eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Beta-blocker

Adhi Sharma, MD, Assistant Professor, Department of Emergency Medicine, Mount Sinai School of Medicine; Chairman, Department of Emergency Medicine, Good Samaritan Hospital Medical Center; Medical Toxicology Consultant, New York City Department of Health and Poison Control Center
Lemeneh Tefera, MD, FAAEM, Attending Physician, Department of Emergency Medicine, Beth Israel Medical Center; Aman Aminzay, MD, Resident, Department of Emergency Medicine, Beth Israel Medical Center, Albert Einstein College of Medicine

Updated: Apr 21, 2009

Introduction

Background

Beta-adrenergic antagonists (ie, beta-blockers) have been in use for nearly 50 years. In addition to their traditional role in treating hypertension and other cardiovascular disorders, beta-blockers are also used for additional purposes such as migraine headaches, hyperthyroidism, glaucoma, anxiety, and various other disorders. As a result of their expanded use, the incidence of overdose with these agents has also increased.

A 48-year-old man presents to the ED after a generalized tonic-clonic seizure. He is noted to be hypotensive (82/55) and bradycardiac (see rhythm strip). The family reports that he is taking a medication for a rapid heart rate. Propranolol is the most common beta-blocker involved in severe beta-blocker poisoning. It is nonselective and has membrane-stabilizing effects that are responsible for CNS depression, seizures, and prolongation of the QRS complex.

Sotalol is associated with the rhythm shown below in both therapeutic doses and toxic ingestions. Sotalol has been used as a class III antiarrhythmic agent to control dangerous ventricular tachydysrhythmias in some individuals. It causes polymorphic ventricular tachycardia (torsade de pointes) in approximately 4% of patients. Rarely, prolongation of the QT interval has been reported with propranolol.

Pathophysiology

Understanding the direct and indirect effects of beta-receptor blockade is crucial to rapid identification and appropriate treatment of beta-blocker toxicity. Beta-blockers act as competitive inhibitors of catecholamines, exerting their effects at both central and peripheral receptors. Blockade of beta-receptors results in decreased production of intracellular cyclic adenosine monophosphate (cAMP) with a resultant blunting of multiple metabolic and cardiovascular effects of circulating catecholamines. Beta1-blockers reduce heart rate, blood pressure, myocardial contractility, and myocardial oxygen consumption. Beta2-receptor blockade inhibits relaxation of smooth muscle in blood vessels, bronchi, the gastrointestinal system, and the genitourinary tract. In addition, beta-adrenergic receptor antagonism inhibits both glycogenolysis and gluconeogenesis, which may result in hypoglycemia.

Other than the direct effects of the beta-adrenoreceptor blockade, toxicity may result from other mechanisms including sodium and calcium channel blockade, centrally mediated cardiac depression, and alteration of cardiac myocyte energy metabolism.

Pharmacology

Numerous brands of beta-blockers are available; they comprise a heterogeneous drug family with toxicologic characteristics that vary between classes. An understanding of the different characteristics of each class is helpful for understanding the various clinical presentations and for guiding therapy.

Nonselective beta-blockers

Propranolol was the first beta-blocker with widespread use; much of the clinical and overdose experience that exists with beta-blockers was provided by case reports and clinical studies of this drug. Propranolol is a nonselective beta-blocker, demonstrating equal affinity for both beta1- and beta2-receptors. Other nonselective beta-blockers include nadolol, timolol, and pindolol. Nonselective beta-blockers exert a wider variety of extracardiac manifestations.

Intrinsic sympathomimetic activity

Some beta-blockers, such as pindolol and acebutolol, also have beta-agonist properties. Although their agonist property is weaker than that of catecholamines, they are capable of stimulating beta-receptors, especially when catecholamine levels are low. Of note, acebutolol has been reported to be particularly lethal in overdose.

Membrane-stabilizing activity

Beta-blockers, such as propranolol, labetalol, and pindolol, can have membrane-stabilizing activity (MSA) (eg, the quinidine-like effects of the class IA antidysrhythmic effects). MSA blocks myocyte sodium channels. This property, usually not evident at therapeutic doses, may significantly contribute to toxicity by prolonging QRS duration and impairing cardiac conduction. Seizures are more commonly observed in drugs with MSA. Beta-blockers with MSA are associated with the largest proportion of fatalities.

Lipid solubility

Lipid solubility is higher in agents such as propranolol and carvedilol but lower in agents such as atenolol and nadolol. It may influence the degree of central nervous system (CNS) effects and utility of hemodialysis or hemoperfusion. High lipid solubility leads to a larger volume of distribution and better CNS penetration. Lipophilic beta-blockers are primarily metabolized by the liver. Propanolol is among these, and its active metabolite (4-OH propranolol) prolongs its biological activity. Conversely, hydrophilic beta-blockers have a small volume of distribution and are eliminated essentially unchanged by the kidneys; this property allows hydrophilic beta-blockers to be removed by hemodialysis.

QT-interval prolongation

The electrophysiologic effects of sotalol deserve special consideration. Unlike other beta-blockers, sotalol has antidysrhythmic properties consistent with the type III antidysrhythmic agents. Class III agents prolong the action potential duration and the effective refractory period of AV and atrioventricular myocytes, which can lengthen the QT-interval duration and result in polymorphic ventricular tachycardia (ie, torsade de pointes). Toxicity with sotalol has been reported to result in ventricular dysrhythmias for as long as 2 days postingestion.

Frequency

United States

The 2007 Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System reported 9291 single exposures to beta-blockers.¹   

International

Propranolol is the most toxic beta-blocker and the most frequently used in suicide attempts worldwide.

