eMedicine Specialties > Critical Care > Medical Topics

Delirium Tremens

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

Updated: Nov 9, 2009

Introduction

Background

Delirium tremens (DTs) is a severe manifestation of alcohol withdrawal. Pearson first described it in 1813 as an acute psychosis following abstinence from alcohol. Although it only occurs in a relatively small number of patients who undergo alcohol withdrawal, it can be fatal. DTs is a medical emergency that requires prompt recognition and treatment.

Pathophysiology

Chronic intake of alcohol affects several of the neurotransmitter systems in the brain. These effects include increased release of endogenous opiates; activation of the gamma-aminobutyric acid-A (GABA-A) receptor and a decrease in GABA-A receptor function, with resultant influx of chloride ions; inhibition of the N -methyl-D-aspartate (NMDA) type of glutamate receptor, which mediates the postsynaptic excitatory effects of glutamate, with up-regulation of this receptor; and 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 andfunction of brain receptors.

Frequency

United States

Fewer than 50% of alcohol-dependent persons develop any significant withdrawal symptoms that require pharmacological treatment upon cessation of alcohol intake. DTs, the most severe manifestation of withdrawal, occurs in 5% of patients with alcohol withdrawal.

Mortality/Morbidity

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

Race

• Patients of white race have a higher risk of developing severe alcohol withdrawal.^{[1 ]}
• Patients of black race have a lower risk of severe alcohol withdrawal.^{[1 ]}

Sex

According to surveys among the US population, men have a higher prevalence of alcohol dependence than women. Research on gender differences among persons with alcohol dependence have found that women are more likely to deny that they have an alcohol problem and frequently minimize problems related to excessive alcohol use. Whether or not gender differences exist in the rates of development of severe alcohol withdrawal are not clear.  

Age

According to surveys, young adult males have the highest prevalence of alcohol dependence and unsafe alcohol use. Unsafe alcohol use is also common among the elderly. According to the US 2000 National Health Interview Survey, the prevalence of heavy drinking is 10% in men over 65 years of age, but only 2% among women in this age group. Among older adults presenting to emergency departments, the prevalence of alcohol abuse and dependence is 10-15%.

Clinical

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 (withdrawal tremulousness) occurs within 6-24 hours following the last drink and is characterized by tremor, anxiety, nausea, vomiting, and insomnia.
• 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 (rum fits) occur within 6-48 hours of alcohol cessation and are characterized by major motor seizures that occur during withdrawal in patients who normally have no seizures and have normal EEGs. These seizures are typically generalized and brief. In the absence of treatment, multiple seizures occur in 60% of patients, but the duration between 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.
• 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, and autonomic hyperactivity (tachycardia and hypertension).

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).^{[2 ]}This survey consists of 10 items and can be administered rapidly at the bedside.

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 for each item except for the last item, which is assigned 0-4 points, with a total possible score of 67.

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.

A score of greater than 15 is seen in patients with moderate-to-severe alcohol withdrawal. Patients with a score 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.

Routine screening for unhealthy alcohol use in patients admitted to the hospital can 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 one and two trauma centers. Such screening tools include AUDIT, CAGE, and AUDIT-C.

Physical

• No specific findings on physical examination are diagnostic for 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.
• Physical examination findings in a patient with DTs may include fever, hypertension, tachycardia, diaphoresis, tremor, agitation, positional nystagmus, global confusion, and disorientation.

Causes

Risk factors for developing DTs include coexisting acute illness, long duration of alcohol intake, large volume of alcohol intake, severe withdrawal symptoms at presentation, prior DTs, prior seizures, prior detoxification, and intense craving for alcohol.

The signs of alcohol withdrawal in critically ill patients, especially if accompanied by delirium, may mimic those of other serious disorders, including sepsis, stroke, intracranial hemorrhage, meningitis, drug toxicity, hepatic encephalopathy, hypoxia, hypoglycemia, and other metabolic disorders. These disorders may need to be excluded before a firm diagnosis of alcohol withdrawal is made. 

