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
~1.1% of outpatients on digitalis glycosides per year develop toxicity, with as many as 10-20% of nursing home residents annually, experience some degree of digoxin-related toxicity.
Prevalence
- In 2009, the American Association of Poison Control Centers' National Poison Data System reported 2,550 cases of cardiac glycoside overdose, including 651 cases of plant cardiac glycoside exposure.
- Digitalis toxicity is the fourth most common adverse drug reaction in hospitals (1).
ETIOLOGY AND PATHOPHYSIOLOGY
- Digitalis inhibits Na+/K+ -ATPase in myocytes, resulting in an increase in intracellular sodium and a decrease in the transmembrane sodium gradient.
- 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 atrioventricular (AV) node conduction.
- The combination of these effects can cause tachyarrhythmias and conduction block, which can present simultaneously.
- Chronic therapy
- Intentional overdose (suicide attempt)
- Accidental overdose (children)
- Prescription/administration error
- Electrolyte disturbances-predominantly potassium balance
- Renal failure (2) 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
- β-Blockers
RISK FACTORS
- Advanced age
- Renal failure
- Hypoxemia
- Electrolyte disturbances
- Hypokalemia
- Hypomagnesemia
- Hypernatremia
- Hypercalcemia
- Acid-base disturbances
- Decompensating heart failure
- Myocardial infarction
- Myocarditis
- Recent cardiac surgery
- Hypothyroidism
- Polypharmacy
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 kidney disease), increase cardiac sensitivity (e.g., ischemia, myocarditis), increase bioavailability by altering gut flora (e.g., macrolides), or decrease protein binding (e.g., hypoalbuminemia).
- Prescribe lower doses of digoxin (0.125 mg/day instead of 0.25 mg/day) (3). Digoxin is effective in heart failure at much lower levels than necessary for rate control in atrial fibrillation.
COMMONLY ASSOCIATED CONDITIONS
- Renal failure
- Heart failure
- Dehydration
- Polypharmacy
DIAGNOSIS
HISTORY
- For patients at risk for toxicity from chronic use, ask about new medications. Acute illnesses such as gastroenteritis or cardiac diseases, which cause kidney failure or dehydration, may predispose to toxicity.
- For suspected accidental overdose in children, obtain a careful history of childproofing and available medications.
- As with all suspected or confirmed intentional ingestions, ask about timing of ingestions and coingestions.
- Signs and symptoms generally nonspecific
- Gastrointestinal symptoms: anorexia, nausea, vomiting, diarrhea
- Visual disturbances (e.g., yellow halos)
- Mydriasis
- Neurologic changes: (may be more pronounced with chronic toxicity) confusion, restlessness, fatigue, headache
- Depression
- Hallucinations
- Neuralgias
- Vertigo
PHYSICAL EXAM
- Bradycardia is frequently encountered.
- Signs and symptoms of hypoperfusion (confusion, abdominal pain may be seen)
DIFFERENTIAL DIAGNOSIS
- Conduction abnormalities
- Sick sinus syndrome
- AV nodal dysfunction
- Toxicity with β-blockers, calcium channel blockers, and Îħ-agonists (e.g., clonidine)
- Electrolyte disturbances
- Other causes of life-threatening arrhythmia
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Na+, K+, Cl-, HCO3-, Mg+, Ca+, BUN, Cr, and cardiac enzyme biomarkers
- Blood glucose to look for hypoglycemia as a potential cause of altered mental status
- Serum (total) digoxin level
- Upper accepted therapeutic range in serum is 2.0 ng/mL, with toxicity more common >2.5 ng/mL (3)[B].
- Serum digoxin level does not necessarily correlate with toxicity because toxicity may occur with plasma digoxin levels within therapeutic range, especially in chronic overdose (4).
- Digoxin level may be falsely high if measured <6 hours after acute ingestion or last dose due to incomplete drug distribution (3).
- Nondigoxin 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 predict poor outcome/death (3)[B].
- Hypokalemia potentiates digoxin toxicity and is more of a concern in chronic use. Concurrent diuretic use is a common precipitating factor.
- Hypomagnesemia and hypercalcemia also predispose to digoxin toxicity.
- Acetaminophen and salicylate levels should be obtained to rule out concurrent overdose.
Diagnostic Procedures/Other
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 (4).
- Characteristic EKG changes ("digitalis effect") can occur at therapeutic levels.
- Prolonged PR interval
- T-wave changes, prolonged QT interval, scooping of ST segment
- EKG changes relatively specific for digitalis toxicity
- Accelerated junctional rhythm
- Ventricular arrhythmias (more common in chronic toxicity)
- Premature ventricular contractions (PVCs, most common rhythm)
- New-onset Mobitz type I AV block
- Nonparoxysmal atrial tachycardia with variable AV block (very specific but uncommon)
- Other associated rhythms
- 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.
- In the setting of toxicity, continuous cardiac monitoring with serial EKGs is very important.
