12 - Treatment of Alcohol Withdrawal
Editors: Shader, Richard I.
Title: Manual of Psychiatric Therapeutics, 3rd Edition
Copyright 2003 Lippincott Williams & Wilkins
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12
Treatment of Alcohol Withdrawal
Richard Saitz
Domenic A. Ciraulo
Richard I. Shader
Ann Marie Ciraulo
Most withdrawal syndromes develop in chronic alcoholic patients who stop drinking or who reduce their intake for whatever reason. However, the development of withdrawal symptoms is possible in any person with any pattern of regular alcohol consumption who ceases drinking or who reduces the level of intake. Clinicians must remember that some patients conceal their use of alcohol. Unanticipated alcohol withdrawal is a not infrequent complication in the care of patients admitted to the hospital for various urgent or elective reasons.
I. Signs and Symptoms of Alcohol Withdrawal
Manifestations of alcohol withdrawal typically are divided into the following two varieties: the mild symptoms and signs that tend to occur early in the course of withdrawal and the more severe symptoms, or complications. Some clinicians think that mild manifestations, if untreated, progress to severe ones and that severe manifestations are invariably preceded by milder ones. However, evidence suggests that these relationships are by no means invariable. Physicians who approach all patients expecting this progression of symptoms may make unnecessary errors. Although delirium (see Chapter 5) is often preceded by progressive adrenergic symptoms, most cases of alcohol withdrawal, even those that manifest with mild symptoms, do not progress to alcohol withdrawal delirium, even without treatment. Treatment can, however, ameliorate the symptoms and can prevent complications of alcohol withdrawal.
A. Mild or Early Symptoms
These can begin any time between a few hours and 10 days after the last drink. Typically, they appear 6 to 48 hours after the cessation of alcohol ingestion. They can be suppressed by continued drinking. Possible manifestations are listed in Table 12.1. Many are not specific to withdrawal, and they should raise concern for coexisting alcohol-related illnesses (e.g., gastritis when abdominal discomfort is prominent; hypophosphatemia, hypocalcemia, or hypokalemia with muscle weakness or cramping). The severity of these symptoms can be quantified with simple-to-use standardized scale, the Clinical Institute Withdrawal Assessment for Alcohol, revised (CIWA-Ar). Scores are useful when communicating with nurses and other physicians caring for the patient, for assessing worsening and improvement, and for helping with decisions regarding medication (Table 12.2). Scores of 8 to 10 or greater usually require treatment with medication, and higher scores represent a risk for severe withdrawal. Although most of the early symptoms are mild, noting that some of the most troubling and significant symptoms, convulsions and hallucinations, can occur in the first 24 to 48 hours is important. Both seizure and hallucinosis can occur without being preceded by mild withdrawal symptoms.
B. Severe Manifestations or Complications
As was previously mentioned, although some withdrawing alcoholic patients have mild or early symptoms before progressing to more advanced or more severe manifestations, others may start with severe symptoms (Table 12.3). Advanced or severe symptoms typically begin 48 to 96 hours after the cessation of drinking. Delirium tremens (DTs) is the classic term that is used to describe the most advanced or severe toxic state. Unfortunately, this term is exceedingly vague, and it conveys numerous nondiagnostic implications, as does the term rum fits. Because of the limitations of the currently popular
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terminology, the diagnosis must be approached with caution and an open mind. Alcohol withdrawal delirium is characterized by confusion and disorientation, as well as by hyperautonomia. It is often preceded by mild symptoms of withdrawal and progressive tachycardia, diaphoresis, and tremor. Alcoholic hallucinosis occurs with an otherwise clear sensorium. Prodromal manifestations can be subtle; slight irritability or intransigence in the patient's demeanor may be the only clues. In some patients, severe tremulousness and auditory hallucinosis can develop without progression to delirium or panic. In others, a grand mal seizure may be the very first manifestation of withdrawal. The differential diagnosis of withdrawal seizures includes head trauma, metabolic disturbances, infection (e.g., meningitis), and other causes of seizures. Untreated or inadequately treated withdrawal can be fatal. The current mortality rate attributed to DTs is about 1%.
TABLE 12.1. MILD OR EARLY SYMPTOMS OF ALCOHOL WITHDRAWAL | |
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C. Predictors of Alcohol Withdrawal Delirium
The alcohol withdrawal (abstinence) syndrome must be understood as a heterogeneous clinical concept with numerous possible combinations of signs, symptoms, and time courses; terms such as impending DTs should be used only when the aspects of the disease process to which they refer are clearly understood. Given the individual variability in timing and duration of alcohol consumption, the varied amounts and concentrations of alcohol in the beverages consumed, and the amount of food eaten with or between drinks, predicting those at high risk for withdrawal seems chancy. Nevertheless, one recent study noted that withdrawal delirium occurred, despite benzodiazepine treatment, only in patients who had the following five risk factors: evidence of a current infection, heart rate above 120 beats per min, the presence of signs of withdrawal when alcohol blood levels were above 100 mg per dL, previous seizures by history, and previous episodes of delirium. Other
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studies have shown that the number of prior episodes of withdrawal delirium correlates positively with the intensity of symptoms in subsequent episodes of withdrawal delirium.
TABLE 12.2. THE CLINICAL INSTITUTE WITHDRAWAL ASSESSMENT SCALE FOR ALCOHOL, REVISEDa | ||||||||||||||||||||||||||||||||||||||||
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II. Criteria for Hospitalization
Abstinent alcoholic patients usually present at acute treatment facilities (emergency departments) of general or psychiatric hospitals with some symptoms already apparent. Admitting physicians must recognize which patients require hospitalization and must treat the least ill patients on an outpatient basis. Because of the unpredictable natural history of the withdrawal syndrome, this is not always an easy choice; errors in judgment are made in both directions. Outpatient detoxification has gained wider acceptance in recent years, as it offers substantial cost savings. For patients with mild to moderate withdrawal and no concurrent active medical or psychiatric conditions, outpatient withdrawal may be as effective as inpatient treatment as long as a significant other is available to assess the patient and daily contact with the health care provider is feasible. Table 12.4 lists criteria for hospitalizing the withdrawing alcoholic patient. Guidelines for treatment of those who are not hospitalized are given in Table 12.5.
III. Hospital Treatment of Alcohol Withdrawal
All newly hospitalized abstinent alcoholic patients should receive the following minimum evaluation: (a) history (from patient, available family and friends, and any previous hospital records); (b) physical examination; and (c) venous blood samples for determinations of the complete blood count with differential; international normalized ratio (INR); blood urea nitrogen; glucose, sodium, potassium, chloride, and bicarbonate levels; serum calcium, magnesium, phosphate, and liver enzymes; bilirubin; and albumin. Measurement of amylase is often indicated when abdominal pain is present. A urine or serum toxic screen for other drugs of abuse is essential because intoxication with some drugs may mimic alcohol intoxication or may alter the signs, symptoms, or course of alcohol withdrawal. Concurrent abuse of long-acting benzodiazepines, for example, may delay the onset of withdrawal symptoms or DTs. Further workup is dictated by the clinical situation. For example, a chest x-ray is indicated when pulmonary symptoms are present or after a seizure; because withdrawal can
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precipitate angina or arrhythmia, an electrocardiogram (ECG) should be conducted for those at the age of 40 years and over or when symptoms or risk factors for heart disease are present. Urinalysis is indicated when electrolytes reveal an acid-base disturbance or renal insufficiency; computed tomography of the brain is indicated when the focal neurologic signs of brain injury are present, particularly with signs of head trauma. Examination of the cerebrospinal fluid is warranted when meningeal signs or fever and confusion are present. The following sections detail the fundamental elements of the medical treatment plan.
TABLE 12.3. LATER OR MORE SEVERE COMPLICATIONS OF ALCOHOL WITHDRAWAL | |
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A. Vitamin Use
Vitamin deficiencies, either clinical or subclinical, exist in many, if not all, chronic alcoholic patients. Because administration of appropriate amounts of water-soluble vitamin supplements carries no hazard, all patients should receive them whether or not clinical manifestations are present.
