eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Digitalis

Donald Schreiber, MD, CM, Associate Professor of Surgery (Emergency Medicine), Stanford University School of Medicine

Updated: Dec 2, 2009

Introduction

Background

The therapeutic properties of cardiac glycosides (eg, digoxin, a product of the foxglove plant) have been known since the days of the Roman Empire. The ancient Romans used red squill, a cardiac glycoside derived from the sea onion, as a diuretic and heart medicine. Cardiac glycosides are found in certain flowering plants such as oleander and lily-of-the-valley. Certain herbal dietary supplements also contain cardiac glycosides.

Physicians first studied digoxin in the 18th century. William Withering published his classic account of foxglove and some of its medical uses in 1785, remarking upon his experience with digitalis. Indians in South America had used cardiac glycosides in their dart poisons. Digitalis toxicity was well known in previous centuries, and some have suggested that the toxic visual symptoms of digitalis may have played a role in Van Gogh's use of swirling greens and yellows.

During the early 20th century, the drug was introduced as treatment of atrial fibrillation. Only subsequently was the value of digitalis for the treatment of congestive heart failure (CHF) established.

The syndrome of digoxin toxicity was originally described in 1785 by Withering.

Pathophysiology

Digoxin's inotropic effect results from the inhibition of the sodium-potassium adenosine triphosphatase (NA⁺/K⁺ ATPase) pump. The subsequent rise in intracellular calcium (Ca⁺⁺) and sodium (NA⁺) coupled with the loss of intracellular potassium (K⁺) increases the force of myocardial muscle contraction (contractility), resulting in a net positive inotropic effect.

Digoxin also increases the automaticity of Purkinje fibers but slows conduction through the atrioventricular (AV) node. Cardiac dysrhythmias associated with an increase in automaticity and a decrease in conduction may result.

The relationship between digoxin toxicity and the serum digoxin level is complex; clinical toxicity results from the interactions between digitalis, various electrolyte abnormalities, and their combined effect on the Na⁺/K⁺ ATPase pump.

Cardiac glycoside toxicity from plants, such as oleander, foxglove, and lily-of-the-valley, is uncommon but potentially lethal. Case reports of toxicity from these sources implicate the preparation of extracts and teas as the usual culprit.

Frequency

United States

Approximately 0.4% of all hospital admissions, 1.1% of outpatients on digoxin, and 10-18% of nursing home patients develop toxicity.

In 2006, the American Association of Poison Control Centers reported an incidence of 2610 toxic digitalis exposures. The overall incidence of digoxin toxicity has decreased because of a number of factors including increased awareness of drug interactions, decreased use of digoxin to treat heart failure and arrhythmias, and the availability of accurate rapid radioimmunoassays to monitor drug levels. Although the number of digitalis exposures is far less than the incidence of calcium channel blocker toxicity (10,031 cases) or beta-blocker toxicity (18,253 cases), the mortality rate from digitalis toxicity is far higher with 22 deaths reported versus 13 deaths from calcium channel antagonists and only 4 deaths attributed to beta-blocker toxicity.^{[1 ]}

Cardiovascular drug poisoning including digitalis toxicity ranks as the third leading cause of death from all poisonings in 2006.

Data from the 2007 Annual Report of the American Association of Poison Control Centers is similar to previous data, with 2565 digitalis exposures reported. However, fatalities were lower, with 10 deaths reported.^{[2 ]}

International

Approximately 2.1% of inpatients on digoxin and 0.3% of all admissions develop toxicity.

Mortality/Morbidity

• Morbidity is usually 4.6-10%; however, morbidity is 50% if the digoxin level is greater than 6 ng/mL.
• Mortality due to digoxin exposure varies with the population studied. Adult mortality depends on underlying comorbidity. In general, older people have a worse outcome than adults who, in turn, have a worse outcome than children.

Age

Advanced age (>80 y) is an independent risk factor and is associated with increased morbidity and mortality.

