Pediatric Digitalis Toxicity 

Digitalis is a plant-derived cardiac glycoside commonly used in the treatment of congestive heart failure, atrial fibrillation, and reentrant SVT.^{[1, 2]} Digoxin is the only available preparation of digitalis in the United States.

Cardiac glycoside poisoning continues to be a problem in the United States because of the wide availability of digoxin and the narrow therapeutic window. Although most digoxin toxicity occurs in the adult population, acute cardiac glycoside toxicity is well described in the pediatric literature.^{[3, 4]} Digoxin-specific fragment antigen binding (Fab) antibody fragments have contributed significantly to the improved morbidity and mortality of toxic patients since their approval in 1986 by the US Food and Drug Administration (FDA).

In 1980, digoxin was one of the 10 most commonly prescribed drugs in the United States. Although its use has declined in recent years^[5] , it is still among the top 50 prescribed drugs in the United States.^[6] Digitalislike compounds are also found in certain plants, such as the common oleander, foxglove, yew berry, dogbane, lily of the valley, and red squill, as well as certain toad species. Herbal exposure usually occurs through the ingestion of plants or the inhalation of smoke from burning plants. Cardiac glycosides account for 2.6% of toxic plant exposures in the United States.^{[7, 8]} Most of these exposures are in children.^[8]

Digitalis has effects on both the automaticity and inotrophy of the heart. Digitalis reversibly binds to the extracytoplasmic surface of the sodium and potassium-activated adenosine triphosphate pump (Na⁺ K⁺ ATPase). In doing so, it inhibits the active transport of sodium and potassium across the cell membrane, leading to a rise in intracellular sodium with each action potential. This causes an increase in the intracellular calcium concentration secondary to either enhanced entry or reduced efflux via the sodium-calcium exchanger.^[9] By a mechanism not completely understood, the increased intracellular calcium concentration leads to improved cardiac inotropy by increasing phases 4 and 0 of the cardiac action potential. Digitalis also has negative chronotropic action, which is partly a vagal effect and partly a direct effect on the sinoatrial (SA) node.

Digitalis affects different myocardial tissue in different ways. While the atria and ventricles may exhibit increased automaticity with causatives tachydysrhythmias, nodal tissue may be slowed leading to prolonged PR interval and AV nodal block.

The therapeutic daily dose of digoxin ranges from 5-15 mcg/kg. The absorption of digoxin tablets is 70-80%; its bioavailability is 95%. The kidney excretes 60-80% of the digoxin dose unchanged. The onset of action by oral (PO) administration occurs in 30-120 minutes; the onset of action with intravenous (IV) administration occurs in 5-30 minutes. The peak effect with PO dosing is 2-6 hours, and that with IV dosing is 5-30 hours. Only 1% of the total amount of digoxin in the body is in the serum; of that amount, approximately 25% is protein bound.

Digoxin has a large volume of distribution: 6-10 L/kg in adults, 10 L/kg in neonates, and as much as 16 L/kg in infants and toddlers. At therapeutic levels, the elimination half-life is 36 hours with renal excretion. In acute digoxin intoxication in toddlers and children, the average plasma half-life is 11 hours. With acute intoxication, plasma concentrations extrapolated to time zero is lower in toddlers than in infants and older children because of their increased volume of distribution and clearance.

The lethal dose of digoxin is considered to be 20-50 times the maintenance dose taken at once. In healthy adults, a dose of less than 5 mg seldom causes severe toxicity, but a dose of more than 10 mg is almost always fatal. In the pediatric population, the ingestion of more than 4 mg or 0.3 mg/kg portends serious toxicity. However, plasma concentration does not always correlate with the risk of toxicity.^[10]

Frequency

United States

In 1999 the American Association of Poison Control Centers (AAPCC) reported approximately 3000 pediatric poisonings associated with cardiac glycoside.^[7] Of these, most were plant ingestions (66%) and digoxin exposures (33%, including therapeutic errors, intentional, and unintentional ingestions). The number of AAPCC reported cases decreased in 2008 to 1000 plant exposures and 300 digoxin poisonings.^[8] Although the number of reporting poison centers decreased in 2008, this number appears to be a true decline of poisonings related to cardiac glycoside.

Mortality/Morbidity

In 2008, there was 1 pediatric fatality in approximately 1300 cardiac glycoside exposures reported to poison control centers.^[8] Overall, morbidity varies from study to study. Combined adult and pediatric data reveal that exposures to cardiac glycoside toxic plants cause no morbidity in most cases. The 2008 AAPCC report has follow-up for 518 patients exposed to digitalis-like plants. Of these, 509 had little to no clinical effects, 17 had moderate effects, and only 1 had major effects. There were no deaths. Of the data available for 1044 patients with digoxin poisoning, 422 had little to no effect, 490 had moderate effects, and 115 had major effects. There were 17 deaths, only one of which was pediatric.

Sex

Pediatric poisonings from any substance are more common in males than in females.^{[8, 7]} However, for digoxin toxicity, a Netherlands study found no difference in incidence between pediatric males and females.^[11] The adult literature suggests women may be more susceptible to adverse effects than men.^{[11, 12]}

Age

Manifestations of digitalis toxicity vary depending on age. For instance, ventricular ectopy is most prevalent in older patients; conduction defects and supraventricular ectopic rhythms are most prevalent in younger patients. Children (≤ 19 y) account for almost 80% of plant exposures and 20% of drug toxicity/poisonings reported to the AAPCC.^[8] In most of these cases, the child was younger than 6 years. One study suggests that adolescents are more susceptible to digoxin on a mg/kg basis.^[3]