Treatment of Delirium Tremens

Treatment of Delirium Tremens

Shuk-Ling Wong, Pharm.D.
Clinical Instructor St. John’s University, Jamaica, NY Clinical Coordinator, Medicine Long Island Jewish Medical Center-Department of Pharmacy Services, New Hyde Park, NY

Alcohol dependence is a major public health problem. The 1990 household survey of the National Institute of Drug Abuse estimated that 103 million people in the United States use alcohol and an estimated 15% become alcoholics. Each year, about 2%–3% of alcoholics experience withdrawal syndromes requiring treatment.1 There are three clinical stages of alcohol withdrawal: minor, major and—the most devastating—delirium tremens (DTs). Minor alcohol withdrawal may begin within 3–6 hours of drinking cessation. Signs and symptoms include anxiety, insomnia, tremulousness, hyperreflexia, hypertension, tachycardia, diaphoresis, nausea, vomiting and craving for alcohol. Major alcohol withdrawal begins in about 24 hours and lasts approximately 1–3 days. Signs and symptoms include auditory and visual hallucinations, anxiety and hyperactivity. Most patients remain oriented at this stage. Delirium tremens begins 2–3 days after drinking is stopped and is characterized by clouding of consciousness, psychosis, severe agitation and death (TABLE 1).2 Seizures may occur prior to DTs. They generally consist of one or two grand mal seizures and rarely develop into status epilepticus. Delirium tremens can be fatal if not treated properly. Therefore, it is important for today’s pharmacist to understand the biochemical abnormalities as well as the advantages and disadvantages of different pharmacologic agents in the management of DTs.

Table 1.
Characteristics of Delirium Tremens
  • Elevated temperature (100.2°F)
  • Tachycardia
  • Elevated blood pressure (>140/90 mmHg)
  • Tremulousness
  • Diaphoresis
  • Hallucinations
  • Disorientation
  • Urinary incontinence
  • Agitation
  • Inability to feed oneself

Delirium tremens is the most serious alcohol withdrawal manifestation. It is characterized by profound confusion, fever, disorientation, frightening visual or auditory hallucinations, and marked autonomic hyperactivity. The syndrome is most commonly seen in persons who have suddenly ceased drinking after a prolonged period of heavy alcohol use.1 Delirium tremens has a gradual onset of 2–3 days post cessation of alcohol. Signs and symptoms peak in 4–5 days and these symptoms can fluctuate for several weeks. Approximately 5% of patients withdrawing from alcohol progress to DTs, and the risk increases with concomitant infections or medical problems. The mortality rate of DTs is about 5%–10% with treatment and can be as high as 20% if not treated.3 Therefore, dramatic action is necessary to curb the effects of this disorder.

Fluid and Biochemical Abnormalities in Delirium Tremens

Many patients who suffer from DTs have fluid depletion. Alcohol suppresses the release of antidiuretic hormone and induces diuresis. At the early stage of alcohol withdrawal, patients may be overhydrated secondary to increases in antidiuretic hormone as alcohol levels fall. However, patients who undergo severe alcohol withdrawal symptoms may have extensive fluid loss due to diaphoresis, hyperthermia and vomiting. Correction of water deficiency is therefore important, and the infusion of fluid is generally clinically required.

Electrolyte imbalance is common in patients with DTs. Hyponatremia, hypokalemia, hypocalcemia, hypophospholemia and hypomagnesemia can occur as a result of dietary deficiency and acid-base imbalances during alcohol ingestion or alcohol withdrawal. Hyponatremia can cause nausea, malaise, lethargy and cramps, which can progress to psychosis, seizures and coma. Hypokalemia can lead to muscle paralysis, weakness, cramps, restless leg syndrome and areflexia. Hypocalcemia can cause tetany and weakness. Hypophospholemia can lead to myocardial failure, muscle weakness, brain dysfunction and blood dyscrasias.4

