Cardiac Glycoside and Digoxin Toxicity

Etiology

Dr. William Withering first utilized the foxglove plant in 1775 to treat dropsy (edema). Digoxin was isolated from Digitalis lanata in 1930 by Dr. Sydney Smith and has been used for hundreds of years to treat heart failure but was only approved by the Food and Drug Administration (FDA) in the late 1990s. More recently, digoxin use has declined due to the development of alternative therapies that have an improved safety profile. However, digoxin still plays a role in the management of specific patients with heart failure and atrial fibrillation.[1] 

Toxicity from digoxin can occur acutely, acute on chronic, or chronically. Acute toxicity occurs without prior background use and can be intentional or inadvertent. Acute on chronic toxicity occurs with an additional bolus of medication in a patient with antecedent background use. Chronic toxicity has no additional bolus of medication but instead occurs when digoxin levels are increased due to decreased clearance, usually due to renal insufficiency.[5] 

Metabolic disturbances, eg, hypokalemia, hypomagnesemia, and hypercalcemia, can make one more prone to toxicity. Multiple drug interactions can decrease digoxin clearance by the renal system. In vitro studies show that amiodarone, verapamil, quinidine, macrolides, itraconazole, and cyclosporine inhibit P-glycoprotein transport in renal cells. The P-glycoprotein is an efflux transport protein, and its inhibition can lead to decreased clearance of digoxin, leading to chronic toxicity.[4] Chronic toxicity is more common than acute intoxication.[6][7][6]

Digoxin Toxicity Risk Factors

Factors that increase the risk of digoxin toxicity include:

• Female sex 
• Advanced age
• Renal insufficiency and end-stage renal disease 
• Hypercalcemia
• Alkalosis
• Hypoxemia
• Acidosis

Digoxin Drug Interactions

Over 426 drugs have been identified to interact with digoxin. A limited medication list that is associated with digoxin toxicity includes:

• Diuretics
• Amiodarone
• Beta-blockers
• Benzodiazepines
• Calcium channel blockers
• Quinidine
• Macrolide antibiotics such as clarithromycin and erythromycin 
• Propylthiouracil
• Amphotericin
• Antifungals such as itroconazole

Ouabain is a cardiac glycoside found in plants from the genera Acokanther. Its toxicity is mainly described from experimental studies, as this glycoside has no clinical use in humans. Oleandrin, found in the plant Nerium oleander, has been associated with human poisonings, both intentional and unintentional. The toxic cardioactive glycoside is found in the whole plant, leaves, stems, roots, fruit, and flowers.

Bufalin, found in toads from the Amphibia class, is associated with toxicity in humans and animals ingesting the toad or its eggs. If provoked by a dog or other animal, the toad will produce the toxin from its parotid gland, which will be secreted onto its skin and can be ingested. Humans can also come into contact with this toxin from Ch'an Su tea, which is utilized in traditional Chinese medicine.[8] 

Epidemiology

As other medication options became available for the treatment of heart failure that had improved safety profiles, the use of digoxin has become less common. As a result, the incidence of digoxin toxicity has also declined. Over the past decade, digoxin use has decreased to approximately 8% of patients being started on it for symptoms of heart failure before discharge from the hospital.[4] Nevertheless, digoxin use is still prevalent enough, and with a narrow therapeutic window, toxicity continues to be a significant problem. Over 4 million prescriptions were dispensed for digoxin as of 2014, which still maintains a role in treatment in specific individuals. Toxicity remains uncommon, with an estimated 8,000 hospital visits annually in the United States.[7] In 2011, according to United States poison control, 2513 cases of digitalis toxicity were reported, of which 27 resulted in death.[9][10]

Epidemiologic data on toxicity from oleandrin and bufalin is less robust. Oleandrin toxicity is seen more commonly in tropical and subtropical climates, where Nerium oleander and Thevetia peruviana growth is more pronounced. Unintentional ingestion by children has been seen, as well as intentional suicidal gestures in adults, which is more common in India and Sri Lanka. Yellow oleander is also used in traditional medicine, which can lead to toxicity with inaccurate dosing. The plant is part of the natural ecosystem in the United States, particularly in the Southwest. Yellow oleander is also grown as an ornamental plant, but toxicity is rare due to its bitter taste. 