Assessment and testing
Neurologic examination will reveal signs of Wernicke encephalopathy when it is present; these include nystagmus, internuclear ophthalmoplegia, cerebellar ataxia, and a characteristic pattern of intellectual deterioration. Immediate administration of thiamine
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mononitrate (vitamin B1) can prevent irreversible brain damage. All patients should receive thiamine (see section III.A.2.a), even when Wernicke encephalopathy is not detected.TABLE 12.4. CRITERIA FOR HOSPITALIZATION OF THE WITHDRAWING ALCOHOLIC
Severe tremulousness, other autonomic symptoms, or hallucinosis
Significant volume depletion, acid-base or electrolyte disturbance
Fever and delirium or seizure
Fever above 38.1 C (100.5 F)
First seizure ever or seizure without prior evaluation
Delirium
Prior alcohol withdrawal delirium
Wernicke encephalopathy (e.g., ataxia, nystagmus, internuclear ophthalmoplegia)
Head trauma with loss of consciousness
Failure to respond to initial outpatient treatment
Presence of significant comorbidity requiring hospitalization
Decompensated liver disease
Respiratory compromise or failure
Pneumonia
Gastrointestinal bleeding
Pancreatitis
Severe malnutrition
Angina
Multiple seizures, particularly with incomplete recovery
Unstable psychiatric illness, such as severe depression, suicide risk, active schizophrenia or bipolar disorder
Need for pharmacologic management with inability to take appropriately as an outpatient
No responsible other person available to help with medication
No health care services available to manage as outpatientPharmacologic management is indicated for significant symptoms (i.e., Clinical Institute Withdrawal Assessment Scale for Alcohol, revised [CIWA-Ar] score > 8 10), prior or current seizure during withdrawal, prior or current delirium or hallucinosis, coexisting acute medical or psychiatric disorder, or preoperative prophylaxis. Significant symptoms of withdrawal (and therefore need of medication) are unlikely when symptoms have not developed after 36 h of abstinence or when dependence duration is 6 or fewer yr. While not absolutely required, hospitalization should be strongly considered for the elderly and for those withdrawing with a blood alcohol level of 150 mg/dL or greater TABLE 12.5. OUTPATIENT MANAGEMENT OF MILD ALCOHOL WITHDRAWAL
History, physical, and laboratory evaluation to look for indications for hospitalization and cooccurring disorders
Intramuscular thiamine, 100 mg, followed by daily multivitamin; folate, 1 mg, and thiamine p.o.
Initial dose of benzodiazepine (chlordiazepoxide [50 100 mg p.o.] or lorazepam [1 2 mg, any route])
Observation for 1 2 h for signs of symptom relief
Provide a 1-d supply of benzodiazepine to be used for symptoms or on a regular basis (e.g., 4 8 doses)
Explanation of instructions to reliable, responsible, caring adult family member or friend
Daily contact with health care provider
Linkage to outpatient alcoholism treatment, primary medical care, and psychiatric care as neededThe megaloblastic anemia characteristic of folic acid deficiency is revealed by complete blood count, determination of serum or red blood cell folate levels, study of the peripheral blood smear, and bone marrow aspiration when indicated.
Elevated INR, in the absence of cirrhosis or other causes of hepatic insufficiency, suggests vitamin K deficiency.
Signs and symptoms of other deficiency states, such as hypovitaminosis C or scurvy (corkscrew hairs, perifollicular hemorrhages, gingival hemorrhage), are not infrequently encountered. Fractures and osteopenia can be seen in vitamin D deficiency, which is not uncommon in alcoholic patients. The diagnosis is made with a serum 25-hydroxy-vitamin D level.
Treatment
All patients should receive thiamine. An initial dose of 100 to 200 mg intramuscularly (i.m.) or intravenously (i.v.) should be given immediately, before the administration of any glucose-containing solutions. This amount is repeated, parenterally or orally, for at least the next 3 consecutive days. (Note: Oral multivitamin preparations usually contain only 5 mg of thiamine.)
All patients should receive folic acid, 1 mg per day i.m. or orally, until normal indexes are obtained.
All patients should receive a daily multivitamin supplement. Tablets containing thiamine or an equivalent may be given once oral intake is tolerated. Typical oral multivitamin preparations contain minimum amounts of B vitamins (e.g., cyanocobalamin [B12], niacinamide, pyridoxine [B6], and riboflavin [B2]) and vitamin C as ascorbic acid (75 to 100 mg). The latter amount should be adequate to treat scurvy. Various parenteral multivitamins are also available. If pellagra is suspected, ensure that the patient has an adequate intake of niacin (100 to 200 mg per day).
If the INR is elevated, vitamin K, 5 to 10 mg, is given subcutaneously; this is repeated at least once because this route may be less effective than oral or i.v. dosing. Intravenous vitamin K, 1 mg, may be given slowly in the case of an urgent need (e.g., bleeding) to correct the INR. Intravenous dosing is rarely associated with anaphylaxis. Oral vitamin K, 5 mg, may be used; this is effective if malabsorption does not occur. Larger doses are of no additional benefit, although, if the INR decreases, repeat dosing is advisable. Failure of this dose to normalize or shorten the prothrombin time over the course of the next 8 hours to 3 days suggests that significant hepatic disease may be present.
When serum 25-hydroxy-vitamin D is low, replenish this with the administration of 50,000 IU of vitamin D weekly for 1 month, followed by a daily multivitamin containing a standard 400 IU of vitamin D.
Hazards from short-term vitamin treatment are essentially nonexistent.
B. Sedation
More than ample evidence suggests that the administration of sedative-hypnotics to abstinent alcoholic patients during withdrawal makes the subjective experience less unpleasant and decreases the morbidity of the withdrawal syndrome. However, in nonmedical settings, alcoholic patients in mild withdrawal are often cared for without sedative-hypnotics. These programs are safe and effective, as long as patients do not have medical or psychiatric illnesses or a history of DTs or seizures (complicated withdrawals). Generally, treatment with sedative-hypnotics is most beneficial when it is begun as early as possible. Alcoholic patients with moderate to severe withdrawal symptoms should receive sedative-hypnotics, as should patients at
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high risk of complicated withdrawal or those who would tolerate complications poorly (e.g., past seizure, concurrent acute medical or psychiatric illness, heart disease). These drugs, however, must be used with caution when cirrhosis and its complications or significant hepatic synthetic dysfunction (e.g., elevated INR, depressed serum albumin) are present. (Note: -Aminobutyric acid A agonists [e.g., benzodiazepines] have been known to aggravate hepatic encephalopathy.)
Assessment. Therapy must be carefully titrated and individualized; fixed regimens alone cannot be considered rational. Larger doses of sedative-hypnotics and more frequent monitoring are needed when the symptoms are severe than when they are mild. The dosage and frequency of administration should be adjusted and titrated so that symptoms are suppressed; a state of light sleepiness is usually desirable. When therapy is inadequate, the symptoms continue, whereas excessive treatment may produce respiratory depression, obtundation, or coma. Achieving the desired therapeutic effect, which is between the two extremes, is not always easy. One way to individualize the treatment is by using a standardized scale, the CIWA-Ar (Table 12.2; see section I.A), to monitor withdrawal.
Treatment. A number of sedative-hypnotics has been successfully used in treating alcohol withdrawal. Each has its benefits and hazards. With whatever drug is chosen, the suggested dosage (Table 12.6) should be given every 1 to 2 hours until adequate sedation is achieved. An alternative strategy is to dose the patient every 6 hours, while providing additional medication when needed between the doses and tapering the regular dose over several days. Initial parenteral therapy is sometimes necessary. Once the symptoms are suppressed, the doses may be reduced in size and the time between them may be lengthened; any further sedative-hypnotic use should occur on an as-needed basis, taking into account the pharmacokinetic properties of the chosen drug.
Although, in general, only symptomatic patients (i.e., CIWA-Ar score of 8 to 10 or greater, seizures or delirium) should receive sedative-hypnotic treatment, those at a high risk for complications as noted above (Tables 12.4 and 12.6) should be treated with at least one dose, even in the absence of symptoms, to prevent the progression of the withdrawal syndrome.
Some clinicians recommend the use of a loading procedure. For example, a long half-life benzodiazepine (e.g., diazepam [20 mg] or chlordiazepoxide [100 mg]) is administered every 1 to 2 hours until mild sedation occurs. Typically, at least three doses (cumulative loading dose of 60 mg of diazepam or 300 mg of chlordiazepoxide) are given under close medical supervision. Proponents of this approach assert that once sedation is achieved, additional doses are rarely necessary. Shorter-acting drugs may be used as long as they are carefully tapered once symptom control is achieved. Rapid or no tapering has been associated with the occurrence of seizures during withdrawal.
