Digitalis Toxicity Workup

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

Approach Considerations

Studies in patients with possible digitalis toxicity include the following:

  • Serum digoxin level
  • Electrolytes
  • Renal function studies
  • Electrocardiogram (ECG)

The serum digoxin level can be used as a guide to the appropriate dosing of medication and to monitor compliance, and can be used to assess toxicity. However, the relationship between digoxin toxicity and the serum digoxin level is complex. Clinical toxicity results from the interactions between digitalis, various electrolyte abnormalities, and their combined effect on the sodium-potassium adenosine triphosphatase (Na+/K+ ATP ase) pump. [15, 19]

Infants and children taking digoxin tolerate higher doses and plasma levels. The pediatric volume of distribution is greater and the half-life of digoxin is less. Pediatric myocardial cells may be less sensitive to the toxic effects of digoxin; decreased sensitivity to dysrhythmias by infants and children may contribute to increased tolerance to digoxin.

The usual therapeutic range for digoxin is 0.5-2 ng/mL. Serum concentrations associated with toxicity overlap between therapeutic and toxic ranges because of the myriad of factors potentiating digoxin toxicity.

False-negative assay results may occur in the setting of acute ingestion of plants containing nondigoxin cardiac glycosides, such foxglove and oleander, even in the setting of profound clinical toxicity. This is caused by nonreactivity or minimal cross-reactivity with the digoxin radioimmunoassay.

Blood levels of the following should be measured:

  • Sodium
  • Potassium
  • Chloride
  • Carbon dioxide
  • Magnesium
  • Calcium
  • Blood urea nitrogen (BUN)
  • Creatinine

If myocardial infarction is a clinical concern, also obtain cardiac markers such as creatine kinase, muscle-bone fraction (CK-MB) or troponin I or T.

Initial potassium levels correlate better with the prognosis than either ECG changes or the initial serum digoxin level. Survival is diminished in patients with hyperkalemia, particularly those with potassium levels greater than 5.5 mg/dL. [20]

Digoxin levels

The development of sensitive and accurate radioimmunoassays has improved the diagnosis and management of digitalis toxicity. Therapeutic digoxin levels vary between laboratories: the lower limit ranges from 0.6-1.3 ng/mL, while the upper limit generally is agreed to be 2.6 ng/mL (see Digoxin level). In chronic toxicity, plasma drug levels are greater than 6 ng/mL.

However, there is significant overlap in levels between patients with toxicity and those without toxicity. Toxicity is related to intracellular levels, not serum levels. Consequently, serum digoxin levels cannot be used as the sole indicator of toxicity, especially after acute ingestion.

Neonates and small infants rarely develop toxic symptoms or ECG abnormalities with serum levels of less than 4-5 ng/mL. Children without cardiovascular disease may tolerate levels as high as 10 ng/mL without serious toxicity, but they may have bradyarrhythmias or conduction delays on ECG. The general rule is that the smaller the infant, the higher the levels may be before toxic effects are observed.

Levels determined less than 6-8 hours after an acute ingestion reflect the initial distribution of the drug but not the actual tissue levels, and do not necessarily predict toxicity. The plasma half-life of digoxin is shortened to 10-25 hours with acute, massive ingestions, compared with a mean value of 36 hours in nontoxic ingestions. Digoxin levels do not equilibrate quickly because of variable absorption and subsequent tissue distribution.

In acute toxicity, repeat the digoxin level after 2-4 hours to guide therapy. The best way to guide therapy is to follow the digoxin level and correlate it with serum potassium concentrations and the patient's clinical and ECG findings.

Digoxinlike immunoreactive substance

Endogenous digoxinlike immunoreactive substance (DLIS) can cause a false-positive result or false elevation on digoxin assays. DLIS is observed in neonates and in patients with any of the following:

  • Renal insufficiency
  • Liver disease or hyperbilirubinemia
  • Subarachnoid hemorrhage
  • Chronic heart failure
  • Diabetes mellitus
  • Acromegaly
  • Pregnant

In some studies, premature infants have had levels as high as 4 ng/mL, with peaks at age 6 days, and positive assay results until they reached 3 months of age. Most authors agree that serum digoxin levels due to DLIS are usually less than 2 ng/mL and that the interference is assay dependent and may vary with the lot of the reagent. Some laboratories use ultrafiltration techniques to eliminate the contribution of DLIS.

