Alcohol Withdrawal Syndrome
Authors: Amanda Hall, MD, Division of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD; Kenneth H. Butler, DO, FACEP, FAAEM, Associate Professor of Surgery, Division of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD.
Peer Reviewers: Gary Hals, MD, PhD, Attending Physician, Department of Emergency Medicine, Palmetto Richland Hospital, Columbia, SC.; Ralph J. Riviello, MD, FACEP, Assistant Professor and Clinical Research Director, Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA.
The recognition and treatment of alcohol withdrawal syndrome (AWS) have challenged emergency practitioners to provide outcome-optimizing care that accounts for the social, physiological, and clinical complications of what can be a serious, life-threatening condition.
Symptoms of alcohol withdrawal occupy a continuum of neuropsychiatric and hemodynamic manifestations that includes tremulousness, hallucinations, seizures, central nervous system (CNS) excitation, and cardiovascular instability. Recognition of alcohol withdrawal syndrome, accompanied by prompt and definitive intervention to prevent complications of seizures, dehydration, and cardiovascular irritability, can be life-saving. Unfortunately, when the patient's history is incomplete or symptoms are not linked to alcohol withdrawal, the diagnosis is likely to be missed, and multimodal interventions that successfully can stabilize the patient may be delayed.
Once the diagnosis of alcohol withdrawal syndrome is confirmed, the treatment of the life-threatening sequelae must be swift. For many years, the pharmacologic agent of choice to treat AWS has been quite controversial. Benzodiazepines, antiepileptic agents, ethanol, and barbiturates have all been the preferred drug at one time or another. In recent years, benzodiazepines have come to the forefront as the drug class of choice, although some agents may offer advantages over others. Several guidelines have been developed to aid the emergency medicine practitioner select the most effective and efficient therapy. This review outlines, in systematic detail, the full range of AWS and risk-directed interventions shown to improve clinical outcomes in AWS. — The Editor
History
“Abrupt withdrawal of alcohol from the chronically intoxicated person is followed by a definite abstinence syndrome which, in some patients, includes convulsions or a delirium or both.” — Isbell and colleagues1
In 1955, Isbell and colleagues confirmed the relationship between alcohol and withdrawal syndrome.1 These investigators showed that the severity of signs and symptoms depends upon the amount and duration of alcohol intake. Withdrawal can happen at any time after the level of alcohol starts to fall. In another landmark paper, Victor and Adams2 showed that delirium tremens is caused by alcohol withdrawal, not by underlying problems (e.g., electrolyte disturbance or infection) stating, “The patient is restless and agitated, requiring restraints…conversation being garbled and unintelligible. Autonomic over-activity is manifested by dilated pupils, tachycardia, and an elevated temperature, attributable occasionally to no other cause other than delirium.”2 Since the 1950s, the relationship between alcohol withdrawal, autonomic instability, seizures, and change in mental status has been well recognized.
Epidemiology and Mortality
The 2003 National Survey on Drug Use and Health, conducted by the U.S. Department of Health and Human Services, reported that 22.6% of Americans older than 12 years reported binge drinking at least once during the 30 days preceding the study. That equals approximately 54 million people. Heavy drinking was reported by 6.8%; the highest prevalence of heavy and binge drinking was in the 18- to 25-year-old group. Statistically, males report more current drinking than females (62.4% compared with 46%). Among 16.1 million heavy drinkers, 32.5% also reported current illicit drug use.3
In a 2004 review article of literature on AWS in critically ill patients, Hodges and Mazur documented that 15-20% of hospitalized patients are ethanol dependent. In addition, up to half of all traumatic injuries occur while under the influence of alcohol.4 Critically ill trauma and medical patients may be suffering from alcohol withdrawal symptoms in addition to concurrent acute medical and traumatic conditions. This fact clearly emphasizes the magnitude of the problem facing emergency physicians who care for them.
In the early part of the 20th century, the mortality from AWS was 35%. Fortunately, the current mortality is less than 1%.5 Delirium tremens, the most malignant form of AWS, has the highest morbidity and mortality. Mortality from AWS comes ultimately from cardiovascular collapse.