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; however, monitor for hypokalemia.
- Do not use calcium salts, which can worsen ventricular arrhythmias by further increasing intracellular calcium (4)[C].
- For chronic toxicity, treat the underlying cause.
MEDICATION
First Line
- Digoxin-specific Fab antibody fragments (Digibind)
- Indications (5)[A]
- Treatment of severe, life-threatening arrhythmias due to digitalis toxicity
- Sustained ventricular arrhythmias
- Advanced AV block
- Asystole
- Hemodynamic instability
- Plasma potassium concentration >5 mEq/L in the setting of acute overdose
- Plasma digoxin concentration >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 (3)
- Each vial contains 40 mg and will bind ~0.5 mg of digoxin
- If serum digoxin level is unknown: no. of vials = total body load (mg)/0.5
- Total body load = dose ingested (mg) for digoxin capsules; total body load = dose ingested (mg) 0.8 for digoxin tablets
- If serum digoxin level known: no. of vials = [(serum digoxin concentration in ng/mL) (patient's weight in kilogram)/100]
- Unknown acute ingestion or drug level
- Empiric dose is 10 to 20 vials (6)[C].
- Dosing for children is the same as for adults.
- Slow administration increases the efficiency and elimination of digoxin (7)[C].
- Onset of action for reversal of digoxin toxicity is rapid (minutes) (3)[C].
- Adverse reactions
- Hypokalemia: Monitor potassium carefully because rapid development of hypokalemia can occur after Digibind therapy (3).
- Exacerbation of heart failure, increased ventricular response in atrial fibrillation, and hypersensitivity reactions can occur (3).
Second Line
- Activated charcoal or cholestyramine (3)[C]
- Consider in acute or overdose settings.
- Increases GI elimination and systemic clearance
- Magnesium: 2 g IV initially; consider maintenance infusion (5)[C].
- Temporary pacing if no Digibind available (5)[C]
- Hemodialysis can be used to treat hyperkalemia, but it is not effective for reversal of toxicity because of the extensive tissue distribution of digoxin (3)[C].
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
All patients with suspected digoxin toxicity who have cardiac dysrhythmias, toxic digoxin levels, or hyperkalemia should be admitted for continuous cardiac monitoring.
- Manage airway.
- IV access/fluid resuscitation
- Supplemental oxygen
- Atropine for symptomatic bradycardia (3)[C]
- Temporary cutaneous pacing (3)[C]
- Hemodynamically unstable patients should receive Digibind as soon as possible (5)[A].
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 â¤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 to 25% of exposures treated in hospitals (8).
REFERENCES
11 Bronstein AC, Spyker DA, Cantilena LRJr, et al. 2008 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 26th Annual Report. Clin Toxicol (Phila). 2009;47(10):911-1084.22 Chan KE, Lazarus JM, Hakim RM. Digoxin associates with mortality in ESRD. J Am Soc Nephrol. 2010;21(9):1550-1559.33 Bauman JL, Didomenico RJ, Galanter WL. Mechanisms manifestations, and management of digoxin toxicity in the modern era. Am J Cardiovasc Drugs. 2006;6(2):77-86.44 Hauptman PJ, Kelly RA. Digitalis. Circulation. 1999;99(9):1265-1270.55 Zipes DP, Camm AJ, Borggrefe M, et al. 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 (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). Circulation. 2006;114:1088-1132.66 Brubacher JR, Ravikumar PR, Bania T, et al. Treatment of toad venom poisoning with digoxin-specific Fab fragments. Chest. 1996;110(5):1282-1288.77 Lapostolle F, Borron SW, Verdier C, et al. Digoxin-specific Fab fragments as single first-line therapy in digitalis poisoning. Crit Care Med. 2008;36(11):3014-3018.88 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(8):1448-1453.
ADDITIONAL READING
- Rajapakse S. Management of yellow oleander poisoning. Clin Toxicol (Phila). 2009;47(3):206-212.
- Roberts DM, Buckley NA. Antidotes for acute cardenolide (cardiac glycoside) poisoning. Cochrane Database Syst Rev. 2006;(4):CD005490.
- Yang EH, Shah S, Criley JM. Digitalis toxicity: a fading but crucial complication to recognize. Am J Med. 2012;125(4):337-343.
CODES
ICD10
- T46.0X1A Poisoning by cardi-stim glycos/drug simlar act, acc, init
- T46.0X2A Poisn by cardi-stim glycos/drug simlar act, self-harm, init
- T46.0X4A Poisoning by cardi-stim glycos/drug simlar act, undet, init
- T46.0X3A Poisn by cardi-stim glycos/drug simlar act, assault, init
ICD9
972.1 Poisoning by cardiotonic glycosides and drugs of similar action
SNOMED
- Poisoning by digitalis glycoside (disorder)
- Digitalis species poisoning (disorder)
CLINICAL PEARLS
- 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.