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Digitalis Toxicity
Updated: Jan 04, 2017
Author: Vinod Patel, MD; Chief Editor: Jeffrey N Rottman, MD

Overview
Practice Essentials
The incidence of digitalis toxicity has declined in recent years, due to decreased use along with
improved technology for monitoring of drug levels and increased awareness of drug interactions.
Nevertheless, cardiac glycoside toxicity continues to be a problem in the United States because
of the wide use of digoxin (a preparation of digitalis) and its narrow therapeutic window.

It is important to learn about the source, amount, time of ingestion, presence of any coingestant,
and patient’s own comorbidities. Acute digitalis toxicity can result from unintentional, suicidal,
or homicidal overdose of the digitalis preparation digoxin, or accidental ingestion of plants that
contain cardiac glycosides. Chronic toxicity in patients on digoxin therapy may result from
deteriorating renal function, dehydration, electrolyte disturbances, or drug interactions.
Alterations in cardiac rate and rhythm from digitalis toxicity may reproduce almost every known
mechanism of dysrhythmia. See the image below.
 Bidirectional tachycardia in a patient
with digitalis toxicity.

Signs and symptoms

Digitalis toxicity produces CNS, visual, GI, and cardiac manifestations. Nausea, vomiting, and
drowsiness are among the most common extracardiac manifestations.

CNS symptoms of digitalis toxicity include the following:

 Drowsiness
 Lethargy
 Fatigue
 Neuralgia
 Headache
 Dizziness
 Confusion or giddiness
 Hallucinations
 Seizures (rare)
 Paresthesias and neuropathic pain

Visual aberration often is an early indication of digitalis toxicity. Yellow-green distortion is most
common, but red, brown, blue, and white distortions also occur. Drug intoxication also may
cause the following:

 Snowy vision
 Photophobia
 Photopsia
  Decreased visual acuity
 Yellow halos around lights (xanthopsia)
 Transient amblyopia or scotomata

GI symptoms in acute or chronic toxicity include the following:

 Anorexia
 Weight loss
 Failure to thrive (in pediatric patients)
 Nausea
 Vomiting
 Abdominal pain
 Diarrhea
 Mesenteric ischemia (a rare complication of rapid IV infusion)

Cardiac symptoms

Cardiac symptoms include the following:

 Palpitations
 Shortness of breath
 Syncope
 Swelling of lower extremities
 Bradycardia
 Hypotension
 Dyspnea

See Clinical Presentation for more detail.

Diagnosis

Studies in patients with possible digitalis toxicity include the following:

 Serum digoxin level

 Electrolytes
 Renal function studies
 ECG

Serum digoxin level

 Therapeutic levels are 0.6-1.3 to 2.6 ng/mL

 Levels associated with toxicity overlap between therapeutic and toxic ranges
 False-negative assay results may occur with acute ingestion of nondigoxin cardiac
glycosides (eg, herbal compunds, such as foxglove or oleander)
 Levels determined less than 6-8 hours after an acute ingestion do not necessarily predict
toxicity
  The 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.

Electrolytes

 In acute toxicity, hyperkalemia is common

 Chronic toxicity is often accompanied by hypokalemia and hypomagnesemia

Electrocardiography

 Digoxin toxicity may cause almost any dysrhythmia

 Classically, dysrhythmias associated with increased automaticity and decreased AV
conduction occur
 Sinus bradycardia and AV conduction blocks are the most common ECG changes in the
pediatric population, while ventricular ectopy is more common in adults
 Nonparoxysmal atrial tachycardia with heart block and bidirectional ventricular
tachycardia are particularly characteristic of severe digitalis toxicity

See Workup for more detail.

Management

Supportive care of digitalis toxicity includes the following:

 Hydration with IV fluids

 Oxygenation and support of ventilatory function
 Discontinuation of the drug, and, sometimes, the correction of electrolyte imbalances

GI decontamination

 Activated charcoal is indicated for acute overdose or accidental ingestion

 Binding resins (eg, cholestyramine) may bind enterohepatically-recycled digoxin

Treatment of electrolyte imbalance

 For hyperkalemia, use insulin plus glucose, and sodium bicarbonate if the patient is
acidotic
 Treatment with digoxin Fab fragments is indicated for a K+ level greater than 5 mEq/L
 Hemodialysis may be necessary for uncontrolled hyperkalemia
 Correct hypokalemia (usually in chronic intoxication)
 Concomitant hypomagnesemia may result in refractory hypokalemia

Digoxin immune Fab

Digoxin immune Fab is considered the first-line treatment for significant dysrhythmias from
digitalis toxicity. Other indications for its use, in the absence of specific contraindications,
include the following:

 Ingestion of massive quantities of digitalis (in children, 4 mg or 0.1 mg/kg; in adults, 10

mg)
 Serum digoxin level greater than 10 ng/mL in adults at steady state (ie, 6-8 hours after
acute ingestion or at baseline in chronic toxicity)
 Hyperkalemia (serum potassium level greater than 5 mEq/L)
 Altered mental status attributed to digoxin toxicity
 Rapidly progressive signs and symptoms of toxicity

Management of dysrhythmias

 In hemodynamically stable patients, bradyarrhythmias and supraventricular arrhythmias

may be treated with supportive care
 Short-acting beta blockers (eg, esmolol) may be helpful for supraventricular
tachyarrhythmias with rapid ventricular rates, but may precipitate advanced or complete
AV block in patients with sinoatrial or AV node depression
 Phenytoin and lidocaine are useful for ventricular tachycardia if immune therapy is
ineffective or unavailable
 Phenytoin may suppress digitalis-induced tachydysrhythmias
 Atropine has proved helpful in reversing severe sinus bradycardia
 Magnesium sulfate may terminate dysrhythmias, but is contraindicated in the setting of
bradycardia or AV block and should be used cautiously in patients with renal failure
 Cardioversion for severe dysrhythmias due to digitalis can precipitate ventricular
fibrillation and asystole but may be used if the patient is hemodynamically unstable and
has a wide, complex tachycardia and if fascicular tachycardia has been ruled out

Criteria for hospital admission

 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

See Treatment and Medication for more detail.

Background
The incidence of digitalis toxicity has declined in recent years, due to decreased use of this drug
along with improved technology for monitoring of drug levels and increased awareness of drug
interactions. Nevertheless, cardiac glycoside toxicity continues to be a problem in the United
States because of the wide use of digoxin (a preparation of digitalis) and its narrow therapeutic
window.

Digitalis is a plant-derived cardiac glycoside commonly used in the treatment of chronic heart
failure (CHF), atrial fibrillation, and reentrant supraventricular tachycardia.[1, 2] Digoxin is the
only available preparation of digitalis in the United States. (See Etiology and Epidemiology.)

Cardiac glycosides are found in certain flowering plants, such as oleander and lily-of-the-valley.
Indigenous people in various parts of the world have used many plant extracts containing cardiac
glycosides as arrow and ordeal poisons. The ancient Egyptians used squill (Urginea maritime) as
a medicine. The Romans employed it as a diuretic, heart tonic, emetic, and rat poison. Digitalis,
or foxglove, was mentioned in the year 1250 in the writings of Welsh physicians. Fuchsius
described it botanically 300 years later and named it Digitalis purpurea.

William Withering published his classic account of foxglove and some of its medical uses in
1785, remarking upon his experience with digitalis. He recognized many of the signs of digitalis
toxicity, noting, "The foxglove, when given in very large and quickly repeated doses, occasions
sickness, vomiting, purging, giddiness, confused vision, objects appearing green or yellow;
increased secretion of urine, slow pulses, even as low as 35 in a minute, cold sweats,
convulsions, syncope, death." (See Presentation and Workup.)

During the early 20th century, as a result of the work of Cushny, Mackenzie, Lewis, and others,
the drug was gradually recognized as specific for treatment of atrial fibrillation. Only
subsequently was the value of digitalis for treatment of CHF established. Cardiac glycosides
enhance cardiac contractility and slow conduction through the atrioventricular (AV) junction by
increasing vagal tone.[3] (See Etiology.)