Clinical

History

• Constitutional symptoms (eg, weakness, fatigue)
• Cardiovascular
  • Palpitations
  • Syncope
  • Dyspnea
• Central nervous system
  • Confusion and somnolence
  • Dizziness without vertigo
  • Agitation, delirium, and hallucinations
  • Headache
  • Paresthesias and neuropathic pain
  • Seizures (extremely rare)
• Ocular
  • Disturbances of color vision with a tendency to yellow-green coloring
  • Blurred vision and diplopia
  • Halos and scotomas
  • Photophobia
• Gastrointestinal
  • Nausea, vomiting, anorexia, and diarrhea
  • Abdominal pain (uncommon)

Physical

Hemodynamic instability is related directly to the presence of a dysrhythmia or acute congestive heart failure (CHF).

• Cardiovascular findings on physical examination relate to the severity of CHF, dysrhythmias, or hemodynamic instability.
  • Digoxin toxicity may cause any dysrhythmia. Classically, dysrhythmias that are associated with increased automaticity and decreased AV conduction occur (ie, paroxysmal atrial tachycardia with 2:1 block, accelerated junctional rhythm, or bidirectional ventricular tachycardia [torsade de pointes], depicted in the images below).
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    Bidirectional tachycardia in a patient with digitalis toxicity.

    
    
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    Torsades de pointes.

    
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  • Premature ventricular contractions (PVCs) are the most common dysrhythmia. Bigeminy or trigeminy occurs frequently.
  • Sinus bradycardia and other bradyarrhythmias are very common. Slow atrial fibrillation with very little variation in the ventricular rate (regularization of the R-R interval) may occur.
  • First-degree heart block, second-degree AV block, complete AV dissociation, and third-degree heart block are also very common.
  • Rapid atrial fibrillation or atrial flutter is rare.
  • Ventricular tachycardia is an especially serious finding.
  • Cardiac arrest from asystole or ventricular fibrillation is usually fatal.
• Gastrointestinal symptoms are common, but the abdominal examination is usually nonspecific.
• Neurological findings are related to changes in sensorium or mental status. Lateralizing findings usually indicate another disease process.
• Visual changes occur, but the pupils are spared, and objective findings are few.
• Drug-induced fever does not occur.