Differential Diagnoses

Other Problems to Be Considered

AIDS and HIV
Cerebral embolism
Cerebral hemorrhage
Cerebral tumors
Encephalitis
Hypoxia
Raised intracranial pressure
Substance intoxication and withdrawal
Toxic ingestions or exposures (eg, methanol, salicylates, ethylene glycol, carbon monoxide, anticholinergics)
Vitamin B-12 deficiency
Thyrotoxicosis

Workup

Laboratory Studies

• Serum ethanol level
• Serum chemistry to include:
  • Sodium
  • Potassium
  • Chloride
  • Bicarbonate
  • Blood urea nitrogen (BUN)
  • Creatinine
  • Magnesium
  • Phosphorous
• 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.
• Others that may be useful in certain patients include measurement of serum lactate and ketone body levels, as well as serum osmolality with calculation of the osmolal gap.  

Imaging Studies

• Chest radiograph
  • About 50% of patients with DTs who present with fever will have an infection, pneumonia being most common.
  • A chest radiograph should be obtained on all patients suspected of having DTs.
• Obtain cervical spine radiographs if any question or suspicion of trauma or head injury exists.
• 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

Procedures

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.

Treatment

Medical Care

Supportive therapy is an important component of the treatment of alcohol withdrawal syndrome and delirium tremens (DTs). This includes providing a calm, quiet, well-lit environment; reassurance; ongoing reassessment; attention to fluid and electrolyte deficits; and treatment of any coexisting addictions. Commonly, these patients have coexisting medical, surgical, and psychiatric conditions that need careful diagnosis and treatment.

• Thiamine is useful in preventing Wernicke encephalopathy (confusion, ataxia, ophthalmoplegia) and 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 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.
• 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.^{[3 ]}
• Administer 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.
• Monitor and replace electrolytes as necessary because people with alcoholism often have low calcium, magnesium, phosphorous, and potassium.  
  • People 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 exacerbates hepatic damage caused by alcohol. Randomized trials have not demonstrated any effect of parenteral magnesium administration on withdrawal symptoms, but because 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 a 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 intravenous 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.
• 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.

Medication

Although thiamine has no effect on the symptoms or signs of alcohol withdrawal or on the incidence of seizures or DTs, thiamine (100 mg PO/IV/IM qd for 3 d) is useful in preventing Wernicke encephalopathy (confusion, ataxia, ophthalmoplegia) 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 the alcohol withdrawal syndrome, including DTs. Not only do they have a high margin of safety, but also prospective randomized clinical trials have demonstrated that benzodiazepines are very effective in treating the symptoms and signs of alcohol withdrawal and in decreasing the incidence of seizures and DTs. The longer-acting benzodiazepines, such as chlordiazepoxide and diazepam, appear to be more effective at preventing the serious complications of seizures and DTs than 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.

Phenobarbital, a long-acting barbiturate, 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 intravenous route. 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. Therefore, only use phenobarbital as an alternative agent when benzodiazepines cannot be used or have not been effective.

An appropriate use for phenobarbital might be the situation in which agitation has not been controlled well with high doses of benzodiazepines. Then, one could administer a small dose of phenobarbital (60-120 mg) and repeat every 30 minutes until sedation occurs. For patients with refractory DTs, propofol recently has been described in case studies as effective in managing patients who are intubated.^{[4 ]}No clinical trial has demonstrated any superiority over benzodiazepines.

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 only be used 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. The recommended dose for atenolol is 50 mg orally once per day for heart rate of 50-79 beats per minute, 100 mg once daily for heart rate greater than 80 beats per minute, and no drug is administered if heart rate is less than 50 beats per minute. 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. No evidence exists to indicate that carbamazepine is effective in prevention or treatment of DTs.

Drugs such as esmolol and midazolam, which have a short half-life and rapid onset of action, can be administered by continuous intravenous 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. 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. Some authorities recommend haloperidol at a dose of 0.5-5 mg IV or IM 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.

Benzodiazepines

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 compared with 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 (patient 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.^{[5 ]}The dosage of benzodiazepine needs to be individualized for each patient. 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 DTs, who often require very high doses of these agents. For the treatment of DTs, benzodiazepines should only be administered 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. Intravenous lorazepam rather than diazepam has been successfully used and may be preferable in the elderly or in those with severe liver disease. 

