AUTHOR INFORMATION

Section 1 of 11

Authored by Donald Schreiber, MD, CM, Associate Professor of Surgery, Stanford University School of Medicine; Consulting Staff, Division of Emergency Medicine, Stanford University Medical Center

Coauthored by Sarah Robertson, MD, Consulting Staff, Department of Emergency Medicine, Kaiser Permanente of Sacramento

Donald Schreiber, MD, CM, is a member of the following medical societies: American College of Emergency Physicians

Edited by Lance W Kreplick, MD, MMM, Medical Director, Department of Emergency Medicine, Regional Medical Center - Bayonet Point; John T VanDeVoort, PharmD, Clinical Assistant Professor, College of Pharmacy, University of Minnesota; John G Benitez, MD, MPH, FACMT, FACPM, FAAEM, Associate Professor, Department of Emergency Medicine, Pediatrics, and Environmental Medicine, University of Rochester; Managing Director, Associate Medical Director, Ruth A Lawrence Poison and Drug Information Center; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Asim Tarabar, MD, Assistant Clinical Professor of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Author's Email:	Donald Schreiber, MD, CM
Editor's Email:	Lance W Kreplick, MD, MMM

eMedicine Journal, January 3 2006, VOLUME 7, Number 1

INTRODUCTION

Section 2 of 11

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

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:

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

  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.

• Internationally: 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 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

Section 3 of 11

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]).

• 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- and 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.

• 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.

DIFFERENTIALS

Section 4 of 11

Congestive Heart Failure and Pulmonary Edema
Gastroenteritis
Heart Block, First Degree
Heart Block, Second Degree
Heart Block, Third Degree
Hypercalcemia
Hyperkalemia
Hypernatremia
Hypokalemia
Hypomagnesemia
Hyponatremia
Plant Poisoning, Glycosides - Cardiac
Plant Poisoning, Herbs
Renal Failure, Acute
Renal Failure, Chronic and Dialysis Complications
Toxicity, Beta-blocker
Toxicity, Calcium Channel Blocker
Ventricular Fibrillation
Ventricular Tachycardia

Other Problems to be Considered:

Arrhythmias
Dehydration
Syncope

WORKUP

Section 5 of 11

Lab 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.

• Measure Na⁺, K⁺, Cl^-, CO^2-, Mg⁺⁺, Ca⁺⁺, BUN, and creatinine levels.

• Obtain cardiac markers 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

Section 6 of 11

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.

• Hemodynamically unstable bradyarrhythmias respond best to Digibind. Atropine may be used for temporary adjuncts. 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 Dilantin may be useful. 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 min up to a loading dose of 15 mg/kg. Avoid procainamide and bretylium.

• Asystole and ventricular fibrillation are very serious findings. Digibind is indicated; however, its effect is limited by poor cardiac blood flow. Nevertheless, the use of digoxin-fab fragments is associated with a 50% survival rate.

• Cardioversion is relatively contraindicated because asystole or ventricular fibrillation may be precipitated.
  • Calcium channel blockers are contraindicated because they may increase digoxin levels.

  • Short-acting beta-blockers (eg, esmolol) may be helpful, but advanced or complete AV block 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.

• 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

Section 7 of 11

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

Drug Category: 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.

Complications of therapy include allergic reactions (relatively rare and more common in patients with allergic histories), worsening CHF, tachyarrhythmias, and hypokalemia. Overall, incidence of complications is very low.

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.

Drug Name	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.
Adult Dose	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 Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
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)

Drug Category: Cardiovascular agents -- May be useful for treatment of bradycardia associated with digoxin overdose.

Drug Name	Atropine (Atropair) -- Enhances sinus node automaticity by blocking acetylcholine effects at AV node, decreasing refractory time and speeding conduction through AV node.
Adult Dose	0.4 mg IV, may repeat q1-2h
Pediatric Dose	0.01-0.03 mg/kg IV
Contraindications	Documented hypersensitivity; thyrotoxicosis, narrow-angle glaucoma, and tachycardia
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
Pregnancy	C - Safety for use during pregnancy has not been established.
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

Drug Category: GI decontaminant -- Activated charcoal is useful in limiting the absorption of ingested digoxin. Most beneficial if administered within 4 h of ingestion.