Mortality/Morbidity

In 2007, the AAPCC reported 413 minor outcomes, 631 moderate outcomes, 61 major outcomes, and 3 fatalities for beta-blocker exposure.¹

Beta-blocker type: Beta-blockers that are lipid soluble and have marked antidysrhythmic (ie, quinidine-like) effects are more lethal (eg, propranolol, sotalol, oxprenolol).

Co-ingestions and state of health: The outcome is significantly worse when these agents are co-ingested with psychotropic or cardioactive drugs. This is true even if the amount of beta-blocker ingested is relatively small. The co-ingestants that most markedly worsen prognosis include calcium channel blockers, cyclic antidepressants, and neuroleptics. These co-ingestions are the most important factor associated with the development of cardiovascular morbidity and mortality. After co-ingestions, the next most significant factor associated with major morbidity and mortality is exposure to a beta-blocker with membrane-stabilizing activity.

Sex

According to the 2004 AAPCC toxic exposure review, 51% of all exposures and 47.6% of all overdose fatalities are in women.²

Age

Of the fatalities reported to the AAPCC, 68% were associated with individuals younger than 50 years. Forty-three percent of all fatalities reported to the AAPCC in 2004 were associated with children younger than 6 years.²

Clinical

History

• Determining the specific type of beta-blocker, quantity, and time of the overdose is ideal. Unfortunately, these details are often not immediately available.
• Information regarding the patient's underlying medical condition may be a clinical clue to the possibility of an overdose.

Physical

The initial evaluation of a comatose patient should include consideration of an occult overdose. If a patient is bradycardic and hypotensive, the clinician should consider a beta-blocker or calcium blocker overdose. Other associated symptoms may include hypothermia, hypoglycemia, and seizures. Myocardial conduction delays with decreased contractility typify the acute beta-blocker ingestion.

• Cardiac output may diminish with resulting hypotension from bradycardia and negative inotropy. Hypotension due to the beta2-receptor blockade can be profound and jeopardize myocardial perfusion, creating a downward spiral of events.
• Beta-blockers that are not sustained-release formulations are all rapidly absorbed from the gastrointestinal tract.
• The first critical signs of overdose can appear 20 minutes postingestion but are more commonly observed within 1-2 hours.
• All clinically significant beta-blocker overdoses develop symptoms within 6 hours.
• Although the half-life of these compounds is usually short (2-12 h), half-lives in the overdose patient may be prolonged because of a depressed cardiac output, reduced blood flow to the liver and kidneys, or because of the formation of active metabolites.
• Saturation kinetics prolong elimination at the type of high plasma concentrations that typically occur with overdose. Delayed absorption from long-acting preparations can significantly increase the apparent elimination half-life. Thus, prolonged effects (>72 h) after massive overdoses are not uncommon.
• Asymptomatic intoxication occurs mainly in healthy persons with tolerance to these drugs who ingest beta-blockers lacking membrane-stabilizing effects or having a partial agonist effect (eg, pindolol). Individual sensitivity to beta-blockade may be significantly reduced in those patients who have tolerated therapeutic doses of up to 4 g of propranolol daily and in patients who have sustained deliberate overdoses of both practolol and propranolol without serious adverse effects.
• Conversely, circulatory collapse may occur in patients with preexisting cardiac failure when sympathetic drive is inhibited by even a small dose of a particular beta-blocker.
• Intermediate toxicity results in a moderate drop in blood pressure (systolic BP >80 mm Hg) and/or bradycardia (heart rate <60 BPM).
• Bradycardia with associated hypotension and shock (systolic BP <80 mm Hg, heart rate <60 BPM) defines severe beta-blocker toxicity. Patients with severe toxicity often manifest extracardiac manifestations of intoxication.
  • Bradycardia, by itself, is not necessarily helpful as a warning sign because slowing of the heart rate and damping of tachycardia in response to stress is observed at therapeutic doses.
  • Although case reports have documented hypotension in the absence of bradycardia, blood pressure usually does not fall before the onset of bradycardia.
  • Bradycardia may be isolated or accompanied by mild conduction disturbances.
• A depressed level of consciousness and seizures may occur as a result of cellular hypoxia from poor cardiac output, a direct CNS effect caused by sodium channel blocking, or even as a result of hypoglycemia. The lipid-soluble agents have increased distribution into the brain, and these agents are associated with severe CNS toxicity.
  • Patients who have taken lipid-soluble beta-blockers, such as propranolol, frequently present with seizures after an overdose.
  • Seizures are generalized and may be multiple but are usually brief, lasting seconds to minutes. Seizures occasionally have been reported after therapeutic use of esmolol and with overdose of alprenolol, metoprolol, and oxprenolol. Seizures are far more common after propranolol overdose.
• Coma may be prolonged, depending on the half-life of the agent involved and the coexisting morbidity.
• Severe memory impairment developed in an 81-year-old woman taking propranolol 20 mg 3 times per day. Effects were associated with an elevated propranolol blood level (163 mcg/L) and resolved after discontinuation of the drug.
• Bronchospasm is a rare complication of beta-blocker therapy or overdose but is more likely in patients who already have bronchospastic disease. Sudden fatality following administration of therapeutic doses of beta-blocker has been reported in 4 patients with asthma. Pulmonary edema had been reported to occur as a result of cardiac failure. Respiratory arrest has also been described with beta-blocker intoxication, especially with propranolol, and is thought to be secondary to a central drug effect.
• Hypoglycemia is relatively uncommon but described in patients with unstable diabetes and in children. Beta-blocking drugs may cause hypoglycemia by inhibiting glycogenolysis.

Causes

• Beta-blocker toxicity in children usually results from exposure to an adult's unattended medications.
• Beta-blocker toxicity in adults usually results from a suicide attempt or an accidental overdose of a routine medication.