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

If the intravenous 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 intravenous 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 oral or intravenous intermittent bolus therapy with long-acting agents.

Patients with DTs whose conditions do not respond to high doses of benzodiazepines may respond to pentobarbital or propofol.

Chlordiazepoxide (Librium, Libritabs, Mitran)

Depresses all levels of CNS, including limbic and reticular formation, possibly by increasing GABA activity, a major inhibitory neurotransmitter. Parenteral form usually used initially. Because of limited experience with IV chlordiazepoxide for severe alcohol withdrawal and DTs, the use of intravenous diazepam or lorazepam is preferred.

Dosing

Adult

Minor withdrawal:
Symptom-triggered therapy (preferred): 50-100 mg PO q1-2h until symptoms are controlled, then prn based on symptoms
Fixed-schedule dosing (not recommended): 50 mg PO q6h for 4 doses, then 25 mg q6h for 8 doses; additional 25- to 50-mg doses prn based on symptoms

Pediatric

Not established

Interactions

Coadministration with alcohols, phenothiazines, barbiturates, and MAOIs increases CNS toxicity

Contraindications

Documented hypersensitivity; narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in patients receiving other CNS depressants, patients diagnosed with low albumin levels, or hepatic failure

Diazepam (Valium, Diazemuls, Diastat)

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.
Individualize dosage and increase cautiously to avoid adverse effects.

Dosing

Adult

Minor withdrawal:
Symptom-triggered therapy (preferred): 10-20 mg PO q1-2h until symptoms controlled, then repeat prn
Fixed-schedule dosing (not recommended): 10 mg PO q6h for 4 doses, then 5 mg q6h for 8 doses; additional 5- to 10-mg doses prn based on symptoms
DTs:
10 mg IV, followed by 5 mg q5min until patient is calm but awake

Pediatric

Not established

Interactions

Increased toxicity of benzodiazepines in CNS with coadministration of phenothiazines, barbiturates, alcohols, and MAOIs

Contraindications

Documented hypersensitivity; narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in elderly patients (>60 y) or hepatic dysfunction, such as cirrhosis or abnormal liver function (prothrombin time >14 s or total bilirubin > 2 mg/dL) because toxicity may increase; caution in patients with renal failure because accumulation of active metabolites can occur; diazepam has a long-acting active metabolite, desmethyldiazepam, which can accumulate after repeated large doses, especially in elderly patients or those with renal insufficiency, although toxic serum levels of diazepam and its metabolite have not been reported in patients with DTs, even after very large doses of drug
Caution in severely depressed patients; be aware that diazepam can produce psychological and physical dependence; rarely, very large doses of diazepam administered IV (several hundred mg daily for several days) have been reported to result in an elevated anion gap metabolic acidosis due to accumulation of the propylene glycol component of the carrier solution; diazepam can produce thrombophlebitis when injected into small peripheral veins

Lorazepam (Ativan)

Sedative hypnotic with short onset of effects and relatively long half-life. By increasing action of GABA, which is major inhibitory neurotransmitter in brain, may depress all levels of CNS, including limbic and reticular formation. When patient must be sedated for longer than 24-h period, this medication is excellent. Commonly used prophylactically to prevent DTs. Has a medium half-life. It is especially useful in elderly persons and in those with hepatic dysfunction because it does not produce active metabolites.

Dosing

Adult

Minor withdrawal:
Symptom-triggered therapy (preferred): 2-4 mg PO/IV/IM q1-2h prn to control symptoms
Fixed-schedule dosing (not recommended): 2 mg PO/IV/IM q6h for 4 doses, then 1 mg q6h for 8 doses; additional 1- to 2-mg doses prn if symptoms not controlled
DTs:
1-2 mg IV q5min until patient is calm but awake

Pediatric

Not established

Interactions

Toxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs

Contraindications

Documented hypersensitivity; preexisting CNS depression; hypotension; narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, or Parkinson disease; rarely, very large doses administered IV (several hundred mg daily for several days) have been reported to produce elevated anion gap metabolic acidosis due to the propylene glycol component

Anesthetic agents

Propofol, an intravenous anesthetic agent, is active on both the glutamate and GABA-A receptors, similar to the alcohol itself, whereas benzodiazepines are active only against the GABA receptors. It may be effective for patients with DTs refractory to benzodiazepines. Due to its rapid onset of hypnosis and anticonvulsant properties, propofol is an alternative treatment for intubated patients with DTs 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 (Diprivan)

Phenolic compound unrelated to other types of anticonvulsants. Has general anesthetic properties when administered IV. Propofol IV produces rapid hypnosis, usually within 40 s. Effects are reversed within 30 min following discontinuation of infusion.