Cardiac glycoside toxicity has been known to result from ingestion of some plants, including
yellow oleander (Thevetia peruviana) and foxglove, and a similar toxidrome has been associated
with the use of herbal dietary supplements that contain cardiac glycosides. A similar glycoside is
reportedly present in Convallaria (Lily of the Valley) (see Anton Chekhov’s book, A Doctor’s
Visit).

Digoxin is among the top 50 prescribed drugs in the United States.[4] In 2011, the American
Association of Poison Control Centers reported 1601 single exposures to cardiac glycoside
drugs.[5] Cardiac glycosides account for 2.6% of toxic plant exposures in the United States.[6, 7]
Most of these exposures are in children.[7] (See Epidemiology.)

Digoxin-specific fragment antigen-binding (Fab) antibody fragments have contributed

significantly to the improved morbidity and mortality of toxic patients since their approval in
1986 by the US Food and Drug Administration (FDA). (See Prognosis, Treatment, and
Medication.)
Pathophysiology
Digoxin and other cardiac glycosides cause direct vasoconstriction in the arterial and venous
system in vascular smooth muscle. The positive inotropic effect of digitalis has the following 2
components:

 Direct inhibition of membrane-bound sodium- and potassium-activated adenosine

triphosphatase (Na+/K+ -ATPase), which leads to an increase in the intracellular
concentration of calcium ([Ca2+]i)
 Associated increase in a slow inward calcium current (iCa) during the action potential
(AP); this current is the result of movement of calcium into the cell, and it contributes to
the plateau of the AP

Digitalis glycosides bind specifically to Na+/K+ -ATPase, inhibit its enzymatic activity, and
impair active transport of extruding sodium and transport of potassium into the fibers (3:2 ratio).
As a result, intracellular sodium ([Na+]i) gradually increases, and a gradual, small decrease in
intracellular potassium ([K+]i) occurs.

Cardiac fiber calcium [Ca2+]i is exchanged for extracellular sodium (3:1 ratio) by a transport
system that is driven by the concentration gradient for these ions and the transmembrane
potential. Increase in [Na+]i is related crucially to the positive inotropic effect of digitalis.

In addition, by a mechanism that is not defined clearly, the increase in [Ca2+]i increases the peak
magnitude of iCa; this change parallels the positive inotropic action. The change in iCa is a
consequence of the increase in [Ca2+]i and not of the increase in [Na+]i. Thus, more calcium is
delivered during the plateau of each AP to activate each contraction.

A fall in intracellular pH accompanies the digoxin-induced increase in [Ca2+] i, which leads to

activation of a sodium/hydrogen exchange pump. This results in extrusion of hydrogen, an
increase in [Na+]i, and greater inotropy.

The mechanism described assumes that Na+/K+ -ATPase is the pharmacologic receptor for
digitalis and that when digitalis binds to these enzymes, it induces a conformational change that
decreases active transport of sodium. Digitalis apparently binds to ATPase in a specific and
saturable manner, producing a conformational change of the enzyme such that the binding site
for digitalis probably is on the external surface of the membrane. Furthermore, the magnitude of
the inotropic effect of digitalis is proportional to degree of inhibition of the enzyme.

Digitalis, in therapeutic concentrations, exerts no effect on the contractile proteins or on the

interactions between them.

Electrophysiologic effects
The electrophysiological effects of cardiac glycosides include the following[8] :

 Decreased resting potential (RP) or maximal diastolic potential (MDP), which slows the
rate of phase-0 depolarization and conduction velocity
 Decrease in action potential duration (APD), which results in increased responsiveness of
fibers to electrical stimuli
 Enhancement of automaticity, which results from an increase in the rate of phase 4
depolarization and from delayed after-depolarization

In general, cardiac glycosides slow conduction and increase the refractory period in specialized
cardiac conducting tissue by stimulating vagal tone. Digitalis has parasympathetic properties,
which include hypersensitization of carotid sinus baroreceptors and stimulation of central vagal
nuclei.

Digoxin also appears to have variable effects on sympathetic tone, depending on the specific
cardiac tissue involved.

Dosage and toxicity

The therapeutic daily dose of digoxin ranges from 5-15 mcg/kg. The absorption of digoxin
tablets is 70-80%; its bioavailability is 95%. The kidney excretes 60-80% of the digoxin dose
unchanged.

The onset of action after oral (PO) administration occurs in 30-120 minutes; the onset of action
with intravenous (IV) administration occurs in 5-30 minutes. The peak effect with PO dosing is
2-6 hours, and that with IV dosing is 5-30 minutes. Only 1% of the total amount of digoxin in the
body is in the serum; of that amount, approximately 25% is protein bound.

Digoxin has a large volume of distribution, being 6-10 L/kg in adults, 10 L/kg in neonates, and
as much as 16L/kg in infants and toddlers. At therapeutic levels, the elimination half-life is 36
hours. In acute digoxin intoxication in toddlers and children, the average plasma half-life is 11
hours. With acute intoxication, plasma concentrations extrapolated to time zero are lower in
toddlers than in infants and older children because of their increased volume of distribution and
clearance.

The lethal dose of digoxin is considered to be 20-50 times the maintenance dose taken at once. In
healthy adults, a dose of less than 5 mg seldom causes severe toxicity, but a dose of more than 10
mg is almost always fatal. In the pediatric population, the ingestion of more than 4 mg or 0.3
mg/kg portends serious toxicity. However, plasma concentration does not always correlate with
the risk of toxicity.[9]

Digoxin in pregnancy

Digoxin is used widely in the acute management and prophylaxis of fetal paroxysmal
supraventricular tachycardia, as well as in rate control of atrial fibrillation. It is an FDA
pregnancy category C drug. An increased digoxin dosage may be necessary during pregnancy
because of enhanced renal clearance and expanded blood volume.

No series has been published regarding toxicity in the pregnant woman. Digoxin-specific Fab
fragments can be used in pregnancy with the caveat that careful monitoring of the fetus must be
maintained. Fetal myocardium has a higher resistance to the toxic effects of digitalis.

Dysrhythmias

Alterations in cardiac rate and rhythm from digitalis toxicity may simulate almost every known
type of dysrhythmia. Although no dysrhythmia is pathognomonic for digoxin toxicity, toxicity
should be suspected when evidence of increased automaticity and depressed conduction is noted.
Underlying these dysrhythmias is a complex influence of digitalis on the electrophysiologic
properties of the heart through the means already discussed, as well as via the cumulative results
of the direct, vagotonic, and antiadrenergic actions of digitalis.

The effects of digoxin vary with the dose and differ depending on the type of cardiac tissue
involved. The atria and ventricles exhibit increased automaticity and excitability, resulting in
extrasystoles and tachydysrhythmias. Conduction velocity is reduced in myocardial and nodal
tissue, resulting in increased PR interval and AV block accompanied by a decrease in the QT
interval.

In addition to these effects, the direct effect of digitalis on repolarization often is reflected in the
electrocardiogram (ECG) by ST segment and T-wave forces opposite in direction to the major
QRS forces. The initial electrophysiologic manifestation of digitalis effects and toxicity usually
is mediated by increased vagal tone.

Early in acute intoxication, depression of sinoatrial (SA) or AV nodal function may be reversed
by atropine. Subsequent manifestations are the result of direct and vagomimetic actions of the
drug on the heart and are not reversed by atropine.

Ectopic rhythms are due to enhanced automaticity, reentry, or both, and may include the
following:

 Nonparoxysmal junctional tachycardia

 Extrasystole
 Premature ventricular contractions
 Ventricular flutter and fibrillation
 Atrial flutter and fibrillation
 Bidirectional ventricular tachycardia

Bidirectional ventricular tachycardia is particularly characteristic of severe digitalis toxicity and

results from alterations in intraventricular conduction, junctional tachycardia with aberrant
intraventricular conduction, or, on rare occasions, alternating ventricular pacemakers.

The following features may also be seen:

  Depression of the atrial pacemakers, resulting in SA arrest
 SA block
 AV block
 Sinus exit block resulting from depression of normal conduction
 Nonparoxysmal atrial tachycardia with block

When conduction and the normal pacemaker are both depressed, ectopic pacemakers may take
over, producing atrial tachycardia with AV block and nonparoxysmal automatic AV junctional
tachycardia. Indeed, AV junctional blocks of varying degrees, alone or with increased ventricular
automaticity, are the most common manifestations of digoxin toxicity, occurring in 30-40% of
cases. AV dissociation may result from suppression of the dominant pacemaker with escape of a
subsidiary pacemaker or inappropriate acceleration of a ventricular pacemaker.