Drug Name	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.
Adult Dose	1 g/kg PO; may repeat in 2-4 h at one-half original dose
Pediatric Dose	<2 years: 1-2 g/kg PO without cathartic >2 years: 1-2 g/kg PO
Contraindications	Documented hypersensitivity; poisoning or overdosage of mineral acids and alkalies; unprotected airway and absent gag reflex
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)
Pregnancy	C - Safety for use during pregnancy has not been established.
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

Drug Category: Resin -- 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.

Drug Name	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.
Adult Dose	4 g PO q6h, in a slurry or with a cathartic (ie, sorbitol)
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; complete biliary obstruction; intestinal obstruction
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
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in constipation and phenylketonuria

Drug Category: Electrolytes -- Magnesium is useful as a temporizing antiarrhythmic agent until digoxin Fab fragments are available.

Drug Name	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.
Adult Dose	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 Dose	Not established
Contraindications	Documented hypersensitivity; heart block; Addison disease; myocardial damage; severe hepatitis
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
Pregnancy	A - Safe in pregnancy
Precautions	Monitor for signs of magnesium toxicity manifested by neuromuscular dysfunction (eg, depressed or absent deep tendon reflexes) or respiratory compromise

FOLLOW-UP

Section 8 of 11

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

Section 9 of 11

Medical/Legal 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

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.

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which electrolyte abnormality usually is precipitated by acute digoxin toxicity?

A: Hyperkalemia
B: Hypokalemia
C: Hypercalcemia
D: Hypernatremia
E: Hyponatremia

The correct answer is A: Digoxin toxicity inhibits the sodium-potassium adenosine triphosphatase (Na⁺/K⁺ ATPase) pump. In acute toxicity, hyperkalemia results. Hypokalemia may precipitate digoxin toxicity but is not caused by acute digoxin toxicity. Hypercalcemia and hypernatremia enhance the toxic effects of digoxin on the Na⁺/K⁺ ATPase pump but are not caused by acute digoxin toxicity. Hyponatremia is not associated with digoxin toxicity.

CME Question 2: Which of the following dysrhythmias is least likely to be found in patients with digoxin toxicity?

A: Accelerated junctional rhythm
B: Sinus bradycardia
C: Premature ventricular contractions (PVCs)
D: Rapid atrial fibrillation
E: Third-degree heart block

The correct answer is D: Digoxin toxicity may cause any dysrhythmia but, because of its effects on the atrioventricular (AV) node (slowed conduction) and Purkinje fibers (increased automaticity), bradycardias and ventricular ectopy are the most common arrhythmias. Thus, junctional rhythm, third-degree heart block, sinus bradycardia, and PVCs are common manifestations of digoxin toxicity. Rapid atrial fibrillation is rare.

Pearl Question 1 (T/F): Myocardial ischemia is a common precipitant of digoxin toxicity.

The correct answer is True: Worsening renal function, hypokalemia, myocardial ischemia, and drug interactions are the most common precipitants of digoxin toxicity.

Pearl Question 2 (T/F): Cardioversion is the treatment of choice for patients with unstable supraventricular arrhythmias in the clinical setting of digoxin toxicity.

The correct answer is False: Cardioversion may precipitate asystole or ventricular fibrillation. Digibind is the preferred treatment.

Pearl Question 3 (T/F): Asymptomatic patients with an acute ingestion of digoxin must be observed for at least 24 hours.

The correct answer is False: In the absence of cardiac arrhythmias, toxic digoxin levels, or hyperkalemia after 6 hours of observation, patients may be discharged from the hospital.

Pearl Question 4 (T/F): Calcium is not the treatment of choice for hyperkalemia in the clinical setting of acute digoxin overdose.

The correct answer is True: Intracellular calcium levels are already elevated in the setting of acute digoxin toxicity as a result of the inhibition of the sodium-potassium adenosine triphosphate (Na⁺/K⁺ ATPase) pump. Ventricular tachycardia or fibrillation may be precipitated. Some case reports and animal studies have suggested the safety of calcium administration, but the current recommendation is to avoid exogenous calcium administration unless the patient is in extremis.