Dosing

Adult

Bolus IV injection of 0.5 mg/kg q10s to a total dose of 2-2.5 mg/kg or by continuous infusion at 25-75 mcg/kg/min

Pediatric

Not established

Interactions

Reduce propofol dose when administered concomitantly with benzodiazepines, opiates, phenothiazines, ethanol, and narcotics; propofol may potentiate neuromuscular blockade of vecuronium; theophylline may weaken effects of propofol, and dose increase may be needed

Contraindications

Documented hypersensitivity; those who are not mechanically ventilated

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Do not administer with blood or blood products using the same IV catheter; patients may develop apnea; may experience a decrease in systemic vascular resistance leading to hypotension; prolonged use (>72 h) may result in hyperlipidemia (hypertriglyceridemia) due to its high lipid load; propofol-induced hypertriglyceridemia may cause pancreatitis in patients with alcohol withdrawal syndrome; monitor serum triglyceride levels when propofol is used for >72 h

Follow-up

Further Inpatient Care

• Indications for hospital admission of a patient with alcohol withdrawal syndrome include delirium tremens (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.
• Once patients with DTs have been stabilized, further dosing with benzodiazepines is needed to manage their alcohol withdrawal. A symptom-triggered dosing regimen, rather than fixed-schedule dosing, is the current preferred regimen. Fixed-dose regimens often result in excessive sedation.
• Alcohol withdrawal seizures are generalized and usually only occur once or recur only once or twice, and these seizures generally resolve spontaneously. If a patient has a seizure that is not typical of an alcohol withdrawal seizure (such as a partial or focal seizure, prolonged seizures, or prolonged post-ictal 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.   
• The use of benzodiazepines has been shown to prevent initial and recurrent seizures. Phenytoin is not indicated for the prophylaxis or treatment of these seizures. 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 both in interventions and assessment of outcomes, definite conclusions about their safety and effectiveness cannot be made.
• 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 intensive care units. 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, intensive care unit 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 has 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. 
• In critically ill patients in intensive care units, symptom-triggered benzodiazepine therapy using very high-dose bolus therapy has been associated with a reduction in the need for mechanical ventilation. The institution of a guideline for intensive care unit patients felt to have "benzodiazepine-refractory" alcohol withdrawal that maximized the bolus dose of benzodiazepine with addition of phenobarbital if necessary, with doses determined by score on the Riker Sedation Analgesia Scale, lead to a reduction in mechanical ventilation with a trend toward reduction in length of stay and nosocomial infection. Single intravenous bolus doses of diazepam of 100-200 mg may be required. 
• Intravenous ethanol infusions have been used in the past, especially in surgical intensive care units, as prophylaxis against alcohol withdrawal among patients with suspected or proven alcohol dependence. Retrospective, uncontrolled, noncomparative case series have reported both successful and unsuccessful use of intravenous ethanol in trauma and burn patients. Comparative or randomized studies have not demonstrated efficacy for this treatment, and this treatment was inferior to diazepam in a prospective, randomized trial.^{[6 ]} As intravenous ethanol has a short duration of action, narrow margin of safety, has toxic effects on gastric mucosa, pancreas, liver, bone marrow and other organs, and requires considerable volumes of fluids for administration, this treatment cannot be recommended.

