Alcohol-Related Disease

Chapter 185


Alcohol-Related Disease




Perspective


As eloquently stated by Paracelsus in the 16th century, “all substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.”



Epidemiology


The disastrous effects and widespread incidence of alcoholism are well known to the emergency physician. Almost all societies that consume alcohol show related health and social problems.1 Motor vehicle collisions, drowning, suicides, homicides, divorce, violent crime, child abuse, unemployment, and disruption of the family are often either directly or indirectly associated with excessive alcohol consumption. The tragic effects of alcohol not only affect the individual drinker but also have far-reaching implications for the family, community, and workplace. In the United States, an estimated 7.6 million visits to the emergency department (ED) a year are related to alcohol, accounting for 7.9% of all ED visits.2 Table 185-1 lists the causes of death related to alcohol abuse.



Alcohol is the most common recreational drug taken by Americans, and per capita consumption is increasing. An estimated 18 million alcoholics live in the United States; with more than 85,000 alcohol-related deaths each year, resulting in 2.3 million years of potential life lost,3 alcohol is the third leading cause of preventable death in the United States.4 Alcoholism permeates all levels of society and is a preventable cause of morbidity and mortality, with a cost to the nation estimated to be greater than $185 billion annually.5


The alcohol-use disorders consist of alcohol dependence, alcohol abuse, and dependence or harmful use. These disorders are common in all developed countries and are more prevalent in men than in women, with lower but still substantial rates in developing countries. However, most people with alcohol-use disorders are difficult to identify because they are likely to have jobs and families and to present with general complaints, such as malaise, insomnia, anxiety, sadness, or a range of medical problems.



Diagnosis


Alcohol dependence is associated with major physiologic consequences and life impairment. Dependence can be identified as repetitive problems, affecting three or more areas of life, and about 80% of people who are diagnosed with dependence at any point still have alcohol-related problems when they are assessed a year or more later.6 Dependence criteria are reliable across different ages, sexes, and most cultural groups. Alcohol abuse is defined by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), as one or more problems with functioning in a 12-month period in a person without dependence: failure in obligations; alcohol use in hazardous situations; recurrent legal problems; or continued use despite social or interpersonal problems.7



Alcohol Screening Questionnaires


Detection of risky drinking behaviors can be through clinical history or the administration of short alcohol screening tools in the ED setting, such as the Alcohol Use Disorders Identification Test (AUDIT), Fast Alcohol Screening Test (FAST), and CAGE questionnaires. The objectives of these screening tools vary; the AUDIT and FAST are focused on detection of recent hazardous or harmful alcohol consumption and associated problems, whereas the CAGE is designed to detect lifetime alcohol dependence.





The AUDIT-C Screening Questionnaire:



The AUDIT-C screening thresholds are ≥4 points for men (sensitivity 86%, specificity 89%) and ≥3 points for women (sensitivity 73%, specificity 91%).


A positive answer to the question Have you ever had a drinking problem? plus evidence of alcohol consumption in the previous 24 hours provides greater than 90% sensitivity and specificity as a screening tool for identification of alcoholism.


Blood tests can be useful if the history is in doubt and can also help patients recognize that alcohol has adversely affected their health. One such marker is γ-glutamyltransferase, an enzyme important in amino acid transport. Results of at least 35 units/L indicate the probability of heavy drinking. A second test is for carbohydrate-deficient transferrin, which measures a change in the structure of a proportion of transferrin that is likely to occur with heavy drinking during a long period; a result of 20 units/L or more indicates heavy drinking. Tests of liver function that measure aspartate transaminase (AST) and alanine transaminase (ALT) can identify heavy drinking and alcohol-use disorders with sensitivities of 25 to 45% and specificities as high as 90%. A ratio of AST to ALT higher than 2, especially if concentrations of these enzymes do not exceed 400 units/L, suggests alcoholic hepatitis. Although many newer biomarkers are not yet available, these newer markers (acetaldehyde adducts) rely on protein modifications by acetaldehyde and play an important role in the pathogenesis of tissue damage in alcoholics (Tables 185-2 and 185-3).