Arrhythmias can cause inadequate tissue perfusion, with resultant central nervous system (CNS)
and renal complications, such as the following:

 Hypoxic seizures
 Encephalopathies
 Loss of vasoregulation
 Acute tubular necrosis

Hyperkalemia is the major electrolytic complication in acute, massive digoxin poisoning. In

pediatric patients, hyperkalemia can be a complication of acute toxicity.

Etiology
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.

Acute overdose or accidental exposure to plants containing cardiac glycosides may cause acute
toxicity. Deteriorating renal function, dehydration, electrolyte disturbances, or drug interactions
usually precipitate chronic toxicity.

The most common precipitating cause of digitalis intoxication is depletion of potassium stores,
which occurs often in patients with heart failure as a result of diuretic therapy and secondary
hyperaldosteronism. Dosing errors, especially in infants receiving parenteral digoxin, is a
frequent cause of digoxin toxicity and is usually associated with high mortality.

Toxicity may also occur via increased bioavailability. Bioavailability varies depending on the
drug formulation. For example, Lanoxin has 25% less bioavailability than Lanoxicaps. Certain
antibiotics that suppress intestinal flora may increase absorption of digoxin.
Acute, nontherapeutic overdose—unintentional, suicidal, or homicidal—can cause toxicity.
Other causes of digitalis toxicity include the following:

 Advanced age
 Myocardial infarction or ischemia
 Hypothyroidism
 Hypercalcemia
 Renal insufficiency[10]
 Hyperthyroidism
 Hypoxemia
 Alkalosis
 Acidosis - Depresses the Na+/K+ ATPase pump and may cause digoxin toxicity
 Myocardial disease

Both acidosis and myocardial ischemia suppress the Na+/K+ ATPase pump. In addition,
myocardial ischemia independently alters myocardial automaticity. Hypothyroid patients are
prone to digoxin toxicity secondary to decreased renal excretion and a smaller volume of
distribution.

Electrolytes

Hypomagnesemia, hypercalcemia, hypernatremia, hyperkalemia, and hypokalemia can aggravate

toxicity.[11] Hypokalemia is usually observed with chronic toxicity or in patients taking
diuretics; it reduces the rate of Na+/K+ ATPase pump turnover and exacerbates pump inhibition
due to digitalis.

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. In
pediatric patients, hyperkalemia is usually a complication of acute toxicity rather than a cause;
however, preexisting hyperkalemia increases the risk of morbidity and mortality.

Medications

Some medications directly increase digoxin plasma levels; other medications alter renal
excretion or induce electrolyte abnormalities.[12] 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 (eg, alprazolam, diazepam) - Have been associated with isolated reports
of digoxin toxicity
 Beta-blockers (eg, 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 and 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,
and 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 - Ephedra increases the risk of cardiac stimulation; natural licorice
causes sodium and water retention and increases potassium loss

Epidemiology
Approximately 0.4% of all hospital admissions in the United States are related to digitalis
toxicity, while about 1.1% of outpatients on digoxin and 10-18% of people in nursing homes
develop this toxicity. According to a large study published in 1990, definite digoxin toxicity
occurred in 0.8% of patients with heart failure treated with digoxin.[13]

A study by See et al estimated that 5156 emergency department (ED) visits for digoxin toxicity
occurred annually in the United States between 2005 and 2010. The study, which used data from
the National Electronic Injury Surveillance System—Cooperative Adverse Drug Event
Surveillance Project, the National Ambulatory Medical Care Survey, and the National Hospital
Ambulatory Medical Care Survey, also estimated that 1% of ED visits for adverse drug events in
patients aged 40 years or older resulted from digoxin toxicity, with this figure rising to 3.3% for
patients aged 85 years or older.[14]

In 2011, the American Association of Poison Control Centers (AAPCC) reported 1,336 single
exposures to plant cardiac glycosides and 1,601 single exposures to drug cardiac glycosides.[5]

The AAPCC reported that the number of digitalis exposures was far less than that of calcium
channel blocker toxicities (5,140 cases) or beta-blocker toxicities (10,485 cases). However, the
mortality rate from digitalis toxicity was far higher, with 27 deaths reported versus 26 deaths
from calcium channel antagonists and 9 deaths attributed to beta-blocker toxicity.[5]
In the United States, hospitalizations for digitalis toxicity declined dramatically from 1991 to
2004.[15] This decline has been attributed to a number of factors, including increased awareness
of drug interactions,[12] replacement of digoxin with other drugs and procedures (eg, catheter
ablation) for the treatment of heart failure and arrhythmias, and the availability of accurate, rapid
radioimmunoassays to monitor drug levels.

Internationally, approximately 2.1% of inpatients are taking digoxin. Of all patients admitted to
the hospital, 0.3% develop digoxin toxicity.

Sexual and age-related differences in incidence

Pediatric poisonings from any substance are more common in males than in females.[6, 7]
However, for digoxin toxicity, a Netherlands study found no difference in incidence between
boys and girls.[16] The adult literature suggests that women may be more susceptible to adverse
effects than are men.[16, 17]

Advanced age (>80 y) is an independent risk factor for digitalis toxicity, being associated with
increased morbidity and mortality. Older individuals with multiple comorbid conditions have a
lower digitalis tolerance than do younger individuals with few or no comorbid conditions.

Manifestations of digitalis toxicity vary depending on age. For instance, ventricular ectopy is
most prevalent in older patients; conduction defects and supraventricular ectopic rhythms are
most prevalent in younger patients. Children (≤19 y) account for almost 80% of plant exposures
and 20% of drug toxicity/poisonings reported to the AAPCC.[7] In most of these cases, the child
was younger than 6 years. One study suggests that adolescents are more susceptible to digoxin
on a mg/kg basis.[18]

Prognosis
Prognosis in digitalis toxicity worsens with increasing age and associated comorbid conditions.
In general, older people have a worse outcome than other adults, who, in turn, have a worse
outcome than children. Morbidity and mortality rates increase if the patient has a new
dysrhythmia, advanced AV block, or other significant ECG abnormality.

The lethal dose of most glycosides is approximately 5-10 times the minimal effective dose and
only about twice the dose that leads to minor toxic manifestations. Morbidity is usually 4.6-10%;
however, morbidity is 50% if the digoxin level is greater than 6 ng/mL.

The 2011 AAPCC report had follow-up data for 471 of the 1,336 patients exposed to plant
cardiac glycosides. Outcomes in these patients were as follows: no clinical effect in 326 patients;
minor effects in 113, moderate effects in 26, major in 5, and 1 death. Outcomes in 1,134 of the
1,601 patients with digoxin poisoning were as follows: no clinical effect in 262, minor in 155,
moderate in 558, major in 132, and 27 deaths.[5]
Patient Education
Clinicians should ensure that patients taking digoxin are aware of the symptoms of digitalis
toxicity. In addition, patients should be educated about drug interactions and about maintaining
adequate hydration. Parents of pediatric patients should be educated about effective home
childproofing and preventive measures.

For patient education information, see the First Aid & Injuries Center and the Mental Health
Center, as well as Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your
Home.

Presentation
History
Most cases of pediatric digitalis poisoning are unintentional ingestions; thus, a good social
history with emphasis on available medications and the extent of home childproofing is
necessary.

In patients who have been taking digoxin, the recent addition of a new drug to their regimen
should be noted. Drugs that can elevate the digoxin level include the following:

 Verapamil
 Diltiazem
 Erythromycin
 Tetracycline
 Paroxetine

In contrast, rifampin increases digitalis metabolism by enzymatic stimulation and thereby

decreases the digoxin level.