Pathophysiology
Alcohol, benzodiazepines, and barbiturates all enhance GABA(gamma-amino butyric acid) minergic tone and produce sedation via the GABAa receptors. When activated, the post-synaptic GABAa receptors hyperpolarize post-synaptic neurons by an inward Cl current without a G protein messenger. Alcohol, benzodiazepines, and etomidate, among others, have GABA receptor activity without identified binding sites, and hence are called indirect agonists. Although the exact mechanism is not known, it is thought that the complex interaction between alcohol, the production of the GABAa subunit, and receptor modulation explains the clinical characteristics of alcohol withdrawal. During withdrawal, GABA synaptic activity is so diminished that inhibitory control of excitatory neurotransmitters and pathways (e.g., glutamate, norepinepherine, and dopamine) is lost resulting in CNS excitation (e.g., seizures, tremors, and hallucinations) and autonomic stimulation (e.g., hypertension, sweating, hyperthermia, and tachycardia).6
There is also an up-regulation of neuronal pathways, to which the NMDA (N-methyl-D-aspartate) subtype of glutamate receptor is the major contributor. This helps explain the “kindling” hypothesis, which notes that withdrawal symptoms become more and more severe with the passage of time. NMDA receptors increase in number and function while GABAa receptor activity diminishes and withdrawal becomes more severe.6 The kindling hypothesis supports prompt aggressive control of even minor signs and symptoms.
The restoration of inhibitory control by administration of GABAa agonists is crucial for treatment of withdrawal. High doses of GABAa agonists such as benzodiazepines are often necessary because of decreased GABA production and increased receptor numbers. Occasionally, such high doses are needed that the excipients may become toxic. In this situation, barbiturates may be better because they open GABA chloride channels without binding GABA.7
The pathophysiology of withdrawal seizures is unclear. The kindling effect described above offers one hypothesis, and some animal studies show a transient lowering of the seizure threshold after cessation of ethanol.8 Ng and colleagues argued that seizures may be an effect of alcohol and not of withdrawal because seizures were seen outside the withdrawal period in 10% of the patients they studied.9 Two studies demonstrate that seizures in alcoholics often are associated with other underlying brain disease (e.g., trauma or tumors), vascular brain lesions, or metabolic disorders.10,11 The commonly presenting patient with a history of alcohol abuse as well as seizure disorder being treated with phenytoin (Dilantin) or another antiepileptic agent indeed may have an organic disease causing the seizures along with alcohol withdrawal. Very often these patients cannot report whether their seizures are associated with alcohol use or another condition.
Clinical Characteristics
Alcohol withdrawal was first described by Victor and Adams as occurring in four distinct stages: tremulousness, seizures, hallucinations, and delirium.2 Clinically, AWS presents as more of a continuum of symptoms. The first sign of AWS may be a brief seizure, tremulousness, or hallucinations. After an initial seizure, symptoms often will progress through CNS excitation (i.e., tachycardia, hypertension, sweating, and hyperthermia) to delirium tremens if not treated aggressively. Status epilepticus is rare, and if present, should prompt further investigation into another etiology. It is difficult to predict who will progress to delerium tremens and who will not. Delerium tremens occurs in fewer than 5% of patients suffering from AWS.5 CNS excitation may begin as a fine intention tremor and progress to formication (i.e., sensation of ants crawling on body).6 In these early stages of CNS excitation, it is important to treat the patient aggressively before vital sign abnormalities occur. Once vital sign abnormalities occur, a rapid clinical deterioration often is impending because of the kindling effect. In its most malignant form, AWS leads to vital sign abnormalities, coma, and eventually cardiovascular collapse and death. Hallucinations with intact sensorium are common. Hallucinations are commonly visual, but they can be auditory as well in up to 20% of patients. Olfactory hallucinations are rare.5 Alcoholic hallucinosis is different from AWS and dissipates as the blood alcohol level drops. Alcoholic hallucinosis often is characterized by persecutory hallucinations and can last for months.
Goldfrank recommends characterizing AWS as with or without intact sensorium rather than using confusing terms (e.g., delirium, delirium tremens, or florid DTs).6 Because AWS exists along such a continuum of symptoms, there can be no single set of definitive criteria.
Differential Diagnosis
Withdrawal syndromes from other sedative-hypnotic agent can present similarly to AWS. Intoxications from cocaine, amphetamines, and monoamine oxidase inhibitors will produce similar autonomic dysfunction, as can anticholinergic toxidromes. Hallucinations and delirium have a wide range of causes. There are many differential diagnoses that must be entertained when considering AWS (See Insert).