Pathophysiology



Causes and Origins


About 40 to 60% of the risk of alcohol-use disorders is explained by genes and the rest through gene-environment associations. The environment includes the availability of alcohol, attitudes toward drinking and drunkenness, peer pressures, levels of stress and related coping strategies, models of drinking, and laws and regulatory frameworks.


First, variations (polymorphisms) in genes for enzymes that metabolize alcohol are generally associated with a lower risk of alcohol-use disorders because they increase sensitivity to alcohol. At least one variant of aldehyde dehydrogenase (the ALDH2*2 allele) produces an aversive response to alcohol. Second, gene forms associated with impulsivity, disinhibition, and sensation seeking contribute to vulnerability to both drug-use and alcohol-use disorders, perhaps through impaired judgment and difficulty in learning from mistakes that could reduce control of alcohol intake. Relevant polymorphisms include variations in receptors for γ-aminobutyric acid (e.g., GABRA2), acetylcholine (e.g., CHRM2), and dopamine (e.g., DRD2). Third, people who have low responsiveness (or low sensitivity) to alcohol are more likely to drink more on each occasion to obtain the desired effect, which increases their risk of alcohol-use disorders but not of other drug-related disorders. Additional genetic mechanisms might regulate dopamine-reward systems.



Definition and Natural History


A precise definition of alcoholism is difficult. A proposed definition encompassing the features of alcoholism is “a primary chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations.” The disease is often progressive and fatal. It is characterized by impaired control over drinking, preoccupation with and use of alcohol despite adverse consequences, and distortions in thinking, most notably denial. Each of these symptoms may be periodic or continuous.8 Alcoholism is present when drinking adversely affects an individual’s physical health, ability to function in society, or interpersonal relationships.


Hazardous or “at-risk” drinking is defined by the National Institute on Alcohol Abuse and Alcoholism as the following:



Harmful drinkers present with negative consequences related to alcohol.


The natural history of alcoholism is variable, and it may appear in any patient despite age or social status. The age at onset of alcoholism continues to decrease. Up to 6% of high school seniors drink daily, and it is not unusual to see children younger than 16 years who have already graduated from an alcohol detoxification program.9 Many individuals also begin drinking heavily after the age of 60 years.


The DSM-IV has two categories for substance disorders that include alcohol abuse: (1) substance abuse and (2) substance dependence.7 The chronic substance abuse of alcohol eventually leads to acquired tolerance, a condition in which larger and larger doses of alcohol are required for the same effect.



Principles of Disease: Metabolism of Alcohol


Ethanol is rapidly absorbed from the stomach and small intestine. It is distributed uniformly to all organ systems, including the placenta. Although 2 to 10% of alcohol is excreted through the lungs, urine, and sweat, the majority is metabolized to acetaldehyde, primarily by alcohol dehydrogenase (ADH). The oxidation of alcohol is a complex process involving three enzyme systems, all contained in the hepatocyte. The class I ADH isoenzymes, ADH1A, ADH1B, and ADH1C, oxidize ethanol, but ADH1B and ADH1C have polymorphic properties with distinct kinetic properties. Acetaldehyde is then quickly converted to carbon dioxide and water, primarily through aldehyde dehydrogenase (ALDH). The common forms of ADH decrease the alcohol concentration in blood by about 4.5 mmol/L ethanol per hour (the equivalent of about one drink per hour).


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At least two variations of ADH genes (ADH1B*2 and ADH1C*1) produce a slightly more rapid breakdown of alcohol and therefore potentially faster production of acetaldehyde, which is rapidly metabolized by ALDH2. However, about 40% of Asian people (Japanese, Chinese, and Koreans) have an inactive ALDH2 mutation that results in much higher acetaldehyde levels after drinking than normal. About 10% of people who are homozygous for this gene form cannot drink alcohol without becoming sick and have almost no risk of alcohol-use disorders, whereas those who are heterozygous have a relatively low rate of alcohol-use disorders.