In China, over 100 traditional medicines contain extracts from toxic toads, including Liushen Pill, Chansu Pill, and Chan Su Analgesic Cream. In the United States, toad toxin is formulated into various aphrodisiac products like “Rock Hard” and “Black Cube.”[11] Fatalities have been reported from inaccurate dosing and administration of these medications, including ingestion of formulations meant to be used topically. More commonly, bufalin toxicity is seen in the veterinary community from interactions between dogs and the bufo toad.[8] 

Pathophysiology

Due to their structural similarity, all cardioactive glycosides share the same mechanism of action. The differences in the lactone ring and sugar moiety lead to changes in toxicokinetics, clinical signs, and potential for arrhythmias.[8] 

The primary mechanism of action of digitalis is the inhibition of the sodium-potassium ATPase pump within the myocyte. This reversible inhibition of the ATPase results in increased intracellular sodium levels. The build-up of intracellular sodium leads to a shift of sodium extracellularly through another channel in exchange for calcium ions. This influx of intracellular calcium results in increased myocyte contractility.

Digoxin also directly affects conduction through increased vagal tone, which leads to decreased chronotrophy. Digoxin stimulates the vagus nerve, leading to prolonged conduction through the sinoatrial (SA) and atrioventricular (AV) nodes. Overall, digoxin slows the conduction and increases the refractory period in cardiac tissue by enhancing vagal tone. With toxic concentrations, digoxin causes arrhythmias due to increased cell excitability and decreased resting potential, resulting in afterdepolarizations and aftercontractions due to spontaneous cycles of calcium release and uptake.[4] These actions of digoxin can result in almost every type of arrhythmia possible, including:

• Extrasystole
• Nonparoxysmal junctional tachycardia
• Ventricular fibrillation
• Premature ventricular contractions
• Atrial fibrillation and flutter
• Bidirectional ventricular tachycardia
• SA and AV node block

Left bundle branch block, right bundle branch block, and intraventricular conduction delay patterns are seen rarely in digoxin toxicity, as the effect on conduction velocity via the His bundle and bundle branches is minimal. Digoxin also exerts neurohormonal effects due to its sympatholytic activity and decreases the concentration of epinephrine and renin. 

Intravenous administration of calcium is contraindicated with people taking digoxin, as it places the patient at higher risks of arrhythmias.[12] The major electrolyte complication in acute digoxin toxicity is hyperkalemia, which can exacerbate cardiac arrhythmias. Digoxin toxicity is often refractory to standard treatment, but even when corrected, no increase in patient survival has been reported.[13]

Histopathology

Digoxin and other cardiac glycosides can cause various histopathologic findings. Myocardial, blood vessel, and focal tubular necrosis within the kidney have been seen in digoxin-poisoned patients. However, the cardiac glycoside ouabain can cause apoptosis without necrosis of the cardiomyocytes. The kidney can show interstitial and tubular necrosis. Bufalin, another cardiac glycoside, has produced edema, hemorrhaging, lung congestion, and cardiomyocyte fragmentation with necrosis, kidney tubular degeneration, and nephritis.[8] 

Toxicokinetics

Digoxin is incompletely absorbed, with a 50% to 90% bioavailability. Genaltinized capsules can improve bioavailability by 100%.[1] Approximately 20% to 25% of digoxin is bound to serum albumin. Digoxin has a large volume of distribution of 6 L/kg, with the distribution phase taking approximately 6 to 8 hours. This distribution makes laboratory analysis challenging if the blood sample is obtained too close to administration. This also means that hemodialysis cannot remove digoxin from the body. 

Digoxin is mainly excreted by the kidney unchanged. A steady state plateau is achieved in patients with normal renal function in 7 to 10 days. The elimination half-life is 1.5 to 2 days but can be as long as a week in patients with renal insufficiency and end-stage renal disease.[1][12][4] Furthermore, many drug interactions lead to decreased clearance of digoxin. Well-known offenders include verapamil, macrolides, and antifungals.

Electrolyte disturbances, including hypomagnesemia, hypercalcemia, and hypokalemia, lead to increased sensitivity to digoxin, making toxicity more likely even with a lower concentration of serum digoxin. This makes diagnosis difficult and has led to the declining use of digoxin over the last several years.

Very little difference exists between subtherapeutic and toxic levels of digoxin. The therapeutic window for digoxin is narrow and difficult to determine. That concentration does not necessarily correlate with toxicity is essential to consider, as cases of clinical toxicity with digoxin levels in the therapeutic range have been documented.