Low levels of magnesium have been implicated as an etiologic factor in DTs.5 Alcohol abuse may cause hypomagnesemia in a number of ways. First, alcohol inhibits magnesium tubular reabsorption, leading to increased magnesium loss through urine. Second, some medical conditions associated with chronic alcoholism may play important roles in hypomagnesemia. These include malnutrition syndrome, acute and chronic pancreatitis, vomiting, and diarrhea. Finally, free fatty acids liberated during alcohol withdrawal bind to magnesium and decrease its serum level. Although alcoholic patients commonly present with hypomagnesemia, there are no controlled studies suggesting that a low serum magnesium level is an absolute factor in DTs.6

Malnutrition is a common problem in chronic alcoholism. An average of eight to ten drinks a day will provide 70–1000 kilocalories. However, this high caloric intake is a poor source of nutrients. In addition, patients who suffer from alcohol abuse experience loss of appetite resulting in inadequate consumption of nutrients such as proteins, minerals and vitamins. Protein deprivation leads to lack of energy, impaired immune function, increased risk of infection and prolonged wound healing. Mineral and vitamin deficiencies can interfere with a variety of biologic functions and interrupt normal metabolism.

Folate deficiency is the most common sign of malnutrition. About 30% of patients with severe alcoholism develop megaloblastic anemia.7 Alcoholism can cause folate deficiency in a number of ways. Most common are: diets with poor sources of folate; decreased folate absorption through the gastrointestinal tract due to alcohol-induced anorexia, vomiting, or esophagitis; decreased retention and storage of folate due to severe liver disease, such as hepatitis and cirrhosis; and impaired tissue affinity for circulating folate caused by alteration of the enterohepatic cycling of folate.

Iron deficiency anemia in chronic alcohol abuse is associated with inadequate dietary intake, gastrointestinal bleeding and abnormal iron metabolism. Impaired iron metabolism results in both sideroblastic anemia and hemosiderosis.7 Sidero-blastic anemia is caused by abnormal pyridoxine function and decreased enzyme activity involved in heme synthesis. Hemosiderosis is the result of tissue accumulation of hemosiderin, an insoluble protein containing as much as 37% iron.

Thiamine deficiency causes peripheral neuropathy in 5%–15% of alcoholics.8 Signs and symptoms include bilateral limb numbness, tingling and paresthesias. Wernicke-Korsakoff syndrome represents a medical emergency in severe alcoholics. Thiamine deficiency is the major cause of this condition.9 Typical symptoms of Wernicke-Korsakoff syndrome include central nervous system (CNS) depression, nystagmus, retinal hemorrhages, wide-based ataxic gait, hypothermia, hypotension and polyneuropathy. Although Wernicke-Korsakoff syndrome is not commonly encountered in clinical practice, it is associated with a 10%–20% mortality rate.

Supportive Drug Therapy

The best management of DTs is prevention by vigorously treating initial signs and symptoms. Appropriate early intervention includes continued abstinence from alcohol, providing patients with adequate nutrition and rest, anticipating the need for fluid and electrolytes, recognizing any CNS symptoms and the use of sedatives.

Once delirium tremens is manifest, treatment includes supportive drug therapy and pharmaceutical intervention. Supportive treatment consists of fluid and electrolyte replacement to correct dehydration and electrolyte imbalances. Pharmaceutical intervention involves replenishing thiamine with a dose of 50–100 mg intramuscularly (IM) or intravenously (IV) for a minimum of three days to treat or prevent Wernicke’s encephalopathy. This is followed by 100 mg oral thiamine daily after the patient resumes oral intake. A multivitamin supplement is often given once daily via intravenous fluid or orally. Administration of magnesium sulfate should be considered only when patients present with symptoms of hypomagnesemia. The usual dose of magnesium is 1 gram IM every six hours for a total of four doses.10

