Delirium Tremens (DTs)

DTs is the most severe manifestation of alcohol withdrawal and clinical manifestations include agitation, global confusion, disorientation, hallucinations, fever, hypertension, diaphoresis, and autonomic hyperactivity (tachycardia and hypertension). Profound global confusion is the hallmark of delirium tremens. DTs is a medical emergency with a high mortality rate, making early recognition and treatment essential. See Prognosis, Clinical Presentation, Differentials, Workup, and Treatment.

Chronic intake of alcohol affects several neurotransmitter systems in the brain. These effects include (1) increased release of endogenous opiates; (2) activation of the inhibitory gamma-aminobutyric acid-A (GABA-A) receptor producing increased GABA inhibition, with a resultant influx of chloride ions; (3) up-regulation of the postsynaptic N-methyl-D-aspartate (NMDA) type of glutamate receptor, which mediates the postsynaptic excitatory effects of glutamate; and (4) interactions with serotonin and dopamine receptors. During withdrawal from alcohol, the loss of GABA-A receptor stimulation causes a reduction in chloride flux and is associated with tremors, diaphoresis, tachycardia, anxiety, and seizures. In addition, the lack of inhibition of the NMDA receptors may lead to seizures and delirium. Excessive nervous system excitability during periods of abstinence from alcohol is related to the effect of alcohol on the number and function of brain receptors.

Ethanol interacts with GABA receptors, enhancing activity. GABA receptors are a family of chloride ion channels that mediate inhibitory neurotransmission. They are pentameric complexes composed of several glycoprotein subunits. Chronic ethanol abuse seems to modify the GABA receptor via several mechanisms, leading to a decrease in GABA activity. Chronic ethanol exposure has been found to alter gene expression and to increase cellular internalization of certain subunits, affecting the type of GABA receptors that are available at the cell surface and the synapse. Chronic ethanol exposure has also been found to alter phosphorylation of GABA receptors, which may alter receptor function.

When ethanol is withdrawn, a functional decrease in the inhibitory neurotransmitter GABA is seen. This leads to a loss of the inhibitory control of excitatory neurotransmitters such as norepinephrine, glutamate, and dopamine.

Ethanol also acts as an NMDA receptor antagonist. Withdrawal of ethanol leads to increased activity of these excitatory neuroreceptors, resulting in the clinical manifestations of ethanol withdrawal: tremors, agitation, hallucinations, seizures, tachycardia, hyperthermia, and hypertension. The clinical manifestations of ethanol withdrawal are due to the combination of effects on the GABA and NMDA receptors. Past episodes of withdrawal lead to increased frequency and severity of future episodes. 

Risk factors

Risk factors for DTs are inconsistent among studies[1, 2] and include the following:

• Prior ethanol withdrawal seizures

• History of DTs

• Concurrent illness and more medical comorbidities

• Daily heavy and prolonged ethanol consumption

• Greater number of days since last drink

• Severe withdrawal symptoms at presentation

• Prior detoxification

• Intense craving for alcohol

• Older age

• Hypokalemia

• Thrombocytopenia

• Elevated blood level of homocysteine

• Presence of structural brain lesions

Using the diagnostic criteria for alcohol use disorder (AUD) listed in DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition), the 12-month and lifetime prevalences of AUD in US noninstitutionalized civilian adults is highest in men (17.6% and 36.0%, respectively), with higher prevalences in whites, Native Americans, younger adults, and previously married and never married adults, as compared with women, African Americans, Asian Americans, and older and married adults.[3] Less than 50% of alcohol-dependent persons develop any significant withdrawal symptoms that require pharmacologic treatment upon cessation of alcohol intake. The lifetime risk for developing delirium tremens (DTs) among individuals with chronic alcohol addiction is estimated at 5-10%. Only 5% of patients with ethanol withdrawal progress to DTs. White patients have a higher risk of developing severe alcohol withdrawal, while black patients have a lower risk.[4] Whether or not sex differences exist in the rates of development of severe alcohol withdrawal is not clear. In any particular alcohol-dependent person, symptoms of withdrawal can differ widely among different withdrawal episodes.

Delirium tremens rarely occurs among pediatric patients, because the physiologic substrate for severe alcohol withdrawal takes time to develop.

Despite appropriate treatment, the current mortality for patients with DTs ranges from 5-15%, but should be closer to 5% with modern ICU management. Mortality was as high as 35% prior to the era of intensive care and advanced pharmacotherapy. The most common conditions leading to death in patients with DTs are respiratory failure and cardiac arrhythmias.

Patients at greatest risk for death are those with extreme fever, fluid and electrolyte imbalance, or an intercurrent illness, such as occult trauma, pneumonia, hepatitis, pancreatitis, alcoholic ketoacidosis, or Wernicke-Korsakoff syndrome.

Alcohol withdrawal syndrome is the clinical syndrome that occurs when people who are physically dependent on alcohol suddenly stop drinking or reduce their alcohol consumption.

Alcohol withdrawal syndrome is divided into four categories:

• Minor withdrawal

• Major withdrawal

• Withdrawal seizures

• Delirium tremens (DTs)

Minor withdrawal

Minor withdrawal (withdrawal tremulousness) occurs within 6-24 hours following the patient’s last drink and is characterized by tremor, anxiety, nausea, vomiting, and insomnia.

Major withdrawal (alcoholic hallucinosis)

Major withdrawal (hallucinations) occurs 10-72 hours after the last drink. The signs and symptoms include visual hallucinations and auditory hallucinations, whole body tremor, vomiting, diaphoresis, and hypertension.

