AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Cardiotoxic plant ingestion
Class I-A cardiac drug toxicity
Clonidine toxicity

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

Laboratory studies in patients with digitalis toxicity are as follows:

• Determination of electrolyte, BUN and creatinine, magnesium, and calcium levels
• • Hyperkalemia is the major electrolytic complication in acute massive digitoxin poisoning.
  • Initial potassium levels are better correlated with the prognosis than either ECG changes or the initial serum digoxin level. In one series, all patients with an initial potassium level greater than 5.5 died, whereas 50% of patients with a serum digoxin level of 5-5.5 died.
  • Hypomagnesemia and hypercalcemia worsen digitalis toxicity.
• Determination of serum digoxin level
• • The recent development of sensitive and accurate radioimmunoassays has improved the diagnosis and management of digitalis toxicity.
  • The therapeutic range is 0.5-2 ng/mL, but significant levels in patients with toxicity and levels in those without toxicity overlap significantly. Digoxin levels cannot be used as the sole indicator of toxicity. Neonates and small infants rarely develop toxic symptoms or ECG abnormalities with serum levels less than 4-5 ng/mL. Children without cardiovascular disease may tolerate levels as high as 10 ng/mL without serious toxicity, but they may have bradyarrhythmias or conduction delays on ECG. The general rule is this: The smaller the infant, the higher the levels may be before toxic effects are observed.
  • levels determined less than 6-8 hours after an acute ingestion reflect the initial distribution of the drug but not the actual tissue levels, and they are not necessarily predictors of toxicity. The plasma half-life of digoxin is shortened to 10-25 hours with acute massive ingestions, compared with a mean value of 36 hours in nontoxic ingestions.
  • Endogenous digoxinlike immunoreactive substance (DLIS) can cause a false-positive result or an elevated digoxin level. DLIS is observed in neonates and in patients with renal insufficiency, liver disease or hyperbilirubinemia, subarachnoid hemorrhage, congestive heart failure, diabetes mellitus, or acromegaly; it may also be present in those who are pregnant or using spironolactone. In some studies, premature infants had levels as high as 4 ng/mL, with peaks at age 6 days, and positive assay results until they were aged 3 months. Most authors agree that serum digoxin levels due to DLIS are usually less than 2 ng/mL and that the interference is assay dependent and may vary with the lot of the reagent. Some laboratories use ultrafiltration techniques to eliminate the contribution of DLIS.
  • Because most digoxin assays measure total rather than free digoxin levels, serum digoxin levels are no longer useful after fragment antigen binding (Fab) administration.

Procedures

• Sinus bradycardia and atrioventricular (AV) conduction blocks are the most common ECG changes in the pediatric population.
• Almost any dysrhythmia may occur except sinus tachycardia, supraventricular tachycardia (SVT), and rapid atrial fibrillation.
• Sinus bradycardia and first-degree or second-degree AV blocks are more common in pediatric patients than in adults, whereas ventricular ectopy is more common in adults.
• Nonparoxysmal atrial tachycardia with a block and bidirectional ventricular tachycardia are particularly characteristic of severe digitalis toxicity.
• Suspect digitalis toxicity when the evidence suggests increased automaticity and depressed conduction.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

General supportive care of digitalis toxicity includes hydration with intravenous (IV) fluids, oxygenation and support of ventilatory function, and correction of electrolyte imbalances.

Most authors recommend potassium supplementation if potassium levels are less than 4 mmol/L. Forced diuresis is not recommended because it has not been shown to increase renal excretion and can worsen electrolyte abnormalities. Dialysis has been shown to produce only small-added clearances.

Digoxin-specific fragment antigen binding (Fab) antibody fragments are extremely effective in the treatment of severe acute digitalis toxicity.

• GI decontamination may be helpful. Activated charcoal is the preferred method of decontamination. Because of the enterohepatic circulation of digoxin and digitoxin, multiple-dose charcoal (1 g/kg/d) may be beneficial.
• • Induced emesis with ipecac syrup is not recommended because of the increased vagal effect.
  • Gastric lavage may be useful early after ingestion because of the prolonged absorption of digoxin; however, lavage can also increase vagal effects because of the placement of the nasogastric tube.
  • Whole-bowel irrigation may be useful, but clinical data are lacking.
  • Steroid-binding resins, such as cholestyramine and colestipol, can prevent the further absorption of digoxin by interrupting the enterohepatic circulation. These agents are especially effective in patients with significant renal insufficiency.
• Digoxin immune Fab is now considered first-line treatment for significant dysrhythmias and should be promptly administered if digoxin toxicity is suspected.^{2, 3, 4}
• • Atropine may be useful in blocking digoxin-induced effects of enhanced vagal tone on the sinoatrial (SA) and atrioventricular (AV) nodes; it has proven helpful in reversing severe sinus bradycardia.
  • Phenytoin is the antiarrhythmic drug of choice for the treatment of digoxin toxicity because it is effective against supraventricular ectopic rhythms and ventricular arrhythmias.
  • Lidocaine is an alternative, but is not effective against supraventricular arrhythmias.
  • Quinidine and procainamide are not used because they intensify the AV block. The intravenous (IV) administration of calcium is absolutely contraindicated because of the increased intracellular calcium concentration in patients with digitoxin toxicity.
  • Cardioversion is generally reserved for the treatment of unstable arrhythmias that are unresponsive to medications such as Digibind. Initial shocks should be at the lowest possible energy levels (10-25 J) because cardioversion can induce intractable ventricular fibrillation.
  • With the availability of digoxin-specific Fab, pacemaker use now has limited value. In one study, the main reason for Fab failure was pacing-induced arrhythmias and delayed or insufficient administration of Fab. This study also had a 36% complication rate with pacing. Generally, pacing should be considered in cases of symptomatic bradycardia or AV block that is unresponsive to medications and in cases in which digoxin-specific Fab is not readily available.

Consultations

• Medical toxicologist
• Local poison control center personnel
• Cardiologist

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Since the introduction of purified digoxin-specific Fab antibody fragments in 1976, the outcome in severe acute digitalis poisoning has been drastically improved. Other supportive medications include phenytoin or lidocaine for arrhythmias, atropine, and magnesium.

Drug Category: Digoxin immune Fab

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.

Drug Category: Antiarrhythmic agents

These agents alter the electrophysiologic mechanisms responsible for arrhythmia. These are used as an alternative to digoxin immune Fab.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Consider the hospital admission of any patient with a history of a large ingested dose, especially if coexisting risk factors increase his or her susceptibility to digoxin toxicity.
• Admit a patient to intensive care unit if he or she has signs or symptoms of toxicity.
• Any patient receiving Fab fragments requires observation in an intensive care setting for at least 24 hours.
• Patients who have had an unintentional exposure but no signs or symptoms of toxicity after 12 hours can be discharged from the hospital.

Deterrence/Prevention

• Individualizing the dosing of cardiac glycosides appears to be the key to their optimal use. The desired plasma concentration endpoint is 2 ng/mL in patients younger than 2 years and 1.5 ng/mL in patients older than 2 years.
• Medical, nursing, and pharmacy staff should carefully monitor the prescription, dispensing, and administration of digitalis. These personnel can help to prevent errors in dosing by paying careful attention to decimal points.

Complications

• Arrhythmias can cause inadequate tissue perfusion with resultant CNS and renal complications such as the following:
• • Hypoxic seizures
  • Encephalopathies
  • Loss of vasoregulation
  • Acute tubular necrosis
• Hyperkalemia is the major electrolytic complication in acute massive digitoxin poisoning. In pediatric patients, hyperkalemia can be a complication of acute toxicity.

Patient Education

• Parents of patient should be educated about the good home childproofing and preventive measures.
• For excellent patient education resources, visit eMedicine's Drug Overdose Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose digitalis toxicity

Special Concerns

• Fetal myocardium has an increased resistance to the toxic effects of digitalis.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Litovitz TL, Normann SA, Veltri JC. 1985 Annual Report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med. Sep 1986;4(5):427-58. [Medline].
2. Smith TW, Butler VP Jr, Haber E, et al. Treatment of life-threatening digitalis intoxication with digoxin- specific Fab antibody fragments: experience in 26 cases. N Engl J Med. Nov 25 1982;307(22):1357-62. [Medline].
3. Woolf AD, Wenger T, Smith TW, Lovejoy FH Jr. The use of digoxin-specific Fab fragments for severe digitalis intoxication in children. N Engl J Med. Jun 25 1992;326(26):1739-44. [Medline].
4. Zucker AR, Lacina SJ, DasGupta DS, et al. Fab fragments of digoxin-specific antibodies used to reverse ventricular fibrillation induced by digoxin ingestion in a child. Pediatrics. Sep 1982;70(3):468-71. [Medline].
5. Antman EM, Wenger TL, Butler VP Jr, et al. Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Final report of a multicenter study. Circulation. Jun 1990;81(6):1744-52. [Medline].
6. Beller GA, Smith TW, Abelmann WH, et al. Digitalis intoxication. A prospective clinical study with serum level correlations. N Engl J Med. May 6 1971;284(18):989-97. [Medline].
7. Bismuth C, Gaultier M, Conso F, Efthymiou ML. Hyperkalemia in acute digitalis poisoning: prognostic significance and therapeutic implications. Clin Toxicol. 1973;6(2):153-62. [Medline].
8. Ekins BR, Watanabe AS. Acute digoxin poisonings: review of therapy. Am J Hosp Pharm. Mar 1978;35(3):268-77. [Medline].
9. Fazio A. Fab fragments in the treatment of digoxin overdose: pediatric considerations. South Med J. Dec 1987;80(12):1553-6. [Medline].
10. Hastreiter AR, van der Horst RL, Chow-Tung E. Digitalis toxicity in infants and children. Pediatr Cardiol. Apr-Jun 1984;5(2):131-48. [Medline].
11. Husby P, Farstad M, Brock-Utne JG, et al. Immediate control of life-threatening digoxin intoxication in a child by use of digoxin-specific antibody fragments (Fab). Paediatr Anaesth. Jul 2003;13(6):541-9. [Medline].
12. Kaufman J, Leikin J, Kendzierski D, Polin K. Use of digoxin Fab immune fragments in a seven-day-old infant. Pediatr Emerg Care. Jun 1990;6(2):118-21. [Medline].
13. Lewander WJ, Gaudreault P, Einhorn A, et al. Acute pediatric digoxin ingestion. A ten-year experience. Am J Dis Child. Aug 1986;140(8):770-3. [Medline].
14. Ordog GJ, Benaron S, Bhasin V, et al. Serum digoxin levels and mortality in 5,100 patients. Ann Emerg Med. Jan 1987;16(1):32-9. [Medline].
15. Rutledge J. Digitalis toxicity in infants and plasma digoxin levels. Pediatr Cardiol. 1985;6(1):51-2. [Medline].
16. Shumaik GM, Wu AW, Ping AC. Oleander poisoning: treatment with digoxin-specific Fab antibody fragments. Ann Emerg Med. Jul 1988;17(7):732-5. [Medline].
17. Aarnoudse AL, Dieleman JP, Stricker BH. Age- and gender-specific incidence of hospitalisation for digoxin intoxication. Drug Saf. 2007;30(5):431-6. [Medline].

Article Last Updated: Nov 6, 2008