Digitalis Toxicity

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.

Toxicitate digitalca

Practici esențiale

Incidența toxicității digitalice a scăzut în ultimii ani, din cauza scăderii utilizării, împreună cu tehnologia
îmbunătățită pentru monitorizarea cantitatii medicamentelor și cre șterea gradului de con știentizare a
interacțiunilor medicamentoase. Cu toate acestea, toxicitatea glicozidului cardiac continuă să fie o
problemă în Statele Unite, din cauza utilizării pe scară largă a digoxinei (un preparat digital) și a ferestrei
sale terapeutice înguste.
Este important să aflați despre sursa:,doza , timpul de ingestie, prezen ța oricărui coingestant și
comorbiditățile proprii ale pacientului. Toxicitatea acută digitală poate rezulta din supradozaj neinten ționat,
suicid sau omucid al digoxinei preparatului digital sau ingestia accidentală a plantelor care con țin glicozide
cardiace. Toxicitatea cronică la pacien ții afla ți în terapia cu digoxină poate rezulta din deteriorarea func ției
renale, deshidratare, tulburări de electroli ți sau interac țiuni medicamentoase. Modificările ritmului cardiac și
ale pulsului cauzate de toxicitatea digitală pot reproduce aproape fiecare mecanism cunoscut de disritmie.
Vezi imaginea de mai jos.
 Bidirectional tachycardia in a patient with
digitalis toxicity.
Tahicardie bidirectionala la un pacient cu intoxicatie digitalica
View Media Gallery
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

Semne si simptome

Toxicitatea digitalica produce manifestări ale SNC, vizuale, GI și cardiace. Gre țurile, vărsăturile și
somnolența sunt printre cele mai frecvente manifestări extracardice.

Simptomele SNC de toxicitate digitalica includ următoarele:

 • somnolența

• Letargie

• Oboseala

• Nevralgia

•Cefalee

• Vertij

• Confuzie sau oboseală

• Halucinații

• Convulsii (rare)
• Parestezii și dureri neuropatice
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)

Aberatia vizuala este adesea o indica ție timpurie a toxicită ții digitale. Distorsiunea galben-verde este cea
mai frecventă, dar apar și distorsiuni ro șii, maro, albastre și albe. Intoxica ția cu medicamente poate
provoca următoarele:

• Vedere înzăpezită

• fotofobie

• fotopsie
• Scăderea acuității vizuale

• Halou galben în preajma luminilor (xanthopsia)

• Ambliopie tranzitorie sau scotomata

Simptomele GI cu toxicitate acută sau cronică includ următoarele:

• Anorexie

Pierdere în greutate

• Stoparea dezvoltarii (la pacienții pediatri)

• Greață

• Vărsături

• Durere abdominală

• Diaree
• Ischemia mezenterică (o complicație rară a infuziei rapide de IV)
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

Simptome cardiace

Simptomele cardiace includ următoarele:

• Palpitații
• Apnee

• Sincopa

• Umflarea extremităților inferioare

• Bradicardia

• Hipotensiune

• Dispnee

Vezi Prezentare clinică pentru mai multe detalii.

Diagnostic

Studiile la pacienții cu posibilă toxicitate digitalica includ următoarele:

• Nivelul seric de digoxină

• Electroliți

• Studii ale funcției renale

• 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.

Nivelul seric de digoxină

• Nivelurile terapeutice sunt de 0,6-1,3 până la 2,6 ng / ml

• Nivelurile asociate cu toxicitatea se suprapun între intervalele terapeutice și cele toxice

• Rezultatele analizei fals-negative pot aparea la ingestia acută de glicozide cardiace nondigoxin (de
exemplu, compuși din plante, cum ar fi foxglove sau oleander)

• Nivelurile determinate la mai puțin de 6-8 ore după o ingestie acută nu prevăd în mod necesar toxicitate
• Cel mai bun mod de a ghida terapia este să urmări ți nivelul digoxinei și să o corela ți cu concentra țiile
serice de potasiu și cu concluziile clinice și ECG ale pacientului .
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.

electroliţi

• În toxicitatea acută, hiperkalemia este frecventă

• Toxicitatea cronică este adesea înso țită de hipokalemie și hipomagnezemie

Electrocardiografie

• Toxicitatea cu dioxinina poate provoca aproape orice disritmie

• Clasic, apar ritmii asociate cu o automatitate crescută și o scădere a conduc ției AV

