Tox and Hound – To Bind or Not To Bind

by Jeanna Marraffa

If you’re the gambling type, then this post is for you! 50/50 are pretty good odds, right? Or are they not and that’s why I never win in Vegas? I digress . . . let’s get back to the poll. Fifty percent of people said that they wouldn’t give digoxin-Fab to a 57-year-old that received 21 mcg/kg digoxin and now has a junctional escape rhythm with an elevated digoxin concentration of 3.2 ng/mL. Fifty percent said they would give digoxin-Fab. I know that only 14 people voted but I think the answer would be split down the middle if 10,000 people voted. Managing digoxin exposures is not for the faint of heart.

Did you know that digoxin is the third most common adverse drug event resulting in hospitalization in patients greater than 65 years of age?¹ This means there is a high likelihood that, at some point, “to bind or not to bind” will come up. Let’s dive in and see if there is anything that can help make the odds of agreement slightly better than 50/50.

Cardioactive glycosides have been used since the Egyptian times. They became widely used after 1785 when the first description of the effects of the foxglove plant was described.² In 2017, digoxin was the 142nd most commonly prescribed medication in the United States.³ Worldwide, there are other pharmaceutical cardiac glycosides prescribed including digitoxin, ouabain, lanatoside C and deslanoside.⁴ This review will only focus on digoxin. It is used for rate control in atrial fibrillation as well as for its inotropic effects in heart failure. It has a narrow therapeutic index. Which basically means that there is a very small window between efficacy and toxicity.

Despite digoxin and cardiac glycosides being around for a long time, the exact mechanism of action is not fully elucidated. In fact, for those of us that have read several editions of Goodman & Gilman’s text, we know that, with every edition, there are different iterations of the pharmacologic mechanism. {Please don’t burst my bubble and tell me that I’m the only one that gets excited for every new edition of that book.}

Here’s the mechanism that is in current favor. Digoxin increases inotropy by increasing intracellular calcium. It accomplishes this through inhibition of Na-K-ATPase. So how does this result in increases in intracellular calcium? Stay with me here. You might remember that sodium lives mostly outside of the cell and potassium mostly inside the cell. And this good, because this sodium gradient is what we use to drive the cardiac action potential. So during contraction, sodium channels open and the sodium comes flooding into the cell. During relaxation, the sodium channels close and potassium leaves the cell. And all would be well in the world if we only needed our heart to beat once. But alas for most of us we need more. So how do we get the sodium inside the cell out and get the potassium outside the cell back in? You guessed it. Na-K-ATPase. So what happens when digoxin blocks some Na-K-ATPase? Well, you get less sodium out and less potassium in. Fortunately, there is another system involved in pumping sodium out of the cell. This is called the Na+/Ca2+ exchanger. This brings sodium in and pushes calcium out (in a 3:1 molar or 3:2 charge ratio). What does this all mean? With each beat, there is more calcium that remains within the myocardial cell, which is then stored in the sarcoplasmic reticulum. With each cell cycle, the increased intracellular calcium causes more calcium to be released (calcium induced calcium release – CICR) from the sarcoplasmic reticulum during systole and thereby increases the force of contraction. In addition, it increases automaticity and shortens the repolarization of both the atria and ventricles with a decreased conduction through the SA and AV nodes, mainly through vagal stimulation.

The therapeutic range for serum digoxin concentrations was historically 0.5 – 2.0 ng/mL, however, most agree that serum concentrations of less than 1 ng/mL resulted in the best therapeutic benefit with the least toxicity.

Clinical Manifestations

The toxic manifestations can be extrapolated from the mechanism of action. In therapeutic use, digoxin slows the heart rate. This is why it has been used to treat tachydysrhythmias. It may also have some marginal increase in the ejection fraction of the heart. This combination of slower heart rate and the increased squeeze is why lots of doctors used it for patients with heart failure and atrial fibrillation. Sounds like a perfect drug.

Well . . . except for the narrow therapeutic index, where toxicity can develop at serum concentrations not much higher than therapeutic.

As digoxin levels increase, more and more calcium builds up in the cell. And since calcium is a positive ion, the cell moves closer and closer to it’s firing threshold. So not surprisingly, digoxin toxicity can pretty much cause any dysrhythmia except a rapidly conducted supraventricular tachydysrhythmia. Remember why this is true? Digoxin causes increased automaticity with impaired conduction through the AV and SA nodes. The pathognomonic ECG finding {or better yet, the question that people love to ask on exams that rarely is seen IRL} is bidirectional ventricular tachycardia.⁵

One of the first manifestations of toxicity are delayed afterdepolarizations (DADs), which appear like U waves on the ECG, and can be thought of as ‘baby PVCs’ or ectopy that hasn’t quite reached the threshold for full electrical depolarization. These can result in a ‘full’ cellular depolarization and this manifests as premature ventricular contractions, which are probably the most common ECG findings.⁶

Who Gets into Trouble with Digoxin?

