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Alcohol Toxicity and Withdrawal

By

Gerald F. O’Malley

, DO, Grand Strand Regional Medical Center;


Rika O’Malley

, MD, Grand Strand Medical Center

Last review/revision Dec 2022
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Alcohol (ethanol) is a central nervous system depressant. Large amounts consumed rapidly can cause respiratory depression, coma, and death. Large amounts chronically consumed damage the liver and many other organs. Alcohol withdrawal manifests as a continuum, ranging from tremor to seizures, hallucinations, and life-threatening autonomic instability in severe withdrawal (delirium tremens). Diagnosis is clinical or based on diagnosis of typical complications (eg, alcohol-related liver disease Alcohol-Related Liver Disease Alcohol consumption is high in most Western countries. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 8.5% of US adults are estimated to... read more Alcohol-Related Liver Disease ).

About half of adults in the US currently drink alcohol, 20% are former drinkers, and 30 to 35% are lifetime abstainers. Alcohol use is also a problem in preteens and teenagers Drug and Substance Use in Adolescents Substance use among adolescents ranges from sporadic use to severe substance use disorders. The acute and long-term consequences range from minimal to minor to life threatening, depending on... read more . For most drinkers, the frequency and amount of alcohol consumption does not impair physical or mental health or the ability to safely carry out daily activities. However, acute alcohol intoxication is a significant factor in injuries, particularly those due to interpersonal violence, suicide, and motor vehicle crashes.

Chronic alcohol abuse interferes with the ability to socialize and work. Although estimates vary across studies, about 13.9% of adults meet criteria for an alcohol use disorder (abuse or dependence) in any given year (1 General reference Alcohol (ethanol) is a central nervous system depressant. Large amounts consumed rapidly can cause respiratory depression, coma, and death. Large amounts chronically consumed damage the liver... read more ). Binge drinking, defined as consuming 5 drinks per occasion for men and 4 drinks per occasion for women, is a particular problem among younger people.

General reference

  • 1. Grant BF, Goldstein RB, Saha T, et al: Epidemiology of DSM-5 alcohol use disorder results from the National Epidemiologic Survey on Alcohol and Related Conditions III. JAMA Psychiatry 72 (8):757–766, 2015. doi: 10.1001/jamapsychiatry.2015.0584

Pathophysiology of Alcohol Toxicity and Withdrawal

One serving of alcohol (one 12-oz can of beer, one 6-oz glass of wine, or 1.5 oz of distilled liquor) contains 10 to 15 g of ethanol. Alcohol is absorbed into the blood mainly from the small bowel, although some is absorbed from the stomach. Alcohol accumulates in blood because absorption is more rapid than oxidation and elimination. The concentration peaks about 30 to 90 minutes after ingestion if the stomach was previously empty.

About 5 to 10% of ingested alcohol is excreted unchanged in urine, sweat, and expired air; the remainder is metabolized, mainly by the liver, where alcohol dehydrogenase converts ethanol to acetaldehyde. Acetaldehyde is ultimately oxidized to CO2 and water at a rate of 5 to 10 mL/hour (of absolute alcohol); each milliliter yields about 7 kcal. Alcohol dehydrogenase in the gastric mucosa accounts for some metabolism; women have lower gastric alcohol dehydrogenase activity than men.

Alcohol exerts its effects by several mechanisms. Alcohol binds directly to gamma-aminobutyric acid (GABA) receptors in the central nervous system, causing sedation. Alcohol also directly affects cardiac, hepatic, and thyroid tissue.

Chronic effects

Tolerance to alcohol develops rapidly; similar amounts cause less intoxication. Tolerance is caused by adaptational changes of central nervous system cells (cellular, or pharmacodynamic, tolerance) and by induction of metabolic enzymes. People who develop tolerance may reach an incredibly high blood alcohol content (BAC). However, ethanol tolerance is incomplete, and considerable intoxication and impairment occur with a large enough amount. But even people who have developed tolerance may die of respiratory depression secondary to alcohol overdose.

