AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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.

For a CME activity, see CME - Beta-Blockers in Hypertension: Should We Discard Them?.

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 most recent data from the American Association of Poison Control Centers (AAPCC) for 2004 report more than 17,000 exposures, including 2467 significant toxic ingestions and 25 deaths.¹ More than 5238 pediatric exposures occurred, of which 4077 were in children younger than 6 years.¹

International

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

Mortality/Morbidity

In 2004, the AAPCC reported 2.4 million toxic exposures and 1184 fatalities.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.¹

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.¹

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab 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

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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.

Drug Category: GI decontaminant

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

Drug Category: 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.

Drug Category: Benzodiazepines

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

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal 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

ACKNOWLEDGMENTS

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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

MULTIMEDIA

Section 11 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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.
	View Full Size Image
Media type:  Rhythm Strip

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.
	View Full Size Image
Media type:  Rhythm Strip

REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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Article Last Updated: Aug 20, 2008