AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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

INTRODUCTION

Section 2 of 11  

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

Background

Native people in various parts of the world have used many plant extracts containing cardiac glycosides as arrow and ordeal poisons. The ancient Egyptians used squill as a medicine. The Romans employed it as a diuretic, heart tonic, emetic, and rat poison. Digitalis, or foxglove, was mentioned in AD 1250 in the writings of Welsh physicians. Fuchsius described it botanically 300 years later and gave it the name Digitalis purpurea.

William Withering published his classic account of foxglove and some of its medical uses in 1785, remarking upon his experience with digitalis. Indians in South America have used cardiac glycosides in their dart poisons. Digitalis toxicity was well known in previous centuries, and some have suggested that the toxic visual symptoms of digitalis may have played a role in Van Gogh's use of swirling greens and yellows.

During the early 20th century, as a result of the work of Cushny, Mackenzie, Lewis, and others, the drug was gradually recognized as specific for treatment of atrial fibrillation. Only subsequently was the value of digitalis for treatment of congestive heart failure (CHF) established. In recent years, cardiac glycosides toxicity has been known to result from ingestion of some plants, including yellow oleander (Thevetia peruviana) and foxglove (D purpurea), and a similar toxidrome has been associated with the use of herbal dietary supplements.

Pathophysiology

Mechanism of action

The positive inotropic effect of digitalis has 2 components.

• Direct inhibition of membrane-bound sodium- and potassium-activated adenosine triphosphatase (Na⁺/K⁺-ATPase), which leads to an increase in the intracellular concentration of calcium ([Ca²⁺]i)
• Associated increase in a slow inward calcium current (iCa) during the action potential (AP) (This current is the result of movement of calcium into the cell, and it contributes to the plateau of the AP.)

Digitalis, in therapeutic concentrations, exerts no effect on the contractile proteins or on the interactions between them.

Digitalis glycosides bind specifically to Na⁺/K⁺-ATPase, inhibit its enzymatic activity, and impair active transport of extruding sodium and transport of potassium into the fibers (3:2 ratio). As a result, intracellular sodium ([Na⁺]i) gradually increases, and a gradual, small decrease in intracellular potassium ([K⁺]i) occurs.

Cardiac fiber [Ca²⁺ ]i is exchanged for extracellular sodium (3:1 ratio) by a transport system that is driven by the concentration gradient for these ions and the transmembrane potential; increase in [Na⁺]i is related crucially to the positive inotropic effect of digitalis.

In addition, by a mechanism that is not defined clearly, the increase in [Ca²⁺]i increases the peak magnitude of iCa; this change parallels the positive inotropic action. The change in iCa is a consequence of the increase in [Ca²⁺]i and not of the increase in [Na⁺]i. Thus, more calcium is delivered during the plateau of each AP to activate each contraction.

A fall in intracellular pH accompanies the digoxin-induced increase in [Ca²⁺ ]i, which leads to activation of a sodium/hydrogen exchange pump. This results in extrusion of hydrogen, an increase in [Na⁺]i, and greater inotropy.

The mechanism described assumes that Na⁺/K⁺-ATPase is the pharmacological receptor for digitalis and that, when digitalis binds to these enzymes, it induces a conformational change that decreases active transport of sodium. Many studies have provided evidence that digitalis binds to ATPase in a specific and saturable manner and that the binding results in a conformational change of the enzyme such that the binding site for digitalis probably is on the external surface of the membrane. Furthermore, the magnitude of the inotropic effect of digitalis is proportional to degree of inhibition of the enzyme.

Electrophysiological effects

The electrophysiological effects of cardiac glycosides include (1) decreased resting potential (RP) or maximal diastolic potential (MDP), which slows the rate of phase-0 depolarization and conduction velocity, (2) decrease in action potential duration (APD), which results in increased responsiveness of fibers to electrical stimuli, and (3) enhancement of automaticity, which results from an increase in the rate of phase-4 depolarization and from delayed after-depolarization.

In general, cardiac glycosides slow conduction and increase the refractory period in specialized cardiac conducting tissue by stimulating vagal tone. Digitalis has parasympathetic properties, which include hypersensitization of carotid sinus baroreceptors and stimulation of central vagal nuclei.