Alcohol-tolerant people are susceptible to alcoholic ketoacidosis Alcoholic Ketoacidosis Alcoholic ketoacidosis is a metabolic complication of alcohol use and starvation characterized by hyperketonemia and anion gap metabolic acidosis without significant hyperglycemia. Alcoholic... read more , especially during binge drinking. Alcohol-tolerant people are cross-tolerant to many other central nervous system depressants (eg, barbiturates, nonbarbiturate sedatives, benzodiazepines).

Chronic heavy alcohol intake typically leads to liver disorders (eg, fatty liver, alcoholic hepatitis Pathology Pathology , cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more ); the amount and duration required vary (see Alcohol-Related Liver Disease Alcohol-Related Liver Disease Alcohol consumption is high in most Western countries. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 8.5% of US adults are estimated to... read more Alcohol-Related Liver Disease ). Patients with a severe liver disorder often have coagulopathy due to decreased hepatic synthesis of coagulation factors, increasing the risk of significant bleeding due to trauma (eg, from falls or vehicle crashes) and of gastrointestinal bleeding Overview of Gastrointestinal Bleeding Gastrointestinal (GI) bleeding can originate anywhere from the mouth to the anus and can be overt or occult. The manifestations depend on the location and rate of bleeding. (See also Varices... read more Overview of Gastrointestinal Bleeding (eg, due to gastritis, from esophageal varices due to portal hypertension Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in North America), schistosomiasis (in endemic areas), or hepatic vascular abnormalities. Consequences... read more ); alcohol abusers are at particular risk of gastrointestinal bleeding.

Chronic heavy intake also commonly causes the following:

On the other hand, low to moderate levels of alcohol consumption ( 1 to 2 drinks/day) may decrease the risk of death due to cardiovascular disorders (1 Pathophysiology reference Alcohol (ethanol) is a central nervous system depressant. Large amounts consumed rapidly can cause respiratory depression, coma, and death. Large amounts chronically consumed damage the liver... read more ). Numerous explanations, including increased high density lipoprotein (HDL) levels and a direct antithrombotic effect, have been suggested. Nonetheless, alcohol should not be recommended for this purpose, especially when there are several safer, more effective approaches to reduce cardiovascular risk.

Special populations

Young children who drink alcohol are at significant risk of hypoglycemia because alcohol impairs gluconeogenesis and their smaller stores of glycogen are rapidly depleted. Women may be more sensitive than men, even on a per-weight basis, because their gastric (first-pass) metabolism of alcohol is less due to lower activity of alcohol dehydrogenase in the gastric mucosa. Drinking during pregnancy may result in fetal alcohol spectrum disorder Fetal Alcohol Syndrome Alcohol exposure in utero increases the risk of spontaneous abortion, decreases birth weight, and can cause fetal alcohol syndrome, a constellation of variable physical and cognitive abnormalities... read more .

Pathophysiology reference

  • 1. Piano MR: Alcohol's effects of the cardiovascular system. Alcohol Res 38(2):219–241, 2017.

Symptoms and Signs of Alcohol Toxicity and Withdrawal

Acute effects

Symptoms progress proportionately to blood alcohol content (BAC). Actual levels required to cause given symptoms vary with tolerance, but in typical users the following occur:

  • 20 to 50 mg/dL (4.3 to 10.9 mmol/L): Tranquility, mild sedation, and some decrease in fine motor coordination

  • 50 to 100 mg/dL (10.9 to 21.7 mmol/L): Impaired judgment and a further decrease in coordination

  • 100 to 150 mg/dL (21.7 to 32.6 mmol/L): Unsteady gait, nystagmus, slurred speech, loss of behavioral inhibitions, and memory impairment

  • 150 to 300 mg/dL (32.6 to 65.1 mmol/L): Delirium and lethargy (likely)

Emesis is common with moderate to severe intoxication; because emesis usually occurs with obtundation, aspiration is a significant risk.

In US states, the legal definition of intoxication is a BAC of 0.08% ( 80 mg/dL, [17.4 mmol/L]); 0.08% is used most commonly.

