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    Cardiac Glycosides Overdose

    Cardiovascular, Toxicology

    Last Updated Jul 09, 2018
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    Context

    • Digoxin (Lanoxin®) is a synthetic cardiac glycoside used in treatment of congestive heart failure, atrial fibrillation and flutter.
    • In Canada, digoxin is available as oral tablets, oral liquid and for intravenous injection.
    • Natural cardiac glycosides include digitoxin, digitalis-leaf or extract, and lanatoside C (extract of Digitalis lanata), various plants (e.g. foxglove, lily-of-the-valley, oleander), homeopathic, herbal and Ayurvedic medicine, and certain toad venoms (Bufo spp., sometimes found in Chinese remedies such as Chan Su, Kyushin, Lu-ShenWan).

    Signs and Symptoms

    • Toxicity can occur with acute or chronic
    • Chronic toxicity is more common in elderly patients with unrecognized impaired renal function, non-individualized digoxin dosage regimens, or interacting drugs.
    • Acute toxicity may be seen after intentional overdose, exposure to cardiac glycoside-containing plants or remedies, or iatrogenic errors.

     

    Cardiac signs and symptoms

    • Common: Bradycardia (can be severe), all degrees of heart block, almost any type of atrial or ventricular dysrhythmia.
    • Less common: Asystole and/or cardiac arrest can occur in severe cases.

     

    Non-cardiac signs and symptoms

    • Common: GI symptoms (nausea and vomiting), confusion, disorientation.
    • Uncommon: Visual disturbances.

     

    Laboratory abnormalities

    • Common: Hyperkalemia (acute toxicity), Hypokalemia (chronic toxicity).
    • Uncommon: Hypomagnesemia (chronic toxicity).

     

    ECG changes

    • Almost any type of atrial or ventricular dysrhythmia can be seen.
    • Bradycardia (can be severe).
    • Any degree of heart block.
    • Junctional or ventricular tachycardia, ectopy.
    • Premature ventricular contractions are common.
    • Accelerated junctional rhythm with or without high-degree AV block.
    • New-onset Mobitz type I AV block, and bidirectional ventricular tachycardia typically indicate digoxin toxicity.

     

    Typical course

    • About 60-85% of pharmaceutical digoxin is absorbed following ingestion.
    • Peak serum levels occur within 2-3 hours.
    • Peak effects occur within 6-12 hours post ingestion.
    • In overdose, cardiac toxicity may occur within 30 minutes.
    • Slowly distributes to tissues over 4-6 hours or longer.
    • Approximately 20-30% protein bound.
    • Primarily eliminated unchanged in urine, with elimination half-life of ~ 36 hours with normal renal function.
    • Elimination is delayed in elderly patients with CHF, and may be up to 4.5 days or longer in anuric patients.
    • Not removed by extracorporeal means.

     

    Mechanism of Toxicity

    • Inhibits cardiac and skeletal muscle Na-K-ATPase pumps resulting in increased intracellular sodium which causes increased activity of Na-Ca pump and intracellular calcium, leading to enhanced myocardial contractility and automaticity.
    • At toxic cardiac glycoside levels, increased automaticity contributes to tachydysrhythmias.
    • Inhibition of Na-K-ATPase also results in hyperkalemia.
    • Hypokalemia may be seen in chronic overdose due to renal excretion of potassium (may be exacerbated by diuretic therapy).
    • Cardiac glycosides also increase vagal tone resulting in sinus bradycardia, various degrees of AV block, and life-threatening dysrhythmias.
    • Death is usually due to asystolic cardiac arrest.

     

    Toxic Dose

    • Toxic dose is not well established.
    • “Therapeutic” serum digoxin levels range from 0.64-1.28 nmol/L (0.5-1.0 ng/mL); however, cardiotoxicity has been reported within therapeutic range, particularly in patients on chronic therapy and in patients with underlying cardiovascular disease.
    • Serum levels > 7.7 nmol/L (6.0 ng/mL) have been associated with severe toxicity and death.
    • Acute ingestion of < 5 mg by an adult or < 2 mg by a child is unlikely to result in life-threatening toxicity.
    • Ingestion of > 10 mg by an adult or > 4 mg by a child may be fatal.
    • In patients with heart disease on chronic digoxin therapy, acute ingestion of < 2 mg may produce toxicity.