Digoxin also appears to have variable effects on sympathetic tone, depending on the specific cardiac tissue involved.

Vasomotor effects

Digoxin and other cardiac glycosides cause direct vasoconstriction in the arterial and venous system through inhibition of the Na⁺/K⁺-ATPase pump in vascular smooth muscle.

Alterations in cardiac rate and rhythm occurring in digitalis toxicity may simulate almost every known type of dysrhythmia. Although no dysrhythmia is pathognomonic for digoxin toxicity, toxicity should be suspected when evidence of increased automaticity and depressed conduction is noted. Underlying these dysrhythmias is a complex influence of digitalis on the electrophysiologic properties of the heart as already discussed, as well as via the cumulative results of the direct, vagotonic, and antiadrenergic actions of digitalis. The effects of digoxin vary with the dose and differ depending on the type of cardiac tissue involved. The atria and ventricles exhibit increased automaticity and excitability, resulting in extrasystoles and tachydysrhythmias. Conduction velocity is reduced in both myocardial and nodal tissue, resulting in increased PR interval and atrioventricular (AV) block accompanied by decrease in QT interval.

In addition to these effects, the direct effect of digitalis on repolarization often is reflected in the ECG by ST segment and T-wave forces opposite in direction to the major QRS forces. The initial electrophysiologic manifestation of digitalis effects and toxicity usually is mediated by increased vagal tone. Early in acute intoxication, depression of sinoatrial (SA) or AV nodal function may be reversed by atropine. Subsequent manifestations are the result of direct and vagomimetic actions of the drug on the heart and are not reversed by atropine.

Ectopic rhythms—such as nonparoxysmal junctional tachycardia, extrasystole, premature ventricular contractions, ventricular flutter and fibrillation, atrial flutter and fibrillation, and bidirectional ventricular tachycardia—are due to enhanced automaticity, reentry, or both.

Bidirectional ventricular tachycardia is particularly characteristic of severe digitalis toxicity and results from alterations of intraventricular conduction, junctional tachycardia with aberrant intraventricular conduction or, on rare occasions, alternating ventricular pacemakers. Depression of the atrial pacemakers resulting in SA arrest also may be seen. Other features are SA block, AV block, and sinus exit block resulting from depression of normal conduction. Nonparoxysmal atrial tachycardia with block is associated with digitalis toxicity.

When conduction and the normal pacemaker are both depressed, ectopic pacemakers may take over, producing atrial tachycardia with AV block and nonparoxysmal automatic AV junctional tachycardia. Indeed, AV junctional block of varying degrees, alone or with increased ventricular automaticity, are the most common manifestations of digoxin toxicity, occurring in 30-40% of patients with recognized digoxin toxicity. AV dissociation may occur because of suppression of the dominant pacemaker with escape of a subsidiary pacemaker or inappropriate acceleration of a ventricular pacemaker.

Frequency

United States

Approximately 0.4% of all hospital admissions are related to digitalis toxicity. Ten to 18% of nursing home patients develop this toxicity.

International

Approximately 2.1% of inpatients are taking digoxin. Of all admissions, 0.3% of patients develop toxicity.

Mortality/Morbidity

• Incidence of digitalis toxicity has declined in recent years because of a decrease in digitalis usage, improvement in digoxin formulation with more predictable drug bioavailability, better understanding of pharmacokinetics, increasing awareness in drug-to-drug interactions, increased appreciation for factors that can increase the risk of toxicity, and availability of other drugs to treat heart failure. The morbidity and mortality rates associated with digitalis toxicity have remained constant over the past 5 years.
• According to the American Association of Poison Control Centers, of the patients reported in 1997 who developed cardiac glycoside toxicity, 34% demonstrated moderate or major morbidity, and 1% died.
• The lethal dose of most glycosides is approximately 5-10 times the minimal effective dose and only about twice the dose that leads to minor toxic manifestations.

Age

Older individuals with multiple comorbid conditions have lower tolerance of digitalis than younger individuals with few or no comorbid conditions, and they are prone to digitalis toxicity.