Limited human data on the kinetics of other cardiac glycosides has been documented. Ingestion of yellow oleander seeds is reported to have erratic and prolonged absorption and is also believed to have a variable terminal half-life.[14]

History and Physical

Clinical History of Cardiac Glycoside Toxicity

A history of previous exposure and chronic digoxin use is necessary to determine if toxicity is acute or chronic. Most reported poisonings result from chronic toxicity, with decreased clearance of digoxin from the body. In cases of acute or acute on chronic toxicity, the timing of the ingestion is essential, as it plays a role in laboratory analysis. 

Clinical signs of toxicity include gastrointestinal, neurologic, and the most concerning cardiac. Most symptoms are nonspecific and include headache, malaise, insomnia, altered mental status, abdominal pain, nausea, and vomiting. Notably, visual changes, especially changes involving colors such as a yellow hue, are better known and specifically seen in digitalis toxicity. Other visual problems include photophobia, photopsia, and diminished visual acuity.[12]

Clinical Signs of Cardiac Glycoside Toxicity

Cardiac manifestations include arrhythmias and rhythm disturbances. No specific arrhythmia for digoxin toxicity has been established, but rather, a range of arrhythmias can be present, including various degrees of AV block, premature ventricular contractions, bradycardia, and even ventricular tachycardia. Bidirectional ventricular tachycardia is a pathognomic rhythm for toxicity, which has alternating QRS complexes at regular intervals through the left bundle fibers.[4] Cardiac arrhythmias are the leading cause of death for those with digoxin toxicity.

Additionally, some patients may have hemodynamic instability depending on the type of arrhythmia, and others may have dyspnea and altered mental status.

Evaluation

The difference between toxicity and therapeutic range is small for digoxin. The therapeutic range is generally accepted at 0.8 to 2.0 ng/mL, with concentrations above 2.4ng/mL being toxic.[1] Diagnosis is difficult and usually made clinically, as levels of digoxin in the blood do not necessarily correlate with toxicity. Patient deaths have been reported while still within the therapeutic range, with patients with atrial fibrillation having a risk of death with a digoxin concentration >1.2 ng/mL.[12] Due to digoxin's large volume of distribution, a falsely elevated concentration can be made if the blood is drawn too soon postingestion. Measuring digoxin concentrations at least 6 hours postingestion is recommended to allow for the distribution phase to be complete.[15] 

Digoxin is primarily cleared by the kidneys, and declining renal function is the most common cause of chronic toxicity. Therefore, renal function must be assessed and, if possible, compared to the patient's prior renal status. Electrolytes must also be evaluated; hypokalemia, hypercalcemia, and hypomagnesemia are known to worsen the effects of toxicity. The inhibition of the sodium-potassium ATPase leads to hyperkalemia and can be used as a marker of toxicity severity. Serial electrocardiograms should be performed, and continuous cardiac monitoring should be utilized as rhythm fluctuation is commonly seen. Electrocardiogram (ECG) findings, sometimes referred to as the digitalis effect, may be seen with therapeutic use. These changes commonly involve the T wave and include flattening, inversion, the scooped appearance of ST-segment, and ST depression in the lateral leads.[16][17]

Knowing that endogenous digoxin-like immunoreactive proteins can result in a false-positive result is vital when interpreting digoxin levels. This is more likely to occur in the following patients:

• Liver or renal disease
• Chronic heart failure
• Subarachnoid hemorrhage
• Acromegaly
• Diabetes
• Pregnancy

Another potential problem is that several assays can measure digoxin and its metabolites, but these assays vary in sensitivity. Further, the tests are hampered by cross-reaction with steroids and cholesterol-like substances. Detection of other cardiac glycosides is variable, depending on the specific assay utilized to determine a digoxin concentration. Unpredictable cross-reactivity is often noted; therefore, results are difficult to interpret. 

Treatment / Management

Toxicity management focuses on early recognition, supportive care, electrolyte correction, and antibody administration in severe cases. Treatment also initially involves efforts to prevent further absorption. Activated charcoal can be administered in the setting of acute ingestion, but gastric lavage is not recommended due to the potential for further bradycardia from vagal nerve stimulation.[12] 

Antibody Treatment

After determining the patient's renal function, electrolyte status, and digoxin concentration, antidotal therapy with Fab fragments must be considered. Digoxin concentration does not necessarily correlate with clinical symptoms of toxicity; however, digoxin concentrations may be used to calculate the amount of antidote therapy with Fab. Although guidelines are unclear, treatment with digoxin immune Fab, also known by the trade name Digibind, is considered first-line therapy for dysrhythmias, including AV block and ventricular tachycardia caused by suspected digoxin toxicity.