Causes

• Deteriorating renal function, dehydration, electrolyte disturbances, or drug interactions usually precipitates chronic toxicity.
• Acute overdose or accidental exposure to plants containing cardiac glycosides may cause acute toxicity.
• Hypokalemia, hypernatremia, or hypomagnesemia increases the toxic cardiovascular effects of digoxin because of their depressive effects on the NA⁺/K⁺ ATPase pump.
  • Digoxin toxicity does not cause hypokalemia, but hypokalemia can worsen digoxin toxicity.
  • Hyperkalemia is the usual electrolyte abnormality precipitated by digoxin toxicity, primarily in the acute setting. Hyperkalemia may be associated with acute renal failure that subsequently precipitates digoxin toxicity. Chronic digoxin toxicity does not usually cause hyperkalemia.
• Acidosis depresses the Na⁺/K⁺ ATPase pump and may cause digoxin toxicity.
• Myocardial ischemia suppresses the Na⁺/K⁺ ATPase pump and independently alters myocardial automaticity. Digoxin toxicity is more likely in this setting.
• Erroneous dosing, especially in infants receiving parenteral digoxin, unfortunately, is a frequent cause of digoxin toxicity and is usually associated with high mortality.
• Hypothyroid patients are prone to digoxin toxicity secondary to decreased renal excretion and a smaller volume of distribution.
• Bioavailability varies depending on the drug formulation.
  • Lanoxin has 25% less bioavailability than Lanoxicaps.
  • Toxicity may occur by increasing bioavailability.
  • Certain antibiotics that suppress intestinal flora may increase absorption of digoxin.
• Drug interactions are one of the most common causes of digoxin toxicity.
  • Some medications directly increase digoxin plasma levels; other medications alter renal excretion or induce electrolyte abnormalities.
  • Drugs that have been reported to cause digoxin toxicity include the following:
    • Amiloride - May reduce the inotropic response to digoxin
    • Amiodarone - Reduces renal and nonrenal clearance of digoxin and may have additive effects on the heart rate
    • Benzodiazepines (alprazolam, diazepam) - Have been associated with isolated reports of digoxin toxicity
    • Beta-blockers (propranolol, metoprolol, atenolol) - May have additive effects on the heart rate; carvedilol may increase digoxin blood levels in addition to potentiating its effects on the heart rate
    • Calcium channel blockers - Diltiazem and verapamil increase serum digoxin levels; not all calcium channel blockers share this effect.
    • Cyclosporine - May increase digoxin levels, possibly due to reduced renal excretion
    • Erythromycin, clarithromycin, and tetracyclines - May increase digoxin levels
    • Propafenone - Increases digoxin level; effects are variable.
    • Quinidine - Increases digoxin level substantially but clinical effect is variable; related drugs such as hydroxychloroquine or quinine may also affect levels.
    • Propylthiouracil - May increase digoxin levels by reducing thyroid hormone levels
    • Indomethacin
    • Spironolactone - May interfere with digoxin assays; may directly increase digoxin levels; may alter renal excretion.
    • Hydrochlorothiazide
    • Furosemide and other loop diuretics
    • Triamterene
    • Amphotericin B - May precipitate hypokalemia and subsequent digoxin toxicity
    • Succinylcholine - Increased risk of dysrhythmias has been reported.
  • Herb/nutraceutical - Avoid ephedra (risk of cardiac stimulation); avoid natural licorice (causes sodium and water retention and increases potassium loss).
• Clinical digoxin toxicity represents a complex interaction between digoxin and various electrolyte and renal abnormalities. A patient with normal digoxin levels (0.5-2 ng/mL) but renal insufficiency or severe hypokalemia may have more serious cardiotoxicity than a patient with high digoxin levels and no renal or electrolyte disturbances.

Differential Diagnoses

Other Problems to Be Considered

Arrhythmias
Dehydration
Syncope

Workup

Laboratory Studies

• Initial digoxin level
  • In acute toxicity, repeat the digoxin level after 2-4 hours to guide therapy.
  • Digoxin levels do not necessarily correlate with toxicity, especially after acute ingestion.
  • Following acute ingestion, digoxin levels do not equilibrate quickly because of variable absorption and subsequent tissue distribution.
  • Toxicity is related to intracellular levels, not serum levels.
  • A digoxin level drawn within 4 hours of an acute ingestion may be incredibly high with no apparent clinical toxicity.
  • To best way to guide therapy is to follow the digoxin level and correlate it with serum potassium concentrations and the patient's clinical and ECG findings.
  • Digoxin levels determined less than 6-8 hours after an acute ingestion reflect the initial distribution of the drug but not the actual tissue levels, and they are not necessarily predictors of toxicity. The plasma half-life of digoxin is shortened to 10-25 hours with acute massive ingestions, compared with a mean value of 36 hours in nontoxic ingestions.
  • Endogenous digoxinlike immunoreactive substance (DLIS) can cause a false-positive result or an elevated digoxin level. DLIS is observed in neonates and in patients with renal insufficiency, liver disease or hyperbilirubinemia, subarachnoid hemorrhage, congestive heart failure, diabetes mellitus, or acromegaly; it may also be present in those who are pregnant or using spironolactone. In some studies, premature infants had levels as high as 4 ng/mL, with peaks at age 6 days, and positive assay results until they were aged 3 months. Most authors agree that serum digoxin levels due to DLIS are usually less than 2 ng/mL and that the interference is assay dependent and may vary with the lot of the reagent.
  • Most digoxin assays measure total rather than free digoxin levels, serum digoxin levels are no longer useful after Fab administration.
    
• Measure Na⁺, K⁺, Cl^-, CO^2-, Mg⁺⁺, Ca⁺⁺, BUN, and creatinine levels.
• Obtain cardiac markers such as CKMB or troponin I or T if myocardial infarction is a clinical concern.
• False-negative assay results may occur in the setting of acute ingestion of nondigoxin cardiac glycosides, such as foxglove and oleander, even in the setting of profound clinical toxicity. This is caused by nonreactivity or minimal cross-reactivity with the digoxin radioimmunoassay.

