Digitalis Toxicity Treatment & Management

Updated: Jan 04, 2017
  • Author: Vinod Patel, MD; Chief Editor: Jeffrey N Rottman, MD  more...
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Treatment

Approach Considerations

The clinical manifestations digoxin toxicity are the same in infants, children, and adults, and the treatment is the same across all these age groups. [21] Treatment of digoxin toxicity should be guided by the patient’s signs and symptoms and the specific toxic effects and not necessarily by digoxin levels alone. Therapeutic options range from simply discontinuing digoxin therapy for stable patients with chronic toxicity to digoxin Fab fragments, cardiac pacing, antiarrhythmic drugs, magnesium, and hemodialysis for severe acute toxicity.

For prehospital care, administration of oxygen, cardiac monitoring, establishment of intravenous (IV) access, and transport are usually the only requirements. Atropine is indicated for hemodynamically unstable bradyarrhythmic patients; lidocaine is indicated for ventricular tachycardia.

Supportive care of digitalis toxicity includes hydration with IV fluids, oxygenation and support of ventilatory function, discontinuation of the drug, and, sometimes, the correction of electrolyte imbalances. Effective management also relies on early recognition that a dysrhythmia and/or noncardiac manifestation may be related to digitalis intoxication.

General principles of management include the following:

  • Assessment of the severity of the toxicity and its etiology (eg, accidental ingestion, unintentional or deliberate overdose, altered digoxin metabolism due to diminished renal clearance or interaction with other drugs)

  • Consideration of factors that influence treatment, including age, medical history, chronicity of digoxin intoxication, existing heart disease and/or renal insufficiency, and ECG changes

  • Continuous hemodynamic assessment, including 12-lead electrocardiogram (ECG) and cardiac monitoring

  • Prompt measurement of electrolyte levels, including potassium and calcium, and of serum creatinine and digoxin levels [22]

  • Intensive care unit admission

Activated charcoal is indicated for acute overdose or accidental ingestion. Binding resins (eg, cholestyramine) may bind enterohepatically-recycled digoxin and digitoxin, although no outcome studies have been performed. Binding resins may be more appropriately used for treatment of chronic toxicity in patients with renal insufficiency. Digoxin immune Fab is extremely effective in the treatment of severe, acute digitalis toxicity.

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GI Decontamination and Enhanced Elimination

The first-line treatment for acute ingestion is repeated dosing of activated charcoal to reduce absorption and interrupt enterohepatic circulation. Activated charcoal is most effective if given within 6-8 hours after the ingestion.

To break enterohepatic circulation, use binding resins, such as cholestyramine and colestipol. Cholestyramine probably is more appropriate for use in treatment of chronic toxicity in patients with renal insufficiency.

Other points to consider include the following:

  • Induced emesis with ipecac syrup is not recommended, because of the increased vagal effect

  • Whole-bowel irrigation may be useful, but clinical data are lacking

  • 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 additional clearance

Gastric lavage increases vagal tone and may precipitate or worsen arrhythmias. Consider pretreatment with atropine if gastric lavage is performed. Treatment with digitalis Fab antibody usually renders gastric lavage unnecessary.

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Treatment of Electrolyte Imbalance

Correct hyperkalemia, hypokalemia, and hypomagnesemia. Correction of electrolyte imbalances may reverse dysrhythmias.

Potassium abnormalities

Treat hyperkalemia by using sodium bicarbonate to correct metabolic acidosis and insulin plus glucose to enhance potassium uptake by cells. Treatment with digoxin Fab fragments is indicated for hyperkalemia with a potassium level greater than 5 mEq/L, and may obviate other forms of treatment. In patients with uncontrolled hyperkalemia, however, instituting hemodialysis may be necessary.

Binding resins (eg, sodium polystyrene sulfonate, 0.5 g/kg orally) also are helpful in binding potassium and enterohepatically recycled digitalis. However, digoxin-induced hyperkalemia reflects an extracellular shift, not an increase in total body potassium. In addition, caution is indicated when using binding resins concurrently with insulin/glucose/bicarbonate or digitalis Fab fragments, as the combination may precipitate hypokalemia, which may worsen clinical toxicity.

Although calcium is often used to ameliorate cardiac toxicity from hyperkalemia, it is not recommended in patients with digoxin toxicity because it can delay after-depolarization and may precipitate ventricular tachycardia or fibrillation. This is based on the fact that intracellular calcium levels are already high in this setting. Anecdotal case reports and animal studies have been published that refute the dangers of calcium administration, but other measures should be preferentially used to treat hyperkalemia unless the patient is in extremis.

Hypokalemia increases digoxin cardiac sensitivity and should be corrected. Use caution when administering potassium to 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 at therapeutic digitalis levels.