An alternative pathway, the microsomal ethanol-oxidizing system (MEOS), is induced by chronic alcohol exposure. The primary component of the MEOS is the molecule cytochrome P450, which exists in several variants. The variant most important for alcohol metabolism is cytochrome P450 2E1 (CYP2E1). Many effects of alcoholism are produced by the toxic byproducts (hydrogen, acetaldehyde), the acceleration of metabolism of other drugs, and activation of hepatotoxic compounds by these metabolic pathways.


Although the liver is the major site of ethanol metabolism, other tissues contribute to its metabolism. ADH is found in the gastric mucosa, but the gastric metabolism of alcohol is decreased in women and those of Asian descent. This increased bioavailability of ethanol or decreased first-pass metabolism may explain the greater vulnerability of women to acute and chronic complications of alcohol.


Alcohol elimination has two phase curves. The alcohol elimination rate approximates zero-order kinetics (constant rate) for lower ethanol levels and first-order kinetics (amount of drug removed over time is proportional to the concentration of the drug) for higher levels, especially in chronic alcoholics; most likely, through induction of the MEOS pathway, the elimination rate is increased at higher blood levels.


The absorption and elimination rates of alcohol vary by individual and depend on many factors: diet, gender, body weight and habitus, speed of consumption, gastric motility, presence of food in the stomach, smoking history, age, whether the person is a chronic alcohol consumer with enzyme induction and high-activity MEOS, advanced cirrhosis, presence of ascites, and state of nourishment.10 There is enormous variation among patients in the rate of disappearance of ethanol from the blood, ranging from 9 to 36 mg/dL per hour in published data. Although the clearance rate may be as high as 36 mg/dL per hour in some chronic drinkers, 20 mg/dL per hour is a reasonable rate to assume in a typical intoxicated ED patient. This holds true for adults, adolescents, and children.11


Physiologic effects vary directly with the blood alcohol level (Table 185-4). Diminished fine motor control and impaired judgment appear with alcohol concentrations as low as 20 mg/dL (0.02 mg%), but wide individual variability exists. Chronic alcoholics can exhibit impressive tolerance. The blood alcohol concentration of a person cannot be accurately determined without quantitative testing. More than 50% of the adult population is obviously intoxicated with a level of 150 mg/dL (0.15 mg%). As the ethanol level rises, the patient’s level of consciousness declines, eventually ending in coma. Death is caused by aspiration or respiratory depression.



Alcohol through passive diffusion will be present anywhere there is water in the body. Hence, expired breath alcohol or saliva can be used to obtain a reliable approximation of blood alcohol concentration in a cooperative patient. This value can be used as a rapid screen for alcohol intoxication.12,13



Differential Considerations


Acute alcohol intoxication is a diagnosis of exclusion. Before it is assumed that a patient’s behavior is caused only by alcohol, other conditions should be considered. Hypoglycemia, hypoxia, carbon dioxide narcosis, mixed alcohol-drug overdose, ethylene glycol poisoning, isopropanol or methanol poisoning, hepatic encephalopathy, psychosis, severe vertigo, postictal state, and psychomotor seizures can be manifested in a manner similar to ethanol intoxication. The possibility of occult head trauma and the presence of associated metabolic disorders should be considered after alcohol intoxication has been established. Shock from gastrointestinal bleeding or sepsis, hypothermia, hyperthermia, and hepatic encephalopathy are all possible. These potentially catastrophic diagnoses are usually detected by a thorough history and physical examination, a blood alcohol level (as coma is rare in chronically intoxicated patients with blood alcohol levels below 200 mg/dL), and close observation (an intoxicated patient’s level of consciousness should constantly improve over time). Adequate history from paramedics and family, repeated physical examinations by the same clinician, and diagnostic adjuncts can help resolve this dilemma.