Haloperidol has been used successfully as adjunctive therapy for rapid control of agitation and alcohol-induced hallucinations.11 Haloperidol blocks dopamine action by binding to the dopamine receptors in the CNS. The mechanism by which haloperidol aborts hallucination may be due to its antidopaminergic properties. The drug is metabolized by the liver, and some evidence indicates extrahepatic metabolism.12 Following IV administration of a single dose, the maximum sedation effect is reported to occur in one hour. Limited data suggest that the metabolite hydroxyhaloperidol has some pharmacologic activity, although its activity appears to be less than that of its parent compound. Haloperidol and its metabolites are eliminated slowly in urine and feces. Dosage adjustment is unnecessary in patients with renal failure.12 The most frequent adverse effect of haloperidol is extrapyramidal reactions. Other side effects are tardive dyskinesia, insomnia, restlessness, euphoria, dry mouth, blurred vision, constipation and urinary retention. In the treatment of DTs, haloperidol can be given in 3 mg IV as adjunctive therapy to benzodiazepine. This dose is then doubled and repeated in 30 minutes if the patient shows little or no response. Successive doses can be doubled every 30 minutes until sufficient control is achieved. A total 24-hour dosage ranging from 100–480 mg of haloperidol in combination with a benzodiazepine has been shown to effectively control severe agitation with no apparent adverse effects.13

Pharmacologic Therapy

Benzodiazepines (TABLE 2) are the drugs of choice for the acute management of DTs due to their superior anticonvulsant activity and minimal side effects. Benzodiazepines facilitate the binding of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, to its receptor site in the CNS. The binding of the GABA receptor increases neuronal membrane permeability to chloride and results in membrane hyperpolarization. This membrane hyperpolarization is believed to mediate the sedative and hypnotic effects.14 Most of the drugs’ commonly observed adverse effects are related to their pharmacologic mechanisms of action. They include sedation, motor incoordination, lightheadedness, confusion, impairment of mental performance, ataxia and anterograde amnesia. Other important adverse effects may include CNS excitation and depression of the cardiovascular and respiratory systems. Benzodiazepines are available in parenteral dosage forms. The IV route is particularly important in patients experiencing DTs, and intensive care monitoring is mandatory. The choice of a particular benzodiazepine is dependent on many factors including pharmacokinetic properties, dosage formulation, presence of liver or renal impairment, and ease of dosage titration. At present, there are four benzodiazepines available in parenteral form—diazepam, chlordiazepoxide, lorazepam and midazolam.

Table 2.
Pharmacokinetics of Benzodiazepines
Drug t1/2
Onset of
Time to Peak
Duration of
Active Metabolites
1/2 in hours)
Chlordiazepoxide 5–30 1–5 0.5–4.0 0.25–1.0 Desmethylderivative (5–30), demoxepam, oxazepam
Diazepam 20–100 1–5 0.5–2.0 0.25–1.0 Desmethyldiazepam (30–200) temazepam, oxazepam
Lorazepam 10–20 2–5 1.0–6.0 12–24 None
Midazolam 1–2 1–5 0.5–1.0 1–5 None
t1/2 = half-life

Diazepam, when administered in 5–10 mg IV doses every 3–4 hours, controls delirium effectively. Dosage and frequency of administration should be titrated to patient response.15 Some clinicians recommend that the dosage not exceed 30 mg within an 8-hour period. Onset of action is usually within 1–5 minutes. The time to peak plasma levels is about 0.5–5 hours, and the duration of action is approximately 15 minutes to 1 hour. Disadvantages of diazepam include pain at injection site with a relatively high frequency of thrombophlebitis, and the presence of pharmacologically active metabolites with long half-lives (20–100 hours). The elderly and patients with hepatic disease may experience substantial accumulation of the parent drug and metabolites. This results in prolonged duration of action. Diazepam may also cause more cardiovascular and respiratory depression than the other benzodiazepines when administered IV at rates greater than 5 mg/min.