Differential Diagnoses

Workup

Laboratory Studies

• A bedside glucose (fingerstick) test should be performed. Beta-blockers may be associated with hypoglycemia, especially in patients with diabetes and in children.
• Hypokalemia may contribute to cardiac arrhythmias.
• Acidosis from poor cardiac perfusion may be manifested by low serum bicarbonate.
• Co-ingestions or concomitant medical conditions may alter other serum electrolytes so these should be monitored closely, especially in patients with seizures or altered mental status.
• Measure cardiac enzymes to rule out myocardial infarction in any hemodynamically unstable patient.
• No studies have been performed to correlate the serum beta-blocker concentration with the outcome of beta-blocker overdose.
• Blood gases (arterial or venous) analysis may be helpful for managing metabolic acidosis from seizures or cardiogenic shock or rare cases of severe bronchospasm, respiratory acidosis, or hypoxia.

Imaging Studies

• In a severe overdose that impairs myocardial contraction, chest radiographs may show evidence of pulmonary edema.

Other Tests

• Electrocardiography
  • ECG results after beta-blocker overdose may include progressively worsening sinus bradycardia, increased PR intervals, loss of atrial activity, atrioventricular junctional rhythm, widening of the QRS complex, atrioventricular block, idioventricular rhythm, and asystole.
  • A prolonged QT interval has been observed after sotalol overdose.
  • Ventricular fibrillation and ventricular tachycardia are uncommon because of the antidysrhythmic effects of most beta-blockers, with the exception of sotalol.

Treatment

Prehospital Care

• Follow standard protocols for bradycardia, hypotension, and seizures. Cardiac monitoring, oxygen administration, and reliable intravenous access are essential.
• Activated charcoal
  • No benefit has been shown for prehospital administration of charcoal; the decision to administer activated charcoal should be made in the ED.
  • Ipecac syrup is contraindicated.

Emergency Department Care

The goal of therapy in beta-blocker toxicity is to restore perfusion to critical organ systems by increasing cardiac output. This may be accomplished by improving myocardial contractility, increasing heart rate, or both. 

• Crystalloid: If hypotensive, administer 20 mL/kg of isotonic intravenous fluids and place the patient in the Trendelenburg position. If the patient is unresponsive to these measures, administer pharmacologic therapies as discussed in the following section.
• The pharmacotherapy of beta-blocker overdose may include a variety of inotropes and chronotropes, such as epinephrine and atropine, for hypotension and bradycardia. These are discussed below in more detail. Please note that the doses of these agents should be titrated to response so that a patient with beta-blocker overdose may require higher doses of these agents than those noted in ACLS protocols. Consultation with a toxicologist can help guide these decisions.
• Glucagon: Because a glucagon bolus can be diagnostic and therapeutic, the clinician can empirically administer glucagon and check for a response.
• Gastric decontamination: Gastric lavage, with appropriate protection of the airway, is preferred over emesis because of the rapid absorption and occasionally precipitous onset of toxicity that may place the patient at risk for aspiration. Gastric lavage may be beneficial if the patient presents to the ED within 1-2 hours of ingestion. Volunteer studies have indicated that multiple dose activated charcoal (MDAC) may be useful in reducing bioavailability of nadolol, probably by removal of the drug through the enterohepatic circulation.
• Benzodiazepines are the drugs of choice if seizures occur.
• Enhanced elimination: Hemodialysis may be useful in severe cases of atenolol overdoses because atenolol is less than 5% protein bound and 40-50% is excreted unchanged in urine. Nadolol, sotalol, and atenolol (low lipid solubility, low protein binding) reportedly are removed by hemodialysis. Acebutolol is dialyzable. Propranolol, metoprolol, and timolol are not removed by hemodialysis. Consider hemodialysis or hemoperfusion only when treatment with glucagon and other pharmacotherapy fails.
• Cardiac pacing/cardiopulmonary resuscitation: Cardiac pacing may be effective in increasing the rate of myocardial contraction. Electrical capture is not always successful and, if capture does occur, blood pressure is not always restored.
  • Reserve cardiac pacing for patients unresponsive to pharmacologic therapy or for those with torsade de pointes unresponsive to magnesium. Multiple case reports describe complete neurologic recovery, even with profound hypotension, if a cardiac rhythm can be sustained.
  • Resuscitation should, therefore, be aggressive and prolonged. Some have postulated the possibility of a protective effect on the CNS from the membrane-stabilizing effects of drugs such as propranolol.
• Insulin: In case reports and animal models, high-dose insulin infusion (in combination with glucose administration to maintain serum glucose levels) has been reported to improve outcomes. The mechanism of action is via the positive inotropic effects of insulin. After consultation with a medical toxicologist, this treatment should be considered for overdoses that are refractory to crystalloids, glucagon, and catecholamine infusions. Of note, because of the risk of iatrogenic hypoglycemia and hypokalemia, the clinician must be particularly vigilant in monitoring these patients' serum glucose and potassium levels.

Consultations

• Regional poison control center and/or a medical toxicologist
• Critical care consultation to assist in the management and subsequent admission
• Nephrologist, in rare instances when hemodialysis may be necessary
• Psychiatric consultation for any patients who report self-harm or where self-harm is suspected

Medication

Because of the nature of overdoses, definitive evidence-based recommendations are limited. However, commonly used agents include crystalloids, atropine, pressors with catecholamine action, glucagon, and phosphodiesterase inhibitors.

GI decontaminant

These agents are used to minimize the absorption of ingested compound.

Activated charcoal (Liqui-Char)

Although most useful if used within 4 h of ingestion, repeated doses may be used, especially with ingestions of sustained-released agents. Limited outcome studies exist, especially when activated charcoal is used more than 1 h postingestion. No data exist to suggest a benefit of multiple dose activated charcoal with beta-blockers, even sustained-release preparations.
May repeat the dose q4h at 0.5 g/kg (alternate use of cathartic; monitor for active bowel sounds).

