INDEX

    Beta Blockers Overdose

    Toxicology

    Last Updated Oct 31, 2018
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    Context

    • Beta blockers are primarily prescribed for antihypertensive, negative chronotropic and antianginal effects. Some agents also indicated treatment of cardiac dysrhythmias, congestive heart failure, migraine headache prophylaxis, and ophthalmic application for glaucoma.
    • Examples include acebutolol (Sectral ®), atenolol (Tenormin ®), betaxolol (Betoptic ®), bisoprolol, carvedilol, esmolol (Brevibloc ®), labetalol (Trandate),  metoprolol (Lopresor), nadolol, pindolol (Visken), propranolol (Inderal-LA), sotalol and timolol (Timoptic , Timoptic-XE).

    Signs and Sympotms

    • Toxicity is mainly due to cardiovascular effects (cardiogenic shock), respiratory arrest, and/or CNS toxicity.
    • Common effects: Bradycardia, hypotension and cardiovascular collapse.
    • Less common effects: CNS effects including seizures may be seen with propranolol.
    • Cardiovascular toxicity following overdose is most common in patients who have co-ingested other cardiac agents (e.g. calcium channel blockers, digoxin) or who have underlying cardiac disease (e.g. congestive heart failure, impaired AV conduction).
    • In patients without cardioactive co-ingestants or cardiac disease, cardiac toxicity and death most commonly occurs in overdoses of beta blockers with membrane-stabilizing activity such as propranolol, and acebutolol.
    • Uncommon effects: Ventricular dysrhythmias (torsades de pointes) can be seen with therapeutic and toxic doses of sotalol.

    Laboratory abnormalities:

    • Hypoglycemia is rare. Hyperglycemia may occur transiently.

    ECG changes can include:

    • Bradycardia
    • AV Block (all levels)
    • QT prolongation with some agents (sotolol)
    • QRS prolongation with agents with membrane stabilizing effects (acebutolol, propranolol).

    Typical Course

    • Toxicity is mainly due to cardiovascular effects (cardiogenic shock), respiratory arrest, and/or CNS toxicity.
    • Bradycardia, hypotension and cardiovascular collapse are the most common effects following overdose. CNS effects including seizures may be seen with propranolol.
    • Severe cardiovascular toxicity following overdose is more common in patients who have co-ingested other cardiac agents (e.g. calcium channel blockers, digoxin) or who have underlying cardiac disease (e.g. congestive heart failure, impaired AV conduction).
    • In isolated ingestions, cardiac toxicity and death most commonly occurs in overdoses of beta blockers with membrane-stabilizing activity such as propranolol.
    • Ventricular dysrhythmias including torsades de pointes can be seen with therapeutic and toxic doses of sotalol. Elimination is delayed in elderly patients with CHF, and may be up to 4.5 days or longer in anuric patients.
    • The majority of beta blockers cannot be removed by extracorporeal means.

    Mechanism of Toxicity

    • Beta adrenergic antagonism at beta-1 adrenergic receptors causes reduced heart rate, conduction velocity and contractility. Non-selective beta blockers also antagonize beta-2 receptors, causing bronchoconstriction and arteriolar vasoconstriction. Beta blockade inhibits gluconeogenesis, although hypoglycemia is rare.
    • Beta-1 selective (cardioselective) agents including acebutolol, atenolol, bisoprolol, esmolol and metoprolol have relatively little effect on beta-2 receptors at therapeutic doses, but lose selectivity with large doses.
    • Membrane stabilizing effects (sodium channel blocking effects) of propranolol (and also acebutolol, nadolol and pindolol) can result in QRS prolongation on ECG, reduced contractility, and ventricular dysrhythmias after overdose.
    • Alpha adrenergic blocking activity of carvedilol and labetalol may result in pronounced hypotension through peripheral vasodilation.
    • Potassium channel blocking effects of sotalol can result in prolonged action potential and QTc interval.

    Toxic Dose

    • Varies with agent, presence of co-ingestants and underlying cardiac disease. Refer to BC Drug and Poison Information Centre (DPIC) Poison Management Manual for referral indication for possibly toxic exposure.
    • Patients who have co-ingested other cardiac drugs such as calcium channel blockers and digoxin, or patients with underlying cardiac disease such as CHF or impaired AV conduction may develop toxicity at lower doses.

    Diagnostic Process

    • Serum levels for beta blockers are not readily available.
    • A history suggesting exposure and combination of physical exam findings and ECG can provide clues to diagnosis.
    • All patients should have basic toxicological investigations (electrolytes, salicylates, acetaminophen, ethanol, and digoxin level where appropriate).

