Dose and efficacy of repeated administrations of digoxin‐specific antibody fragments: Case report of foxglove poisoning

Digifab® is indicated for digoxin poisoning. One vial contains 40 mg of digoxin-specific antibody fragments (Fab) for intravenous administration. In cases of pharmaceutical digoxin poisoning, the necessary dose for complete neutralization is obtained by defined calculation. An empirical dose of 20 vials can be used in case of life-threatening poisoning without available serum digoxin level or estimation of amount ingested. Administration of initially 10 vials followed by 10 further vials is possible to avoid febrile reactions.1 In cases of digoxin and cardiac glycosides plant poisoning, there are no official recommendations; the Digifab® dose administered is empirical. A 71-year-old woman, 55 kg, without cardiac history or long-term medication and whose diet included vegetable and plant juice obtained using a juice extractor that cold presses ingredients, ingested plant juice made with accidentally picked young foxglove leaves. Vomiting followed within half an hour, and she was first taken to a nearby hospital with diffuse and non-specific repolarization disorders, atrial fibrillation, third degree atrioventricular block (AVB) with heart rate of 30 to 40 beats per minute (bpm), curved ST segment depression (Figure 1A), hyperkalaemia and hypercalcaemia (Table 1). She was transiently confused and described black dots and yellow-coloured vision. Bradycardia persisted despite atropine and isoprenaline, requiring transfer to our cardiac intensive care unit the next day. During transfer, she presented ventricular tachycardia and torsades de pointes requiring defibrillation three times and stoppage of cardiotonic drugs. Once arrived, serum digoxin assay was performed and showed 4.12 ng/mL digoxin level 20 hours after ingestion. Then, she received 5 repeated administrations of Digifab® over 6 days, amounting to 600 mg (15 vials) in total: initial dose of 120 mg on day 1 (20 hours after ingestion) then 80 mg 4 hours afterwards, 80 mg on day 2, 120 mg on day 5 and 200 mg on day 6. Vomiting disappeared within 4 days. Confusion subsided within 2 days, and dyschromatopsia persisted for 5 days. Third and second degree AVB persisted for 9 days. Curved ST segment depression still persisted at 10 days (Figure 1B-D). Heart rate normalized at 50 bpm after 15 days of hospitalization under telemetric monitoring. The trans-thoracic ultrasound did not find mitral or aortic valve disease, no segmental kinetic disorder and ventricle morphology was normal. The patient went back home after 15 days of hospitalization. The follow-up consultation one month later showed asymptomatic cardiovascular situation with sinus rhythm at 56 bpm without repolarization disorder (Figure 1E). H20 (before the first administration of Digifab®) D2 (before the third administration of Digifab®) D3 D6 (before the fifth administration of Digifab®) Total bilirubin (µmol/L) Symptoms correspond to common digitalis intoxication signs (bradycardia, vomiting, vision disturbance and confusion). Presence of curved segment ST, typical sign of digitalis impregnation, may suggest impregnation by former plant juice ingestions containing digitalis glycosides. In this case, Digifab® appeared ineffective in view of persisting symptoms after each administration and signs persist a long time, such as bradycardia 14 days after onset of treatment. Resolution is usually observed during antidote infusion with correction of toxic effects in the following hours.2 Symptoms may have been resolved by physiological clearance of toxins from the body. Digoxin-Fab has strong affinity for digoxin, sufficient cross-reactivity with digitoxin and can neutralize with weaker affinity other cardiac glycosides by their structural similarities requiring higher doses for effective binding.2 In cases of cardiac glycosides plant poisoning, antidote dose should not be correlated with serum digoxin level due to cross-reactivity with other cardiac glycosides which interfere with immunoassay. The digoxin quantitative value does not correspond to the degree of toxicity; digoxin-Fab dose should depend on severity of clinical signs.3 Therefore, higher loading dose could have been considered due to clinical severity and the low risk of adverse effects of Digifab® which are usually moderate-hypersensitivity reactions: skin rash, urticaria, oedema and shivers.2 However, Digifab® single or multiple toxic dose has not been determined.4 Administration 20 hours after ingestion may seem late, but a case report describes improvement in symptoms within one hour after administration of 200 mg of digoxin-Fab for a patient and 400 mg for a second one, 4 days after foxglove ingestion.3 No other cardiotonic glycosides assay was made to identify foxglove species although Digitalis purpurea is suspected because of its geographic distribution. Heteroside compositions depend on foxglove species and the best described are those of Digitalis purpurea and Digitalis lanata: D lanata leaf contains digoxin precursor and up to 1% cardiotonic heterosides whereas D purpurea leaf contains digitoxin and between 0.1% and 0.4% cardiotonic heterosides 5 (Table 2). Digitoxin assay would have been interesting because digitoxin and digoxin pharmacokinetics are different; for example, mean residence time is longer for digitoxin than digoxin that may promote persistence of clinical signs. Moreover, pharmacokinetics of other heterosides in foxglove extract is not described and remains non-controlled concerning half-life, distribution, protein binding, storage compartment, metabolism and excretion. Besides, their synergistic action can cause more complex toxicity. Cardiotonic heterosides block the Na+/K+ ATPase pump which consists of three subunits for which several isoforms have been identified: four isoforms of α, three of β and seven of FXYD subunit. Multiple α-β-FXYD assemblies are possible with specific affinities depending on the isoforms.6 However, heterosides' affinity for each isoform is not defined. Some may have stronger affinity for Na+/K+ ATPase pump than for digoxin-Fab which may explain its ineffectiveness in neutralizing. Possible rebound intoxication with glycosides in storage compartment or involved in enterohepatic cycling such as digitoxin may require repeated administrations of Fab or maintenance dose after the loading dose over 8 hours of continuous intravenous infusion which could be considered to allow the antidote to continuously bind cardiac glycosides. Moreover, necessity of multiple doses activated charcoal may be discussed to interrupt enterohepatic cycling and intestinal absorption.7 Digifab® recommended loading dose infusion duration from 15 to 30 minutes could be increased to optimize neutralization because rapid Fab infusion could cause early antibody elimination in view of digoxin redistribution on tissue targets. In addition, half-life of Digifab® (10 to 20 hours) is shorter than digoxin (39 hours) and digitoxin (161 hours).2 Finally, a lack of response to the antibody is also possible. In this case, repeated Digifab® administrations with 600 mg dose in total were not enough to resolve signs of foxglove poisoning without other treatment. Higher loading dose could have been considered, and antibody infusion duration could be reassessed. It is currently difficult to establish standardized case management. The authors thank the Poison Control Center of Angers for their help in the patient case management (Angers University Hospital, 4 rue Larrey, 49100 Angers). The authors report no conflict of interest.