• Bradicardia sinusală și blocurile de conducere AV sunt cele mai frecvente modificări ale ECG la popula ția
pediatrică, în timp ce ectopia ventriculară este mai frecventă la adul ți

• Tahicardie atrială nonparoxistică cu blocaj cardiac și tahicardie ventriculară bidirec țională sunt deosebit
de caracteristice toxicității severe digitale
Consultați Workup pentru mai multe detalii.
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.

administrare

Îngrijirea asociata toxicității digitale include următoarele:

• Hidratarea cu fluide IV

• Oxigenarea și susținerea funcției ventilatorii

• Întreruperea medicamentului și, uneori, corectarea dezechilibrelor de electroli ți

Decontaminarea GI

• Cărbunele activat este indicat pentru supradozaj acut sau ingestie accidentală
• Rășinile de legare (de exemplu, colestiramina) pot lega digoxina reciclată enterohepatic

Tratamentul dezechilibrului electrolitului

• Pentru hiperkalemie, utilizați insulină plus glucoză și bicarbonat de sodiu dacă pacientul este acidotic

• Tratamentul cu fragmente de digoxină Fab este indicat pentru un nivel K + mai mare de 5 mEq / L

• Hemodializa poate fi necesară pentru hiperkalemia necontrolată

• Hipokalemie corectă (de obicei în stare de ebrietate cronică)

• Hipomagneziemia concomitentă poate duce la hipokalemie refractară

Digoxin imun Fab

Fabul imunitar la Digoxin este considerat tratamentul de primă linie pentru rritmii semnificative cauzate de
toxicitatea digitală. Alte indicații pentru utilizarea sa, în absen ța contraindica țiilor specifice, includ
următoarele:

• Ingerarea unor cantități masive de digitalis (la copii, 4 mg sau 0,1 mg / kg; la adul ți, 10 mg)

• Nivelul seric de digoxină mai mare de 10 ng / ml la adul ți în stare de echilibru (adică, la 6-8 ore de la
ingestia acută sau la nivelul inițial în toxicitate cronică)

• Hiperkalemie (nivel seric de potasiu mai mare de 5 mEq / L)

• Stare mentală modificată atribuită toxicită ții digoxinei

• Semne și progresivitate rapidă a simptomelor de toxicitate

Managementul disrmiilor

• La pacienții stabili hemodinamic, bradiriotmiile și aritmiile supraventriculare pot fi tratate cu ajutorul

tehnicilor adiacente

• Blocantele beta cu acțiune scurtă (de exemplu, esmolol) pot fi de ajutor pentru tahiaritmii
supraventriculare cu rate ventriculare rapide, dar pot precipita bloc AV avansat sau complet la pacien ții cu
depresie ganglionară sinoatrială sau AV

• Fenitoina și lidocaina sunt utile pentru tahicardia ventriculară dacă terapia imunitară este ineficientă sau
nu este disponibilă

• Fenitoina poate suprima tahidritmiile induse de digital

• Atropina s-a dovedit utilă în inversarea bradicardiei sinusale severe

• Sulfatul de magneziu poate încheia disritmii, dar este contraindicat în administrarea bradicardiei sau a
blocului AV și trebuie utilizat cu precau ție la pacien ții cu insuficien ță renală

• Cardioversia pentru ritmii severe datorate digitalisului poate precipita fibrilarea ventriculară și asistolul, dar
poate fi utilizată dacă pacientul este instabil hemodinamic și are o tahicardie largă și complexă și dacă este
exclusă tahicardia fasciculară

Criterii pentru internarea în spital

• Disritmii cardiace noi

• Bradyarrhythmias severe

• Bloc AV avansat

• Prelungirea acută a intervalului QRS

• Anomalii severe de electroliți, în special hipokalemie sau hiperkalemie

• Deshidratarea

• Incapacitatea de a se îngriji de sine

• Ideea suicidară
Consultați Tratamentul și medicamentele pentru mai multe detalii.
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 CHFestablished. 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 ([Ca 2+]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 [Ca 2+]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 [Ca 2+] 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.
istory
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.
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
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.
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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
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 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.
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