Chlordiazepoxide and diazepam have been shown to be equally effective in the treatment of DTs. Chlordiazepoxide is metabolized by the liver and produces active metabolites that might accumulate in the elderly and patients with hepatic dysfunction. The drug’s half-life is about 5–30 hours. Onset of action is usually within 1–5 minutes. Time to peak plasma level ranges from 30 minutes to 4 hours, and duration of action lasts from 15 minutes to 1 hour. The drug has other disadvantages in that it must be refrigerated, kept out of light, and be reconstituted prior to administration. In the treatment of DTs, chlordiazepoxide is given IV at 25–100 mg every 3–4 hours until agitation is controlled. Doses over 500 mg in 24 hours are not recommended.16 Although chlordiazepoxide has been used effectively in treatment of DTs, intravenous administration is not recommended because air bubbles form on the surface of the solution. Therefore, the drug should not be considered as first-line treatment.

Lorazepam has a relatively short half-life (10–20 hours) and produces no active metabolites. The drug is primarily eliminated through glucuronidation and does not rely on hepatic enzyme oxidation. Onset of action occurs about 2–5 minutes after IV injection. The time to peak plasma level ranges from 1–6 hours, and the duration of action is from 12–24 hours. In the treatment of DTs, the dosage of lorazepam is 1–4 mg IV every 1–3 hours, and dosage should be adjusted according to patient response.11 The manufacturer recommends not exceeding a maximum single dose of 4 mg IV and a maximum 24-hour dose of 240 mg. The drug has fewer adverse effects on cardiovascular and respiratory function than the other benzodiazepines.

Midazolam differs from the other benzodiazepines in the following ways: it has a much shorter half-life (1–2 hours), a shorter duration of action (1–5 hours), an extremely short onset of action after IV injection (1–5 minutes), a low frequency of pain or thrombophlebitis on injection, and increased water solubility allowing greater stability in aqueous solutions. Clinical experience with midazolam in controlling DTs is limited. The recommended starting dose is 1–5 mg/hour by continuous IV infusion. Dosage should be adjusted according to patient response. The highest dose requirement recorded is 20 mg/hour for a period of 24 hours with no adverse effects.11


Currently, there is no universal protocol for the treatment of DTs. Although diazepam and chlordiazepoxide have frequently been used, they display many disadvantages compared to newer agents such as lorazepam and midazolam. Effective titration of a short-acting benzodiazepine without active metabolites is desirable. Both diazepam and chlordiazepoxide undergo hepatic metabolism and produce pharmacologically active metabolites. Both parent drug and metabolites result in prolonged half-lives and may accumulate in the elderly or patients with liver disease. Lorazepam and midazolam have the advantages of short action and ease of titration, and they produce no active metabolites. Rapid onset of action is important for efficient control of DTs. Midazolam and diazepam are the most lipophilic benzodiazepines with the fastest onset of action. Although lorazepam is the least lipid-soluble of the parenteral benzodiazepines, it offers a prompt onset of action within 2–5 minutes after IV injection. Lorazepam offers many advantages over diazepam and chlordiazepoxide, especially in elderly and hepatically dysfunctional patients.

In summary, midazolam continuous IV infusion is the most effective agent for treating DTs (TABLE 3). Nevertheless, more clinical experience is needed.11

Table 3.
Treatment of Delirium Tremens
Drugs Dosage and Administration
25–100 mg IV every 3 hours until agitation is controlled. (Maximum dose is 500 mg/24 hours.)
5–10 mg IV every 3–4 hours. Titrate dose and frequency to patient response.
1–4 mg/hour IV (continuous infusion) or 1–4 mg every 1–3 hours (interval dosing). Adjust dosage to patient response. Dosage not to exceed 240 mg/24 hours.
1–20 mg/hour (continuous IV drip). Adjust dosage to patient response.
Supportive drug therapy
Start with 3 mg IV. Successive doses can be doubled every 30 minutes. (Total 24-hour dose ranges: 100–480 mg)
100 mg IM or IV, followed by 100 mg PO daily.
One daily. Can be given via IV infusion or PO.
Magnesium sulfate
1 g IM every 6 hours for a total of 4 doses.
IV = intravenously; IM = intramuscularly; PO = orally; g = gram; mg = milligram

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