Withdrawal seizures

Withdrawal seizures occur within 6-48 hours of alcohol cessation; they are major motor seizures that take place during withdrawal in patients who normally have no seizures and have normal electroencephalograms (EEGs). These seizures are typically generalized and brief. In the absence of treatment, multiple seizures occur in 60% of patients, but the duration between the first and last seizure is usually less than 6 hours. Only 3% of patients go on to develop status epilepticus.

An alcohol withdrawal seizure is frequently the first sign of alcohol withdrawal, and no other signs of withdrawal may be present after the seizure abates. About 30-40% of patients with alcohol withdrawal seizures progress to DTs.

Alcohol withdrawal seizures usually occur only once or recur only once or twice, and they generally resolve spontaneously. If a patient has seizures that are not typical of alcohol withdrawal seizures (such as partial or focal seizures, prolonged seizures, or seizures with a prolonged postictal state) or has signs of significant head trauma, then the underlying cause of the seizure should be investigated. Alcohol-dependent patients have increased rates of idiopathic epilepsy, traumatic brain injury, stroke, and intracranial mass lesions. Moreover, seizures in alcohol-dependent patients may be caused by concomitant use of stimulant drugs, such as cocaine or amphetamines, or by withdrawal from sedative agents, such as benzodiazepines or barbiturates.

Delirium tremens

DTs is the most severe manifestation of alcohol withdrawal. It occurs 3-10 days following the last drink. Clinical manifestations include agitation, global confusion, disorientation, hallucinations, fever, high blood pressure, diaphoresis, and autonomic hyperactivity (tachycardia and hypertension). Profound global confusion is the hallmark of delirium tremens.

CIWA-Ar scale

The most objective and best-validated tool to assess the severity of alcohol withdrawal is the Clinical Institute Withdrawal Assessment for Alcohol, Revised (CIWA-Ar),[5] shown below. This survey consists of 10 items and can be administered rapidly at the bedside in about 5 minutes. The 10 items include nausea and vomiting, anxiety, tremor, sweating, auditory disturbances, visual disturbances, tactile disturbances, headache, agitation, and clouding of sensorium. Zero to 7 points are assigned to each item, except for the last item, which is assigned 0-4 points, with a total possible score of 67.

Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar). The CIWA-Ar is not copyrighted and may be reproduced freely. This assessment for monitoring withdrawal symptoms requires approximately 5 minutes to administer. The maximum score is 67 (see instrument). Patients scoring less than 10 do not usually need additional medication for withdrawal. From Sullivan JT, Sykora K, Schneiderman J, et al. Assessment of alcohol withdrawal: The revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar). British Journal of Addiction 1989;84:1353-1357.

This scale has been demonstrated to have high reliability, reproducibility, and validity, based on comparisons with ratings by experienced clinicians, and has been shown to be usable in detoxication units, psychiatry units, and hospital medical/surgical wards.

The CIWA-Ar scale is intended only for patients who have been drinking recently. It relies on patients’ ability to respond to questions about their symptoms. Patients must be able to communicate and have a clear enough sensorium to reply logically, because many of the items require coherent answers. The CIWA-Ar scale has not been validated in complex medical patients, postsurgical patients, and critically ill patients. Therefore, the CIWA-Ar may not be applicable or reliable in critically ill patients, particularly in mechanically ventilated patients, as it relies on patient communication for information regarding nausea, vomiting, anxiety, tactile and auditory disturbances, and headache.

The CIWA-Ar has been revised for use in medical ICU patients,[6] but it has not been well studied or validated in this population.

A score of greater than 15 is seen in patients with moderate to severe alcohol withdrawal. Patients with a score of greater than 15 or those who have a history of alcohol withdrawal seizures should be treated with medication upon presentation. These patients need to be monitored carefully for the development of DTs. Patients with a score of 8-15, who have mild alcohol withdrawal, should probably also receive drug treatment. Careful and frequent monitoring with the CIWA-Ar is particularly helpful in patients receiving treatment with symptom-triggered drug therapy (also known as prn therapy) and can help avoid over- and under-medication complications that may occur with scheduled benzodiazepine protocols.

A revised version of the CIWA-Ar, called the CIWA-AD, thought to be more user-friendly, is a shorter version (8 items plus pulse measurement), with pulse as a scored item. The 3 CIWA-Ar items assessing the patient’s subjective report of perceptual disturbances are compressed down to a single item. The CIWA-AD is copyrighted, whereas the CIWA-Ar is not.[7]

The RASS (Richmond Agitation Sedation Scale) and Riker SAS (Sedation Agitation Scale) are agitation/sedation scales used in the ICU and appear to have similar efficacy in delirium assessment.[8] They have been recommended for use to monitor drug therapy in ICU patients with severe alcohol withdrawal syndrome but have not been validated in ICU patients for this indication.

No specific findings on physical examination are diagnostic for delirium tremens (DTs). However, DTs often presents with a coexisting illness, so a careful physical examination should be performed in order to uncover any potentially serious illness that may be present. The patient should be assessed for stigmata of chronic liver disease. Evaluation for signs of trauma should also be included.

