Digoxin Toxicity

Digoxin inhibits the sodium-potassium ATPase pump, raising intracellular calcium (positive inotropy) and increasing vagal tone and automaticity. The therapeutic range is 0.5 to 0.9 ng/mL for heart failure (up to 2.0 ng/mL for atrial fibrillation rate control). Toxicity may occur within the range in the presence of hypokalemia, hypomagnesemia and hypercalcemia.

Patterns

• Chronic toxicity (the most common, in older patients with renal impairment): accumulation, with normal or modestly raised potassium
• Acute overdose: ingestion of over 10 mg in an adult (over 4 mg in a child, or 0.1 mg/kg) is dangerous, with hyperkalemia reflecting pump inhibition

Interacting drugs that raise levels: amiodarone, verapamil, diltiazem, clarithromycin, quinidine, propafenone, spironolactone, dronedarone, and drugs that cause hypokalemia (loop and thiazide diuretics). Serum potassium over 5.0 mmol/L in acute poisoning predicts poor outcome, and over 5.5 mmol/L indicates high mortality without antidote. Complications: ventricular arrhythmia, high-grade atrioventricular block, asystole and cardiac arrest. Plant sources (foxglove, oleander) cause the same syndrome.

• Gastrointestinal: anorexia, nausea, vomiting, abdominal pain
• Neurological and visual: confusion, drowsiness, delirium, blurred vision, yellow-green discoloration and halos
• Cardiac: sinus bradycardia, atrioventricular block of any degree, atrial tachycardia with block, premature ventricular beats (bigeminy), bidirectional ventricular tachycardia, ventricular fibrillation, and a "reverse tick" ST depression
• Hyperkalemia in acute poisoning, and hypokalemia in chronic poisoning from diuretics
• Red flags: any arrhythmia, hyperkalemia, hypotension, syncope and high-grade block

1. 12-lead ECG and continuous monitoring.
2. Serum digoxin level at least 6 hours after the last dose (distribution phase over 6 hours falsely elevates earlier samples), repeated at 6 to 12 hours. A level over 2 ng/mL indicates possible toxicity, but treatment is based on clinical signs and potassium. Falsely raised levels occur after antibody therapy (total digoxin remains high while free digoxin is bound).
3. Potassium, magnesium, calcium, creatinine and estimated glomerular filtration rate.
4. Thyroid function and a drug history, including herbal sources.

Differentials: drug-induced bradyarrhythmia (beta blockers, calcium channel blockers), conduction system disease, ischemia, hyperkalemia of other cause, other causes of nausea and delirium.

1. Stop digoxin, give oxygen, cardiac monitoring and IV access.
2. Electrolytes:
   • Replace potassium cautiously when low, aiming for 4.0 to 5.0 mmol/L.
   • Magnesium sulfate 2 g IV over 20 minutes for ventricular arrhythmia, or when magnesium is low.
   • Hyperkalemia over 5.5 mmol/L in acute poisoning: give digoxin-specific antibody fragments first. If unavailable, use regular insulin 10 units IV with 50 mL of 50% dextrose, and calcium is acceptable.
3. Digoxin-specific antibody fragments (Fab): each 40 mg vial binds about 0.5 mg of digoxin.
   • Indications: life-threatening arrhythmia or high-grade block, hemodynamic instability, potassium over 5.0 mmol/L in acute poisoning, acute ingestion of over 10 mg (adult) or 4 mg (child), steady-state level over 10 ng/mL (over 15 ng/mL at 6 hours after acute ingestion), or rapidly worsening features.
   • Dose by level: number of vials equals serum digoxin (ng/mL) multiplied by body weight (kg) divided by 100.
   • Dose by amount: number of vials equals the dose ingested in mg divided by 0.5 (multiplied by 0.8 for bioavailability).
   • Empiric dose: acute poisoning of unknown amount, 10 vials (400 mg) IV over 30 minutes (as a bolus in cardiac arrest). Chronic poisoning, 3 to 6 vials IV. Children: 1 to 2 vials for chronic toxicity, with dose by weight formula for acute.
   • Monitor potassium (it falls rapidly after Fab), heart failure and atrial fibrillation (rate control returns after digoxin is reversed). Response begins in 20 to 30 minutes.
4. Bradycardia with hemodynamic effect: atropine 0.5 to 1 mg IV every 3 to 5 minutes (maximum 3 mg). Temporary transvenous pacing is risky because it may induce ventricular fibrillation, so use only after Fab fails.
5. Ventricular arrhythmia: Fab first, magnesium, then lidocaine 1 to 1.5 mg/kg IV, followed by infusion at 1 to 4 mg/min. Avoid class Ia antiarrhythmics and, if cardioversion is needed, use the lowest energy (25 to 50 J) because of the risk of asystole.
6. Gut decontamination: activated charcoal 50 g orally (children 1 g/kg) within 1 to 2 hours for acute ingestion, with repeated doses of 25 g every 4 hours in the first 24 hours (digoxin undergoes enterohepatic recirculation).
7. Hemodialysis does not remove digoxin because of its large volume of distribution.

Follow-up: observation on a monitored bed until digoxin-related ECG changes resolve and the potassium is stable. Review the need for digoxin, the dose adjustment for renal function (reduce by 50% in impaired function), and interacting drugs. Counsel on symptoms of toxicity and on regular level monitoring.