Intoxicatia digitalica

Intoxicatia digitalica (cu glicozizi cardiaci) se produce cel mai frecvent prin supradozare in
cursul tratamentului, in cadrul tentativelor de suicid si prin ingestia accidentala a tei din
care se extrage (oleandru). Glicozidele cardiace actioneaza prin inhibitia ATP-azei sodice-
potasice, ducand astfel la cresterea intracelulara a Na+ si Ca2+ si la scaderea K+.
Digoxinul se absoarbe si se distribuie lent. Nivelul seric este posibil sa nu fie proportional cu
efectele farmacologice in primele 8 ore dupa ingestia unei doze terapeutice. Digoxinul se
leaga in proportie de 25-30% de proteinele plasmatice, are un lum larg de distributie (5-6 1/
kg corp) si se fixeaza in musculatura scheletica, ficat, cord. Eliminarea este predominant
renala. Timpul de injumatatire variaza intre 36 si 45 ore, este crescut in insuficienta hepatica
si cea renala si poate fi redus in cazul ingestiei unor supradoze. Aproximativ 60% dintr-o
priza este eliminata ca atare, renal, restul fiind meta-bolizata hepatic pana la meoliti inactivi.
Concentratia serica terapeutica medie este 0,6-2,5 nmol/1 (0,5-2 ng/ml).
Manifestari clinice Simptomele intoxicatiei cuprind varsaturi, confuzie, delir si ocazional
halucinatii, afectarea acuitatii vizuale, foto fobie, scotoame si tulburari in perceptia culorilor.
La nivel cardiac se produce aritmie sinusala, bradicardie sinusala si toate gradele de bloc
atrioventricular. Contractiile ventriculare premature, bigeminismul, tahicardia ventriculara si
fibrilatia pot fi manifestari ale toxicitatii digitalice. Combinatia tahiaritmie supraventriculara
si bloc AV este foarte sugestiva pentru intoxicatia digitalica. in timp ce bradiaritmiile si
hipokalemia sunt frecvente in intoxicatia cronica, tahiaritmiile si hiperkalemia se intalnesc in
general in intoxicatiile acute. Similar, nivelul seric al digoxinului poate fi crescut
nesemnificativ sau chiar corespunzator valorii terapeutice in intoxicatia cronica, in timp ce in
supradozarea acuta concentratia sa serica este semnificativ crescuta. Toxicitatea se manifesta
clinic cand concentratia serica a digoxinului depaseste 3,8-6,4 nmol (3-5 ng/ml), valori\'de 64-
77 nmol/1 (50-60 ng/ml) fiind intalnite in supradozari acute.
Diagnostic Diagnosticul este confirmat prin depistarea unui nivel seric crescut de digoxin.
Deoarece screeningurile toxicologice nu determina glicoizii cardiaci, un nivel cantitativ al
medicamentelor trebuie sa fie de regula cerut in mod specific.