Clinical findings associated with DTs may include the following:

• Tachycardia

• Hyperthermia

• Hypertension

• Tachypnea

• Diaphoresis

• Tremor

• Mydriasis

• Altered mental status

• Severe psychomotor agitation

• Fever

• Positional nystagmus

• Global confusion

• Disorientation

Complications of delirium tremens (DTs) include the following:

• Cardiac arrhythmias

• Oversedation

• Respiratory depression, respiratory arrest, intubation

• Aspiration pneumonitis

Despite appropriate treatment, the current mortality for patients with DTs ranges from 5-15%, but should be closer to 5% with modern ICU management. Mortality was as high as 35% prior to the era of intensive care and advanced pharmacotherapy. The most common conditions leading to death in patients with DTs are respiratory failure and cardiac arrhythmias.

Patients at greatest risk for death are those with extreme fever, fluid and electrolyte imbalance, or an intercurrent illness, such as occult trauma, pneumonia, hepatitis, pancreatitis, alcoholic ketoacidosis, or Wernicke-Korsakoff syndrome.

Serum, imaging, and cerebrospinal fluid (CSF) studies are important in the assessment of patients with alcohol withdrawal. Moreover, routine screening for unhealthy alcohol use in patients admitted to the hospital can be used to detect patients who are at risk for developing alcohol withdrawal. The American College of Surgeons Committee on Trauma mandates routine screening for unhealthy alcohol use for level 1 and 2 trauma centers. Screening tools include the Alcohol Use Disorders Identification Test (AUDIT), AUDIT-C, and the CAGE screening test.

Serum chemistry studies should include:

• Sodium

• Potassium

• Chloride

• Bicarbonate

• Blood urea nitrogen (BUN)

• Creatinine

• Magnesium

• Phosphorous

• Liver function tests

• Creatine phosphokinase - Some patients develop rhabdomyolysis

• Lipase

• Ketones

Serum ethanol concentration is important to assess, because patients who exhibit withdrawal while ethanol is still present in the serum are likely to have a more severe course. Additional laboratory tests include the following:

• Serum glucose

• Complete blood count with differential

• Drug screen, if suspicion of drug use is present

Measure serum anticonvulsant levels if the patient is known or suspected to be taking anticonvulsant medication. Other studies that may be useful in certain patients include measurement of serum lactate, as well as serum osmolality, with calculation of the osmolal gap.

About 50% of patients with delirium tremens (DTs) who present with fever will have an infection, pneumonia being most common. A chest radiograph should be obtained in all patients suspected of having DTs. If there is any suspicion of trauma or head injury, imaging of the cervical spine (plain radiography or CT scanning) and head CT scanning should be performed.

Computed tomography (CT) scanning of the head is performed selectively. Indications for a head CT scan include the following:

• New-onset seizure

• Seizures occurring over longer than a 6-hour period

• More than 6 seizures

• Focal seizures

• Evidence of head trauma

• Focal neurologic deficits

• A prolonged postictal state

• Deteriorating level of consciousness

Patients with alcohol withdrawal syndrome who have had a seizure and continue to be obtunded should have a lumbar puncture if no signs of increased intracranial pressure are present. Some patients may not have the classic signs of meningitis, such as nuchal rigidity, and the cerebrospinal fluid (CSF) of these patients should be examined to rule out meningitis. CSF pleocytosis is often present after withdrawal seizures, even in the absence of infection or intracranial bleeding. However, CSF pleocytosis after seizures should not be attributed solely to the seizures without a search for a treatable infectious cause.

Even in the absence of seizures, perform lumbar puncture if any suspicion of meningitis exists (fever, lethargy, confusion, or headache). The absence of nuchal rigidity does not reliably rule out meningitis in these patients.

Special concerns in the treatment of alcohol withdrawal include the following:

• Failure to consider the diagnosis of alcohol withdrawal syndrome in patients with altered mental status, abnormal vital signs, or single simple seizure

• Failure to treat patients with severe alcohol withdrawal syndrome with adequate doses of benzodiazepines, because these patients may require extremely large doses of parenteral benzodiazepines

• Making the assumption that all seizures in people with alcoholism are due to alcohol withdrawal without considering other causes of seizures, such as infection, hemorrhage, or trauma

• Failure to exclude other etiologies of altered mental status in patients with suspected alcohol withdrawal

• Failure to admit patients to the hospital with signs and symptoms of major withdrawal or delirium tremens (DTs)

• Failure to diagnose such conditions as hypoglycemia and pancreatitis

• Failure to administer thiamine in patients presenting with alcohol withdrawal

• Failure to use adequate chemical sedation with use of physical restraints

The administration of a sympatholytic drug (ie, clonidine, beta-blocker), either alone or with inadequate doses of benzodiazepines, can potentially cause problems, because the use of these drugs provides a false sense of security by correcting some of the autonomic manifestations of withdrawal in a patient who may be progressing to DTs. Sympatholytic drugs should not be administered unless adequate doses of benzodiazepines also are administered.

Phenytoin is not effective in preventing or treating alcohol withdrawal seizures. Seizures due to alcohol withdrawal are best prevented and treated with benzodiazepines. A Cochrane systematic review concluded that clinical trials have not shown a benefit for anticonvulsant therapy in treatment of alcohol withdrawal syndrome, but because of the heterogeneity of the trials in interventions and in the assessment of outcomes, definite conclusions about their safety and effectiveness cannot be made.

The use of neuroleptic drugs (phenothiazines, butyrophenones) alone to treat agitation or hallucinations caused by alcohol withdrawal potentially can cause problems, because these drugs are not effective in preventing or treating DTs and may increase the risk of seizures. The administration of a small dose of a butyrophenone, such as haloperidol, may be useful as adjunctive therapy to treat agitation and hallucinations, as long as adequate doses of benzodiazepines have been administered.