Other Tests

• ECG
  • Digoxin effects on the baseline ECG include downward scooping of the ST segment and inverted T waves. These findings are not indicative of toxicity.
  • New QRS prolongation, varying degrees of AV block, and arrhythmias may signify digoxin toxicity. Comparison with previous ECGs is helpful.
  • Rhythm strips may be necessary to facilitate arrhythmia analysis.

Treatment

Prehospital Care

• Oxygen, cardiac monitoring, IV access, and transport are usually the only requirements.
• Atropine is indicated for hemodynamically unstable bradyarrhythmias; lidocaine is indicated for ventricular tachycardia.

Emergency Department Care

Guide treatment of patients with digoxin toxicity by their signs and symptoms and the specific toxic effects. Treatment should not necessarily be driven by digoxin levels alone. Therapeutic options range from simply discontinuing digoxin therapy for patients who are stable with chronic toxicity to fab fragments, pacemaker, antiarrhythmic drugs, magnesium, and hemodialysis for acute severe ingestions.

• Initiate supportive therapy with oxygen, cardiac monitoring, and IV access.
• Activated charcoal is indicated for acute overdose or accidental ingestion. Cholestyramine binds enterohepatically-recycled digoxin and digitoxin, although no outcome studies have been performed.
  • Gastric lavage increases vagal tone and may precipitate or worsen arrhythmias. Consider pretreatment with atropine if gastric lavage is performed.
  • The availability of a digitalis-fab antibodies (Digibind) antidote usually renders gastric lavage unnecessary.
• Management of dysrhythmias varies, depending on the presence or absence of hemodynamic instability, the nature of the arrhythmia, the presence or absence of electrolyte disturbances, and the preferences of toxicology and/or cardiology consultants.
  • Bradyarrhythmias that are hemodynamically stable may be treated with observation and discontinuation of the drug. Ensure proper hydration to optimize renal clearance of excess drug. GI binding agents (eg, charcoal, cholestyramine) may be utilized to bind enterohepatically-recycled digitalis.
  • Hemodynamically stable supraventricular arrhythmias may be treated conservatively with observation and discontinuation of digoxin. In the setting of rate-related ischemia or hemodynamic instability, Digibind is the treatment of choice.
  • Short-acting beta-blockers (eg, esmolol) may be helpful for supraventricular tachyarrhythmias with rapid ventricular rates, but advanced or complete AV block may be precipitated. Calcium channel blockers are contraindicated because they may increase digoxin levels.
  • Hemodynamically unstable bradyarrhythmias respond best to Digibind. Atropine may be used for temporary adjuncts because it improves AV nodal conduction. Cardiac pacing has been used successfully, but it can lower the fibrillatory threshold and induce arrhythmias.
  • PVCs, bigeminy, or trigeminy may be observed unless the patient is hemodynamically unstable, in which case lidocaine may be effective.
  • Ventricular tachycardia responds best to Digibind. Lidocaine and phenytoin may be useful because they depress the enhanced ventricular automaticity without significantly slowing AV conduction. Phenytoin may reverse digitalis-induced prolongation of AV nodal conduction. Phenytoin has been shown to dissociate the inotropic and dysrhythmic action of digitalis, thus suppressing digitalis-induced tachydysrhythmias without diminishing the contractile effects. In addition, phenytoin can terminate supraventricular dysrhythmias induced by digitalis, whereas lidocaine has not been as effective. Lidocaine may be given in boluses of 100 mg, according to advanced cardiac life support (ACLS) guidelines. If lidocaine is successful, begin a maintenance infusion at 1-4 mg/min. Phenytoin has been administered in boluses of 100 mg every 5-10 minutes up to a loading dose of 15 mg/kg. Avoid procainamide and bretylium.
  • Asystole and ventricular fibrillation are very ominous findings. Digibind is indicated; however, its effect is limited by poor cardiac blood flow. Nevertheless, the use of digoxin-fab fragments has been associated with a 50% survival rate in isolated case reports.