TRATAMENT
Decontaminarea gastrointestinala se va efectua cat mai curand posibil. Deoarece inducerea
varsaturilor si tubajul gastric pot produce stimulare vagala, agravand astfel blocul de
conducere deja existent, se prefera administrarea carbunelui medicinal. Deoarece acesta creste
si eliminarea meolitilor activi ai digoxinului, se r administra doze regulate. Diureza,
hemodializa si hemoperfuzia sunt ineficiente. Vor fi corectate anomaliile potasice, calcice si
magneziemice. Stimularea electrica poate fi necesara atunci cand bradicardia sinusala si
blocul de grad II sau III produc hipotensiune si nu exista raspuns la atropina, izoproterenol
sau terapie cu anticorpi. Pentru tratarea tahiaritmiei ventriculare se pot folosi sulfatul de
magneziu (in doza mentionata la intoxicatiile cu antiarit-mice), fenitoinul sau xilina.
Anticorpii specifici (fragmente Fab antidigoxin) pot fi folositi pentru tratamentul intoxicatiilor
potential letale, care nu raspund la masurile enumerate mai sus. Consecutiv administrarii lor,
aritmiile cardiace si hiper-potasemia se remit in decurs de o ora; anticorpii se administreaza
intravenos timp de 30 minute daca nu a aparut stopul cardiac, situatie in care se r injecta un
bolus. Complexul medicament-anticorp se excreta urinar si are un timp de injumatatire de 16-
20 ore. La pacientii cu insuficienta renala, complexele formate se meolizeaza si se elimina
intr-o perioada variabila, de zile pana la saptamani. Desi nivelul digoxinululi liber scade rapid
la zero dupa administrarea anticorpilor specifici, dozarile uzuale nu diferentiaza digoxinul
liber de cel legat de anticorpi si, drept urmare, asemenea determinari nu sunt corelabile cu
toxicitatea reziduala dupa o asemenea terapie. Anticorpii prezinta reactivitate incrucisata cu
alte glicozide cardiace (in afara digoxinului), dar in aceste situatii sunt necesare doze mai
mari.
Fiecare 40 mg de asemenea solutie neutralizeaza 0,6 mg digoxin. Producatorul
medicamentului pune la dispozitie formule si ele cu ajutorul carora se poate calcula doza de
anticorpi necesara, in functie de greutatea corporala si de concentratia serica (postdistributie)
sau de cantitatea de digoxin ingerata. Din pacate, toxicitatea poate deveni manifesta inainte de
distributia completa a drogului sau inainte ca nivelurile sale serice sa fie disponibile.
Cantitatea ingerata prin supradozare este posibil sa nu fie cunoscuta, preparatul de anticorpi
este scump si dozele calculate sunt deseori mai mari decat cantitatea necesara. Din aceste
considerente se sugereaza urmatoarea abordare terapeutica. La pacientii cu intoxicatie
digitalica cronica, la care incarcarea corporala totala cu digoxin nu depaseste cu mult pe cea
terapeutica si la care digoxinul este indispensabil din punctul de vedere al efectelor sale
inotrop pozitive, se va incepe terapia cu 1-2 fiole din solutie cu anticorpi specifici. in
supradozarea acuta, nivelurile digitalelor sunt mult mai mari si se incepe cu 5-l0 fiole. Aceste
doze se pot repeta la neie.
Cardiac glycoside toxicity continues to be a problem in the United States because of the wide
availability of digoxin (a preparation of digitalis) and a narrow therapeutic window. Digitalis
is a plant-derived cardiac glycoside commonly used in the treatment of congestive 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. Certain herbal dietary supplements also contain cardiac glycosides. 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 as a medicine. The Romans
employed it as a diuretic, heart tonic, emetic, and rat poison. Digitalis, or foxglove, was
mentioned in AD 1250 in the writings of Welsh physicians. Fuchsius described it botanically
300 years later and gave it the name 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. (See Etiology.)[3]
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.
Digoxin is among the top 50 prescribed drugs in the United States. [4] Cardiac glycosides
account for 2.6% of toxic plant exposures in the United States. [5, 6] Most of these exposures are
in children. (See Epidemiology.)[6]
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.)
Mechanism of action
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 [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 [Ca 2+]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. Many studies have provided evidence that digitalis
binds to ATPase in a specific and saturable manner and that the binding results in 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 (1) decreased resting potential
(RP) or maximal diastolic potential (MDP), which slows the rate of phase-0 depolarization
and conduction velocity; (2) decrease in action potential duration (APD), which results in
increased responsiveness of fibers to electrical stimuli; and (3) enhancement of automaticity,
which results from an increase in the rate of phase-4 depolarization and from delayed after-
depolarization.[7]
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.
Electrocardiographic/vasomotor effects
Digoxin and other cardiac glycosides cause direct vasoconstriction in the arterial and venous
system through inhibition of the Na+/K+ -ATPase pump in vascular smooth muscle.
Dosage and toxicity
The therapeutic daily dose of digoxin ranges from 5-15mcg/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 by 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 6-10L/kg in adults, 10L/kg in neonates, and
as much as 16L/kg in infants and toddlers. At therapeutic levels, the elimination half-life is 36
hours with renal excretion. 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 5mg seldom causes severe toxicity, but a dose of
more than 10mg is almost always fatal. In the pediatric population, the ingestion of more than
4mg or 0.3mg/kg portends serious toxicity. However, plasma concentration does not always
correlate with the risk of toxicity.[8]
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 a category C
drug. 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 an increased resistance to the toxic effects of digitalis.
Patient education
Increase patient awareness about the symptoms of digitalis toxicity. In addition, educate
patients about drug interactions and about maintaining adequate hydration. Parents of
pediatric patients should be educated about good home childproofing and preventive
measures.
For patient education information, see the First Aid and Injuries Center and the Mental Health
Center, as well as Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your
Home.
Alterations in cardiac rate and rhythm occurring in 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—such as nonparoxysmal junctional tachycardia, extrasystole, premature
ventricular contractions, ventricular flutter and fibrillation, atrial flutter and fibrillation, and
bidirectional ventricular tachycardia—are due to enhanced automaticity, reentry, or both.
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.
Depression of the atrial pacemakers, resulting in SA arrest, also may be seen. Other features
are SA block, AV block, and sinus exit block resulting from depression of normal conduction.
Nonparoxysmal atrial tachycardia with block is associated with digitalis toxicity.
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 block of varying degrees, alone or with
increased ventricular automaticity, are the most common manifestations of digoxin toxicity,
occurring in 30-40% of patients with recognized digoxin toxicity. AV dissociation may occur
because of 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 digitoxin poisoning. In
pediatric patients, hyperkalemia can be a complication of acute toxi
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.
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.
Deteriorating renal function, dehydration, electrolyte disturbances, or drug interactions
usually precipitate chronic toxicity. Acute overdose or accidental exposure to plants
containing cardiac glycosides may cause acute toxicity.
Erroneous dosing, 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[9]