Treatment
There are four main principles of treatment:
1. Restore inhibitory tone to the CNS by using long-acting benzodiazepines or barbiturates.
2. Identify and correct any fluid and electrolyte
deficiencies.
3. Evaluate for concurrent illness.
4. Allow the patient to recover with the least amount of physical restraint to decrease the risk of hyperthermia and rhabdomyolysis.
Any evaluation of AWS requires an assessment of the severity of the withdrawal. The most commonly used instrument for this purpose is the revised Clinical Institute Withdrawal Assessment–Alcohol scale (CIWA-Ar) (See Insert),12 which scores patients on 10 categories of symptoms. The maximum score possible is 67.12 This scoring system can be used when assessing patients and their need for medication. It is well documented as reliable and valid in a variety of settings. A high score is predictive of seizures and delirium.13
In a meta-analysis of literature on the pharmacologic management of AWS, Mayo-Smith and colleagues recommended medication choices to treat acute AWS.14 Six prospective trials all demonstrated that benzodiazepines were more effective than placebo in reducing signs and symptoms of AWS. All showed a decrease in incidence of seizures (i.e., risk reduction of seizures 7.7 per 100 patients treated [P = 0.003]), as well as delirium (i.e., risk reduction of delirium 4.9 per 100 patients treated [P =0.04]). In their review, they found few data concerning the comparative efficacy in reducing delirium; however, there is some evidence that longer-acting benzodiazepines are more effective in preventing seizures.
Benzodiazepines
In 2004, Mayo-Smith and colleagues reviewed the evidence and made recommendations for the treatment of AWS.15 Agents with rapid onset (e.g., diazepam) control agitation more quickly (level II evidence). (See Table 1 for grades of recommendation and Table 4 for definition of levels of evidence ). Agents with longer duration of action (e.g., diazepam) may provide a smoother treatment course with fewer breakthrough symptoms. Agents with shorter duration of activity (e.g., lorazepam) may have a lower risk of prolonged sedation. These shorter-acting agents are more appropriate in patients at risk for over-sedation (e.g., the elderly and those with liver disease [level III evidence]). The cost of different benzodiazepines can vary considerably and may be a factor in the choice of agent. If symptoms are not controlled with large doses of benzodiazepines, Mayo-Smith and associates recommended the use of pentobarbital or propofol (grade C recommendation).
Table 1. Grades of Recommendation
Table 4. Levels of Evidence
There has been much controversy and debate in recent years over the most effective dosing regimen for the treatment of AWS with benzodiazepines or other agents. Most authors recommend using the CIWA-Ar assessment scale in deciding on a dosing regimen. In 1997, Mayo-Smith and colleagues14 reviewed the literature and recommended that whichever dosing regiment is used, the CIWA-Ar scale (or other assessment scale) is an appropriate method of determining the need for therapy. A CIWA-Ar score of 8-10 is considered mild, so supportive care may be all that is needed (level I evidence). A score of 8-15 is considered moderate withdrawal and should prompt the use of pharmacotherapy with benzodiazepines. Severe withdrawal occurs with a score greater than 15; these patients run the risk of major complications. They should be treated very aggressively with medication (level I evidence). In patients with a history of withdrawal seizures or co-morbid conditions, it is reasonable to provide one of the recommended medications at the time of presentation regardless of severity of withdrawal symptoms (level III evidence).
Two primary dosing regimens are discussed in the literature: fixed-dose regimen and symptom-triggered regimen. In a fixed-dose regimen, a patient is given a specific dose of medication at fixed intervals regardless of symptoms at the time; then further medication can be given for breakthrough symptoms between fixed doses. A symptom-triggered method is one in which a patient is assessed periodically using one of the assessment scales and given medication based on symptomatology. Only three prospective randomized controlled trials have studied the difference between fixed and symptom-triggered dosing regimens. In 1993, Manikin and associates studied chlordiazepoxide and concluded that both the total amount of medication used and the duration of treatment needed were less in the symptom-triggered group (100 vs 425 mg and 9 vs 68 hr).16 A second study in 1994 also concluded that symptom-triggered therapy used significantly less medication in total and significantly shortened the duration of treatment.17
In 2002, Daeppen and colleagues studied 117 patients in an alcohol abuse treatment program. They found that the symptom-triggered approach is safe, comfortable, and associated with a decrease in the quantity of medication used and the duration of treatment. The symptom-triggered group used an average of 37.5 mg of oxazepam versus 231.4 mg in the fixed group (P < 0.001). The duration of treatment was 20.0 hours in the symptom-triggered group and 62.7 hours in the fixed group (P < 0.001).18 In 2001, however, Jaegger and colleagues performed a retrospective analysis on symptom-triggered vs fixed dosing regimens and drew a somewhat different conclusion. Their review found that the evidence supported symptom-triggered dosing because it decreased the incidence of delirium tremens —especially in patients without a history of that condition— but it did not shorten the duration of treatment.19 Examples of symptom-triggered dosing regimens and fixed dosing regimens are presented in Tables 2 and 3, respectively.