Management


Comatose or stuporous patients need to have airway and ventilation evaluated and managed with endotracheal intubation as necessary. Thiamine (100 mg intravenously [IV]) to prevent or to treat Wernicke-Korsakoff syndrome, glucose (dextrose, 25 to 50 g IV) for hypoglycemia, and naloxone (0.8 mg IV) for possible opioid ingestion should be considered in comatose patients. As magnesium is a necessary cofactor for thiamine metabolism, consider magnesium 2 g IV. When possible, hypoglycemia should be documented before the empirical administration of glucose. With the airway maintained and respirations supported, the patient’s liver eventually metabolizes the alcohol, and most patients recover.


Glucose (dextrose, 25 g IV) produces a dramatic response in alcohol-induced hypoglycemic patients. Unlike hypoglycemia of other causes, alcohol-induced hypoglycemia may be unresponsive to glucagon because of depleted liver glycogen stores. Although Wernicke’s encephalopathy is a medical emergency, alcohol-induced hypoglycemia is a much more common condition with serious and permanent morbidity if it is left untreated. Therefore, thiamine can be given in a timely fashion, but glucose therapy should not be delayed.14


Intoxicated patients require evaluation and treatment in the ED regardless of their obstreperousness. Inappropriate discharge and failure to diagnose are two common areas of liability in treatment of the alcohol-dependent patient. The theoretic liability for detention by reasonable restraint is less than the potential liability for injury sustained by the alcohol-dependent patient or an innocent bystander after premature discharge. Discharge can be considered when a patient is clinically sober and able to dress, walk, and function independently as judged and well documented by the treating clinician. Under ideal circumstances, another concerned, sober adult is available and willing to take responsibility for and remain with the patient for the next 24 to 48 hours.



Alcohol Withdrawal Syndrome




Differential Considerations


Alcohol withdrawal syndrome can initially be confused with acute schizophrenia, encephalitis, drug-induced psychosis, thyrotoxicosis, anticholinergic poisoning, and withdrawal from other drugs of the sedative-hypnotic type. It may be difficult to differentiate between alcohol withdrawal and alcohol-induced hypoglycemia.


Signs of alcohol withdrawal usually begin 6 to 24 hours after a decrease in the patient’s usual intake of alcohol. If patients manifest withdrawal 3 to 4 days or more after their last drink, drugs with a longer half-life should be considered. The barbiturate and benzodiazepine withdrawal syndromes usually progress more slowly, with a higher frequency of seizures later (7 days versus 2 days), and status epilepticus is more common than with alcohol withdrawal.



Clinical Features


Isbell’s classic study in 1955 confirmed the relationship between alcohol and the withdrawal syndrome.16 He documented that the severity of signs and symptoms depends on both the dose and the duration of ethanol consumption. The withdrawal syndrome may occur any time after the blood alcohol level starts to fall. Therefore, only a reduction, not the abrupt cessation, of ethanol intake may result in withdrawal.


Minor alcohol withdrawal occurs as early as 6 hours and usually peaks at 24 to 36 hours after cessation of or significant decrease in alcohol intake. It is characterized by mild autonomic hyperactivity: nausea, anorexia, coarse tremor, tachycardia, hypertension, hyper-reflexia, sleep disturbances (e.g., insomnia, vivid dreams), and anxiety.17


Major alcohol withdrawal occurs after more than 24 hours and usually peaks at 50 hours but occasionally takes up to 5 days to be manifested after the decline or termination of drinking. The syndrome is characterized by pronounced anxiety, insomnia, irritability, tremor, anorexia, tachycardia, hyper-reflexia, hypertension, fever, decreased seizure threshold, auditory and more commonly visual hallucinations, and finally delirium.18


Delirium tremens is a life-threatening manifestation of alcohol withdrawal and consists of gross tremor, frightening visual hallucinations, profound confusion, agitation, and a hyperadrenergic syndrome characterized by temperature above 101° F, blood pressure higher than 140/90 mm Hg, and tachycardia. It seldom appears before the third post-abstinence day. Only 5% of patients hospitalized for alcohol withdrawal have delirium tremens.