The use of alcohol to prevent or treat alcohol withdrawal and DTs is not recommended. Alcohol has multiple toxicities, including pancreatitis, hepatitis, cardiomyopathy, gastritis, and bone marrow suppression. It also has a short half-life and requires monitoring of blood levels when used intravenously, and its use may make it appear to the patient with alcoholism who is beginning recovery that alcohol intake is being condoned. Alcohol treatment has not been shown in controlled trials to be effective in preventing seizures or DTs.

Large amounts of sedatives may be required to achieve adequate control of symptoms. Sometimes, the airway must be controlled to permit the safe administration of adequate doses of sedatives.

Concurrent illnesses such as pneumonia, pancreatitis, hepatitis, and trauma should be identified and treated.

Indications for hospital admission of a patient with alcohol withdrawal syndrome include DTs; severe symptoms, such as hallucinations, disorientation, confusion, autonomic hyperactivity, or extreme agitation; the presence of a medical or surgical condition requiring treatment; a recent history of head injury with loss of consciousness; recurrent seizures; partial seizures; or focal neurologic findings upon examination.

Some authorities advocate the use of a protocolized dose escalation strategy in treating patients with DTs in the ICU. In this strategy, patients with DTs are treated with escalating doses of diazepam with titration of phenobarbital according to the patient's score on the Richmond Agitation Sedation Scale (RASS) (goal 0 to -2) or the Riker Sedation Agitation Scale (RSAS) (goal 3-4). In this approach, diazepam is administered intravenously at escalating doses every 10-15 minutes up to 100-150 mg per dose (or lorazepam IV up to 30 mg per dose) with calculation of the RASS or RSAS after each dose. If the patient reaches the goal, then that dose is used as the maintenance dose. If the goal on the sedation score is not reached, phenobarbital is administered intravenously at repeated doses of 65-260 mg until the desired goal is reached. In retrospective cohort studies, this strategy, compared with a nonprotocolized strategy, appeared to be effective in reducing rates of oversedation, mechanical ventilation, or, for those who were intubated, length of intubation and ICU stay.[9, 10, 11] If symptoms persist or the patient becomes oversedated due to medications, mechanical ventilation and treatment with ketamine, dexmedetomidine, or propofol should be considered.[12, 13, 14]

Supportive therapy is an important component of the treatment of alcohol withdrawal syndrome and delirium tremens (DTs). Such therapy includes providing a calm, quiet, well-lit environment; reassurance; ongoing reassessment; attention to fluid and electrolyte deficits; and treatment of any coexisting addictions. Commonly, patients with alcohol withdrawal syndrome have coexisting medical, surgical, and psychiatric conditions that need careful diagnosis and treatment. Multivitamins and folate are frequently administered to these patients, but no evidence exists that vitamins other than thiamine have any benefit in the acute setting.[15]

Administer intravenous (IV) fluids for rehydration, as necessary. Most patients with severe alcohol withdrawal are significantly dehydrated, and their fluid requirements range from 4-10 L in the first 24 hours. Because hypoglycemia is common in these patients due to depleted glycogen stores, a 5% dextrose solution (in 0.90% or 0.45% saline) should be used to prevent hypoglycemia.

Aspiration precautions are often necessary. This may include placing the patient in the left lateral decubitus position or intubating the patient, depending on the patient's level of consciousness. Also, the patient should not be administered any oral medications or fluids.

Monitor and replace electrolytes as necessary, because persons with alcoholism often have low calcium, magnesium, phosphorous, and potassium

Thiamine is useful in preventing Wernicke encephalopathy, an acute disorder due to thiamine deficiency manifested by confusion, ataxia, and ophthalmoplegia, as well as the chronic Korsakoff syndrome, which is manifested by memory impairment and amnesia. Thiamine has no effect on the symptoms or signs of alcohol withdrawal or on the incidence of seizures or DTs. Routine use of thiamine is recommended because the development of Wernicke encephalopathy or Korsakoff syndrome is disastrous in these patients and can remain unrecognized. Because orally administered thiamine may have poor enteral absorption in individuals with alcoholism, high-risk patients should receive parenteral thiamine at 100-250 mg once daily for several days. Although it has been a commonly held belief that thiamine must be given before administering glucose to hypoglycemic patients with suspected thiamine deficiency to prevent Wernicke encephalopathy, there is a lack of evidence that this is the case.[16] Current evidence suggests that it is prolonged glucose administration without thiamine supplementation that is a risk factor for the development or worsening of Wernicke encephalopathy. A delay in administering glucose to hypoglycemic patients cannot be recommended, and prompt supplementation with thiamine should be done as soon as feasible.

Persons with alcoholism frequently have large total body deficits of magnesium. Symptoms and signs of magnesium deficiency include hyperactive reflexes, weakness, tremor, refractory hypokalemia, reversible hypoparathyroidism with hypocalcemia, and cardiac dysrhythmias. Serum magnesium levels are often normal in spite of a total body magnesium deficit with significant intracellular magnesium deficiency. Magnesium levels that are initially low may return to normal even though a total body deficiency persists. In animal studies, magnesium deficiency has exacerbated hepatic damage caused by alcohol.

There is insufficient evidence about the benefits or harms of magnesium supplementation to prevent or treat alcohol withdrawal.[17] However, because the administration of magnesium is safe in the absence of renal insufficiency, consider routine administration of magnesium in patients with alcohol withdrawal. In severe deficiency, the deficit is about 1-2 mEq/kg of body weight.