Table 2. Example of Symptom-Triggered Dosing Regimen
Table 3. Example of Fixed-Schedule Dosing Regimen
Barbiturates
For alcohol withdrawal symptoms resistant to benzodiazepines, barbiturates are a good alternative. Barbiturates often are used by alcohol detoxification programs in the United States, but there are no controlled trials to support their use. However, several uncontrolled trials have studied their effectiveness.14 Barbiturates have a low abuse potential, they are long acting, and they can be administered in oral, intramuscular, or intravenous form. They do present an increased risk of respiratory depression. Phenobarbital is a long-acting barbiturate. An example of dosing is to start with a 260-mg bolus IV over 5 minutes and then repeat in 30 minutes at 130 mg over 3 minutes until the desired effect is achieved. Any hypotension associated with administration usually responds to fluid bolus. Pentobarbital is a shorter-acting barbiturate. It can be bloused IV at 3-5 mg/kg and then given as an infusion at 100 mg/hr. Very high doses of barbiturates never fail to ultimately control AWS because they directly open GABAa chloride channels. If given for longer than 24 hours, the pharmacokinetics of pentobarbital change, such that they have a longer duration of effect.6
If barbiturates are not sufficient to control AWS, propofol is another option. Propofol is rapid in onset and easily titratable, but it carries a high risk of respiratory depression. Most patients will need to be ventilated. Propofol appears to act as a GABA agonist and an NMDA receptor antagonist.6
Neuroleptic Agents
Neuroleptic agents have been used for decades to control the symptoms of AWS. However, several studies have shown that they are not only less effective than sedative-hypnotic agents but also more dangerous because they lower the seizure threshold. Yet, neuroleptic agents still are used occasionally by some clinicians in the acute treatment of AWS. They decrease the seizure threshold, impair heat regulation, and fail to correct the underlying neurologic cause of AWS.20,21,22,23 One study showed a mortality of 6% in patients treated with neuroleptic agents for alcohol withdrawal.24 In Mayo-Smith’s 2004 review, a meta-analysis of five controlled trials compared sedatives with neuroleptic agents. It revealed that sedative-hypnotic agents are more effective than neuroleptic agents in decreasing mortality associated with AWS. The relative risk of using Neuroleptic agents was 6.6 (95% CI, 1.2–34.7). A review of four controlled trials also showed that sedative-hypnotic agents are better than neuroleptic agents in reducing duration of delirium.15
Mayo-Smith’s 2004 review advises that neuroleptic agents are not recommended as sole agents in controlling AWS because they increase mortality, are associated with longer duration of delirium, and are associated with more complications (grade A recommendation). They may be used in conjunction with benzodiazepines in certain circumstances (e.g., persistent agitation or hallucinations).
Adjunctive Agents
Beta-adrenergic agents also have been used to control the hypertension and tachycardia associated with AWS. These agents decrease the autonomic manifestations of AWS but do not address the underlying derangements of the syndrome. No recent studies have shown whether they increase or decrease seizures during AWS, but some beta-blockers (e.g., propranolol) have been shown to produce delirium. There is no evidence that they improve outcome; they may worsen delirium (level V evidence).14 Beta-blockers may be used in conjunction with other agents in some circumstances for control of persistent hypertension or tachycardia (grade C recommendation).15 Most importantly, beta-blockers can mask the autonomic signs and symptoms of withdrawal, making it more difficult to assess the true need for emergent treatment.