Dosing

Adult

1 g/kg PO (first dose usually with cathartic), up to 50-100 g

Pediatric

1-2 g/kg PO (<2 y: omit cathartic), up to 15-30 g

Interactions

May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix with sherbet, milk, or ice cream (decreases absorptive properties)

Contraindications

Documented hypersensitivity; poisoning or overdosage of mineral acids and alkalis; unprotected airway with absent gag reflex

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor for active bowel sounds before readministration to minimize risk of charcoal ileus; not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before administering activated charcoal; after emesis with ipecac, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black

Cardiovascular agents

These agents are used for symptomatic bradycardia and/or hypotension. Catecholamines are considered a primary treatment for more severe cases of beta-blocker poisoning.

Atropine (Atropair)

Enhances sinus node automaticity by blocking the effects of acetylcholine at the AV node, decreasing refractory time and speeding conduction through the AV node.

Dosing

Adult

Hypotension: 0.5-1 mg IV with repeated doses at 5-min intervals until desired response
Cardiac arrest: 1 mg IV repeated at 3- to 5-min intervals; minimal dose: 0.5 mg IV
Maximal dose: 0.04 mg/kg IV or 3 mg IV is fully vagolytic

Pediatric

Hypotension: 0.02 mg/kg IV; minimum dose 0.1 mg IV
Cardiac arrest: Maximum single dose of 0.5 mg IV for children and 1 mg for adolescents; may repeat dose once; not to exceed 1 mg for children and 2 mg for adolescents

Interactions

Coadministration with other anticholinergics have additive effects; pharmacologic effects of atenolol and digoxin may increase; antipsychotic effects of phenothiazines may decrease; tricyclic antidepressants with anticholinergic activity may increase effects

Contraindications

Documented hypersensitivity; thyrotoxicosis; narrow-angle glaucoma; tachycardia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Avoid in Down syndrome or children with brain damage to prevent hyperreactive response; avoid in coronary heart disease, tachycardia, congestive heart failure, cardiac arrhythmias, and hypertension; caution in peritonitis, ulcerative colitis, hepatic disease, and hiatal hernia with reflux esophagitis; in prostatic hypertrophy, prostatism can have dysuria and may require catheterization

Glucagon

Considered DOC by many. Stimulates production of cAMP through nonadrenergic pathways. Result is enhanced myocardial contractility, heart rate, and AV conduction.
An upper dose limit has not been established.

Dosing

Adult

3-10 mg IV bolus followed by 2-5 mg/h infusion

Pediatric

150 mcg/kg IV over 1 min; followed 2-5 mg/h infusion

Interactions

May enhance effects of anticoagulants (although onset may be delayed); monitor prothrombin activity and for signs of bleeding in patients receiving anticoagulants; adjust dose accordingly

Contraindications

Documented hypersensitivity; pheochromocytoma

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor blood glucose levels in hypoglycemic patients until they are asymptomatic; effective in treating hypoglycemia only if sufficient liver glycogen is present; because hepatic glycogen availability is necessary to treat hypoglycemic patients glucagon has virtually no effects in patients with starvation, adrenal insufficiency, or chronic hypoglycemia; nausea may cause increased vagal tone; avoid phenol toxicity by diluting in D5W

Epinephrine (adrenalin)

Agents with combined alpha- and beta-selective properties may be necessary to maintain blood pressure. A beta-agonist may competitively antagonize the effect of the beta-blocker.
The amount of beta-agonist required might be several orders of magnitude above those recommended in standard ACLS protocols

Dosing

Adult

1 mcg/min IV; titrate to effect

Pediatric

0.1 mcg/kg/min IV; titrate to effect

Interactions

Guanethidine may increase effect of direct-acting vasopressors, possibly resulting in severe hypertension; TCAs may potentiate pressor response of direct-acting vasopressors; phenytoin, alpha- and beta-adrenergic blockers, general anesthesia, and MAOIs increase and prolong effects of epinephrine

Contraindications

Documented hypersensitivity; tachyarrhythmias; tachycardia; heart block caused by digitalis intoxication; ventricular arrhythmias, which require inotropic therapy; angina pectoris; uncorrected hypovolemia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

By increasing myocardial oxygen requirements while decreasing effective coronary perfusion, may have a deleterious effect on the injured or failing heart; in some patients, presumably with organic disease of the AV node and its branches, may paradoxically worsen heart blocks or precipitate Adams-Stokes attacks; caution in coronary artery disease, coronary insufficiency, diabetes, or hyperthyroidism and sensitivity to sympathomimetic amines; if heart rate >110 BPM, may be advisable to decrease infusion rate or temporarily discontinue infusion

Dopamine (Intropin)

Agents with combined alpha- and beta-selective properties may be necessary to maintain blood pressure. A beta-agonist may competitively antagonize the effect of the beta-blocker.
The amount of beta-agonist required might be several orders of magnitude above those recommended in standard ACLS protocols. In a canine model, the doses of isoproterenol and dopamine had to be increased 15 and 5 times, respectively, in order to effect similar hemodynamic changes that occurred before beta-blockade with 1 mg/kg propranolol.

