480

THE ALCOHOLS: ETHANOL, ETHYLENE GLYCOL, METHANOL, AND ISOPROPYL ALCOHOL

CHAP

TER

69

Louis J. Ling, MD

1. Isapatientwithalteredmentalstatus,whosmellsofalcohol,simplyintoxicated?In most cases, yes. However intoxicated patients are at increased risk for injury, immunosuppression, poor nutrition, poor thermal regulation, and many medical conditions. Every patient assumed to be drunk (only) needs a thoughtful initial evaluation and subsequent serial evaluations.

2. Howshouldintoxicatedpatientsbeevaluated?Patients who arrive primarily with intoxication and without a history of trauma or injury should have vital signs taken; a rapid scan for recent trauma; a rapid glucose determination; and assessment for level of consciousness, responsiveness, and respiratory depression. Examination should include a look for unequal pupils, ecchymosis, deformity, and palpation everywhere for abdominal and bony tenderness. If no concerns are identified, it is important to return and reexamine the patient every hour or two to ensure that the patient is improving.

3. Whenshouldanacutelyintoxicatedpatientbeintubated?Hypopnea and hypoventilation are rarely the issue, but the inability of the patient to protect the airway is. For patients who are heavily intoxicated but not deemed to require intubation, lateral decubitus positioning is preferred. Restraining a patient supine or prone can be dangerous because of the risk of aspiration and airway compromise.

4. Whichmedicationsarebestformanagementofalcoholwithdrawal?Benzodiazepines, usually diazepam or lorazepam, can be given orally, intravenously, or in combination and titrated by clinical response. Patients with mild withdrawal (normal vital signs, no hallucinosis) may be discharged with a 2- to 3-day course of a single agent (e.g., lorazepam, 1–2 mg twice a day). Haloperidol is an appropriate adjunct for hallucinosis. Theoretical concerns over haloperidol lowering seizure threshold and exacerbating hemodynamic abnormalities have not been substantiated. More severe withdrawal syndromes require increasingly aggressive therapy with these same agents while under observation by medical personnel.

5. Whatisanappropriatework-upforalcoholwithdrawalseizures(AWDs)?Typically, AWDs occur approximately 6 to 96 hours after the last drink and in clusters of one to four seizures. The seizures are usually generalized and self-limited. Coincident features of withdrawal may be lacking, and lateralizing findings during the seizure, the postictal state, or both, are often present because of underlying structural pathology.

In a first-time evaluation, other causes of or contributors to seizures should be sought. Laboratory studies (i.e., electrolytes, glucose, magnesium, calcium, toxicologic screen) are rarely useful unless history or physical examination is suggestive. Noncontrast computed tomography (CT) shows traumatic, infectious, vascular, or other abnormalities in nearly 10% of patients Generally, electroencephalography is not integral to the work-up. Lumbar puncture is indicated when meningitis, meningoencephalitis, or subarachnoid hemorrhage is suspected.

Subsequent visits for suspected AWDs demand scrupulous history and physical examination to ensure that other pathologic causes have not developed in the interim. If the presentation

Chapter 69 THE ALCOHOLS: ETHANOL, ETHYLENE GLYCOL, METHANOL, AND ISOPROPYL ALCOHOL 481

matches prior episodes and the findings on current neurologic examination are baseline, no other work-up, including CT, is necessary. Lingering postictal confusion warrants a check of glucose and electrolytes. If the history or examination has changed significantly or is worrisome, the clinician should start from scratch.

6. HowshouldAWDsbemanaged?n Acute: As with all seizures, ensure a patent airway and administer 50% dextrose (D50) and

benzodiazepines intravenously (as needed). An observation period of 6 hours is optimal because recurrent seizures are common within this period. Benzodiazepines in the immediate and 2-day postseizure period decrease the incidence of additional seizures during this time.

n Chronic: Patients whose seizures have an epileptogenic focus (e.g., old subdural) should have an anticonvulsant, such as phenytoin, administered. However, compliance is typically poor. In the patient with pure AWDs, long-term anticonvulsant therapy is contraindicated. Physicians must resist the imperative to prescribe something unless there is clear justification.

7. CanAWDsbeprevented?Benzodiazepines in the acute withdrawal period, particularly in patients with a history of AWDs, can decrease seizures.

