of active metabolites with oxazepam may prevent prolonged effects if oversedation occurs. By 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 common occurrence 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 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, for the prevention of withdrawal in asymptomatic patients known to be at risk, and for those with mild and minimal symptoms. (See 'Prophylaxis' below and "Ambulatory management of alcohol withdrawal".)
Following IV administration, patients should be converted to oral dosing as soon as possible based on their clinical response.
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 ensures safety and comfort but does not obscure the neurologic examination. By contrast, an older patient with preexisting cardiopulmonary disease may benefit from heavier sedation achieved more rapidly but must be closely monitored due to the greater risk imposed by the high systemic stress of major withdrawal or oversedation. The latter approach (rapidly performed, heavier sedation) is often referred to as "front-loading," as opposed to "symptom-triggered therapy."
Although no evidence-based data help to define which patients are most in need of a front-loading strategy, one simple assessment would be to determine if the patient is likely to be harmed by prolonged periods of hypertension and tachycardia (eg, frail, older adults, underlying cardiovascular disease) or by complications from prolonged physical restraint. All such patients likely require ICU admission. Explicit criteria for ICU admission are provided (table 3). (See 'Disposition and monitoring' below.)
For front loading, a variety of dosing schedules can be used. We generally give 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, but the longer interval required to wait to determine a peak effect of lorazepam almost contradicts the concept of front loading. 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). If diazepam is unavailable, we favor midazolam for rapid symptom control.
While IV therapy is reasonable for patients not requiring front loading, equivalent doses of oral chlordiazepoxide are on the order of 25 to 100 mg, which can be repeated hourly.
Fixed schedule therapy, in which a benzodiazepine is given at fixed intervals even if symptoms are absent, is often administered despite evidence against this strategy [44-47]. A fixed dose schedule strategy is most useful for preventing withdrawal in patients who are 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 — A symptom-triggered approach is recommended for most patients to treat alcohol withdrawal when pharmacotherapy is indicated. It 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 (CIWA-Ar), a measure of withdrawal severity (table 4) [48], or some equivalent assessment. A calculator to determine the CIWA-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. By contrast, an interval of four to six hours is reasonable for stable patients with mild symptoms receiving oral benzodiazepines.
When the score is elevated (any score of 8 or greater on the CIWA-Ar), additional medication is given. For acute withdrawal, we give diazepam 5 to 10 mg IV (lorazepam 2 to 4 mg IV in patients with severe liver disease) or chlordiazepoxide 25 to 100 mg orally (oxazepam 10 to 30 mg orally in patients with severe liver disease).
In some patients with severe alcohol withdrawal, including those who require tracheal intubation and mechanical ventilation, assessment scales such as the CIWA-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 5). We aim for a score of 0 to -2 when using the RASS to manage such patients. (See "Sedative-analgesic medications in critically ill adults: Selection, initiation, maintenance, and withdrawal", section on 'Monitoring'.)
Multiple randomized and observational studies support this simple concept of giving the patient the therapy they need, only when they need it [44-47,49]. 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 [44]. Patients in the symptom-triggered group required less medication (median 100 versus 425 mg) and a shorter treatment period (median 9 versus 68 hours) and had similar or better clinical outcomes.
Front-loading therapy — In contrast to symptom-triggered therapy, front-loading therapy consists of administering higher initial doses of benzodiazepine to prevent or achieve more rapid control of alcohol withdrawal symptoms. This approach is most appropriate for patients who are at greater risk of experiencing dangerous complications should they develop severe withdrawal. As one example, an older adult with a history of cardiovascular disease and DT would be good candidate. Dosing for front-loading therapy is described above. (See 'Dosing' above.)
Disposition and monitoring — Patients being treated for moderate or severe alcohol withdrawal must be closely monitored, and many require admission to an ICU. A table of ICU admission criteria is provided (table 3). Older patients are at greater risk for DT and may not tolerate the systemic stress of major withdrawal. Standard monitoring includes continual assessment of vital signs, pulse oximetry, fluid and electrolyte status, and neurologic function. (See 'Delirium tremens' above.)
Refractory delirium tremens — Some patients have refractory DT despite treatment with high-dose benzodiazepines, possibly because of low endogenous GABA concentrations or acquired conformational changes in the GABA receptor [50,51]. Refractory DT is not clearly defined; the disorder is also referred to as "resistant alcohol withdrawal" [52]. The condition 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 [53]. In such cases, as with any dangerous toxicologic disorder, we recommend obtaining assistance from a medical toxicologist or poison control center. (See 'Additional resources' below.)
