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ALCOHOLISM
JOHN C.M. BRUST

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Ethanol Intoxication
Ethanol–Drug Interactions
Ethanol Dependence and Withdrawal
Wernicke-Korsakoff Syndrome
Alcoholic Cerebellar Degeneration
Alcoholic Polyneuropathy
Alcoholic Amblyopia
Pellagra
Alcoholic Liver Disease
Hypoglycemia
Alcoholic Ketoacidosis
Infection in Alcoholics
Trauma in Alcoholics
Alcohol and Cancer
Alcohol and Stroke
Alcoholic Myopathy
Central Pontine Myelinolysis and Marchiafava-Bignami Disease
Alcoholic Dementia
Fetal Alcohol Syndrome
Treatment of Chronic Alcoholism
Suggested Readings
In the United States, 7% of all adults and 19% of adolescents are “problem drinkers”: addicted to ethanol or, even if abstinent most of the time, likely to get into trouble when they drink. Ethanol-related deaths exceed 100,000 each year, accounting for 5% of all deaths in the United States. The devastation is direct (from intoxication, addiction, and withdrawal) or indirect (from nutritional deficiency or other ethanol-related diseases).
ETHANOL INTOXICATION
Ethanol acts at many levels of the neuraxis and affects a number of neurotransmitter systems, especially t-aminobutyric acid and glutamate. Like general anesthetics, ethanol disrupts (“fluidizes”) the phospholipid bilayer of cell membranes. How much of its actions on neurotransmitter receptors and protein channels is indirectly the result of this less specific effect is uncertain.
To obtain a mildly intoxicating blood ethanol concentration (BEC) of 100 mg/dL, a 70-kg person must drink about 50 g (2 oz) of 100% ethanol. Following zero-order kinetics, ethanol is metabolized at about 70 to 150 mg/kg of body weight per hour, with a fall in BEC of 10 to 25 mg/dL per hour. Thus, most adults require 6 hours to metabolize a 50-g dose, and the ingestion of only 8 g of additional ethanol per hour would maintain the BEC at 100 mg/dL.
Symptoms and signs of acute ethanol intoxication are due to cerebral depression, possibly at first of the reticular formation with cerebral disinhibition and later of the cerebral cortex itself. Manifestations depend not only on the BEC but also on the rate of climb and the person's tolerance, which is related less to increased metabolism than to poorly understood adaptive changes in the brain. At any BEC, intoxication is more severe when the level is rising than when it is falling, when the level is reached rapidly, and when the level has only recently been achieved. A single BEC determination therefore is not a reliable indicator of drunkenness, and the correlations of Table 157.1 are broad generalizations. Death from respiratory paralysis may occur with a BEC of 400 mg/dL and survival may occur at 700 mg/dL; a level of 500 mg/dL would be fatal in 50% of individuals.

TABLE 157.1. CORRELATION OF SYMPTOMS WITH BLOOD ETHANOL CONCENTRATION (BEC)

Low-to-moderate BECs cause slow saccadic eye movements and interrupted jerky pursuit movements that may impair visual acuity. Esophoria and exophoria cause diplopia. With a BEC of 150 to 250 mg/dL, there is increased electroencephalogram (EEG) beta activity (“beta buzz”); higher BECs cause EEG slowing. During sleep, suppression of the rapid eye movement (REM) stage is followed by REM rebound after a few hours.
The term pathologic intoxication refers to sudden extreme excitement with irrational or violent behavior after even small doses of ethanol. Episodes are said to last for minutes or hours, followed by sleep and, on awakening, amnesia for the events that took place. Delusions, hallucinations, and homicide may occur during bouts of pathologic intoxication. Some cases are probably psychologic dissociative reactions; others may be due to the kind of paradoxic excitation that sometimes follows barbiturate administration.
The term alcoholic blackout refers to amnesia for periods of intoxication, sometimes lasting several hours, even though consciousness at the time did not seem to be disturbed. Although sometimes considered a sign of physiologic dependence, blackouts also occur in occasional drinkers. Their nature is uncertain.
Acute ethanol poisoning causes more than 1,000 deaths each year in the United States. In stuporous alcoholic patients, subdural hematoma, meningitis, and hypoglycemia are important diagnostic considerations, but it is equally important to remember that ethanol intoxication alone can be fatal.
Blood ethanol causes a rise of blood osmolality, about 22 mOsm/L for every 100 mg/dL of ethanol; however, there are no transmembrane shifts of water, and the hyperosmolarity does not cause symptoms. Ethanol overdose should be considered in any comatose patient whose serum osmolarity is higher than predicted by calculation of the sum of serum sodium, glucose, and urea.
Patients stuporous or comatose from ethanol intoxication are generally managed similarly to those poisoned by other depressant drugs (Table 157.2). Death comes from respiratory depression, and artificial ventilation in an intensive care unit is the mainstay of treatment. Hypovolemia, acid–base or electrolyte imbalance, and abnormal temperature require attention, and if there is any uncertainty about the blood glucose level, 50% glucose is given intravenously, along with parenteral thiamine. Because ethanol is rapidly absorbed, gastric lavage does not help unless other drugs have been ingested. In obstreperous or violent patients, sedatives (including phenothiazines and haloperidol) should be avoided because they may push patients into stupor and respiratory depression. When a patient is being addressed, he or she may be alert but then lapse into stupor or coma when stimuli are decreased.