Carbamazepine is used widely in Europe for the treatment of AWS. Several methodologically sound studies show it to be superior to placebo and equal in efficacy to barbital and oxazepam in mild to moderate AWS. Data comparing efficacy in treating seizures and delirium are very limited.14 Depakote also has been used. It has an antikindling effect, and it is a GABA enhancer. In one study, it significantly affected the course of alcohol withdrawal and reduced the need for treatment with benzodiazepines.25 Neither carbamazepine or valproic acid is recommended in the routine treatment of AWS.
Magnesium often is added to the emergency department (ED) regimen of medications given to any alcohol abuser. This practice comes from long-standing tradition and observation that the magnesium levels of patients who abuse alcohol are often low. However, the benefit of giving a one-time dose of magnesium to these patients is questionable. The one reported double blind, placebo-controlled randomized trial involving intramuscular administration of magnesium as a supplement to benzodiazepines showed no significant difference in severity of withdrawal signs and symptoms.26 Another study showed that magnesium levels in alcohol-dependent patients are usually normal on presentation, decrease during course of withdrawal, and spontaneously revert to normal again as symptoms subside.27 This is without any intervention to correct the hypomagnesemia. Therefore, there appears to be no role for the empiric administration of magnesium to the patient with AWS in the ED.
Ethanol
The administration of intravenous or oral ethanol for AWS has long been a controversial treatment option for physicians. It is quite controversial to give a patient the exact drug we advocate against in our practice. In some respects, however, it seems an obvious choice; no other agent perfectly reverses the symptoms of alcohol withdrawal. The literature on ethanol as treatment for AWS has great variation in quality of methodology and results, which makes a fair evaluation of its efficacy and safety very difficult.28 Three prospective studies have shown that intravenous ethanol was successful in preventing or reversing AWS.29,30,31 Two controlled trials, however, showed the opposite (i.e., that patients given alcohol therapy had progression of symptoms and that alcohol failed to prevent symptoms of AWS if they were not already present).32,33 A single randomized controlled trial showed no difference between ethanol and benzodiazepines in controlling AWS.34
In addition to lacking good evidence to support its use, ethanol is toxic to the liver, and administration requires very close monitoring. It also has toxic effects on the gastrointestinal, hematologic, and neurologic systems, making its use very unfavorable.
Phenytoin
Some patients who come to the ED because of injury, seizure, or alcohol withdrawal symptoms reveal during the history-taking that they have a prescription for Dilantin but have not taken the drug “for weeks.” Many of them do not know if the Dilantin is being used for control of seizures related to withdrawal from alcohol, epilepsy, or another condition (e.g., head trauma, metabolic derangement, or infection). The treating physician may find it difficult to ascertain the reason for the medication and then decide whether to renew the prescription.
In 1997, the American Society of Addiction Medicine published the following guidelines for the use of phenytoin in the treatment of seizures related to alcohol withdrawal:8
1. For patients with AWS and no history of seizures: Phenytoin is not recommended as routine prophylaxis against seizures (grade A recommendation).
2. For patients with AWS and a history of seizures not related to alcohol: Phenytoin or other anticonvulsants in addition to other sedative-hypnotic agents, is recommended (grade C recommendation).
3. For patients with AWS and a history of alcohol withdrawal seizure: Evidence is limited and conflicting, and expert opinion is mixed as to the benefit of adding phenytoin to adequate sedative-hypnotic medication. Therefore, sedative-hypnotic agents alone or in conjunction with phenytoin are both acceptable (grade C recommendation).
4. For patients with AWS and other possible causes of seizure disorder (e.g., head injury, focal brain lesion, meningitis, encephalitis, or a family history of seizures): There is no clear evidence in the literature and no clear consensus among experts as to the benefit of phenytoin. In this case, either sedative-hypnotic agents alone or in conjunction with phenytoin are acceptable (grade C recommendation).
5. Intravenous phenytoin is not recommended for patients with isolated, acute alcohol withdrawal seizure (grade A recommendation). Long-term prophylaxis with phenytoin, except when indicated for seizure disorder unrelated to alcohol, is not recommended (grade C recommendation).
In summary, phenytoin is recommended for use in patients with seizures unrelated to alcohol withdrawal. However, the important consideration in this situation is that very often the etiology of a patient’s seizures is unknown. This fact is especially true in the ED where we often see a patient for the first time, and the patient’s history is unknown. If the etiology of the seizure is unclear in the acute setting of AWS, it is recommended to first use sedative-hypnotic agents; then, it is acceptable to consider the addition of phenytoin if seizures are uncontrolled.
