What are the toxic effects of digoxin?

Digoxin overdose

Also known as: Cardiac glycoside toxicity, digoxin toxicity, digoxin poisoning

1. Description of the problem

Digoxin is commonly used for the treatment of atrial fibrillation, especially with co-existing congestive heart failure. Cardiac glycosides, including digoxin, inhibit the sodium-potassium-ATPase, resulting in increased intracellular sodium and increased extracellular potassium. The increased intracellular sodium ultimately results in increased intracellular calcium and increased inotropy. The excessive intracellular calcium can result in delayed after-depolarizations, which may result in premature contractions and dysrhythmias.

Digoxin toxicity can occur in the acute or chronic setting. Acute toxicity is more likely to result in a younger individual following an acute overdose. Nausea, vomiting, hyperkalemia, and dysrhythmias are common. Chronic digoxin toxicity frequently occurs in the elderly as a result of decreased clearance of digoxin, due to either declining renal function or drug-drug interactions. Nausea, malaise, and weakness are common findings in chronic digoxin toxicity.

Acute digoxin toxicity differs significantly from chronic digoxin toxicity Acute digoxin toxicity is likely to cause gastrointestinal symptoms, such as anorexia, nausea, vomiting, and abdominal pain. Visual changes, including alteration in the color vision, are well described. Hyperkalemia is commonly observed, and is prognostic (see below).

Chronic toxicity, in contrast, is harder to diagnose, and has a more insidious onset of symptoms. The gastrointestinal symptoms can be less pronounced than in acute toxicity. Neurologic manifestations, such as lethargy, fatigue, confusion, and weakness, are common. Hyperkalemia or hypokalemia can be observed.

Key management points

The key points in management are as follows: 1) Assessment and stabilization of the airway, breathing, and circulation. 2) Determine if there are any indications for giving digoxin immune Fab fragments. 3) Administer an appropriate dose of Fab fragments as indicated.

2. Emergency Management

Certainly any patient with an unprotected airway should have advanced airway measures, including endotracheal intubation, performed. If hyperkalemia or life-threatening dysrhythmias are present, the patient should receive digoxin immune Fab fragments.

Management points not to be missed

Obtain a serum potassium concentration.

Obtain a 12-lead electrocardiogram.

Monitor for signs of end-organ hypoperfusion, including adequacy of mentation and renal perfusion.

Administer digoxin immune Fab fragments as indicated.

3. Diagnosis

The diagnosis of digoxin toxicity is primarily a clinical diagnosis based on symptoms, as well as the electrocardiogram and potassium. Digoxin levels can be obtained, but should not be the sole basis for determining digoxin toxicity.

Because of the narrow therapeutic index of digoxin, patients can be digoxin toxic with therapeutic digoxin concentrations. Furthermore, an elevated digoxin concentration does not translate to digoxin toxicity.

Various other cardiac glycosides, including plants (e.g., oleander, lily of the valley, etc.) can cause cardiac glycoside toxicity. In these patients, a detectable digoxin concentration can help confirm the diagnosis, but because the assay is designed specifically to measure digoxin, interpretation of the absolute value of the level is not helpful, and the level can be used only to confirm exposure, not assess degree of exposure.

Free digoxin concentrations can be obtained to help differentiate between endogenous digoxin-like substances, as well as measuring circulating digoxin concentrations after antidotal therapy.

Normal lab values

A therapeutic serum digoxin concentration should be 0.8-2.0 ng/mL.

Normal serum potassium concentration should be 3.5-5 mEq/L.

How do I know this is what the patient has?

The constellation of gastrointestinal symptoms, along with hyperkalemia and an electrocardiogram demonstrating AV blocks, bradycardia, or ventricular dysrhythmias, along with a digoxin concentration in the upper limit of normal or elevated digoxin concentration should make the clinician suspect acute digoxin toxicity.

The finding of weakness and malaise, especially in an elderly patient with impaired renal function, who is on digoxin should make the clinician suspect chronic digoxin toxicity.

Differential diagnosis

Hyperkalemia is most often observed with renal failure or exogenously administered potassium. Other medications can occasionally cause hyperkalemia, as could some endocrine disturbances.

