Delirium Tremens (DTs)

Back

Background

Delirium tremens (DTs) is the most severe form of ethanol withdrawal manifested by altered mental status (global confusion) and sympathetic overdrive (autonomic hyperactivity), which can progress to cardiovascular collapse. 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. (See Etiology.)

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.

Etiology

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When ethanol is withdrawn, a functional decrease in the inhibitory neurotransmitter GABA is seen.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. This is the phenomenon known as kindling.

Risk factors

Risk factors for delirium tremens are inconsistent among studies,[1] include the following:

Epidemiology

About 9% of US adults meet the criteria for an alcohol-use disorder. 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 chronic alcoholics is estimated at 5-10%. Only 5% of patients with ethanol withdrawal progress to delirium tremens. White patients have a higher risk of developing severe alcohol withdrawal, while black patients have a lower risk.[2] 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.

Prognosis

Complications of delirium tremens (DTs) include the following:

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.

History

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

Alcohol withdrawal syndrome is divided into 4 categories:

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 and auditory hallucinations, whole body tremor, vomiting, diaphoresis, and hypertension.

Withdrawal seizures

Withdrawal seizures (rum fits) 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, hypertension, 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),[3] 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.


View Image

Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar). The CIWA-Ar is not copyrighted and may be reproduced freely. This assess....

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,[4] 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.[5]

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.[6] 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.

Physical Examination

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. A search for signs of trauma should also be included.

Clinical findings associated with DTs may include the following:

Approach Considerations

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

Serum chemistry studies should include:

Other Laboratory Studies

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:

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.

Imaging Studies

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:

Lumbar Puncture

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.

Approach Considerations

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

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.

Supportive Care

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.[7]

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

Thiamine is useful in preventing Wernicke encephalopathy (confusion, ataxia, ophthalmoplegia) and Wernicke-Korsakoff syndrome. 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 Wernicke-Korsakoff syndrome is disastrous in these patients and can remain unrecognized. Because orally administered thiamine may have poor enteral absorption in alcoholic patients, high-risk patients should receive parenteral thiamine at 100-250 mg once daily for several days.

Magnesium

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.

Randomized trials have not demonstrated any effect of parenteral magnesium administration on withdrawal symptoms, but 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.

Benzodiazepines

In critically ill patients in intensive care units (ICUs), symptom-triggered benzodiazepine treatment using very-high-dose bolus therapy has been associated with a reduction in the need for mechanical ventilation. Fixed-dose regimens often result in excessive sedation.

A guideline was instituted for ICU patients thought to have benzodiazepine-refractory alcohol withdrawal that maximized the bolus dose of benzodiazepine, with the addition of phenobarbital if necessary, and with doses determined by the score on the Riker Sedation Analgesia Scale.[8] This led to a reduction in mechanical ventilation, with a trend toward reduction in length of stay and nosocomial infection. Single IV bolus doses of diazepam of 100-200 mg may be required.

Ethanol

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.[9] 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.

CIWA-Ar Scale

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.

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.

Outpatient Care

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 2 forms of naltrexone (oral and extended-release injectable). Topiramate, SSRIs, baclofen, and odansetron may also be effective but are not FDA approved. All these agents are, at-best, only modestly effective in the short term.[10]

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 alcoholics 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.

Deterrence/prevention

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.[10]

Medication Summary

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 Wernicke-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.[11] 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.

The longer-acting benzodiazepines, such as chlordiazepoxide and diazepam, appear to be more effective at preventing the serious complications of seizures and DTs than are shorter-acting benzodiazepines such as alprazolam and oxazepam. Most experts recommend that intermittent IV 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 propofol, and occasionally other drugs, may be added.[12]

Phenobarbital, a long-acting barbiturate with a half-life of 80-120 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.

However, compared with benzodiazepines, even at high doses, phenobarbital has a greater risk of respiratory depression and hypotension and has a lower overall safety profile. It is generally recommended to be reserved for use as an alternative agent when benzodiazepines cannot be used or have not been effective.[13] Some authorities have recommended phenobarbital 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.

An appropriate use for phenobarbital might be a situation in which agitation has not been controlled well with high doses of benzodiazepines. Then, one could administer a small dose of phenobarbital and repeat every 30 minutes until sedation occurs.