BIBLIOGRAPHY

Section 11 of 11

• 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 1990 Jun; 81(6): 1744-52[Medline].
• Benowitz N: Cardiac glycosides. In: Olson K, ed. Poisoning and Drug Overdose. 4th ed. 2004:155-7.
• Carter BL, Small RE, Garnett WR: Monitoring digoxin therapy in two long-term facilities. J Am Geriatr Soc 1981 Jun; 29(6): 263-8[Medline].
• Colt HG, Shapiro AP: Drug-induced illness as a cause for admission to a community hospital. J Am Geriatr Soc 1989 Apr; 37(4): 323-6[Medline].
• Doi SA, Landless PN: Digoxin in clinical practice: sorting out the facts. Br J Clin Pract 1995 Sep-Oct; 49(5): 257-61[Medline].
• Eddleston M, Rajapakse S, Rajakanthan S, et al: Anti-digoxin Fab fragments in cardiotoxicity induced by ingestion of yellow oleander: a randomised controlled trial. Lancet 2000 Mar 18; 355(9208): 967-72[Medline].
• Ellenhorn A: Digitalis. In: Ellenhorn's Medical Toxicology. 2nd ed. Lippincott Williams & Wilkins; 1997:451-456.
• Fazio A: Fab fragments in the treatment of digoxin overdose: pediatric considerations. South Med J 1987 Dec; 80(12): 1553-6[Medline].
• Fenton F, Smally AJ, Laut J: Hyperkalemia and digoxin toxicity in a patient with kidney failure. Ann Emerg Med 1996 Oct; 28(4): 440-1[Medline].
• Fisch C, Knoebel SB: Recognition and therapy of digitalis toxicity. Prog Cardiovasc Dis 1970 Jan; 13(1): 71-96[Medline].
• Fleisher G, Ludwig S: Textbook of Pediatric Emergency Medicine. Lippincott Williams & Wilkins; 1993:768-9.
• Goodman LS, Gilman AG: The Pharmacologic Basis of Therapeutics. 7th ed. McGraw-Hill; 1985:716-47.
• Green SM, Naftel J: Antiarrhythmic efficacy of magnesium in the setting of life-threatening digoxin toxicity. Am J Emerg Med 1989 May; 7(3): 347-8[Medline].
• Hack JB, Woody JH, Lewis DE, et al: The effect of calcium chloride in treating hyperkalemia due to acute digoxin toxicity in a porcine model. J Toxicol Clin Toxicol 2004; 42(4): 337-42[Medline].
• Ibanez C, Carcas AJ, Frias J, Abad F: Activated charcoal increases digoxin elimination in patients. Int J Cardiol 1995 Jan 27; 48(1): 27-30[Medline].
• Lacy CF, Armstrong LL, Goldman MP: Drug Information Handbook. 13th ed. 2005.
• Lip GY, Metcalfe MJ, Dunn FG: Diagnosis and treatment of digoxin toxicity. Postgrad Med J 1993 May; 69(811): 337-9[Medline].
• Mahdyoon H, Battilana G, Rosman H, et al: The evolving pattern of digoxin intoxication: observations at a large urban hospital from 1980 to 1988. Am Heart J 1990 Nov; 120(5): 1189-94[Medline].
• Ordog GJ, Benaron S, Bhasin V, et al: Serum digoxin levels and mortality in 5,100 patients. Ann Emerg Med 1987 Jan; 16(1): 32-9[Medline].
• Pahor M, Guralnik JM, Gambassi G, et al: The impact of age on risk of adverse drug reactions to digoxin. For The Gruppo Italiano di Farmacovigilanza nell' Anziano. J Clin Epidemiol 1993 Nov; 46(11): 1305-14[Medline].
• Park MK: Use of digoxin in infants and children, with specific emphasis on dosage. J Pediatr 1986 Jun; 108(6): 871-7[Medline].
• Rosen P, Barkin R: Toxicologic problems: Common cardiac medications. In: Emergency Medicine: Concepts and Clinical Practice. 3rd ed. Mosby-Year Book; 1992:2541.
• Steiner JF, Robbins LJ, Hammermeister KE, et al: Incidence of digoxin toxicity in outpatients. West J Med 1994 Nov; 161(5): 474-8[Medline].
• Van Deusen SK, Birkhahn RH, Gaeta TJ: Treatment of hyperkalemia in a patient with unrecognized digitalis toxicity. J Toxicol Clin Toxicol 2003; 41(4): 373-6[Medline].
• Wofford JL, Hickey AR, Ettinger WH, Furberg CD: Lack of age-related differences in the clinical presentation of digoxin toxicity. Arch Intern Med 1992 Nov; 152(11): 2261-4[Medline].

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