Extracardiac symptoms

Central nervous system (CNS) symptoms of digitalis toxicity include the following:

 Drowsiness
 Lethargy
 Fatigue
  Neuralgia
 Headache
 Dizziness
 Confusion or giddiness
 Hallucinations
 Seizures (rare)
 Paresthesias and neuropathic pain

Visual aberration often is an early indication of digitalis toxicity. Yellow-green distortion is most
common, but red, brown, blue, and white distortions also occur. Drug intoxication also may
cause the following:

 Snowy vision
 Photophobia
 Photopsia
 Decreased visual acuity
 Yellow halos around lights (xanthopsia)
 Transient amblyopia or scotomata

Gastrointestinal (GI) symptoms in acute or chronic toxicity include the following:

 Anorexia
 Weight loss
 Failure to thrive (in pediatric patients)
 Nausea
 Vomiting
 Abdominal pain
 Diarrhea
 Mesenteric ischemia (a rare complication of rapid IV infusion)

Cardiac symptoms

Cardiac symptoms include the following:

 Palpitations
 Shortness of breath
 Syncope
 Swelling of lower extremities
 Bradycardia
 Hypotension
 Dyspnea

Physical Examination
Patients can have an asymptomatic period of from several minutes to several hours after the oral
ingestion of a single toxic dose. Clinical signs may be subtle or obvious, depending on the
severity of toxicity. Acute toxicity is rarely subtle, whereas chronic toxicity may be difficult to
diagnose. Nausea, vomiting, and drowsiness are among the most common extracardiac
manifestations. Visual changes usually affect patients with chronic toxicity. Emphasis should be
placed on the vital signs and the neurologic and cardiovascular findings.

The patient's mentation may change according to the severity of digoxin toxicity, as well as
associated comorbid conditions. Although the patient may note visual changes, the pupils are
spared and objective findings are few. Drug-induced fever does not occur.

The pulse may be irregular if the patient has atrial fibrillation or arrhythmia arising from the
digoxin toxicity itself. Hypotension may be observed if the patient has chronic heart failure or
dehydration secondary to decreased oral intake. Neck findings include increased jugular venous
pressure.

Hemodynamic instability is related directly to the presence of a dysrhythmia or to acute

exacerbation of chronic heart failure (CHF). Associated cardiomegaly may be identified.
Cardiovascular findings on physical examination relate to the severity of CHF, dysrhythmias, or
hemodynamic instability.

The respiratory rate is sometimes increased. Basal crepitations are associated with CHF.
Although GI symptoms are common, the abdominal examination is usually nonspecific. An
enlarged liver secondary to CHF (ie, hepatic congestion) may be palpated. Hepatojugular reflux
is present. Pedal edema is noted if the patient has renal failure or decompensated CHF.

Neurologic findings are related to changes in sensorium or mental status. Lateralizing findings
usually indicate another disease process.

DDx
Diagnostic Considerations
Conditions to consider in the differential diagnosis of digitalis toxicity include the following:

 Sepsis
 Gastroenteritis
 Aseptic meningitis
 Sinus node dysfunction
 Organophosphate toxicity
 Heart failure
 Ventricular tachycardia
  Arrhythmias
 Syncope
 Cardiotoxic plant ingestion
 Class Ia cardiac drug toxicity
 Clonidine toxicity
 Dehydration
 Hypomagnesemia
 First-degree heart block
 Second-degree heart block
 Third-degree heart block

Differentials

Acute Kidney Injury

Beta-blocker toxicity

Calcium channel blocker toxicity

Hypercalcemia

Hyperkalemia

Hypernatremia

Hypoglycemia

Hypokalemia

Hyponatremia

Workup

Workup
Approach Considerations
Studies in patients with possible digitalis toxicity include the following:

 Serum digoxin level

 Electrolytes
 Renal function studies
  Electrocardiogram (ECG)

The serum digoxin level can be used as a guide to the appropriate dosing of medication and to
monitor compliance, and can be used to assess toxicity. However, 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
sodium-potassium adenosine triphosphatase (Na+/K+ ATP ase) pump.[15, 19]

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.

The usual therapeutic range for digoxin is 0.5-2 ng/mL. Serum concentrations associated with
toxicity overlap between therapeutic and toxic ranges because of the myriad of factors
potentiating digoxin toxicity.

False-negative assay results may occur in the setting of acute ingestion of plants containing
nondigoxin cardiac glycosides, such foxglove and oleander, even in the setting of profound
clinical toxicity. This is caused by nonreactivity or minimal cross-reactivity with the digoxin
radioimmunoassay.

Blood levels of the following should be measured:

 Sodium
 Potassium
 Chloride
 Carbon dioxide
 Magnesium
 Calcium
 Blood urea nitrogen (BUN)
 Creatinine

If myocardial infarction is a clinical concern, also obtain cardiac markers such as creatine kinase,
muscle-bone fraction (CK-MB) or troponin I or T.

Initial potassium levels correlate better with the prognosis than either ECG changes or the initial
serum digoxin level. Survival is diminished in patients with hyperkalemia, particularly those
with potassium levels greater than 5.5 mg/dL.[20]

Digoxin levels

The development of sensitive and accurate radioimmunoassays has improved the diagnosis and
management of digitalis toxicity. Therapeutic digoxin levels vary between laboratories: the lower
limit ranges from 0.6-1.3 ng/mL, while the upper limit generally is agreed to be 2.6 ng/mL (see
Digoxin level). In chronic toxicity, plasma drug levels are greater than 6 ng/mL.
However, there is significant overlap in levels between patients with toxicity and those without
toxicity. Toxicity is related to intracellular levels, not serum levels. Consequently, serum digoxin
levels cannot be used as the sole indicator of toxicity, especially after acute ingestion.

Neonates and small infants rarely develop toxic symptoms or ECG abnormalities with serum
levels of less than 4-5 ng/mL. Children without cardiovascular disease may tolerate levels as
high as 10 ng/mL without serious toxicity, but they may have bradyarrhythmias or conduction
delays on ECG. The general rule is that the smaller the infant, the higher the levels may be
before toxic effects are observed.

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 do not necessarily predict 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. Digoxin levels do not equilibrate quickly because of
variable absorption and subsequent tissue distribution.

In acute toxicity, repeat the digoxin level after 2-4 hours to guide therapy. The 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.

Digoxinlike immunoreactive substance

Endogenous digoxinlike immunoreactive substance (DLIS) can cause a false-positive result or

false elevation on digoxin assays. DLIS is observed in neonates and in patients with any of the
following:

 Renal insufficiency
 Liver disease or hyperbilirubinemia
 Subarachnoid hemorrhage
 Chronic heart failure
 Diabetes mellitus
 Acromegaly
 Pregnant

In some studies, premature infants have had levels as high as 4 ng/mL, with peaks at age 6 days,
and positive assay results until they reached 3 months of age. 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. Some laboratories use ultrafiltration
techniques to eliminate the contribution of DLIS.

Other confounding variables

While most patients metabolize less than 20% of digoxin, 10% of the population metabolizes as
much as 55% of digoxin to initially active metabolites. Not all the radioimmunoassays in routine
use measure each of these metabolites. Additionally, the antibodies used in a digoxin
immunoassay can cross-react with numerous compounds, including steroids and spironolactone.
Because most digoxin assays measure total rather than free digoxin levels, serum digoxin levels
are no longer useful after Fab fragment administration.

Electrolyte Evaluation
In acute toxicity, hyperkalemia is common owing to inactivation of the Na+/K+ -ATPase pump.
Initial potassium levels correlate better with the prognosis than either ECG changes or the initial
serum digoxin level. In one series, all patients with an initial potassium level greater than 5.5
mg/dL died, whereas 50% of patients with a serum digoxin level of 5-5.5 mg/dL died.[20]

In contrast, long-term digoxin users often develop hypokalemia because of concurrent diuretic
use. The condition should be corrected promptly, as treating hypokalemia may help to improve
cardiac glycoside-related arrhythmia.

Long-term digoxin users also often have hypomagnesemia secondary to diuretic usage. These
patients may have intracellular magnesium depletion despite a normal serum magnesium level.
Importantly, magnesium is a cofactor of the Na+/K+ -ATPase pump, and alterations of its
concentration will affect the pump's actions.

