Contrasting rates of reversal of digoxin toxicity by digoxin-specific IgG and Fab fragments

Both heterologous IgG and Fab fragments of appropriate affinity and specificity have been shown capable of reversing advanced cardiac glycoside toxicity. Fab fragments are more rapidly excreted and theoretically have a smaller risk of unwanted immunologic effects, but relative rates of toxicity reversal have not been established. Rates of reversal of advanced digoxin toxicity by digoxin-specific IgG and Fab fragments were therefore compared in a dog model of advanced digoxin intoxication. Initial studies confirmed more rapid distribution of sheep Fab fragments (M.W. 50,000) than of the parent IgG molecule (M.W. 150,000) after intravenous injection. Twenty-five pentobarbital-anesthetized dogs were given 0.3 mg/kg digoxin intravenously, resulting in rapid onset of ventricular tachycardia in all animals. Eight dogs subsequently given nonspecific IgG or Fab died in asystole or ventricular fibrillation an average of 55 minutes after digoxin administration. Ten of 11 dogs given 1.33 moles of binding sites per mole of digoxin as intact IgG returned to sinus rhythm at a mean time of 85 minutes after antibody infusion. In contrast, six of six dogs given an equivalent dose of specific Fab fragments returned to sinus rhythm in a significantly shorter mean time of 36 minutes (P less than 0.01). Variability of time to arrhythmia reversion was less in Fab-treated dogs. These data demonstrate a decisive advantage of specific Fab fragments over intact IgG for potential clinical use in advanced, life-threatening digoxin intoxication.