Metabolism

Between 2% and 10% of ingested ethanol is excreted intact by the kidneys and lungs, but the major fraction is metabolized by hepatic alcohol dehydrogenase (ADH) to acetaldehyde by the following reaction²:

At high blood ethanol levels, a particular isoform of the hepatic microsomal cytochrome P450 enzyme (CYP2E1) provides an additional, albeit normally minor, oxidative pathway for ethanol metabolism:

This alternative pathway is inducible with chronic ethanol exposure. Minor amounts of ethanol can also be metabolized by peroxisomal catalase:

Acetaldehyde produced by any of the preceding reactions is converted by hepatic acetaldehyde dehydrogenase (ALDH) to acetate:

Acetate can then enter the tricarboxylic acid cycle and ultimately be metabolized to carbon dioxide (CO₂) and water. Polymorphisms in the dehydrogenase enzymes can result in increased production rates or diminished metabolic clearance of acetaldehyde. As a consequence, some individuals experience marked vasodilation, facial flushing, tachycardia, and other unpleasant symptoms after ethanol consumption because of the effects of excessive acetaldehyde accumulation. Alleles leading to this reaction are particularly prevalent in persons of Chinese or Japanese descent but are uncommon in Caucasians.²

Metabolic conversion of ethanol to acetaldehyde and acetate by dehydrogenases raises the ratio of reduced nicotinamide adenine dinucleotide (NADH) relative to its oxidized form (NAD⁺). This change in intracellular redox state favors conversion of pyruvate to lactate by lactate dehydrogenase (LDH) and can thereby raise the blood lactate concentration:

The resulting increase in blood lactate level is usually small, however, and the presence of lactic acidosis should prompt consideration of an alternative cause such as circulatory shock or seizures.³

Ethanol elimination generally follows zero-order kinetics, with elimination rates of 5 to 10 g/h in nonhabituated subjects, approximately corresponding to a fall in blood ethanol concentration of 10 to 25 mg/dL/h. This rate can more than double in individuals who are chronically habituated to high doses of ethanol.

Clinical Manifestations

Excessive chronic ingestion of ethanol plays a causative role in a number of important diseases such as cirrhosis, hepatitis, pancreatitis, cardiomyopathy, and malignancies. Ethanol use can result in gastrointestinal hemorrhage by several mechanisms including gastritis, ulcers, esophageal varices, and Mallory-Weiss tears.

Acute intoxication can induce cardiac dysrhythmias, particularly atrial fibrillation. As denoted by the descriptive sobriquet, “holiday heart syndrome,” this phenomenon frequently occurs during an alcoholic binge. A variety of neurologic abnormalities are associated with chronic alcoholism, including Wernicke-Korsakoff syndrome, chronic cerebellar ataxia, Marchiafava-Bignami syndrome, and central pontine myelinolysis.⁴ Wernicke encephalopathy can manifest as lethargy, confusion, truncal ataxia, nystagmus, and ophthalmoplegia, whereas Korsakoff dementia manifests as retentive memory impairment, confabulation, and learning deficits.⁵

Acutely, ethanol has well-known, dose-dependent inebriating and sedating effects (Table 171-1), although remarkable variability in this relationship is observed in some individuals.⁴ These central nervous system (CNS) effects appear to be at least partly caused by interference with N-methyl-D-aspartate receptor and perhaps γ-aminobutyric acid receptor function.^4,6,7 The cognitive, behavioral, perceptual, and psychomotor effects of ethanol intoxication play a causative role in a substantial proportion of deaths and injuries involving motor vehicle–related trauma, accidental drownings, residential fires, homicides, and suicides. The legal driving threshold for blood ethanol concentration is 80 mg/dL in the United States for operators aged 21 years or older. Tachycardia, mydriasis, diaphoresis, hypotension, and hypothermia can occur in cases of marked intoxication. Blood ethanol concentrations of approximately 350 mg/dL have been associated with fatal outcomes, although many patients have survived much higher levels, including one subject who reportedly survived a level of 1500 mg/dL.⁸

TABLE 171-1 Relationship Between Blood Ethanol Concentration and Clinical Manifestations*

* This information serves only as an imperfect guide, because considerable variability and overlap is possible, and individuals with chronic heavy ethanol exposure often develop learned tolerance.

