CONTENTS

therapeutic use of digoxin

• Patient selection
• Dosing & monitoring

digoxin & cardiac glycoside poisoning

• Physiology of cardiac glycosides
• Pharmacokinetics of digoxin
• Epidemiology
• Clinical manifestations
• EKG features
• Differential diagnosis
• Digoxin levels
• Treatment
  • Decontamination
  • Digoxin-specific antibody fragments
  • Hemodynamic stabilization
  • Electrolyte management

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therapeutic use of digoxin

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role of digoxin & selecting candidates for digitization

overview: role of digoxin for AF in the ICU

• Digoxin may have a role in rate control for selected patients (as described below).
• (Digoxin may actually tend to reduce the likelihood of conversion into sinus rhythm, so it doesn't have any role in a rhythm-control strategy.)

optimal candidates for digoxin have:

• (1) Chronic AF
  • Digoxin tends to perpetuate AF, rather than favoring cardioversion back to normal sinus rhythm.
  • Digoxin may be less effective in rate control of paroxysmal AF, so it shouldn't be used as a sole therapy for paroxysmal AF. (Griffin 2022)
• (2) Heart failure with reduced ejection fraction:
  • Digoxin is the only agent which reduces heart rate while simultaneously functioning as a positive inotrope.
  • Digoxin may be uniquely beneficial for patients with heart failure whose hemodynamics are very tenuous, who may have difficulty tolerating a negative inotrope.
• (3) Mild or moderate tachycardia for which immediate control isn't necessary:
  • Digoxin takes several hours to work and it's not tremendously potent.
  • Digoxin is less effective in hyperadrenergic states, since it functions primarily as a vagotonic agent.
• (4) Adequate renal function:
  • The presence of preserved renal function makes dosing of digoxin easier and a bit safer.
  • This isn't an absolute requirement, because careful dosing and monitoring within the ICU allow digoxin to be given safely even in the presence of renal dysfunction.

if digoxin fails

• Digoxin is not an extremely powerful agent, so it may fail to achieve optimal heart rate control.
• If digoxin does fail, it may be combined with a beta-blocker or diltiazem.
  • The presence of digoxin may reduce the required dose of beta-blocker or diltiazem, thereby improving hemodynamic stability. (31700500) In particular, the combination of digoxin plus a beta-blocker may work well for some patients with systolic heart failure.

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digoxin dosing & monitoring

IV digoxin loading (digitalization)

• Digoxin takes a little while to work, but if given intravenously it may take effect within several hours. When initiated in the ICU, digoxin will nearly always be started with intravenous loading doses.
• Total IV loading dose: (package insert, 23616674)
  • Normal renal function: 8-12 mcg/kg ideal body weight (usually ~600-1,000 mcg).
  • Renal insufficiency: 6-10 mcg/kg ideal body weight.
  • Err on the lower end in patients with renal dysfunction, hypothyroidism, and/or reduced muscle mass.
• Typically, 50% of the total loading dose is given initially, followed by 25% given twice, every six hours. The first IV dose (typically ~400-600 mcg) takes effect within roughly 1-4 hours. Monitor for effect. If an adequate heart rate is achieved, then subsequent doses may be omitted. If bradycardia occurs, further administration should be held.

maintenance doses

• Typical maintenance dose:
  • Patients <70 years old with normal renal function: 250 mcg daily.
  • Patients over 70 years old –or- with renal dysfunction: 125 mcg daily.
  • Patients who are both >70 YO –and- have renal dysfunction: 62.5 mcg daily.
• The table below provides typical maintenance doses, based on the patient's renal function and body weight. (Package insert)
• Digoxin has a long half-life (~36-48 hours, or longer in renal insufficiency). Therefore, steady state may not be reached until about a week after a dose adjustment.

monitoring digoxin levels

• Drug level must be checked several hours after the last digoxin dose, to allow for distribution (e.g., >8 hours after an oral dose). Ideally this should be a trough level.
• The safest approach to digoxin dosing in the ICU among tenuous or dynamic patients is to closely monitor the digoxin level:
  • Check a trough digoxin level daily with AM labs.
  • Adjust the daily dose as needed, depending on the trough level.
  • As the patient stabilizes, digoxin levels may be spaced out.
• A therapeutic level is ~0.5-2 ng/mL
  • 0.5-1.2 ng/mL might be the optimal concentration for outpatients. (38033089)
  • 1-2 ng/mL levels may improve contractility, so these aren't unreasonable levels for closely monitored ICU patients.

