Delirium Tremens

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 and function of brain receptors.

Frequency:

• In the US: 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.

Treatment
Medical Care: Supportive therapy is an important component of the treatment of alcohol withdrawal syndrome and 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.

• 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.

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.

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 (also known as prn therapy) has been shown in prospective, randomized, controlled trials to be superior to fixed-dose drug therapy, with less medication use and a shorter duration of therapy. The dosage of benzodiazepine needs to be individualized for each patient. 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.

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.

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 >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

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