Laboratory Manifestations

Blood ethanol concentration correlates at least approximately with the manifestations of intoxication (see Table 171-1). In chronic alcoholic subjects, a blood ethanol concentration below 250 mg/dL is an unlikely explanation for alterations in consciousness and should prompt a search for an alternative cause.⁸ Numerous other blood test abnormalities can be seen in intoxicated subjects, particularly in patients with chronic ethanol abuse: hyponatremia, hypokalemia, hypomagnesemia, hypophosphatemia, hypoglycemia, thrombocytopenia, and coagulopathy. Elevated activities of various circulating enzymes including amylase, lipase, creatine phosphokinase, transaminases, and γ-glutamyl transpeptidase, can occur as a reflection of alcohol-induced pancreatitis, rhabdomyolysis, hepatitis, or cirrhosis. The latter can also result in hyperbilirubinemia and hypoalbuminemia.

Treatment

In the absence of associated illness or injury (Table 171-2), mild to moderate intoxication requires no special treatment other than abstinence and a period of observation. Regardless of the degree of intoxication, withdrawal precautions are recommended for chronic imbibers, particularly those with a history of heavy chronic use or alcohol withdrawal manifestations. The treatment of severe ethanol intoxication is largely supportive. As with any patient who presents to the hospital in an unconscious state, initial empirical treatment should include IV thiamine, dextrose, and naloxone, once adequate airway, ventilation, and perfusion are ensured. Gastric lavage and activated charcoal administration are of dubious value for hastening removal of ethanol from the body.^9–12

TABLE 171-2 Concomitant or Complicating Disorders Associated with Alcohol Intoxication or Withdrawal

The unconscious, stuporous, or delirious patient with ethanol intoxication can present a diagnostic challenge. Historical information is often lacking or inadequate, and the physical examination can be compromised by lack of cooperation. A central concern is that another disorder may be present in lieu of or in addition to ethanol intoxication. The other disorder may be chiefly responsible for the alteration in consciousness or may require specific urgent treatment. For example, inebriated subjects are at high risk for trauma (e.g., battery, falls, motor vehicle accidents) and therefore should be evaluated for physical injuries. Subdural hematoma is a particular concern, and any findings or suspicion of head injury should prompt cranial imaging by computed tomography. Chronic ethanol abuse also predisposes to infection, particularly aspiration pneumonia. Pneumococcal or Listeria meningitis, although not as common, is a consideration in the intoxicated patient with an altered sensorium, fever, and other compatible findings. Additional potentially confounding problems include concomitant toxic ingestions or drug overdoses, psychiatric disorders, alcohol withdrawal, and in patients with advanced cirrhosis, hepatic encephalopathy or spontaneous bacterial peritonitis.

A thorough evaluation for common associated illnesses and injuries should include physical and laboratory examinations for evidence of head, neck, and somatic trauma, rhabdomyolysis, pancreatitis, hepatic dysfunction, coagulopathy, blood dyscrasias, and fluid and electrolyte derangements. Accordingly, routine laboratory testing should include a complete blood count, prothrombin and partial thromboplastin times, serum assays for electrolytes (including sodium, potassium, chloride, total CO₂ content, magnesium, and phosphorus), glucose, liver and kidney function tests, and amylase, lipase, transaminases, and creatine phosphokinase activities. Screening for alternative or concomitant intoxications or overdoses is occasionally fruitful.¹³ Identification of metabolic acidosis should prompt investigation for alcoholic ketoacidosis, lactic acidosis, renal failure, and relevant toxic ingestions, particularly methanol and ethylene glycol. Microbiological cultures are indicated if there are signs of serious infection.

Intravenous thiamine and a multivitamin preparation containing folate are routinely administered to hospitalized patients with alcohol intoxication or withdrawal. Parenteral thiamine (50 or 100 mg) is given during the initial phase of management, regardless of the level of sensorium, to prevent or treat Wernicke-Korsakoff syndrome.⁵

Hydration is necessary in some intoxicated patients. Dextrose-containing saline solutions are usually the fluid of choice to correct dehydration and prevent hypoglycemia. Dextrose administration is traditionally preceded by thiamine dosing. Patients with hypoglycemia require rapid IV injection of dextrose followed by a continuous dextrose infusion titrated to the results of frequent serial blood glucose tests. Hypokalemia, hypomagnesemia, and hypophosphatemia should be corrected with the use of appropriate oral or parenteral supplementation. Patients with anemia may require further investigation for gastrointestinal hemorrhage. Patients requiring admission to an intensive care unit (ICU) should have a chest radiograph as well as electrocardiographic evaluation.