  • Quinidine, procainamide, and bretylium are contraindicated. Both quinidine and procainamide worsen AV, SA, and His-Purkinje conductivity. Additionally, quinidine reduces digoxin tissue binding and renal clearance, thereby increasing digoxin levels. Bretylium can precipitate ventricular dysrhythmia.
• Cardioversion is relatively contraindicated because asystole or ventricular fibrillation may be precipitated.
• Consider magnesium therapy as a temporizing antiarrhythmic agent until fab fragments are available. It may be lifesaving when ventricular tachycardia or ventricular fibrillation is present. Intravenous magnesium sulfate, 2 g over 5 minutes, has been shown to terminate digoxin-toxic cardiac arrhythmias in patients with and without overt disease. Aside from successful replacement of intracellular magnesium, it also may act as an indirect antagonist of digoxin at the supraphysiologic level.
  • After an initial bolus of 2 g intravenously, a maintenance infusion at 1-2 g/h is initiated.
  • Monitor magnesium levels approximately every 2 hours. The therapeutic goal is a level between 4 and 5 mEq/L.
• Correct electrolyte abnormalities, especially hypokalemia and hypomagnesemia. Dysrhythmias may be reversed with correction of electrolyte imbalances.
  • Treat hyperkalemia when K⁺ level is greater than 5.5 mEq/L.
  • Calcium is not recommended to treat hyperkalemia in this setting because ventricular tachycardia or ventricular fibrillation may be precipitated. This is based on the fact that intracellular calcium levels are already high in the setting of digoxin toxicity. However, anecdotal case reports and animal studies have been published that refute the dangers of calcium administration. Unless the patient is in extremis, other measures should be preferentially used to treat hyperkalemia.
  • Sodium bicarbonate and/or glucose and insulin are indicated.
  • Treatment with digoxin-fab fragments is indicated for hyperkalemia with K⁺ level greater than 5 mEq/L.
  • Kayexalate (0.5 g/kg PO) also is helpful in binding potassium and enterohepatically-recycled digitalis. However, digoxin-induced hyperkalemia reflects an extracellular shift, not an increase in total body potassium.
  • Caution is indicated when using Kayexalate concurrently with insulin/glucose/bicarbonate and/or Digibind because hypokalemia may be precipitated, which may worsen clinical toxicity.
• Digoxin-fab fragments (Digibind) are generally indicated for the following:
  • Dysrhythmias associated with hemodynamic instability.
  • Altered mental status attributed to digoxin toxicity.
  • Hyperkalemia with K⁺ greater than 5 mEq/L.
  • Serum digoxin level greater than 10 ng/mL in adults at steady state (ie, 6-8 h post acute ingestion or at baseline in the clinical setting of chronic toxicity).
  • Ingestion greater than 10 mg in adults (40 X 0.25 mg tablets) or greater than 0.3 mg/kg in children.

Consultations

• Medical toxicologist
• Cardiology
• Regional poison control center

Medication

The goals of pharmacotherapy are to reduce toxic levels of digitalis, prevent complications, and reduce morbidity.

Antidote

For hemodynamic instability, refractory dysrhythmias, and severe or refractory hyperkalemia. Agent has reversed noncardiac digitalis-associated complications (eg, thrombocytopenia).

In chronic toxicity, plasma drug levels are >6 ng/mL; in acute ingestion, do not base treatment on plasma drug levels alone.

Initially administering one-half doses is the best way in patients with chronic toxicity who are dependent on digoxin. This avoids completely reversing the clinical effects of digoxin and precipitating complications. Depending on the patient's status, additional antidote may be administered later. Agent is excreted renally. When administered to anephric patients, digitalis toxicity may recur within 7-14 days, as digoxin unbinds (recrudescence toxicity). Plasmapheresis may be performed or Digibind readministered in such situations.

