This is a classic. While it isn’t as common these days, the mechanism is still interesting. Take a look!

What is the on Digitalis toxicity?

The usual suspects: Digoxin, foxglove, lily of the valley, and oleander (both yellow and white), bufo toads. #dangerouslyseductive #lookscandeceive


Cardiac glycosides are steroid molecules with a carbohydrate side chain. #bigbadmolecule #lookatthesizeofthatthing #structures

Calcium-Induced Calcium Release (CICR): Cellular depolarizationopens voltage gated calcium channels causing calcium influxwhich induces calcium release by the SR. #tellMEsomethingIdontkno

Digoxin inhibits the Na/K ATPase causing more calcium in, more SR calcium, and ultimately, better SQUEEZE. #moarSQUEEZEplz


Digoxin increases automaticity, shortens the QT interval, and ultimately, can predispose one to arrhythmia. GET AN EKG! The most common arrhythmia is PVC’s, the most characteristic is bidirectional ventricular tachycardia,. #itgoesbothways

Because digoxin makes the AV node refractory to conduction via vagal parasympathetic stimulation, it is almost impossible to have SVT in digoxin toxicity #anythingbutSVT


Normal digoxin levels are from .5-2.0ng/mL and the therapeutic window is narrow. Get a level at 6 hours post ingestion. #TrenchRun

Give DigiFab if: K>5mEq/L in acute poisoning, unstable dysrhythmia, chronic elevation with symptoms, Dig level >15 or >10 after 6 hrs, acute ingestion of 10mg (child, 4mg), or intake of nondigoxin cardioactive steroid #DisIsImportant #GivingIsCaring

Digoxin levels will generally cross-react with other cardiac glycosides. A dig level can still be positive in cardiac glycosides such as foxglove or oleander, but don’t use the level itself to guide care. #qualitativeNOTquantitative

Symptoms of chronic cardiac glycoside poisoning include both neurologic and GI manifestations: yellow vision, weakness, confusion, lethargy, with nausea/vomiting, abdominal pain. #IseeFUNNYwithGASTRO

Typically in acute overdoses,  bradycardia is seen, which could be atropine-responsive as it is vagally mediated. #AtropinePlz #DontForgetDigiFab


In acute toxicity, hyperkalemia can develop due to Na/K ATPase inhibition, K>5.0 is an independent indicator of poor prognosis. #alltheKontheoutside

Calcium administration is controversial, although newer data suggests safety, but older animal data suggests risk of cardiac tetany #stoneheart


-Give DigiFab! This is the antidote of digitalis poisoning. Can adjust dosing for weight or ingested dose, but if sick, give 10 vials up front. #SlugEmWithVials

When to suspect?

Toxicity from cardiac glycosides, such as digoxin, can present as acute and chronic poisoning. Although falling out of favor due to safer alternatives and no reduction in mortality, digoxin is still being utilized for heart failure as well as atrial fibrillation. However, exposure to natural forms of cardiac glycosides have occurred, in particular from flowering plants such as foxglove, lily of the valley, or oleander. Also, bufo toads can also possess cardioactive steroids in their skin, and in their salivary/venom glands and toxicity generally occurs with ingestion of the dried toads instead of its topical application.

 


Chronic toxicity is usually due to digoxin accumulation, from causes like P-glycoprotein inhibition or renal insufficiency. P-glycoprotein is an efflux pump that normally excretes digoxin, however, with introduction of verapamil or amiodarone, digoxin clearance can decrease, inducing toxicity.

-Facts of Digoxin: Onset: 1.5-6hrs PO 5-30minutes IV, max effect in 4-6 hrs PO, 1.5-3 hrs IV, 40-90% absorption. Volume of distribution is 5-7 L/kg, Half life is 1.6 days. 60-80% elimination via kidneys, 7% enterohepatic circulation.

 

Mechanism of Action
Digoxin works by blocking the sodium channel ATPase. Normally this pumps out sodium, and brings in potassium. Instead, sodium continues to accumulate, and a sodium/calcium exchanger (normally sodium in, calcium out) reverses because it is dependent on the concentration gradient (where the cell now is high in sodium ) and spits out sodium and brings in more calcium. More calcium in, more sarcoplasmic calcium through calcium-induced calcium release, more actin-myosin cross-bridging, and ultimately better squeeze (increased inotropy).

Presentation

When patients present with digoxin poisoning, they generally have three particular organ systems to pay attention to: heart, brain, and the gut. Starting with the heart, the most common arrhythmia observed is PVCs due to increased automaticity. Given its ability to slow cardiac conduction and increase vagal tone (increases ACh release from vagal nerves), all forms of AV nodal blockade (except Mobitz type II) Given earlier repolarization and increased ectopy, many other dysrhythmias can occur such as ventricular tachycardia and ventricular fibrillation.

Besides arrhythmias, digitalis can be observed from the classical features on EKG dubbed as the digitalis effect: T wave peaking or inversion, shortening of the QT segment, scooping of the ST segment or ST depression, and U wave amplitude increase. That all said, these EKG findings are not indicative of prognosis: they simply imply presence of digitalis.

However, what ARE associated with a poor prognosis are hyperkalemia and ventricular dysrhythmias. In one study, K of 5.0 to 5.5 associated with 50% mortality, and K>5.5 associated with 100% mortality in acute toxicity!

Beyond the heart, digitalis can increase vagal parasympathetic tone, which is likely to contribute to its GI symptoms—many patients with digitalis toxicity will present with nausea, vomiting, diarrhea, and abdominal pain. Generally, GI symptoms will occur earliest in setting of toxicity.