If in the ED setting it is possible to ascertain that a patient’s seizures are the result of alcohol withdrawal, only then is there no need for long-term prophylaxis with phenytoin. If the etiology is in question—as it is frequently—then, it is better to continue long-term prophylaxis with phenytoin until the etiology can be made clear.
Conclusion
The relationship between the cessation of excessive alcohol intake and AWS was established in the 1950s. Patients with this syndrome can present with a multitude of clinical characteristics: mild tremor, agitation, seizures, hallucinations, and cardiovascular collapse; and they can present with any combination of symptoms, making the diagnosis of AWS challenging.
The CIWA-Ar score is a useful tool in guiding treatment regimens. Benzodiazepines are the standard in treatment for all manifestation of AWS. The symptom-triggered method appears to be the most efficient and effective. Phenytoin, long used in the management of AWS, is not supported by the current literature for the treatment of acute AWS, including seizures. Prophylaxis with phenytoin also is not supported unless a patient suffers from non-alcohol-related seizure disorder. Adjunctive therapies, including beta-blockers and Neuroleptic Agents, are not safe to use as sole agents in AWS but may be useful in the treatment of persistent hypertension and hallucinations. The administration of ethanol has very limited support in the current literature, and its side effects are considerable.
Treatment must be instituted promptly once the syndrome is recognized. Early recognition is the key because appropriate treatment can be life-saving.
References
1. Isbell H, Frasier HF, Wikler A, et al. An experimental study of the etiology of “rum fits” and delirium tremens. QJ Study Alcohol 1955; 16:1.
2. Victor M, Adams RD. The effect of alcohol on the nervous system. Res Publ Assoc Res Nerv Ment Dis 1953; 32.
3. U.S. Department of Health and Human Services. 2003 National Survey on Drug Use and Health.
4 . Hodges B, Mazur J. Intravenous ethanol for the treatment of alcohol withdrawal syndrome in critically ill patients. Pharmacotherapy 2004; 24:1578-1585.
5. Calvin C, Wax PM. Withdrawal Syndromes. In: Ford MD, Delaney KA, Ling LG, Erikson T, eds. Clinical Toxicology. 1st ed. Philadelphia, Pa: W.B. Saunders Co; 2001:582-590.
6. Hamilton R. Substance Withdrawal. In: Goldfrank LR, Flomenbaum NE, Lewin NA, et al., eds. Toxicologic Emergencies. 7th ed. New York, N.Y.: McGraw-Hill; 2002:1059-1074.
7. Hamilton RJ. Drug Withdrawal syndromes. In: Viccellio P, Bania T, Brent J, et al., eds. Emergency Toxicology. 2nd ed. Philadelphia, Pa: Lippincott-Raven Publishers; 1998:947-956.
8. Kasser CC. ASAM Clinical Practice Guidelines. The role of phenytoin in the management of alcohol withdrawal syndrome. 1997. Online article. Available online at: www.asam.org/publ/dilantin.htm. Accessed March 17, 2005.
9. Ng SK, Hauser WA, Brust JC et al., Alcohol consumption and withdrawal in new-onset seizures. NEJM 1988;319:666-673.
10. Earnest MP, Yarnell PR. Seizure admission to a city hospital: The role of alcohol. Epilepsia 1976;17:387-399.
11. Deisenhammer E, Klingler D, Tragner H. Epileptic seizures in alcoholism and diagnostic value of EEG after sleep deprivation. Epilepsia 1984;25:526-530.
12. Sullivan JT, Sykora K, Schneiderman J, et al. Assessment of alcohol withdrawal: The revised Clinical Institute Assessment for Alcohol scale (CIWA-Ar). Br J Addiction 1989;84:1353-1357.
13. Foy A, March S, Drinkwater V. Use of an objective clinical scale in the assessment and management of alcohol withdrawal in a large general hospital. Alcoholism: Clin Exp Res 1988;12:360-364.
14. Mayo-Smith MF, Cushman P, Hill AJ, et al. Pharmacologic management of alcohol withdrawal: A meta-analysis and evidence-based practice guideline. JAMA 1997;278:1-24.
15. Mayo-Smith MF, Beecher LH, Fischer TL, et al. Management of alcohol withdrawal delirium: An evidence based practice guideline. JAMA 2004; 64:1405-1412.