Magnesium may also serve as a temporizing antiarrhythmic agent until Fab fragments are available. It may be life-saving in patients with ventricular tachycardia or ventricular fibrillation. Aside from successful replacement of intracellular magnesium, it also may act as an indirect antagonist of digoxin at the supraphysiologic level.

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Digoxin Immune Therapy

Digoxin immune Fab (Digibind) is an immunoglobulin fragment that binds with digoxin. It is currently considered first-line treatment for significant dysrhythmias (eg, severe bradyarrhythmia, second- or third-degree heart block, ventricular tachycardia or fibrillation) from digitalis toxicity. This agent should be promptly administered if digoxin toxicity is suspected as the cause of such arrhythmias. [18, 23, 24]

Other indications for immunotherapy with digoxin Fab fragment include the following:

  • Ingestion of massive quantities of digitalis (in children, 4 mg or 0.1 mg/kg; in adults, 10 mg)

  • Serum digoxin level greater than 10 ng/mL in adults at steady state (ie, 6-8 hours after acute ingestion or at baseline in chronic toxicity)

  • Hyperkalemia (serum potassium level greater than 5 mEq/L)

  • Altered mental status attributed to digoxin toxicity

  • Rapidly progressive signs and symptoms of toxicity

In a retrospective study, Hauptman et al used the Premier Perspective Comparative Hospital Database (Premier Inc., Charlotte, North Carolina) to identify patients who were diagnosed with digoxin toxicity and/or who received digoxin immune fab (DIF) over a 5-year period (2007 to 2011). One-fifth of cases received DIF treatment, most within 2 days of hospitalization. Predictors of DIF treatment were urgent/emergent admission, hyperkalemia, arrhythmia associated with digoxin toxicity, acute renal failure, and suicidal intent. [25]

Digoxin immune Fab is packaged in a 40-mg vial and must be reconstituted with 4 mL of sterile water for IV injection, furnishing an iso-osmotic solution. For small infants, this preparation can be diluted further with sterile isotonic saline. Once the product is reconstituted, it should be used immediately or, if refrigerated, used within 4 hours. It is administered IV over 30 minutes via a 0.22-μm membrane filter. In an unstable clinical situation, this agent is administered by IV bolus.

A loading dose of Fab followed by a maintenance infusion is beneficial to the optimization of 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, administration of 4-6 vials as a loading dose, followed by 0.5 mg/min for 8 hours and then 0.1 mg/min for about 6 hours, appears to be safe and effective.

Recent data provide evidence that for cases of digoxin poisoning, current methods for calculating the dose of anti-digoxin Fab overstate the dose required. In addition, data suggest that in patients with chronic digoxin poisoning, the efficacy of anti-digoxin Fab may be minimal. [26]

Initially administering half doses is the best approach in patients with chronic toxicity who are dependent on digoxin. This avoids completely reversing the clinical effects of digoxin and precipitating complications. Depending on the patient's status, additional doses may be administered later.

A response is typically observed within 20-30 minutes after infusion. The elimination half-life of the drug-antibody complex is about 16 hours (range, 20-30 h). Affinity for digitoxin is 10 times less than for digoxin. In a case series that included pediatric patients, there was a 90-93% response rate within minutes or hours, with complete resolution within 180 minutes in as many as 79% of patients. The mean time to the initial response was 19 minutes; complete resolution of symptoms occurred in 88 minutes.

Digoxin levels drawn after administration of Fab fragments may be exponentially higher because many assays for measuring digoxin measure total digoxin (including digoxin bound to Fab fragments). This may be misinterpreted as a therapeutic failure and worsening toxicity. Conventional digoxin assays remain unreliable for 1-2 weeks after the therapy. Assays that measure only free digoxin are accurate and should reflect true posttreatment levels, but these assays are not available at most hospitals.

Complications

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 has occurred in patients who were treated with standard therapy, as well as with Fab fragments. Clinically adverse phenomena have occurred in fewer than 10% of patients treated with immunotherapy.

Other untoward effects of Fab include anaphylaxis and serum sickness, because it is a sheep protein; these reactions are uncommon. Allergy to Fab fragments tends to occur in patients who have multiple allergies.

The elimination half-life of the 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 within 7-14 days, because the Fab complex is eliminated more rapidly than digoxin is released from tissue-binding sites. Plasmapheresis may be performed or the agent readministered in such situations.

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Management of Dysrhythmias

Management of dysrhythmias varies, depending on the following factors:

  • Presence or absence of hemodynamic instability

  • Nature of the dysrhythmia

  • Presence or absence of electrolyte disturbances

  • Preferences of toxicology and/or cardiology consultants

In hemodynamically stable patients, bradyarrhythmias and supraventricular arrhythmias may be treated with observation and supportive care. Discontinue the drug and ensure proper hydration to optimize renal clearance of excess drug. Gastrointestinal (GI) binding agents (eg, activated charcoal, cholestyramine) may be used to bind enterohepatically recycled digitalis. For patients with rate-related ischemia or hemodynamic instability, digoxin Fab fragments is the treatment of choice.