Digoxin levels drawn after administration may be exponentially higher because many assays for measuring digoxin measure total digoxin (including digoxin bound to Digibind). This may be misinterpreted as a therapeutic failure and worsening toxicity. Assays that measure only free digoxin are accurate and should reflect true posttreatment levels. Knowledge of your laboratory's digoxin assay is critically important in evaluating therapeutic effect.

Digoxin-Fab fragments (Digibind)

Composed of digoxin-specific antibody fragments prepared from the IgG of sheep immunized with digoxin. The smaller Fab fragment avidly binds digoxin but is minimally immunogenic in humans and is excreted renally. Each vial of the drug contains 40 mg of Digoxin-specific antibody fragments.

Dosing

Adult

Chronic toxicity:

Number of vials = digoxin level (ng/mL) X weight (kg)/100 (eg, a 50-kg patient with a digoxin level of 5 ng/mL would be given 2.5 vials)

Acute overdose:

Number of vials = total amount ingested (mg) X 0.8/0.5 (eg, a patient who overdosed on 30 X 0.25 mg tablets would receive 30 X 0.25 X 0.8/0.5 vials, or 12 vials)

Substitute 1 for 0.8 from the above equation if ingestion is digitoxin instead of digoxin

Unknown acute ingestion or unknown drug level:

If amount ingested is unknown or digoxin level unavailable, rapidly administer 10 vials, which usually is adequate to reverse toxicity; a repeat dose with 10 vials is indicated if there is no or only partial clinical response

In the setting of chronic toxicity where the drug level is not immediately available, administer 6 vials

Administer calculated dose IV over 30 min; effects should occur within 30 min

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Prolonged monitoring for digitalis toxicity is recommended in patients with renal failure; caution when interpreting lab results during therapy (encountering elevated serum digoxin levels is common)

Cardiovascular agents

Cardiovascular agents may be useful for treatment of bradycardia associated with digoxin overdose.

Atropine (Atropair)

Enhances sinus node automaticity by blocking acetylcholine effects at AV node, decreasing refractory time and speeding conduction through AV node.

Dosing

Adult

0.4 mg IV, may repeat q1-2h

Pediatric

0.01-0.03 mg/kg IV

Interactions

Coadministration with other anticholinergics have additive effects; pharmacologic effects of atenolol and digoxin may increase with atropine; antipsychotic effects of phenothiazines may decrease with this medication; TCAs may increase effects

Contraindications

Documented hypersensitivity; thyrotoxicosis, narrow-angle glaucoma, and tachycardia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in Down syndrome and/or children with brain damage to prevent hyperreactive response; caution in coronary heart disease, congestive heart failure, cardiac arrhythmias, and hypertension; caution in peritonitis, ulcerative colitis, hepatic disease, and hiatal hernia with reflux esophagitis; in prostatic hypertrophy, prostatism can have dysuria and may require catheterization

GI decontaminant

Activated charcoal is useful in limiting the absorption of ingested digoxin. Most beneficial if administered within 4 h of ingestion.

Activated charcoal (Liqui-Char)

Prevents absorption by adsorbing drug in intestine. Multidose charcoal may interrupt enterohepatic recirculation and enhance elimination by enterocapillary exsorption. Theoretically, by constantly bathing the GI tract with charcoal, intestinal lumen serves as a dialysis membrane for reverse absorption of drug from intestinal villous capillary blood into intestine. Supplied as an aqueous mixture or in combination with a cathartic (usually sorbitol 70%). Does not dissolve in water.
For maximum effect, administer within 30 min of ingesting poison.

Dosing

Adult

1 g/kg PO; may repeat in 2-4 h at one-half original dose

Pediatric

<2 years: 1-2 g/kg PO without cathartic
>2 years: 1-2 g/kg PO

Interactions

May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases absorptive properties)

Contraindications

Documented hypersensitivity; poisoning or overdosage of mineral acids and alkalies; unprotected airway and absent gag reflex

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before administering activated charcoal; after emesis with ipecac, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black; protect airway in patients with depressed level of consciousness; if using multiple dose charcoal, monitor for presence of bowel sounds to minimize risk of charcoal ileus and vomiting with subsequent pulmonary aspiration

Resin

Resin is used in management of hypercholesterolemia and can bind drugs that are enterohepatically recycled. Upwards of 30% of a digoxin dose (higher in some individuals) and the majority of a digitoxin dose are enterohepatically recycled.

