eMedicine Specialties > Cardiology > Arrhythmias

Digitalis Toxicity: Treatment & Medication

Author: Vinod Patel, MD, Medical Director, Jefferson Family Medicine Center; Clinical Assistant Professor, Department of Family Medicine, State University of New York at Buffalo
Coauthor(s): Paul Arthur James, MD, IAFP Endowed Chair in Rural Medicine, Associate Professor of Family Medicine, Department of Family Medicine, University of Iowa College of Medicine
Contributor Information and Disclosures

Updated: Dec 22, 2008

Treatment

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

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:

• Ingestion of massive quantities of digitalis (children 4 mg or 0.1 mg/kg, adults 10 mg)
• Hyperkalemia (>5 mEq/L)
• Digoxin-induced ventricular dysrhythmias or high-grade AV block
• Rapidly progressive signs and symptoms of toxicity
• Cardiac arrest or cardiogenic shock in a patient with suspected digoxin toxicity
• 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.

Possible idiosyncratic allergic reactions are very rare but need to be considered in patients with known sheep protein allergy. One must also be aware about possible volume overload causing exacerbation of congestive heart failure with chronic digitalis therapy and hypokalemia due to movement of potassium into the cell. Fab fragment interferes with conventional assay and digoxin measurement is unreliable for 1-2 weeks after the therapy.

Immunotherapy

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

Digoxin immune Fab (Digibind)

Immunoglobulin fragment with specific and high affinity for both digoxin and digitoxin molecules. Removes digoxin or digitoxin molecules from tissue-binding sites.
Each vial contains 40 mg of purified digoxin-specific antibody fragments, which will bind approximately 0.6 mg of digoxin or digitoxin.

Anticholinergics

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

Atropine sulfate

Increases heart rate through vagolytic effects, causing increase in cardiac output.

Binding agents

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

Activated charcoal (Insta-Char, Actidose-Aqua)

Network of pores present in activated charcoal absorbs 100-1000 mg of drug per g of charcoal. Does not dissolve in water.
For maximum effect, administer within 30 min after ingesting toxic agents.

Cholestyramine (Questran)

Used to break enterohepatic circulation. It probably is used more appropriately in chronic toxicity with renal insufficiency.

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