The earlier statistic that digoxin is the third leading cause of hospitalization due to adverse drug events in patients older than 65 years of age gives a glimpse into who is at most risk for developing toxicity.

Digoxin is primarily renally cleared so patients with renal insufficiency are at high risk for development of toxicity. Elderly patients are also at increased risk because of their inherent reduction in creatinine clearance, hypoperfusion, changes in body composition and electrolyte abnormalities.⁷

Digoxin is also susceptible to numerous drug-drug interactions. It is a substrate for the p-glycoprotein efflux transporter and drugs such as clarithromycin, amiodarone, verapamil cause an increase in serum digoxin concentrations from decreased extrusion.^8–10 Digoxin is also inactivated in the gastrointestinal tract by an enteric bacterium, primarily Eubacterium lentum.¹¹ Antibiotics will inhibit the inactivation of digoxin through changes in gut flora resulting in an increased bioavailability of digoxin and subsequently increased serum concentrations. While all antibiotics can do this, the macrolide antibiotics have the highest incidence. A recent study showed that 2.3% of hospitalizations for digoxin toxicity could have been prevented if clarithromycin was not prescribed.¹²

Another very significant, and common, drug interaction is between digoxin and diuretics. Diuretics, specifically loop diuretics, can cause electrolyte abnormalities, mainly hypokalemia, and hypomagnesemia. Hypokalemia enhances the effect of digoxin and is associated with dysrhythmias. As serum potassium decreases, the ability for digoxin to bind to and inhibit the Na-K-ATPase pump increases. A recent retrospective cohort study found that the combination of diuretics with digoxin resulted in increased hospitalizations and a higher incidence of ventricular arrhythmias.¹³

And, of course, albeit rare, there are the acute overdoses of digoxin.

The Danger Signs

Other than the tried and true gut feeling of “god, that patient looks siiiiick”, are there clues that help you make the decision of when a patient will need digoxin-Fab? {I am a huge fan of listening to your gut, by the way . . . }

It’s the potassium, riiight ???

Treat if the serum potassium is greater than 5 mEq/L. I know we’ve all heard this at one point. But, maybe what most of us forget is that this only holds true in the setting of acute digitoxin poisoning. Back in 1973, pre-digoxin-Fab, Bismuth et al. evaluated patients with acute digitoxin poisoning.¹⁴ And the results were pretty astounding. Serum potassium between 5 mEq/L and 5.5 mEq/L was associated with a 50% mortality. And serum potassium greater than 5.5 mEq/L was associated with a 100% mortality. But, remember, this was acute poisoning secondary to digitoxin.

Can the same numbers be extrapolated to the chronically poisoned patient? Remember, the majority of patients with chronic toxicity have some degree of renal dysfunction, hence why they became digoxin toxic, and any hyperkalemia is often secondary to the inability of the kidneys to clear potassium rather than due to the Na-K-ATPase inhibition in skeletal muscle, as with acute poisoning. Now, don’t get me wrong . . . hyperkalemia can be bad, regardless. But, I don’t think that the same thought process should be used when interpreting the serum potassium in acute versus chronic digoxin exposed patients. Hypokalemia in chronically exposed patients is actually a not-so-great thing. Hypokalemia decreases the ability of the sodium-potassium pump to do its job effectively and this can exacerbate sodium-potassium pump inhibition by digoxin and can worsen toxicity.¹⁵

Using just isolated potassium in your decision to treat a chronically exposed digoxin poisoned patient isn’t the answer.⁸

It’s a digoxin level, then, riiight???

Interpretation of a serum digoxin concentration can be difficult. It requires first the differentiation: is this an acute ingestion or chronic? If you determine that this is a chronic exposure, there are other very important considerations:

1. What is the level? Though the therapeutic range reported by most laboratories document concentrations between 0.5 – 2.0 ng/mL, most agree that serum concentrations of < 1.0 ng/mL are efficacious while limiting the risk of toxicity.
2. When was the last dose ingested? Digoxin levels measured within 6 hours (pre-distribution) from the last dose are falsely elevated and leave you shaking your head and confused as to what they mean.
3. What, if any, concurrent metabolic abnormalities are occurring?
4. What does the patient look like? What are their vital signs? What does the ECG show?
5. What other medications are they on?

If your first answer is that this is an acute ingestion, most would say that a serum concentration of > 10-15 ng/mL warrants treatment with digoxin-Fab.¹⁶

If your first answer is that this is a chronic ingestion, utilizing all of the above-stated factors is essential. An isolated supratherapeutic digoxin concentration should not be the only factor when determining if a patient requires antidotal therapy.

It’s the rhythm then, riiight???