Benzodiazepines. Benzodiazepines remain the drugs of choice for the treatment of alcohol withdrawal (Table 12.6). They are safe and effective, and they produce minimal or infrequent cardiovascular or respiratory depression. They are the only drugs that have been proven to prevent seizures and delirium in clinical trials.
The pharmacokinetic characteristics of different benzodiazepines influence drug therapy. The longer-acting agents most frequently used to treat withdrawal are diazepam and chlordiazepoxide, although any longer-acting benzodiazepine would be effective. The longer-acting agents have the advantage of being somewhat self-tapering because of their own long-acting active metabolites. This can be a disadvantage, however, when drug metabolism is slowed (e.g., in the elderly or in patients with cirrhosis). The shorter-acting agents, which include
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lorazepam and oxazepam, are metabolized directly to their glucuronide conjugates, which are water soluble and which are eliminated by the kidney. The metabolism of lorazepam and oxazepam is not influenced by cirrhosis or aging. However, they usually require multiple doses over a 24-hour period, and they must be tapered more carefully than diazepam or chlordiazepoxide. Other shorter-acting benzodiazepines may also be used, and recent experience suggests that the use of midazolam, given i.v., may be effective in severe alcohol withdrawal, though it offers no advantage over diazepam or lorazepam. For alcohol withdrawal seizures, one dose of a benzodiazepine, preferably lorazepam, should be administered regardless of symptoms. For agitated alcohol withdrawal delirium, i.v. lorazepam or diazepam should be given every 5 minutes untilP.153
a calm, but awake, state is achieved. Continuous monitoring of vital signs, oxygen saturation, and the ECG are essential. Restraints (on the patient's side or prone with the head of the bed elevated to avoid aspiration) may be necessary for patient safety (see Chapter 26).TABLE 12.6. RECOMMENDED REGIMENS FOR THE MANAGEMENT OF ALCOHOL WITHDRAWAL
Dosing Fixed (or regular) schedule dosing: administer drug q.i.d., taper by 50% each d for 2 3 d, and then stop. Reassess frequently and give additional medication as needed (i.e., when Clinical Institute Withdrawal Assessment Scale for Alcohol, revised [CIWA-Ar] score 8 10). Symptom-triggered (front-loading) dosing: administer medication every 1 2 h as needed (i.e., when CIWA-Ar 8 10). When no symptoms are present, provide one dose of sedative (see text). Available agents
Drug Dosage Comments Benzodiazepines Long acting Chlordiazepoxide 50 100 mg p.o. Many active metabolites provide smooth taper; metabolism prolonged in elderly or those with hepatic synthetic dysfunction; avoid i.m. route due to erratic absorption Diazepam 10 20 mg p.o., 5 mg i.v. Less desirable for outpatients because of initial euphoria. i.v. dose should be used every 5 min for delirium; metabolic issues same as for chlordiazepoxide Short acting Initial dosing same as for other sedatives listed, but important to taper administration of a regularly scheduled dose (e.g., q.i.d.) over 2 3 d to avoid late withdrawal; choose when significant hepatic synthetic dysfunction or tenuous respiratory function is present Lorazepam 1 2 mg p.o., i.v., i.m., s.l. Oxazepam 30 60 mg p.o. No parenteral forms available Barbiturates Phenobarbital 100 200 mg p.o. No randomized trial evidence for efficacy; long acting; induces hepatic microsomal enzymes; narrow toxic-therapeutic index (respiratory depression), which makes this option less desirable Abbreviations: i.m., intramuscular; i.v., intravascular; p.o., orally; q.i.d., four times a day; s.l., sublingual. Benzodiazepine receptor antagonists have also been used to reverse the effects of alcohol in overdose, both with and without concomitant benzodiazepine ingestion. Flumazenil is commonly used for this purpose. Although results with flumazenil (0.1 to 0.2 mg per kg i.v.) in normal volunteers who are intoxicated solely with alcohol have not been promising, positive outcomes have been observed in actual emergency department use, especially when sedative-hypnotics have also been ingested. The use of flumazenil may transiently increase the risk of seizures, especially in the withdrawing patient or in the patient receiving concomitant antidepressant therapy with imipramine or bupropion, for example.
-Adrenergic receptor antagonists (beta-blockers). Both propranolol, 10 to 40 mg four times daily, and atenolol, 50 to 100 mg per day, have been used to treat alcohol withdrawal, but they are rarely used as sole therapy except in the mildest cases. Many centers use -adrenergic receptor antagonists, in addition to benzodiazepines, because of their antiarrhythmic effects. -Adrenergic receptor antagonists may also reduce the required dose of a given benzodiazepine. Caution is advised, however, because -adrenergic receptor antagonists do not prevent seizures or delirium. Furthermore, propranolol is contraindicated in patients with asthma, insulin-dependent diabetes, or congestive heart failure. Toxic confusional states have also been reported with propranolol use in alcohol withdrawal.
Because atenolol is a relatively cardioselective 1-adrenergic receptor antagonist, alcoholic patients with mild asthma may tolerate lower doses of this drug, but a 2-adrenergic receptor agonist (i.e., a bronchodilator, such as albuterol) should be readily available. (Note: Receptor selectivity diminishes with increasing amounts of atenolol.) The main utility of -adrenergic receptor antagonists in alcohol withdrawal is in patients with ischemic heart disease, severe tachycardia, or hypertension unresponsive to benzodiazepine treatment.
Barbiturates. Before the introduction of the benzodiazepines, barbiturates were a first-line treatment for alcohol withdrawal. Some clinicians still use phenobarbital as their primary agent for detoxification. Dosage guidelines for the use of phenobarbital are given in Table 12.6. Because barbiturates are more likely than benzodiazepines to cause respiratory depression, because they also interact with many other drugs via their enzyme-inducing properties (see Chapter 29), and because controlled trials do not exist to support their efficacy for preventing withdrawal complications, most clinicians view barbiturates as second-line treatments.
An additional problem in the United States has been inconsistent availability of the oral formulations of the short-acting and intermediate-acting barbiturates, such as amobarbital. In the rare patients who are unresponsive to benzodiazepines, some clinicians choose amobarbital, preferring this agent over phenobarbital because of its shorter duration of action that gives the clinician greater control of the level of sedation. However, as with the short-acting benzodiazepines, careful tapering is required.
2-Adrenergic agonists. Clonidine (0.1 mg twice a day to 0.2 to 0.3 mg three times a day) and other 2-adrenergic agonists can be given to reduce the hyperadrenergic symptoms of alcohol withdrawal. Although these drugs may reduce anxiety, tension, blood pressure, heart rate, tremor, or sweating, they do not prevent seizures, delirium, or hallucinations. That clonidine may cause hypotension
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and drowsiness should be noted, however. 2-Adrenergic agonists may be useful adjuncts for treating severe hypertension in alcohol withdrawal or for coexisting opiate withdrawal, but they are not recommended as first-line therapy.Carbamazepine. This drug is an anticonvulsant (see Chapter 19) that is structurally related to the tricyclic antidepressants. Although it is approved by the United States Food and Drug Administration for use in partial complex seizures, generalized tonic-clonic seizures, mixed seizures, or trigeminal neuralgia, several studies have noted efficacy in the alcohol withdrawal syndrome. A typical approach is to administer carbamazepine in doses of 600 to 800 mg per day during the first 48 hours of abstinence and then to reduce the dose by 200 mg per day. The most common early adverse reactions encountered are dizziness, sedation, unsteadiness, nausea, and vomiting. Fewer rebound withdrawal symptoms and less sedation may occur than are seen with lorazepam, but experience with carbamazepine use in alcoholic patients is limited. When taken for other disorders, its most serious adverse reaction is suppression of the hematopoietic system; furthermore, the risk of developing aplastic anemia and agranulocytosis is estimated to be five to eight times greater in patients taking carbamazepine than in the general population. In the general population, the risk of agranulocytosis is approximately 6 per 1 million population per year; the risk of aplastic anemia is 2 per 1 million population per year. The actual frequency of these reactions during carbamazepine treatment of alcohol withdrawal is unknown.
Cardiovascular, dermatologic, and hepatic toxicities have also been reported with carbamazepine use. Given its potential for toxicity, carbamazepine is not recommended as a first-line agent for treatment of the alcohol withdrawal syndrome.