Dosing

Adult

Begin at 2-5 mcg/kg/min IV progressing in 5-10 mcg/kg/min increments prn

Pediatric

Administer as in adults

Interactions

Guanethidine may increase effect of direct-acting vasopressors, possibly resulting in severe hypertension; TCAs may potentiate pressor response of direct-acting vasopressors; phenytoin, alpha- and beta-adrenergic blockers, general anesthesia, and MAOIs increase and prolong effects of dopamine

Contraindications

Documented hypersensitivity; tachyarrhythmias; tachycardia; heart block caused by digitalis intoxication; ventricular arrhythmias, which require inotropic therapy; angina pectoris; uncorrected hypovolemia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

By increasing myocardial oxygen requirements while decreasing effective coronary perfusion, may have a deleterious effect on the injured or failing heart; in some patients, presumably with organic disease of the AV node and its branches, may paradoxically worsen heart blocks or precipitate Adams-Stokes attacks; caution in coronary artery disease, coronary insufficiency, diabetes, or hyperthyroidism and sensitivity to sympathomimetic amines; if heart rate >110 BPM, may be advisable to decrease infusion rate or temporarily discontinue infusion

Isoproterenol (Isuprel)

Agents with combined alpha- and beta-selective properties may be necessary to maintain blood pressure. A beta-agonist may competitively antagonize the effect of the beta-blocker.
The amount of beta-agonist required might be several orders of magnitude above those recommended in standard ACLS protocols. In a canine model, the doses of isoproterenol and dopamine had to be increased 15 and 5 times, respectively, in order to effect similar hemodynamic changes that occurred before beta-blockade with 1 mg/kg propranolol.

Dosing

Adult

2-4 mcg/min IV; titrate to effect

Pediatric

0.1 mcg/kg/min IV; titrate to effect

Interactions

Guanethidine may increase effect of direct-acting vasopressors, possibly resulting in severe hypertension; TCAs may potentiate pressor response of direct-acting vasopressors

Contraindications

Documented hypersensitivity; tachyarrhythmias; tachycardia; heart block caused by digitalis intoxication; ventricular arrhythmias, which require inotropic therapy; angina pectoris; uncorrected hypovolemia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

By increasing myocardial oxygen requirements while decreasing effective coronary perfusion, may have a deleterious effect on the injured or failing heart; in some patients, presumably with organic disease of the AV node and its branches, may paradoxically worsen heart blocks or precipitate Adams-Stokes attacks; caution in coronary artery disease, coronary insufficiency, diabetes, or hyperthyroidism and sensitivity to sympathomimetic amines; if heart rate >110 BPM, may be advisable to decrease infusion rate or temporarily discontinue infusion

Inamrinone - formerly amrinone (Inocor)

Produces vasodilation and increases inotropic state. More likely to cause tachycardia than dobutamine. May exacerbate myocardial ischemia. Case reports describe as effective when other agents fail.

Dosing

Adult

0.75 mg/kg IV initial, followed by 5-10 mcg/kg/min maintenance infusion; additionally, 0.75 mg/kg may be given 30 min after therapy begins; not to exceed 10 mg/kg/d

Pediatric

Not established
Suggested dosing: 0.75 mg/kg IV initial, followed by 10 mcg/kg/min maintenance infusion; infants may require larger doses

Interactions

Coadministration with diuretics may result in hypovolemia and decrease in filling pressure; cardiac glycosides have additive effects on inamrinone; admixing with furosemide or dextrose may cause precipitation

Contraindications

Documented hypersensitivity; uncorrected hypovolemia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Discontinue therapy if symptoms of liver toxicity develop; correct hypokalemia before giving therapy

Calcium chloride

Moderates nerve and muscle performance by regulating action potential excitation threshold. At high doses, propranolol blocks the calcium channels that may induce asystole, AV block, and depressed myocardial contraction.

Dosing

Adult

100-1000 mg slow IV push of 10% solution

Pediatric

20-25 mg/kg IV push

Interactions

Coadministration with digoxin may cause arrhythmias; with thiazides, may induce hypercalcemia; may antagonize effects of calcium channel blockers, atenolol, and sodium polystyrene sulfonate; precipitates with sodium bicarbonate and may be sclerosing to peripheral veins

Contraindications

Ventricular fibrillation not associated with hyperkalemia; digitalis toxicity; hypercalcemia; renal insufficiency; cardiac disease

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Administer slowly (not to exceed 0.5-1 mL/min) to avoid extravasation; hypercalcemia may occur in renal failure; calcium gluconate may be less effective

Magnesium sulfate

Acts as antiarrhythmic agent and diminishes frequency of PVCs, particularly when secondary to acute ischemia. Used to treat torsade de pointes associated with sotalol intoxication.

Dosing

Adult

2 g IV over 1-2 min, followed by a second 2 g bolus and infusion of 3-20 mg/min in patients not responding to the initial bolus or with recurrence of arrhythmias

Pediatric

25-50 mg/kg diluted to 10 mg/mL for IV infusion over several min

Interactions

Concurrent use with nifedipine may cause hypotension and neuromuscular blockade; may increase neuromuscular blockade observed with aminoglycosides and potentiate neuromuscular blockade produced by tubocurarine, vecuronium, and succinylcholine; may increase CNS effects and toxicity of CNS depressants, betamethasone, and cardiotoxicity of ritodrine

Contraindications

Documented hypersensitivity; heart block; Addison disease; myocardial damage; severe hepatitis

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

May alter cardiac conduction leading to heart block in digitalized patients; monitor respiratory rate, deep tendon reflex, and renal function when electrolyte is administered parenterally; caution when administering magnesium dose because may produce significant hypertension or asystole; in overdose, calcium gluconate, 10-20 mL IV of 10% solution, can be given as antidote for clinically significant hypermagnesemia

Insulin (Novolin, Humulin)

High-dose insulin therapy with euglycemia was associated with significant improvement in survival, compared with high-dose infusions of epinephrine and glucagon in an anesthetized canine model as well as case series of human overdose. This intriguing therapy is still highly investigational but should be considered when other therapies are failing.
Dextrose infusion of 10-75 g/h may be required. Consult a toxicologist if this regimen is considered.