When magnesium is administered intravenously to patients without renal insufficiency, about 50% of the dose is excreted into the urine and not retained by the body. About half of the deficit should be replaced in the first 24 hours. For a 70-kg person with normal renal function, 4-6 g of magnesium sulfate (32-48 mEq of magnesium) is administered by continuous IV infusion on the first day, followed by half that amount daily for 4 days. Alternatively, the same daily dose of magnesium can be administered intramuscularly at 6- to 8-hour intervals. Oral administration of magnesium-containing antacids can be effective but is limited by the development of diarrhea.

As mentioned previously, in critically ill patients in ICUs, symptom-triggered benzodiazepine treatment titrated to the RASS or RSAS, using very-high-dose bolus therapy, with addition of phenobarbital as needed, has been associated with a reduction in the need for mechanical ventilation and possibly a reduced length in the ICU. Fixed-dose regimens often result in excessive sedation or failure to reach the sedation goal.

Intravenous ethanol infusions have been used in the past, especially in surgical ICUs, as prophylaxis against alcohol withdrawal among patients with suspected or proven alcohol dependence. Retrospective, uncontrolled, noncomparative case series have reported the successful and unsuccessful use of IV ethanol in trauma and burn patients.

Comparative or randomized studies have not demonstrated efficacy for this treatment, and this therapy was inferior to diazepam in a prospective, randomized trial.[18] As IV ethanol has a short duration of action; a narrow margin of safety; and toxic effects on the gastric mucosa, pancreas, liver, and bone marrow and on other organs, and requires considerable volumes of fluids for administration, this treatment cannot be recommended.

Using the Revised Clinical Institute for Withdrawal Assessment for Alcohol (CIWA-Ar) scale may not be appropriate for guiding symptom-triggered therapy in patients who have complex medical problems or who are postsurgical, critically ill, or in an ICU. Studies demonstrating the effectiveness of the CIWA-Ar scale in safely managing alcohol withdrawal were performed in medically stable ward patients. Patients with complex medical issues, postsurgical patients, ICU patients, and critically ill patients were generally excluded from these trials. The CIWA-Ar scale has not been validated in these patients. The RSAS or RASS may be preferred in ICU patients.

Moreover, the CIWA-Ar protocol and symptom-triggered therapy have been applied inappropriately to patients who had not been drinking for many weeks and who were not able to communicate, resulting in misdiagnosis and delayed diagnosis of other causes of delirium, as well as severe benzodiazepine intoxication due to inappropriate medication use. Postoperative delirium, for which there are many etiologies, has been misdiagnosed as alcohol withdrawal and the CIWA-Ar applied inappropriately with subsequent mistreatment. Patients with complicated medical and surgical comorbidities are not appropriate candidates for symptom-triggered therapy guided by the CIWA-Ar scale.

The issue of alcohol dependence should be addressed prior to hospital discharge, because detoxification from alcohol in the hospital is not sufficient to prevent a patient’s return to hazardous alcohol use. Treatment to prevent relapse frequently requires extended management over long periods of time. Alcohol cessation programs and support groups, such as Alcoholics Anonymous, should be recommended.

Pharmacologic aids to alcohol cessation should be considered, because they may prevent relapse in patients who have been treated for alcohol dependence. Use of these agents for the long-term treatment of alcohol dependence can be initiated after detoxification to alcohol has been completed. FDA-approved medications used for the treatment of alcoholism include disulfiram, acamprosate, and two forms of naltrexone (oral and extended-release injectable). Gabapentin or baclofen also may be effective but are not FDA approved for alcohol abuse.[19, 20] All these agents are, at best, only modestly effective in the short term.

Cognitive behavioral therapy and motivational enhancement therapy (which are sometimes combined with pharmacologic therapy) have been used successfully to prevent relapse.

Chronic alcoholism is associated with depression as well as anxiety disorder, and the risk of suicide among individuals with alcohol addiction is high. Therefore, persons with alcohol withdrawal should be screened for depression and anxiety disorder after recovery from the alcohol withdrawal state, and they referred to a mental health provider for further assessment and treatment as necessary.

To prevent hazardous alcohol use, routine screening and brief intervention for high-risk alcohol use should be performed in primary care settings and in emergency departments; this may reduce alcohol consumption and adverse consequences in risk drinkers who are not alcohol dependent. Use of the AUDIT or CAGE questionnaire is helpful in screening.

Protocols for screening persons at risk for hazardous alcohol use, followed by a brief intervention (5-10 min) carried out by a clinician, nurse, or social worker, have been shown to result in a reduction in alcohol consumption and alcohol-related injuries and decreased readmissions to the emergency department. Computer-based screening and counseling programs may be useful when clinicians do not have time to perform screening and face-to-face intervention.

The effectiveness of brief interventions for heavier drinkers and in the acute care setting is unknown. Chronic, severe alcohol dependence is frequently resistant to existing methods of interventions, but pharmacotherapy with brief medical management counseling may reduce heavy drinking in these alcohol-dependent persons.[21, 22]

Although thiamine has no effect on the symptoms or signs of alcohol withdrawal or on the incidence of seizures or delirium tremens (DTs), thiamine (100 mg PO/IV/IM qd for 3 d) is useful in preventing Wernicke encephalopathy and Korsakoff syndrome. Multivitamins (PO/IV qd) and folate (1 mg PO/IV qd) are frequently administered to these patients, but no evidence exists that vitamins, other than thiamine, have any benefit in the acute setting.