Management


Family, friends, bystanders, or paramedics often give more reliable historical data than the patient does. Accurate vital signs are essential. This may require a rectal temperature. Hyperthermia, hypothermia, tachypnea, or tachycardia may suggest serious disorders that often accompany the alcohol-dependent patient. These disorders should be considered during this first assessment.


A rapid, thorough examination should be performed with attention to the level of consciousness, signs of hepatic failure, or coagulopathy. Signs of trauma are sought, such as subcutaneous emphysema, ecchymosis, subconjunctival hemorrhage, hemotympanum, or Battle’s sign, and palpation is done for occult injuries. The neurologic examination should search for focal findings, including central facial nerve palsy, hemiparesis, and asymmetry of pupillary response.


The alcohol withdrawal syndrome should be promptly recognized and treated to provide relief from anxiety and hallucinations; to halt progression to major withdrawal and withdrawal seizures; to allow detection of a treatable primary psychiatric illness; to prepare the patient for long-term alcohol abstinence with the lowest risk of new drug dependence; and to calm the patient and allow adequate examination for the detection of medical illnesses that typically accompany alcoholism, such as gastritis, dehydration, pancreatitis, pneumonia, electrolyte disorders, and hepatitis.


In combination with appropriate chemical sedation, detention by reasonable restraint may be an option to prevent potential injury that patients may inflict on themselves or the hospital staff. These appropriate measures need to be instituted, and decision-challenged patients should not be permitted to sign an “against medical advice” form and be discharged.


Patients suffering from alcohol withdrawal should receive pharmacologic intervention along with supportive care. The ideal drug for alcohol withdrawal would have a rapid onset, wide margin of safety, metabolism not dependent on liver function, and limited abuse potential. Although no one drug class fits all these requirements, benzodiazepines are clearly the mainstay of treatment.




Benzodiazepines.: The benzodiazepines have superior anticonvulsant activity, have the least respiratory and cardiac depressive effect of all the CNS depressants, and can be given parenterally in the uncooperative patient. By interacting with receptors linked to the GABA-associated chloride ion channel, benzodiazepines substitute for the withdrawal of the GABA-potentiating effect of alcohol and abate withdrawal signs and symptoms.19 Numerous benzodiazepines have been studied, but there is no evidence of clear superiority of any one benzodiazepine.


Lorazepam has good bioavailability with oral, intramuscular, and intravenous routes. It is rapidly and completely absorbed from intramuscular sites in agitated patients with no intravenous access. Lorazepam’s half-life is intermediate (7-14 hours), and it reaches a steady state in 36 to 48 hours without active metabolites. Excessive sedation, confusion, and ataxia are potential complications of all benzodiazepines with prolonged half-lives. Lorazepam is metabolized (conjugated) in the liver, yielding inactive products. Although the half-life of lorazepam increases in patients with cirrhosis or liver failure, it is much less than the increase with chlordiazepoxide. Lorazepam’s elimination is only minimally altered in patients with renal failure and in the elderly. Lorazepam may be given intravenously in a dose of 1 to 4 mg, depending on the severity of the withdrawal. Dosing can be repeated at 5- to 15-minute intervals for patients in severe withdrawal. Although it is not ideal, an intramuscular dose of 1 to 4 mg can be used every 30 to 60 minutes until the patient is calm and then every hour as needed for light somnolence. The oral schedule for moderate withdrawal is 6 mg/day in three divided doses, tapering the amount by 1 to 2 mg/day during 4 to 6 days.