Dosing

Adult

Not established
Suggested dosing: 0.5-1 U/kg/h IV with frequent boluses of dextrose

Pediatric

Not established

Interactions

Medications that may decrease hypoglycemic effects of insulin include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin; medications that may increase hypoglycemic effects of insulin include calcium, ACE inhibitors, alcohol, tetracyclines, beta-blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone

Contraindications

Documented hypersensitivity; hypoglycemia; inability to closely monitor serum glucose concentrations

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Investigational; hyperthyroidism may increase renal clearance of insulin and may need more insulin to treat hyperkalemia; hypothyroidism may delay insulin turnover, requiring less insulin to treat hyperkalemia; monitor glucose carefully; dose adjustments of insulin may be necessary in patients with renal and hepatic dysfunction

Benzodiazepines

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

Lorazepam (Ativan)

Benzodiazepines are considered the treatment of choice for beta-blocker–induced seizures. Of the benzodiazepines, lorazepam has the longest anticonvulsant activity (4-6 h) and is preferred. By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.
Important to monitor patient's blood pressure after administering dose. Adjust prn.

Dosing

Adult

0.05-0.10 mg/kg IV over 2 min

Pediatric

0.03-0.05 mg/kg IV; not to exceed 4 mg/dose

Interactions

Toxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs

Contraindications

Documented hypersensitivity; preexisting CNS depression; hypotension; narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, Parkinson disease, shock, respiratory depression, or glaucoma

Diazepam (Valium)

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Is second-line therapy for seizures.

Dosing

Adult

0.10 mg/kg IV over 2 min; may repeat q5-10min

Pediatric

0.2-0.5 mg/kg/dose IV over 2 min; may repeat q5-15min

Interactions

Increases toxicity of benzodiazepines in CNS with coadministration of phenothiazines, barbiturates, alcohols, and MAOIs

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; hypotension

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution with other CNS depressants, low albumin levels, hepatic disease (may increase toxicity), shock, respiratory depression, or glaucoma

Phenobarbital (Barbita, Luminal)

May be necessary to control status epilepticus.

Dosing

Adult

15-20 mg/kg IV over 20 min

Pediatric

10-20 mg/kg IV; not to exceed 1 mg/kg/min

Interactions

May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); coadministration with alcohol may produce additive CNS effects and death; chloramphenicol, valproic acid, and MAOIs may increase phenobarbital toxicity; rifampin may decrease phenobarbital effects; induction of microsomal enzymes may result in decreased effects of oral contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy); menstrual irregularities also may occur

Contraindications

Documented hypersensitivity; severe respiratory disease; marked impairment of liver function; hypotension; nephritic patients

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia because adverse reactions can occur; caution in myasthenia gravis and myxedema

Follow-up

Further Inpatient Care

• Noninvasive monitoring techniques
  • Simple methods of monitoring include repeat physical examinations, serial electrocardiograms, and continuous measurement of urinary output with a Foley catheter.
  • End points of therapy may include a heart rate more than 60 beats per minute, blood pressure of greater than 90 mm Hg systolic, and evidence of good organ perfusion (improved mentation or urine output).
• Invasive monitoring techniques: The best monitoring methods for patients with severe toxicity are early insertion of an arterial blood pressure catheter and central venous pressure readings.

Further Outpatient Care

• Patients who initially present without symptoms and remain asymptomatic can be safely discharged after an observation period of 6 hours. Increased caution is necessary if sustained-release products are ingested or child poisoning is involved. In these cases, admission to the hospital for 24 hours is recommended.
• To avoid recurrent complications, adjust dosages or change medications for patients who have experienced adverse drug reactions due to combination therapy with calcium channel blockers or impaired metabolism caused by renal or hepatic dysfunction. These changes should be made in concert with the patient's primary care physician. If there is any suspicion of suicidality, and the patient is medically clear of any toxic overdose, the disposition planning should be made in concert with the consulting psychiatrist.

Transfer

• Because of the potential for rapid deterioration, only asymptomatic patients who have been observed for a period of 6 hours should be considered stable for transfer.
• If intensive care monitoring or therapy is not available, transfer the unstable patient to the closest facility with the necessary capabilities for care, including a medical toxicologist.

Prognosis

• The prognosis mainly depends on the initial response to therapy 6-12 hours postingestion because drug levels are likely to have peaked at this time.
• Underlying cardiac or pulmonary disease places the patient at increased risk for poor outcome.

Patient Education

• For excellent patient education resources, visit eMedicine's Drug Overdose Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize beta-blocker toxicity as a cause of bradycardia and hypotension when a history of intentional overdose is lacking
• Failure to adequately monitor a patient on multiple cardiac vasopressors
• Medically clearing a patient with beta-blocker toxicity before a 6-hour observation period
• Failure to consult a psychiatrist for the evaluation of a patient who reports self-harm or where self-harm is suspected
• Failure to administer large enough doses of antidotes, including catecholamines, glucagon, calcium, and potentially insulin

Special Concerns

Intravenous fat emulsion (IFE) has traditionally been used as a component of parenteral nutrition therapy. However, in the past decade, IFE has been demonstrated to reduce the mortality of local anesthetic toxicity in animal models as well as in case reports.^3,4,5,6,7 It has been postulated that the IFE provides a "lipid sink" for fat-soluble drugs, removing them from the target organs. Animal models have shown improved mortality for both verapamil and propanolol toxicity.^8,9 Though still in its infancy, IFE therapy may prove to be a useful treatment adjunct when used specifically for propanolol toxicity. Any consideration of its use is only recommended in consultation with a toxicologist familiar with the administration of IFE as an antidote.

