Anne Yim, MD,
Resident Physician, Department of Emergency
Medicine, Kings County Hospital and State University of New
York Downstate Medical Center
Nothing to disclose.
Coauthor(s)
Sage W Wiener, MD,
Assistant Professor, Department of Emergency
Medicine, State University of New York Downstate, Director of
Medical Toxicology, Department of Emergency Medicine, Kings
County Hospital Center
Nothing to disclose.
Specialty Editor(s)
J Stephen Huff, MD,
Associate Professor, Emergency Medicine and
Neurology, Department of Emergency Medicine, University of
Virginia Health Sciences Center
Nothing to disclose.
John D Halamka, MD, MS,
Associate Professor of Medicine, Harvard
Medical School, Beth Israel Deaconess Medical Center; Chief
Information Officer, CareGroup Healthcare System and Harvard
Medical School; Attending Physician, Division of Emergency
Medicine, Beth Israel Deaconess Medical
Center
Nothing to disclose.
John T VanDeVoort, PharmD,
Regional Director of Pharmacy, Sacred Heart
& St. Joseph's Hospitals
Nothing to disclose.
William K Chiang, MD,
Associate Professor, Department of Emergency
Medicine, New York University School of Medicine; Chief of
Service, Department of Emergency Medicine, Bellevue Hospital
Center
Nothing to disclose.
Chief Editor
Barry E Brenner, MD, PhD, FACEP,
Professor of Emergency Medicine, Professor of
Internal Medicine, Program Director, Emergency Medicine,
University Hospitals, Case Medical Center
Nothing to disclose.
Background
Delirium tremens (DT) is the most severe form of ethanol withdrawal manifested by altered mental status and sympathetic overdrive, which can progress to cardiovascular collapse. The syndrome was first described by Thomas Sutton in 1813, but the link to alcohol abstinence was not made until the 1950s with the work of Victor and Adams.[1, 2] Delirium tremens is a medical emergency with a high mortality rate, making early recognition and treatment essential.
Ethanol interacts with GABA receptors enhancing activity. GABA receptors are a family of chloride ion channels that mediate inhibitory neurotransmission. They are pentameric complexes composed of several glycoprotein subunits. Chronic ethanol abuse seems to modify the GABA receptor via several mechanisms leading to a decrease in GABA activity. Chronic ethanol exposure has been found to alter gene expression and increase cellular internalization of certain subunits affecting the type of GABA receptors that are available at the cell surface and the synapse. Chronic ethanol exposure has also been found to alter phosphorylation of GABA receptors, which may alter receptor function. When ethanol is withdrawn, a functional decrease in the inhibitory neurotransmitter GABA is seen. This leads to a loss of the inhibitory control of excitatory neurotransmitters such as norepinephrine, glutamate, and dopamine.
Ethanol also acts as an N -methyl D-aspartate receptor antagonist. Withdrawal of ethanol leads to increased activity of these excitatory neuroreceptors, resulting in the clinical manifestations of ethanol withdrawal: tremors, agitation, hallucinations, seizures, tachycardia, hyperthermia, and hypertension. Past episodes of withdrawal lead to increased frequency and severity of future episodes. This is the phenomenon known as kindling.
Fewer than 50% of ethanol-dependent persons develop significant withdrawal syndrome requiring pharmacologic treatment.
Only 5% of patients with ethanol withdrawal progress to delirium tremens (DT).
Mortality/Morbidity
The mortality rate for delirium tremens may be as high as 35% if untreated but is less than 5% with early recognition and treatment.
Patients at greatest risk for death are those with extreme fever, fluid and electrolyte imbalance, or intercurrent illness such as occult trauma, pneumonia, hepatitis, pancreatitis, alcoholic ketoacidosis, or Wernicke-Korsakoff syndrome.
Race
Patients of white race have a higher risk of developing severe alcohol withdrawal.[3]
Patients of black race have a lower risk of severe alcohol withdrawal.[3]
Sex
Prevalence of alcohol abuse is approximately 7% in males and 3% in females.
Incidence of withdrawal symptoms is lower in females than in males.
Age
Prevalence of alcohol abuse is highest among young adults, but delirium tremens rarely occurs among pediatric patients because the physiological substrate for severe alcohol withdrawal takes time to develop.
Alcohol withdrawal syndrome occurs when the blood alcohol level falls below a certain threshold in patients with a long history of alcohol consumption. Manifestations progress from mild withdrawal to its most severe and fatal form, delirium tremens (DT). Patients may have any manifestation of mild withdrawal independently (eg, patients may have alcohol withdrawal seizures or alcoholic hallucinosis without alcoholic tremulousness), and any form of mild withdrawal may progress to delirium tremens.