A number of adjunctive treatments are used to manage patients with refractory DT [41,54]. Barbiturates (specifically phenobarbital) can be very effective in this patient population when given with a benzodiazepine [53,55]. Benzodiazepines, which increase the frequency of GABA chloride channel opening, and barbiturates, which increase the duration of channel opening, may work synergistically. We do not advocate the use of phenobarbital as monotherapy for acute alcohol withdrawal.
In patients thought to have refractory DT, we give phenobarbital 130 to 260 mg IV, repeated every 15 to 20 minutes, until symptoms are controlled. Doses will vary depending on patient age, severity of withdrawal, and other clinical factors, with those at higher risk for adverse drug effects receiving smaller doses. Patients at higher risk from phenobarbital include older adults and patients with cardiovascular disease, chronic obstructive pulmonary disease, and volume depletion. Clinicians with limited experience using phenobarbital as an adjunct therapy for alcohol withdrawal are encouraged to seek assistance. Evidence is limited, but as a general rule of thumb, we do not exceed cumulative doses of 15 mg/kg in the first 24 hours. (See 'Additional resources' below.)
Once withdrawal symptoms are well controlled, maintenance dosing of phenobarbital is much less, typically around 130 to 260 mg IV total per day divided among two or three doses. This dosing continues for about three to five days, and then the drug is tapered (as would be done for a benzodiazepine) at a rate of no more than a 10 percent reduction per day while observing closely for any recurrence of withdrawal symptoms.
In 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) [55]. However, the results of this study are limited by its small sample size, overlapping confidence intervals, and extensive uncontrolled use of other medications, including opioids, propofol, and neuroleptics [56]. While several subsequent studies lend support for the combined use of phenobarbital and benzodiazepines [57,58] or phenobarbital alone [59], these finding are not universal [60]. The authors of a retrospective review of 86 ICU patients treated at a single hospital for alcohol withdrawal suggest that phenobarbital alone may be safe and effective treatment, but all patients in their study received benzodiazepines prior to ICU admission, and there was a high incidence of intubation from oversedation [61]. Many studies that support early administration or monotherapy with phenobarbital use an inadequate regimen of lorazepam as a comparator.
Thus, while it is premature to recommend early administration of phenobarbital routinely, its use in patients who are both too ill for oral medications and receiving parenteral medications with limited active metabolites (lorazepam) seems reasonable. However, because of the risks of cardiovascular and respiratory failure associated with phenobarbital, the absence of genuine comparative trials (ie, phenobarbital versus a benzodiazepine with active metabolites such as chlordiazepoxide or diazepam), and the proven benefits of symptom-triggered therapy with long-acting benzodiazepine, we continue to recommend against the use of phenobarbital as a single agent.
Another reasonable alternative treatment for refractory DT 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 [62,63].
Importantly, tracheal intubation and mechanical ventilation are frequently necessary if phenobarbital or propofol are used.
Some preliminary evidence supports the use of dexmedetomidine in patients with refractory DT [64]. While this approach appears promising, we advise caution until well-performed, controlled trials of safety and efficacy are available.
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:
●Ethanol
●Antipsychotics (eg, haloperidol)
●Anticonvulsants (eg, carbamazepine)
●Centrally acting alpha-2 agonists (eg, clonidine, dexmedetomidine)
●Beta blockers (eg, propranolol)
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 DT. Many of these agents have an appropriate role in the outpatient management of minor alcohol withdrawal or of alcohol use disorder.
●Ethanol – Ethanol should not be used as therapy in the setting of acute alcohol withdrawal. It is difficult to titrate, associated with many adverse metabolic and end-organ effects, and clearly inferior to benzodiazepines [65]. Of note, the metabolism and kinetics of ethanol have not been well studied in the critically ill.
●Antipsychotics – Phenothiazines and butyrophenones (including haloperidol) lower the seizure threshold and should not be used routinely in the withdrawing alcoholic [66]. These drugs may also interfere with heat dissipation and do not exhibit cross-tolerance with ethanol.
Treatment with antipsychotics would only be appropriate when a decompensated thought disorder (such as schizophrenia) coexists with ethanol withdrawal and any symptoms associated with ethanol withdrawal have been definitively treated with benzodiazepines. In our experience, such occurrences are rare, even in patients with known thought disorders.
If a clinician determines that antipsychotic therapy is indicated, we recommend an electrocardiogram (ECG) to screen for QT prolongation (a contraindication to many antipsychotic medications) and the correction of electrolyte abnormalities (such as hypokalemia and hypomagnesemia, which are common in alcoholics) before any medication is administered.