CLINICAL

Section 3 of 11  

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

History

• Withering recognized many of the signs of digitalis toxicity: "The foxglove, when given in very large and quickly repeated doses, occasions sickness, vomiting, purging, giddiness, confused vision, objects appearing green or yellow; increased secretion of urine, slow pulses, even as low as 35 in a minute, cold sweats, convulsions, syncope, death."
• Extracardiac symptoms
• • Central nervous system: Drowsiness, lethargy, fatigue, neuralgia, headache, dizziness, and confusion may occur.
  • Ophthalmic: Visual aberration often is an early indication of digitalis toxicity. Yellow-green distortion is most common, but red, brown, blue, and white also occur. Drug intoxication also may cause snowy vision, photophobia, photopsia, and decreased visual acuity.
  • GI: In acute and chronic toxicity, anorexia, nausea, vomiting, abdominal pain, and diarrhea may occur. Mesenteric ischemia is a rare complication of rapid intravenous infusion.
  • Many extracardiac toxic manifestations of cardiac glycosides are mediated neurally by chemoreceptors in the area postrema of the medulla.
• Cardiac symptoms
• • Palpitations
  • Shortness of breath
  • Syncope
  • Swelling of lower extremities
  • Bradycardia
  • Hypotension

Physical

• General: Patient's mentation may change according to severity of digoxin toxicity, as well as associated comorbid conditions.
• Vital signs: Pulse may be irregular depending on arrhythmias secondary to atrial fibrillation or arising from the digoxin toxicity itself. Hypotension may be observed if patient has CHF or dehydration secondary to decreased oral intake.
• Neck: Findings include increased jugular venous pressure.
• Cardiovascular: Findings may relate to severity of CHF. Associated cardiomegaly may be identified.
• Respiratory: Sometimes, respiratory rate is increased. Basal crepitations are associated with CHF.
• GI: Enlarged liver is secondary to CHF (ie, hepatic congestion). Hepatojugular reflux is present.
• Neurological: Signs include changes in mental status.
• Extremities: Pedal edema is noted if patient has renal failure or decompensated CHF.

Causes

The most common precipitating cause of digitalis intoxication is depletion of potassium stores, which occurs often in patients with heart failure as a result of diuretic therapy and secondary hyperaldosteronism.

• Other causes include the following:
• • Advanced age
  • Myocardial infarction or ischemia
  • Hypothyroidism
  • Hypercalcemia
  • Renal insufficiency
• Also consider drug interactions. Drugs that have been reported to potentiate digoxin toxicity include the following:
• • Quinidine
  • Erythromycin
  • Verapamil, diltiazem, nifedipine
  • Captopril
  • Anticholinergic drugs
  • Ibuprofen
  • Amiodarone

DIFFERENTIALS

Section 4 of 11  

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

Other Problems to be Considered

Congestive heart failure
Arrhythmias
Pulmonary edema
Syncope
Drugs causing bradycardias such as calcium channel blockers or beta-blockers

WORKUP

Section 5 of 11  

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

Lab Studies

• Plasma digoxin levels
• • The plasma digoxin level can be used to monitor both compliance and toxicity and can be used as a guide to appropriate dosing of medication.
  • Therapeutic levels vary—the lower limit ranges from 0.6-1.3 ng/mL while the upper limit is generally agreed to be 2.6 ng/mL. Serum concentration levels associated with toxicity overlap between therapeutic and toxic ranges because of the myriad of factors potentiating digoxin toxicity.
  • Therapeutic levels vary; the lower limit ranges from 0.6-1.3 ng/mL, while the upper limit generally is agreed to be 2.6 ng/mL. Serum concentrations associated with toxicity overlap between therapeutic and toxic ranges because of the myriad of factors potentiating digoxin toxicity.
  • Because of the delayed onset of action of digoxin, at least 6 h must elapse between dosage and drawing a digoxin level specimen in order to prevent spuriously elevated levels. Strict adherence to levels without regard to clinical manifestations can result in inappropriate and costly intervention.
  • Other confounding variables include digoxin metabolites, drugs, and endogenous digoxinlike factors. While most patients metabolize <20% of digoxin, 10% of the population metabolizes as much as 55% of digoxin to initially active metabolites. Not all routinely used radioimmunoassays (RIAs) measure each of these metabolites. Additionally, the antibodies used in digoxin immunoassay can cross-react with numerous compounds, including steroids and other drugs (eg, spironolactone). Finally, serum from neonates, pregnant women, patients with renal or hepatic failure, and patients with essential hypertension may cross-react with the digoxin antibody owing to endogenous digitalislike factors produced by these individuals. These substances may account for 50% of serum digoxin levels measured by RIAs in specific patients.
• Electrolyte evaluation
• • Hyperkalemia: In acute toxicity, hyperkalemia is common owing to inactivation of the Na⁺/K⁺-ATPase pump. It is a predictor of morbidity and mortality and also reflects the degree of poisoning.
  • Hypokalemia: Long-term digoxin users very often develop hypokalemia because of concurrent diuretic use. It should be corrected promptly and may help to improve cardiac glycoside-related arrhythmia.
  • Hypomagnesemia: Long-term digoxin users often have hypomagnesemia secondary to diuretic usage. Intracellular magnesium depletion may occur in long-term diuretic use despite normal serum magnesium level. Importantly, magnesium is a cofactor of the Na⁺/K⁺-ATPase pump, and alterations of its concentration will affect the pump's actions.
• Renal function: Obtain BUN and creatinine to assess renal function.

