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 , it is still among the top 50 prescribed drugs in the United States. 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.
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. 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.
In 1999 the American Association of Poison Control Centers (AAPCC) reported approximately 3000 pediatric poisonings associated with cardiac glycoside. 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. 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. 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. 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. 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.
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.
Doses with errors in prescription, dispensing, or administration
Acute nontherapeutic overdose can cause toxicity.
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 (Na+ K+ 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, hypercalcemia, and hypernatremia can aggravate toxicity.
Concomitant use of the following drugs can exacerbate digitalis toxicity:
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.
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 Fab fragment administration.
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).
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.
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 immune Fab is now considered first-line treatment for significant dysrhythmias and should be promptly administered if digoxin toxicity is suspected (see indications below, Medications).[14, 3, 15]
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 and lidocaine are useful antiarrhythmics for the treatment of digoxin toxicity if Fab fragments are ineffective or unavailable.
Quinidine and procainamide should be avoided because they intensify AV block.
Cardioversion is generally reserved for the treatment of unstable arrhythmias that are unresponsive to medications such as digoxin-specific Fab. 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.
Electrolyte imbalances may worsen digitalis toxicity.
Potassium supplementation is generally recommended in the setting of hypokalemia (K+< 3meq/L) and first-degree AV block or Wenckebach. Potassium supplementation is also recommended in low-normal potassium levels (K+< 4 meq/L) and ventricular tachycardia, premature ventricular contractions, or supraventricular tachycardia with AV block.
Potassium administration is generally contraindicated in the setting of Mobitz II or third-degree AV block.
Magnesium administration may be beneficial in cases of hypomagnesemia, although it is unclear how well magnesium levels correlate with digitalis toxicity.
Calcium should not be routinely administered, as it can induce ventricular arrhythmias.
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).
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]
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.
Kenneth T Kwon, MD, Director of Pediatric Emergency Medicine, Associate Clinical Professor, Department of Emergency Medicine, University of California at Irvine Medical Center, Co-Director, Pediatric Emergency Services, Mission Regional Medical Center/Children's Hospital of Orange County at Mission
Disclosure: Nothing to disclose.
Megan Boysen, MD, Resident Physician, Department of Emergency Medicine, University of California Irvine Medical Center
Disclosure: Nothing to disclose.
William T Zempsky, MD, Associate Director, Assistant Professor, Department of Pediatrics, Division of Pediatric Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center
Disclosure: Nothing to disclose.
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Jeffrey R Tucker, MD, Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center
Disclosure: Merck Salary Employment
Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Disclosure: Nothing to disclose.
Timothy E Corden, MD, Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin