Digoxin Toxicity

Etiology

Digoxin exhibits its therapeutic and toxic effects by poisoning the sodium-potassium ATPase. The subsequent increase in intracellular sodium leads to increased intracellular calcium by decreasing calcium expulsion through the sodium-calcium cation exchanger. Higher intracellular calcium increases inotropy, which can be of symptomatic benefit in CHF. At toxic levels, automaticity can also be increased. Digoxin also increases vagal tone by decreasing dromotropy at the AV node. This can be used to control atrial tachydysrhythmias.

Epidemiology

Approximately 1% of patients with heart failure treated with digoxin develop toxicity. Additionally, 1% of adverse drug effects in patients greater than age 40 are due to digoxin toxicity; the incidence rises to greater than 3% in patients over age 85. Plant ingestions account for 80% of pediatric exposure; the remaining 20% of pediatric ingestions arise from medications. In general, ventricular dysrhythmias are more common in the elderly, whereas supraventricular dysrhythmias are more common in children.

Pathophysiology

Increased intracellular calcium from the poisoning of the Na-K transporter and AV nodal blockade from increased vagal tone are the primary causes of digoxin toxicity. The former leads to increased automaticity and inotropy, leading to decreased dromotropy. Hyperkalemia can be a marker of severe toxicity in acute poisoning. The role of potassium is less clear in chronic toxicity, although it has been linked to higher mortality despite traditional teaching that hypokalemia worsens the dysfunction at the Na-K transporter.[5][6][7]

Toxicokinetics

Digoxin's therapeutic half-life is between 30 and 40 hours, but this may change in overdose. Digoxin excretion is primarily renal, and for this reason, patients with poor or worsening renal function, such as the elderly or those with chronic kidney disease, are more likely to develop toxicity. Digoxin levels start to plateau at 6 hours after tissue redistribution has occurred; earlier levels may thus be misleadingly high. Cardiovascular toxicity may have delayed manifestation of up to 8 to 12 hours post-ingestion.

History and Physical

Gastrointestinal upset is the most common symptom of digoxin toxicity. Patients also may report visual symptoms, which classically present as a yellow-green discoloration, and cardiovascular symptoms, such as palpitations, dyspnea, and syncope. Elderly patients frequently present with vague symptoms, such as dizziness and fatigue. The most important historical detail in evaluating a random digoxin level is the time of the last dose.

Evaluation

For patients with acute digoxin toxicity, it is critical to obtain an ECG, a basic metabolic panel, and digoxin levels on arrival. These tests should be repeated at 6 hours post-ingestion. Digoxin's effect on the ECG is characterized by diffuse scooping of the ST segments, which can be seen with therapeutic levels and is not associated with toxicity. The most common ECG abnormality is frequent PVCs, although the "pathognomonic" ECG finding is bidirectional ventricular tachycardia. However, this has been reported in aconitine poisoning.[8][9][10] In the setting of acute overdose, acetaminophen and aspirin levels can help screen for occult overdose. In chronic toxicity, the cause of toxicity should be sought. Common causes include infection, renal failure, and accidental overdose. Serum digoxin levels do not always correlate with toxicity, given variable tissue levels and other factors affecting digoxin's toxicodynamic effects.

Treatment / Management

Digoxin-specific antibody antigen-binding fragments (DSFab) are an effective antidote that directly binds digoxin. DSFab is indicated for life-threatening toxicity, including:

• Ventricular arrhythmias
• High-grade heart blocks
• Hypotension
• Symptomatic bradycardia
• Potassium greater than 5 meq/L in acute overdose
• Acute ingestions greater than 10 mg in an adult or greater than 4 mg in a child
• Digoxin Concentration greater than 15 ng/mL measured at any time
• Digoxin Concentration greater than 10 ng/mL measured 6 hours post-ingestion.

Empiric dosing of DSFab can be given at a dose of 10 to 20 vials for critically ill patients after acute overdose, 3 to 6 vials for chronic toxicity in adults, or 1 to 2 vials for chronic toxicity in children. DSFab also can be dosed as follows:

• (0.8 times the ingested dose)/0.5 = Number of vials of DSFab for acute overdose
• (Digoxin level (steady state) x Weight (kg))/100 = Number vials of DSFab for acute or chronic overdose

DSFab fragments also can be given for poisoning with natural toxins, but the dosing is unclear. The typical DSFab infusion lasts over 30 minutes, but it may be given as a bolus for critical patients. The onset of the effect is approximately 20 minutes, and the complete effect is usually seen within 90 minutes. Care should be taken to completely reverse digoxin in patients who are chronically taking digoxin, as reversal may exacerbate their underlying disease. These patients should be closely monitored afterward for the same reasons. If DSFab is unavailable, treatments such as multidose-activated charcoal, atropine, and antidysrhythmics such as phenytoin or lidocaine may be employed. Cardioversion and pacing may induce dysrhythmias and are typically not used, but they may be needed in patients without other therapeutic options. Dialysis also may be indicated in patients with acute renal failure or refractory hyperkalemia; however, it is not useful as a treatment for digoxin toxicity itself. Disposition depends on the patient's symptoms, stability, and potassium and digoxin levels.

Differential Diagnosis

Bidirectional ventricular tachycardia, classically described as pathognomonic for digoxin toxicity, may also be seen in aconitine (wolfsbane, monkshood) poisoning and in patients that have familial catecholaminergic polymorphic ventricular tachycardia.[11]