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.[14]

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.[12] 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.[15]

Clonidine and beta-blockers have been used to treat the hyperadrenergic state of alcohol withdrawal. Although these agents may correct some of the autonomic manifestations of withdrawal, they have not been demonstrated to have any effect on seizures or DTs, and they should be used only in conjunction with benzodiazepines in the treatment of patients with alcohol withdrawal. The recommended dose for clonidine is 0.2 mg orally bid, but this dose should be individualized. Beta-blockers may obscure the vital sign abnormalities that occur early in alcohol withdrawal and prevent early recognition of more severe alcohol withdrawal. They should not be used alone, but only when combined with adequate sedative-hypnotic drug therapy. Beta-blockers that have been recommended include atenolol, metoprolol, propranolol, and labetalol. The usual contraindications for clonidine and beta-blockers apply.

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.[16]

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.[17] 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.

Chlordiazepoxide

Clinical Context:  Chlordiazepoxide depresses all levels of the central nervous system (CNS), 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)

Clinical Context:  Diazepam depresses all levels of CNS (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)

Clinical Context:  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 CNS, 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.

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.[18] 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.[19] Aggressive treatment of severe alcohol withdrawal syndrome with diazepam may decrease the need for intubation.[8]

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.

Propofol (Diprivan)

Clinical Context:  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.

Class Summary

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.

Phenobarbital

Clinical Context:  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)

Clinical Context:  Short-acting barbiturate with sedative, hypnotic, and anticonvulsant properties and can produce all levels of CNS mood alteration.

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.

Dextrose (D-Glucose)

Clinical Context:  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)

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

Folic acid (Folacin-800)

Clinical Context:  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

Clinical Context:  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 CNS 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.

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.

Author

Michael James Burns, MD, FACEP, FACP, Health Science Clinical Professor, Department of Emergency Medicine, Department of Internal Medicine, Division of Infectious Diseases, University of California Irvine School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

James B Price, MD, Attending Emergency Physician, Mission Hospital; Clinical Faculty, Department of Emergency Medicine, Harbor-UCLA Medical Center

Disclosure: Nothing to disclose.

Michael E Lekawa, MD, FACS, Associate Clinical Professor of Surgery, University of California, Irvine School of Medicine; Chief, Department of Surgery, Division of Trauma and Critical Care, Director of Trauma Services, Director of Surgical Intensive Care Unit, Director of Student Critical Care Teaching Program, Medical Director of Surgery Clinics, University of California, Irvine Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Michael R Pinsky, MD, CM, Dr hc, FCCP, MCCM, Professor of Critical Care Medicine, Bioengineering, Cardiovascular Disease, Clinical and Translational Science and Anesthesiology, Vice-Chair of Academic Affairs, Department of Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine

Disclosure: LiDCO Ltd Honoraria Consulting; iNTELOMED Intellectual property rights Board membership; Edwards Lifesciences Honoraria Consulting

Additional Contributors

Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve University School of Medicine

Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas Medical Society, New York Academy of Medicine, New York Academy of Sciences, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

William K Chiang, MD Associate Professor, Department of Emergency Medicine, New York University School of Medicine; Chief of Service, Department of Emergency Medicine, Bellevue Hospital Center

William K Chiang, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

William G Gossman, MD Associate Clinical Professor of Emergency Medicine, Creighton University School of Medicine; Consulting Staff, Department of Emergency Medicine, Creighton University Medical Center

William G Gossman, MD is a member of the following medical societies: American Academy of Emergency Medicine

Disclosure: Nothing to disclose.

J Stephen Huff, MD Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia School of Medicine

J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Lisa Kirkland, MD, FACP, CNSP, MSHA Assistant Professor, Department of Internal Medicine, Division of Hospital Medicine, Mayo Clinic; ANW Intensivists, Abbott Northwestern Hospital

Lisa Kirkland, MD, FACP, CNSP, MSHA is a member of the following medical societies: American College of Physicians, Society of Critical Care Medicine, and Society of Hospital Medicine

Disclosure: Nothing to disclose.

Harold L Manning, MD Professor, Departments of Medicine, Anesthesiology and Physiology, Section of Pulmonary and Critical Care Medicine, Dartmouth Medical School

Harold L Manning, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Sage W Wiener, MD Assistant Professor, Department of Emergency Medicine, State University of New York Downstate Medical Center; Assistant Director of Medical Toxicology, Department of Emergency Medicine, Kings County Hospital Center

Sage W Wiener, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Anne Yim, MD Resident Physician, Department of Emergency Medicine, Kings County Hospital and State University of New York Downstate Medical Center

Anne Yim, MD is a member of the following medical societies: American College of Emergency Physicians

Disclosure: Nothing to disclose.