As one dosing regimen, diazepam, 5 mg IV every 5 to 10 minutes (2.5 mg/min), can be given in major withdrawal until the patient is calm. The dose can be repeated in 5 to 10 minutes. If the second dose of 5 mg is not working, consider 10 mg for the third and fourth doses every 5 to 10 minutes. If this is not effective, consider 20 mg for the fifth and subsequent dose until adequate sedation is obtained.20,21






Alcohol-Related Seizures


Among the many medical problems related to alcohol abuse, the differential diagnosis and management of seizures remain among the most challenging and controversial (Box 185-1). Patients presenting to the ED with seizures should be questioned about alcohol intake. Of seizure patients presenting to an ED, 20 to 40% will have their seizures related to alcohol use or abuse.23 Alcohol is a causative factor in 11 to 24% of patients with status epilepticus.24,25 In states where alcohol sales are restricted on Sundays, EDs see a spike in alcohol-related seizures on Mondays.26



BOX 185-1   Differential Diagnosis of Alcohol-Related Seizures




The primary consideration in the initial care of seizure patients who use alcohol is the recognition of treatable, life-threatening causes. These causes include but are not limited to CNS infection, metabolic disorders, and intracranial hemorrhage. Alcohol may act in one of several ways to produce seizures in patients with or without underlying foci: by its partial or absolute withdrawal after a period of chronic intake, by an acute alcohol-related metabolic disorder (e.g., hypoglycemia, hyponatremia), by creation of a situation leading to cerebral trauma, by precipitation of seizures in patients with idiopathic or post-traumatic epilepsy, or by lowering of the seizure threshold in patients with prior existing intracerebral disease states. Moreover, alcoholics are more susceptible to other disorders associated with seizures, including neurosyphilis, acquired immunodeficiency syndrome (AIDS), brain abscess, and meningitis.27–29



Alcohol Withdrawal Seizures


Descriptions of alcohol withdrawal seizures are based on data collected by Victor and Brausch.30 Seizures occurred 6 to 48 hours after the cessation of drinking. Ninety percent had one to six generalized tonic-clonic seizures. Sixty percent experienced multiple seizures within a 6-hour period. However, seizure recurrence can be reduced to 3% with lorazepam administration after the initial seizure.31 The incidence of partial seizures, common with post-traumatic epilepsy, is increased in alcohol withdrawal. The term alcohol withdrawal seizure is reserved for seizures with the characteristics described by Victor and Brausch.30 The term alcohol-related seizure is used to refer to all seizures in the aggregate associated with alcohol use, including this subset of alcohol withdrawal seizure.



Patients Presenting with Normal Findings on Neurologic Examination



New-Onset Alcohol-Related Seizures


Patients with new-onset alcohol-related seizure should be thoroughly evaluated. This includes alcoholics who claim to have had seizures but for whom no documentation or an appropriate work-up is available. Metabolic disorders, toxic ingestion, infection, and structural abnormalities should be considered. Laboratory and radiographic testing to include electrolyte values and blood urea nitrogen, creatinine, glucose, and anticonvulsant levels and brain computed tomography (CT) scan may be necessary. Of 259 patients presenting with their first alcohol-related seizure, clinical management was changed in 3.9% on the basis of head CT results.32


If the initial physical examination findings, imaging studies, and laboratory test results are within normal limits, patients who remain seizure free and symptom free with no sign of withdrawal after 4 to 6 hours of observation may be discharged. It may be unclear whether the patient has had a pure alcohol withdrawal seizure or a new-onset seizure disorder in the setting of alcohol ingestion. Long-term treatment with antiepileptic drugs is not useful in unprovoked new-onset seizures that have resolved or when a clear relation to alcohol consumption can be identified.


Optimal outpatient treatment includes follow-up and referral to a detoxification or rehabilitation program. Ideally, the help of a concerned family member or friend who is not a drinking partner and can remain with the patient for at least 1 or 2 days is helpful.