Alcoholic tremulousness occurs 6-12 hours after cessation or decrease of alcohol intake and is characterized by autonomic hyperactivity; anxiety, tremors, hypertension, tachycardia, nausea, vomiting, or diarrhea.
Alcohol withdrawal seizures or "rum fits" occur at 6-48 hours after last drink, most commonly within the first 24 hours. They are usually generalized tonic clonic, self-limited, and rarely progress to status epilepticus.
Alcoholic hallucinosis (formerly known as Kraepelin's hallucinatory insanity) occurs 10-72 hours after the last drink. These hallucinations may often be visual, but they can also be auditory, tactile (formication), or olfactory. Outside of hallucinations, sensorium is intact.
Delirium tremens usually occurs 3-7 days after the last drink. It is differentiated from the less severe forms of withdrawal by altered sensorium and autonomic instability. Confusion, obtundation, and delirium are the hallmarks of delirium tremens. Other findings include severe agitation, hyperpyrexia, tachycardia, hypertension, and diaphoresis.
Physical examination findings in delirium tremens (DT) are generally nonspecific. A thorough physical examination should be performed to assess for level of consciousness, other serious illnesses, signs of trauma, and stigmata of chronic liver disease.
Physical examination findings may include the following:
Serum ethanol concentration – This is important because patients who exhibit withdrawal while ethanol is still present in the serum are likely to have a more severe course.
Complete blood count with differential
Urinalysis
Blood cultures
Further laboratory studies as indicated by clinical scenario
Morbidity and mortality from delirium tremens (DT) are secondary to a hyperadrenergic state and other associated medical problems (eg, infections, fluid and electrolyte abnormalities). The goal is to blunt the hyperadrenergic state and treat associated medical problems.
Secure airway appropriately
Oxygen supplementation
Large-bore intravenous line
Fluid resuscitation with crystalloid solution
Cardiac monitor
Bedside glucose testing with supplementation if needed
Thiamine administration (100 mg IV) to treat or prevent Wernicke encephalopathy
Sedation with benzodiazepines
Check electrolytes, replace as needed
Physical restraints often needed to ensure patient and staff safety (use in conjunction with chemical restraints)
Parenteral benzodiazepines are the drugs of choice for treatment of delirium tremens (DT). Patients may require massive doses to achieve sedation. In patients refractory to benzodiazepine therapy alone, barbiturates or propofol should be added.[4]
Benzodiazepines are the medication of choice because they have a high therapeutic index and superior anticonvulsant effects. They act on the benzodiazepine-GABA-chloride receptor complex having a similar GABA potentiating effect to alcohol. No clear evidence suggests superiority of any particular benzodiazepine, but longer-acting benzodiazepines such as diazepam and chlordiazepoxide are generally preferred. Diazepam has an ideal pharmacologic profile because of its rapid onset of action and prolonged duration of effects due to active metabolites, allowing the dose to be safely and rapidly escalated until control of the patient’s symptoms is achieved.
Benzodiazepine dose required may be highly variable and should be titrated until the patient is calm and peaceful. For some patients, several hundred milligrams of a diazepam equivalent may be required over the first few hours. Symptom-triggered therapy with intermittent boluses is superior to a fixed dose taper or infusion of benzodiazepines.[5, 6] Therapy may be guided by the CIWA-A score, an assessment tool used to determine the severity of alcohol withdrawal.
Barbiturates such as phenobarbital and pentobarbital are also useful to treat delirium tremens. However, compared with benzodiazepines, they have a lower therapeutic index and can cause respiratory depression and hypotension. Barbiturates should be reserved for patients refractory to or unable to take benzodiazepines.[7] These patients all need ICU monitoring, and many will need to be intubated and mechanically ventilated.
Propofol has been described in case series to be successful in the treatment of refractory delirium tremens in intubated patients. It has effects on NMDA and GABA receptors.
Ethanol is not recommended as there is little evidence regarding its use in withdrawal, and it has many potential adverse effects such as hepatotoxicity, hyponatremia, hypoglycemia, hypotension, and depression of level of consciousness.