Bradycardia or conduction disturbances can be seen with other medications, including beta blockers and calcium channel blockers. Underlying cardiac disease, including acute ischemia, can certainly present with acute conduction disturbances and nausea.

Some patients, including neonates, pregnant women, and patients with renal failure, subarachnoid hemorrhage, liver failure, and acromegaly, can have endogenous digoxin-like substances, causing falsely elevated digoxin concentrations.

Confirmatory tests

A serum digoxin concentration can be obtained to help confirm exposure to digoxin. It is important to remember that an elevated digoxin concentration does not imply digoxin toxicity. Similarly, a patient can be toxic from a cardiac glycoside while having a therapeutic digoxin concentration.

4. Specific Treatment

The first priority in treatment is ensuring the patient has an adequate airway and breathing. Patients who are bradycardic can receive atropine 0.5 mg IV, although any response is likely to be transient and minimal.

Patients should be assessed for the administration of digoxin-specific Fab fragments (antibodies). Those patients who are hyperkalemic or have life-threatening dysrhythmias should receive digoxin immune Fab fragments.

Cardiac glycoside-induced hyperkalemia should be treated with digoxin-specific Fab fragments. These antibodies will effectively reduce the hyperkalemia due to cardiac glycosides. Patients with underlying renal dysfuntion who are hyperkalemic from their underlying renal failure, however, may need traditional treatments for hyperkalemia. However, if the hyperkalemia is thought to be due to a cardiac glycoside, including digoxin, the primary treatment is simply the digoxin-specific antibodies.

Traditionally, the administration of calcium to treat digoxin-induced hyperkalemia has been contraindicated. Newer data have called that into question. However, given that treating the hyperkalemia with agents other than digoxin immune Fab fragments does not reduce mortality, it is safest to continue to avoid calcium in cases of recognized digoxin-induced hyperkalemia.

It should be noted that digoxin is not removed effectively by extracorporeal elimination techniques, including hemodialysis.

Drugs and dosages

The decision to treat a cardiac glycoside-poisoned patient should be based on the presence of hyperkalemia or life-threatening dysrhythmias.

For acute toxicity with an unknown digoxin concentration and unknown amount ingested, 10 vials can be empirically administered for adults, or 5 vials for children. For chronic toxicity, these doses will likely over-estimate the amount of digoxin immune Fab fragment needed. One vial of digoxin immune fragments binds to 0.5 mg of digoxin.

If the digoxin concentration is known, and the patient has ingested digoxin, the following formula can be used: Number of vials = (serum digoxin concentration) x (patient weight in kilograms) / 100. The patient’s weight should be in kilograms, and the digoxin concentration should be in ng/mL. In cases of chronic toxicity without overt hemodynamic instability, one could consider a “partial reversal” in which half of the calculated reversal dosage is administered.

For an acute ingestion, if the amount of digoxin is known, the amount of vials to be administered = (amount of digoxin ingested in mg) / (0.5)

Refractory cases

Patients with renal failure may have recurrence of their symptoms after the digoxin molecule separates from the Fab fragments. This dissociation can occur several days after the initial treatment, and should be treated with additional Fab fragments.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

Following administration of digoxin immune Fab fragments, any hyperkalemia due to cardiac glycoside toxicity should improve. In addition, dysrhythmias should correct over the ensuing half-hour.

Alternative diagnosis

If an adequate dose of digoxin immune Fab fragments has been administered and there is no change in the hemodynamics, one should consider searching for alternative etiologies.

Follow-up

Patients should have their electrolytes and electrocardiogram observed. Measurement of digoxin concentrations is unreliable following the administration of digoxin immune Fab fragments.

Pathophysiology

Digoxin, like other cardiac glycosides, inhibits the sodium-potassium-ATPase. This inhibition results in a rise in extracellular potassium and a rise in intracellular sodium. The increased intracellular sodium results in increased intracellular calcium via the sodium/calcium exchanger. The increased intracellular calcium is responsible for increased inotropy at therapeutic dosages, and for increased after-depolarizations and dysrhythmias at toxic dosing.

