Digitalis Toxicity – Causes, Symptoms, Diagnosis, Treatment and Ongoing care

Basics

Description

  • A life-threatening condition resulting from intoxication by digitalis (digoxin) when used for chronic therapy, from accidental or intentional overdose, or from ingestion of naturally occurring compounds containing cardiac glycosides (e.g., foxglove, oleander)
  • Can be acute or chronic
  • System(s) affected: Cardiovascular; Gastrointestinal; Ocular; Central Nervous System

Epidemiology

Incidence

About 1.1% of outpatients on digitalis glycosides per year develop toxicity, with as many as 10–20% of nursing home residents annually experiencing some degree of digoxin-related toxicity.

Prevalence

In 2007, the American Association of Poison Control Centers’ National Poison Data System reported more than 2,500 cases of cardiac glycoside overdose.

Risk Factors

  • Advanced age
  • Renal failure
  • Hypoxemia
  • Electrolyte disturbances:
    • Hypokalemia
    • Hypomagnesemia
    • Hypernatremia
    • Hypercalcemia
  • Acid–base disturbances
  • Decompensating congestive heart failure
  • Myocardial infarction
  • Myocarditis
  • Recent cardiac surgery
  • Hypothyroidism
  • Cor pulmonale

General Prevention

  • Use caution when prescribing digitalis if the patient is taking medications that interfere with digoxin metabolism or clearance.
  • Adjust dosing when there are circumstances that increase total body levels of the drug (e.g., acute or chronic renal failure), increase cardiac sensitivity (e.g., ischemia, myocarditis), or increase bioavailability by altering gut flora (e.g., macrolides).
  • Prescribe lower doses of digoxin (0.125 mg/day instead of 0.25 mg/day) (1). Digoxin is effective in heart failure at much lower levels than necessary for rate control in atrial fibrillation.

Pathophysiology

  • Digitalis inhibits Na+-K+-ATPase in myocytes, resulting in an increase in intracellular sodium and a decrease in the transmembrane sodium gradient.
  • The loss of the sodium gradient decreases the drive of the Na+-Ca2+transporter, leading to increased intracellular calcium and thus increased inotropy.
  • At high/toxic digoxin concentrations, elevated intracellular calcium generates small depolarizations, and the additive effects of these depolarizations produce dysrhythmias.
  • Digitalis also acts on the parasympathetic system resulting in increased vagal tone and slowing AV node conduction.
  • The combination of these effects can cause tachyarrhythmias and conduction block, which can present simultaneously.

Etiology

  • Chronic therapy
  • Intentional overdose (suicide attempt)
  • Accidental overdose (children)
  • Prescription/administration error
  • Electrolyte disturbances
  • Renal failure or any condition that decreases clearance of the drug
  • Poisoning with plants containing cardiac glycosides (e.g., oleander, foxglove, lily of the valley)
  • Concurrent use of medications:
    • Antibiotics: Rifampin, tetracycline, macrolides
    • Selective serotonin reuptake inhibitors (SSRIs)
    • Calcium channel blockers: Diltiazem, verapamil
    • Antiarrhythmics: Quinidine, amiodarone
    • Diuretics: Spironolactone
    • β-blockers

Commonly Associated Conditions

  • Renal failure
  • Congestive heart failure
  • Dehydration
  • Syncope

Digitalis, Heart failure, Electrocardiography, Drug overdose, Heart disease, Digitalis purpurea, digitalis glycosides, poison control centers, chronic renal failure, electrolyte disturbances, myocardial infarction, acid base disturbances,

Diagnosis

History

  • For patients at risk for toxicity from chronic use, ask about new medications or new or worsened cardiac or renal disease.
  • For suspected accidental overdose in children, a careful history of childproofing and available medications should be obtained.
  • As with all suspected or confirmed intentional ingestions, ask about timing of ingestions and coingestions.
  • Signs and symptoms generally nonspecific:
    • Anorexia
    • Nausea
    • Vomiting
    • Diarrhea
    • Visual disturbances (e.g., yellow halos)
    • Mydriasis
    • Confusion
    • Fatigue
    • Restlessness
    • Weakness
    • Headache
    • Depression
    • Hallucinations
    • Neuralgias
    • Vertigo