Many varying pharmacotherapeutic management recommendations exist for alcohol withdrawal and DTs. Even many authoritative textbooks and journal articles have made recommendations for use of pharmacotherapeutic agents that have never been tested in clinical trials for this condition.

Benzodiazepines are considered the drugs of choice for the management of all stages of alcohol withdrawal syndrome, including DTs. They act on the benzodiazepine-GABA-chloride receptor complex, having a similar GABA-potentiating effect as alcohol. Prospective, randomized clinical trials have demonstrated the effectiveness of benzodiazepines in treating the symptoms and signs of alcohol withdrawal and have also shown a protective benefit against seizures.[23] Although they are thought by many to have a high margin of safety, the heterogeneity of the trials in interventions and in assessment of outcomes prevent definitive conclusions about safety and harms.

For the treatment of minor or moderate alcohol withdrawal (in patients able to take oral therapy), symptom-triggered therapy (also known as prn therapy) has been shown in prospective, randomized, controlled trials to be superior to fixed-dose drug therapy, with less medication use and a shorter duration of therapy.[24] The dosage of benzodiazepine needs to be individualized for each patient. The successful use of symptom-triggered therapy requires motivated and attentive nursing.

Most experts recommend that intermittent intravenous bolus dosing of diazepam or lorazepam is the treatment of choice for drug therapy of DTs. In patients refractory to benzodiazepine therapy alone, barbiturates or other adjuncts may be added.[11] A review of four randomized controlled trials of front-loaded diazepam concluded that it produces a rapid calming effect with few untoward adverse effects in medically ill patients, required much less total dose of benzodiazepines, and resulted in a shorter duration of treatment, but may result in over sedation and respiratory depression in very elderly persons or those with severe liver disease.[25]

Phenobarbital, a long-acting barbiturate with a half-life of 50-140 hours and a duration of sedation of 4-10 hours, has been used successfully in the treatment of alcohol withdrawal and DTs. It has well-documented anticonvulsant activity, is inexpensive, and can be administered by the oral, intramuscular, or IV route. Although its mechanism of action is mediated by GABA at the GABA-A receptor, its mechanism of action is different from the benzodiazepines as well as the short-acting barbiturates. While benzodiazepines increase the frequency of chloride channel opening caused by GABA-A receptor activation requiring the presence of presynaptic GABA, phenobarbital enhances GABA-A chloride currents by increasing the duration of chloride channel opening. Therefore, phenobarbital and benzodiazepines may have synergistic clinical effects, supporting the use of phenobarbital as an adjunct to benzodiazepines. Phenobarbital can be used as a first-line agent to be given as an initial single large dose up to 10 mg/kg or preferably as repeated small doses (65, 130, or 260 mg IV per dose) for loading until the patient is calm, to be followed by use of benzodiazepines on an as-needed, symptom-triggered basis.[26]

A single dose of intravenous phenobarbital given in the emergency department may decrease the subsequent ICU admission rate and decrease the total dose of benzodiazepine and decrease the use of continuous lorazepam infusions required during the hospital course, without any increased adverse effects.[26]

Some patients are discharged from the emergency department (ED) or hospital to a setting where medical supervision of detoxification and withdrawal is not available. If this is the case, treatment with a sedative agent that has a long duration of action, such as phenobarbital or a long-acting benzodiazepine (eg, diazepam, chlordiazepoxide), in the ED or hospital may be preferable and safer. Because the effect of these drugs may persist for several days after the last dose, this avoids the less desirable option of prescribing sedative agents for patients to take at home in an unsupervised manner. A patient who is discharged home to a nonmedically supervised environment with a prescription for a benzodiazepine or other sedative-hypnotic agent may misuse the drug, will often resume alcohol at the same time, and may resell the drugs or share them with other persons.

For patients with refractory DTs, propofol has been described in case studies as effective in managing patients who are intubated.[13] It has effects on NMDA and GABA receptors. No clinical trial has demonstrated any superiority over benzodiazepines.

Use of intravenous dexmedetomidine, an alpha-2 receptor antagonist with sedative and sympatholytic properties, is also an option for refractory DTs. It alleviates agitation, causes less respiratory depression, and may be given without mechanical ventilation, unlike propofol. It has been used with benzodiazepines as adjunctive therapy and may reduce total benzodiazepine dosage, but with the risk of producing bradycardia and hypotension.[27]  A 2015 review of English-language studies of dexmedetomidine for alcohol withdrawal, none of which was of high quality, found that dexmedetomidine appears to reduce benzodiazepine requirements and decreases sympathomimetic responses, but without convincing evidence that it improves clinical endpoints, including need for mechanical ventilation or length of stay.[28]  

Ketamine is another NMDA antagonist with less potential for respiratory depression. Two small studies found that ketamine as an adjunct reduced benzodiazepine requirements in patients with DTs. Another retrospective study found that the adjunctive use of ketamine resulted in decreased length of ICU stay and mechanical ventilation.[12, 29, 30]

Clonidine and beta-blockers may control some of the autonomic symptoms but do not treat or prevent the DTs. As they can mask the severity of alcohol withdrawal syndrome, they should not be used.

Carbamazepine has been shown in some clinical trials to be effective in treating patients with minor symptoms of alcohol withdrawal and has been used extensively in Europe as monotherapy. There is insufficient evidence indicating that carbamazepine or other anticonvulsants are effective in the prevention or treatment of more severe manifestations of alcohol withdrawal, including DTs, but they appear to have limited side effects in this population.[31]

Drugs such as esmolol and midazolam, which have a short half-life and rapid onset of action, can be administered by continuous IV infusion and have been used in critically ill patients with DTs. Clinical studies have not shown them to be superior, or even equal, in overall effectiveness compared with longer-acting agents.