Chloral hydrate. This agent is also effective in alcohol withdrawal, but its associated adverse effects make it unacceptable for routine use. Gastric irritation leads to nausea and vomiting; gastric necrosis may occur with toxic doses. Chloral hydrate interacts with alcohol and displaces drugs like warfarin from their protein-binding sites. The typical initial oral doses in alcohol withdrawal are 1 to 2 g. No parenteral form is currently available.
Paraldehyde. Once a mainstay of treatment in the alcohol withdrawal syndrome, paraldehyde is no longer used in the United States. It is a noxious, malodorous liquid that may cause gastric irritation, hepatotoxicity, and respiratory depression. Large volumes were necessary when it was given parenterally, and injection site complications sometimes developed.
Chlormethiazole. This sedative-hypnotic agent is used in some countries for the treatment of alcohol withdrawal; it is not approved for use in the United States, and it has been withdrawn from use in some other countries. The usual doses are three capsules or tablets, each containing 192 mg of chlormethiazole base, every 6 hours for 2 days, followed by two capsules or tablets every 6 hours for the next 4 days. Treatment usually lasts no longer than 9 days. It may cause oversedation in some cases; fatalities have also been reported. It has a high potential for abuse and dependence.
Antipsychotic agents. When delirium occurs in the course of alcohol withdrawal, antipsychotic agents may be indicated (see Chapters 5 and 20). With some of these agents (e.g., chlorpromazine, thioridazine), clinicians must be concerned about avoiding hypotension or lowering the seizure threshold. The risk of hypotension can be reduced by avoiding certain conventional antipsychotic agents, such as the aliphatic phenothiazines (e.g., chlorpromazine, promazine) and the aliphatic thioxanthenes (e.g., chlorprothixene).
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Loxapine may also cause hypotension and may lower the seizure threshold. Of these two adverse effects, hypotension is the more serious, and some fatalities have been reported following i.m. or i.v. use of chlorpromazine in DTs.Although delirium during alcohol withdrawal should primarily be treated with benzodiazepines, haloperidol is often added in doses of 0.5 to 5 mg i.m. or i.v. every 2 hours to treat psychotic symptoms and hallucinations. A reasonable strategy is to begin with lower haloperidol doses and to increase them as necessary. Augmenting the effects of haloperidol by the judicious use of i.v. benzodiazepines (e.g., lorazepam, 1 to 2 mg i.v. every 5 minutes) may also be helpful. (Note: Any benzodiazepine use may cause greater than usual sedation or respiratory depression when evidence of compromised hepatic function [e.g., elevated serum ammonia or INR or depressed serum albumin] is seen.)
Miscellaneous agents. Other agents have been used to treat alcohol withdrawal, but none has proved superior to the benzodiazepines. Valproate, bromocriptine, antihistamines, and calcium channel blocking agents have been employed, but none of these are recommended for routine clinical use. Gabapentin has shown some promise because it does not affect mental status as often as the benzodiazepines, but its efficacy remains to be established. Ethanol should not be used for alcohol withdrawal except in the setting of methanol or ethylene glycol ingestion. Ethanol is toxic and difficult to administer appropriately, and it may interfere with engagement with the overall treatment plan.
C. Volume Repletion
Although many concomitant conditions, such as rhabdomyolysis, alcoholic ketoacidosis, starvation, vomiting, and diarrhea, in alcoholic patients in alcohol withdrawal require i.v. fluid administration, one cannot assume all patients are volume depleted. Administration of volume (i.e., saline solution) could be dangerous if the patient is not volume depleted and when unrecognized alcoholic cardiomyopathy coexists. In young, healthy adults who are volume depleted, little danger exists in administering fluids. Treatment should clearly be individualized.
Assessment. Appraisal of the withdrawing alcoholic's state of fluid balance is notably difficult. Usually reliable indicators can be misleading.
Skin turgor assessment must be approached with caution. Poorly nourished alcoholic patients may have reduced subcutaneous connective tissue, and they may thus appear to be volume depleted when they in fact are not. The inner aspect of the thigh is the most reliable location for this assessment.
Body weight is useful, if a recent weight from a previous admission is available. However, weight loss may be due to poor nutrition as much as to volume depletion. Once a baseline weight has been obtained on admission, daily changes in weight are a valuable indicator of volume status. For this reason, all withdrawing alcoholic patients should be weighed daily. Unless the initial volume depletion was severe, weight gain should be no greater than 0.5 to 1 kg per day.
Blood urea nitrogen levels also can be deceiving. They may be inappropriately high if renal disease is present or if blood is present in the gastrointestinal tract. Misleadingly low values can occur because of poor protein intake or from failures in urea synthesis secondary to liver disease.
Thirst or dry mucous membranes also are not reliable markers. Hyperventilation is common in alcohol withdrawal, and this can produce drying of mucous membranes in the absence of volume depletion.
Postural vital signs (a seated or standing and supine blood pressure and pulse) with a significant drop in blood pressure or a rise in pulse indicate a significant volume deficit.
Hematocrit values appear normal in many alcoholic patients who are anemic when in a normal state of hydration. Because of hemoconcentration, their hematocrit values then appear normal when they are dehydrated.
Urinalysis is valuable if renal function is normal. A urine specific gravity greater than 1.025 or a sodium concentration of less than 10 mEq per L in a spot urine sample strongly suggests volume depletion. Ketonuria can occur with decreased oral intake or persistent vomiting.
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Treatment. When the patient is not seriously ill and he or she can tolerate oral intake, the individual will correct fluid deficits and will maintain normal hydration when given ad libitum access to water and a diet containing normal amounts of sodium chloride. Patients who cannot eat or drink or who are significantly volume depleted must be given parenteral fluids. If the history, physical examination, body weight, and laboratory studies suggest that a fluid deficit is present, the deficit must be corrected in addition to the administration of maintenance fluids.
Approximate daily maintenance requirements are water (30 to 40 mL per kg), sodium (40 to 80 mEq), and potassium (30 to 60 mEq). These should be given by continuous infusion with 5% dextrose in a normal saline solution so that calories are provided and hypoglycemia is avoided (see section IV.B.2). Potassium chloride (20 to 40 mEq) and magnesium sulfate (1 to 2 g) can be added to each liter of fluid provided renal function is normal.
Fluid and electrolyte deficits should be corrected as indicated. Deficits developing during hospitalization from vomiting, fever, diaphoresis, or marked hyperactivity can be avoided by increasing the maintenance therapy.
Hazards. The approach to parenteral fluid and electrolyte administration must be modified when cirrhosis is present or when sodium metabolism is abnormal (see section IV.B.1 and V.B.5).
D. Potassium Balance
Even when parenchymal liver disease is not present, most chronic alcoholic patients have a total body potassium deficit. This can contribute to symptoms such as depression, fatigue, and muscle weakness. When the deficit is severe and when it is superimposed on sympathetic nervous system hyperactivity during alcohol withdrawal, fatal cardiac arrhythmias may ensue. Most patients, therefore, should receive potassium supplementation.
Assessment. Serum potassium is the only measurement readily available to most clinicians. Potassium is primarily an intracellular cation. Of a normal total body potassium content of 3,000 to 3,500 mEq, less than 1% is found in serum. Consequently, serum potassium can appear to be normal despite a total body deficit. In addition, when the serum potassium is less than 3.0 to 3.2, the total body deficit may be several hundred milliequivalents or more. Patients who have received long-term diuretic therapy without potassium supplementation invariably have a potassium deficit. This is especially likely with thiazide diuretics and furosemide. Furthermore, alcoholic patients are often magnesium deficient, and magnesium is required for renal reabsorption of potassium. The influence of pH on serum potassium must also be remembered. Respiratory alkalosis due to hyperventilation is frequently found in alcohol withdrawal. This results in an influx of potassium into cells, thus lowering the serum concentration without changing the total body store. Systemic acidosis does the reverse, and serum potassium rises.
Treatment. Potassium chloride is the supplement of choice.
When serum potassium is normal (above 4.0 in a patient with heart disease), the danger of cardiac arrhythmias due to hypokalemia
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is slight. Replacement can proceed slowly at a rate of 60 to 100 mEq per day. A normal diet usually contains ample potassium, and supplements should not be necessary once oral intake resumes.A low serum potassium in the absence of alkalosis almost always indicates a total body deficit. Potassium chloride concentrations of more than 60 to 80 mEq per L are extremely irritating when given i.v. The maximum replacement rate is 30 to 40 mEq per h. This should be continued until the serum potassium is 3.5 mEq or more. The usual replacement dose is 100 to 140 mEq per day. Oral therapy is preferable whenever possible.
