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]
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.
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.
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]
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]
Most cases of pediatric digitalis poisoning are unintentional ingestions; thus, a good social history with emphasis on available medications and the extent of home childproofing is necessary.
Patients can have an asymptomatic period of several minutes to several hours after the oral administration of a single toxic dose. Clinical signs may be subtle or obvious, depending on the severity of toxicity. Acute toxicity is rarely subtle, and chronic toxicity may be difficult to diagnose. CNS changes, most notably nausea, vomiting, and drowsiness are the most common extracardiac manifestations. Visual changes usually affect patients with chronic toxicity.
Emphasis should be placed on the vital signs and the neurologic and cardiovascular findings.
Laboratory studies in patients with digitalis toxicity are as follows:
General supportive care of digitalis toxicity includes hydration with intravenous (IV) fluids, oxygenation and support of ventilatory function, discontinuation of the drug, and sometimes the correction of electrolyte imbalances.
Fab antibody fragments are extremely effective in the treatment of severe acute digitalis toxicity (see below).
Since the approval of purified digoxin-specific Fab antibody fragments by the FDA in 1986, the outcome in severe acute digitalis poisoning has been drastically improved. Other supportive medications may include phenytoin or lidocaine for arrhythmias, atropine, and possibly electrolyte supplementation (see above, Treatment).
Clinical Context: 50,000-Da molecule derived from IgG fragment of sheep antidigoxin antibodies. This relatively pure Fab product is safe and extremely effective. Indications for use include life-threatening arrhythmias (eg, severe bradyarrhythmia, second- or third-degree heart block, ventricular tachycardia or fibrillation), initial potassium level >5 mmol/L, digoxin serum levels >10 ng/mL at 6-8 h after ingestion, digoxin serum levels >15 ng/mL in acute ingestion, and ingestion >10 mg in healthy adults or >4 mg in children.
Binds free digoxin in vascular and interstitial space and decreases free plasma digoxin levels by binding intracellular digoxin from its binding sites in heart and interstitial and intravascular spaces. Raises intravascular levels of inactive antibody-bound digoxin to very high levels, which decrease over several days as it is excreted renally. Response typically observed within 20-30 min; elimination half-life of drug-antibody complex is about 16 h.
Affinity for digitoxin is 10 times less than for digoxin. In recent case series including pediatric patients, 90-93% response rate within minutes or hours, with complete resolution within 180 min in as many as 79% of patients. Mean time to initial response was 19 min; complete resolution of symptoms in 88 min. Each vial contains 40 mg Fab and binds 0.6 mg of digoxin.
This agent is used in the management of poisoning, overdoses, prevention of toxic effects, and metabolic disorders in which toxic substances accrue. In cases of digitalis toxicity, specific antidigoxin antibodies are used to treat hemodynamically unstable or life-threatening arrhythmias and hyperkalemia. Digoxin immune Fab has also been used to treat cardiac glycoside toxicity from oleander and toad venom.[17, 18]
Clinical Context: Anticholinergic agent used to increase heart rate by means of vagolytic effects, increasing cardiac output.
Clinical Context: Depresses spontaneous depolarization in ventricular tissues.
Clinical Context: Class IB antiarrhythmic that increases electrical stimulation threshold of ventricle, suppressing automaticity of conduction through the tissue.
These agents alter the electrophysiologic mechanisms responsible for arrhythmia. These are used as an alternative to digoxin immune Fab.