Further 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 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. 
• Pharmacological aids to alcohol cessation should be considered because they may prevent relapse in patients who have been treated for alcohol dependence. Disulfiram, naltrexone, acamprosate, and topiramate have been used in the long-term treatment of alcohol dependence and are initiated after detoxification to alcohol has been completed.
• Cognitive behavioral therapy and motivational enhancement therapy (which are sometimes combined with pharmacological therapy) have been used successfully to prevent relapse.
• To prevent hazardous alcohol use, routine screening for alcohol use should be performed in primary care settings. The use of the CAGE questionnaire or the Alcohol Use Disorders Identification Test (AUDIT) questionnaire is useful in screening.
• Protocols for screening persons at risk for hazardous alcohol use, followed by brief intervention (5-10 minutes) carried out by clinicians, nurses, or social workers, 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.

Miscellaneous

Medicolegal Pitfalls

• Failure to consider the diagnosis of alcohol withdrawal syndrome in patients with altered mental status or abnormal vital signs is a potential pitfall.
• Failure to treat patients with severe alcohol withdrawal syndrome with adequate doses of benzodiazepines is a potential pitfall 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, is a potential pitfall.
• Failure to exclude other etiologies of altered mental status in patients with suspected alcohol withdrawal is a potential pitfall.
• Failure to admit patients to the hospital with signs and symptoms of major withdrawal or delirium tremens (DTs) is a potential pitfall.
• Use of a sympatholytic drug (ie, clonidine, atenolol) alone or with inadequate doses of benzodiazepines can potentially cause problems because 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.
• Use of phenytoin to prevent or treat alcohol withdrawal seizures is not recommended. Phenytoin is not effective in preventing or treating alcohol withdrawal seizures. Seizures due to alcohol withdrawal are best prevented and treated with benzodiazepines.
• 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. Use 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 appear to condone alcohol intake in the patient with alcoholism who is beginning recovery. Alcohol treatment has not been shown in controlled trials to be effective in preventing seizures or DTs.

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Keywords

delirium tremens, DTs, severe alcohol withdrawal syndrome, alcohol withdrawal, alcoholism, acute psychosis, chronic intake of alcohol, withdrawal seizures, hallucinations, Clinical Institute Withdrawal Assessment for Alcohol

Contributor Information and Disclosures

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
Michael James Burns, MD, FACEP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, American College of Physicians, American Society of Tropical Medicine and Hygiene, California Medical Association, Infectious Diseases Society of America, Phi Beta Kappa, Royal Society of Tropical Medicine and Hygiene, and Society for Academic Emergency 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
James B Price, MD is a member of the following medical societies: Alpha Omega Alpha and American College of Emergency Physicians
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
Michael E Lekawa, MD, FACS is a member of the following medical societies: American Association for the Surgery of Trauma, American College of Surgeons, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

Medical Editor

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.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Harold L Manning, MD, Associate 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.

CME Editor

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine
Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians
Disclosure: Nothing to disclose.

Chief Editor

Michael R Pinsky, MD, CM, FCCP, FCCM, Professor of Critical Care Medicine, Bioengineering, Cardiovascular Disease and Anesthesiology, Vice-Chair, Academic Affairs, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Michael R Pinsky, MD, CM, FCCP, FCCM is a member of the following medical societies: American College of Chest Physicians, American College of Critical Care Medicine, American Heart Association, American Thoracic Society, Association of University Anesthetists, Shock Society, and Society of Critical Care Medicine
Disclosure: LiDCO Ltd Honoraria Consulting; iNTELOMED Intellectual property rights Board membership; Edwards Lifesciences Honoraria Consulting; Applied Physiology, Ltd Honoraria Consulting; Cheetah Medical Consulting fee Consulting

Clinical guidelines

Mayo-Smith MF, Beecher LH, Fischer TL, Gorelick DA, Guillaume JL, Hill A, Jara G, Kasser C, Melbourne J. Management of alcohol withdrawal delirium. An evidence-based practice guideline. Arch Intern Med 2004 Jul 12;164(13):1405-12.^{[ 7 ]}

Physical detoxification services for withdrawal from specific substances. In: Center for Substance Abuse Treatment (CSAT). Detoxification and substance abuse treatment. Rockville (MD): Substance Abuse and Mental Health Services Administration (SAMHSA); 2006 Jan 18. p. 41-111. (Treatment improvement protocol (TIP); no. 45).

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