Multimedia

Media file 1: A 48-year-old man presents to the ED after a generalized tonic-clonic seizure. He is noted to be hypotensive (82/55) and bradycardiac (see rhythm strip). The family reports that he is taking a medication for a rapid heart rate. Propranolol is the most common beta-blocker involved in severe beta-blocker poisoning. It is nonselective and has membrane-stabilizing effects that are responsible for CNS depression, seizures, and prolongation of the QRS complex.

Media file 2: Sotalol is associated with the rhythm shown below in both therapeutic doses and toxic ingestions. Sotalol has been used as a class III antiarrhythmic agent to control dangerous ventricular tachydysrhythmias in some individuals. It causes polymorphic ventricular tachycardia (torsade de pointes) in approximately 4% of patients. Rarely, prolongation of the QT interval has been reported with propranolol.

References

1. Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Heard SE. 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 25th Annual Report. Clin Toxicol (Phila). Dec 2008;46(10):927-1057. [Medline].

2. Watson WA, Litovitz TL, Rodgers GC, et al. 2004 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 2005;23(5):589-666. [Medline].

3. Weinberg GL, VadeBoncouer T, Ramaraju GA, Garcia-Amaro MF, Cwik MJ. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology. Apr 1998;88(4):1071-5. [Medline].

4. Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med. May-Jun 2003;28(3):198-202. [Medline].

5. Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ, Eisenkraft JB. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology. Jul 2006;105(1):217-8. [Medline].

6. Litz RJ, Popp M, Stehr SN, Koch T. Successful resuscitation of a patient with ropivacaine-induced asystole after axillary plexus block using lipid infusion. Anaesthesia. Aug 2006;61(8):800-1. [Medline].

7. Foxall G, McCahon R, Lamb J, Hardman JG, Bedforth NM. Levobupivacaine-induced seizures and cardiovascular collapse treated with Intralipid. Anaesthesia. May 2007;62(5):516-8. [Medline].

8. Cave G, Harvey MG, Castle CD. The role of fat emulsion therapy in a rodent model of propranolol toxicity: a preliminary study. J Med Toxicol. Mar 2006;2(1):4-7. [Medline].

9. Bania TC, Chu J, Perez E, Su M, Hahn IH. Hemodynamic effects of intravenous fat emulsion in an animal model of severe verapamil toxicity resuscitated with atropine, calcium, and saline. Acad Emerg Med. Feb 2007;14(2):105-11. [Medline].

10. Anthony T, Jastremski M, Elliott W, et al. Charcoal hemoperfusion for the treatment of a combined diltiazem and metoprolol overdose. Ann Emerg Med. Nov 1986;15(11):1344-8. [Medline].

11. Ball S. Congestive heart failure from betaxolol. Case report. Arch Ophthalmol. Mar 1987;105(3):320. [Medline].

12. Benatar SR, Opie LH. Sudden death in asthmatics receiving beta-blockers. S Afr Med J. Aug 28 1982;62(10):308-9. [Medline].

13. Benowitz N. Beta-Adrenergic receptor blocker overdose. In: Winchester JF, eds. Haddad LM, Clinical Management of Poisoning and Drug Overdose. WB Saunders Co: 1990:1315-26.

14. Brimacombe J. Use of calcium chloride for propranolol overdose. Anaesthesia. Oct 1992;47(10):907-8. [Medline].

15. Cox J, Starbuck M. Hyperkalemic cardiac arrest during an infusion of potassium chloride following an overdose of propranolol. Resuscitation. Dec 1986;14(4):255-6. [Medline].

16. DeWitt CR, Waksman JC. Pharmacology, pathophysiology and management of calcium channel blocker and beta-blocker toxicity. Toxicol Rev. 2004;23(4):223-38. [Medline].

17. du Souich P, Caille G, Larochelle P. Enhancement of nadolol elimination by activated charcoal and antibiotics. Clin Pharmacol Ther. May 1983;33(5):585-90. [Medline].

18. Farhangi V, Sansone RA. QTc prolongation due to propranolol overdose. Int J Psychiatry Med. 2003;33(2):201-2. [Medline].

19. Fisher CM. Amnestic syndrome associated with propranolol toxicity: a case report. Clin Neuropharmacol. Oct 1992;15(5):397-403. [Medline].

20. Hume L, Forfar JC. Hyperkalaemia and overdose of antihypertensive agents. Lancet. Dec 3 1977;2(8049):1182. [Medline].

21. Kerns W 2nd, Kline J, Ford MD. Beta-blocker and calcium channel blocker toxicity. Emerg Med Clin North Am. May 1994;12(2):365-90. [Medline].

22. Kerns W II, Schroeder D, Williams C, et al. Insulin improves survival in a canine model of acute beta-blocker toxicity. Ann Emerg Med. Jun 1997;29(6):748-57. [Medline].

23. Kollef MH. Labetalol overdose successfully treated with amrinone and alpha-adrenergic receptor agonists. Chest. Feb 1994;105(2):626-7. [Medline].

24. Kulling P, Eleborg L, Persson H. Beta-adrenoceptor blocker intoxication: epidemiological data. Prenalterol as an alternative in the treatment of cardiac dysfunction. Hum Toxicol. Apr 1983;2(2):175-81. [Medline].

25. Lane AS, Woodward AC, Goldman MR, et al. Massive propranolol overdose poorly responsive to pharmacologic therapy: use of the intra-aortic balloon pump. Ann Emerg Med. Dec 1987;16(12):1381-3. [Medline].

26. Langemeijer JJ, de Wildt DJ, de Groot G, et al. Centrally induced respiratory arrest: main cause of death in beta-adrenoceptor antagonist intoxication. Hum Toxicol. Jan 1986;5(1):65. [Medline].

27. Lifshitz M, Zucker N, Zalzstein E. Acute dilated cardiomyopathy and central nervous system toxicity following propranolol intoxication. Pediatr Emerg Care. Aug 1999;15(4):262-3. [Medline].