    Clinical Pitfalls

    • Recognition of additional toxicity of some beta blockers (propranolol, acebutolol, sotalol).
    • Managing patients with coingestions of other cardiotoxic drugs and/or pre-existing cardiac disease.

    Recommended Treatment

    • Asymptomatic patients should have vital signs and continuous cardiac monitoring for at least 6 hours post ingestion of an immediate release preparation (except sotalol). Monitor at least 12 hours following ingestion of a sustained release preparation or sotalol. An ECG should be obtained on admission and prior to discharge in asymptomatic patients.
    • Symptomatic patients should be monitored until symptoms resolve.
    • Administer activated charcoal. Consider gastric lavage in patients presenting within the first hour following massive ingestion. Whole bowel irrigation may be considered with ingestion of sustained release preparations.
    • Protect airway and assist ventilation as needed.
    • Monitor vital signs, ECG, electrolytes, glucose, and renal function.
    • Treatment of bradycardia and hypotension may involve different therapies that may need to be started in parallel:
      • Atropine, IV fluids, and vasopressors followed quickly by high dose insulin therapy with glucagon as an interim measure (see below).
      • Lipid emulsion therapy (LET) can be considered in patients with cardiac arrest or cardiovascular collapse not responding to standard therapies.
      • Other measures to consider in patients not responding to the above, include: calcium, phosphodiesterase inhibitors, and nonpharmacologic therapies (see below)
      • Ventricular dysrhythmias not responding to correction of bradycardia:
        • Sodium bicarbonate boluses for QRS widening or ventricular dysrhythmias in patients exposed to propranolol or other membrane stabilizing beta blockers.
        • IV magnesium sulfate or overdrive pacing for treatment of torsades de pointes in sotalol poisoning; lidocaine may also be effective.
      • Bronchospasm should be managed with inhaled beta2 bronchodilators.
      • Seizures should be treated with IV benzodiazepines.
      • Hypoglycemia should be treated with IV glucose.
      • Hemodialysis may be necessary for renal failure or correction of refractory metabolic acidosis. Hemodialysis has been reported to remove nadolol acebutolol, sotolol and atenolol (NASA). Continuous venovenous hemodiafiltration (CVVHDF) has been used in a case of atenolol overdose.
      • Extra corporeal membrane oxygenation (ECMO) can be considered in severe overdoses not responding to high dose insulin and/or LET. Early consultation or referral/transfer to an ECMO center may be appropriate.

    Details of Therapies

    • Vasopressors: Choice of agent is controversial, but practical recommendation is to use something readily available and familiar, e.g. norepinephrine or dopamine. Titrate to effect as very high doses may be required. Start at usual rate and titrate up rapidly.
    • High-dose insulin (HDI) therapy improves cardiac function without increasing myocardial work. Early initiation of HDI therapy is recommended as response may take 30-90 minutes. Start with 1 unit/kg insulin bolus with 50 mL D50W, followed by infusion.
    • Glucagon may improve bradycardia and hypotension and should be given early in treatment. Consider early addition of other therapies (e.g. high-dose insulin therapy, above) as clinical effects of glucagon is transient, hospital supplies are usually limited, and glucagon may induce vomiting. Start with 3-10 mg bolus (0.05-0.15 mg/kg in children) followed by infusion.
    • Lipid emulsion therapy (Intralipid ®) may be considered in patients with cardiac arrest or cardiovascular collapse unresponsive to therapies listed above.
    • Calcium may improve blood pressure but not heart rate. Calcium chloride is preferred over calcium gluconate (3 times more concentrated) but can be irritating if given peripherally. Dose: Adult: 10-20 mL of 10% calcium chloride, or 30-60 mL of 10% calcium gluconate.
    • Phosphodiesterase inhibitors such as milrinone may be useful but use is often limited by vasodilation which can worsen hypotension.
    • Non-pharmacologic therapies: Transvenous pacing may be ineffective. Intraaortic balloon pump, cardiopulmonary bypass and ECMO have been used but require time to set up.

    Criteria For Transfer To Another Facility

    Consult

    • Decisions to administer specific and advanced therapies (HDI, intralipid, ECMO) should be reviewed with BC Drug and Poison Information Centre 604-682-5050, 1-800-567-8911, dpic.org.

    Criteria For Safe Discharge Home

    • After observation periods have been met and the patient’s psychiatric condition has been treated if the overdose was intentional.

    Quality Of Evidence?

    Justification

    Case Reports and Case Series

    Low

    References

    Poison Management Manual,  BC Drug and Poison Information Centre, 2015

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