Other Tests

• Electrocardiogram may be necessary to facilitate the diagnosis, the type of rhythm, and arrhythmia. The rhythm may be as follows:
• • Nonspecific
  • • Premature ventricular contractions (PVCs), especially bigeminal and multiform
    • First-, second- (Wenckebach), and third-degree AV block
    • Sinus bradycardia
    • Sinus tachycardia
    • SA block or arrest
    • Atrial fibrillation with slower ventricular response
    • Atrial tachycardia
    • Junctional (escape) rhythm
    • AV dissociation
    • Ventricular bigeminy and trigeminy
    • Ventricular tachycardia
    • Torsade de pointes
    • Ventricular fibrillation
  • More specific, but not pathognomonic
  • • Atrial fibrillation with slow, regular ventricular rate (ie, AV dissociation)
    • Nonparoxysmal junctional tachycardia (rate 70-130 beats per minutes [bpm])
    • Atrial tachycardia with block (atrial rate usually 150-200 bpm)
    • Bidirectional ventricular tachycardia

TREATMENT

Section 6 of 11  

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

Medical Care

Effective management relies on early recognition that a dysrhythmia and/or noncardiac manifestation may be related to digitalis intoxication. General principles of management include (1) assessment of the severity of the problem and the etiology of toxicity (eg, diminished renal clearance, the dose medicated, concurrent medications, and whether overdosage is accidental or intentional); (2) factors that influence treatment, including age, medical history, chronicity of digoxin intoxication, existing heart disease and/or renal insufficiency, and, importantly, ECG changes; (3) continuous hemodynamic assessment, including 12-lead ECG and cardiac monitoring, as well as intensive care unit (ICU) admission and intravenous (IV) access; and (4) prompt measurement of electrolyte levels, including potassium and calcium, serum creatinine, and digoxin levels.