Other confounding variables

While most patients metabolize less than 20% of digoxin, 10% of the population metabolizes as much as 55% of digoxin to initially active metabolites. Not all the radioimmunoassays in routine use measure each of these metabolites. Additionally, the antibodies used in a digoxin immunoassay can cross-react with numerous compounds, including steroids and spironolactone. Because most digoxin assays measure total rather than free digoxin levels, serum digoxin levels are no longer useful after Fab fragment administration.

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Electrolyte Evaluation

In acute toxicity, hyperkalemia is common owing to inactivation of the Na+/K+ -ATPase pump. Initial potassium levels correlate better with the prognosis than either ECG changes or the initial serum digoxin level. In one series, all patients with an initial potassium level greater than 5.5 mg/dL died, whereas 50% of patients with a serum digoxin level of 5-5.5 mg/dL died. [20]

In contrast, long-term digoxin users often develop hypokalemia because of concurrent diuretic use. The condition should be corrected promptly, as treating hypokalemia may help to improve cardiac glycoside-related arrhythmia.

Long-term digoxin users also often have hypomagnesemia secondary to diuretic usage. These patients may have intracellular magnesium depletion despite a normal serum magnesium level. Importantly, magnesium is a cofactor of the Na+/K+ -ATPase pump, and alterations of its concentration will affect the pump's actions.

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Electrocardiography

Digoxin toxicity may cause almost any dysrhythmia. Classically, dysrhythmias associated with increased automaticity and decreased atrioventricular (AV) conduction occur (ie, paroxysmal atrial tachycardia with 2:1 block, accelerated junctional rhythm, or bidirectional ventricular tachycardia [torsade de pointes]; see the images below) Sinus bradycardia and AV conduction blocks are the most common ECG changes in the pediatric population, while ventricular ectopy is more common in adults. [11]

Bidirectional tachycardia in a patient with digita Bidirectional tachycardia in a patient with digitalis toxicity.
Bidirectional tachycardia in a patient with digita Bidirectional tachycardia in a patient with digitalis toxicity.

Premature ventricular contractions (PVCs) are the most common dysrhythmia. Bigeminy or trigeminy occurs frequently. Sinus bradycardia and other bradyarrhythmias are very common. Slow atrial fibrillation with very little variation in the ventricular rate (regularization of the R-R interval) may occur. First-, second-, and third-degree heart block and complete AV dissociation are also very common, while rapid atrial fibrillation and atrial flutter are rare.

Ventricular tachycardia is an especially serious finding. Cardiac arrest from asystole or ventricular fibrillation is usually fatal.

Nonparoxysmal atrial tachycardia with heart block and bidirectional ventricular tachycardia are particularly characteristic of severe digitalis toxicity.

Digoxin effects on the baseline ECG include downward scooping of the ST segment and inverted T waves. These findings are not indicative of toxicity. New QRS prolongation, varying degrees of AV block, and arrhythmias may signify digoxin toxicity. Comparison with previous ECGs is helpful. Rhythm strips may be necessary to facilitate arrhythmia analysis

Nonspecific ECG findings include the following:

  • Premature ventricular contractions, especially bigeminal and multiform
  • First-, second- (Wenckebach), and third-degree AV block
  • Sinus bradycardia
  • Sinus tachycardia
  • Sinoatrial block or arrest
  • Atrial fibrillation with slower ventricular response
  • Atrial tachycardia
  • Junctional (escape) rhythm
  • AV dissociation
  • Ventricular bigeminy and trigeminy
  • Ventricular tachycardia
  • Torsade de pointes
  • Ventricular fibrillation

More specific, but not pathognomonic, ECG findings include the following:

  • Atrial fibrillation with a slow, regular ventricular rate (ie, AV dissociation)
  • Nonparoxysmal junctional tachycardia (rate 70-130 beats per minute [bpm])
  • Atrial tachycardia with block (atrial rate usually 150-200 bpm)
  • Bidirectional ventricular tachycardia
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