TABLE 157.2. TREATMENT OF ACUTE ETHANOL INTOXICATION

In a nonhabitual drinker, a BEC of 400 mg/dL takes 20 hours to return to zero. The only practical agent that might accelerate ethanol metabolism and elimination is fructose, but this causes gastrointestinal upset, lactic acidosis, and osmotic diuresis. (An imidazobenzodiazepine drug has been developed that reverses symptoms of mild-to-moderate ethanol intoxication; it is available for experimental use only.) Hemodialysis or peritoneal dialysis can be used for BECs greater than 600 mg/dL; for severe acidosis; for concurrent ingestion of methanol, ethylene glycol, or other dialyzable drugs; or for severely intoxicated children. Analeptic agents such as ethamivan, caffeine, or amphetamine have no useful role and can cause seizures and cardiac arrhythmia. Although patients are often depleted of magnesium, administration of magnesium sulfate may further depress the sensorium in intoxicated patients. Reports suggesting that naloxone hydrochloride (Narcan) benefits patients with ethanol intoxication require confirmation.
ETHANOL–DRUG INTERACTIONS
The combination of ethanol with other drugs, often in suicide attempts, causes 2,500 deaths annually, or 13% of all drug-related fatalities. Ethanol is often taken with marijuana, barbiturates, opiates, cocaine, hallucinogens, and inhalants—with varying interactions. Alcoholics often abuse barbiturates, and although ethanol and barbiturates are cross-tolerant, they lower the lethal dose of either alone or when taken acutely in combination. Ethanol with chloral hydrate (Mickey Finn) may be especially dangerous.
Impaired judgment and respiratory depression are also hazards when ethanol is combined with hypnotics, such as methaqualone (Quaalude), sedating antihistamines, antipsychotic agents, and tranquilizers such as meprobamate and benzodiazepines. Hypnotic drugs with long half-lives may cause potentially dangerous incoordination when ethanol is consumed the following day.
The cross-tolerance of ethanol with general anesthetics such as ether, chloroform, or fluorinated agents raises the threshold to sleep induction, but synergistic interaction then increases the depth and length of the anesthetic stage reached. Tricyclic antidepressants do not have a consistent effect; desipramine hydrochloride antagonizes the effects of ethanol, and amitriptyline potentiates them. Ethanol and morphine, repeatedly used, can increase each other's potency, and methadone addicts not only frequently become alcoholics but also can then develop a characteristic encephalopathy. Death has followed ethanol taken with propoxyphene hydrochloride. A mild reaction resembling that caused by disulfiram (Antabuse) occurs when patients combine ethanol with sulfonylureas such as tolbutamide (Orinase) or with some antibiotics, including chloramphenicol, griseofulvin, isoniazid, metronidazole, and quinacrine hydrochloride.
ETHANOL DEPENDENCE AND WITHDRAWAL
The term hangover refers to the headache, nausea, vomiting, malaise, nervousness, tremulousness, and sweating that can occur in anyone after brief but excessive drinking. Hangover does not imply ethanol addiction, but ethanol withdrawal does imply addiction and encompasses several disorders (Table 157.3), which may occur alone or in combination after reduction or cessation of drinking. Severity depends on the length and degree of a particular binge.