Neuroleptic drug therapy is inferior to sedative-hypnotic drug therapy in reducing mortality or the duration of severe alcohol withdrawal.[32] Neuroleptic drugs are associated with more adverse effects, including lowering of seizure threshold, hypotension, prolonged QT interval, and neuroleptic malignant syndrome. These precautions apply to the older neuroleptics. Little experience with the newer neuroleptics (atypical antipsychotics) exists in the treatment of alcohol withdrawal.

As the extreme hyperglutamatergic and hyperdopaminergic states that occur in severe alcohol withdrawal are thought to be responsible for paranoia, hallucinations, and agitated delirium, there may be a role for small titrated doses of dopamine antagonists (eg, haloperidol) in highly agitated patients, provided that adequate treatment with GABA coverage (benzodiazepines, phenobarbital) has been administered. Some authorities recommend haloperidol at a dose of 0.5-5 mg intravenously or intramuscularly every 30-60 minutes or the same dose orally every 4 hours for severe agitation, perceptual disturbances, or disturbed thinking not adequately controlled by high-dose benzodiazepines.

Class Summary

By acting on the GABA receptor, benzodiazepines produce a cross-tolerance to alcohol, thus reducing the hemodynamic and peripheral symptoms of alcohol withdrawal. The dose of benzodiazepine used should be based on the patient's symptoms and signs of alcohol withdrawal, including vital signs and amount of agitation. The longer-acting agents appear to be superior to the short-acting agents and may result in a smoother withdrawal course, with less breakthrough and rebound symptoms, although a risk of excessive sedation exists in certain patient groups (elderly patients, patients with liver failure) with the longer-acting agents.

For the treatment of minor or moderate alcohol withdrawal (in patients able to take oral therapy), symptom-triggered therapy (also known as prn therapy) has been shown in prospective, randomized, controlled trials to be superior to fixed-dose drug therapy, with less medication use and a shorter duration of therapy. The dosage of benzodiazepine needs to be individualized for each patient. The successful use of symptom-triggered therapy requires motivated and attentive nursing.

Drug regimens and doses recommended for minor withdrawal are not appropriate for patients with delirium tremens (DTs), who often require very high doses of these agents. For the treatment of DTs, benzodiazepines should be administered only parenterally.

For patients with severe withdrawal symptoms, including DTs, the benzodiazepine dose should be front loaded. That is, large doses should be administered intravenously at short intervals until the patient is calm but easily aroused. Then additional doses are administered only as needed. Most authorities recommend intravenous diazepam as the first choice for front-loading treatment of severe alcohol withdrawal. Because of its long serum half-life, and the even longer half-life of its active metabolite (desmethyldiazepam), additional doses may not be required once the patient is calm.

Longer-acting benzodiazepines (especially those with active metabolites) provide less fluctuation in blood levels and allow a more gradual physiologic taper. A review of 4 randomized controlled trials of front-loaded diazepam concluded that it produces a rapid calming effect with few untoward adverse effects in medically ill patients, required much less total dose of benzodiazepines, and resulted in a shorter duration of treatment, but may result in over sedation and respiratory depression in very elderly persons or those with severe liver disease. Aggressive treatment of severe alcohol withdrawal syndrome with diazepam may decrease the need for intubation.

Intravenous lorazepam, which has an intermediate serum half-life and no active metabolites, has been successfully used and may be preferable in elderly persons or in those with severe liver disease. Reports describe a higher incidence of late-onset alcohol withdrawal seizures with use of shorter-acting benzodiazepines such as oxazepam or lorazepam.

No controlled studies show superiority of shorter-acting agents (propofol, pentobarbital, lorazepam, and midazolam) over diazepam or other long-acting benzodiazepines.

If the IV route is not available, then intramuscular lorazepam (or midazolam as an alternative) is recommended. Diazepam and chlordiazepoxide should not be administered intramuscularly, because absorption is erratic.

The use of continuous IV infusions of short-acting benzodiazepines (lorazepam, midazolam) has been reported, but these infusions have required very large amounts of drug and are very expensive. No evidence indicates that continuous infusion therapy with short-acting agents leads to better outcomes than does oral or intravenous intermittent bolus therapy with long-acting agents.

Patients with DTs who do not respond to high doses of benzodiazepines may respond to the addition of phenobarbital, propofol, or possibly dexmedetomidine to the treatment regimen.

Chlordiazepoxide

Chlordiazepoxide depresses all levels of the central nervous system, including the limbic and reticular formations, possibly by increasing the activity of GABA, a major inhibitory neurotransmitter. The parenteral form is usually used initially. Because of limited experience with IV chlordiazepoxide for severe alcohol withdrawal and DTs, the use of IV diazepam or lorazepam is preferred.

Diazepam (Valium, Diastat)

Diazepam depresses all levels of central nervous system (eg, the limbic and reticular formations), possibly by increasing the activity of GABA. Individualize the dosage and increase cautiously to avoid adverse effects.

Because of its rapid onset, prolonged duration of effects, and high therapeutic index, diazepam is the drug of choice. Volumes of literature exist regarding the use of diazepam for ethanol withdrawal. The onset of action is within 5 minutes after IV administration. It has an active metabolite (desmethyldiazepam) that has a longer duration of action than that of diazepam.

