Delirium Tremens (DTs) Medication

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. Benzodiazepines not only have a high margin of safety, they are, according to prospective, randomized, clinical trials, 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 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 should be added.^[6]

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 IV 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, use phenobarbital only as an alternative agent when benzodiazepines cannot be used or have not been effective.^[7]

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 (60-120 mg) and repeat every 30 minutes until sedation occurs.

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.^[6] It has effects on NMDA and GABA receptors. 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 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. The recommended dose for atenolol is 50 mg orally once per day for a heart rate of 50-79 beats per minute and 100 mg once daily for a heart rate greater than 80 beats per minute; no drug is administered if the 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 the 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 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.^[8] 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 intravenously or intramuscularly every 30-60 minutes or the same dose orally every 4 hours for severe agitation, perceptual disturbances, or disturbed thinking not adequately controlled by high-dose benzodiazepines.

Class Summary

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

For the treatment of minor or moderate alcohol withdrawal (in patients able to take oral therapy), symptom-triggered therapy (also known as prn therapy) has been shown in prospective, randomized, controlled trials to be superior to fixed-dose drug therapy, with less medication use and a shorter duration of therapy.^[9] 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. 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.

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 or propofol to the treatment regimen.

Chlordiazepoxide

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)

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)

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

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

Propofol (Diprivan)

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

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

Phenobarbital

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

Pentobarbital (Nembutal)

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

Class Summary

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

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

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

Dextrose (D-Glucose)

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

Thiamine (Vitamin B-1)

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

Folic acid (Folacin-800)

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

Magnesium sulfate

Magnesium sulfate is used to treat and prevent seizures. It decreases the amount of acetylcholine liberated at the endplate by the motor nerve impulse. The drug blocks neuromuscular transmission associated with seizure activity. Magnesium also exercises 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.