Digoxin toxicity

Background

• Digoxin (digitalis) is a cardiac glycoside used for atrial fibrillation rate control and heart failure
• Narrow therapeutic index (therapeutic level: 0.5-2.0 ng/mL)
• Mechanism of action: inhibits Na/K-ATPase → increased intracellular calcium → increased contractility
• Also increases vagal tone (AV nodal blockade)
• Toxicity occurs from:
  • Acute ingestion (intentional overdose, accidental)
  • Chronic accumulation (most common — renal insufficiency, drug interactions, dehydration)
• Drug interactions that increase digoxin levels:
  • Amiodarone (increases level by ~50%), verapamil, diltiazem, quinidine
  • Macrolide antibiotics (erythromycin, clarithromycin)
  • Cyclosporine, itraconazole
• Conditions that increase sensitivity to digoxin:
  • Hypokalemia (most important — K and digoxin compete for same binding site)
  • Hypomagnesemia, hypercalcemia, hypothyroidism, renal failure
• Mortality without antidote: up to 20-30% in significant poisoning

Clinical Features

GI (Often Earliest)

• Nausea, vomiting, anorexia (most common symptoms)
• Abdominal pain, diarrhea

Cardiac (Most Dangerous)

• Almost ANY dysrhythmia can occur
• Classic: increased automaticity + decreased conduction
• Most common arrhythmia: PVCs
• Highly suggestive rhythms:
  • Bidirectional ventricular tachycardia (nearly pathognomonic)
  • Atrial tachycardia with AV block (PAT with block)
  • Accelerated junctional rhythm
  • Regularized atrial fibrillation (AF with complete heart block + junctional escape)
• Sinus bradycardia, AV block (1st, 2nd, 3rd degree)
• Ventricular fibrillation / asystole (in severe toxicity)

Neurologic

• Visual disturbances: xanthopsia (yellow-green halo vision), blurred vision, photophobia
• Confusion, delirium, weakness, fatigue
• Drowsiness

Metabolic

• Hyperkalemia in acute toxicity (Na/K-ATPase inhibition → K moves extracellularly)
  • K >5.0 in acute digoxin poisoning is a marker of severe toxicity
  • In chronic toxicity, K is often low (from concurrent diuretic use)

Differential Diagnosis

• Other causes of bradycardia with heart block
• Beta-blocker or calcium channel blocker overdose
• Hyperkalemia
• Oleander or foxglove poisoning (contain cardiac glycosides)
• Other causes of bidirectional VT: catecholaminergic polymorphic VT, aconitine

Evaluation

• ECG (look for dysrhythmias, ST changes)
  • Digitalis effect (scooped ST depression, "Salvador Dali mustache") ≠ toxicity
  • Digitalis toxicity = arrhythmias
• Digoxin level:
  • Therapeutic: 0.5-2.0 ng/mL
  • Draw level ≥6 hours after last dose (allows tissue distribution)
  • Level >2.0 suggests toxicity but clinical correlation is essential
  • Level may be falsely elevated after Digibind (measures bound + unbound)
• BMP: potassium (critical — hypokalemia worsens toxicity), creatinine, magnesium, calcium
• Magnesium level (hypomagnesemia increases digoxin sensitivity)

Management

Digoxin-Specific Antibody Fragments (DigiFab/Digibind)

• Definitive antidote — highly effective
• Indications for empiric dosing:
  • Life-threatening arrhythmias (VT, VF, symptomatic bradycardia, high-grade AV block)
  • Hyperkalemia >5.0 mEq/L in acute poisoning
  • Hemodynamic instability
  • Digoxin level >10 ng/mL (acute) or >4 ng/mL (chronic) with symptoms
• Dosing:
  • If amount ingested known: # vials = (body load in mg × 0.8) / 0.5
  • If level known: # vials = (level ng/mL × weight kg) / 100
  • Empiric dosing: 10-20 vials for acute life-threatening toxicity; 3-6 vials for chronic toxicity
  • Onset: 30-60 minutes
• Each vial binds ~0.5 mg digoxin
• Post-Digibind: total digoxin level rises (bound to antibody) but free digoxin decreases

Supportive Measures

• Correct hypokalemia to >4.0 mEq/L (in chronic toxicity)
• Correct hypomagnesemia: magnesium sulfate 2g IV
• Calcium: CONTROVERSIAL in digoxin toxicity
  • Traditional teaching: avoid calcium (risk of "stone heart")
  • Recent evidence suggests risk may be overstated, but use with extreme caution
  • If hyperkalemic arrest, may give calcium but administer Digibind simultaneously
• Atropine for symptomatic bradycardia: 0.5-1 mg IV (may repeat)
• Activated charcoal if acute ingestion within 1-2 hours and protected airway
• Avoid electrical cardioversion if possible (may precipitate VF in digitalis toxicity)
• If cardioversion unavoidable: use lowest effective energy

What to Avoid

• No calcium (controversial — may worsen toxicity)
• No Class IA antiarrhythmics (procainamide, quinidine — worsen conduction)
• Minimize cardioversion
• No beta-blockers (worsen bradycardia/AV block)

Refractory Cases

• Lidocaine (for ventricular arrhythmias not responsive to Digibind)
• Phenytoin (can improve conduction through AV node; historical use)
• Temporary pacing for complete heart block refractory to atropine and Digibind
• Consider hemodialysis — does NOT effectively remove digoxin (highly protein/tissue bound) but may help if Digibind unavailable

Disposition

• Admit all symptomatic patients to monitored bed or ICU
• ICU for arrhythmias, hemodynamic instability, or Digibind administration
• Continuous telemetry for minimum 12-24 hours
• Serial digoxin levels are NOT useful post-Digibind (measures total, not free)
• Poison control: 1-800-222-1222

See Also

• Toxicology
• Atrial fibrillation
• Heart failure
• Hyperkalemia
• Cardiac arrest
• Beta-blocker toxicity
• Calcium channel blocker overdose

References

• Hauptman PJ, Kelly RA. Digitalis. Circulation. 1999;99(9):1265-1270. PMID 10069797
• Hack JB, Lewin NA. Cardioactive steroids. In: Goldfrank's Toxicologic Emergencies. 10th ed. McGraw-Hill. 2015.
• Chan BS, Buckley NA. Digoxin-specific antibody fragments in the treatment of digoxin toxicity. Clin Toxicol. 2014;52(8):824-836. PMID 25089630
• Levine M, et al. The effects of intravenous calcium in patients with digoxin toxicity. J Emerg Med. 2011;40(1):41-46. PMID 18814997