Hyperthyroidism

Hypoxemia

Alkalosis

Acidosis - Depresses the Na+/K+ ATPase pump and may cause digoxin toxicity
 
Myocardial disease
Myocardial ischemia suppresses the Na+/K+ ATPase pump and independently alters
myocardial automaticity. Digoxin toxicity is more likely in this setting.
Hypothyroid patients are prone to digoxin toxicity secondary to decreased renal excretion and
a smaller volume of distribution.
Electrolytes
Hypomagnesemia, hypercalcemia, hypernatremia, and hypokalemia can aggravate toxicity.[10]
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 can also worsen toxicity. 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.
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.
Medications
Some medications directly increase digoxin plasma levels; other medications alter renal
excretion or induce electrolyte abnormalities.[11] Drugs that have been reported to cause
digoxin toxicity include the following:
 Amiloride - May reduce the inotropic response to digoxin
 Amiodarone - Reduces renal and nonrenal clearance of digoxin and may have additive
effects on the heart rate
 Benzodiazepines (alprazolam, diazepam) - Have been associated with isolated reports
of digoxin toxicity
 Beta blockers (propranolol, metoprolol, atenolol) - May have additive effects on the
heart rate; carvedilol may increase digoxin blood levels in addition to potentiating its
effects on the heart rate
 Calcium channel blockers - Diltiazem and verapamil increase serum digoxin levels;
not all calcium channel blockers share this effect.
 Cyclosporine - May increase digoxin levels, possibly due to reduced renal excretion
 Erythromycin, clarithromycin, and tetracyclines - May increase digoxin levels
 Propafenone - Increases digoxin level; effects are variable.
 Quinidine - Increases digoxin level substantially but clinical effect is variable; related
drugs, such as hydroxychloroquine 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 - Avoid ephedra (risk of cardiac stimulation); avoid natural licorice
(causes sodium and water retention and increases potassium loss)
Occurrence in the United States
Approximately 0.4% of all hospital admissions 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.[12]
In 2006, the American Association of Poison Control Centers (AAPCC) reported an incidence
of 2610 toxic digitalis exposures. The overall incidence of digoxin toxicity has decreased due
to a number of factors, including increased awareness of drug interactions, decreased use of
digoxin to treat heart failure and arrhythmias, and the availability of accurate, rapid
radioimmunoassays to monitor drug levels.
Although the number of digitalis exposures was far less than the incidence of calcium
channel-blocker toxicities (10,031 cases) or beta-blocker toxicities (18,253 cases), the
mortality rate from digitalis toxicity was far higher, with 22 deaths reported versus 13 deaths
from calcium channel antagonists and 4 deaths attributed to beta-blocker toxicity.[13]
Cardiovascular drug poisoning, including digitalis toxicity, ranked as the third leading cause
of death from all poisonings in 2006.
Data from the 2007 annual AAPCC report was similar to previous data, with 2565 digitalis
exposures reported. However, fatalities were lower, with 10 deaths reported.[14]
International occurrence
Approximately 2.1% of inpatients are taking digoxin. Of all admissions, 0.3% of patients
develop toxicity.
Sex-related demographics
Pediatric poisonings from any substance are more common in males than in females. [5, 6]
However, for digoxin toxicity, a Netherlands study found no difference in incidence between
pediatric males and females.[15] The adult literature suggests that women may be more
susceptible to adverse effects than are men.[15, 16]
Age-related demographics
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.[6] 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.[17]
In 1999, the AAPCC reported approximately 3000 pediatric poisonings associated with
cardiac glycoside.[5] Of these, most were plant ingestions (66%) and digoxin exposures (33%,
