• Digoxin (Lanoxin®) is a synthetic cardiac glycoside used in treatment of congestive heart failure, atrial fibrillation and flutter.
• Natural cardiac glycosides include various plants (foxglove, lily-of-the-valley, oleander), and certain toad venoms (Bufo spp).

Signs and Symptoms

• Toxicity can occur with acute or chronic exposures.
• Chronic toxicity is more common in elderly patients with unrecognized impaired renal function or drug interactions that affect digoxin clearance.
• Acute toxicity occurs with intentional overdose, exposure to cardiac glycoside-containing plants or remedies, or iatrogenic errors.

Cardiac

• 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.

Non-cardiac

• Common: Nausea and vomiting, confusion, disorientation.
• Uncommon: Visual disturbances.

Laboratory abnormalities

• Common: Hyperkalemia (classic in 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.

Typical course

• 60-85% of pharmaceutical digoxin is absorbed following ingestion.
• Peak effects occur within 6-12 hours post ingestion.
• In overdose, cardiac toxicity may occur within 30 minutes.
• Not removed by extracorporeal means.

Mechanism of Toxicity

• Inhibits cardiac and skeletal muscle Na-K-ATPase pumps resulting in increased intracellular sodium which increases activity of Na-Ca pump and intracellular calcium, leading to enhanced myocardial contractility and automaticity.
• At toxic levels, increased automaticity contributes to tachydysrhythmias.
• Inhibition of Na-K-ATPase also results in hyperkalemia.
• Hypokalemia may be seen in chronic overdose
• Death is usually due to asystolic cardiac arrest.

Toxic Dose

• Toxic dose is not well established.
• “Therapeutic” 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.
• 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.

• Serum levels do not correlate well with toxic effects:
  • interpret 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; correlate with clinical effects.

• Relying on digoxin levels to confirm diagnosis.
• The presence of concomitant cardiac medications contributing to the clinical picture.

• 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 free serum digoxin levels (usually NOT available). Note: Serum total digoxin 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
  • • Indications
      • 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.
    • Dosing of antidote is based on serum digoxin level, or the amount ingested.
    • Other cardiac glycoside poisonings.
      • DigiFab ® can be used to reverse the effects of non-pharmaceutical cardiac glycosides.
    • 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:
    • 0.5 – 1 mg  q 15 minutes up to maximum of 3 mg.
  • Magnesium may be beneficial even in patients with normal levels:
    • MgSO₄ 2 grams IV over 15 minutes.
  • 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.

• Avoid
  • Beta-blockers, procainamide, amiodarone – may worsen AV block.

• Hyperkalemia
  • Usually responds to antidotal therapy.
  • If antidote not immediately available, treatment with intravenous insulin/dextrose, and/or sodium bicarbonate may be useful.
    • Humulin R 10 Units IV + 50 CC D50W.
    • NaHCO₃ 1 – 2 ampules (1 ml/kg).
  • 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.

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

• Patients often require higher level of care and may require transfer. Consult BC Drug and Poison Information Centre (DPIC) for further discussions.
  • 604-682-5050, 1-800-567-8911, dpic.org.

• Asymptomatic patients should be monitored for at least 12 hours after ingestion as toxicity can be delayed.
• Patients should be monitored a minimum of 2-3 days following cardiac glycoside toxicity.
• Psychiatric consultation should be sought if the overdose was intentional.

1. Poison Management Manual, BC Drug and Poison Information Centre, 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.