8. Whoisatriskforalcohol-inducedhypoglycemia(AIH)?Whatistheclinicalpresentation?AIH results from: a. Insufficient glycogen stores b. Alcohol-induced impairment of gluconeogenesis

The three groups vulnerable to AIH are: a. Chronic alcoholics b. Binge drinkers c. Young children

AIH may occur during intoxication or up to 20 hours after the last drink. Manifestations of neuroglycopenia (e.g., headache, depressed mental status, seizure, or coma) predominate. Evidence of catecholamine excess, typical of insulin-induced hypoglycemia (tremulousness, diaphoresis, anxiety), is unusual. Seizures are a frequent presentation in children. Localized central nervous system signs, including a stroke-like picture (alcohol-induced hypoglycemic hemiplegia), often occur in adults.

9. Whatcausesalcoholicketoacidosis(AKA)?This common metabolic disturbance occurs early after heavy binge drinking and is heralded by starvation and vomiting and occasionally shortness of breath (Kussmaul respirations) and abdominal pain. Ketoacidosis results from accumulation of acetoacetate and, particularly, b-hydroxybutyrate. Because the latter is not measurable on routine blood and urine tests, the patient may have trace or absent ketones at presentation. Similarly, as the patient improves and b-hydroxybutyrate is metabolized to acetoacetate, there may be a paradoxical spike in urine and serum ketones.

At presentation, serum pH and bicarbonate average 7.1 and 10, respectively. These values vary widely because of the frequently overlapping ketoacidosis (metabolic acidosis), withdrawal-related hyperventilation (respiratory alkalosis) and protracted emesis (metabolic alkalosis). When all three are coincident, the result is a triple acid-base disturbance. This allows you to interpret arterial blood gases and electrolytes pretty much any way you wish and be at least partially correct. Decreased body stores of potassium and phosphate are typical. In AKA, serum glucose is usually normal or low, a distinguishing feature from diabetic ketoacidosis.

Chapter 69 THE ALCOHOLS: ETHANOL, ETHYLENE GLYCOL, METHANOL, AND ISOPROPYL ALCOHOL482

10. HowshouldAKAbemanaged?Treatment consists of rehydration with dextrose-containing crystalloid, antiemetics if needed, benzodiazepines for withdrawal, and multivitamins, potassium, and phosphate as indicated. Bicarbonate is rarely required, and insulin therapy is proscribed. Metabolic abnormalities usually resolve with 12 to 16 hours of therapy.

11. Whatistherelationshipbetweenalcoholandmetabolicacidosis?n Ethanol: Acute ethanol ingestion results in a mild increase in the lactate-to-pyruvate ratio.

Clinically significant metabolic acidosis does not ensue.n AKA: This ethanol abstinence syndrome produces marked elevations in acetoacetate and

b-hydroxybutyrate with resultant and occasionally profound increased anion gap metabolic acidosis. During the correction phase, a non-anion gap, hyperchloremic picture often develops (because some of the bicarbonate-bound ketoacids are excreted in the urine) on the road to normalization.

n Ethylene glycol and methanol: Toxic metabolites of these compounds produce increased anion-gap metabolic acidosis. In the suspected alcoholic patient who presents with significant metabolic acidosis, a quick method of distinguishing the presence of ethylene glycol or methanol from AKA is the osmolal gap. If this exceeds 25 mOsm/Kg, it is 88% specific for the presence of ethylene glycol or methanol.

n Isopropyl alcohol: A significant portion of isopropyl alcohol is metabolized to acetone. This is a ketone but not a ketoacid, causing ketosis and ketonuria but not acidosis.

12. Howiscoagulationaffectedinachronicalcoholic?Bone marrow depression from ethanol, folate deficiency, and hypersplenism secondary to portal hypertension all cause thrombocytopenia. Platelet counts less than 30,000/mL, resulting from alcohol usage alone, are unlikely. Qualitative platelet defects also occur.

Hepatocyte loss from chronic alcohol abuse depletes all coagulation factors except VIII, particularly II, VII, IX, and X. Alcoholics often have inadequate vitamin K, a requisite cofactor for the production of factors II, VII, IX, and X because of hepatobiliary dysfunction and poor diet. When faced with gastrointestinal hemorrhage in a chronic alcoholic, an intravenous vitamin K supplementation trial is warranted. The far more likely culprit is hepatocellular destruction, however, for which vitamin K would not be helpful. Vitamin K does not begin to restore factor levels for 2 to 6 hours, so for emergent scenarios, fresh frozen plasma provides immediate factor supplementation.