Oxygenation may be assessed either by pulse oximetry or by arterial blood gas analysis, and supplemental oxygen should be provided as necessary. Administration of vitamin K, fresh frozen plasma, or platelet transfusions may be necessary if there is gastrointestinal or other hemorrhage and coagulopathy or severe thrombocytopenia. The level of consciousness should be monitored periodically. Hemodialysis has been employed and is effective at removing ethanol from the body, but in general, this modality poses greater risks than simply providing supportive care and allowing physiologic ethanol elimination. Its use might be warranted in rare cases of profound life-threatening ethanol intoxication, or if there are other reasons for dialysis.^14,15

Metabolism

Although the precise metabolic mechanisms that lead to the development of AKA are incompletely understood, several mechanisms appear to be operative. Abnormal insulin and counterregulatory hormone levels occur,¹⁶ but the disorder is distinct from simple starvation and diabetes mellitus. Ethanol results in inhibition of gluconeogenesis and depletion of glycogen stores, leading to low glucose availability, particularly when coupled with fasting. Hypoglycemia causes release of epinephrine, cortisol, and growth hormone, as well as decreased insulin production; these are all factors that favor ketone synthesis. Ethanol metabolism results in a surfeit of acetate and NADH, which promotes lactate and ketone production. Marked ketonemia results in acidosis and ketonuria. The latter causes osmotic diuresis, intravascular volume depletion, and electrolyte losses. Thus, starvation, dehydration, excessive acetate production, an altered redox state, hormonal imbalances, and perhaps genetic predisposition are all potentially involved.¹⁷

The so-called ketone bodies that accumulate in all forms of endogenous ketoacidosis are acetone, β-hydroxybutyrate, and acetoacetate. Acetone is only a minor product produced by decarboxylation of acetoacetate, either spontaneously or catalyzed by acetoacetate decarboxylase (AAD):

Acetone is excreted in the breath and urine, where it may be detected by physical examination or urinalysis, respectively. β-Hydroxybutyrate and acetoacetate are interconvertible by the enzyme β-hydroxybutyrate dehydrogenase (βHD), and the two compounds normally exist in equilibrium:

In both AKA and diabetic ketoacidosis (DKA), β-hydroxybutyrate is quantitatively the more important molecule. However, the ratio of β-hydroxybutyrate to acetoacetate tends to be higher in AKA (typically 5 : 1 but sometimes exceeding 10 : 1),¹⁸ compared with DKA (typically 3 : 1).

Clinical Manifestations

AKA characteristically develops 24 to 72 hours after an alcoholic debauch as the blood ethanol concentration is declining, during which time the subject ceases ethanol consumption and has little or no caloric intake. Gastrointestinal symptoms predominate and include anorexia, nausea, epigastric pain, and vomiting.^19,20 The subject usually has a temporary aversion to food and alcoholic beverages and complains of malaise. On physical examination, there is a clear sensorium in most cases. The odor of acetone may be detectable on the subject’s breath. Tachypnea or Kussmaul respirations may be evident if there is marked acidemia. Tachycardia and other signs of volume depletion may be apparent. In some cases, manifestations of underlying cirrhosis (e.g., jaundice, ascites, ecchymoses, hemorrhoids) or other disorders commonly associated with chronic alcohol abuse (see Table 171-2) may be present.

Laboratory Manifestations

The key laboratory findings in AKA are metabolic acidosis, ketonemia, and ketonuria in the presence of a normal, low, or mildly elevated blood glucose concentration. Ethanol may be detectable in the blood, but it is not a requirement for the diagnosis and is frequently not detectable by the time the patient presents to the hospital. If the acidosis is clinically significant, elevation of the serum anion gap is expected. Other causes of metabolic acidosis must be excluded. Simple starvation can cause mild ketoacidosis, but with simple starvation the serum total CO₂ content or bicarbonate concentration generally remains above 18 mmol/L. DKA and renal failure are readily excluded by routine blood glucose and creatinine measurements. Lactic acidosis may be suggested by the associated clinical setting (e.g., seizures, hypotension), but it should be excluded by direct assay. Mild degrees of hyperlactatemia can occur in AKA, but concentrations greater than 3 mmol/L should prompt consideration of occult hypoperfusion, seizures, or another cause. Occult toxic ingestions also require exclusion, particularly ingestions of methanol, ethylene glycol, and salicylate intoxication.^15,21–24 Ingestion of exogenous acetone or isopropanol can cause marked ketosis due to acetonemia, but in isolation these intoxications are not associated with anion gap elevation or metabolic acidosis unless the poisoning is severe enough to cause seizures or circulatory shock, thereby resulting in lactic acidosis.

