Digoxin has been used less and less frequently in recent years as a cardiac medication to treat heart failure or atrial fibrillation, and clinicians as a result have become less familiar with the subtleties of managing digoxin toxicity, a potentially life-threatening condition.
If the busy emergency physician is confronted with a digoxin-toxic patient and makes the mistake of consulting the Physicians' Drug Reference (www.pdr.net), he may see this about the IV dose of digoxin-specific Fab fragments (DS-Fab): “800 mg (20 vials) IV; this dose should be adequate to treat most life-threatening overdoses.”
He might be tempted on a busy night with patients pouring in and the backup growing to biblical proportions to put in an order for 20 vials of DigiFab and move on to the next patient. Several things are wrong, however, with the PDR recommendation, besides the frustrating vagueness of the term “life-threatening overdose.” A hospital is unlikely to have 20 vials of DS-Fab in stock, and we still do not have a randomized, controlled trial or other solid evidence establishing precise indications or optimal dosing despite more than four decades of experience using DS-Fab to treat digoxin toxicity.
The wholesale price of one vial (40 mg) of DS-Fab is $3,538 (up from approximately $800 before 2011), according to Drugs.com. Of course, the amount billed to the patient will likely be much higher. That order for 20 vials of DS-Fab will end up costing $70,760, approximately the cost of a 2018 Lexus LS. If I were the patient, I'd rather have the Lexus.
One vial of DS-Fab will bind 0.5 mg digoxin. The package insert for DigiFab—now the only DS-Fab product available in the United States—says the number of vials required to completely reverse the ingested dose in an acute ingestion of digoxin can be estimated with this formula: the number of vials needed = the amount of digoxin ingested (in mg)/0.5.
This calculation was often mistakenly used in the past to determine the dose of DS-Fab that should be given in every case. But this certainly overestimates the dose of antidote required for several reasons. First, the bioavailability of PO digoxin is only 60-80 percent, meaning that a significant portion of the ingested dose will never enter the blood or peripheral compartment. (Clin Toxicol [Phila] 2014;52:824.) Second, vomiting, a common symptom of digoxin toxicity, will further decrease the absorbed dose. Third, activated charcoal will reduce the absorbed dose even further. Reversing the entire absorbed dose of digoxin is not essential for a good clinical outcome.
Less is More
If the serum digoxin concentration is known, the number of DS-Fab vials theoretically required for complete reversal is often estimated using this formula: the number of vials needed = (serum digoxin concentration) x (patient's weight in kg)/100. Again, this almost certainly overestimates the optimal dose of antidote. If the digoxin level was drawn less than six hours from the time of ingestion, the result can be misleadingly high because distribution of the drug will not yet be complete. In chronic overdose, it is not only unnecessary but also unwise to completely reverse digoxin if the patient depends on digoxin for treating heart failure or atrial fibrillation with rapid ventricular response.
We do not yet know how to determine the optimal dose of DS-Fab for all situations, but a growing consensus among toxicologists holds that we have used way too much in most past cases. “The total body burden of digoxin is often overestimated. Furthermore, the incidence of life-threatening dysrhythmias, even in reported large ingestions, is low, suggesting most patients do not require Fab fragments,” according to the ninth edition (2018) of Rosen's Emergency Medicine.
The authors recommend giving two vials of DS-Fab to hemodynamically stable patients with acute toxicity, to be repeated if the patient deteriorates. They recommend giving one vial of DS-Fab to stable patients with manifestations of chronic toxicity, to be repeated after 60 minutes if symptoms persist.
Certainly, a full neutralizing dose of DS-Fab can be given in cardiac arrest and peri-arrest situations or if a digoxin-toxic patient is rapidly deteriorating. A recommended adult empiric dose of antidote is 10 vials in acute overdose and three to six vials in chronic toxicity if neither the serum digoxin level nor the amount ingested is known. Many fewer vials of DS-Fab are likely required, if any antidote is required at all, in less dire situations.
Any patient with significant digoxin toxicity requires careful observation, preferably in an intensive care setting, so that deterioration or instability can be detected and treated early. Digoxin is excreted primarily through the kidney, so adequate volume repletion is important, especially in patients who may have developed gastrointestinal manifestations such as anorexia, vomiting, and diarrhea.
This, however, must be done extremely cautiously when there is history or evidence of heart failure. Bedside echocardiography looking at left ventricular systolic function and inferior vena cava diameter respiratory variation can help guide this process. Consultation with a local poison center can provide valuable advice on all aspects of treatment in cases where using DS-Fab is necessary or considered.
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