28. Link MS, Foote CB, Sloan SB, et al. Torsade de pointes and prolonged QT interval from surreptitious use of sotalol: use of drug levels in diagnosis. Chest. Aug 1997;112(2):556-7. [Medline].

29. Litovitz TL, Klein-Schwartz W, White S, et al. 1999 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 2000;18(5):517-74. [Medline].

30. Love JN. Acebutolol overdose resulting in fatalities. J Emerg Med. Apr 2000;18(3):341-4. [Medline].

31. Love JN. Beta blocker toxicity after overdose: when do symptoms develop in adults?. J Emerg Med. Nov-Dec 1994;12(6):799-802. [Medline].

32. Love JN. Beta-blocker toxicity: a clinical diagnosis. Am J Emerg Med. May 1994;12(3):356-7. [Medline].

33. Love JN, Howell JM, Litovitz TL, et al. Acute beta blocker overdose: factors associated with the development of cardiovascular morbidity. J Toxicol Clin Toxicol. 2000;38(3):275-81. [Medline].

34. Love JN, Litovitz TL, Howell JM, et al. Characterization of fatal beta blocker ingestion: a review of the American Association of Poison Control Centers data from 1985 to 1995. J Toxicol Clin Toxicol. 1997;35(4):353-9. [Medline].

35. McVey FK, Corke CF. Extracorporeal circulation in the management of massive propranolol overdose. Anaesthesia. Sep 1991;46(9):744-6. [Medline].

36. Megarbane B, Karyo S, Baud FJ. The role of insulin and glucose (hyperinsulinaemia/euglycaemia) therapy in acute calcium channel antagonist and beta-blocker poisoning. Toxicol Rev. 2004;23(4):215-22. [Medline].

37. Newton CR, Delgado JH, Gomez HF. Calcium and beta receptor antagonist overdose: a review and update of pharmacological principles and management. Semin Respir Crit Care Med. Feb 2002;23(1):19-25. [Medline].

38. Prichard BN, Battersby LA, Cruickshank JM. Overdosage with beta-adrenergic blocking agents. Adverse Drug React Acute Poisoning Rev. Summer 1984;3(2):91-111. [Medline].

39. Prichard BN, Tomlinson B, Walden RJ, et al. The beta-adrenergic blockade withdrawal phenomenon. J Cardiovasc Pharmacol. 1983;5 Suppl 1:S56-62. [Medline].

40. Reith DM, Dawson AH, Epid D, et al. Relative toxicity of beta blockers in overdose. J Toxicol Clin Toxicol. 1996;34(3):273-8. [Medline].

41. Smit AJ, Mulder PO, de Jong PE, et al. Acute renal failure after overdose of labetalol. Br Med J (Clin Res Ed). Nov 1 1986;293(6555):1142-3. [Medline].

42. Taboulet P, Cariou A, Berdeaux A, et al. Pathophysiology and management of self-poisoning with beta-blockers. J Toxicol Clin Toxicol. 1993;31(4):531-51. [Medline].

43. Trummel J, Ford M, Austin P. Ingestion of an unknown alcohol. Ann Emerg Med. Mar 1996;27(3):368-74. [Medline].

44. Weinstein RS. Recognition and management of poisoning with beta-adrenergic blocking agents. Ann Emerg Med. Dec 1984;13(12):1123-31. [Medline].

45. Yuan TH, Kerns WP II, Tomaszewski CA, et al. Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol. 1999;37(4):463-74. [Medline].

Keywords

beta-blocker toxicity, beta-blocker poisoning, beta-blocker overdose, beta-adrenergic antagonist overdose, beta-adrenergic antagonist toxicity, hypertension, postmyocardial infarction, migraine headaches, essential tremors, thyrotoxicosis, glaucoma, anxiety, propranolol, nadolol, timolol, pindolol, acebutolol, labetalol, sotalol, oxprenolol, practolol, esmolol, alprenolol, metoprolol, quinidinelike effects, Vaughan-Williams class I antiarrhythmic effects, QT interval prolongation, prolonged QT interval, multifocal premature ventricular contractions, PVCs, bigeminy, ventricular tachycardia, ventricular fibrillation, torsade de pointes, seizures, hypoglycemia

Contributor Information and Disclosures

Author

Adhi Sharma, MD, Assistant Professor, Department of Emergency Medicine, Mount Sinai School of Medicine; Chairman, Department of Emergency Medicine, Good Samaritan Hospital Medical Center; Medical Toxicology Consultant, New York City Department of Health and Poison Control Center
Adhi Sharma, MD is a member of the following medical societies: American College of Clinical Toxicologists, American College of Emergency Physicians, and American College of Medical Toxicology
Disclosure: Nothing to disclose.

Coauthor(s)

Lemeneh Tefera, MD, FAAEM, Attending Physician, Department of Emergency Medicine, Beth Israel Medical Center
Lemeneh Tefera, MD, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine
Disclosure: Nothing to disclose.

Aman Aminzay, MD, Resident, Department of Emergency Medicine, Beth Israel Medical Center, Albert Einstein College of Medicine
Aman Aminzay, MD is a member of the following medical societies: American College of Emergency Physicians
Disclosure: Nothing to disclose.

Medical Editor

David C Lee, MD, Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School
David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

John G Benitez, MD, MPH, FACMT, FACPM, FAAEM, Associate Professor, Department of Medicine, Clinical Pharmacology Division, Vanderbilt University; Managing Director, Tennessee Poison Center
John G Benitez, MD, MPH, FACMT, FACPM, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Society for Academic Emergency Medicine, Undersea and Hyperbaric Medical Society, and Wilderness Medical Society
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the medical review of this article by Lada Kokan, MD.

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