The high ratio of β-hydroxybutyrate to acetoacetate seen in AKA has clinical relevance when interpreting laboratory tests. A common assay for ketone bodies uses the semiquantitative nitroprusside reaction. Nitroprusside reacts colorimetrically with acetone and acetoacetate but not with β-hydroxybutyrate. As a result, and in comparison with DKA, the degree of ketonemia detectable in AKA is often disproportionately low relative to the degree of metabolic acidosis present. Therefore, severe metabolic acidosis due to DKA is typically associated with marked levels of ketosis, whereas severe acidemia in AKA may appear to be associated with only mild to moderate ketosis by nitroprusside-based testing. In milder cases of AKA, those associated with a mild degree of metabolic acidosis in which the acidosis is due mostly to elevation of β-hydroxybutyrate, the acetoacetate and acetone levels may not be sufficiently elevated to yield detectable ketosis by the nitroprusside test.

Because vomiting and dehydration are frequent manifestations in AKA, metabolic alkalosis can complicate the acid-base derangement. The combination of metabolic acidosis (from ketoacidosis) and metabolic alkalosis (from vomiting and volume contraction) can result in arterial pH and blood gas values that underestimate the severity of one or both of these metabolic disturbances. For example, mild metabolic alkalosis can be obscured by the presence of moderate or severe metabolic acidosis. Rarely, both metabolic processes are present and of approximately equal severity. In this situation, blood pH and bicarbonate concentration can be within normal limits despite the acid-base disturbances.²³ Or, the metabolic alkalosis can predominate and obscure the acidosis. The serum anion gap can aid in detecting these situations. An abnormally high anion gap suggests metabolic acidosis even if no acid-base disorder is evident by arterial blood gas analysis. In the face of a wide serum anion gap, the quotient of the delta anion gap (i.e., the subject’s anion gap minus the average normal anion gap) divided by the delta bicarbonate (i.e., the average normal bicarbonate concentration minus the subject’s blood bicarbonate concentration) should equal unity in organic metabolic acidoses if there is no metabolic alkalosis.²⁵ A quotient well above unity (e.g., >1.2) is evidence of concomitant metabolic alkalosis.

Treatment

Alternative explanations for the metabolic acidosis should be promptly excluded.²⁴ As in acute alcohol intoxication, the initial assessment should focus on identifying relevant alternative, underlying, or complicating illnesses or injuries that may require specific urgent therapy. Although patients with AKA sometimes have severe metabolic acidemia, the acid-base disturbance usually responds rapidly to IV hydration and ample dextrose administration.¹⁷ Rapid infusion of 50 mL of 50% dextrose is indicated if hypoglycemia is identified. Five percent dextrose in normal saline is infused IV, at a high rate initially, to correct any hypovolemia or hypoglycemia and provide substrate for metabolic correction of the ketoacidosis. Thereafter, dextrose-containing normal or half-normal saline can be substituted at a high maintenance infusion rate, titrated to ongoing fluid losses. Ample dextrose administration is key to reversing the metabolic acidosis. The blood glucose concentration should be monitored frequently to allow detection of recurrent hypoglycemia or any intolerance to the provided glucose load.

In addition to specific tests related to acid-base imbalances, the same screening laboratory studies listed for acute alcohol intoxication should be evaluated. Serial acid-base and serum electrolyte testing is performed to monitor the response of the acidosis to treatment and to monitor for specific electrolyte abnormalities. Sodium bicarbonate and insulin are rarely if ever necessary. Potassium, magnesium, or phosphorus supplementation is provided if a deficiency is found by blood testing. Thiamine and multivitamins are indicated routinely. Because vomiting is common, the patient should be given nothing by mouth initially. Gastric intubation may be indicated if there is recent or ongoing vomiting, evidence of pancreatitis, or suspicion of gastrointestinal hemorrhage. Ethanol withdrawal precautions are observed.

Clinical Manifestations

The syndrome is traditionally classified into four stages, although the stages do not always follow the indicated sequence, and not every patient develops every stage.²⁹ The time of development of each stage is also quite variable, and overlaps can occur. A typical temporal sequence is described.