●Anticonvulsants – Sustained anticonvulsant therapy has no role in patients with isolated alcohol withdrawal seizures. The overwhelming majority of seizures from withdrawal are self-limited and do not require treatment with anticonvulsants. If status epilepticus ensues, phenobarbital or propofol may be used for short-term management in conjunction with benzodiazepines while an underlying cause is investigated. (See 'Withdrawal seizures' above.)
While carbamazepine, gabapentin, and valproic acid may have a role in the outpatient management of mild alcohol withdrawal, convincing evidence that these medications effectively treats patients with DT or other severe symptoms is lacking [67]. (See "Ambulatory management of alcohol withdrawal".)
●Centrally acting alpha-2 agonists ‒ Pending more convincing studies, we believe that centrally acting alpha-2 agonists (eg, dexmedetomidine, clonidine) should not be used as a primary treatment for acute severe alcohol withdrawal, and we do not recommend them as adjuncts for routine care.
No controlled trials demonstrate that dexmedetomidine or clonidine prevent important outcomes, such as the development of seizures or DT. Despite this, clinicians increasingly report using these medications as adjunct therapy for alcohol withdrawal. While these drugs may reduce some symptoms of withdrawal as defined by CIWA-Ar or RASS scores [68], it is unclear whether their ability to reduce catecholaminergic findings is beneficial given that these agents are not cross-tolerant with alcohol and other GABA agonists. Dexmedetomidine seems to reduce benzodiazepine requirements [69], but this outcome is far from beneficial if benzodiazepines constitute definitive therapy. Furthermore, the use of dexmedetomidine is associated with increased cost and more episodes of bradycardia and hypotension [69].
●Beta blockers – Beta blockers may reduce minor symptoms of withdrawal, but they have not been shown to prevent the development of seizures or DT. We believe they should not be used for the treatment of acute severe alcohol withdrawal. However, patients with known cardiovascular disease should be given their maintenance medications after sedation and volume resuscitation, as sustained tachycardia and hypertension may contribute to cardiovascular morbidity, especially in older adults.
●Baclofen – Baclofen, a selective agonist of the GABA-B receptor used to treat reversible spasticity, has been studied as a therapy for acute alcohol withdrawal, but its effectiveness in controlling severe symptoms remains unproven [70-73]. We believe baclofen should not be used for the treatment of acute severe alcohol withdrawal.
PROPHYLAXIS — Patients with a history of seizures, delirium tremens (DT), 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, or with oxazepam if severe liver disease is present. Should more severe symptoms develop, patients are treated for active withdrawal in standard fashion. (See 'Management' above.)
For prophylaxis, we give chlordiazepoxide 25 to 100 mg every six hours for one day, followed by 25 to 50 mg every six hours for an additional two days. A similar regimen can be used with oxazepam 10 to 30 mg. Monitoring is no different from patients in active withdrawal. Patients should be reassessed frequently and additional doses of medication given each hour if a score of 8 or greater is achieved on the Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar). If such scores are reached, prophylaxis has failed and patients should be treated for active withdrawal (table 4) [48].
For patients requiring mechanical ventilation who are admitted to a critical care unit and who are thought to be at risk for severe alcohol withdrawal, we suggest providing intravenous (IV) sedation with a gamma-aminobutyric acid (GABA) agonist, such as a benzodiazepine or propofol. Dexmedetomidine is not a good sedative choice for these patients. Should signs of withdrawal appear, we begin standard treatment with a benzodiazepine given IV. (See 'Management' above and "Sedative-analgesic medications in critically ill adults: Selection, initiation, maintenance, and withdrawal".)
For patients on mechanical ventilation who do not require sedation but who are at risk for severe alcohol withdrawal, we suggest providing standard prophylaxis measures as described above, although the risk of precipitating an episode of intensive care unit (ICU) delirium must be weighed against the benefit of preventing withdrawal.
We recommend against the use of baclofen as prophylactic therapy for critical care patients at risk of alcohol withdrawal. In a multicenter randomized trial, patients on mechanical ventilation and at risk for alcohol withdrawal (n = 314) were treated with high-dose baclofen or placebo plus standard care [74]. Although the trial reported a reduction in agitation events in the baclofen treatment group, events were largely transient and not clearly related to withdrawal. Furthermore, both the duration of intubation and ICU stay were significantly longer in the baclofen group. Mortality was also higher in the baclofen group, but the difference did not achieve statistical significance.
Asymptomatic or minimally symptomatic patients at lower risk for seizures or DT 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 (or oxazepam 10 mg) every hour as needed when a score of 8 or greater is achieved on the CIWA-Ar.
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 "Alcohol use disorder: Psychosocial treatment".)