Electrocardiography
Digoxin toxicity may cause almost any dysrhythmia. Classically, dysrhythmias associated with
increased automaticity and decreased atrioventricular (AV) conduction occur (ie, paroxysmal
atrial tachycardia with 2:1 block, accelerated junctional rhythm, or bidirectional ventricular
tachycardia [torsade de pointes]; see the images below) Sinus bradycardia and AV conduction
blocks are the most common ECG changes in the pediatric population, while ventricular ectopy
is more common in adults.[11]
 Bidirectional tachycardia in a patient
with digitalis toxicity.

Bidirectional tachycardia in a patient

with digitalis toxicity.

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-, second-, and third-degree heart block and complete AV dissociation
are also very common, while rapid atrial fibrillation and atrial flutter are rare.

Ventricular tachycardia is an especially serious finding. Cardiac arrest from asystole or

ventricular fibrillation is usually fatal.

Nonparoxysmal atrial tachycardia with heart block and bidirectional ventricular tachycardia are
particularly characteristic of severe digitalis toxicity.

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
Nonspecific ECG findings include the following:

 Premature ventricular contractions, especially bigeminal and multiform

 First-, second- (Wenckebach), and third-degree AV block
 Sinus bradycardia
 Sinus tachycardia
 Sinoatrial block or arrest
 Atrial fibrillation with slower ventricular response
 Atrial tachycardia
 Junctional (escape) rhythm
 AV dissociation
 Ventricular bigeminy and trigeminy
 Ventricular tachycardia
 Torsade de pointes
 Ventricular fibrillation

More specific, but not pathognomonic, ECG findings include the following:

 Atrial fibrillation with a slow, regular ventricular rate (ie, AV dissociation)

 Nonparoxysmal junctional tachycardia (rate 70-130 beats per minute [bpm])
 Atrial tachycardia with block (atrial rate usually 150-200 bpm)
 Bidirectional ventricular tachycardia

Treatment
Approach Considerations
The clinical manifestations digoxin toxicity are the same in infants, children, and adults, and the
treatment is the same across all these age groups.[21] Treatment of digoxin toxicity should be
guided by the patient’s signs and symptoms and the specific toxic effects and not necessarily by
digoxin levels alone. Therapeutic options range from simply discontinuing digoxin therapy for
stable patients with chronic toxicity to digoxin Fab fragments, cardiac pacing, antiarrhythmic
drugs, magnesium, and hemodialysis for severe acute toxicity.

For prehospital care, administration of oxygen, cardiac monitoring, establishment of intravenous

(IV) access, and transport are usually the only requirements. Atropine is indicated for
hemodynamically unstable bradyarrhythmic patients; lidocaine is indicated for ventricular
tachycardia.

Supportive care of digitalis toxicity includes hydration with IV fluids, oxygenation and support
of ventilatory function, discontinuation of the drug, and, sometimes, the correction of electrolyte
imbalances. Effective management also relies on early recognition that a dysrhythmia and/or
noncardiac manifestation may be related to digitalis intoxication.

General principles of management include the following:

 Assessment of the severity of the toxicity and its etiology (eg, accidental ingestion,
unintentional or deliberate overdose, altered digoxin metabolism due to diminished renal
clearance or interaction with other drugs)
 Consideration of factors that influence treatment, including age, medical history,
chronicity of digoxin intoxication, existing heart disease and/or renal insufficiency, and
ECG changes
 Continuous hemodynamic assessment, including 12-lead electrocardiogram (ECG) and
cardiac monitoring
 Prompt measurement of electrolyte levels, including potassium and calcium, and of
serum creatinine and digoxin levels[22]
 Intensive care unit admission

Activated charcoal is indicated for acute overdose or accidental ingestion. Binding resins (eg,
cholestyramine) may bind enterohepatically-recycled digoxin and digitoxin, although no
outcome studies have been performed. Binding resins may be more appropriately used for
treatment of chronic toxicity in patients with renal insufficiency. Digoxin immune Fab is
extremely effective in the treatment of severe, acute digitalis toxicity.

GI Decontamination and Enhanced Elimination

The first-line treatment for acute ingestion is repeated dosing of activated charcoal to reduce
absorption and interrupt enterohepatic circulation. Activated charcoal is most effective if given
within 6-8 hours after the ingestion.

To break enterohepatic circulation, use binding resins, such as cholestyramine and colestipol.
Cholestyramine probably is more appropriate for use in treatment of chronic toxicity in patients
with renal insufficiency.

Other points to consider include the following:

 Induced emesis with ipecac syrup is not recommended, because of the increased vagal
effect
 Whole-bowel irrigation may be useful, but clinical data are lacking
 Forced diuresis is not recommended, because it has not been shown to increase renal
excretion and can worsen electrolyte abnormalities
 Dialysis has been shown to produce only small additional clearance
Gastric lavage increases vagal tone and may precipitate or worsen arrhythmias. Consider
pretreatment with atropine if gastric lavage is performed. Treatment with digitalis Fab antibody
usually renders gastric lavage unnecessary.

Treatment of Electrolyte Imbalance

Correct hyperkalemia, hypokalemia, and hypomagnesemia. Correction of electrolyte imbalances
may reverse dysrhythmias.

Potassium abnormalities

Treat hyperkalemia by using sodium bicarbonate to correct metabolic acidosis and insulin plus
glucose to enhance potassium uptake by cells. Treatment with digoxin Fab fragments is indicated
for hyperkalemia with a potassium level greater than 5 mEq/L, and may obviate other forms of
treatment. In patients with uncontrolled hyperkalemia, however, instituting hemodialysis may be
necessary.

Binding resins (eg, sodium polystyrene sulfonate, 0.5 g/kg orally) also are helpful in binding
potassium and enterohepatically recycled digitalis. However, digoxin-induced hyperkalemia
reflects an extracellular shift, not an increase in total body potassium. In addition, caution is
indicated when using binding resins concurrently with insulin/glucose/bicarbonate or digitalis
Fab fragments, as the combination may precipitate hypokalemia, which may worsen clinical
toxicity.

Although calcium is often used to ameliorate cardiac toxicity from hyperkalemia, it is not
recommended in patients with digoxin toxicity because it can delay after-depolarization and may
precipitate ventricular tachycardia or fibrillation. This is based on the fact that intracellular
calcium levels are already high in this setting. Anecdotal case reports and animal studies have
been published that refute the dangers of calcium administration, but other measures should be
preferentially used to treat hyperkalemia unless the patient is in extremis.

Hypokalemia increases digoxin cardiac sensitivity and should be corrected. Use caution when
administering potassium to patients with renal insufficiency.

Concomitant hypomagnesemia may result in refractory hypokalemia. Hypomagnesemia

increases myocardial digoxin uptake and decreases cellular Na+/K+ -ATPase activity. Patients
with hypomagnesemia, hypokalemia, or both may become cardiotoxic at therapeutic digitalis
levels.

Magnesium may also serve as a temporizing antiarrhythmic agent until Fab fragments are
available. It may be life-saving in patients with ventricular tachycardia or ventricular fibrillation.
Aside from successful replacement of intracellular magnesium, it also may act as an indirect
antagonist of digoxin at the supraphysiologic level.
Digoxin Immune Therapy
Digoxin immune Fab (Digibind) is an immunoglobulin fragment that binds with digoxin. It is
currently considered first-line treatment for significant dysrhythmias (eg, severe
bradyarrhythmia, second- or third-degree heart block, ventricular tachycardia or fibrillation)
from digitalis toxicity. This agent should be promptly administered if digoxin toxicity is
suspected as the cause of such arrhythmias.[18, 23, 24]

Other indications for immunotherapy with digoxin Fab fragment include the following:

 Ingestion of massive quantities of digitalis (in children, 4 mg or 0.1 mg/kg; in adults, 10

mg)
 Serum digoxin level greater than 10 ng/mL in adults at steady state (ie, 6-8 hours after
acute ingestion or at baseline in chronic toxicity)
 Hyperkalemia (serum potassium level greater than 5 mEq/L)
 Altered mental status attributed to digoxin toxicity
 Rapidly progressive signs and symptoms of toxicity

In a retrospective study, Hauptman et al used the Premier Perspective Comparative Hospital

Database (Premier Inc., Charlotte, North Carolina) to identify patients who were diagnosed with
digoxin toxicity and/or who received digoxin immune fab (DIF) over a 5-year period (2007 to
2011). One-fifth of cases received DIF treatment, most within 2 days of hospitalization.
Predictors of DIF treatment were urgent/emergent admission, hyperkalemia, arrhythmia
associated with digoxin toxicity, acute renal failure, and suicidal intent.[25]

Digoxin immune Fab is packaged in a 40-mg vial and must be reconstituted with 4 mL of sterile
water for IV injection, furnishing an iso-osmotic solution. For small infants, this preparation can
be diluted further with sterile isotonic saline. Once the product is reconstituted, it should be used
immediately or, if refrigerated, used within 4 hours. It is administered IV over 30 minutes via a
0.22-μm membrane filter. In an unstable clinical situation, this agent is administered by IV bolus.