Fab fragments are highly effective in binding the digoxin molecule with minimal detrimental adverse effects. The antibody fragments form complexes and are excreted via the urine. Empiric treatment of acute toxicity consists of 10 vials of Fab fragments for adults and 5 vials for children when the dose ingested is unknown, and digoxin levels are unable to be obtained. Treatment with digoxin-specific antibodies will lead to hypokalemia, and serum potassium should be monitored frequently.[18][19]

The 80 mg antidote binds 1 mg of digoxin, so if the amount of digoxin ingested is known, a specific amount of antidote can be administered. More commonly, the dosage is calculated utilizing the weight of the patient and the serum digoxin concentration, which is obtained using the following calculation:

• Dose (number of vials)=[Serum digoxin concentration ( µg/L) x weight (kg)]/100 [4]

Notably, serum digoxin concentration cannot be measured following Fab fragment administration, leading to an inaccurately high measurement due to the bound digoxin-Fab within the circulation. Digoxin and digoxin-Fab complexes are not removed by hemodialysis.[20] (A1)

Supportive Care and Antiarrhythmic Therapies

Hydration, oxygenation, and close cardiac monitoring are necessary. The ECG must be continuously monitored for dysrhythmias, and any electrolyte disturbances should be corrected.

Hyperkalemia can often be seen with digoxin toxicity, with standard potassium lowering therapy, including intravenous calcium administration. Calcium use with digoxin toxicity is contraindicated due to the theoretical concern for a condition known as "stone heart." This is due to the belief that calcium will potentiate the positive inotropic effect of digoxin, leading to an irreversible noncontractile state of the heart where the heart cannot relax during diastole.[21] Multiple studies have not shown this to be a concern in clinical practice, although a true randomized control trial cannot be performed due to ethical considerations.[22](B3)

Theoretical concern has arisen regarding that if digoxin is neutralized with antibodies, the patient may develop an exacerbation of their heart failure, leading to worsening of the arrhythmias. However, studies have not shown evidence that this is correct, as no increased length of stay or lower heart failure hospitalization risk postdischarge was found.[7] However, the antibody treatment may have adverse effects, including serum sickness and anaphylaxis.

Supraventricular tachycardia tends to be managed with short-acting beta-blockers. Phenytoin has been shown to suppress digoxin-induced tachyarrhythmias as well. Another option is lidocaine when managing ventricular arrhythmias. Atropine may be used to manage bradycardia. The use of magnesium is not recommended as it can worsen bradycardia and AV blocks. Cardioversion is not recommended as it can precipitate ventricular arrhythmias; instead, defibrillation may be used according to ACLS protocol.

Differential Diagnosis

Differential diagnoses that should also be considered when evaluating cardiac glycoside and digoxin toxicity include:

• Acute kidney injury
• Beta-blocker toxicity
• Calcium channel blocker toxicity
• Cardiac glycoside plant poisoning 
• Clonidine toxicity 
• Hypercalcemia
• Hyperkalemia
• Hypernatremia
• Hypoglycemia
• Hypokalemia
• Hypomagnesemia
• Hyponatremia
• Sinus node dysfunction
• Sick sinus syndrome 
• Third-degree atrioventricular heart block (complete heart block)

Prognosis

The prognosis depends on the time of presentation, age, and associated comorbidity, including renal function. The mortality is increased when the toxicity is associated with a heart block or a new arrhythmia. Severe digoxin toxicity is estimated to have a mortality of about 20%.[12]

With acute digoxin ingestions, the potassium level upon presentation can be used to determine prognosis. In a study of 91 patients, all patients with a serum potassium level above 5.5 mEq/L died, 50% of patients with a serum potassium level between 5.0 and 5.5 mEq/L died, and no patients died with a level below 5.0 mEq/L.[13] Moreover, potassium level was able to prognosticate death more accurately than initial ECG changes or serum digoxin level. 

Complications

Complications of cardiac glycoside and digoxin toxicity include:

• Heart failure
• Nodal block
• Cardiovascular collapse 
• Anaphylaxis associated with digibind