Potassium replacement is futile when magnesium deficiency coexists and is left untreated.
Hazards. The risks are those of hyperkalemia. Potassium should not be given unless urine output is adequate. Renal insufficiency necessitates caution and a reduced dosage. Serum potassium concentrations should be determined at least daily during replacement therapy, but more frequent determination is preferred until a safe range (e.g., greater than 3.3 mEq but less than 6.0 mEq) is achieved. Intravenous potassium chloride should be given by continuous infusion, never by bolus injection. The ECG should be monitored if large amounts of potassium are given i.v. Administration of potassium chloride with potassium-sparing diuretics, such as spironolactone, amiloride, and triamterene, or other medications such as angiotensin-converting enzyme inhibitors that promote potassium retention may be hazardous, even when thiazide diuretics are coadministered, and patients should be closely monitored.
E. Magnesium Balance
The metabolism of potassium and magnesium is similar. Most alcoholic patients are magnesium depleted regardless of serum concentrations. Magnesium deficiency can contribute to symptoms of lethargy and weakness and to hypokalemia. Hypomagnesemia has also been suggested to lower the seizure threshold and to lead to cardiac arrhythmias. Magnesium sulfate (1 to 2 g i.v., added to i.v. fluids) is preferable when i.v. fluids are being given. Several oral preparations (e.g., magnesium gluconate, magnesium oxide, and magnesium hydroxide as commonly found in antacids) are available. Their use is limited by their main side effect, diarrhea. The aluminum that is often combined with antacids counteracts this effect, but it should be avoided because it can exacerbate hypophosphatemia. Combination antacids containing calcium carbonate rather than aluminum are preferable for minimizing diarrhea. Treatment is continued until the magnesium levels normalize and clinical improvement occurs. If magnesium deficiency or hypokalemia is present, one can assume that the total body deficit is approximately 1 to 2 g of elemental magnesium. Ideally, this should be replaced over 4 or 5 days, keeping in mind that half of the replaced magnesium is excreted in the urine.
F. Phosphate
Hypophosphatemia is common in persons withdrawing from alcohol. Serum levels can be misleading when rhabdomyolysis or starvation coexist, as these result in a false elevation that rapidly drops with the administration of glucose and fluids or refeeding. Oral supplementation is preferable; milk contains about 1 g per L of phosphorus and calcium. For patients who cannot tolerate oral fluid intake (skim milk, potassium phosphate tablets, or oral carbonated phosphates as found in cathartics), several parenteral phosphorous preparations are commercially available. These should be used only with close monitoring of serum calcium and phosphorus when the patient cannot take anything orally and when the serum phosphorus is less than 1 mg per dL due to the risk of hypocalcemia and cardiac effects. A total daily oral dose of 2 to 3 g of elemental phosphorus is given in two to four divided doses. Mild diarrhea is a frequent adverse effect. Supplemental treatment is continued until the phosphate levels return to normal.
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G. Calcium
Hypocalcemia is commonly seen in alcoholic patients. Hypomagnesemia causes reversible hypoparathyroidism, which can cause a depressed serum calcium. The serum calcium may appear to be even lower because of a low serum albumin. When the corrected serum calcium is low, treatment with magnesium will usually correct the abnormality. Treatment with oral or i.v. calcium is futile because the problem is not the body stores of calcium, even though osteopenia is not uncommon, but rather the regulation of the serum level. Calcium supplementation will not raise the serum levels.
H. Prophylactic anticonvulsants
The indications for prophylactic anticonvulsant therapy in alcohol withdrawal are extremely limited.
Assessment depends largely on history.
Most patients either have no history of seizures, or they have had convulsions only during prior episodes of alcohol withdrawal.
A smaller subgroup of patients is known to have grand mal seizures that occur apart from the alcohol abstinence syndrome. Almost all of these individuals are or should be receiving maintenance anticonvulsant therapy. However, many have stopped taking their medication. Categorizing these patients into the following two groups may be useful: those who have continued taking anticonvulsants up to the present and those who have stopped taking them 5 or more days earlier.
Treatment depends on the category into which the patient falls.
With no seizure history or with seizures during alcohol withdrawal only, no evidence exists to suggest that prophylactic phenytoin or other anticonvulsants will prevent withdrawal seizures. Sedative-hypnotics have anticonvulsant activity in themselves. Adequate treatment of the abstinence syndrome with sedative-hypnotics minimizes the likelihood of seizures.
Patients known to have an underlying seizure disorder are at risk of developing convulsions during alcohol withdrawal.
When patients have been taking phenytoin or another anticonvulsant reliably, their daily maintenance doses should be continued. Most patients require 300 to 400 mg per day of phenytoin. The dose can be given as a single dose. When oral intake is precluded, the maintenance dose of phenytoin should be given i.v. at a rate not exceeding 50 mg per minute. Phenytoin should not be given by i.m. injection because it is incompletely absorbed. However, an ester preparation, fosphenytoin (75 mg = 50 mg of phenytoin), can be given i.m. As soon after admission as possible, the serum phenytoin concentration should be determined and should be used to guide therapy. The effective serum concentration range is 10 to 20 g per mL or whatever level has previously been associated with seizure control for that individual. The dosage should be adjusted to keep serum concentrations in this range, rather than keeping them fixed according to an arbitrary dosing regimen.
If phenytoin or another anticonvulsant maintenance was stopped 5 or more days before admission, then the total body anticonvulsant stores are usually depleted. In this circumstance, a loading dose of phenytoin should be given (phenytoin, 10 to 15 mg per kg i.v., should be administered slowly not faster than 50 mg per min). This procedure requires about 20 minutes in a 70-kg patient. Each injection of phenytoin into a vein or catheter should be followed by an injection of sterile saline through the same needle or catheter to avoid local venous irritation. After the loading dose, an oral maintenance dose of 100 mg is given every 6 to 8 hours. In the absence of status epilepticus, a slower rate of administration of the loading dose
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may be preferable (e.g., 10 to 15 mg per kg over 4 to 6 hours). Intravenous phenytoin can cause mild atrioventricular block or hypotension; the blood pressure and ECG should be monitored continuously. Although fosphenytoin avoids these effects, it is also considerably more expensive. Phenytoin is the drug of choice, even when the patient has required another anticonvulsant, because adequate serum levels can be achieved rapidly. Phenobarbital is a reasonable alternative for this purpose.The hazards of parenteral phenytoin are that it is given in a propylene glycol solvent vehicle that can cause bradycardia or hypotension when given in a rapid bolus. For this reason i.v. phenytoin should be given at no faster than 50 mg per min. Addition of phenytoin to i.v. fluids should be avoided because solubility problems may lead to precipitation. Long-term administration of phenytoin can produce malabsorption of folic acid and vitamin D. These possibilities should be considered in newly admitted alcoholic patients who have already received phenytoin as outpatients.
I. Aftercare
Withdrawal from alcohol or acute detoxification is only the first step in management for the alcoholic patient. Detoxification does not reduce the rate of relapse. All patients treated for withdrawal should be offered treatment for alcohol dependence, including counseling or pharmacotherapy, such as supervised disulfiram or naltrexone (see Chapter 11). Active psychiatric disorders, most commonly mood disorders, coexist in half of all patients with addictions; these should be treated without delay. Finally, alcoholic patients should avoid acetaminophen because of the risk of hepatic necrosis and fulminant liver failure due to toxic metabolites that accumulate as a result of fasting and underlying liver disease leading to depleted glutathione stores. No dose of acetaminophen is known to be safe in the setting of alcohol use.
IV. Recognition and Therapy of Complications
Complications of the alcohol withdrawal syndrome must be assessed and dealt with promptly. Sequelae such as infection and metabolic derangements can be rapidly fatal when they are unrecognized, but they are readily reversible with sound medical treatment. Multiple complications often coexist, and they may go unrecognized because they are mistakenly attributed to the withdrawal syndrome.