including therapeutic errors and intentional and unintentional ingestions). The number of
AAPCC reported cases decreased in 2008 to 1000 plant exposures and 300 digoxin
poisonings.[6] Although the number of reporting poison centers decreased in 2008, this number
appears to be a true decline of poisonings related to cardiac glycoside.
Prognosis
Prognosis in digitalis toxicity is poor with increasing age and associated comorbid conditions.
Morbidity and mortality rates increase if the patient has a new dysrhythmia, advanced AV
block, or other significant ECG abnormality.
Incidence of digitalis toxicity has declined because of a decrease in digitalis usage,
improvement in digoxin formulation with more predictable drug bioavailability, better
understanding of pharmacokinetics, improved laboratory radioimmunoassay, increased
awareness in drug-to-drug interactions,[11] increased appreciation for factors that can increase
the risk of toxicity, and availability of other drugs to treat heart failure and techniques like
catheter ablation therapy for supraventricular tachycardias. The morbidity and mortality rates
associated with digitalis toxicity have remained constant over the past few years.
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
6ng/mL. Mortality due to digoxin exposure varies with the population studied. Adult
mortality depends on underlying comorbidity. In general, older people have a worse outcome
than other adults, who, in turn, have a worse outcome than children.
In 2008, approximately 1 pediatric fatality occurred in 1300 cardiac glycoside exposures
reported to poison control centers.[6] Overall, morbidity varies from study to study. Combined
adult and pediatric data reveal that exposures to cardiac glycoside toxic plants cause no
morbidity in most cases. The 2008 AAPCC report had follow-up data for 518 patients
exposed to digitalislike plants. Of these patients, 509 suffered little to no clinical effect, 17
suffered moderate effects, and only 1 suffered major effects. There were no deaths. Of the
data available for 1044 patients with digoxin poisoning, 422 suffered little to no effect, 490
suffered moderate effects, and 115 suffered major effects. There were 17 deaths, only 1 of
which was pediatric
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.
Extracardiac symptoms
CNS symptoms 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 also occur. Drug intoxication also may cause
snowy vision, photophobia, photopsia, decreased visual acuity, yellow halos around lights
(xanthopsia), and 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
The recent addition of a new drug, such as verapamil, diltiazem, erythromycin, tetracycline,
or paroxetine, should be noted because these drugs can elevate the digoxin level. Rifampin
increases digitalis metabolism by enzymatic stimulation and thereby decreases the digoxin
level.
Patients can have an asymptomatic period of from several minutes to several hours after the
oral administration of a single toxic dose. Clinical signs may be subtle or obvious, depending
on the severity of toxicity. Acute toxicity is rarely subtle, and 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.
General symptoms
The patient's mentation may change according to the severity of digoxin toxicity, as well as
associated comorbid conditions. Visual changes occur, but the pupils are spared, and objective
findings are few. Drug-induced fever does not occur.
Vital signs
The pulse may be irregular, depending on arrhythmias secondary to atrial fibrillation or
arising from the digoxin toxicity itself. Hypotension may be observed if the patient has CHF
or dehydration secondary to decreased oral intake.
Neck findings
Symptoms include increased jugular venous pressure.
Cardiovascular symptoms
Digoxin toxicity may cause any dysrhythmia. Classically, dysrhythmias associated with
increased automaticity and decreased AV conduction occur (ie, paroxysmal atrial tachycardia
with 2:1 block, accelerated junctional rhythm, or bidirectional ventricular tachycardia [torsade
de pointes], depicted in the images below).

