ToxCard: Digoxin Toxicity

Authors: Kaley El-Arab, MD, (Emergency Medicine Resident, Atrium Health’s Carolinas Medical Center), Christine Murphy, MD (Emergency Medicine Attending, Medical Toxicologist, Atrium Health’s Carolinas Medical Center) // Reviewed by: James Dazhe Cao, MD (@JamesCaoMD, Associate Professor of EM, Medical Toxicology, UT Southwestern Medical Center, Dallas, TX); Alex Koyfman, MD (@EMHighAK); and Brit Long, MD (@long_brit)

Case:

A 64-year-old male with a history of atrial fibrillation on metoprolol and digoxin presented to the emergency department for worsening shoulder pain after a recent a closed reduction with percutaneous pin fixation of a humerus fracture from a fall one week prior. He takes his medications as prescribed and last took his medications the morning of presentation to the emergency department, including an unknown post-operative antibiotic. Although he reported lightheadedness and palpitations, he denied any nausea, vomiting, loss of appetite, weight loss, confusion, visual disturbances, or other change in symptoms. Other than eating vegetables, he denied other plant ingestions. Initial vital signs were heart rate 40s-60s beats/min in atrial fibrillation with frequent ectopy on his cardiac monitor, blood pressure 77/41 mmHg, respiratory rate 20 breaths/min, oxygen saturation 98% on room air, temperature 98.5°F, and GCS 15. On exam, his percutaneous fixation site appeared erythematous, edematous, and was actively draining purulent material.

Questions:

1. What is digoxin? Where does it come from and what is its mechanism of action?
2. How does digoxin toxicity present clinically?
3. Are there differences in presentation of patients with acute digoxin toxicity versus chronic digoxin toxicity?
4. What is the management of digoxin toxicity?

Background:

• Digoxin is a cardioactive steroid with therapeutic uses in congestive heart failure and atrial tachydysrhythmias¹
• Nonpharmacologic sources of cardiac glycosides include²:
  • Plants such as foxglove, lily of the valley, oleander, yellow oleander, etc.
  • Bufo toad species
  • Photinus firefly species
• Mechanism of action:^{2, 3}
  • Increases vagal tone which slows conduction at the atrioventricular (AV) node, leading to decreased heart rate
  • Reversible inhibition of Na-K ATPase, which increases extracellular potassium and intracellular sodium
  • This, in turn, decreases the activity of the Na-Ca channel, causing increased intracellular calcium which has a positive inotropic effect
• Narrow therapeutic index
  • 5-2 ng/mL
• Drug interactions
  • Excretion occurs via P-glycoprotein into the intestine or proximal renal tubule; other drugs can induce or inhibit activity of P-glycoprotein and alter digoxin concentrations⁴
    • Inducers like increase removal of digoxin which lowers its concentration⁴
    • Inhibitors like antiarrhythmics such as verapamil and amiodarone, macrolides including azithromycin, azoles, antimalarials, anti-depressants, antipsychotics, HIV protease inhibitors, etc. decrease the removal of digoxin leading to elevated concentrations⁴
  • Digoxin is partially plasma protein bound, and some drugs cause a decrease in serum protein binding of digoxin
  • Antibiotics can decrease gastrointestinal (GI) flora which inactivates digoxin, leading to increased digoxin concentration⁵

Clinical Presentation:

• Acute digoxin toxicity²
  • Usually related to an intentional overdose
    • Symptoms are typically noted following an ingestion of 2-3 mg in adults³
    • An acute ingestion of > 5-10 mg is more likely to cause lethal toxicity in adults^2,3
    • In pediatric patients, ingestions of > 0.1 mg/kg will likely lead to symptoms, and fatalities are reported with acute ingestions of > 4 mg^2,3
  • Patients may be asymptomatic for several hours
  • GI symptoms (nausea, vomiting) are usually the first sign of developing toxicity
  • Central nervous system (CNS) manifestations include weakness and confusion
  • Hyperkalemia, which if >5 mmol/L, is associated with increased mortality⁶
  • Cardiac dysrhythmias
    • Digoxin toxicity increases adrenergic stimulation while slowing AV nodal conduction⁷
    • Serial ECGs may show nearly any dysrhythmia other than a supraventricular tachycardia, which would exclude digoxin toxicity²
    • Ectopic beats, slow atrial fibrillation, and accelerated junctional rhythms are some of the more common ECG abnormalities⁸
    • Classic findings include bidirectional ventricular tachycardia and atrial tachycardias with slowed ventricular conduction or high degree AV block⁹
    • The ECG from this case (Figure 1) is consistent with digoxin toxicity as it has ectopy and rate-controlled atrial fibrillation

• Chronic Digoxin Toxicity^2,10
  • Usually occurs in the setting of renal impairment or medication change
  • Insidious onset over days to weeks
  • Can occur at therapeutic concentrations
  • GI symptoms include anorexia, nausea, vomiting, abdominal pain, weight loss
  • CNS symptoms include weakness, anhedonia, confusion, headache, hallucinations, seizures, and visual disturbances – most notably a yellow discoloration around lights.
  • Cardiac symptoms include dysrhythmias as described above and hypoperfusion usually secondary to dysrhythmia or hypovolemia from GI symptoms.
  • Electrolyte derangements such as hypokalemia are associated with increased risk for dysrhythmias

Diagnosis:

• A history of digoxin prescription with nonspecific gastrointestinal, neurologic symptoms, or cardiac dysrhythmia should raise suspicion for digoxin toxicity.
• Information in the patient’s history that will help in making the diagnosis and in guiding management include:
• Time of acute ingestion or most recent dose
• Estimation of the amount ingested or if extra doses were taken intentionally or accidentally
• Recent medication changes
• Timing and onset of symptom
• Other co-ingestions such as drugs, plants, or if hallucinogenic toad licking/smoking was involved

Laboratory Testing:

• Get a digoxin concentration on presentation and 6 hours after last dose or time of acute ingestion^2,11
  • Digoxin has a large volume of distribution which takes about 6 to 8 hours to fully distribute into the tissues, and concentrations drawn prior to 6 hours post-ingestion may appear falsely elevated¹
  • Many labs will report a therapeutic range of 0.5-2.0 ng/mL²
    • Toxicity can be seen at concentrations in the therapeutic range and serum concentrations should be interpreted in clinical context
  • Falsely elevated digoxin concentrations can occur when endogenous digoxin-like immunoreactive substance or medications like spironolactone cross-react with the immunoassay²
    • Endogenous digoxin-like immunoreactive substance is found in patients with a variety of medical conditions such as pregnancy, liver disease, and hypothermia
    • Indications of falsely elevated concentrations include a clinical picture that does not correlate with the reported concentration
  • Digoxin concentrations can qualitatively detect plant or animal sources of cardiac glycosides, but the concentration does not correlate with clinical toxicity²
  • Digoxin concentration laboratory values typically report total serum digoxin concentration²
    • If a patient has received Digoxin-Specific Antibody Fragments (DSFab, e.g., DigiFab), the total serum digoxin concentration will be misleading as it will pick up digoxin which has been bound by DSFab
    • If it is clinically necessary to recheck a digoxin concentration, ensure it is a free digoxin concentration which will measure unbound digoxin. In many hospitals, this is a send out test
  • Fingerstick glucose for anyone with altered mental status to ensure not missed hypoglycemia
  • A basic metabolic panel to check potassium, sodium, and calcium concentrations, as well as renal function
  • Co-ingestion labs including acetaminophen and salicylate concentrations should be obtained if there is a concern for acute toxicity or an intentional ingestion
  • Urine pregnancy test in females of reproductive age

Management:

• ABCs for initial stabilization
  • Consider atropine, cardiac pacing, and cardioversion
• GI decontamination with activated charcoal in acute ingestions, when appropriate
  • Can be multidose (every 2-4 hours x 3-4 doses) due to enterohepatic recirculation, however there is some debate about this in the literature
• Correct electrolyte derangements
• Antidote is DSFab (see ToxCard: DigiFab for Digoxin Toxicity for indications and dosing)¹²
• No role for hemodialysis for digoxin removal but may be needed for management of renal failure or hyperkalemia

Case Followup:

• Despite the patient’s complaint focusing on his recent fracture and signs of postoperative infection, the emergency department physician noticed that patient’s bradycardia and hypotension were unlikely to be from sepsis alone. The patient was initially stabilized with IV fluids, broad-spectrum antibiotics, and vasopressors. The digoxin concentration returned elevated at 3.22 ng/mL, lactic acid 1.8 mmol/L, K 4.5 mmol/L, and Cr 2.63 mg/dL up from baseline of 0.77 mg/dL. Toxicology was consulted and recommended DSFab due to the patient’s elevated concentration, cardiac ectopy, and hypotension. Following DSFab administration, the patient had improvement in heart rate and was titrated off pressors. CT showed an intramuscular abscess at the site of his previous fracture, and the patient went for IR-guided drainage and received a course of antibiotics with improvement. Recent antibiotics and acute kidney injury were likely underlying causes of this patient’s digoxin toxicity.

Clinical Pearls:

• Digoxin is a cardiac glycoside with a narrow therapeutic index²
• Changes in renal function and drugs like other antiarrhythmics, antimicrobials, anti-epileptic drugs, anti-depressants, antipsychotics, and HIV protease inhibitors can alter free digoxin concentrations⁴
• Patients on digoxin with nonspecific GI, neurologic symptoms, or cardiac dysrhythmia should raise suspicion for digoxin toxicity
• Hyperkalemia can be a marker of toxicity, and there is increased mortality in patients with acute overdoses and a potassium > 5 mmol/L⁵
• If clinically stable, obtain digoxin concentration 6 hours after ingestion/most recent dose, in addition to a basic metabolic panel and an ECG
• Management focuses on ABCs, charcoal in acute ingestions, supportive care, and in some cases, reversal with DSFab

References:

1. Gheorghiade M, Adams KF Jr, Colucci WS. Digoxin in the management of cardiovascular disorders. Circulation 2004; 109:2959.
2. Hack J. Cardioactive steroids. In Goldfrank’s Toxicological Emergencies, 11^th edition (2019). Editors: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. McGraw Hill; New York.
3. Micromedex Drug Information, Digoxin. Available at: http://micromedex.com/ Accessed January 7, 2022
4. Wessler JD, Grip LT, Mendell J, Giugliano RP. The P-Glycoprotein Transport System and Cardiovascular Drugs. J Am Coll Cardiol 2013; 61(25):2495-2502.
5. Lindenbaum J, Rund DG, Butler VP, et al: inactivation of digoxin by the gut flora: Reversal by antibiotic therapy. N Engl J Med 1981; 305:789-794.
6. Bismuth C, Gaultier M, Conso F, Efthymiou ML. Hyperkalemia in acute digitalis poisoning: prognostic significance and therapeutic implications. Clin Toxicol 1973; 6:153.
7. Hauptman PJ, Kelly RA. Digitalis. Circulation 1999; 99:1265.
8. Li-Saw-Hee FL, Lip GY. Digoxin revisited. QJM 1998; 91:259.
9. Ma G, Brady WJ, Pollack M, Chan TC. Electrocardiographic manifestations: digitalis toxicity. J Emerg Med 2001; 20:145.
10. Bhatia SJ. Digitalis toxicity–turning over a new leaf? West J Med 1986; 145:74.
11. Doherty JE, de Soyza N, Kane JJ, et al: Clinical pharmacokinetics of digitalis glycosides. ProgCardiovascDis 1978; 21:141-158.
12. Garcia A. DigiFab for Digoxin Toxicity. http://www.emdocs.net/toxcard-digoxin-toxicity-2/ Accessed February 13, 2022.