13. Howshouldthecombativealcoholicpatientbemanaged?When the patient or staff is in jeopardy, the first step is physical restraint of the patient. A sufficient number of competent personnel and restraint devices are necessary. Closed head injury, hypoxia, or a full bladder may be the source of distress and should be excluded, managed, or relieved.

For chemical sedation, haloperidol (5–10 mg intravenous push) has rapid onset of sedation (5 minutes), but repeat doses may be required. This agent is not detrimental to airway patency, ventilation, or hemodynamics. There is a 5% to 10% incidence of extrapyramidal reactions, usually within 12 to 24 hours. Droperidol (2.5–5 mg intramuscularly) is another effective butyrophenone, but it received a black-box warning in 2004 due to reports of QT prolongation and torsades de pointes. In any case, haloperidol and droperidol have been shown to be relatively comparable in efficacy and side effects.

14. WhenisanintoxicatedpatientsafetodischargefromtheED?From a management perspective, there are two fundamental concerns:n Acute intoxication obfuscates the verification of certain diagnoses and the exclusion of

others.n A physician who discharges an acutely intoxicated (i.e., incompetent) patient may be

held accountable for the actions of that patient subsequent and proximate to discharge from the ED.

Chapter 69 THE ALCOHOLS: ETHANOL, ETHYLENE GLYCOL, METHANOL, AND ISOPROPYL ALCOHOL 483

The degree of clinical intoxication at a specific serum alcohol level is variable in accordance with the patient’s chronicity and severity of drinking. A veteran drinker with a level in excess of 500 mg/dL can look less drunk than a teenager at 100 mg/dL. Documentation of the discharge examination includes mental status, gait, and the fact that the patient is clinically sober. Particular attention should be paid to potential abdominal or closed head trauma. The patient should be discharged to an appropriate environment. Serum or breath alcohol determinations sometimes can be helpful at the outset of care but unneeded at discharge.

KEY POINTS: ALCOHOL-RELATED DISORDERS

1. Airway protection: Clinical judgment is the key factor in determining whether an acutely intoxicated patient requires intubation for airway protection.

2. Phenytoin should only be given to patients with clear indication of an epileptogenic focus. Otherwise, its use for prevention of alcohol withdrawal seizures is strictly proscribed.

3. Discharge documentation: The critical determination in the discharge of the patient is the progression to and documentation of clinically sober.

15. Mustthiaminebeadministeredbeforeglucoseinthealcoholicpatient?Wernicke-Korsakoff syndrome develops over hours to days. The precipitous initiation of Wernicke-Korsakoff syndrome by dextrose has not been substantiated. The consequences of neuroglycopenia begin within 30 minutes and are easily prevented. In alcoholic patients with known or suspected hypoglycemia, promptly administer glucose and deliver thiamine empirically as soon afterward as possible. Because magnesium is a cofactor of thiamine and because alcoholics are frequently hypomagnesemic, 2 g of IV magnesium should be administered when there is suspicion of Wernicke-Korsakoff syndrome.

16. Isitdangeroustoadministerthiamineintravenously?Orally administered thiamine is often absorbed poorly in the alcoholic patient. The intramuscular route is painful and can result in hematomas or abscesses, particularly in patients with impaired coagulation status. The experience with intravenous thiamine is extensive. Thiamine may be given as part of fluid hydration with multivitamin preparations or by bolus infusion.

17. Isthereacureforahangover?Probably not, at least not one with solid scientific credentials. There is no shortage of remedies, however, from the well-worn “hair of the dog that bit you” (i.e., start drinking again) to a more recently acclaimed concoction of vitamin B6, nonsteroidal anti-inflammatories, and hydration. The only sure-fire measure is the avoidance of drinking in the first place.

18. AretherespecificcriteriaforthediagnosisofWernicke-Korsakoffsyndrome?Criteria require two of the following four signs to be present: a. Dietary deficiencies b. Oculomotor abnormalities c. Cerebellar dysfunction d. Either an altered mental state or mild memory impairment.

19. Whyisitimportanttounderstandthemetabolismofmethanol?The metabolites of methanol are the toxins and depend on alcohol dehydrogenase (ADH) for their conversion from the non-toxic parent methanol. Ethanol and fomepizole both saturate ADH and greatly slow the metabolism of methanol to the toxic metabolite. Folate is a cofactor in the breakdown of formic acid, and in monkeys (and other primates) folate supplementation

Chapter 69 THE ALCOHOLS: ETHANOL, ETHYLENE GLYCOL, METHANOL, AND ISOPROPYL ALCOHOL484

maximizes its metabolism and decreases injury. Knowledge of the metabolism directs the treatment.