Bidirectional tachycardia in a patient with digitalis toxicity.

Bidirectional tachycardia in a patient with digitalis toxicity.

Hemodynamic instability is related directly to the presence of a dysrhythmia or to acute CHF.
Associated cardiomegaly may be identified. Cardiovascular findings on physical examination
relate to the severity of CHF, dysrhythmias, or hemodynamic instability.
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.
Respiratory symptoms
The respiratory rate is sometimes increased. Basal crepitations are associated with CHF.
GI symptoms
GI symptoms are common, but the abdominal examination is usually nonspecific. An
enlarged liver occurs secondary to CHF (ie, hepatic congestion). Hepatojugular reflux is
present.
Neurologic symptoms
Neurologic findings are related to changes in sensorium or mental status. Lateralizing findings
usually indicate another disease process.
Findings in the extremities
Pedal edema is noted if the patient has renal failure or decompensated CHF.
Conditions to consider in the differential diagnosis of digitalis toxicity include the following:
 Sepsis
 Sinus node dysfunction
 Calcium channel blocker toxicity
 Beta-blocker toxicity
 Organophosphate toxicity
 Congestive heart failure
 Acute renal failure
 Ventricular fibrillation
 Ventricular tachycardia
 Arrhythmias
 Syncope
 Cardiotoxic plant ingestion
 Class I-A cardiac drug toxicity
 Clonidine toxicity
 Dehydration
 Hypomagnesemia
 First-degree heart block
 Second-degree heart block
 Third-degree heart block
Differential Diagnoses

Acute Renal Failure

Gastroenteritis

Hypercalcemia

Hyperkalemia

Hypernatremia

Hypoglycemia

Hypokalemia

Hyponatremia

Meningitis, Aseptic

The plasma digoxin level can be used to monitor compliance and toxicity and can be
used as a guide to the appropriate dosing of medication.

Therapeutic digoxin levels vary; the lower limit ranges from 0.6-1.3 ng/mL, while the
upper limit generally is agreed to be 2.6 ng/mL. Serum concentrations associated with
 toxicity overlap between therapeutic and toxic ranges because of the myriad of factors
potentiating digoxin toxicity.

Measure Na+, K+, Cl-, CO2-, Mg++, Ca++, blood urea nitrogen (BUN), and creatinine
levels. Obtain cardiac markers such as creatine kinase MB or troponin I or T if
myocardial infarction is a clinical concern.

False-negative assay results may occur in the setting of acute ingestion of nondigoxin
cardiac glycosides, such as foxglove and oleander, even in the setting of profound
clinical toxicity. This is caused by nonreactivity or minimal cross-reactivity with the
digoxin radioimmunoassay.

Initial potassium levels are better correlated 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 died, whereas 50% of patients with a serum digoxin
level of 5-5.5 died.[18]

The development of sensitive and accurate radioimmunoassays has improved the
diagnosis and management of digitalis toxicity.

The therapeutic range is 0.5-2 ng/mL, but significant levels in patients with toxicity
and levels in those without toxicity overlap significantly. Consequently, digoxin levels
cannot be used as the sole indicator of toxicity.

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 they are not necessarily
predictors of toxicity. The plasma half-life of digoxin is shortened to 10-25 hours with
acute, massive ingestions, compared with a mean value of 36 hours in nontoxic
ingestions.

In acute toxicity, repeat the digoxin level after 2-4 hours to guide therapy. Digoxin
levels do not necessarily correlate with toxicity, especially after acute ingestion.
Following acute ingestion, digoxin levels do not equilibrate quickly because of
variable absorption and subsequent tissue distribution. Toxicity is related to
intracellular levels, not serum levels.