The first stage occurs 6 to 24 hours or more after the last drink or after a somewhat longer period of markedly decreased ethanol intake. Manifestations include anxiety, restlessness, decreased attention, tremulousness, insomnia, and craving for alcoholic beverages. Stage 2, which occurs about 24 hours after the onset of abstinence, is characterized by hallucinations, misperceptions, irritability, and vivid dreams.³⁰ Hallucinations may be auditory, but more often they are visual or tactile. Formication, the delusional sensation of insects crawling on the skin, and vivid or threatening visual hallucinations are particularly common. During this stage, the patient may appear otherwise lucid or somewhat confused, hypervigilant, and easily startled or misled. In stage 3, which commonly occurs 7 to 48 hours after cessation of drinking, seizures occur, usually of the grand mal variety.⁴ The seizures classically manifest as a cluster of brief tonic-clonic convulsions, at one time referred to as “rum fits.” They are more likely to occur in subjects with a history of repeated withdrawal episodes.³² A relatively lucid interval ranging from hours to 2 or 3 days is sometimes seen between stages 3 and 4. Stage 4 manifests 2 to 6 days or more after initiation of abstinence and consists of a global confusional state associated with signs of neuronal excitation and severe autonomic hyperactivity. Vernacular usage notwithstanding, the term delirium tremens specifically refers to stage 4 of withdrawal. Only a small minority of individuals with alcohol withdrawal develop delirium tremens. Tremors, hallucinations, and seizures are common during this stage. As is characteristic of delirium in general, the degree of confusion and disorientation can wax and wane. Hyperadrenergic manifestations may include diaphoresis, flushing, mydriasis, tachycardia, hypertension, and low-grade fever.⁴

Laboratory Manifestations

There are no specific laboratory manifestations of ethanol withdrawal. Laboratory abnormalities are a reflection of any concomitant or underlying disorders such as cirrhosis, coagulopathy, gastrointestinal bleeding, infection, pancreatitis, or aspiration pneumonitis. Electrolyte disorders are common, particularly hypokalemia, hypomagnesemia, and hypophosphatemia. Serum creatine phosphokinase activity should be evaluated because rhabdomyolysis is a common complicating problem and if severe can lead to renal failure or compartment syndrome.

Treatment

Early-stage withdrawal with mild symptoms does not generally require treatment in an ICU setting. Full-blown delirium tremens, on the other hand, often requires more vigilant monitoring than can be provided on many general medical or surgical units. Comorbid conditions that should prompt special consideration for ICU admission include acute coronary syndromes, congestive heart failure, severe sepsis, acute gastrointestinal bleeding, pancreatitis, hepatic failure, spontaneous bacterial peritonitis, hypothermia, and hyperthermia. Other factors to consider include advanced age, renal failure, severe electrolyte deficiencies, marked rhabdomyolysis, symptomatic hypoglycemia, recurrent or prolonged seizures, cardiac dysrhythmias, hypotension, and respiratory or airway compromise.

Initial steps in management include ensuring that a patent airway is present and that ventilation, oxygenation, and perfusion are adequate; establishing IV access; and excluding serious coexisting or complicating disorders. Subsequent treatment focuses mainly on judiciously titrated sedation and vigilant monitoring for progression of the syndrome or development of complications. All patients with alcohol withdrawal are given prophylactic multivitamin supplements including parenteral thiamine and folate, and fluid deficits and electrolyte deficiencies are corrected.³³ Routine administration of magnesium sulfate in the absence of hypomagnesemia has not been shown to be beneficial.^34,35 Prophylaxis against deep vein thrombosis is recommended.

A calm, nonthreatening, protective environment with frequent verbal orientation and reassurance is provided to allay anxiety and fear and to minimize agitation. This approach may suffice in milder cases, but more advanced withdrawal necessitates pharmacologic intervention. The principle underlying this pharmacotherapy is that administration of a cross-tolerant agent to achieve light to moderate sedation will ameliorate the severe manifestations of withdrawal (including autonomic and psychomotor hyperactivity), provide subjective relief, protect the patient from self-harm, and allow specific therapeutic interventions until spontaneous recovery occurs.