Adjuvant therapies
Neuroleptics have been shown to be inferior to sedative-hypnotics in reducing mortality and duration of alcohol withdrawal delirium. Drugs such as haloperidol (Haldol) should not be used, as they lower seizure threshold and can prolong QTc, while doing nothing to address the underlying pathophysiology.[4]
Sympatholytic agents such as clonidine and beta-blockers have been studied in mild-moderate ethanol withdrawal. There is no evidence regarding their effectiveness in delirium tremens. These drugs decrease sympathetic drive improving hypertension and tachycardia but have no GABA effects and hence are ineffective in preventing seizures. For this reason, they should not be used as sole therapies. Beta-blockers may be helpful to prevent cardiac complications in withdrawal patients with known coronary artery disease. However, use of these drugs is controversial as normalization of vitals signs may mask progression of withdrawal, leading to inadequate treatment of withdrawal. When benzodiazepines are used appropriately, with escalation of dose to clinical effect, sympatholytics are rarely necessary.
Anticonvulsants carbamazepine and valproic acid have been shown to be effective in treatment of mild-to-moderate withdrawal. No role exists for use of phenytoin in treatment of ethanol withdrawal or withdrawal seizures. However, it can be used to treat underlying primary seizure disorder.
Phenytoin is not helpful in patients with delirium tremens and seizures. Benzodiazepines or barbiturates effectively treat both seizures and other manifestations of delirium tremens.
These agents bind to benzodiazepine receptors in the benzodiazepine-GABAa-chloride receptor complex to enhance the binding of GABA, causing enhanced chloride flux, hyperpolarization of the membrane, and neuro-inhibitory effects. First-line agents for delirium tremens.
Clinical Context:
Because of rapid onset, prolonged duration of effects, and high therapeutic index, diazepam is drug of choice. Volumes of literature exist regarding usage of diazepam for ethanol withdrawal. Onset of action is within 5 min after IV administration. Has active metabolite (desmethyl-diazepam) that has longer duration of action than diazepam.
These agents have direct effects on benzodiazepine-GABAa-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.
Clinical Context:
Has direct effects on benzodiazepine-GABAa-chloride receptor complex in enhancing chloride flux. May be useful in patients refractory to benzodiazepines. 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.
Propofol is an anesthetic agent with action at NMDA and GABA receptors. It has advantages of rapid onset of action and rapid metabolic clearance. It is a good alternative for alcohol withdrawal resistant to benzodiazepines. Because of respiratory depression, intubation is required.
Clinical Context:
Phenolic compound that is a sedative-hypnotic agent used for induction and maintenance of anesthesia or sedation. Has also been shown to have anticonvulsant properties.
These agents are used to treat the hypoglycemia, nutrient, and electrolyte deficiencies associated with 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 magnesium deficient due to a 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 due to 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.
Clinical Context:
Monosaccharide absorbed from intestine and distributed, stored, and used by tissues. Parenterally injected dextrose used in patients unable to obtain adequate oral intake. Direct oral absorption results in rapid increase of blood glucose concentrations. Effective in small doses; 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).
Clinical Context:
Used to treat and prevent seizures. Decreases amount of acetylcholine liberated at endplate by motor nerve impulse. Blocks neuromuscular transmission associated with seizure activity. Magnesium also has CNS depressant effects by blocking the NMDA receptor. Monitor carefully; large doses 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 antidote for clinically significant hypermagnesemia.
Upon discharge, patients should be counseled to abstain from alcohol.
Consider referral to inpatient detoxification or alcohol rehabilitation program.
Various types of outpatient programs are available.
The Substance Abuse and Mental Health Services Administration (SAMHSA) of the US Department of Health and Human Services offers an extensive listing of drug and alcohol treatment facilities by location. SAMHSA helpline: (800) 662-HELP (4357) with help in English and Spanish, or TDD at (800) 487-4889.
Girard DE, Kumar KL, McAfee JH. Alcohol intoxication and withdrawal. Med Rounds. 1988;1:158-164.
Grant BF et al. The 12-Month Prevalence and Trends in DSM–IV Alcohol Abuse and Dependence: United States, 1991–1992 and 2001–2001. Drug and Alcohol Dependence. 2004;74 (3):223-234.
Hamilton RJ. Substance Withdrawal. In: Goldfrank LR, et al. Goldfrank's Toxicologic Emergencies. 7. McGraw-Hill Professional Publishing; 2002:1059-1073.
Schuckit MA. Alcoholism and drug dependency. In: Harrison's Principles of Internal Medicine. 1991:2146-2151.
Shabbir HF, Ilksoy N, Greenwald JL. Alcohol Withdrawal Syndromes. In: Williams MV, et al. Comprehensive Hospital Medicine: An Evidence Based Approach. 1. WB Saunders; 2007.