To best way to guide therapy is to follow the digoxin level and correlate it with serum
potassium concentrations and the patient's clinical and ECG findings.

DLIS

Endogenous digoxinlike immunoreactive substance (DLIS) can cause a false-positive
result or an elevated digoxin level. DLIS is observed in neonates and in patients with
renal insufficiency, liver disease or hyperbilirubinemia, subarachnoid hemorrhage,
CHF, diabetes mellitus, or acromegaly; it may also be present in those who are
pregnant or using spironolactone.

In some studies, premature infants had levels as high as 4 ng/mL, with peaks at age 6
days, and positive assay results until they were aged 3 months. Most authors agree that
serum digoxin levels due to DLIS are usually less than 2 ng/mL and that the
interference is assay dependent and may vary with the lot of the reagent. Some
laboratories use ultrafiltration techniques to eliminate the contribution of DLIS.

Other variables

Other confounding variables include digoxin metabolites and drugs. 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 routinely used
 radioimmunoassays measure each of these metabolites. Additionally, the antibodies
used in 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.

Initial potassium levels are better correlated 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 died, whereas 50% of patients with a serum digoxin
level of 5-5.5 died.[18]

Hyperkalemia

In acute toxicity, hyperkalemia is common owing to inactivation of the Na +/K+
-ATPase pump. It is a predictor of morbidity and mortality and also reflects the degree
of poisoning.

Hypokalemia

Long-term digoxin users very often develop hypokalemia because of concurrent
diuretic use. The condition should be corrected promptly; treating hypokalemia may
help to improve cardiac glycoside-related arrhythmia.

Hypomagnesemia

Long-term digoxin users often have hypomagnesemia secondary to diuretic usage.
Intracellular magnesium depletion may occur in long-term diuretic use 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 may be necessary to facilitate the diagnosis, the type of rhythm, and
arrhythmia. Suspect digitalis toxicity when the evidence suggests increased automaticity and
depressed conduction. Sinus bradycardia and AV conduction blocks are the most common
ECG changes in the pediatric population, while ventricular ectopy is more common in adults.
[10]
(Almost any dysrhythmia may occur, but rapid atrial fibrillation or flutter is rare.)
Nonparoxysmal atrial tachycardia with a 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
 SA 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 slow, regular ventricular rate (ie, AV dissociation)
 Nonparoxysmal junctional tachycardia (rate 70-130 beats per minutes [bpm])
  Atrial tachycardia with block (atrial rate usually 150-200 bpm)
 Bidirectional ventricular tachycardia
General 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.
Fab antibody fragments are extremely effective in the treatment of severe, acute digitalis
toxicity
General principles of management include the following:

Assessment of the severity of the problem and the etiology of toxicity (eg, diminished
renal clearance, the dose medicated, concurrent medications, and whether overdosage
is accidental or intentional)

Factors that influence treatment, including age, medical history, chronicity of digoxin
intoxication, existing heart disease and/or renal insufficiency, and, importantly, ECG
changes

Continuous hemodynamic assessment, including 12-lead ECG and cardiac monitoring,
as well as intensive care unit admission and IV access

Prompt measurement of electrolyte levels, including potassium and calcium, and of
serum creatinine, and digoxin levels[19]
Transfer
Transfer hemodynamically unstable patients to a tertiary care center equipped with medical
intensive care unit/critical care unit capabilities. Notification of and discussion of treatment
with the regional poison center also is important.
Consultations
The following consultations may be employed:
 Cardiologists
 Nephrologists
 Regional poison centers
 Medical toxicologists
Monitoring and follow-up
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;
lab results should be normalized.
Suicidal, depressed patients should be cleared by a psychiatry consult for prevention of
repeated toxic ingestion before discharge.
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.
The first-line treatment for acute ingestion is gastric lavage with repeated dosing of activated
charcoal to reduce absorption and interrupt enterohepatic circulation. It is most effective if
ingestion has occurred within 6-8 hours.
Pretreatment with atropine has been recommended to decrease the incidence of AV block or
bradycardia as a result of increased vagal tone caused by gastric lavage.
To break enterohepatic circulation, use binding resins, such as cholestyramine and colestipol.
Cholestyramine probably is used more appropriately in chronic toxicity with renal
insufficiency.
Other points to consider include the following:
 
Induced emesis with ipecac syrup - Not recommended, because of the increased vagal
effect

Whole-bowel irrigation - May be useful, but clinical data are lacking

Forced diuresis - 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-added clearances

In acute settings, hyperkalemia is more common, while in chronic intoxication,
hypokalemia and hypomagnesemia are common (owing to concurrent use of
diuretics).