ADH Folate Methanol →Formaldehyde →Formic Acid → CO2 1 H2O

(toxic) (toxic) (nontoxic)

20. Listthesignsandsymptomsofmethanolpoisoning.

Gastrointestinal toxicityn Nausea and vomitingn Abdominal painCentral nervous system toxicityn Headachen Decreased level of consciousnessn ConfusionOcular toxicityn Retinal edeman Hyperemia of the discn Decreased visual acuityOther toxicityn Metabolic acidosis

KEY POINTS: METHANOL

1. Symptoms and acidosis are delayed.

2. Osmolal gap is often absent.

3. Persistent acidosis correlates with a poor prognosis.

4. Fomepizole, ethanol, and dialysis can all be used to treat the poisoned patient.

21. Whyisitimportanttounderstandthemetabolismofethyleneglycol?As with methanol, ethanol and fomepizole saturate ADH, inhibiting conversion of ethylene glycol into its harmful metabolites. Pyridoxine (vitamin B6) and thiamine are cofactors in the final steps to form nonharmful end products and should be given to ensure maximal metabolism. Oxalate crystals may not appear until late in the course of the poisoning (Fig. 69-1).

22. Whyarethesymptomsofethyleneglycolandmethanoloverdoseoftendelayed?It may take 6 to 12 hours for sufficient quantities of the toxic metabolites to accumulate and cause symptoms. The delay in symptoms is even greater with concurrent ethanol intoxication because the ethanol slows down the rate of methanol and ethylene glycol metabolism and delays the appearance of the toxic metabolites.

KEY POINTS: ETHYLENE GLYCOL

1. Symptoms and acidosis are often delayed.

2. Urinary oxalate crystals, fluorescence, early osmolal gap, and metabolic acidosis all suggest ethylene glycol poisoning.

3. Fomepizole, ethanol, and dialysis can all be used to treat the poisoned patient.

Chapter 69 THE ALCOHOLS: ETHANOL, ETHYLENE GLYCOL, METHANOL, AND ISOPROPYL ALCOHOL 485

23. Howaremethanolandethyleneglycolpoisoningssimilar?Methanol and ethylene glycol are metabolized initially by ADH. Methanol is metabolized further to formic acid, and ethylene glycol is metabolized to glycolic acid, glyoxylic acid, oxalate, and several nontoxic metabolites. Because of these end products, both poisons result in metabolic acidosis with an anion gap. Because of their low molecular weight, both increase the osmolar gap.

24. Whatisananiongap?A normal anion gap is the difference between measured and unmeasured anions (e.g., various proteins, organic acids, phosphates) and measured and unmeasured cations (e.g., potassium, calcium, and magnesium). The anion gap can be calculated from the formula:

Anion gap 5 (Na1) 2 (HCO32 1 Cl2)

25. Whatcausesanincreasedaniongap?When metabolic acidosis results from an ingestion of nonvolatile acids, there are increased hydrogen ions with positive charges. Because there is an equal increase in unmeasured negatively charged anions but no increase in chloride, the difference between the measured cations and measured anions is increased, causing an increased anion gap. The normal anion gap is about 6 to 10 mEq/L. The causes of increased anion gap can be remembered by the mnemonic AMUDPILES.

A 5 Alcohol, M 5 Methanol, U 5 Uremia, D 5 Diabetic ketoacidosis, P 5 Paraldehyde, I 5 Iron, Isoniazid (INH), L 5 Lactate, E 5 Ethylene glycol, S 5 Salicylate

26. Whatisanosmolalgap?Small atoms and molecules in solution are osmotically active, and this activity can be measured by a depression in the freezing point or an elevation in the boiling point of the solution. If there is an increase in low-molecular-weight molecules, such as acetone, methanol, ethanol, mannitol, isopropyl alcohol, or ethylene glycol, the osmolality is greater than what is calculated from the usual serum molecules. The difference between the actual measured osmolality and the calculated osmolality is the osmolal gap, and a gap greater than about 10 mOsm is considered abnormal.

Figure 69-1. Metabolism of methanol and ethylene glycol.