• GI decontamination and/or enhanced elimination
• • First-line treatment for acute ingestion is gastric lavage with repeated dosing of activated charcoal to reduce absorption and interrupt enterohepatic circulation. It is most effective if ingestion has occurred within 6-8 hours.
  • Pretreatment with atropine has been recommended to decrease the incidence of AV block or bradycardia as a result of increased vagal tone because of gastric lavage.
  • To break enterohepatic circulation, use binding resins, such as cholestyramine and colestipol. Cholestyramine probably is used more appropriately in chronic toxicity with renal insufficiency.
• Electrolyte imbalance
• • In acute settings, hyperkalemia is more common, while in chronic intoxication, hypokalemia and hypomagnesemia are common owing to concurrent use of diuretics.
  • Standard treatment for hyperkalemia, including bicarbonate, glucose, and insulin, is useful. Ion exchange resins, such as Kayexalate, can be used as well; however, if digoxin antibody therapy is anticipated, then other forms of treatment for hyperkalemia are not necessary.
  • The use of calcium can be disastrous because it can delay after-depolarization and be proarrhythmic. In patients with uncontrolled hyperkalemia, instituting hemodialysis may be necessary.
  • Hypokalemia increases digoxin cardiac sensitivity and should be corrected. Use caution in patients with renal insufficiency.
  • Concomitant hypomagnesemia may result in refractory hypokalemia. Hypomagnesemia increases myocardial digoxin uptake and decreases cellular Na+/K⁺-ATPase activity. Patients with hypomagnesemia, hypokalemia, or both may become cardiotoxic even with therapeutic digitalis levels. A common dose of 1-2 g/h with serial monitoring of serum magnesium levels, telemetry, respiratory rate, deep tendon reflexes, and blood pressure is appropriate. Magnesium is contraindicated in the setting of bradycardia or AV block and should be used cautiously in patients with renal failure.
• Antidysrhythmics
• • If the patient with short- or long-term ingestion develops a digitalis-induced dysrhythmia, management of the dysrhythmia is directed toward the cause of the rhythm disturbance. Aside from correcting obvious electrolyte abnormalities, an antidysrhythmic may be indicated, especially in the absence of, or delay in administering, immunotherapy.
  • The drugs of choice for management of ventricular irritability due to digitalis toxicity include phenytoin and lidocaine because they depress the enhanced ventricular automaticity without significantly slowing AV conduction. Phenytoin may reverse digitalis-induced prolongation of AV nodal conduction. Phenytoin has been shown to dissociate the inotropic and dysrhythmic action of digitalis, thus suppressing digitalis-induced tachydysrhythmias without diminishing the contractile effects. In addition, phenytoin can terminate supraventricular dysrhythmias induced by digitalis, whereas lidocaine has not been as effective. Atropine is recommended for improving AV nodal conduction and is used in bradyarrhythmias.
  • Quinidine, procainamide, and bretylium are contraindicated. Both quinidine and procainamide worsen AV, SA, and His-Purkinje conductivity. Additionally, quinidine reduces digoxin tissue binding and renal clearance, thereby increasing digoxin levels. Bretylium can precipitate ventricular dysrhythmia.
  • Beta-adrenergic blockers can decrease automaticity and slow conduction velocity induced by a catecholamine surge from digitalis intoxication and can shorten the refractory period of atrial and ventricular muscle. In the presence of SA or AV node depression, however, they may depress activity further; therefore, a short-acting beta-blocker is recommended in rapid atrial conduction.
  • Intravenous magnesium sulfate, 2 g over 5 minutes, has been shown to terminate digoxin-toxic cardiac arrhythmias in patients with and without overt disease. Aside from successful replacement of intracellular magnesium, it also may act as an indirect antagonist of digoxin at the supraphysiologic level.
  • Temporary pacing is an alternative for patients with nodal blocks before any other medical interventions are attempted; however, retrospective studies have shown that pacing may increase adverse outcomes in some patients and suggested that immunotherapy should be attempted prior to initiating pacemaker activity. For more information on immunotherapy, see Medication.
• Electrical cardioversion
• • Cardioversion for severe dysrhythmias due to digitalis is hazardous and can precipitate ventricular fibrillation and asystole. However, if the patient is hemodynamically unstable and has a wide, complex tachycardia and fascicular tachycardia has been ruled out, cardioversion will need to be used early.
  • If the history is consistent with digitalis intoxication, a minimal effective dose is best. Some clinicians have suggested using 10-25 joules initially in ventricular tachycardia/ventricular fibrillation, but most clinicians suggest starting at 50-100 joules for a wide, complex ventricular tachycardia, rather than the 200 joules recommended in the advanced cardiac life support (ACLS) protocols.

Consultations

• Cardiologists
• Nephrologists
• Regional poison centers
• Medical toxicologists

MEDICATION

Section 7 of 11  

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

Immunotherapy probably is the most valuable recent addition to treatment of digoxin and digitoxin intoxication. In both hemodynamically stable and unstable patients, it is a first-line therapy. Introduced in 1976 but not commercially available until a decade later, digoxin-specific Fab fragments are the product of papain digestion of sheep immunoglobulin G (IgG) produced in response to antigenic carrier proteins coupled to digoxin. The advantages of digoxin-specific Fab compared to whole IgG antibodies include larger volume of distribution and more rapid onset of action. Ultimately, the commercial product (Digibind) is a relatively pure Fab product that is very safe and extremely effective. Onset of action ranges from 20-90 minutes, and digoxin is removed irreversibly from the myocardium and other specific binding sites. A complete response generally occurs within 4 h.