Toxicity or overdose

In alcohol-naïve people, a BAC of 300 to 400 mg/dL (65.1 to 86.8 mmol/L) often causes unconsciousness, and a BAC 400 mg/dL (86.8 mmol/L) may be fatal. Sudden death due to respiratory depression or arrhythmias may occur, especially when large quantities are drunk rapidly. Other common effects include hypotension and hypoglycemia.

The effect of a particular BAC varies widely; some chronic drinkers seem unaffected and appear to function normally with a BAC in the 300 to 400 mg/dL (65.1 to 86.8 mmol/L) range, whereas nondrinkers and social drinkers are impaired at a BAC that is inconsequential in chronic drinkers.

Chronic effects

Withdrawal

A continuum of symptoms and signs of central nervous system (including autonomic) hyperactivity may accompany cessation of alcohol intake.

A mild alcohol withdrawal syndrome includes tremor, weakness, headache, sweating, hyperreflexia, and gastrointestinal symptoms. Tachycardia may be present and blood pressure can be slightly elevated. Symptoms usually begin within about 6 hours of cessation. Some patients have generalized tonic-clonic seizures (called alcohol-related seizure, or rum fits) but usually not > 2 in short succession. Seizures generally occur 6 to 48 hours after cessation of alcohol.

Alcoholic hallucinosis (hallucinations without other impairment of consciousness) follows abrupt cessation from prolonged, excessive alcohol use, usually within 12 to 24 hours. Hallucinations are typically visual. Symptoms may also include auditory illusions and hallucinations that frequently are accusatory and threatening; patients are usually apprehensive and may be terrified by the hallucinations and by vivid, frightening dreams.

Alcoholic hallucinosis may resemble schizophrenia, although thought is usually not disordered and the history is not typical of schizophrenia. Symptoms do not resemble the delirious state of an acute organic brain syndrome as much as does delirium tremens (DT) or other pathologic reactions associated with withdrawal. Consciousness remains clear, and the signs of autonomic lability that occur in DT are usually absent. When hallucinosis occurs, it usually precedes DT and is transient.

Delirium tremens usually begins 48 to 72 hours after alcohol withdrawal; anxiety attacks, increasing confusion, poor sleep (with frightening dreams or nocturnal illusions), profuse sweating, and severe depression also occur. Fleeting hallucinations that arouse restlessness, fear, and even terror are common. Typical of the initial delirious, confused, and disoriented state is a return to a habitual activity; eg, patients frequently imagine that they are back at work and attempt to do some related activity.

Autonomic lability, evidenced by diaphoresis and increased pulse rate and temperature, accompanies the delirium and progresses with it. Mild delirium is usually accompanied by marked diaphoresis, a pulse rate of 100 to 120 beats/minute, and a temperature of 37.2 to 37.8° C. Marked delirium, with gross disorientation and cognitive disruption, is accompanied by significant restlessness, a pulse of > 120 beats/minute, and a temperature of > 37.8° C; risk of death is high.

During delirium tremens, patients are suggestible to many sensory stimuli, particularly to objects seen in dim light. Vestibular disturbances may cause them to believe that the floor is moving, the walls are falling, or the room is rotating. As the delirium progresses, resting tremor of the hand develops, sometimes extending to the head and trunk. Ataxia is marked; care must be taken to prevent self-injury. Symptoms vary among patients but are usually the same for a particular patient with each recurrence.

Diagnosis of Alcohol Toxicity and Withdrawal

  • Usually a clinical diagnosis

  • Acute intoxication: Sometimes blood alcohol content (BAC) and a rapid blood glucose test

  • Chronic use: Complete blood count, magnesium, liver tests, and PT/PTT

  • Withdrawal: Evaluation to rule out central nervous system injury and infection

In acute alcohol intoxication, laboratory tests are generally not helpful; diagnosis is usually made clinically. Exceptions include fingerstick glucose to rule out hypoglycemia and sometimes tests to determine BAC. Confirmation by breath or blood alcohol levels is useful for legal purposes (eg, to document intoxication in drivers or employees who appear impaired). BAC levels do not always correlate to level of intoxication; for a given BAC level, chronic drinkers may have less impairment compared to a person who does not drink regularly. However, finding a low BAC in patients who have altered mental status is helpful because it expedites the search for an alternate cause.

