Delirium Tremens

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.

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. In 60% of patients, the seizures are multiple, but only 3% of patients go on to develop status epilepticus. 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 tool to assess the severity of alcohol withdrawal is the Clinical Institute Withdrawal Assessment for Alcohol, Revised (CIWA-Ar).

• This survey consists of 10 items and can be administered rapidly at the bedside.

• 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.

• A score of greater than 15 is considered to be significant for alcohol withdrawal, and these patients need to be monitored carefully for the development of DTs.

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.

DIFFERENTIALS

Alcoholic Ketoacidosis
Brain Abscess
Chronic Renal Failure
Diabetic Ketoacidosis
Encephalopathy, Hepatic
Encephalopathy, Hypertensive
Encephalopathy, Uremic
Head Trauma
Hepatic Failure
Hypoglycemia
Meningitis
Myxedema Coma or Crisis
Opioid Abuse
Toxicity, Cocaine
Toxicity, Heroin
Uremia
Wernicke-Korsakoff Syndrome

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

Lab 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.

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 series 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 often is 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 DTs. This includes providing a calm quiet 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.

• Multivitamins and folate frequently are administered to these patients, but no evidence exists that vitamins, other than thiamine, have any benefit in the acute setting.

• Administer IV fluids for rehydration, as necessary. Most patients with severe alcohol withdrawal are significantly dehydrated, and their fluid requirements range from 4-10 liters 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 often are normal in spite of a total body magnesium deficit, and magnesium levels that are initially low may return to normal even though a total body deficiency persists. 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 often are 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

Though 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) frequently are 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 to 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. 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 to longer-acting agents.

Drug Category: 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 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 (patient able to take oral therapy), symptom-triggered therapy has been shown in prospective randomized controlled trials to be superior to fixed-dose drug therapy, with less medication use and a shorter duration of therapy. The dosage of benzodiazepine needs to be individualized for each patient. 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.

The use of continuous 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.

Drug Name	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.
Adult Dose	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 Dose	Not established
Contraindications	Documented hypersensitivity; narrow-angle glaucoma
Interactions	Coadministration with alcohols, phenothiazines, barbiturates, and MAOIs increases CNS toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in patients receiving other CNS depressants, patients diagnosed with low albumin levels, or hepatic failure

Drug Name	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.
Adult Dose	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 Dose	Not established
Contraindications	Documented hypersensitivity; narrow-angle glaucoma
Interactions	Increased toxicity of benzodiazepines in CNS with coadministration of phenothiazines, barbiturates, alcohols, and MAOIs
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in elderly patients (>60 y) or hepatic dysfunction, such as cirrhosis or abnormal liver function (prothrombin time >14 s or total bilirubin >2mg/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

Drug Name	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.
Adult Dose	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 Dose	Not established
Contraindications	Documented hypersensitivity; preexisting CNS depression; hypotension; narrow-angle glaucoma
Interactions	Toxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs
Pregnancy	D - Unsafe in pregnancy
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

Drug Category: 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.

Drug Name	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.
Adult Dose	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 Dose	Not established
Contraindications	Documented hypersensitivity; those who are not mechanically ventilated
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
Pregnancy	B - Usually safe but benefits must outweigh the risks.
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:

• Once patients with DTs have been stabilized, further dosing with benzodiazepines will be 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 are single or recur only once or twice. These seizures generally resolve spontaneously. If a patient has a seizure that is not typical of an alcohol withdrawal seizure (such as a focal seizure), the underlying cause of the seizure should be investigated.

• 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.

• 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 on examination.

Further Outpatient Care:

• As an outpatient, the issue of alcohol dependence must be addressed.

• Alcohol cessation programs and support groups, such as Alcoholics Anonymous, should be recommended.

• In addition, pharmacologic aids to alcohol cessation can be considered. Disulfiram is the most commonly used medication for this purpose, and naltrexone has been used more recently with some limited success.

MISCELLANEOUS

Medical/Legal 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 DTs is a potential pitfall.

• Use of a sympatholytic drug (ie, clonidine, atenolol) alone or with inadequate doses of benzodiazepines potentially can 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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Constructed by Dr N.A. Nematallah Consultant in perioperative medicine and intensive therapy, Al Razi Orthopedic Hospital , State of Kuwait, email : razianesth@freeservers.com