Standard treatment for hyperkalemia, including bicarbonate, glucose, and insulin, is
useful. Ion exchange resins, such as Kayexalate, can be used as well; however, if
digoxin antibody therapy is anticipated, then other forms of treatment for
hyperkalemia are not necessary.

The use of calcium can be disastrous because it can delay after-depolarization and be
proarrhythmic. In patients with uncontrolled hyperkalemia, instituting hemodialysis
may be necessary.

Hypokalemia increases digoxin cardiac sensitivity and should be corrected. Use
caution in 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 even with therapeutic digitalis levels. A common dose of 1-2 g/h with
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.[20]
Antidysrhythmics
If the patient with short- or long-term ingestion develops a digitalis-induced dysrhythmia,
management of the dysrhythmia is directed toward the cause of the rhythm disturbance. Aside
from correcting obvious electrolyte abnormalities, an antidysrhythmic may be indicated,
especially if there is an absence of, or a delay in administering, immunotherapy.
Digoxin immune Fab is now considered first-line treatment for significant dysrhythmias and
should be promptly administered if digoxin toxicity is suspected.[17, 21, 22]
Phenytoin and lidocaine are useful antiarrhythmics for the treatment of digoxin toxicity if Fab
fragments are ineffective or unavailable.[20] They depress the enhanced ventricular
automaticity without significantly slowing AV conduction. Phenytoin may reverse digitalis-
induced prolongation of AV nodal conduction. Phenytoin has been shown to dissociate the
inotropic and dysrhythmic action of digitalis, thus suppressing digitalis-induced
tachydysrhythmias without diminishing the contractile effects. In addition, phenytoin can
terminate supraventricular dysrhythmias induced by digitalis, whereas lidocaine has not been
as effective.
Atropine may be useful in blocking digoxin-induced effects of enhanced vagal tone on the SA
and AV nodes; it has proven helpful in reversing severe sinus bradycardia.
Quinidine, procainamide, and bretylium are contraindicated. Quinidine and procainamide
worsen AV, SA, and His-Purkinje conductivity. Additionally, quinidine reduces digoxin
tissue binding and renal clearance, thereby increasing digoxin levels. Bretylium can
precipitate ventricular dysrhythmia.[20]
Beta-adrenergic blockers can decrease automaticity and slow conduction velocity induced by
a catecholamine surge from digitalis intoxication and can shorten the refractory period of
atrial and ventricular muscle. In the presence of SA or AV node depression, however, they
may depress activity further; therefore, a short-acting beta-blocker is recommended in rapid
atrial conduction.
IV magnesium sulfate, 2 g over 5 minutes, has been shown to terminate digoxin-toxic cardiac
arrhythmias in patients with and without overt disease. Aside from successful replacement of
intracellular magnesium, it also may act as an indirect antagonist of digoxin at the
supraphysiologic level.
Temporary pacing is an alternative for patients with nodal blocks before any other medical
interventions are attempted. However, retrospective studies have shown that pacing may
increase adverse outcomes in some patients and have suggested that immunotherapy should
be attempted prior to initiating pacemaker activity.
Electrical Cardioversion
Cardioversion for severe dysrhythmias due to digitalis is hazardous and 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/ventricular
fibrillation, but most clinicians suggest starting at 50-100 joules for a wide, complex
ventricular tachycardia, rather than at the 200 joules recommended in the advanced cardiac
life support (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.
Postimmunotherapy Treatment
After treatment with Fab fragments, the serum digoxin level will rise considerably. The
digoxin level cannot be used as a guide to treatment after administration of Fab fragments.
Free digoxin levels can be used, but most hospitals do not have this assay available. 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 because the Fab complex is eliminated more
rapidly than digoxin is released from tissue-binding sites.
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 foreign
protein; these reactions are uncommon. Allergy to Fab fragments is associated with patients
who have multiple allergies.
Hemodialysis
Hemodialysis and activated charcoal hemoperfusion have no role in the management of