Clinicians should not assume that a high BAC in patients with apparently minor trauma accounts for their obtundation, which may be due to intracranial injury or other abnormalities. Such patients should also have additional evaluation to search for evidence of trauma or toxicity due to other substances.

Chronic alcohol abuse and dependence are clinical diagnoses; experimental markers of long-term use have not proved sufficiently sensitive or specific for general use. Screening tests such as AUDIT (Alcohol Use Disorders Identification Test) or the CAGE questionnaire can be used. However, heavy alcohol users may have a number of metabolic derangements that are worth screening for, so complete blood count, electrolytes (including magnesium), liver tests (including coagulation profile [PT/PTT]), serum ammonia, and serum albumin are often recommended.

In severe withdrawal and toxicity, symptoms may resemble those of central nervous system injury or infection. Because concomitant medical and surgical conditions can occur simultaneously with alcohol withdrawal, medical evaluation with CT and lumbar puncture may be needed. Patients with mild symptoms do not require routine testing unless improvement is not marked within 2 to 3 days. A clinical assessment tool for severity of alcohol withdrawal is available.

Treatment of Alcohol Toxicity and Withdrawal

  • Supportive measures

  • For withdrawal, benzodiazepines and sometimes also phenobarbital or propofol

Toxicity or overdose

Treatment of alcohol toxicity may include the following:

  • Airway protection

  • Sometimes IV fluids with thiamin, magnesium, and vitamins

The first priority is ensuring an adequate airway Airway Establishment and Control Airway management consists of Clearing the upper airway Maintaining an open air passage with a mechanical device Sometimes assisting respirations (See also Overview of Respiratory Arrest.) read more ; endotracheal intubation and mechanical ventilation are required for apnea or inadequate respirations. IV hydration is needed for hypotension or evidence of volume depletion but does not significantly enhance ethanol clearance. When IV fluids are used, a single dose of thiamin 100 mg IV is given to treat or prevent Wernicke encephalopathy Wernicke Encephalopathy Wernicke encephalopathy is characterized by acute onset of confusion, nystagmus, partial ophthalmoplegia, and ataxia due to thiamin deficiency. Diagnosis is primarily clinical. The disorder... read more . Many clinicians also add multivitamins and magnesium to the IV fluids.

Pearls & Pitfalls

  • IV hydration does not significantly enhance ethanol clearance.

Disposition of the acutely intoxicated patient depends on clinical response, not a specific BAC.

Withdrawal

Patients with severe alcohol withdrawal or delirium tremens should be managed in an intensive care unit until these symptoms abate. Treatment may include

  • IV thiamin to prevent Wernicke encephalopathy

  • Benzodiazepines or phenobarbital to manage agitation and/or seizures

Thiamin 100 mg IV is given to prevent Wernicke encephalopathy.

Alcohol-tolerant people are cross-tolerant to some drugs commonly used to treat withdrawal (eg, benzodiazepines).

Benzodiazepines are the mainstay of therapy. Dosage and route depend on degree of agitation, vital signs, and mental status. Diazepam, given 5 to 10 mg IV or orally hourly until sedation occurs, is a common initial intervention; lorazepam 1 to 2 mg IV or orally is an alternative. Chlordiazepoxide 50 to 100 mg orally every 4 to 6 hours, then tapered, is an older acceptable alternative for less severe cases of withdrawal.

Phenobarbital 10 mg/kg (ideal body weight) IV may be used as an alternative, or in conjunction with benzodiazepines if benzodiazepines alone are ineffective, but respiratory depression is a risk with concomitant use. Carbamazepine, gabapentin, or valproic acid (when there is no liver disease or pregnancy) may also be used as an adjunct to benzodiazepines or when benzodiazepines are contraindicated (1 Treatment reference Alcohol (ethanol) is a central nervous system depressant. Large amounts consumed rapidly can cause respiratory depression, coma, and death. Large amounts chronically consumed damage the liver... read more ).