Lorazepam (Ativan)

Lorazepam is a sedative hypnotic with a rapid onset of action and a medium duration of effect. By increasing the action of GABA, which is major inhibitory neurotransmitter in brain, it may depress all levels of the central nervous system, including the limbic and reticular formations. When the patient must be sedated for more than 24 hours, this medication is excellent, although it may require frequent redosing. Although diazepam is the preferred benzodiazepine, lorazepam is an excellent alternative and is especially useful in elderly persons and in those with severe hepatic dysfunction. It is commonly used prophylactically to prevent DTs. It can be given intramuscularly in patients lacking intravenous access.

Ketamine (Ketalar)

Ketamine is an NMDA antagonist with less potential for respiratory depression. Two small studies have found that ketamine as an adjunct can reduce benzodiazepine requirements in patients with DTs.

Propofol (Diprivan)

Propofol, an IV anesthetic agent, is active on the glutamate and GABA-A receptors, similar to alcohol itself, whereas benzodiazepines are active only against the GABA receptors. Due to its rapid onset of hypnosis and anticonvulsant properties, propofol is an alternative treatment for intubated patients with delirium tremens (DTs) who are refractory to high-dose benzodiazepines. Advantages to its use are that it is easily titratable, with predictable effects, and has a rapid metabolic clearance.

Propofol is a phenolic compound unrelated to other types of anticonvulsants. It has general anesthetic properties when administered intravenously. Propofol IV produces rapid hypnosis, usually within 40 seconds. The effects are reversed within 30 minutes, following the discontinuation of infusion. Propofol has also been shown to have anticonvulsant properties.

Dexmedetomidine (Precedex)

Dexmedetomidine is an alpha-2-agonist that is used for sedation and anesthesia. It has been evaluated for use in alcohol withdrawal syndrome. Specifically, studies have shown that it can reduce the short-term benzodiazepine requirement and can provide sedation without respiratory depression. However, it can cause hypotension and bradycardia. Keep in mind, it does not target the underlying mechanism of alcohol withdrawal (GABA receptors), so it does not prevent the progression of alcohol withdrawal syndrome.

Class Summary

These agents have direct effects on the benzodiazepine ̶ GABA-A ̶ chloride receptor complex in enhancing chloride flux. Barbiturates may be useful in patients refractory to benzodiazepines. Respiratory depression is common at large doses. Ventilatory support may be required.

Phenobarbital

Phenobarbital has direct effects on the benzodiazepine-GABA-A-chloride receptor complex in enhancing chloride flux. It may be useful in patients refractory to benzodiazepines. The drug exhibits anticonvulsant properties in anesthetic doses. Because a barbiturate-induced respiratory depression may occur, especially after previous benzodiazepine therapy, early mechanical ventilation should be considered.

Pentobarbital (Nembutal)

Pentobarbital is a short-acting barbiturate with sedative, hypnotic, and anticonvulsant properties and can produce all levels of central nervous system mood alteration.

Class Summary

These agents are used to treat the hypoglycemia and nutrient and electrolyte deficiencies associated with delirium tremens (DTs). Alcoholics usually are deficient in thiamine, which functions as a cofactor for a number of important enzymes, such as pyruvate dehydrogenase, transketolase, and alpha-ketoglutarate dehydrogenase. Deficiency leads to Wernicke encephalopathy, peripheral neuropathy, cardiomyopathy, and metabolic acidosis.

Alcoholics often are also magnesium deficient, due to poor nutritional status and malabsorption. Magnesium stabilizes membranes, helps in the maintenance of potassium and calcium homeostasis, and may protect against seizures and arrhythmias.

Patients suffering from alcoholism may also develop hypoglycemia, due to malnutrition and poor glycogen stores. Additionally, gluconeogenesis is impaired because of a relative reduced redox state resulting from alcohol metabolism, which uses NAD+ as a cofactor for alcohol dehydrogenase and aldehyde dehydrogenase. The relative excess of NADH shifts the pyruvate-to-lactate ratio toward lactate, decreasing the substrate for gluconeogenesis.

Dextrose (D-Glucose)

Dextrose is a monosaccharide absorbed from the intestine and distributed, stored, and used by tissues. Parenterally injected dextrose is used in patients who are unable to obtain adequate oral intake. Direct oral absorption results in a rapid increase of blood glucose concentrations. Dextrose is effective in small doses; there is no evidence of toxicity. Concentrated dextrose infusions provide higher amounts of glucose and increased caloric intake, with minimal fluid volume. Use 1 ampule of 50 mL of a 50% glucose solution (25 g).

Thiamine (Vitamin B-1)

This is used to treat thiamine deficiency, including Wernicke encephalopathy.

Folic acid (Folacin-800)

Dietary deficiency of folic acid is common in alcoholics. Folic acid is an important cofactor for enzymes used in the production of red blood cells.

Magnesium sulfate

Magnesium sulfate is used to treat and prevent seizures. It decreases the amount of acetylcholine liberated at the endplate by the motor nerve impulse. The drug blocks neuromuscular transmission associated with seizure activity. Magnesium also exercises central nervous system depressant effects by blocking the NMDA receptor. Monitor patients carefully; large doses of magnesium sulfate may cause respiratory depression, hyporeflexia, and bradycardia. Infusion should be discontinued if reflexes are absent or if magnesium levels exceed 6-8 mEq/L. Calcium chloride, 10 mL IV of a 10% solution, can be given as an antidote for clinically significant hypermagnesemia.