Short-acting beta blockers (eg, esmolol) may be helpful for supraventricular tachyarrhythmias with rapid ventricular rates, but these agents may precipitate advanced or complete atrioventricular (AV) block in patients with sinoatrial or AV node depression. Calcium channel blockers are contraindicated because they may increase digoxin levels.

Premature ventricular contractions (PVCs), bigeminy, or trigeminy may require only observation unless the patient is hemodynamically unstable, in which case lidocaine may be effective. Ventricular tachycardia responds best to digoxin immune therapy, but phenytoin and lidocaine are useful if immune therapy is ineffective or unavailable. [27] These drugs depress the enhanced ventricular automaticity without significantly slowing AV conduction; indeed, 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.

Lidocaine may be given in boluses of 100 mg, according to advanced cardiac life support (ACLS) guidelines. If this is successful, begin a maintenance infusion at 1-4 mg/min. Phenytoin has been administered in boluses of 100 mg every 5-10 minutes, up to a loading dose of 15 mg/kg.

Atropine may be useful in blocking digoxin-induced effects of enhanced vagal tone on the sinoatrial (SA) and AV nodes. It has proved helpful in reversing severe sinus bradycardia.

Magnesium sulfate, 2 g IV over 5 minutes, has been shown to terminate dysrhythmias in digoxin-toxic patients with and without overt cardiac disease. After the initial bolus, a maintenance infusion at 1-2 g/h is initiated. Monitor magnesium levels approximately every 2 hours. The therapeutic goal is a level between 4 and 5 mEq/L. 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. It is unclear how well magnesium levels correlate with digitalis toxicity. [27]

Asystole and ventricular fibrillation are very ominous findings. Digoxin immune therapy is indicated in such cases; however, its effect is limited by poor cardiac blood flow. Nevertheless, the use of immune therapy has been associated with a 50% survival rate in isolated case reports.

Quinidine and procainamide are contraindicated. These agents worsen SA, AV, and His-Purkinje conductivity. Additionally, quinidine reduces digoxin tissue binding and renal clearance, thereby increasing digoxin levels. Bretylium, which is no longer available in the United States, is also contraindicated, as it can precipitate ventricular dysrhythmia. [27]

Electrical cardioversion and pacing

Cardioversion for severe dysrhythmias due to digitalis is hazardous; it can precipitate ventricular fibrillation and asystole. However, if the patient is hemodynamically unstable and has a wide, complex tachycardia and if 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 or fibrillation, but most clinicians suggest starting at 50-100 joules for a wide, complex ventricular tachycardia, rather than at the 200 joules recommended in ACLS protocols.

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 demonstrated a 36% complication rate with pacing.

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Hospital Admission

Admission criteria include the following:

  • New cardiac dysrhythmias

  • Severe bradyarrhythmias

  • Advanced AV block

  • Acute prolongation of the QRS interval

  • Severe electrolyte abnormalities, especially hypokalemia or hyperkalemia

  • Dehydration

  • Inability to care for self

  • Suicidal ideation

Admit patients with cardiac abnormalities to a monitored bed. Intensive care unit (ICU) admission criteria include the following:

  • Hemodynamic instability

  • Refractory dysrhythmias

  • Hyperkalemia

  • Renal failure

Admit patients receiving digoxin immune Fab to the ICU or critical care unit (CCU). 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 exhibit no signs or symptoms of toxicity after 12 hours can be discharged from the hospital.

Transfer may be indicated if patient is unstable and the hospital has no ICU or CCU capabilities or no appropriate consultants (eg, toxicologist, cardiologist, intensivist) or when digoxin immune therapy (if indicated) is not available. Treatment is best discussed with the regional poison control center and the patient's primary care provider.

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Prevention

Digoxin toxicity may develop in patients with dehydration, worsening renal function, or new electrolyte disturbances. Drug interactions are an important causative factor. Careful patient monitoring, including drug levels, is required in these clinical settings.

Advanced age decreases the volume of distribution and renal clearance. Elderly patients and those with chronic renal failure require lower maintenance doses.

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Consultations

The following consultations may be employed:

  • Cardiologists

  • Nephrologists

  • Regional poison control centers

  • Medical toxicologists

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Long-Term Monitoring

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. In the absence of cardiac dysrhythmias, toxic digoxin levels, or hyperkalemia, patients may be discharged with appropriate follow-up care.

Patients with chronic toxicity and noncardiac symptoms may be discharged if factors that led to the toxicity have been corrected (eg, electrolyte disorders, dehydration, drug-drug interactions) and proper care can be ensured. Discontinue use of the drug. Arrange follow-up care in the next 24 hours with a primary care provider. Patients who have taken an intentional overdose should be cleared by a psychiatry consult before discharge.

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