A. Fever
Fever during alcohol withdrawal becomes more common with the increasing severity of the withdrawal syndrome. Hyperpyrexia per se is a symptom, not a disease. Epidemiologic studies suggest that fever in this setting is commonly due to volume depletion or pulmonary infection. Alcoholic hepatitis is another common cause of low-grade fever; acute pancreatitis can also be associated with fever. However, statistics do not apply to individual patients. In any abstinent alcoholic patient, a fever greater than 38.1 C (100.5 F) should suggest infection until this has been proved otherwise. A systematic search for a source of infection must be undertaken. Common sites of infection are the lungs (e.g., Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, mixed bacterial, Mycobacterium tuberculosis); the meninges; the peritoneum; and the urinary tract, especially with Foley catheters or obstruction. Infection can also be catheter related. Aspiration pneumonias are not uncommon. M. tuberculosis is becoming more prevalent, and it should be suspected in patients who have been homeless or have lived in shelters. Fever during an acute confusional state necessitates examination of the cerebrospinal fluid. Fever and ascites indicate examination of the peritoneal fluid to identify spontaneous bacterial peritonitis.
B. Metabolic disturbances
Recognition and therapy of abnormalities in fluid, potassium balance, and magnesium balance were discussed earlier in sections III.D.2 and III.E. Common metabolic disturbances include the following.
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Hyponatremia can be iatrogenic, due to excessive parenteral administration of sodium-free solutions, but it may also be seen in beer drinkers. It is often observed when patients have been vomiting and have been replacing losses with water or other hypotonic fluids. Treatment consists of the restriction of free water if its nature is iatrogenic; however, in the case of volume depletion with hyponatremia, treatment consists of i.v. isotonic saline. When hyponatremia is severe (less than 110 mEq per L) or when it is accompanied by objective neuropsychiatric symptoms, hypertonic sodium chloride solution can be given i.v. with caution. Rapid administration of hypertonic sodium chloride solution has been associated with central pontine myelinolysis. The serum sodium should increase by no more than 0.5 mEq per h.
Hypoglycemia is a significant danger in abstinent alcoholic patients. Glycogen depletion, hepatic disease, and poor caloric intake can contribute to the hypoglycemia. All parenteral solutions should contain 5% dextrose in addition to other needed solutes. Whenever unexplained obtundation occurs, a blood sample should be drawn to determine the glucose level, and a 50 mL bolus of 50% glucose solution should immediately be given i.v. while awaiting the results of the test.
Alkalosis is usually due to hyperventilation (i.e., respiratory alkalosis). Alkalosis is important because it lowers extracellular potassium and magnesium concentrations, causing weakness and possibly a lowered seizure threshold. Therapy consists of sedation and supplements of potassium and magnesium, as described in sections III.D.2 and III.E.
Acidosis is important to recognize because it may be the only clue of a toxic ingestion of ethylene glycol, antifreeze (glycolic acidosis), or methanol (formic acidosis). These toxic acids are osmotically active. When an anion gap is present, measured serum osmolality should be compared to calculated osmolality to determine whether a significant gap exists to detect these ingestions. Anion gap acidosis may also occur after a seizure, as a sign of sepsis (lactic acidosis), or as a result of diabetic or alcoholic ketoacidosis. Alcoholic ketoacidosis can present with hypoglycemia or hyperglycemia and a mild or severe acidosis, and this should be treated with i.v. dextrose (5%) in isotonic saline, with insulin as needed according to the blood sugar, accompanied by monitoring of the serum pH or serum bicarbonate. Urine ketones are often undetectable initially because -hydroxybutyrate predominates at the outset and this is not detected by urine dipstick tests. The most common nonanion gap acidosis in alcoholic patients is due to diarrhea.
C. Alcoholic Hepatitis
Alcoholic hepatitis is a complication not of alcohol withdrawal per se but of the drinking episode before abstinence. Clinical characteristics include an enlarged and tender liver, low-grade fever, leukocytosis, mild hepatic function abnormalities, and fatty infiltration of the liver on histologic study. Elevated serum -glutamyl transferase and an elevated ratio (i.e., greater than 1.0) of aspartate aminotransferase to alanine aminotransferase are indicators of liver inflammation or necrosis. The syndrome can occur in all individuals after an alcohol binge, and, in theory, it is completely reversible once drinking stops. Repeated episodes of alcoholic hepatitis in chronic alcoholic patients can lead to irreversible damage (cirrhosis) eventually. Most patients presenting with clinical episodes of alcoholic hepatitis have some degree of cirrhosis. Fatality rates in hospitalized patients are quite high. At the present time, the only specific therapy for all cases is cessation of drinking. Corticosteroids (prednisolone) have been shown to reduce mortality in severe cases of alcoholic hepatitis, when INR and bilirubin are significantly elevated and hepatic encephalopathy is present without gastrointestinal bleeding. Pentoxifylline also shows promise for this indication. Malnutrition is strongly related to mortality in patients with alcoholic hepatitis. Caloric intake should be ensured, and, when significant malnutrition is present,
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oxandrolone, an anabolic steroid, can be added to decrease mortality. Propylthiouracil and colchicine may help once cirrhosis is present, although this has not yet been reliably established. Liver transplantation is an option for end-stage liver disease once the patient has achieved a stable abstinence.
D. Hematologic disorders
Several hematologic abnormalities occur in alcoholic patients, and these can complicate alcohol withdrawal.
Coagulopathy. This can occur on the basis of liver disease or vitamin K deficiency. Coagulopathy associated with intractable bleeding requires the administration of plasma.
Thrombocytopenia. Alcohol ingestion can transiently reduce the platelet count to extremely low levels. This effect is rapidly reversible, and it probably is of little consequence. A rebound thrombocytosis is often noted after several days of abstinence.
Impaired granulocyte function. Alcohol depresses granulocyte function. This may explain the increased susceptibility of alcoholics to bacterial infection or the occasional finding of a slightly low or normal white blood cell count during serious systemic infection.
Anemia
Anemia in alcoholic patients is assessed by the following methods.
Examination of a peripheral blood smear.
Reticulocyte count, mean corpuscular volume, and red cell distribution width.
More expensive less essential measures, including serum concentration determinations of iron, iron-binding capacity, ferritin, vitamin B12, and folate.
Common etiologies of anemia are as follows:
Iron deficiency secondary to chronic gastrointestinal blood loss.
Megaloblastic processes that are usually due to folic acid deficiency or poor utilization. Vitamin B12 deficiency is rarely the cause.
Idiopathic anemia that apparently is secondary to bone marrow depression by alcohol.
In most alcoholic patients, anemia is due to a combination of all three.
Treatment depends on the etiology, and ultimately it involves treatment of the underlying causes.
If bone marrow aspirate or a combination of serum indicators, history, and physical examination (e.g., blood loss) reveal iron deficiency, then iron therapy is given. Oral therapy is preferable.
All alcoholics should be assumed to be folate deficient, whether they are anemic or not. Folic acid (1 mg per day) is given.
Cessation of alcohol ingestion is the only therapy for acute alcoholic thrombocytopenia and idiopathic alcoholic anemia.
V. Modifications of Therapy when Major Associated Diseases Coexist
Several disease states are notoriously common in alcoholic patients. Some, such as cirrhosis and gastrointestinal bleeding, are a direct consequence of alcoholism; others, like chronic obstructive pulmonary disease, are not causally related, but they are frequently associated with alcoholism. Treatment of alcohol withdrawal may have to be modified when one or more of these problems is present. Not infrequently, hospital admission occurs because of an associated disease, and a withdrawal syndrome develops only after the patient is hospitalized.
A. Neurologic Problems
Head trauma, even when it is seemingly minor, should always raise the question of intracranial bleeding. Patients with any evidence of head trauma should be observed carefully for the appearance of focal neurologic
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signs, such as focal weakness, unilateral mydriasis, lateralizing seizures, increased intracranial pressure, papilledema, vomiting, hypertension, bradycardia, or depression of consciousness. Findings consistent with any of these conditions necessitate urgent neurologic or neurosurgical consultation and brain imaging.Wernicke encephalopathy is an acute neurologic illness characterized by ophthalmoplegia, ataxia, and confusion. Eye signs include nystagmus, lateral rectus palsies, conjugate gaze palsies, anisocoria, and slowly reactive pupils. Treatment is with parenteral thiamine, 50 to 100 mg per day. Maximum improvement may take several weeks. Unfortunately, some symptoms, such as ataxia and nystagmus, may persist. During the acute phase, the mortality rate may be 15% to 20%.
Most patients who survive Wernicke encephalopathy go on to develop Korsakoff syndrome (alcohol amnestic disorder). Korsakoff syndrome is characterized by amnesia; recent memory is affected to a greater extent than is the remote memory. Patients may appear indifferent to their memory loss, filling in memory gaps with fabrications (confabulation). Even after thiamine treatment and the cessation of drinking, the amnestic syndrome may not improve in about half of patients with the disorder.
