Treating digoxin toxicity: is less more?

August 29, 2014, 3:35 pm

Digifab★★★☆☆

Digoxin-specific antibody fragments in the treatment of digoxin toxicity. Chan BSH, Buckley NA. Clin Toxicol 2014 Aug 4 [Epub ahead of print]

Abstract

This long detailed paper seems to be a manifesto masquerading as a review article. It is quite informative and well worth reading. But I’d keep in mind that the authors appear to have a (not so) hidden agenda: to decrease the dose of digoxin-specific antibody fragments administered in most cases of acute and chronic digoxin toxicity.

The authors state their objective up front:

To review the pharmacology, efficacy, effectiveness, indications, safety and dosage of digoxin-Fab. On the basis of the reviewed data. to propose a regimen of administering digoxin-fab to patients with digoxin poisoning based on pharmacokinetic principles.

Although they identified 140 relevant citations, they are not clear on exactly how these were selected. (Their reference list contains only 69 papers.) They note that there have been no randomized clinical trials on digoxin toxicity.

The authors say this about indications for using digoxin-specific antibody fragments:

There is general agreement that digoxin-Fab is indicated in patients with life-threatening tachy-bradyarrhythmias, hyperkalaemia (> 6 mmol/L) or haemodynamic instability with concentrations (e.g. digoxin > 2 μg/L or > 2.6 nmol/L) that support digoxin may be a contributing cause.

They point out that in acute toxicity, dose calculations based on serum digoxin levels taken before distribution is complete (approximately 6 hours) may overestimate the amount of digoxin-Fab required. They argue that 2 vials of digoxin would likely neutralize all free digoxin in the central compartment in cases of acute overdose, with clinical benefit evident within 60 minutes. The dose could be repeated if there were no clinical response.

Chronic toxicity usually involves a much lower total body load than in cases of acute ingestion, and lower doses of digoxin-Fab are generally recommended. Therefore:

. . . we recommend giving 1 vial (40 mg) at a time and observe for clinical response. If none is observed after 60 min, a second ampoule of digoxin-Fab may be administered, to neutralize digoxin re-distributing from the peripheral compartment.

The authors may very well be correct that much lower doses of digoxin-Fab than those generally used may suffice. However, I think there are a number of weaknesses in their argument and would be reluctant to adopt their suggestions at this time. With regard to acute toxicity, it would be hard to titrate the need for additional doses of digoxin-Fab, since clinical effect will not be evident for 30 minutes to an hour. When treating actual or potentially life-threatening toxicity, it seems to me risky to delay getting a reliably sufficient dose of antidote on board as soon as possible. Although the authors’ suggestions are based on pharmacokinetic modeling, there are not enough clinical data available to indicate whether their 2-vials-and-observe” protocol would be safe and effective.

I’m even more doubtful about their recommendation for treating chronic poisoning  If the indication is life-threatening toxicity, giving a single vial and then observing for an hour seems foolish. The one advantage to this is to save on the cost of digoxin-Fab. (The current price of a vial of Digibind is $728 USD.) since with chronic toxicity relatively few vials of digoxin-Fab are required in most cases, this protocol would not produce significant savings.

Of course, in treating stable patients without signs of immediate life-threatening manifestations of digoxin poisoning, the incremental start-low-and-titrate-to-response method may work just fine. Unfortunately, this paper in my opinion does not distinguishing adequately between truly life-threatening cases and those that are less dire. It is, however, dense with good information and definitely worth a look. II found it  extremely helpful to think through the authors’ recommendations and see if they made sense.

 

 

 

 

 

It has recently been suggested that the therapeutic blood level of digoxin be reduced from 0.8-2.0 μg/L to 0.5-0.8 μg/L in patients with congestive heart failure. (Contrary to the authors’ implication, I do not believe that this suggestion has been universally accepted.)

 

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