Seizures in the Alert Patient with a History of Seizures during Prior Withdrawal


The risk of seizure increases significantly in alcoholic patients with manifestations of alcohol withdrawal who relate a history of alcohol withdrawal seizure.33,34 Detoxification with benzodiazepines reduces alcohol withdrawal seizure and should be initiated early because most seizures occur within the first 24 hours after alcohol withdrawal. An initial dose of 2 mg of lorazepam or 5 mg of diazepam can be given intravenously. These doses frequently need to be repeated.35 The patient should be observed for 4 to 6 hours before discharge is considered. The prescription of benzodiazepines or antiepileptic drugs on discharge carries its own hazards. Benzodiazepines (other than a short 3- to 6-day tapering dose for withdrawal) may increase the potential risk of addiction. In a noncompliant patient, antiepileptic drugs, such as phenytoin, may paradoxically increase the number of seizures. The poorly compliant alcoholic patient may do better without outpatient anticonvulsants for a concurrent seizure disorder.33 The ideal disposition is referral to a detoxification or rehabilitation unit.



Patients with an Abnormal Neurologic Presentation



New-Onset Partial Seizures


Partial seizures account for 24 to 51% of alcohol-related seizures.36 Conversely, studies have shown that 17 to 21% of patients with partial alcohol-related seizure have structural lesions: hematomas, tumors, vascular abnormalities, or stroke.37 These primary causes of partial alcohol-related seizure, such as prior head trauma, may be easily missed in the history taking. As a result, an emergent CT scan is indicated to evaluate new-onset partial seizures. The patient with a history of a focal alcohol-related seizure who has been previously evaluated does not require an emergency CT scan, provided a return to baseline occurs promptly. A patient presenting with a focal alcohol-related seizure with subsequent normal neuroimaging findings can be managed with supportive care, observation for 4 to 6 hours, and a benzodiazepine for withdrawal signs or symptoms. Appropriate follow-up should be arranged.




Patients Taking Phenytoin-Anticonvulsant


Phenytoin has no significant benefit over placebo in prevention of recurrence of uncomplicated (e.g., no old subdural) alcohol withdrawal seizure. Considering the risks of phenytoin and no demonstrated benefit in the setting of alcohol withdrawal seizure, it is not indicated for the treatment of alcohol withdrawal seizure. The sudden withdrawal of phenytoin may potentiate the convulsive effects of alcohol withdrawal.23,38


A patient currently taking antiepileptic drugs for an antecedent seizure disorder who presents with a seizure while intoxicated falls into a different category. Such an episode could be an isolated event in a usually compliant patient without a history of chronic alcohol abuse. In this patient, a seizure in the setting of a subtherapeutic antiepileptic drug level may represent the consequences of noncompliance with antiepileptic medication or sleep deprivation versus alcohol withdrawal seizure.33



Other Clinical Features and Management



Cardiovascular Effects


Acute and chronic ethanol consumption can affect the mechanical function of the heart, produce dysrhythmias, and exacerbate coronary artery disease (CAD). It may alter myocardial function by direct toxic effects, by associated hypertension, or indirectly by altering specific electrolytes. Acute intoxication can decrease cardiac output in both alcoholic and nonalcoholic patients with preexisting cardiac disease.38


Studies have linked moderate alcohol consumption (two to four drinks per day in men and one or two in women) to a protective effect from CAD. Low to moderate alcohol consumption decreases platelet aggregation, raises plasma levels of endogenous tissue plasminogen activator,39 and lowers insulin resistance. Experimental data suggest that alcohol may have antioxidant properties, produce effects on smooth muscles through interactions with nitric oxide, and alter plasma total homocysteine levels.40,41 The red versus white wine hypothesis rests on human studies showing short-term cardiovascular benefits achieved by de-alcoholized red but not white wine and many studies on isolated tissues or organs assessing the effects of polyphenols in red wine, especially resveratrol. Therefore, red wine potentially has beneficial effects beyond alcohol content.42


Studies suggest that moderate alcohol consumption, through a reduced risk of CAD, may also protect individuals from congestive heart failure (Box 185-2).43 All of these beneficial effects are lost in heavy drinkers, in whom chronic alcoholism is associated with hypertension and congestive cardiomyopathy.