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physiology of cardiac glycosides

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mechanism of action of digoxin

• (1) Digoxin inhibits the cardiac Na/K antiporter. This causes an increase in intracellular sodium and a decrease in intracellular potassium.
  • The decrease in intracellular potassium is what causes hyperkalemia in patients with digoxin overdose.
• (2) The increase in intracellular sodium causes an increase in excretion of sodium through the Na/Ca exchanger, which in turn increases intracellular calcium levels.
• (3) Increased intracellular calcium increases inotropy.
• (4) Increased inotropy often causes a reflexive increase in vagal tone. For patients in atrial fibrillation, increased vagal tone will decrease the conduction rate through the atrioventricular node, thereby slowing the ventricular rate.

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pharmacokinetics of digoxin

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• The oral bioavailability is 40-90%. Onset of action occurs 2-6 hours after ingestion.
• The digoxin molecule is too large to be removed via hemodialysis.
• The volume of distribution is ~6 liters/kg.
• Excretion occurs mainly via the kidneys. The half-life is ~40 hours (with variation depending on renal function).
• Digoxin is secreted into the urine by P-glycoprotein:
  • P-glycoprotein inhibitors will increase digoxin levels, for example:
    • Amiodarone, carvedilol, ranolazine, ticagrelor.
    • Verapamil, tacrolimus, cyclosporine.
    • Azithromycin, erythromycin, clarithromycin.
    • Azole antifungals.
  • P-glycoprotein inducers will decrease digoxin levels, for example:
    • Carbamazepine, fosphenytoin, phenobarbital.
    • Rifampin.

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epidemiology

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digoxin intoxication

• Most cases of digoxin intoxication are chronic and unintentional, due to gradual accumulation of digoxin over time. Precipitating factors for chronic intoxication may include the following:
  • (a) Digoxin is renally cleared, so any cause of kidney injury may cause accumulation.
  • (b) Drug interactions can reduce digoxin metabolism (see above).
  • (c) Tissue sensitivity to digoxin may be increased by hypokalemia, hypomagnesemia, hypercalcemia, myocardial ischemia, and hypoxemia.

other cardiac glycosides

• Various cardiac glycosides are found in plants (e.g., oleander, henbane, foxglove, milkweed, lily of the valley). Ingestion of these plants is not uncommon in some locales.
• Bufadienolide is a cardioactive steroid found in the skin of Bufo toads, which is utilized as an aphrodisiac.

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clinical manifestations

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acute vs. chronic toxicity

• Acute toxicity: Generally starts with gastrointestinal symptoms, with neurologic symptoms developing later (as the drug subsequently distributes to the brain).
• Chronic toxicity: Insidious onset of neurologic symptoms, with fewer gastrointestinal symptoms.

a variety of arrhythmias may be seen:

• Sinus bradycardia or high-degree AV block.
• Supraventricular tachycardias with atrioventricular block are classic for digoxin toxicity:
  • Atrial fibrillation with slow ventricular rate.
  • Atrial fibrillation with junctional escape rhythm.
  • Focal atrial tachycardia with AV block.
• Junctional tachycardia.
• Ventricular arrhythmias are more often seen in chronic toxicity:
  • Ventricular bigeminy.
  • Ventricular tachycardia, ventricular fibrillation.
  • Bidirectional ventricular tachycardia strongly suggests the presence of digoxin.

GI

• Anorexia, nausea/vomiting.
• Abdominal pain.
• Diarrhea.

neurologic

• Delirium.
• Fatigue.
• Visual disturbances (altered color perception, blurred vision, photophobia, diplopia, blindness).
• Seizures rarely may occur.

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EKG features

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1) some uncommon arrhythmias may particularly suggest the possibility of digoxin toxicity

• Bidirectional ventricular tachycardia.
• Paroxysmal atrial tachyarrhythmias with AV block.
• Junctional tachycardia.(28572865)

2) EKG revealing digitalis effect

• Digitalis effect refers to the following morphological pattern:
  • Scooped ST segment with ST depression (“Salvador Dali mustache”).
  • Flattened/inverted T-wave, which may be followed by a prominent U-wave.
  • Shortened QT interval.
• Digitalis effect reveals the presence of digoxin, but doesn't correlate with clinical digoxin toxicity. So this may be helpful to identify patients with exposure to cardiac glycosides – but it is otherwise nonspecific (especially in a patient who is known to be on digoxin).

3) Paced EKGs

• A pacemaker may impair the ability to diagnose digoxin toxicity:
  • It may prevent the occurrence of some arrhythmias (e.g., bradydysrhythmias).
  • It may obscure the presence of digitalis effect.

