eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Toxicology

Toxicity, Digitalis

Author: Kenneth T Kwon, MD, Director of Pediatric Emergency Medicine, Associate Clinical Professor, Department of Emergency Medicine, University of California at Irvine Medical Center
Contributor Information and Disclosures

Updated: Nov 6, 2008

Introduction

Background

Digitalis is a cardiac glycoside with many important therapeutic considerations. Although these concerns are predominant in the adult population, acute digitalis poisoning in the pediatric population is well described in the literature. Despite improved pharmacologic knowledge, digitalis poisoning continues to be a serious problem in infants and children because of its wide availability and narrow therapeutic index. The availability of digoxin-specific fragment antigen binding (Fab) antibody fragments has considerably improved the outlook of patients with severe forms of digitalis poisoning.

Digoxin is the most widely used cardiac glycoside and the only digitalis preparation in common therapeutic use in the United States. In 1980, digoxin was the eighth most widely prescribed drug in the United States; many recent surveys list it among the top 10 drugs prescribed in office practice. 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 in certain toad species. Herbal exposure usually occurs through the ingestion of plants or the inhalation of smoke from burning plants. Cardiac glycoside toxicity accounts for 2.6% of reported cases of toxicity due to plant ingestion.

Pathophysiology

Digitalis inhibits the active transport of sodium and potassium across cell membranes by binding to a specific site on the extracytoplasmic surface of the alpha subunit of the sodium-activated and potassium-activated adenosine triphosphatase (NaK ATPase) pump; this binding is a reversible process. The net result is an increase in the intracellular sodium and calcium concentrations and a decrease in the intracellular potassium concentration. Digitalis increases phase 4 of the action potential in most myocardial tissue, leading to a reduction of conduction velocity with increased automaticity and ectopic activity. Improved inotropy is due to an increased concentration of cytosolic calcium ions during systole. Digitalis also has a negative chronotropic action, which is partly a vagal effect and partly a direct effect on the sinoatrial (SA) node.

The therapeutic daily dose of digoxin ranges from about 0.005 mg/kg in premature infants to as much as 0.75 mg in adults. 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.

The volume of distribution is 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 does of less than 5 mg seldom causes severe toxicity, but a does 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.

Frequency

United States

The prevalence of digitalis toxicity in the pediatric population are difficult to establish. As many as 15% of hospitalized adults are receiving digoxin therapy, and the prevalence of digoxin toxicity is as high as 30%. In 1985, the American Association of Poison Control Centers (AAPCC) National Data Collection System (Toxic Exposure Surveillance System) reported 1015 cases of cardiac glycoside overdose, of which 584 involved children younger than 6 years, and 56 involved children aged 6-17 years.¹ Of all adult and pediatric patients, 842 cases (83%) were nonintentional.

Mortality/Morbidity

Overall mortality rates vary among different pediatric studies; rates of 10-24% were reported before the introduction of digoxin-specific Fab antibody fragments. The overall mortality rate and rate of response to Fab therapy in children are similar to those in adults. The mortality rate as a direct result of cardiac toxicity is 3-21%.

Sex

The incidence of digitalis poisoning is higher in males than in females; males also have a higher mortality rate.

Age

Manifestations of digitalis toxicity vary depending on age; populations at the extremes of age are most susceptible. For instance, ventricular ectopy is most prevalent in older patients; conduction defects and supraventricular ectopic rhythms are most prevalent in younger patients.

Most cases of cardiac glycoside toxicity related to plant ingestion occur in children younger than 6 years. Of the 1015 cases of cardiac glycoside overdose reported by the AAPCC in 1985, 584 involved children younger than 6 years, and 56 involved children aged 6-17 years.¹ In 80% of reported cases of digitalis toxicity in toddlers, children had found and ingested their grandparents' medications.

Clinical

History

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.

• CNS
  • Lethargy or drowsiness
  • Confusion or giddiness
  • Headaches
  • Hallucinations
  • Visual changes, including aberrations in color vision (chromatopsia) and yellow halos around lights (xanthopsia), transient amblyopia or scotomata, and decreased visual acuity
  • Seizures (rare)
  • Syncope
• GI system
  • Nausea and vomiting
  • Diarrhea
  • Anorexia, weight loss, or failure to thrive
  • Abdominal pain
• Cardiovascular system (see Procedures)

Physical

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.

Causes

• Therapeutic administration can cause toxicity.
  • Usual therapeutic doses
  • Doses with errors in prescription, dispensing, or administration
• Acute nontherapeutic overdose can cause toxicity.
  • Unintentional
  • Suicidal
  • Homicidal
• The main causes of digitalis toxicity in the pediatric population include the following:
  • Erroneous dosing in infants, which is usually parenteral and frequently fatal
  • Unintentional ingestion in younger children, which is rarely fatal
  • Intentional ingestion in older children and young adults, which results in variable mortality rates. In addition, many suicide attempts with digitalis ingestion have been reported in the pediatric population.
• Electrolytic abnormalities can worsen digitalis toxicity.
  • Hypokalemia can worsen toxicity. Hypokalemia is usually observed with chronic toxicity or in patients taking diuretics. Hypokalemia reduces the rate of sodium-activated and potassium-activated adenosine triphosphatase (NaK ATPase) pump turnover and exacerbates pump inhibition due to digitalis.
  • Hyperkalemia can also worsen toxicity. In pediatric patients, hyperkalemia is usually a complication of acute toxicity rather than a cause; however, preexisting hyperkalemia increases the risk of morbidity and mortality.
  • Hypomagnesemia and hypercalcemia aggravate toxicity.
• Concomitant use of the following drugs can exacerbate digitalis toxicity:
  • Quinidine, procainamide, amiodarone, calcium channel blockers, beta-blockers
  • Diuretics, including spironolactone
  • Erythromycin and tetracycline: These agents can increase serum digoxin levels by inactivating an enteric bacterium (Eubacterium species) that is present in 10% of the population. This bacterium inactivates digoxin in the GI tract.
• Other risk factors include the following:
  • Renal dysfunction
  • Hypothyroidism
  • Hypoxemia
  • Alkalosis
  • Myocardial disease
  • Extremes of age

• Search for CME/CE on This Topic »

• Toxicity, Digitalis (Emergency Medicine)
• Digitalis Toxicity (Cardiology)
• Plant Poisoning, Glycosides - Cardiac (Emergency Medicine)
• Hyperkalemia (Emergency Medicine)

• Drug Overdose Overview
• Activated Charcoal
• Drug Overdose Center
• Poisoning - First Aid and Emergency Center
• Poisoning Overview
• Poisoning Causes
• Poisoning Symptoms
• Poisoning Treatment
• Poison Proofing Your Home

• Serotonin Toxicity, ECG Abnormalities Seen With Escitalopram Overdose
• Genetically Diverse Mouse Panel Predicts Individual Variability in Drug Toxicity
• "Substantial" Toxicity With Peginterferon Use: FDA Staff

• Dronedarone: A New Treatment for Atrial Fibrillation
• Why the NIH Trial to Assess Chelation Therapy (TACT) Should Be Abandoned
• Life-Threatening Condition (III)