Immediately following IV administration, digoxin-specific antibodies bind intravascular free digoxin. They then diffuse into the interstitial space, binding free digoxin there. A concentration gradient is established, which facilitates movement of intracellular digoxin and digoxin that is dissociated from its binding sites (external surface of Na⁺/K⁺-ATPase enzyme) in the heart into interstitial or intravascular spaces. Intravascular concentration of inactive, antibody-bound digoxin rises substantially. The elimination kinetics of Fab antibody–bound digoxin depend on the patient's renal function and capacity for urinary elimination.

Digoxin-specific antibody fragments are not only effective but also very safe. Review of the numerous cases of digoxin intoxication treated with digoxin-specific Fab fragments over the past decade has revealed impressive results.

Indications for immunotherapy include the following: (1) ingestion of massive quantities of digitalis (children 4 mg or 0.1 mg/kg, adults 10 mg), (2) hyperkalemia (>5 mEq/L), (3) digoxin-induced ventricular dysrhythmias or high-grade AV block, (4) rapidly progressive signs and symptoms of toxicity, (5) cardiac arrest or cardiogenic shock in a patient with suspected digoxin toxicity, and (6) postdistribution serum digoxin levels greater than 5 ng/mL.

According to the manufacturer, Digibind should be administered IV over 30 minutes via a 0.22-um membrane filter. The 40-mg vial must be reconstituted with 4 mL of sterile water for IV injection, furnishing an iso-osmotic solution. This preparation can be diluted further with sterile isotonic saline (for small infants). Once reconstituted, use it immediately or, if refrigerated, use within 4 h. In an unstable clinical situation, Digibind is administered by IV bolus. Studies have shown that a loading dose of Fab followed by a maintenance infusion is beneficial to optimize binding to Fab. The loading dose immediately captures digoxin already in the vascular space, and the maintenance dose provides enough Fab to continue to draw digoxin from the tissue into the serum to be bound. In acute intentional overdose, 4-6 vials given as a loading dose, followed by 0.5 mg/min for 8 h and then 0.1 mg/min for about 6 h, appears to be safe and effective.

Drug Category: Immunotherapy

This agent improves clinical aspects of digitalis toxicity. It may increase solubilization and removal of immune complexes.

Drug Category: Anticholinergics

These agents may improve sinus node and AV node conduction by inhibiting vagal activity.

Drug Category: Binding agents

These agents are used to prevent or reduce absorption of toxic agents.

FOLLOW-UP

Section 8 of 11  

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

Further Inpatient Care

• Postimmunotherapy treatment
• • After treatment with Fab fragments, the serum digoxin level will rise considerably. Digoxin level cannot be used as a guide to treatment after administration of Fab fragments
  • Free digoxin levels can be used, but most hospitals do not have this assay available. The elimination half-life of digoxin Fab complex is 20-30 hours, although clearance is related directly to the glomerular filtration rate and consequently is prolonged in renal insufficiency. Recrudescence of digoxin toxicity is possible because the Fab complex is eliminated more rapidly than digoxin is released from tissue-binding sites.
  • Significantly, in a long-term digoxin user who requires Fab treatment for digitalis toxicity, administration can precipitate worsening heart failure by removing the beneficial inotropic activity of digoxin, causing hypokalemia and atrial arrhythmia with rapid ventricular response. Hypokalemia occurred in patients who were treated with standard therapy as well as Fab fragments. Clinically adverse phenomena have occurred in fewer than 10% of patients treated with immunotherapy.
  • Other untoward effects of Digibind include anaphylaxis and serum sickness because it is a foreign protein; these reactions are uncommon. Allergy to Fab fragments is associated with patients who have multiple allergies.
• Hemodialysis
• • Hemodialysis (HD) and activated charcoal hemoperfusion (HP) have no role in the management of digitalis intoxication. Without the use of Fab, these procedures are not indicated because the molecular weight of digoxin is too large for HD to be successful. In addition, the volume of distribution of digoxin is too large to make either approach feasible. Hemodialysis is superfluous after administration of Fab and HP.
  • Digoxin-specific antibody fragments are effective even in anephric patients, although symptoms may recur 7–14 days later, possibly indicating the need for another dose of Fab.
  • Hemoperfusion through columns with antidigoxin antibodies bound to agarose polyacrolein microsphere beads has been accomplished, but the availability of Fab in the United States makes this modality outdated.
  • Continuous arteriovenous hemofiltration in an experimental model has failed to remove the digoxin-Fab complex.