Alcoholic dementia is an impairment of both short-term and long-term memory that is accompanied by impaired judgment, a personality change, or other disturbances in abstract thinking. It should be differentiated from Korsakoff syndrome, which affects the memory but spares the other intellectual functions.
Hepatic encephalopathy is not usually confused with alcohol withdrawal, but agitation and tremor may be the only signs in the early stages. The characteristic tremor is asterixis. The later stages involve obtundation, and these could be confused with an atypical presentation of alcohol withdrawal delirium. When cirrhosis is present in a patient with suspected alcohol withdrawal, precipitants of encephalopathy, such as gastrointestinal bleeding, infection, and recent sedative use, should be sought.
Other neurologic consequences of alcoholism include cerebellar degeneration, corpus callosum degeneration (Marchiafava-Bignami disease), and central pontine myelinolysis.
B. Gastrointestinal Effects
Alcoholic patients commonly develop esophagitis, gastritis, duodenitis, or peptic ulcerations, all of which can lead to serious blood loss. Superficial gastritis due to alcohol or aspirin or both is the usual cause of gastrointestinal bleeding in alcoholic patients, but the etiology must be determined by carefully conducted endoscopy. Superficial gastritis usually ceases rapidly after antacid administration and abstinence from alcohol. Nasogastric suction may be used for comfort. Peptic ulcer disease is the next most common cause of bleeding. Treatment with a proton pump inhibitor and antibiotics when Helicobacter pylori infection (an important etiology factor in most duodenal and many gastric ulcers) is present is usually successful. Conservative therapy (e.g., H2-receptor blocking agents) is usually successful.
Bleeding from esophageal varices is catastrophic, intractable, and often fatal. Initial emergent management after i.v. access is obtained and blood products are transfused is endoscopic ligation, banding, or sclerosis. Somatostatin or octreotide (50 g per h) should be started and continued for 1 to 3 days. Vasopressin is no longer used for this indication because of its unclear efficacy in the acute setting and its association with vasospasm and cardiac ischemia. Balloon tamponade is the next step, but this is fraught with complications. Transjugular intrahepatic portosystemic shunts can decrease the bleeding when endoscopy fails, although these shunts do increase the risk of encephalopathy and their long-term
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safety and efficacy are not known. -Adrenergic receptor antagonists (e.g., propranolol, nadolol) and isosorbide mononitrate can decrease recurrent variceal bleeding. Surgical portosystemic shunts can also decrease recurrence, but they increase the risk for encephalopathy and do not decrease mortality.Alcoholic steatosis (fatty liver) presents as an enlarged, nontender, smooth liver. This is a direct consequence of alcohol, and it is reversible with abstinence. Dietary restriction of fat may be beneficial.
Alcoholic hepatitis, as discussed earlier, usually presents as fever, anorexia, nausea, vomiting, weight loss, right upper quadrant pain, jaundice, or leukocytosis (see section IV.C). Most patients have concurrent cirrhosis. The presence of ascites, encephalopathy, elevated INR (prolonged prothrombin time), hyperbilirubinemia, and rising serum creatinine are poor prognostic signs. Although mild cases usually show clinical recovery, repeated episodes may lead to irreversible liver injury.
Hepatitis C is more prevalent in alcoholic patients than it is in the general population. Risk factors include injection drug use and blood transfusion. Although sexual transmission in monogamous relationships is rare, multiple sex partners confers a greater risk of hepatitis C. The clinical course of hepatitis is indolent over 15 to 20 years, but alcohol use and human immunodeficiency virus infection both independently and synergistically increase the rapidity of progression to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Current treatment for alcoholic patients in remission is polyethylene glycolated (pegylated) interferons with ribavirin for 1 year. Side effects include hemolysis, depression, and flu-like symptoms.
Alcoholic cirrhosis usually causes a slow development of symptoms in patients over the course of many years of drinking alcohol. The symptoms may begin as weakness, fatigue, anorexia, or a loss of muscle mass. As the disease progresses, bruising, jaundice, ascites, gastroesophageal varices, or encephalopathy may develop. Renal dysfunction may occur in the later stages of the illness. On physical examination, the liver is nodular; it may be enlarged, of normal size, or even smaller than normal. Secondary signs include spider angiomas, palmar erythema, splenomegaly, or clubbed fingers. In men, hormonal changes may result in testicular atrophy, gynecomastia, or decreased body hair.
Coexistence of the alcohol withdrawal syndrome with cirrhosis is prognostically grave. This indicates continued alcohol consumption, despite irreversible alcohol-induced liver damage. The following modifications in therapy are necessary.
Medications
Sedative-hypnotics must be administered with the utmost caution. Even small doses can precipitate hepatic coma. Careful titration is the only rational approach, with underdosage preferred to oversedation. When cirrhosis is present, benzodiazepines are the safest choice of drugs, particularly lorazepam and oxazepam. The belief that paraldehyde is safe in liver disease is unfounded only a small proportion of paraldehyde excretion is via the lungs; hepatic metabolism is its major route of elimination.
Antidepressants, such as fluoxetine and sertraline, should be used with caution, even at lower-than-usual doses. Some clinicians suggest that they not be used at all. Cirrhotic liver impairment typically reduces biotransformation. Fluoxetine's elimination half-life, for example, may be increased from its usual range of 2 to 3 days to 7 to 8 days.
Acetaminophen use should be avoided because of the risk of hepatic necrosis even with usually recommended doses. Aspirin and nonsteroidal antiinflammatory agents should also be
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avoided, not only because of the antiplatelet effects and the risk of bleeding but also because of sodium retention.
Fluid and electrolyte therapy. In cirrhosis, these therapies must take into account any abnormalities in sodium metabolism. In cirrhotic patients, sodium retention occurs despite total body sodium overload. Sodium intake should be restricted. Total body sodium and water excess may occur when the intravascular volume is depleted. In general, sodium, either orally or parenterally, should be avoided. However, when significant volume depletion (e.g., hypotension, poor organ perfusion) occurs, isotonic saline should not be withheld, even though it will expand the extracellular space and worsen the peripheral edema and ascites. Blood is the volume-expanding agent of choice when anemia coexists because it remains in the intravascular space. Albumin, although it has a role in large volume paracentesis and in helping to replace intravascular volume, has very short-lived effects; it is not used for diuresis or routine volume replacement. All i.v. solutions should contain 5% dextrose to provide calories and to avoid hypoglycemia. Potassium depletion can be very severe in cirrhosis, and supplements are invariably required. Hyponatremia is common, and, although it is generally well tolerated, sodium and free water restriction are often necessary. Diuresis of ascitic fluid should be undertaken gently with a weight loss of no more than 1 kg per day. Spironolactone, 100 to 400 mg per day, is the diuretic of choice. The addition of furosemide helps the diuresis and assists in avoiding hyperkalemia. Large-volume paracentesis (4 to 6 L), followed by i.v. albumin to avoid renal insufficiency and hyponatremia, is associated with fewer complications than is treatment with diuretics. The hazards of coadministration of potassium chloride with spironolactone must be remembered.
Infection. Infection can precipitate a hepatic coma, so it must be treated aggressively. Ascitic fluid is an ideal culture medium, and it should always be examined in the evaluation of fever. Spontaneous bacterial peritonitis may be present even if leukocytosis, abdominal pain, and tenderness are not present. High-risk patients with ascites, particularly those who have had spontaneous bacterial peritonitis, should take prophylactic norfloxacin or ciprofloxacin.
Hepatorenal syndrome is acute renal insufficiency secondary to severe liver disease. Signs include mild hypotension, oliguria, low urinary sodium (i.e., less than 10 mEq per L), and hypertonic urine. Signs of advanced hepatic disease are also present. The kidneys themselves are normal, and no characteristic histopathologic changes have occurred. Renal hypoperfusion due to vasoconstriction is thought to be the primary etiologic factor. No effective treatment exists for the hepatorenal syndrome at this time. Surgical procedures, such as placement of a peritoneovenous shunt or liver transplantation, are the only approaches that have had any degree of success. Neither dialysis nor medical approaches, such as volume expansion, steroids, antibiotics, pressor agents, prostaglandins, or transfusions, seem to benefit these patients. However, every patient should receive a trial of volume expansion with isotonic fluids or blood products, as if volume depletion was the cause of the renal insufficiency, because prerenal azotemia is often indistinguishable from the hepatorenal syndrome initially.