From the top, CNS disturbances include the classical vision changes of yellow vision (xanthopsia), scotomata, confusion, headache, fatigue, and paresthesias.  That said, these neurological or gastrointestinal symptoms are generally reversible and attention should generally be placed towards the cardiac presentation/symptoms.

A digoxin level is generally therapeutic between 0.5-2.0 ng/mL, . For healthy adults, a single dose less than 5mg rarely causes toxicity—the average digoxin dose generally is <0.75mg.

Chronic toxicity generally occurs within the elderly, for only a 2-3 fold increase in their therapeutic dose can induce toxicity.

The benefit of a digoxin level is that it can pick up other digitalis substances such as Bufo toxins or oleander given the cross-reactivity given molecular similarity. That said, the disadvantage is that the cross-reactivity is not close to 100% nor can it differentiate between digoxin and other digitalis, therefore the level itself is not useful.

Management

Ultimately, symptomatic life-threatening digitalis toxicity is quickly managed with digoxin-specific Fab fragments, which both bind to and inactivate the digoxin. While symptomatic bradycardia, tachyarrhythmias, or significant hyperkalemia can occur in digitalis toxicity, treat all of these abnormalities with administration of the antidote first and foremost.

-EKG, first and foremost. Put the patient on the monitor!

-Get a digoxin level: .5-2.0ng/mL is therapeutic and get it at 6 hours given the high volume of distribution for the drug.

-Indications for DigiFab:

  1. Any digoxin related life-threatening dysrhythmias regardless of level.
  2. Potassium >5mEq/L in acute poisoning.
  3. Chronic elevation with significant GI sx or AMS.
  4. SDC>15ng/mL or 10ng/ml 6 hrs post-ingestion regardless of presentation.
  5. Acute ingestion of 10mg of digoxin in adult, or 4mg in a child
  6. nondigoxin cardioactive steroid (such as oleander). (Goldfrank recommends 10-20 vials in acute poisoning, and 3-6 or 1-2 vials for adults and children, respectively)

-If there’s significant bradycardia, and/or there is no antidote available, administration of atropine may help.  0.5mg IV, every 5 minutes as necessary. Pacing has been reported to temporize, but fab fragments are definitive.

-Cardiovert unstable rhythms (v-tach or v-fib) but leave other stable dysrhythmias alone. You can risk worsening the rhythm with cardioversion!

-If potassium is >5mEq/L, DigFab is indicated! Correct HYPOkalemia before giving Digifab in settings of dysrhythmias.

-Generally, the antidote dosing is 0.6mg/vial if the amount ingested is known. Technically, 1 vial DigiBind and DigiFab will bind to: .5mg and .6mg of digoxin, respectively.

-The fab fragments are generally benign and well-tolerated, except for patients having a papaya or sheep allergy-DO NOT ADMINISTER unless directed by a toxicologist!

-Although designed for digoxin, in non-digoxin cardiac glycoside toxicity, empiric administration of a larger dose (10-20 vials) is warranted given the digoxin level does not have 100% cross-reactivity for an accurate level, and cross-reactivity of the Fab fragments is not 100% to other digitalis. Bottom line: Generally, 5-10 vials of Digifab does the trick (more if not digoxin), and run it over 30 minutes (unless in arrest, just bolus it).

-Like with many poisonings, activated charcoal is not recommended routinely for PO digitalis toxicity unless within 1-2 hours of ingestion, no active vomiting and their airway is secured. Goldfrank’s suggests that there is significant enterohepatic circulation and thus can be beneficial to administer even late (1g/kg of body weight ever 2-4 hrs up to 4 doses).

-Electrolyte abnormalities can occur with digoxin toxicity. Hyperkalemia (hypokalemia in chronic digitalis toxicity) and hypomagnesia can both occur. Our general gut instinct is to give calcium, when potassium can be greater than 5.5, and with EKG changes. There is a historical account of calcium bolus producing cardiac tetany, or “stone heart.” Newer evidence says calcium may be safe in digoxin toxicity, however, the evidence still does not support the administration of IV calcium. Continue to pursue administering the antidote. You can still give IV insulin, dextrose, bicarbonate, and kayexalate. Hypomagnesemia worsens the inward calcium current, thus reversing this can be beneficial. Increasing magnesium can counter calcium binding, counter ventricular irritability, and blocks potassium from leaking out of the cell. With low magnesium, you can give magnesium sulfate (2-3 g over a minute) (Goldfrank’s: 2g over 20 minutes, with drip of 1-2g/H). Do not give magnesium in bradycardia, AV block, or renal insufficiency.

-Arrythmias can also be managed with other adjuncts such as IV phenytoin of 25mg/min (total 15mg/kg) (Goldfrank’s: 50mg/min or 100mg boluses every 5 minutes [max 1000mg in adults), lidocaine (1mg/kg), or magnesium sulfate (2-3g over a minute). Reduce your power settings if you need to defibrillate.

References

Digitalis (cardiac glycoside) poisoning. In: UpToDate, Grayzel J (Ed.), UpToDate, Waltham, MA, 2017.

Kashani JS. 2015. Chapter 325: Cardiac Glycosides. In: Ling L , Wolfson AB, editors.  Harwood-Nuss’ Clinical Practice Of Emergency Medicine. 6th ed. Philadelphia (PA): Wolters Kluwer. p. 1409-1412.

Nelson L., et al. Goldfrank’s Toxicologic Emergencies

Text written by: Alex Huh, MD
Podcast by: Joshua Shulman, MD
Reviewed by: Joshua Shulman, MD

 

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