    Diagnostic Process

    • Serum levels do not correlate well with toxic effects and must be interpreted in conjunction with clinical presentation and laboratory data.
    • Levels drawn < 6-8 hours post-ingestion are higher than post-distribution phase levels and do not correlate with clinical effects.
    • Early levels should be repeated within 2-4 hours if patient is showing no evidence of clinical toxicity (particularly if time of ingestion is unknown).
    • Many other cardiac glycosides cross-react with standard digoxin immunoassay; reported results may not correlate with clinical effects.

     

    Clinical Pitfalls

    • Relying on digoxin levels to confirm diagnosis.
    • The presence of concomitant cardiac medications that may be more predominantly contributing to the clinical picture.

    Recommended Treatment

    • Consult BC Drug and Poison Information Centre (DPIC) for case discussion.
      • 604-682-5050, 1-800-567-8911, dpic.org.
    • Administer activated charcoal in recent, acute ingestion. Repeat doses of activated charcoal have not been shown to affect outcome.
    • Monitor vital signs, ECG, serum electrolytes, renal function.
    • Monitor specific digoxin serum levels. Note: Many digoxin serum levels measured by standard immunoassays after administration of digoxin-specific antibodies are unreliable and cannot be used to monitor therapy.

     

    • Antidotal therapy: Digoxin-specific antibodies, Fab fragments (DigiFab®). Rapidly reverses toxic cardiac and extracardiac effects of acute or chronic digoxin toxicity in most patients.
      • Digoxin poisoning
        • Digoxin-specific antibodies are indicated in the following situations:
          • Any potential digoxin-related life-threatening dysrhythmia OR
          • Serum digoxin level > 12.8 nmol/L (10 ng/mL) measured > 6 hours post-ingestion in an acute ingestion, OR
          • Acute ingestion of > 10 mg in an adult (4 mg in a child), OR
          • Serum potassium > 5.5 mmol/L in an acute ingestion.
        • Other cardiac glycoside poisonings
          • There are varying degrees of cross-reactivity between digoxin-specific antibodies and other digitalis glycosides. DigiFab ® can be used to reverse the effects of many non-pharmaceutical cardiac glycosides, including foxglove, oleander, and toad venom
        • Dosing of antidote is based on serum digoxin level, or the amount ingested
        • Empiric dosing of 10 vials (5 in children) in the following situations:
          • Strong suspicion of digoxin toxicity in the absence of serum levels
          • Non-pharmaceutical glucoside exposure
    • Non-antidotal therapy (if antidote is not immediately available):
      • Atropine for bradycardia and varying degrees of heart block.
      • Lidocaine and phenytoin as they have little effect on conduction.
      • Magnesium may be beneficial even in patients with normal levels.
      • External transvenous pacing in patients with severe bradycardia and/or slow ventricular rate due to refractory AV block (caution: insertion of transvenous pacemakers may worsen some dysrhythmias).
      • Cardioversion may precipitate serious dysrhythmias.
    • Treatments to avoid
      • Beta-blockers, procainamide, amiodarone – as may worsen AV block.
    • Hyperkalemia
      • Usually responds to antidotal therapy.
      • If antidote note immediately available, treatment with intravenous insulin/dextrose, and/or sodium bicarbonate may be useful.
      • Theoretical risk with IV calcium as may precipitate dysrhythmias; however, case reports of inadvertent calcium administration resulted in no adverse effects.
    • Hypokalemia (usually in chronic toxicity)
      • Replace and monitor closely as administration of antidote may result in rapid drop in serum potassium.
    • Hemodialysis is not useful to remove digoxin but may be required to treat renal failure, or life-threatening hyperkalemia unresponsive to other therapeutic measures.
    • Monitoring
      • Clinical symptoms and dysrhythmias generally resolve within 60-90 minutes following antidote administration. Persistent symptoms and/or arrhythmias should prompt investigations for alternative diagnoses.

    Criteria For Hospital Admission

    • Dysrhythmias, hypotension or severe electrolyte disturbances will require admission to a monitored setting (telemetry, CCU, ICU).

    Criteria For Transfer To Another Facility

    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

    Related Information

    Reference List

    1. Poison Management Manual, BC DPIC, 2015.


    2. Janssen RM, Berg M, Ovakim DH. Two cases of cardiac glycoside poisoning from accidental foxglove ingestion. CMAJ. 2016 Jul 12;188(10):747–50.


    3. Eddleston M, Ariaratnam CA, Sjöström L, Jayalath S, Rajakanthan K, Rajapakse S, et al. Acute yellow oleander (Thevetia peruviana) poisoning: cardiac arrhythmias, electrolyte disturbances, and serum cardiac glycoside concentrations on presentation to hospital. Heart. 2000 Mar;83(3):301–6.


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