Cholestyramine (Questran)

Forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic re-uptake of intestinal bile salts. Shown to decrease digoxin levels following therapeutic dosing and acute or chronic digitalis toxicity. However, agent may not change ultimate outcome because of prolonged administration time necessary.

Dosing

Adult

4 g PO q6h, in a slurry or with a cathartic (ie, sorbitol)

Pediatric

Not established

Interactions

Inhibits absorption of numerous drugs, including warfarin, vitamin K, thyroid hormone, amiodarone, NSAIDs, methotrexate, digitalis glycosides, glipizide, chlorothiazide, propranolol, phenobarbital, phenylbutazone, folic acid, phenytoin, imipramine, niacin, methyldopa, tetracyclines, clofibrate, hydrocortisone, penicillin G

Contraindications

Documented hypersensitivity; complete biliary obstruction; intestinal obstruction

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in constipation and phenylketonuria

Electrolytes

Magnesium is useful as a temporizing antiarrhythmic agent until digoxin Fab fragments are available.

Magnesium

Possesses antiarrhythmic properties that are beneficial with treatment of digoxin toxicity. May be a lifesaving adjunct in treatment of digoxin-induced ventricular tachycardia or ventricular fibrillation.

Dosing

Adult

2 g IV bolus over 2 min, followed by 1-2 g/h infusion
Monitor levels q2h; therapeutic goal is 4-5 mEq/L

Pediatric

Not established

Interactions

Concurrent use with nifedipine may cause hypotension and neuromuscular blockade; may increase neuromuscular blockade seen with aminoglycosides and potentiate neuromuscular blockade produced by tubocurarine, vecuronium, and succinylcholine; may increase CNS effects and toxicity of CNS depressants, betamethasone, and cardiotoxicity of ritodrine

Contraindications

Documented hypersensitivity; heart block; Addison disease; myocardial damage; severe hepatitis

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Monitor for signs of magnesium toxicity manifested by neuromuscular dysfunction (eg, depressed or absent deep tendon reflexes) or respiratory compromise

Follow-up

Further Inpatient Care

• Admission criteria
  • New cardiac dysrhythmias
  • Severe bradyarrhythmias
  • Advanced AV block
  • Acute prolongation of the QRS interval
  • Severe electrolyte abnormalities, especially hypokalemia or hyperkalemia
  • Dehydration
  • Inability to care for self
  • Suicidal ideation
• Admit patients with cardiac abnormalities to a monitored bed.
• ICU admission criteria include hemodynamic instability, refractory dysrhythmias, hyperkalemia, and renal failure. Admit patients receiving Digibind to ICU or critical care unit (CCU).

Further Outpatient Care

• Observe patients with acute ingestion on a cardiac monitor for 6 hours. In the absence of cardiac dysrhythmias, toxic digoxin levels, or hyperkalemia, patients may be discharged with appropriate follow-up care.
• Patients with chronic toxicity and noncardiac symptoms may be discharged if factors that led to the toxicity have been corrected (eg, electrolyte disorders, dehydration, drug-drug interactions) and proper care can be ensured. Discontinue use of the drug. Arrange follow-up care in the next 24 hours with a primary care provider.
• Intentional overdose requires psychiatric follow-up.

Transfer

• Transfer may be indicated if patient is unstable and the hospital has no ICU or CCU capabilities, no appropriate consultants (eg, toxicologist, cardiologist, intensivist), or when Digibind (if indicated) is not available. Treatment is best discussed with the regional poison control center and the patient's primary practitioner.