ADDITIONAL RESOURCES
Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)
Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Alcohol use disorders and withdrawal" and "Society guideline links: General measures for acute poisoning treatment".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topic (see "Patient education: Alcohol withdrawal (The Basics)")
SUMMARY AND RECOMMENDATIONS — A table summarizing the emergency management of alcohol withdrawal is provided (table 6).
●Dangerous diagnoses can mimic or coexist with alcohol withdrawal – Alcohol withdrawal remains a clinical diagnosis. It may be necessary to perform extensive testing (eg, lumbar puncture and cranial computed tomography [CT]) to rule out other diagnoses as many patients with alcohol use disorder do not stop drinking spontaneously and present with overt withdrawal symptoms that may mask other disorders. Conditions such as infection, trauma, metabolic derangements, drug overdose, hepatic failure, and gastrointestinal bleeding can mimic or coexist with alcohol withdrawal. (See 'Excluding alternative diagnoses' above.)
●Symptoms of alcohol withdrawal – Alcohol withdrawal syndromes encompass symptoms ranging from mild tremulousness to life-threatening delirium tremens (DT). A table summarizing the timing of withdrawal symptoms is provided (table 1). (See 'Minor withdrawal symptoms' above and 'Withdrawal seizures' above and 'Alcoholic hallucinosis' above and 'Delirium tremens' above.)
●Delirium tremens (DT) – DT is a syndrome characterized by agitation, disorientation, hallucinations, and autonomic instability (tachycardia, hypertension, hyperthermia, and diaphoresis) in the setting of acute reduction or abstinence from alcohol. DT is associated with a mortality rate of up to 5 percent, but the rate can be substantially higher if the condition goes untreated. Alcoholic hallucinosis and DT are distinct clinical entities. Patients at risk and those who fail to respond appropriately to initial doses of sedatives should be monitored closely and treated aggressively (table 3). (See 'Delirium tremens' above.)
●Risk factors for DT include:
•A history of sustained drinking
•A history of DT
•A history of alcohol withdrawal seizures
•Age greater than 30
•The presence of a concurrent illness
•The presence of significant alcohol withdrawal in the presence of an elevated ethanol level
•A longer period (more than two days) between the last drink and the onset of withdrawal
The best predictor for clinically significant alcohol withdrawal is a score of 4 or higher on the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) (table 2).
●Initial treatment and stabilization – Patients in alcohol withdrawal require medical treatment and observation. We suggest that patients who present with signs and symptoms of moderate or severe alcohol withdrawal be treated with benzodiazepines (Grade 2B). We give diazepam 5 to 10 mg intravenously (IV), repeated every 5 to 10 minutes until symptoms are controlled. Lorazepam may also be used (2 to 4 mg IV, repeated every 15 to 20 minutes). The general goal of sedation is a calm but alert state. Patients at greater risk for adverse outcomes may need heavier sedation. IV benzodiazepines should be continued until it is clear that the patient is no longer delirious and at high risk for aspiration, and that absorption from the gut is reliable. (See 'Treatment of psychomotor agitation with benzodiazepines' above.)
●Assessment tool for benzodiazepine dosing – We recommend that benzodiazepines be dosed and administered using a validated assessment tool, such as the Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar) (table 4) (Grade 1A). This requires formally assessing patients at regular intervals. Evaluation intervals as frequent as every 10 to 15 minutes are appropriate for patients with severe symptoms; an interval of four to six hours is reasonable for stable patients with mild symptoms. For acute withdrawal, we give diazepam 5 to 10 mg IV (or chlordiazepoxide 25 to 100 mg orally) for any score of 8 or greater on the CIWA-Ar. (See 'Symptom-triggered therapy' above.)
●Monitoring and intensive care unit (ICU) admission criteria – Patients with moderate or severe alcohol withdrawal need close monitoring, some in an ICU setting. Criteria for ICU admission are summarized in the following table (table 3). (See 'Disposition and monitoring' above.)
●Refractory DT management – For DT refractory to aggressive treatment with high-dose benzodiazepines, we suggest treatment with phenobarbital or propofol (Grade 2C). Patients receiving these agents require ICU admission and will likely require mechanical ventilation (table 6). (See 'Refractory delirium tremens' above.)
●Asymptomatic patients at risk for withdrawal – Asymptomatic or minimally symptomatic patients at risk for alcohol withdrawal but admitted to the hospital for other reasons should be closely monitored and may be treated prophylactically with oral benzodiazepines. We use chlordiazepoxide. For patients on mechanical ventilation who are at risk for severe alcohol withdrawal, the preferred sedatives are GABA agonists, such as a benzodiazepine or propofol. (See 'Prophylaxis' above.)