A loading dose of Fab followed by a maintenance infusion is beneficial to the optimization of

binding to Fab. The loading dose immediately captures digoxin already in the vascular space,
and the maintenance dose provides enough Fab to continue to draw digoxin from the tissue into
the serum to be bound. In acute, intentional overdose, administration of 4-6 vials as a loading
dose, followed by 0.5 mg/min for 8 hours and then 0.1 mg/min for about 6 hours, appears to be
safe and effective.

Recent data provide evidence that for cases of digoxin poisoning, current methods for calculating
the dose of anti-digoxin Fab overstate the dose required. In addition, data suggest that in patients
with chronic digoxin poisoning, the efficacy of anti-digoxin Fab may be minimal.[26]
Initially administering half doses is the best approach 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 doses may be
administered later.

A response is typically observed within 20-30 minutes after infusion. The elimination half-life of
the drug-antibody complex is about 16 hours (range, 20-30 h). Affinity for digitoxin is 10 times
less than for digoxin. In a case series that included pediatric patients, there was a 90-93%
response rate within minutes or hours, with complete resolution within 180 minutes in as many
as 79% of patients. The mean time to the initial response was 19 minutes; complete resolution of
symptoms occurred in 88 minutes.

Digoxin levels drawn after administration of Fab fragments may be exponentially higher because
many assays for measuring digoxin measure total digoxin (including digoxin bound to Fab
fragments). This may be misinterpreted as a therapeutic failure and worsening toxicity.
Conventional digoxin assays remain unreliable for 1-2 weeks after the therapy. Assays that
measure only free digoxin are accurate and should reflect true posttreatment levels, but these
assays are not available at most hospitals.

Complications

In a long-term digoxin user who requires Fab treatment for digitalis toxicity, administration can
precipitate worsening heart failure by removing the beneficial inotropic activity of digoxin,
causing hypokalemia and atrial arrhythmia with rapid ventricular response.

Hypokalemia has occurred in patients who were treated with standard therapy, as well as with
Fab fragments. Clinically adverse phenomena have occurred in fewer than 10% of patients
treated with immunotherapy.

Other untoward effects of Fab include anaphylaxis and serum sickness, because it is a sheep
protein; these reactions are uncommon. Allergy to Fab fragments tends to occur in patients who
have multiple allergies.

The elimination half-life of the digoxin-Fab complex is 20-30 hours, although clearance is
related directly to the glomerular filtration rate and consequently is prolonged in renal
insufficiency. Recrudescence of digoxin toxicity is possible within 7-14 days, because the Fab
complex is eliminated more rapidly than digoxin is released from tissue-binding sites.
Plasmapheresis may be performed or the agent readministered in such situations.

Management of Dysrhythmias
Management of dysrhythmias varies, depending on the following factors:
  Presence or absence of hemodynamic instability
 Nature of the dysrhythmia
 Presence or absence of electrolyte disturbances
 Preferences of toxicology and/or cardiology consultants

In hemodynamically stable patients, bradyarrhythmias and supraventricular arrhythmias may be

treated with observation and supportive care. Discontinue the drug and ensure proper hydration
to optimize renal clearance of excess drug. Gastrointestinal (GI) binding agents (eg, activated
charcoal, cholestyramine) may be used to bind enterohepatically recycled digitalis. For patients
with rate-related ischemia or hemodynamic instability, digoxin Fab fragments is the treatment of
choice.

Short-acting beta blockers (eg, esmolol) may be helpful for supraventricular tachyarrhythmias
with rapid ventricular rates, but these agents may precipitate advanced or complete
atrioventricular (AV) block in patients with sinoatrial or AV node depression. Calcium channel
blockers are contraindicated because they may increase digoxin levels.

Premature ventricular contractions (PVCs), bigeminy, or trigeminy may require only observation
unless the patient is hemodynamically unstable, in which case lidocaine may be effective.
Ventricular tachycardia responds best to digoxin immune therapy, but phenytoin and lidocaine
are useful if immune therapy is ineffective or unavailable.[27] These drugs depress the enhanced
ventricular automaticity without significantly slowing AV conduction; indeed, 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 this 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.

Atropine may be useful in blocking digoxin-induced effects of enhanced vagal tone on the
sinoatrial (SA) and AV nodes. It has proved helpful in reversing severe sinus bradycardia.

Magnesium sulfate, 2 g IV over 5 minutes, has been shown to terminate dysrhythmias in

digoxin-toxic patients with and without overt cardiac disease. After the initial bolus, 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. Serial monitoring of serum
magnesium levels, telemetry, respiratory rate, deep tendon reflexes, and blood pressure is
appropriate.
Magnesium is contraindicated in the setting of bradycardia or AV block and should be used
cautiously in patients with renal failure. It is unclear how well magnesium levels correlate with
digitalis toxicity.[27]

Asystole and ventricular fibrillation are very ominous findings. Digoxin immune therapy is
indicated in such cases; however, its effect is limited by poor cardiac blood flow. Nevertheless,
the use of immune therapy has been associated with a 50% survival rate in isolated case reports.

Quinidine and procainamide are contraindicated. These agents worsen SA, AV, and His-Purkinje
conductivity. Additionally, quinidine reduces digoxin tissue binding and renal clearance, thereby
increasing digoxin levels. Bretylium, which is no longer available in the United States, is also
contraindicated, as it can precipitate ventricular dysrhythmia.[27]

Electrical cardioversion and pacing

Cardioversion for severe dysrhythmias due to digitalis is hazardous; it can precipitate ventricular
fibrillation and asystole. However, if the patient is hemodynamically unstable and has a wide,
complex tachycardia and if fascicular tachycardia has been ruled out, cardioversion will need to
be used early.

If the history is consistent with digitalis intoxication, a minimal effective dose is best. Some
clinicians have suggested using 10-25 joules initially in ventricular tachycardia or fibrillation,
but most clinicians suggest starting at 50-100 joules for a wide, complex ventricular tachycardia,
rather than at the 200 joules recommended in ACLS protocols.

With the availability of digoxin-specific Fab, pacemaker use now has limited value. In one study,
the main reason for Fab failure was pacing-induced arrhythmias and delayed or insufficient
administration of Fab. This study also demonstrated a 36% complication rate with pacing.

Hospital Admission
Admission criteria include the following:

 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. Intensive care unit (ICU)
admission criteria include the following:

 Hemodynamic instability
 Refractory dysrhythmias
 Hyperkalemia
 Renal failure

Admit patients receiving digoxin immune Fab to the ICU or critical care unit (CCU). Any patient
receiving Fab fragments requires observation in an intensive care setting for at least 24 hours.

Patients who have had an unintentional exposure but exhibit no signs or symptoms of toxicity
after 12 hours can be discharged from the hospital.

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

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.

Consultations
The following consultations may be employed:

 Cardiologists
 Nephrologists
 Regional poison control centers
 Medical toxicologists
Long-Term Monitoring
Patients with accidental exposure and no sign of toxicity after 12 hours can be discharged home
with appropriate follow-up. Observe patients for at least 6 hours on a cardiac monitor. 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. Patients who have taken an intentional overdose should
be cleared by a psychiatry consult before discharge.

Medication
Medication Summary
The goals of pharmacotherapy are to reduce toxic levels of digitalis, prevent complications, and
reduce morbidity. Activated charcoal and binding resins can reduce gastrointestinal absorption of
ingested digoxin and bind enterohepatically cycling digitalis.