Deterrence/Prevention

• Digoxin toxicity may develop in patients with dehydration, worsening renal function, or new electrolyte disturbances. Drug interactions are an important causative factor. Careful patient monitoring, including drug levels, is required in these clinical settings.
• Advanced age decreases the volume of distribution and renal clearance. Elderly patients and those with chronic renal failure require lower maintenance doses.

Complications

• Refer to complications of Digibind therapy, as outlined in the Medication section.

Prognosis

• Morbidity and mortality rates increase if the patient has a new dysrhythmia, advanced AV block, or other significant ECG abnormality.

Patient Education

• Educate the patient to be aware of possible drug interactions when starting any new medication.

Miscellaneous

Medicolegal Pitfalls

• Failure to consider the diagnosis in patients with dysrhythmias, electrolyte abnormalities, or renal insufficiency
• Cardioverting the digoxin-toxic patient with an unstable supraventricular arrhythmia
• Administration of intravenous calcium to treat hyperkalemia if digoxin toxicity is suspected or confirmed unless the patient is in extremis
• Failure to arrange psychiatric follow-up in cases of intentional overdose
• Erroneous parenteral dosing in neonates and infants

Special Concerns

• Infants and children taking digoxin tolerate higher doses and plasma levels.
  • The pediatric volume of distribution is greater and the half-life of digoxin is less.
  • Pediatric myocardial cells may be less sensitive to the toxic effects of digoxin.
  • Decreased sensitivity to dysrhythmias by infants and children may contribute to increased tolerance to digoxin.
  • Infants and children manifest the same signs of toxicity as adults.
  • The treatment of toxicity in pediatric patients is the same as in adults.

Multimedia

Media file 1: Bidirectional tachycardia in a patient with digitalis toxicity.

Media file 2: Torsades de pointes.

References

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2. Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Heard SE. 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 25th Annual Report. Clin Toxicol (Phila). Dec 2008;46(10):927-1057. [Medline].

3. Antman EM, Wenger TL, Butler VP, et al. Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Final report of a multicenter study. Circulation. Jun 1990;81(6):1744-52. [Medline].

4. Benowitz N. Cardiac glycosides. In: Olson K, ed. Poisoning and Drug Overdose. 4^th ed. 2004:155-7.

5. Carter BL, Small RE, Garnett WR. Monitoring digoxin therapy in two long-term facilities. J Am Geriatr Soc. Jun 1981;29(6):263-8. [Medline].

6. Colt HG, Shapiro AP. Drug-induced illness as a cause for admission to a community hospital. J Am Geriatr Soc. Apr 1989;37(4):323-6. [Medline].

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Keywords

digitalis toxicity, digoxin toxicity, cardiac glycoside toxicity, foxglove plant, digoxin poisoning, acute digoxin overdose, digoxin overdose, acute ingestion of digoxin, cardiac glycoside overdose

Contributor Information and Disclosures

Author

Donald Schreiber, MD, CM, Associate Professor of Surgery (Emergency Medicine), Stanford University School of Medicine
Donald Schreiber, MD, CM is a member of the following medical societies: American College of Emergency Physicians
Disclosure: Abbott Point of Care Inc Research Grant and Speaker''''''''''''''''s Bureau Speaking and teaching; Bristol-Myers Squibb Inc Honoraria Speaking and teaching; Sanofi-Aventis, Inc Honoraria Speaking and teaching; Nanosphere Inc Grant/research funds Research; Singulex Inc Grant/research funds Research

Medical Editor

Lance W Kreplick, MD, MMM, FAAEM, FACEP, Medical Director of Hyperbaric Medicine, Fawcett Wound Management and Hyperbaric Medicine; Consulting Staff in Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC
Lance W Kreplick, MD, MMM, FAAEM, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physician Executives
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

John G Benitez, MD, MPH, FACMT, FACPM, FAAEM, Associate Professor, Department of Medicine, Clinical Pharmacology Division, Vanderbilt University; Managing Director, Tennessee Poison Center
John G Benitez, MD, MPH, FACMT, FACPM, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Society for Academic Emergency Medicine, Undersea and Hyperbaric Medical Society, and Wilderness Medical Society
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

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