Early digoxin-specific antibody fragments for treating patients at risk of life-threatening digoxin toxicity

To the Editor:

Chan and Buckley have nicely reviewed the treatment of digoxin toxicity using digoxin-specific antibody fragments (Fab).¹ They highlighted the safety and effectiveness of digoxin-Fab in reversing the clinical manifestations, but emphasized the limited indications in patients presenting with life-threatening poisoning, that is, bradyarrhythmias, ventricular arrhythmias, hyperkalemia (> 6 mmol/L), and hemodynamic instability with elevated digoxin concentrations (> 2.6 nmol/L). Based on interesting pharmacokinetic modeling showing that the real digoxin body burden is not as large as usually estimated, they suggested administering bolus doses of digoxin-Fab lower than recommended, that is, 80 mg in acute and 40 mg in chronic poisoning, repeated as required according to clinical parameters. However, due to concerns regarding cost-effectiveness, they did not recommend treating non-life-threatening digoxin toxicity. Accordingly, they did not consider the role of reducing the neutralizing digoxin-Fab dose in improving the final outcome in less severely poisoned patients.

Infra-molar neutralization of digoxin molecules to reduce toxicity is worth considering.² This concept has been validated in several experimental studies. However, as correctly stated by the authors, the lowest effective dose of digoxin-Fab as well as the most efficient dosing regimen is currently not established in humans. Limiting the digoxin-Fab dose regimen at least allows the cost-effectiveness of this expensive antidote to be improved.

In France, since the early nineties, digoxin-Fab has been used as the first-line therapy for digoxin poisoning.³ However, in contrast to Chan and Buckley's recommendations,¹ the early administration of a half-molar dose of digoxin-Fab rather than that of the equimolar dose, usually recommended in life-threatening poisoning, is routinely used as a strategy to prevent further worsening of toxicity in patients with poor prognosis, even if they are initially not or only mildly symptomatic. Poor prognosis is defined by the presence of at least three of the following criteria in the absence of any life-threatening toxicity: 1- male gender; 2- age of greater than 55 years; 3- underlying heart disease; 4- bradycardia with second- or third-degree atrioventricular block; 5- heart rate between 40 and 60/min refractory to administration of 1 mg of atropine, regardless of the conduction disturbances; and 6- hyperkalemia of greater than 4.5 mmol/L. These prognosticators, determined in the early eighties when the ratio of acute digitoxin versus digoxin poisonings was 10/1,⁴ are also used in chronic poisoning; however, prophylaxis is usually indicated if at least one of the final three criteria is present. Based on a retrospective chart review, this strategy has been demonstrated to reduce mortality rate (7.6%) in comparison to strategies limiting digoxin-Fab administration only to patients with life-threatening conditions, even if we agree that many other factors may have contributed to this apparent reduction in fatalities.⁵ As acknowledged by the authors,¹ cardiologists and emergency physicians seem reluctant to use digoxin-Fab and prefer waiting for the onset of life-threatening conditions before administering this useful antidote. Delaying digoxin-Fab administration to digoxin-poisoned patients at risk may result in fatal arrhythmias or worsening organ functions despite the adequacy of the applied supportive treatments, precluding the success of digoxin toxicity reversal using digoxin-Fab, as already suggested.³ In agreement with the pharmacokinetic hypotheses presented by Chan and Buckley,¹ 40–80 mg of digoxin-Fab could be sufficient to successfully avoid recrudescence of symptoms in these poisoned patients with non-life-threatening toxicity, as shown with the initial dose of 2 (1–3) [median (25th–75th percentiles)] and the cumulative dose of 3 (1–4) digoxin-Fab vials administered to such patients in our center.⁵ A slower administration rather than a bolus injection may also be appropriate, but this remains to be determined. Thus, in contrast to Chan and Buckley's conclusions,¹ we would like to strongly encourage increasing the widespread availability of digoxin-Fab to facilitate its early use, especially as prophylaxis in the chronically poisoned elderly who are at further risk of deterioration. Accordingly, a prospective non-randomized study in the Paris area showed promising results regarding the benefit of early digoxin-Fab administration in the ambulance before hospital admission in reducing digoxin toxicity-related morbidities and mortality in generally vulnerable elderly patients at risk of developing more severe toxicity.⁶

Declaration of interest

The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.