Immunotherapy with digoxin Fab fragments has been an extremely valuable addition to the
treatment of digoxin and digitoxin intoxication. In hemodynamically stable or unstable patients,
it is a first-line therapy. Antidysrhythmic agents may be indicated in hemodynamically unstable
patients.

Antidotes, Other
Class Summary
Activated charcoal is useful in limiting the absorption of ingested digoxin. It is most beneficial if
administered within 4 hours of ingestion. Cholestyramine resin 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.
Digoxin immune Fab is used for the treatment of hemodynamic instability, refractory
dysrhythmias, and severe or refractory hyperkalemia. This agent has reversed noncardiac
digitalis-associated complications (eg, thrombocytopenia).[28, 29]

Digoxin immune Fab (DigiFab)

Digoxin immune Fab is an immunoglobulin fragment with specific and high affinity for digoxin
and digitoxin molecules. A 50,000-Da molecule, Fab is derived from the IgG fragment of sheep
antidigoxin antibodies produced in response to antigenic carrier proteins coupled to digoxin. This
relatively pure Fab product is safe and extremely effective. It removes digoxin or digitoxin
molecules from tissue-binding sites. Each vial contains 40 mg of purified digoxin-specific
antibody fragments, which will bind approximately 0.6 mg of digoxin or digitoxin.

The advantages of digoxin-specific Fab compared with whole IgG antibodies include larger
volume of distribution and more rapid onset of action. Onset of action ranges from 20-90
minutes, and digoxin is removed irreversibly from the myocardium and other specific binding
sites. A complete response generally occurs within 4 hours.

Immediately following IV administration, digoxin-specific antibodies bind intravascular free

digoxin. They then diffuse into the interstitial space, binding free digoxin there. A concentration
gradient is established, which facilitates movement of intracellular digoxin and digoxin that is
dissociated from its binding sites (external surface of Na+/K+-ATPase enzyme) in the heart into
interstitial or intravascular spaces.

Intravascular concentration of inactive, antibody-bound digoxin rises substantially. The

elimination kinetics of Fab antibody–bound digoxin depend on the patient's renal function and
capacity for urinary elimination.

Fab binds free digoxin in vascular and interstitial space and decreases free plasma digoxin levels
by binding intracellular digoxin from its binding sites in the heart and in interstitial and
intravascular spaces. Fab raises intravascular levels of inactive antibody-bound digoxin to very
high levels, which decrease over several days as it is excreted renally.

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

Activated charcoal (Kerr Insta-Char, Actidose-Aqua, EZ-

Char)
Activated charcoal prevents absorption by adsorbing drug in the intestine. A network of pores
present in activated charcoal absorbs 100-1000 mg of drug per gram of charcoal. Multidose
charcoal may interrupt enterohepatic recirculation and enhance elimination by enterocapillary
exsorption.
Theoretically, by constantly bathing the GI tract with charcoal, the intestinal lumen serves as a
dialysis membrane for the reverse absorption of drug from the intestinal villous capillary blood
into the intestine. The charcoal is supplied as an aqueous mixture or in combination with a
cathartic (usually sorbitol 70%). It does not dissolve in water. For maximum effect, administer
the charcoal within 30 minutes of poison ingestion.

Cholestyramine (Questran, Prevalite)

Cholestyramine forms a nonabsorbable complex with bile acids in the intestine, which, in turn,
inhibits enterohepatic reuptake of intestinal bile salts. It has been shown to decrease digoxin
levels following therapeutic dosing and acute or chronic digitalis toxicity. However, this agent
may not change the ultimate outcome, because a prolonged administration time is necessary.

Anticholinergic Agents
Class Summary
These agents may improve sinus and atrioventricular (AV) node conduction by inhibiting vagal
activity. They are used as an alternative to digoxin immune Fab.

Atropine IV/IM (AtroPen)

Atropine increases the heart rate through vagolytic effects, causing an increase in cardiac output.

Anticonvulsants, Hydantoins
Class Summary
Phenytoin may reverse digitalis-induced prolongation of the action potential in myocardial cells
and may suppress digitalis-induced tachydysrhythmias.

Phenytoin (Dilantin, Phenytek)

Phenytoin prolongs effective refractory period and depresses spontaneous depolarization in
ventricular tissues.
Local Anesthetics, Amides
Class Summary
Class Ib antidysrhythmics 1b increase electrical stimulation threshold of ventricle by suppressing
automaticity of conduction.

Lidocaine (Xylocaine-Cardiac)
Lidocaine is a class IB antiarrhythmic that increases the electrical stimulation threshold of the
ventricle, suppressing the automaticity of conduction through the tissue. It combines with fast
sodium channels and thereby inhibits recovery after repolarization, resulting in decreased
myocardial excitability and conduction velocity.

Electrolyte Supplements, Parenteral

Class Summary
Magnesium is useful as a temporizing antiarrhythmic agent until digoxin Fab fragments are
available. It may be a lifesaving adjunct in the treatment of digoxin-induced ventricular
tachycardia or ventricular fibrillation.

Magnesium sulfate (MgSO4)

Magnesium sulfate possesses antidysrhythmic properties that are beneficial in treatment of
digoxin toxicity. It slows the rate of sinoatrial node impulse formation and prolongs conduction
time.

Contributor Information and Disclosures

Author

Vinod Patel, MD Medical Director, Jefferson Family Medicine Center; Clinical Associate
Professor, Department of Family Medicine, University of Buffalo, State University of New York
School of Medicine and Biomedical Sciences

Vinod Patel, MD is a member of the following medical societies: American Academy of Family
Physicians, American Medical Association, North American Primary Care Research Group

Disclosure: Nothing to disclose.

Coauthor(s)

Paul Arthur James, MD Professor and Head, Department of Family Medicine, Donald J and
Anna M Ottilie Endowed Chair in Family Medicine, University of Iowa, Roy J and Lucille A
Carver College of Medicine

Paul Arthur James, MD is a member of the following medical societies: American Academy of
Family Physicians, American Medical Association, North American Primary Care Research
Group, Phi Beta Kappa, Society of Teachers of Family Medicine

Disclosure: Nothing to disclose.

Chief Editor

Jeffrey N Rottman, MD Professor of Medicine, Department of Medicine, Division of

Cardiovascular Medicine, University of Maryland School of Medicine;
Cardiologist/Electrophysiologist, University of Maryland Medical System and VA Maryland
Health Care System

Jeffrey N Rottman, MD is a member of the following medical societies: American Heart

Association, Heart Rhythm Society

Disclosure: Nothing to disclose.

Acknowledgements

John G Benitez, MD, MPH Associate Professor, Department of Medicine, Medical Toxicology,
Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center

John G Benitez, MD, MPH is a member of the following medical societies: American Academy
of Clinical Toxicology, 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.

Megan Boysen, MD Resident Physician, Department of Emergency Medicine, University of

California Irvine Medical Center
Megan Boysen, MD, is a member of the following medical societies: American Academy of
Emergency Medicine, American College of Emergency Physicians, and Society for Academic
Emergency Medicine

Disclosure: Nothing to disclose.

Timothy E Corden, MD Associate Professor of Pediatrics, Co-Director, Policy Core, Injury

Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital
of Wisconsin

Timothy E Corden, MD is a member of the following medical societies: American Academy of

Pediatrics, Phi Beta Kappa, Society of Critical Care Medicine, and Wisconsin Medical Society

Disclosure: Nothing to disclose.

Lance W Kreplick, MD, FAAEM, MMM 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, FAAEM, MMM, is a member of the following medical societies:
American Academy of Emergency Medicine and American College of Physician Executives

Disclosure: Nothing to disclose.