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differential diagnosis

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common differential diagnostic considerations:

• Calcium channel blocker intoxication or beta-blocker intoxication.
• Alpha-agonist intoxication (e.g., clonidine) – may cause greater somnolence and miosis than digoxin.
• Hypothyroidism.
• Hypothermia.
• Myocardial infarction.
• Hyperkalemia of any etiology.
  • BRASH syndrome.
• Chronic cardiac conduction system disease.

related differential diagnoses

• Differential diagnosis of bradycardia.
• Differential diagnosis of delirium.

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digoxin levels

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when to check a digoxin level:

• (1) A patient who is chronically on digoxin, with any of the following:
  • Renal failure.
  • Acutely ill enough to require hospital admission.
  • Any signs or symptoms suggestive of digoxin poisoning.
• (2) Clinical constellation suggestive of cardiac glycoside intoxication.

timing of the digoxin level

• Digoxin requires >6 hours to distribute into the tissues, after oral intake. Only post-distribution levels reflect the severity of intoxication and help calculate the dose of antiserum.(27041802)
• For acute intoxication, check a baseline digoxin level and then repeat another level six hours after the ingestion.
• For chronic intoxication, a single digoxin level is adequate, provided that it is obtained >6 hours after the last dose.

interpretation of the digoxin level in digoxin intoxication

• Therapeutic level: 0.5-2 ng/ml (0.6-2.6 nM/L).
  • For chronic outpatient therapy, 0.5-1 ng/mL (0.6-1.2 nM/L) is probably ideal.
• Potentially scary:
  • Chronic intoxication: >4 ng/ml (>5.1 nM/L).
  • Acute intoxication: >10 ng/ml (>12.8 nM/L).
• However, serum digoxin levels don't correlate well with tissue levels and clinical toxicity.
  • Toxicity can occur with mildly elevated levels, or even levels at the top of the “therapeutic” range.
  • Patients can have elevated digoxin levels, without clinical toxicity.
• After receiving antibody fragments, levels are meaningless (the lab will measure free and also bound digoxin).

interpretation of the “digoxin level” in intoxication with other cardiac glycosides

• For patients with non-digoxin glycosides, digoxin level may be used as a qualitative assay.
• A positive “digoxin level” may suggest the presence of a cardiac glycoside, but the exact level lacks clinical significance.
• The performance characteristics with different glycosides is largely unknown, but in the appropriate context this could help support the diagnosis of a non-digoxin cardiac glycoside intoxication.

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decontamination

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• Activated charcoal may be given if a patient presents within roughly an hour of an acute digoxin ingestion.
• By the time patients develop symptoms of digoxin toxicity, they will be outside the window of time when decontamination is beneficial.

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digoxin-specific antibody fragments (DSFab)

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💡Assess need for DSFab early and order promptly, because the time delay from ordering to clinical benefit is generally at least ~2 hours.

indications

• Stronger indications:
  • Significant dysrhythmia or hemodynamic instability.
  • Potassium over 5-5.5 mEq/L (if hyperkalemia appears to be caused by an acute digoxin intoxication).
• Weaker indications:
  • Acute ingestion of >10 mg.
  • Moderate to severe GI symptoms.
  • Serum digoxin level >10-12 ng/ml drawn >6 hours after ingestion.
  • Renal failure.
  • Altered mental status.
• 💡 Most indications for DSFab are not well defined. When in doubt, consult a toxicologist or poison control (in the United States 1-800-222-1222).

potential complications from DSFab

• Hypokalemia (due to potassium shifting into cells).
• Exacerbation of heart failure or atrial fibrillation, due to sudden withdrawal of digoxin therapy.
• Serum sickness.
• Anaphylaxis.

dose

• Two brands are available, Digibind and DigiFab, which seem interchangeable.
• DSFabs is dosed in vials. Each vial contains 40mg of antibody fragments, which neutralize 0.5 mg of digoxin.
• Formulae for calculating the number of vials required:
  • Chronic poisoning: Number of vials is estimated as (digoxin level in ng/ml)x(wt in kg)/100. However, lower doses may be considered initially, for patients with chronic digoxin toxicity who are clinically stable (e.g., initiate therapy with three vials and follow clinically to determine whether additional treatment is warranted).(33476509)
  • Acute ingestion of known dose: Number of vials is estimated as (mg of digoxin ingested)x(1.6)
  • Empiric administration if levels are unknown:
    • Acute toxicity: give 5 vials (if hemodynamically stable) or 10 vials (if unstable), reevaluate clinically in 30 minutes.
    • Chronic toxicity: start with 3-6 vials, reevaluate clinically.
  • MDCalc online calculator can also help to determine the number of vials of DSFab.
• Some clinical response should be seen within ~20 minutes, with a full response occurring within very roughly ~~1.5-3 hours.
• DSFab may be effective in non-digoxin cardiac glycoside intoxication (e.g., plant or animal toxins). Digoxin levels in these situations are not quantitatively meaningful, so DSFab must be dosed empirically based on clinical severity. For patients with critical cardiac dysfunction, 10-20 vials may be utilized.(26505271) Larger doses may be needed than for digoxin intoxication, since DSFab may have lower affinity for non-digoxin cardiac glycosides.