16. Manikant S, Tripathi BM, Chawan BS. Loading dose diazepam therapy for alcohol withdrawal state. Indian J Med Res 1993;98: 170-173.
17. Saitz R, Mayo-Smith MF, et al. Individualized treatment for alcohol withdrawal: A randomized double-blinded controlled trial. JAMA 1994;272:519-523.
18. Daeppen JB, Gache P, Landry U, et al. Symptom-triggered vs. fixed-schedule doses of benzodiazepines for alcohol withdrawal. Arch Int Med 2002;162:1117-1121.
19. Jaegger TM, Lohr RH, Pankratz VS, et al. Symptom-triggered treatment for alcohol withdrawal syndrome in medical inpatients. Mayo Clinic Proceedings 2001;76:1275-1277.
20. Blum K, Eubanks JD, Wallace JE, et al. Enhancement of alcohol withdrawal convulsions in mice by haloperidol. Clin Toxicol 1976;9:427-434.
21. Greenblatt DJ, Gross PL, Harris J, et al. fatal hyperthermia following haloperidol therapy on sedative-hypnotic withdrawal. J Clin Psychiatry 1978;39:673-675.
22. Greenland P, Southwick WH. Hyperthermia associated with chlorpromazine and full sheet restraint. Am J Psychiatry 1978;135:1234-1235.
23. Uzbay IT, Akarsu ES, Kayaalp SO. Effects of bromocriptine and haloperidol on alcohol withdrawal syndrome in rats. Pharmacol Biochem Behav 1994;49:969-974.
24. Athen D. Comparative investigation of chlormethiazole and neuroleptic agents in the treatment of alcohol delirium. Acta Psychiatr Scand Suppl 1986;329:167-170.
25. Reoux JP, Saxon AJ, Malte CA. Divalproex sodium in alcohol withdrawal: A randomized double-blind placebo-controlled clinical trial. Alcohol Clin Exp Res 2001;25:1324-1329.
26. Wilson A, Vulcano B. A double blind, placebo-controlled trial of magnesium sulfate in the ethanol withdrawal syndrome. Alcoholism: Clin Exp Res 1984;8:542-545.
27. Ragland G. Electrolyte abnormalities in the alcoholic patient. Emerg Med Clinics N Am 1990;8:761-769.
28. Hodges B, Mazur J. Intravenous athanol for the treatment of alcohol withdrawal syndrome in critically ill patients. Pharmacotherapy 2004;24:1578-1585.
29. Craft PP, Foil MB, Cunningham PR, et al. Intravenous ethanol for alcohol detoxification in trauma patients. South Med J 1994;87: 47-54.
30. Hansborough JF, Zapata-Sirvent RL, Carroll WJ, et al. Administration of intravenous alcohol for prevention of withdrawal in alcoholic burn patients. Am J Surg 1984;148:266-269.
31. Wilkens L, Ruschulte H, Ruckoldt M, Et al. Standard calculation of ethanol elimination rate is not sufficient to provide ethanol substitution therapy in the postoperative course of alcohol-dependent patients. Intensive Care Med 1998;24:459-463.
32. Golbert TM, Sanz CJ, Rose HD, et al. Comparative evaluation of treatments of alcohol withdrawal syndrome. JAMA 1967;201: 99-102.
33. Eggers V, Tio J, Neumann T, et al. Blood alcohol concentration for monitoring ethanol treatment to prevent alcohol withdrawal in the intensive care unit. Intensive Care Med 2002;28:1475-1482.
34. Spies CD, Dubise N, Funk W, et al. Prophylaxis of alcohol withdrawal syndrome in alcohol dependent patients admitted to the ICU after tumour resection. Br J Anaesth 1995;75:734-739.
Once the diagnosis of alcohol withdrawal syndrome is confirmed, the treatment of the life-threatening sequelae must be swift. For many years, the pharmacologic agent of choice to treat AWS has been quite controversial. Benzodiazepines, antiepileptic agents, ethanol, and barbiturates have all been the preferred drug at one time or another. In recent years, benzodiazepines have come to the forefront as the drug class of choice, although some agents may offer advantages over others. Several guidelines have been developed to aid the emergency medicine practitioner select the most effective and efficient therapy. This review outlines, in systematic detail, the full range of AWS and risk-directed interventions shown to improve clinical outcomes in AWS.
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