Digitalis Toxicity Treatment & Management

General 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. Fab antibody fragments are extremely effective in the treatment of severe, acute digitalis toxicity

General principles of management include the following:

• 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)
• Factors that influence treatment, including age, medical history, chronicity of digoxin intoxication, existing heart disease and/or renal insufficiency, and, importantly, ECG changes
• Continuous hemodynamic assessment, including 12-lead ECG and cardiac monitoring, as well as intensive care unit admission and IV access
• Prompt measurement of electrolyte levels, including potassium and calcium, and of serum creatinine, and digoxin levels^[19]

Transfer

Transfer hemodynamically unstable patients to a tertiary care center equipped with medical intensive care unit/critical care unit capabilities. Notification of and discussion of treatment with the regional poison center also is important.

Consultations

The following consultations may be employed:

• Cardiologists
• Nephrologists
• Regional poison centers
• Medical toxicologists

Monitoring and follow-up

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; lab results should be normalized.

Suicidal, depressed patients should be cleared by a psychiatry consult for prevention of repeated toxic ingestion before discharge.

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.

The 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 caused by 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.

Other points to consider include the following:

• Induced emesis with ipecac syrup - Not recommended, because of the increased vagal effect
• Whole-bowel irrigation - May be useful, but clinical data are lacking
• Forced diuresis - 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

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. It is unclear how well magnesium levels correlate with digitalis toxicity.^[20]

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 if there is an absence of, or a delay in administering, immunotherapy.

Digoxin immune Fab is now considered first-line treatment for significant dysrhythmias and should be promptly administered if digoxin toxicity is suspected.^{[17, 21, 22]}

Phenytoin and lidocaine are useful antiarrhythmics for the treatment of digoxin toxicity if Fab fragments are ineffective or unavailable.^[20] 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 may be useful in blocking digoxin-induced effects of enhanced vagal tone on the SA and AV nodes; it has proven helpful in reversing severe sinus bradycardia.

Quinidine, procainamide, and bretylium are contraindicated. 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.^[20]

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.

IV 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 have suggested that immunotherapy should be attempted prior to initiating pacemaker activity.

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 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/ventricular fibrillation, but most clinicians suggest starting at 50-100 joules for a wide, complex ventricular tachycardia, rather than at the 200 joules recommended in the advanced cardiac life support (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.

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.

After treatment with Fab fragments, the serum digoxin level will rise considerably. The 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 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 because the Fab complex is eliminated more rapidly than digoxin is released from tissue-binding sites.

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 foreign protein; these reactions are uncommon. Allergy to Fab fragments is associated with patients who have multiple allergies.

Hemodialysis and activated charcoal hemoperfusion 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 high for hemodialysis 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 hemoperfusion.

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.