Phenothiazines and haloperidol are not recommended initially because they may lower the seizure threshold. For patients with a significant liver disorder, a short-acting benzodiazepine (lorazepam) or one metabolized by glucuronidation (oxazepam) is preferred. (NOTE: Benzodiazepines may cause intoxication, physical dependence, and withdrawal in patients with alcohol use disorder and therefore should not be continued after the detoxification period. Carbamazepine 200 mg orally 4 times a day may be used as an alternative and then tapered.) For severe hyperadrenergic activity or to reduce benzodiazepine requirements, short-term therapy (12 to 48 hours) with titrated beta-blockers (eg, metoprolol 25 to 50 mg orally or 5 mg IV every 4 to 6 hours) and clonidine 0.1 to 0.2 mg IV every 2 to 4 hours can be used, but only as an adjunct and only if absolutely necessary.

A seizure, if brief and isolated, needs no specific therapy; however, some clinicians routinely give a single dose of lorazepam 1 to 2 mg IV as prophylaxis against another seizure. Repeated or longer-lasting (ie, > 2 to 3 minutes) seizures should be treated and often respond to lorazepam 1 to 3 mg IV. Routine use of phenytoin is unnecessary and unlikely to be effective. Outpatient therapy with phenytoin is rarely indicated for patients with simple alcohol withdrawal seizures when no other source of seizure activity has been identified because seizures occur only under the stress of alcohol withdrawal, and patients who are withdrawing or heavily drinking may not take antiseizure drugs.

Delirium tremens may be fatal and thus must be treated promptly with high-dose IV benzodiazepines, preferably in an intensive care unit. Dosing is higher and more frequent than in mild withdrawal. Very high doses of benzodiazepines may be required, and there is no maximum dose or specific treatment regimen. Diazepam 5 to 10 mg IV or lorazepam 1 to 2 mg IV every 10 minutes is given as needed to control delirium; some patients require several hundred milligrams over the first few hours. In patients with severe symptoms, evidence suggests dosing regimens of diazepam starting at 10 mg IV with doubling of the dose every 10 to 15 minutes until the patient is sedated is efficacious. Patients refractory to high-dose benzodiazepines may respond to phenobarbital 120 to 240 mg IV every 20 minutes as needed; however, if phenobarbital is used after benzodiazepines, respiratory depression can be significant. As an alternative, phenobarbital may be used as the first agent.

Severe drug-resistant DT can be treated with a continuous infusion of lorazepam, diazepam, midazolam, propofol, or dexmedetomidine, usually with concomitant mechanical ventilation. Physical restraints should be avoided if possible to minimize additional agitation, but patients must not be allowed to escape, remove IVs, or otherwise endanger themselves. Intravascular volume must be maintained with IV fluids, and thiamin must be given promptly. Appreciably elevated temperature with DT is a poor prognostic sign.

Treatment reference

Drugs Mentioned In This Article

Drug Name Select Trade
Ablysinol
Albuked , Albumarc, Albuminar, Albuminex, AlbuRx , Albutein, Buminate, Flexbumin, Kedbumin, Macrotec, Plasbumin, Plasbumin-20
Luminal, Sezaby
Diprivan, Fresenius Propoven
Diastat, Dizac, Valium, VALTOCO
Ativan, Loreev XR
Librium
Carbatrol, Epitol , Equetro, Tegretol, Tegretol -XR
Active-PAC with Gabapentin, Gabarone , Gralise, Horizant, Neurontin
Depacon, Depakene, Depakote, Depakote ER, Stavzor
Haldol, Haldol Decanoate
Serax
KAPSPARGO, Lopressor, Toprol XL
Catapres, Catapres-TTS, Duraclon, Kapvay, NEXICLON XR
Dilantin, Dilantin Infatabs, Dilantin-125, Phenytek
Nayzilam, Versed, Versed Syrup
IGALMI, Precedex
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