rebound

• DSFab is generally excreted in the kidneys with a half-life of ~15-20 hours. Digoxin has a longer half-life (~40 hours). Therefore, it is possible that DSFab could be renally excreted and subsequently free digoxin levels could begin to rise again – leading to rebound toxicity.
• Rebound can occur ~20 hours after DSFab is given, but it may occur up to ten days later in patients with renal dysfunction.
• The treatment of rebound is readministration of DSFab. The decision to treat must be based on symptoms and EKG findings, rather than digoxin levels (since digoxin levels will be unreliable after administration of DSFab).

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hemodynamic stabilization

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volume resuscitation

• Fluid should often be used carefully, because many patients on digoxin have severe underlying heart disease.
• Bedside echocardiography may help assess the potential benefit from fluid resuscitation.

bradycardia

• ⚠️ The best treatment is generally DSFab.
• Atropine is a good temporizing measure (since patients with digoxin toxicity have excess vagal tone). A reasonable dosing scheme might be to start with 1 mg and repeat as needed, to a maximum total cumulative dose of 3 mg.(26505271)
• 🛑 Avoid pacing or beta-agonists if possible, as these may provoke ventricular tachycardia.

tachycardia

• ⚠️ The best treatment is generally DSFab.
• Avoid cardioversion if possible for supraventricular tachycardias, given concern for inducing ventricular tachycardia.
• For ventricular tachycardia, lidocaine may be the first-line agent.
  • Amiodarone or procainamide may be less useful, due to a risk of exacerbating poor AV conduction.
• If hypomagnesemia is present, this should be corrected.

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electrolyte management

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hypomagnesemia

• Hypomagnesemia may exacerbate digoxin toxicity (since magnesium is a cofactor in the Na/K exchange channel).
• Treat hypomagnesemia aggressively, particularly in patients who are having arrhythmias (more on this here).

hypokalemia

• Hypokalemia is a favorable prognostic sign, but it doesn't guarantee a good outcome (for example, the patient may have an independent disease process causing hypokalemia).
• Hypokalemia may exacerbate digoxin toxicity, so it must be treated aggressively (more on this here).
• If DSFab is administered, this may cause potassium to enter the cells – thereby exacerbating the hypokalemia. In severe hypokalemia, DSFab may be withheld initially, to prevent the development of severe hypokalemia (similar to the way an insulin infusion is initially withheld in a patient with diabetic ketoacidosis who is hypokalemic).

hyperkalemia

• Hyperkalemia is a poor prognostic sign. Among one series of patients with acute digoxin intoxication prior to the availability of DSFab, all patients with potassium levels above 5.5 mM died.(4715199)
• DSFab is the preferred treatment for hyperkalemia.
• Treatment of hyperkalemia may be initiated while awaiting DSFab, if hyperkalemia is believed to be causing clinical harm (e.g., contributing to AV block and bradycardia).(33476509)
• Treatment of hyperkalemia while awaiting DSFab may include the following:
  • IV insulin and glucose.
  • Isotonic bicarbonate fluid resuscitation.
  • Potassium-wasting diuretics plus crystalloid (to facilitate renal potassium excretion).
  • Oral potassium binder (sodium zirconium cyclosilicate).
  • More on the management of hyperkalemia here.
• Avoid treating hyperkalemia too aggressively:
  • 💡 In the context of digoxin intoxication, hypokalemia is more dangerous than mild hyperkalemia. Mild hyperkalemia could theoretically help drive potassium into cardiomyocytes via Na/K-ATPase, which could theoretically be beneficial (figure below).
  • DSFab will cause a potassium shift into cells, so aggressive treatment of hyperkalemia plus DSFab could cause an overshoot hypokalemia.
• ⚠️ Calcium is contraindicated for the management of hyperkalemia due to severe digoxin intoxication.
  • It's debated whether calcium is safe in this context, but there is no compelling evidence of benefit here, so calcium is probably best avoided.

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Make sure to check the digoxin level of any sick patient who is chronically on digoxin.
• Digoxin takes about six hours to distribute in the body, so levels obtained <6 hours after the last dose may be artificially high. Don't panic – just repeat a level >6 hours after the last dose.
• Consider whether digoxin antibody fragments are indicated early (there is a substantial time delay between ordering these and seeing a clinical improvement).

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