Epidemiology

In the 1780s, the foxglove plant (from which digoxin is derived) was used in the treatment of congestive heart failure. It continues to be used more than 230 years later for treatment of atrial fibrillation, especially if there is co-existing congestive heart failure or left ventricular dysfunction. In recent years, the number of patients admitted with digoxin toxicity has remained stable, although the use of digoxin immune Fab fragments has increased.

Prognosis

The prognosis for acute digoxin toxicity directly correlates with the mortality. Without digoxin immune Fab fragments, a potassium level greater than 5 mEq/L is associated with a 50% mortality, while a potassium level greater than 5.5 mEq/L is associated with a 100% mortality.

Special considerations for nursing and allied health professionals.

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What's the evidence?

EPIDEMIOLOGY

Eicchorn, EJ, Gheorghidae, M. “Digoxin”. Prog Cardiovasc Dis.. vol. 44. 2002. pp. 251-66.

Hussain, Z, Swindle, J, Hauptman, PJ. “Digoxin use and digoxin toxicity in the Post-DIG Trial Era”. J Card Fail.. vol. 12. 2006. pp. 343-6.

PATHOPHYSIOLOGY

Smith, TW. “Digoxin. Mechanisms of action and clinical use”. N Engl J Med.. vol. 318. 1988. pp. 358-65.

Matthews, GG. Cellular physiology of nerve and muscle. 1998.

Demiryurek, AT, Demiryurek, S. “Cardiotoxicity of digitalis glycosides: roles of autonomic pathways, autocoids, and ion channels”. Auton Autacoid Pharmacol.. vol. 25. 2005. pp. 35-52.

CLINICAL PRESENTATION

Cauffield, JS, Gums, JG, Grauer, K. “The serum digoxin concentration: ten questions to ask”. Am Fam Physician.. vol. 56. 1997. pp. 495-503.

Ma, G, Brady, WJ, Pollack, M. “Electrocardiographic manifestations: digitalis toxicity”. J Emerg Med. vol. 20. 2001. pp. 145-52.

Bismuth, C, Gaultier, M, Conso, F. “Hyperkalemia in acute digitalis poisoning: prognostic significance and therapeutic implications”. Clin Toxicol. vol. 6. 1973. pp. 153-62.

Eddleston, M, Rajapakse, S, Rajakanathan, K. “Anti-digoxin Fab fragments in cardiotoxicity induced by ingestion of yellow oleander: A randomized controlled trial”. Lancet. vol. 355. 2000. pp. 967-72.

Lip, GYH, Metcalfe, MJ, Dunn, FG. “Diagnosis and treatment of digoxin toxicity”. Postgrad Med J.. vol. 69. 1993. pp. 337-9.

Bayer, MJ. “Recognition and management of digitalis intoxication: Implications for emergency medicine”. Am J Emerg Med.. vol. 9. 1991. pp. 29-32.

Dasgupta, A. “Endogenous and exogenous digoxin-like immunoreactive substances”. Am J Clin Pathol.. vol. 118. 2002. pp. 132-40.

TREATMENT

Bismuth, C, Gaultier, M, Conso, F. “Hyperkalemia in acute digitalis poisoning: prognostic significance and therapeutic implications”. Clin Toxicol. vol. 6. 1973. pp. 153-62.

Antman, EM, Wenger, TL, Butler, VP. “Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: final report of a multicenter study”. Circulation. vol. 81. 1990. pp. 1744-52.

Bayer, MJ. “Recognition and management of digitalis intoxication: Implications for emergency medicine”. Am J Emerg Med.. vol. 9. 1991. pp. 29-32.

Hauptman, PJ, Kelly, RA. “Digoxin”. Circulation.. vol. 99. 1999. pp. 1265-70.

Levine, M, Nikkanen, H, Pallin, DJ. “The effects of intravenous calcium in patients with digoxin toxicity”. J Emerg Med. 2009; Feb 5.

Smith, TW. “New advances in the assessment and treatment of digitalis toxicity”. J Clin Pharmacol.. vol. 25. 1985. pp. 522-8.

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