Chapter 69 THE ALCOHOLS: ETHANOL, ETHYLENE GLYCOL, METHANOL, AND ISOPROPYL ALCOHOL486

27. Howisanosmolalgapcalculated?One formula is 2 3 Na1 (mEq/L) 1 glucose (mg/dL)/18 1 blood urea nitrogen (BUN) (mg/dL)/2.8 1 ethanol (mg/dL)/4.3. The inclusion of the ethanol level excludes patients who have an elevated osmolal gap from ethanol ingestion alone. Using International System (SI) units, the calculated osmolality 5 2 3 Na (mEq/L) 1 glucose (mmol/L) 1 BUN (mmol/L) 1 ethanol (mmol/L). The calculated osmolality is 285 6 5 mOsm/L. A toxic ethylene glycol level of 25 mg/dL can be predicted to increase the osmolal gap 5 mOsm/L. Because of the small effects on the osmolality and the imprecision of the measurement, this test is not precise enough to be definitive so a normal osmolal gap does not exclude toxic levels of methanol or ethylene glycol. The laboratory must use the method of freezing-point depression so that volatile alcohols contributing to an osmolal gap are not boiled away during a boiling point elevation procedure.

28. Whatcomesfirst,theaniongaportheosmolalgap?With initial absorption, the small parent molecules cause an early osmolal gap, but with metabolism, acidic metabolites are formed causing a late metabolic anion-gap acidosis.

29. Howtoxicaremethanolandethyleneglycol?Death is reported after 15 to 30 mL (1–2 tablespoons) of methanol. Others have survived larger ingestions, however. A minimal lethal dose for ethylene glycol is approximately 1–2 mL/kg.

30. Whatisthetoxicityofethyleneglycol?Initially, there is central nervous system intoxication and gastrointestinal irritation, followed by metabolic acidosis. Renal failure occurs frequently and typically is delayed in presentation. Cranial nerve deficits are a rare complication.

31. Whyisethyleneglycolsodangeroustoanimals?Ethylene glycol is a frequent cause of death in animals who ingest antifreeze (especially dogs, who drink almost anything). The taste is sweet and a small volume is deadly. The cause of death for these animals may not be apparent because toxicity is delayed, and death occurs long after the animal has left the scene.

32. Whydoesantifreezehavesuchabrightcolor?Antifreeze is a bright color that fluoresces with ultraviolet (UV) light so that leaks from auto radiators can be detected more easily. If the mouth and the urine are examined with a UV light, fluorescein can be detected in about 30% of patients after ingestion. A positive test should encourage immediate treatment, but a negative test misses two thirds of ingestions.

33. Howshouldpatientswithmethanolandethyleneglycolpoisoningbetreated?Airway protection is paramount in patients with decreased level of consciousness or respiratory depression. Small volumes and rapid absorption limit the effectiveness of gastric lavage and charcoal. Acidosis (pH ,7.2) should be treated aggressively with sodium bicarbonate. Ethanol and 4-methylpyrazole (4-MP) are antidotes that competitively block the conversion of methanol and ethylene glycol to their toxic metabolites, allowing for elimination of the unchanged poison without injury.

34. Whataretheindicationsforethanolor4-MPtherapy?They should be used if ethylene glycol or methanol levels exceed 20 mg/dL; if acidosis is present, regardless of drug level; and if there is a history of a toxic ingestion while awaiting confirmatory blood methanol or ethylene glycol levels.

Chapter 69 THE ALCOHOLS: ETHANOL, ETHYLENE GLYCOL, METHANOL, AND ISOPROPYL ALCOHOL 487

35. Howdoyouchoosebetweenfomepizole(4-MP)andethanol?Ethanol is difficult to give consistently; ethanol blood levels are required to adjust the dose and infusion can cause pain, resulting in the use of a central catheter. Ethanol may cause hypoglycemia and respiratory depression, especially in children. These patients usually require the close monitoring of an intensive care unit (ICU). 4-MP is replacing ethanol because it does not cause sedation, does not require blood testing, is easily given as a bolus, and does not require ICU management.

36. Howdoyouuse4-MP?The dose is 15 mg/kg every 12 hours and is increased to every 4 hours during dialysis. Typical treatment is for 48 hours.

37. Whataretheindicationsforhemodialysis?Dialysis used to be the primary treatment for these poisons and should be done in patients with blood levels greater than 50 mg/dL, when the metabolic acidosis is not correctable, with pending renal failure, or with visual symptoms in a methanol overdose. Many clinicians recommend dialysis when blood levels exceed 25 mg/dL, if dialysis is readily available. Hemodialysis can be avoided with prolonged fomepizole treatment.