TABLE 157.3. ETHANOL WITHDRAWAL SYNDROMES

Tremulousness, the most common ethanol withdrawal symptom, usually appears in the morning after several days of drinking. It is promptly relieved by ethanol, but if drinking cannot continue, tremor becomes more intense, with insomnia, easy startling, agitation, facial and conjunctival flushing, sweating, anorexia, nausea, retching, weakness, tachypnea, tachycardia, and systolic hypertension. Except for inattentiveness and inability to fully recall the events that occurred during the binge, mentation is usually intact. Symptoms subside in a few days, but it may be 2 weeks before they completely disappear.
Perceptual disturbances, with variable insight, occur in about 25% of ethanol-addicted patients and include nightmares, illusions, and hallucinations, which are most often visual but may be auditory, tactile, olfactory, or a combination of these. Imagery includes insects, animals, or people. Hallucinations are usually fragmentary, lasting minutes at a time for several days. Sometimes, however, auditory hallucinations of threatening content last much longer, and occasionally, a persistent state of auditory hallucinosis with paranoid delusions that resembles schizophrenia develops in these patients and may require care in a mental hospital. Repeated bouts of acute auditory hallucinosis may predispose to the chronic form.
Ethanol can precipitate seizures in any epileptic; seizures usually occur the morning after weekend or even single-day drinking rather than during inebriation. Alcohol-related seizures affecting alcoholics not otherwise epileptic have traditionally been considered a withdrawal phenomenon, usually occurring within 48 hours of the last drink in persons who have abused ethanol chronically or in binges for months or years. The minimal duration of drinking sufficient to cause seizures is uncertain, but the risk is dose-related, beginning at only 50-g absolute ethanol daily. Seizures usually occur singly or in a brief cluster; status epilepticus is infrequent. Focal features are present in 25% and do not consistently correlate with evidence of previous head injury or other structural cerebral pathology. Alcohol seizures sometimes accompany tremulousness or hallucinosis, but they may occur in otherwise asymptomatic individuals. Their frequent appearance during active drinking or after more than 1 week of abstinence suggests that mechanisms other than withdrawal play a role in some individuals.
The diagnosis of alcohol-related seizures depends on an accurate history and exclusion of other cerebral lesions. Because reliable follow-up is unlikely, a seizure workup should be done, including computed tomography (CT) or magnetic resonance imaging and examination of cerebrospinal fluid (CSF). Fewer than 10% of patients with rum fits have spontaneous EEG abnormalities, compared with 50% of those with idiopathic epilepsy. A reported high frequency of electrographic photomyoclonic and photoconvulsant responses during ethanol withdrawal was not borne out by subsequent studies.
In contrast to tremor, hallucinosis, or seizures, which usually occur within 1 or 2 days of abstinence, delirium tremens usually begins from 48 to 72 hours after the last drink. Patients with delirium tremens are often hospitalized for other reasons. Delirium tremens may follow withdrawal seizures either before the postictal period has cleared or after 1 or 2 asymptomatic days, but when seizures occur during a bout of delirium tremens, some other diagnosis (e.g., meningitis) should be considered.
Symptoms typically begin and end abruptly, lasting from hours to a few days. There may be alternating periods of confusion and lucidity. Infrequently, relapses may prolong the disorder for a few weeks. Patients are typically agitated, inattentive, and grossly tremulous, with fever, tachycardia, and profuse sweating. They pick at the bed clothes or stare wildly about and intermittently shout at or try to fend off hallucinated people or objects. “Quiet” delirium is infrequent. Mortality is as high as 15%; death is usually due to other diseases (e.g., pneumonia or cirrhosis), but it may be attributed to unexplained shock, lack of response to therapy, or no apparent cause.
Treatment of ethanol withdrawal includes prevention or reduction of early symptoms, prevention of delirium tremens, and management of delirium tremens after it starts (Table 157.4). Sedatives have been recommended for recently abstinent alcoholics or those with mild early withdrawal symptoms, with theoretical consideration given to cross-tolerance with ethanol. Popular agents include paraldehyde, barbiturates, and benzodiazepines. With any of these agents, the aim is to give a loading dose likely to cause symptoms of mild intoxication (calming, dysarthria, ataxia, fine nystagmus), and then to adjust subsequent doses to avoid intoxication and tremulousness. After 1 or 2 days, dosage is gradually tapered, with reinstitution of intoxicating doses should withdrawal symptoms reappear. Beta-adrenergic blocking agents dampen alcohol withdrawal tremor and have been reported to decrease agitation and autonomic signs as well, reducing the need for benzodiazepines or other sedatives.

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