Diagnostic Tests & Interpretation

Lab

Initial lab tests

  • Na+, K+, Cl-, HCO3-, Mg+, Ca+, blood urea nitrogen (BUN), Cr, and cardiac enzyme biomarkers
  • Serum digoxin level: Total:
    • The accepted therapeutic range in serum is 0.8–2.0 ng/mL (for rate control in atrial fibrillation), with toxicity more common above 2.5 ng/mL (1)[B].
    • Toxicity may occur with plasma digoxin levels within therapeutic range, especially in chronic overdose (2)[C].
    • Digoxin level may be falsely high if measured <6 hours after acute ingestion or last dose (1)[C].
    • Non-digoxin cardiac glycoside (e.g., foxglove, oleander) may cross-react and generate a positive/elevated level; a negative level does not rule out exposure.
  • Free serum digoxin level:
    • Free levels are useful for monitoring response to therapy after digoxin-specific Fab antibody fragments are given (Fab bound to digoxin increases the total digoxin level).
  • Potassium:
    • In acute toxicity, hyperkalemia can be common, life-threatening, and predictive of lethality (1)[B].
    • Hypokalemia potentiates digoxin toxicity.

Diagnostic Procedures/Surgery

  • Electrocardiogram (EKG):
    • Digoxin has been reported to cause a wide variety of rhythm disturbances, so consider the diagnosis with any sudden change in cardiac rhythm. Look for rhythms that suggest increased automaticity and/or delayed conduction (2)[C].
    • Characteristic EKG changes (“digitalis effect”) can occur at therapeutic levels:
      • Prolonged PR segment
      • T-wave changes, prolonged QT interval, scooping of ST segment
    • EKG changes relatively specific for digitalis toxicity:
      • Accelerated junctional rhythm
      • Bidirectional ventricular tachycardia
      • New-onset Mobitz type I AV block
      • Nonparoxysmal atrial tachycardia with AV block
    • Other associated rhythms:
      • Ventricular ectopy, premature ventricular contractions
      • High-degree heart block
      • Sinus bradycardia
      • Sinus bradycardia with junctional tachycardia
      • Ventricular fibrillation or tachycardia
      • Atrial flutter
    • Digoxin toxicity is less likely to cause supraventricular tachycardia, rapid atrial fibrillation, or Mobitz Type II AV block.
  • For suspected intoxication with naturally occurring cardiac glycosides, consider early consultation with a medical toxicologist or poison control center for help in identifying the toxic source and to guide treatment decisions.

Differential Diagnosis

  • Conduction abnormalities:
    • Sick sinus syndrome
    • AV nodal dysfunction
  • Medication effect
  • Electrolyte disturbances
  • Other causes of life-threatening arrhythmia

Treatment

Medication

First Line

  • Digoxin-specific Fab antibody fragments (Digibind)
  • Indications:
    • Treatment of severe, life-threatening arrhythmias due to digitalis toxicity (3)[A]:
      • Sustained ventricular arrhythmias
      • Advanced AV block
      • Asystole
    • Hemodynamic instability
    • Plasma potassium concentration >5 mEq/L in the setting of acute overdose
    • Plasma digoxin concentration above 10 ng/mL (at steady state)
    • Acute ingestion of >10 mg digoxin in adults or >4 mg in children
  • Dosage of Digibind:
    • If possible, obtain a total digoxin level before administration.
    • Use free levels to monitor treatment response.
    • To calculate Digibind dosage (1)[A]:
      • Number of vials = Ingested amount (mg) × 0.8/0.5
      • Number of vials = Digoxin level (ng/mL) × weight (kg)/100
    • Unknown acute ingestion or drug level:
      • Empiric dose is 10 vials (4)[C].
    • Dosing for children is the same as for adults.
    • Slow administration increases the efficiency and elimination of digoxin (5)[C].
    • Onset of action for reversal of digoxin toxicity is rapid (minutes) (1)[C].
  • Adverse reactions:
    • Hypokalemia: Monitor potassium carefully, since rapid development of hypokalemia can occur after Digibind therapy (1)[A].
    • Exacerbation of heart failure, increased ventricular response in atrial fibrillation, and hypersensitivity reactions can occur (1)[A].