Kenneth T Kwon, MD Director of Pediatric Emergency Medicine, Associate Clinical Professor,

Department of Emergency Medicine, University of California at Irvine Medical Center, Co-
Director, Pediatric Emergency Services, Mission Regional Medical Center/Children's Hospital of
Orange County at Mission

Kenneth T Kwon, MD is a member of the following medical societies: American Academy of

Emergency Medicine, American Academy of Pediatrics, American College of Emergency
Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Ronald J Oudiz, MD, FACP, FACC, FCCP Professor of Medicine, University of California, Los
Angeles, David Geffen School of Medicine; Director, Liu Center for Pulmonary Hypertension,
Division of Cardiology, LA Biomedical Research Institute at Harbor-UCLA Medical Center

Ronald J Oudiz, MD, FACP, FACC, FCCP is a member of the following medical societies:
American College of Cardiology, American College of Chest Physicians, American College of
Physicians, American Heart Association, and American Thoracic Society

Disclosure: Actelion Grant/research funds Clinical Trials + honoraria; Encysive Grant/research

funds Clinical Trials + honoraria; Gilead Grant/research funds Clinical Trials + honoraria; Pfizer
Grant/research funds Clinical Trials + honoraria; United Therapeutics Grant/research funds
Clinical Trials + honoraria; Lilly Grant/research funds Clinical Trials + honoraria; LungRx
Clinical Trials + honoraria; Bayer Grant/research funds Consulting

Justin D Pearlman, MD, PhD, ME, MA Director of Advanced Cardiovascular Imaging, Professor
of Medicine, Professor of Radiology, Adjunct Professor, Thayer Bioengineering and Computer
Science, Dartmouth-Hitchcock Medical Center

Justin D Pearlman, MD, PhD, ME, MA is a member of the following medical societies:
American College of Cardiology, American College of Physicians, American Federation for
Medical Research, International Society for Magnetic Resonance in Medicine, and Radiological
Society of North America

Disclosure: Nothing to disclose.

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: Nothing to disclose.

Thomas P Smith, Jr, MD Clinical Assistant Professor, Department of Medicine, Division of

Cardiology, State University of New York at Buffalo; Associate Regional Medical Director,
Merck & Co, Inc

Thomas P Smith, Jr, MD is a member of the following medical societies: American College of
Cardiology, American College of Physicians, and American Heart Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical
Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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.

Jeffrey R Tucker, MD Assistant Professor, Department of Pediatrics, Division of Emergency

Medicine, University of Connecticut and Connecticut Children's Medical Center
Disclosure: Merck Salary Employment

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and 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.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center
College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

References

1. Gheorghiade M, van Veldhuisen DJ, Colucci WS. Contemporary use of digoxin in the
management of cardiovascular disorders. Circulation. 2006 May 30. 113(21):2556-64.
[Medline].
2. Ali KM. Collateral effects of antiarrhythmics in pediatric age. Curr Pharm Des. 2008.
14(8):782-7. [Medline].
3. Ahmed A, Waagstein F, Pitt B, et al. Effectiveness of digoxin in reducing one-year
mortality in chronic heart failure in the Digitalis Investigation Group trial. Am J Cardiol.
2009 Jan 1. 103(1):82-7. [Medline]. [Full Text].
4. The Internet Drug Reference Top 300 Prescriptions for 2005. RxList. Available at
http://www.rxlist.com/script/main/art.asp?articlekey=79509. Accessed: March 4, 2010.
5. Bronstein AC, Spyker DA, Cantilena LR Jr, Rumack BH, Dart RC. 2011 Annual Report
of the American Association of Poison Control Centers' National Poison Data System
(NPDS): 29th Annual Report. Clin Toxicol (Phila). 2012 Dec. 50(10):911-1164.
[Medline].
6. Litovitz TL, Klein-Schwartz W, White S, et al. 1999 Annual Report of the American
Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg
Med. 2000 Sep. 18(5):517-74. [Medline].
7. Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Giffin SL. 2008
Annual Report of the American Association of Poison Control Centers' National Poison
Data System (NPDS): 26th Annual Report. Clin Toxicol (Phila). 2009 Dec. 47(10):911-
1084. [Medline].
8. Eisner DA, Kashimura T, Venetucci LA, Trafford AW. From the ryanodine receptor to
cardiac arrhythmias. Circ J. 2009 Sep. 73(9):1561-7. [Medline]. [Full Text].
9. Koren G, Parker R. Interpretation of excessive serum concentrations of digoxin in
children. Am J Cardiol. 1985 Apr 15. 55(9):1210-4. [Medline].
10. Cepeda Piorno J, Pobes Martinez de Salinas A, Gonzalez Garcia ME, Fernandez
Rodriguez E. [Use of MDRD equation to detect occult renal failure and reduce the risk of
digitalis overdose]. Nefrologia. 2009. 29(2):150-5. [Medline]. [Full Text].
11. Thacker D, Sharma J. Digoxin toxicity. Clin Pediatr (Phila). 2007 Apr. 46(3):276-9.
[Medline].
12. Chan AL, Wang MT, Su CY, Tsai FH. Risk of digoxin intoxication caused by
clarithromycin-digoxin interactions in heart failure patients: a population-based study.
Eur J Clin Pharmacol. 2009 Dec. 65(12):1237-43. [Medline].
13. Mahdyoon H, Battilana G, Rosman H, Goldstein S, Gheorghiade M. 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].
14. See I, Shehab N, Kegler SR, Laskar SR, Budnitz DS. Emergency department visits and
hospitalizations for digoxin toxicity: United States, 2005 to 2010. Circ Heart Fail. 2014
Jan. 7(1):28-34. [Medline]. [Full Text].
15. Haynes K, Heitjan D, Kanetsky P, Hennessy S. Declining public health burden of digoxin
toxicity from 1991 to 2004. Clin Pharmacol Ther. 2008 Jul. 84(1):90-4. [Medline].
16. Aarnoudse AL, Dieleman JP, Stricker BH. Age- and gender-specific incidence of
hospitalisation for digoxin intoxication. Drug Saf. 2007. 30(5):431-6. [Medline].
17. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for
the treatment of heart failure. N Engl J Med. 2002 Oct 31. 347(18):1403-11. [Medline].
18. Woolf AD, Wenger T, Smith TW, Lovejoy FH Jr. The use of digoxin-specific Fab
fragments for severe digitalis intoxication in children. N Engl J Med. 1992 Jun 25.
326(26):1739-44. [Medline].
19. Yang EH, Shah S, Criley JM. Digitalis toxicity: a fading but crucial complication to
recognize. Am J Med. 2012 Apr. 125(4):337-43. [Medline].
20. Bismuth C, Gaultier M, Conso F, Efthymiou ML. Hyperkalemia in acute digitalis
poisoning: prognostic significance and therapeutic implications. Clin Toxicol. 1973.
6(2):153-62. [Medline].
21. 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].
22. Kirrane BM, Olmedo RE, Nelson LS, Mercurio-Zappala M, Howland MA, Hoffman RS.
Inconsistent approach to the treatment of chronic digoxin toxicity in the United States.
Hum Exp Toxicol. 2009 May. 28(5):285-92. [Medline].
23. Smith TW, Butler VP Jr, Haber E, et al. Treatment of life-threatening digitalis
intoxication with digoxin-specific Fab antibody fragments: experience in 26 cases. N
Engl J Med. 1982 Nov 25. 307(22):1357-62. [Medline].
24. Zucker AR, Lacina SJ, DasGupta DS, et al. Fab fragments of digoxin-specific antibodies
used to reverse ventricular fibrillation induced by digoxin ingestion in a child. Pediatrics.
1982 Sep. 70(3):468-71. [Medline].
25. Hauptman PJ, Blume SW, Lewis EF, Ward S. Digoxin toxicity and use of
digoxin immune fab: insights from a national hospital database. JACC Heart Fail. 2016
May. 4(5):357-64. [Medline].
26. Roberts DM, Gallapatthy G, Dunuwille A, Chan BS. Pharmacological treatment of
cardiac glycoside poisoning. Br J Clin Pharmacol. 2016 Mar. 81(3):488-95. [Medline].
27. Kelly RA, Smith TW. Recognition and management of digitalis toxicity. Am J Cardiol.
1992 Jun 4. 69(18):108G-118G; disc. 118G-119G. [Medline].
28. Brubacher JR, Ravikumar PR, Bania T, Heller MB, Hoffman RS. Treatment of toad
venom poisoning with digoxin-specific Fab fragments. Chest. 1996 Nov. 110(5):1282-8.
[Medline].
29. Rajapakse S. Management of yellow oleander poisoning. Clin Toxicol (Phila). 2009 Mar.
47(3):206-12. [Medline].