This is probably the best indicator for when a chronically poisoned digoxin patient requires digoxin-Fab. Life-threatening dysrhythmias are an indication for digoxin-Fab. Increases in intracellular calcium cause delayed afterdepolarizations, which are essentially changes in membrane potential caused by CICR from the sarcoplasmic reticulum. This appears as U waves on the ECG. The increased intracellular calcium leads to membrane changes that can then result in bringing the cell to threshold triggering a true depolarization at the wrong time, resulting in a PVC.¹⁷ Remember, digoxin can result in nearly any dysrhythmia. Both myocardial irritability and alterations in conduction result in dysrhythmias.

But . . . be careful . . . the lack of ECG changes early after acute overdose doesn’t mean that the ingestion is insignificant. After an acute overdose, ECG changes aren’t expected for the first several hours after ingestion.

You’ve made the decision to treat….now what?

How much digoxin-Fab should be given?

I’m sure all of us can recite the dose the dose that we learned for digoxin-Fab . . . 10-20 vials for an acute overdose and 3-6 vials for chronic poisoning. I know that you all know the equations that can help estimate the dose. I’m going to leave them here to jog my own memory.

# vials = [Serum digoxin concentration (ng/mL) x Pt weight (kg)]/100

OR

# vials = [Amount ingested (mg)/0.5] x 80%

The calculations above likely overestimate the dose of digoxin-Fab needed. There is also not great data for the lowest effective dose for digoxin-Fab. Depending on where you work, it likely takes at least 60-90 minutes for a level to return. In an acute ingestion with a sick patient, you don’t have time to wait on a level. What should you do? For chronic overdoses, most patients need less than 3-6 vials and usually, only 1-2 vials are needed.⁸ In a chronically poisoned patient, where you have the time to wait for a serum concentration and the last dose was at least 6 hours ago, the calculation above can be used to calculate dose.

What do the “nay-sayers” say?

Full Disclosure. I will tell you that I tend to be on the side of wanting a patient to get digoxin-Fab. If a patient is sick and digoxin could be causing some of the problem, why not take that out of the picture? That’s my philosophy. There are alot of very smart people that don’t necessarily have the same thought process. But what is their reasoning?

Digoxin-Fab is expensive. Depending on where you look, each vial is approximately $800 – $1000. But, if we had an antidote that cost $100,000 with 100% efficacy, not one of us would blink an eye.

Varying opinions are based on data regarding the efficacy of digoxin-Fab. A recent review paper by Chan and Buckley looked at 10 case series of digoxin poisoning. The response rates to digoxin-Fab in these case series varied from 50% to 80-90%.⁸ A prospective observational study from Australia followed patients with supratherapeutic digoxin concentrations and signs or symptoms attributable to digoxin. 36 patients were recruited into the study and had received digoxin-Fab. Digoxin concentrations dropped to 0, as expected, after digoxin-Fab but there was no significant change in clinical outcomes. Heart rate improved by only 8 beats per minute and there was little to no change on blood pressure. The other interesting finding in this paper is that one to two vials initially bound all of the free digoxin regardless of the serum concentration.¹⁸ These results confirm what all of us knew . . . these patients have multiple comorbidities. This study is one of the reasons that some say that the dose for chronically exposed patients should be 1-2 vials regardless of the serum concentration.

This argument has those people that are fans of the administration of digoxin-Fab saying, well, yes, but wouldn’t you much rather take digoxin off the table (by giving definitive therapy) and then move on to the other big problems?

To Bind or Not to Bind?

OK . . . so the question really is . . . when do you pull the trigger and administer digoxin-Fab? While each patient is different and sometimes you have to go with your gut, these are the general indications for patients that need an antidote. {These do not include your gut feeling of “geesh, this person is siiick and I should take digoxin off the table and give digoxin-Fab} The poison center is always available to discuss and help with dosing at 1-800-222-1222.

• Acute Ingestions:
  • Serum potassium greater than 5 mEq/L
  • Serum digoxin concentration ≥ 15 ng/mL at any time or ≥ 10 ng/mL 6 hours post-ingestion
  • Any digoxin related life threatening dysrhythmia
• Chronic Ingestions:
  • Any digoxin related life threatening dysrhythmia
  • Supratherapeutic digoxin concentration with hemodynamic instability; dysrhythmias or altered mental status
  • A patient with normal vital signs and no ectopy on ECG with an elevated digoxin concentration DOES NOT need digoxin-Fab. But they do need repeat digoxin levels, be on a cardiac monitor and be followed closely

Here’s the poll question again

Has your answer to the poll changed? Are we still at 50/50? After review of the literature and writing this post, my answer is still the same . . . I think this person should get digoxin-Fab.

Here’s my final thought . . . if you have a patient that is chronically on digoxin, has a supratherapeutic level with hemodynamic instability (e.g. bradycardia, hypotension) and has ECG changes, then treat with digoxin-Fab. They may get better or they may not but then you can remove digoxin from your differential and move on to attempting to ‘fix’ the other reasons why they are so sick.

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