References

  1. Eyer F, Schuster T, Felgenhauer N, Pfab R, Strubel T, Saugel B. Risk assessment of moderate to severe alcohol withdrawal--predictors for seizures and delirium tremens in the course of withdrawal. Alcohol Alcohol. Jul-Aug 2011;46(4):427-33. [View Abstract]
  2. Chan GM, Hoffman RS, Gold JA, Whiteman PJ, Goldfrank LR, Nelson LS. Racial variations in the incidence of severe alcohol withdrawal. J Med Toxicol. Mar 2009;5(1):8-14. [View Abstract]
  3. Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict. Nov 1989;84(11):1353-7. [View Abstract]
  4. Watling SM, Fleming C, Casey P, Yanos J. Nursing-based protocol for treatment of alcohol withdrawal in the intensive care unit. Am J Crit Care. Jan 1995;4(1):66-70. [View Abstract]
  5. Reoux JP, Oreskovich MR. A comparison of two versions of the clinical institute withdrawal assessment for alcohol: the CIWA-Ar and CIWA-AD. Am J Addict. Jan-Feb 2006;15(1):85-93. [View Abstract]
  6. Khan BA, Guzman O, Campbell NL, Walroth T, Tricker J, Hui SL. Comparison and agreement between the Richmond Agitation-Sedation Scale and the Riker Sedation-Agitation Scale in evaluating patients' eligibility for delirium assessment in the ICU. Chest. Jul 2012;142(1):48-54. [View Abstract]
  7. Krishel S, SaFranek D, Clark RF. Intravenous vitamins for alcoholics in the emergency department: a review. J Emerg Med. May-Jun 1998;16(3):419-24. [View Abstract]
  8. Gold JA, Rimal B, Nolan A, Nelson LS. A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens. Crit Care Med. Mar 2007;35(3):724-30. [View Abstract]
  9. Weinberg JA, Magnotti LJ, Fischer PE, et al. Comparison of intravenous ethanol versus diazepam for alcohol withdrawal prophylaxis in the trauma ICU: results of a randomized trial. J Trauma. Jan 2008;64(1):99-104. [View Abstract]
  10. Friedmann PD. Clinical practice. Alcohol use in adults. N Engl J Med. Jan 24 2013;368(4):365-73. [View Abstract]
  11. Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of the Alcohol Withdrawal Syndrome. Cochrane Database Syst Rev. 2011;(6):CD008537. [View Abstract]
  12. McCowan C, Marik P. Refractory delirium tremens treated with propofol: a case series. Crit Care Med. Jun 2000;28(6):1781-4. [View Abstract]
  13. Hendey GW, Dery RA, Barnes RL, Snowden B, Mentler P. A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal. Am J Emerg Med. May 2011;29(4):382-5. [View Abstract]
  14. Rosenson J, Clements C, Simon B, Vieaux J, Graffman S, Vahidnia F. Phenobarbital for Acute Alcohol Withdrawal: A Prospective Randomized Double-blind Placebo-controlled Study. J Emerg Med. Mar 2013;44(3):592-598.e2. [View Abstract]
  15. Foster C, Mueller S, Vanderweide L, Kiser T, Fish D, MacLaren R. Addition of dexmedetomidine to the standard of care for severe alcohol withdrawal [abstr]. Critic Care Med. Dec 2012;40(12):doi: 10.1097/01.ccm.0000424341.32883.e7.
  16. Minozzi S, Amato L, Vecchi S, Davoli M. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev. 2010;(3):CD005064. [View Abstract]
  17. Mayo-Smith MF, Beecher LH, Fischer TL, et al. Management of alcohol withdrawal delirium. An evidence-based practice guideline. Arch Intern Med. Jul 12 2004;164(13):1405-12. [View Abstract]
  18. Jaeger TM, Lohr RH, Pankratz VS. Symptom-triggered therapy for alcohol withdrawal syndrome in medical inpatients. Mayo Clin Proc. Jul 2001;76(7):695-701. [View Abstract]
  19. Muzyk AJ, Leung JG, Nelson S, Embury ER, Jones SR. The role of diazepam loading for the treatment of alcohol withdrawal syndrome in hospitalized patients. Am J Addict. Mar 2013;22(2):113-8. [View Abstract]

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.

Average annual deaths from alcohol.

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.