BOX 185-2


Risks and Benefits of Light, Moderate, and Heavy Drinking



image



Modified from Klatsky A: Drink to your health? Sci Am 288:74, 2003. Copyright © Scientific American, Inc.


Up to one third of chronic alcoholic patients have left ventricular dysfunction demonstrated by radionuclide ventriculography, usually coexisting with skeletal muscle disease. Those who stop using alcohol may have an improved ejection fraction during the course of 3 years.44 Although the primary functional abnormality of alcoholic cardiomyopathy was thought to be a depression in systolic function, it is now appreciated that an impairment in diastolic function is present in one third of alcoholics who have a normal systolic function; in many, systolic dysfunction and diastolic dysfunction coexist. Excess alcohol consumption affects not only the cardiomyocytes but striated skeletal muscle as well. Women appear to be more sensitive than men to the toxic effects of alcohol on striated muscle and are at greater risk for cardiomyopathy and myopathy as well as for skeletal myopathy for any given lifetime amount of alcohol.44


Heavy alcohol consumption has a detrimental effect on those with preexisting CAD. It can reduce exercise tolerance, induce coronary vasoconstriction, and raise heart rate and blood pressure.45 Additive cardiovascular effects of ethanol and nicotine contribute to dysrhythmias and sudden death in patients with CAD. In one study, nearly half the patients with alcohol withdrawal had prolongation of the QT interval. Prolonged QT can precipitate a dysrhythmia, resulting in sudden death.46 There is an increased incidence of sudden death among heavy drinkers regardless of concomitant CAD or smoking.


Supraventricular (usually atrial fibrillation) and ventricular (usually transitory ventricular tachycardia) dysrhythmias, labeled “holiday heart,” have been documented in alcoholic patients who have been drinking heavily. One study reported that alcohol contributes to or causes new-onset atrial fibrillation in approximately two thirds of patients younger than 65 years. Tachydysrhythmias as a result of episodic drinking commonly revert to sinus rhythm with abstinence and do not require immediate intervention if the patient is hemodynamically stable.


Alcohol also affects cardiac function indirectly by lowering potassium and magnesium levels. Data from the Framingham Heart Study indicate that patients with lower levels of potassium and magnesium have higher rates of dysrhythmias.47



Pulmonary Effects


Alcohol reduces the mobilization of alveolar macrophages and their bactericidal capacity. Their impairment is greatest in alcoholics with hepatic cirrhosis. In alcoholic patients, the lungs are more vulnerable to oxidative stress and injury. There is evidence that chronic alcohol consumption decreases the level of glutathione, promoting inflammation and remodeling of the lung tissue.48 These effects, along with aspiration, decreased airway sensitivity, concomitant smoking, and malnutrition, probably account for the increased incidence of pneumonia, particularly lobar pneumonia, among alcoholic patients.49 Alcohol abuse is also associated with an increased likelihood of intensive care unit admission and a longer hospital length of stay than for non-alcoholic patients with community-acquired pneumonia.50


At least 80% of alcoholics are smokers, making it difficult to distinguish between alcohol-induced and tobacco-induced injury to the lungs. The high prevalence of respiratory disease in alcoholics is largely caused by smoking. Patients with sepsis and chronic alcohol abuse are at least twice as likely to require mechanical ventilation and have a twofold to fourfold risk for development of the acute respiratory distress syndrome.50


Alcohol induces bronchospasm in some asthmatics and increases ventricular ectopy and sleep apnea in patients with chronic obstructive pulmonary disease. Alcoholic patients with hepatic cirrhosis can have hypoxemia as a result of precapillary shunting in their lungs. Hyperventilation and respiratory alkalosis are also seen with hepatic cirrhosis. One or two drinks per day has been found to decrease the risk of pulmonary embolus and deep venous thrombosis in elderly patients.51

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