Further Outpatient Care

• Patients with accidental exposure and no sign of toxicity after 12 hours can be discharged home with appropriate follow-up. Observe patients for at least 6 hours on a cardiac monitor, and lab results should be normalized.
• Suicidal, depressed patients should be cleared by a psychiatry consult for prevention of repeated toxic ingestion before discharge.

Transfer

Transfer hemodynamically unstable patients to a tertiary care center equipped with medical intensive care unit/critical care unit (MICU/CCU) capabilities. Notifying of the and discussing the treatment of the poisoning with the regional poison center also is important.

Deterrence/Prevention

• Dosage adjustment with frequent laboratory monitoring, especially if the patient has chronic renal failure
• Adequate hydration
• Supplementation of potassium chloride in patients with diuretic therapy

Prognosis

Prognosis is poor with increasing age and associated comorbid conditions.

Patient Education

• Increase patient awareness about the symptoms of digitalis toxicity.
• Educate patients about drug interactions.
• Educate patients about maintaining adequate hydration.
• For excellent patient education resources, visit eMedicine's Drug Overdose Center, Poisoning - First Aid and Emergency Center and Mental Health and Behavior Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

MISCELLANEOUS

Section 9 of 11  

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

Medical/Legal Pitfalls

Failure to provide psychiatric follow-up with suicidal ingestion is a potential pitfall. Others are failure to follow up on digitalis level with new medication prescription, a hospitalized elderly patient with recent normal outpatient digitalis level on "same" dose, regular rhythm in a patient with chronic atrial fibrillation, and teenager drug overdose.

Special Concerns

• Digoxin in pregnancy
• • Digoxin is used widely in the acute management and prophylaxis of fetal paroxysmal supraventricular tachycardia (SVT), as well as in rate control of atrial fibrillation. It is a category C drug. Increased digoxin dosage may be necessary during pregnancy because of enhanced renal clearance and expanded blood volume.
  • No series has been published regarding toxicity in the pregnant woman. Digoxin-specific Fab fragments can be used in pregnancy with the caveat that careful monitoring of the fetus must be maintained.

ACKNOWLEDGMENTS

Section 10 of 11  

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

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Thomas P Smith Jr, MD to the development and writing of this article.

REFERENCES

Section 11 of 11

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

• Barrueto F, Jortani SA, Valdes R, et al. Cardioactive steroid poisoning from an herbal cleansing preparation. Ann Emerg Med. Mar 2003;41(3):396-9. [Medline].
• Binder WD, Lewander WJ. Digoxin. In: Viccellio P, ed. Emergency Toxicology. Philadelphia, Pa: Lippincott-Raven; 1998:707-721.
• Dribben WH, Kirk MA. Digitalis glycosides. In: Tintinalli JE, Kelan G, Stapzcynsky JP, eds. Emergency Medicine: A Comprehensive Study Guide. 5^th ed. New York, NY: McGraw-Hill; 1999:1139-42.
• Hoffman BF, Bigger T Jr. Digitalis and allied cardiac glycosides. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8^th ed. New York, NY: Pergamon Press; 1990:814-39.
• Howland MA. Prescription medications, digoxin-specific antibody fragments. In: Goldfrank LR, Flomenbaum NE, Lewin NA, Weis, eds. Goldfrank's Toxicologic Emergencies. 6^th ed. Norwalk, Conn: Appleton & Lange; 1998:48:801-807.
• Lewin NA. Prescription medications, cardiac glycosides. In: Goldfrank LR, Flomenbaum NE, Lewin NA, Weis, eds. Goldfrank's Toxicologic Emergencies. 6^th ed. Appleton & Lange; 1998:791-800.
• Roberts DJ. Common cardiovascular drugs. In: Rosen P, ed. Emergency Medicine, Concepts and Clinical Practice. 2^nd ed. St Louis, Mo: Mosby; 1992:1307-12.
• Smith TW, Antman EM, Friedman PL, et al. Digitalis glycosides: mechanisms and manifestations of toxicity. Part I. Prog Cardiovasc Dis. Mar-Apr 1984;26(5):413-58. [Medline].

Article Last Updated: May 26, 2006