Second Line

  • Activated charcoal (1)[C]:
    • Consider in acute or overdose settings
    • Increases GI elimination and systemic clearance
  • Magnesium: 2 g IV initially, consider maintenance infusion (3)[C]
  • Temporary pacing if no Digibind available (3)[C]
  • Hemodialysis can be used to treat hyperkalemia, but is not effective for reversal of toxicity because of the extensive tissue distribution of digoxin (1)[C].

Additional Treatment

General Measures

  • Discontinue digoxin and other medications that interact with digoxin or exacerbate dysrhythmias.
  • Correct electrolyte abnormalities and monitor potassium levels:
    • Maintain potassium in high–normal range.
    • Treat hyperkalemia with sodium bicarbonate, insulin, glucose, and Kayexalate.
    • Treat hypokalemia cautiously.
    • Do not use calcium salts, which can worsen ventricular arrhythmias by further increasing intracellular calcium (2)[C].
  • For chronic toxicity, treat the underlying cause.

In-Patient Considerations

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Initial Stabilization

  • Manage airway
  • IV access/fluid resuscitation
  • Supplemental oxygen
  • Atropine for symptomatic bradycardia (1)[C]
  • Temporary cutaneous pacing (1)[C]
  • Hemodynamically unstable patients should receive Digibind as soon as possible (3)[A].

Admission Criteria

All patients with suspected digoxin toxicity who have cardiac dysrhythmias, toxic digoxin levels, or hyperkalemia should be admitted for continuous cardiac monitoring.

IV Fluids

Administration of appropriate IV fluids depends on underlying etiology for toxicity (e.g., decompensated congestive heart failure vs acute renal failure secondary to dehydration).

Discharge Criteria

Patients should remain in the hospital until the signs and symptoms have resolved and the serum digoxin level ≤2 ng/mL.

Ongoing Care

Follow-Up Recommendations

  • Psychiatric referral is indicated for all intentional overdoses.
  • In chronic toxicity, close follow-up by a primary care physician or cardiologist is recommended if digoxin therapy is continued after discharge.

Patient Monitoring

  • Digoxin levels should be monitored in acute toxicity. However, Digibind administration can interfere with the assay and give unreliable results.
  • Electrolytes, especially potassium, should be carefully monitored.
  • Medications that may have precipitated or contributed to digoxin intoxication should be discontinued and restarted when clinical symptoms have resolved.
  • EKG and cardiac monitoring should continue until resolution of dysrhythmias.

Prognosis

Moderate/major morbidity or death has been reported from 20–25% of exposures treated in hospitals (6).

References

1. Bauman JL, Didomenico RJ, Galanter WL. Mechanisms, manifestations, and management of digoxin toxicity in the modern era. Am J Cardiovasc Drugs.2006;6:77–86.

2. Hauptman PJ, Kelly RA. Digitalis. Circulation. 1999;99:1265–70.

3. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death-executive summary: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines. Circulation. 2006;114:1088–1132.

4. Brubacher JR, Heller MB, Ravikumar PR, et al. Treatment of Toad Venom Poisoning with Digoxin-Specific Fab Fragments. Chest. 1996;110:1282–1288.

5. Lapostolle F, Borron S, Verdier C, et al. Digoxin-specific Fab fragments as single first-line therapy in digitalis poisoning. Crit Care Med. 2008;36(11):3014–3018.

6. Lapostolle F, Borron SW, Verdier C, et al. Assessment of digoxin antibody use in patients with elevated serum digoxin following chronic or acute exposure. Intensive Care Med. 2008;34:1448–1453.

Additional Reading

Rajapakse S. Management of yellow oleander poisoning. Clinical Toxicology.2009;47(3):206–212.

Roberts DM, Buckley N. Antidotes for acute cardenolide (cardiac glycoside) poisoning (Review). Cochrane Database of Systematic Reviews. 2006; Issue 4.

Codes

ICD9

972.1 Poisoning by cardiotonic glycosides and drugs of similar action

Snomed

12876009 Poisoning by digitalis glycoside (disorder)

Clinical Pearls

  • The onset of vague symptoms accompanied by dysrhythmia should raise suspicion of toxicity by digitalis or other cardiac glycosides (e.g. foxglove, oleander).
  • Toxicity may develop even when digoxin serum levels are within normal therapeutic range.
  • Digoxin-specific Fab antibody fragments are the treatment of choice for severe, life-threatening arrhythmias due to digitalis toxicity.

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