The agent of choice is a benzodiazepine given orally in milder cases or IV in more severe withdrawal states.^{30,33,36–38} Limited evidence suggests that symptom-triggered dosing is superior to fixed-schedule benzodiazepine dosing.³⁹ Individualized dosing requires the expert judgment of an experienced clinician, but practicality often necessitates substitution of protocol-driven dosing schemes. These typically use a quantitative assessment scale such as the Revised Clinical Institute Withdrawal Assessment Scale for Alcohol to score the degree of withdrawal manifestations.^40,41 Lorazepam can be administered IV in incremental doses, starting with 1 or 2 mg, followed by intermittent (e.g., every 2-6 hours) IV dosing or a continuous IV infusion (e.g., initiated at 1 mg/h and titrated to effect).^29,42 Alternatively, midazolam can be employed, beginning with 2 to 4 mg by IV injection, followed by 2 mg/h by continuous IV infusion, which may be titrated to effect. Diazepam is another option, given initially in titrated doses of 5 to 10 mg at intervals as frequent as every 10 minutes if necessary until a calm but awake level of consciousness is achieved. Subsequent dosing at 5 to 20 mg every 4 to 6 hours is typically required with this agent. Prolonged administration of diazepam can lead to prolonged duration of sedation due to accumulation of the parent drug and an active metabolite, both of which have long half-lives. This effect is less likely to occur with lorazepam.

Oral benzodiazepines have been employed commonly in mild cases of withdrawal that do not require IV sedation.^30,31 These agents also can be used in more serious cases after the severe manifestations have abated and parenteral benzodiazepines are no longer required. Typical oral chlordiazepoxide dosage is 25 to 100 mg every 6 to 12 hours. Intramuscular administration is sometimes employed, but it entails a less predictable dose-response due to erratic absorption, and there is the potential for a depot effect.

Other sedative-hypnotic drugs can be effective but are not considered first-line therapeutic agents.^33,36 Barbiturates have a long history of successful use. The most commonly used agent is phenobarbital, which can be difficult to titrate because of its long duration of action. The shorter-acting barbiturate, pentobarbital, also has been employed. Oral ethanol and, in the past, paraldehyde have been used but have been discouraged, in part because of the risks of aspiration and gastric irritation, but also because their use can be interpreted as reinforcing the acceptability of using alcoholic beverages, either in general or for treatment of withdrawal symptoms. The latter criticism has also been directed at the use of ethanol administered IV for this purpose. A randomized trial examining IV ethanol administration for alcohol withdrawal prophylaxis in trauma ICU patients found no advantage compared to benzodiazepine management.⁴³ Propofol is effective, but it is not a first-line agent and is not recommended unless an endotracheal tube is in place and mechanical ventilation is used.²⁹ Regardless of the specific sedative agent employed, appropriate dose titration is crucial. The goal is to ameliorate the manifestations of withdrawal without causing excessive sedation. Sedation should be titrated with the use of an objective sedation scale such as the Ramsay Sedation Scale,⁴⁴ the Riker Sedation-Agitation Scale,⁴⁵ or the Richmond Agitation-Sedation Scale.⁴⁶ The goal should be to achieve a calm awake state or, if that is not feasible, a state of light somnolence from which the patient can easily be aroused and is able to respond verbally.

Clonidine may be administered if hyperautonomic symptoms are prominent.^47–49 Typical oral dosing is 0.1 to 0.2 mg every 6 to 12 hours. β-Adrenergic receptor blockers are not recommended for routine use, but barring contraindications, they may be considered in selected cases as adjunctive agents for controlling severe hyperadrenergic manifestations. Haloperidol and other neuroleptic agents are not routinely used, because they can lower the threshold for seizures. In selected cases, haloperidol may be used in conjunction with benzodiazepines for marked agitation or hallucinations, but this agent or similar drugs should probably not be used as monotherapy.³⁶

Seizure precautions should be instituted for all patients in withdrawal. Withdrawal seizures are managed primarily with benzodiazepines, which usually are effective at the doses used for sedation.⁴² In refractory cases, higher doses may be necessary but may necessitate endotracheal intubation and mechanical ventilation. Concomitant use of other anticonvulsants also can be considered. Barbiturates may be used for this purpose, but phenytoin is usually ineffective unless the seizures are due to a specific cause other than alcohol withdrawal, such as underlying epilepsy or a complicating acute disorder of the CNS (e.g., meningitis, head trauma).^33,50,51 In such cases, phenytoin is usually the anticonvulsant of choice. A variety of other anticonvulsant and sedative drugs have been studied for potential use in treating alcohol withdrawal, including valproic acid, baclofen, γ-hydroxybutyrate, gabapentin, oxcarbazepine, and carbamazepine. However, data on safety and efficacy are limited, particularly for hospitalized patients and those with comorbid illness.^52–59

Once severe manifestations have been controlled with parenteral sedation for a period of at least 24 hours, tapering of the dose can be attempted. If tapering of sedation is tolerated, further gradual tapering is attempted, with the goal of substituting oral for parenteral benzodiazepine administration. This process typically takes up to several days, but there is substantial variability.