Pancreatitis, especially the acute form, should be suggested by the presence of severe abdominal pain, fever, and leukocytosis. Serum amylase and lipase levels should be determined when pancreatitis is suspected. Chronic pancreatitis can present with pain and normal amylase and lipase levels.
As with gastrointestinal bleeding, sedative-hypnotics must be given in doses that are sufficient to prevent the patient from pulling
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out the nasogastric tube or i.v. catheters. Because many patients may require opioid analgesics as well (i.e., meperidine is usually preferred to avoid sphincter of Oddi problems from morphine), the possibility of additive central nervous system depression should be considered.Fluid and electrolyte therapy must be vigorous. Patients with acute pancreatitis can lose large amounts of fluid volume into the retroperitoneal space. The hematocrit should be taken frequently. Hypocalcemia can occur in pancreatitis and can lower the seizure threshold. Serum calcium should be measured in all patients with pancreatitis. Calcium supplements (1 g calcium chloride or gluconate) are given i.v. when the level of calcium is critically low.
Malabsorption syndromes are common in chronic pancreatitis, and they can produce deficiencies of vitamins A, D, and K. Hypocalcemia can result from hypovitaminosis D; this emphasizes the importance of measuring serum calcium. Vitamin K deficiency increases the possibility of coagulopathy and bleeding. The INR should be measured, and parenteral vitamin K, 5 mg, should be given when indicated.
Hyperglycemia can be associated with acute or chronic pancreatitis due to inadequate insulin secretion. Fingerstick blood glucose levels should be measured in all patients with pancreatitis, and insulin should be given when indicated.
Although exocrine deficiency in chronic pancreatitis can be diagnosed by the N-benzoyl-L-tyrosyl-p-aminobenzoic acid test to detect chymotrypsin deficiency or the reference standard secretin test to detect impaired duodenal bicarbonate secretion, these tests are not often conducted. Exocrine deficiency is usually diagnosed clinically by the symptoms of greasy stools and chronic pain in the setting of recurrent pancreatitis and by calcifications on abdominal radiograph. In addition to vitamin supplementation, particularly of the fat-soluble vitamins, patients should be placed on a low-fat diet (less than 50 g of fat per day) and should be given oral pancreatic enzyme supplements. The pain is quite difficult to manage, and it often requires opioids, medications used for neuropathic pain, or nerve blocks.
Fever may result from pancreatic abscess or necrosis, an infected pseudocyst, or aspiration pneumonia.
Surgical therapy may be indicated in some cases of severe necrotizing or hemorrhagic pancreatitis or when abscesses or pseudocysts develop.
Adult respiratory distress syndrome may develop. This is characterized by high-permeability pulmonary edema, and it is typically treated with mechanical ventilation.
Other gastrointestinal effects of alcohol include an increased risk of many types of cancer, including those of the upper digestive tract.
C. Cardiovascular Effects
Patients with alcoholic cardiomyopathy present with fatigue, dyspnea on exertion, orthopnea, or palpitations. On an ECG, they may show atrial fibrillation, conduction defects, abnormal P waves, or decreased QRS voltage. Chest x-ray reveals cardiomegaly. Echocardiography is often conducted. The heart tissue shows muscle fiber hypertrophy and degeneration, fibrosis, and endocardial fibroelastosis. Some systolic function may return with abstinence from alcohol.
Atrial fibrillation, which is sometimes called the holiday heart syndrome, may develop in patients without heart disease during periods of excessive alcohol consumption or withdrawal.
Hypertension is commonly seen in alcohol dependence and in alcoholic patients during withdrawal, but this typically resolves without specific drug treatment. Chronic medication treatment may be necessary if hypertension persists after the resolution of alcohol withdrawal.
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D. Endocrine Effects
Plasma cortisol is increased in alcoholic patients, and a cushingoid syndrome may develop. Other endocrine effects may be influenced by liver disease. In male alcoholic patients, testosterone clearance is enhanced, and its synthesis is depressed, while estrogen levels rise. One clinical presentation includes testicular atrophy, breast enlargement, loss of facial hair, impotence, or decreased libido. Women with alcoholism may have amenorrhea, luteal phase dysfunction, anovulation, early menopause, or hyperprolactinemia.
E. Chronic Obstructive Pulmonary Disease
The nonsmoking alcoholic patient is a rarity, particularly at urban hospitals. Chronic obstructive pulmonary disease, therefore, usually coexists with alcoholism. When significant pulmonary disease is present, arterial blood gas determinations should be a routine aspect of assessment.
Sedative-hypnotics again require careful titration. Oversedation can precipitate carbon dioxide retention, narcosis, or coma. Benzodiazepines are the safest of the currently available drugs. When carbon dioxide retention is present, shorter-acting benzodiazepines are preferred. Barbiturates are hazardous. Hypoxia or carbon dioxide narcosis or both should be considered whenever an alteration in mental status occurs. Hypoxia can cause agitation, both of which are made worse by treatment with sedative-hypnotic drugs rather than oxygen.
Fluid and electrolyte therapy must account for the possibility of cor pulmonale. Physical examination, chest x-ray, and ECG can diagnose this entity. Sodium must be administered cautiously when cor pulmonale is present.
Infection is a significant threat to the patient with chronic obstructive pulmonary disease. Pulmonary infection should be carefully considered as the etiology of fever when fever occurs. Superinfection with hospital-acquired antibiotic-resistant organisms is prognostically grave. This usually occurs during ongoing antibiotic therapy in patients receiving assisted ventilation through tracheostomies or endotracheal tubes.
F. Alcohol-Related Birth Defects (Fetal Alcohol Syndrome)
Maternal alcohol ingestion is associated with central nervous system effects, growth deficiency, and facial abnormalities in the fetus. Children show a characteristic facial appearance; they have short palpebral fissures (eye openings), thin hypoplastic upper lips, and an absent or diminished philtrum (the depression in the center above the upper lip). Their ears are often posteriorly rotated and they have an altered shape, and the midface is flattened. Central nervous system effects include impaired intellectual functions that persist throughout development.
The amount of maternal alcohol ingestion that leads to the fetal alcohol syndrome is unknown, but most clinicians conservatively advise women to avoid alcohol during pregnancy. A continuum of dysmorphic and dysfunctional effects likely occurs, ranging from subtle deficits to the full syndrome. The rate of fetal alcohol syndrome seems to be particularly high in African Americans and Southwest Plains Indians. The effects of paternal alcoholism on conception and fetal development are unknown.
G. Trauma
Trauma and related orthopedic complications, such as ankle fracture, and multiple trauma from motor vehicle crashes and interpersonal violence are not uncommon. Interventions for alcoholism are known to decrease these consequences. The management of withdrawal is often complicated by the need for anesthesia and brain injury, making the assessment and dosing of prophylaxis and treatment with sedation difficult.
H. Pneumonia
A common reason for hospitalization in alcoholic patients is pneumonia. As with other acute medical, surgical, and psychiatric illnesses, prophylactic sedation should be administered to prevent complicated withdrawal in these high-risk patients. Common causes of community-acquired pneumonia
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in patients with alcoholism are aspiration of anaerobic and microaerophilic oral flora; the so-called atypical bacteria, such as mycoplasma, chlamydia, and legionella; tuberculosis; and pneumocystis.
I. Human immunodeficiency virus
Human immunodeficiency virus is more prevalent in persons with alcoholism than it is in the general population. Alcohol consumption has been associated with high-risk sexual practices. Consideration should be given to human immunodeficiency virus testing when risk factors are present and when the patient is ready to hear the results.
J. Pellagra
This condition is difficult to diagnose, and it can occur in alcoholic patients with nutritional deficiencies. Symptoms can include a rash in sun-exposed areas, diarrhea, abdominal discomfort, nausea and vomiting, glossitis, cognitive impairment, insomnia, anxiety, depression, psychosis, seizure, ataxia, and paraparesis. The diagnosis is clinical, and treatment is with niacin. Because of the difficulty with diagnosis, the difficulty in distinguishing symptoms caused by withdrawal from alcohol from other coexisting illnesses, and the simplicity of treatment, a multivitamin is routinely recommended, although additional niacin may be required if symptoms persist (see section III.A.2).
ADDITIONAL READING
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