38. Whatifdialysisisunavailable?Patients with ethylene glycol poisoning can be treated successfully with 4-MP alone without dialysis if there is no acidosis or renal failure. Because the half-life of ethylene glycol is prolonged to 17 hours, the treatment may be extended but avoids invasive treatment of dialysis. In methanol poisoning, 4-MP slows the metabolism and increases the half-life of methanol to 30-52 hours. The use of 4-MP alone would not suffice for these patients.

39. Howisisopropylalcoholpoisoningdifferentfrommethanolandethyleneglycolpoisoning?Isopropyl or rubbing alcohol is metabolized in the liver to acetone, which results in measurable ketonemia in the serum. Acetone is excreted by the kidney, resulting in ketonuria, and is exhaled through the lungs, giving patients an acetone aroma on their breath. Because these metabolites are not acidic, isopropyl alcohol poisoning does not result in metabolic acidosis and is far less toxic than either methanol or ethylene glycol.

40. Whatarethesymptomsofisopropylalcoholingestion?Isopropyl alcohol has a three-carbon chain rather than the two-carbon chain of ethanol. Because of this, it crosses the blood-brain barrier faster and is about twice as intoxicating as ethanol. Because it is commonly found in concentrated solutions and is more potent, the central nervous system depression can occur rapidly and can continue from residual poison in the stomach. Isopropyl alcohol is much more irritating than ethanol to the gastric mucosa and often causes abdominal pain, vomiting, and hematemesis.

41. Whyisisopropanolsofrequentlyabused?Isopropanol is easy and legal to obtain; rubbing alcohol is 70% isopropanol. Unlike consumable beer, wine, and liquor, it is not taxed and is very inexpensive.

42. Whattreatmentisadvisableforisopropylalcoholpoisoning?Patients need observation to watch for respiratory depression similar to patients intoxicated with ethanol. An isopropyl alcohol level is roughly equivalent to an ethanol level twice as high. An isopropyl level usually does not add greatly to clinical observation. In the rare instance of coma or hypertension corresponding to isopropyl levels greater than 500 mg/dL, intubation and ventilation may be necessary, and hemodialysis can greatly enhance removal of isopropyl alcohol from the body. An antidote is not available for isopropyl alcohol (nor is one needed).

Chapter 69 THE ALCOHOLS: ETHANOL, ETHYLENE GLYCOL, METHANOL, AND ISOPROPYL ALCOHOL488

KEY POINTS: ISOPROPANOL

1. Symptoms and toxicity are completely different from methanol and ethylene glycol.

2. Ketosis occurs, but acidosis does not.

3. Supportive treatment is adequate in almost all cases.

BIBLIOGRAPHY

1. Caravati EM, Erdman AR, Christianson G, et al: Ethylene glycol exposure: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol 43(5):327–245, 2005.

2. D’Onofrio G, Rathlev NK, Ulrich AS, et al: Lorazepam for the prevention of recurrent seizures related to alcohol. N Engl J Med 341:609–610, 1999.

3. Glaser DS: Utility of the serum osmol gap in the diagnosis of methanol or ethylene glycol ingestion. Ann Emerg Med 27:343–346, 1996.

4. Hovda KE, Andersson KS, Urdal P, et al:. Methanol and formate kinetics during treatment with fomepizole. Clin Toxicol 43(4):221–227, 2005.

5. Mayo-Smith MF: Pharmacological management of alcohol withdrawal: a meta-analysis and evidence-based practice guideline. JAMA 278:144–151, 1997.

6. McDonald AJ, 3rd, Wang N, Camargo CA, Jr: US emergency department visits for alcohol-related diseases and injuries between 1992. and 2000. Arch Intern Med 164:531, 2004.

7. Paasma R, Hovda KE, Tikkerberi A, et al:. Methanol mass poisoning in Estonia: outbreak in 154 patients. Clin Toxicol 45(2):152–157, 2007.

8. Rathlev NK, Ulrich A, Shieh TC, et al: Etiology and weekly occurrence of alcohol-related seizures. Acad Emerg Med 9:824, 2002.

9. Shale JH, Shale CM, Mastin WD: A review of the safety and efficacy of droperidol for the rapid sedation of severely agitated and violent patients. J Clin Psychiatry 64:500, 2003.

10. Wiese JG, Shlipak MG, Browner WS: The alcohol hangover. Ann Intern Med 132:897–902, 2000.

ACKNOWLEDGMENT

The editors gratefully acknowledge the contributions of John A. Marx, MD, author of this chapter in the previous edition.