digitalis intoxication. Without the use of Fab, these procedures are not indicated, because the
molecular weight of digoxin is too high for hemodialysis to be successful. In addition, the
volume of distribution of digoxin is too large to make either approach feasible. Hemodialysis
is superfluous after administration of Fab and hemoperfusion.
Digoxin-specific antibody fragments are effective even in anephric patients, although
symptoms may recur 7-14 days later, possibly indicating the need for another dose of Fab.
Hemoperfusion through columns with antidigoxin antibodies bound to agarose polyacrolein
microsphere beads has been accomplished, but the availability of Fab in the United States
makes this modality outdated.
Continuous arteriovenous hemofiltration in an experimental model has failed to remove the
digoxin-Fab complex.
Medication Summary
The goals of pharmacotherapy are to reduce toxic levels of digitalis, prevent complications,
and reduce morbidity. Immunotherapy 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. Introduced in 1976, but not commercially available until a
decade later, digoxin-specific Fab fragments are the product of papain digestion of sheep
immunoglobulin G (IgG) produced in response to antigenic carrier proteins coupled to
digoxin.
The advantages of digoxin-specific Fab compared with whole IgG antibodies include larger
volume of distribution and more rapid onset of action. The commercial product (Digibind) is a
relatively pure Fab product that is very safe and extremely effective. 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.
Indications for immunotherapy include the following:
 Ingestion of massive quantities of digitalis (children, 4 mg or 0.1 mg/kg; adults 10 mg)
 Hyperkalemia (>5 mEq/L)
 Digoxin-induced ventricular dysrhythmias or high-grade AV block
 Rapidly progressive signs and symptoms of toxicity
 Cardiac arrest or cardiogenic shock in a patient with suspected digoxin toxicity
 Postdistribution serum digoxin levels greater than 5 ng/mL
According to the manufacturer, Digibind should be administered intravenously over 30
minutes via a 0.22-um membrane filter. The 40-mg vial must be reconstituted with 4 mL of
sterile water for IV injection, furnishing an iso-osmotic solution. This preparation can be
diluted further with sterile isotonic saline (for small infants). Once the product is
reconstituted, use it immediately or, if refrigerated, use it within 4 hours. In an unstable
clinical situation, Digibind is administered by IV bolus.
Studies have shown that 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.
Possible idiosyncratic allergic reactions are very rare but need to be considered in patients
with known sheep protein allergy. One must also be aware of possible volume overload
causing exacerbation of CHF with chronic digitalis therapy and hypokalemia due to the
movement of potassium into the cell.
Fab fragment interferes with conventional assay, and digoxin measurement is unreliable for 1-
2 weeks after the therapy.
Antidotes, Other

Class Summary

This agent improves clinical aspects of digitalis toxicity; it may increase solubilization and
removal of immune complexes. In chronic toxicity, plasma drug levels are greater than 6
ng/mL; in acute ingestion, do not base treatment on plasma drug levels alone.

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).[23, 24]

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

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

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

Activated charcoal is useful in limiting the absorption of ingested digoxin. It is most

beneficial if administered within 4 hours of ingestion.

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

View full drug information

Digoxin immune Fab (Digibind)

Digoxin immune Fab is an immunoglobulin fragment with specific and high affinity for
digoxin and digitoxin molecules. 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.

A 50,000-Da molecule, Fab is derived from the IgG fragment of sheep antidigoxin antibodies.
This relatively pure Fab product is safe and extremely effective. Indications for use include
life-threatening arrhythmias (eg, severe bradyarrhythmia, second- or third-degree heart block,
ventricular tachycardia or fibrillation), an initial potassium level of more than 5 mmol/L,
digoxin serum levels of more than 10 ng/mL at 6-8 hours after ingestion, digoxin serum levels
of over 15 ng/mL in acute ingestion, and ingestion of more than 10 mg in healthy adults or
more than 4 mg in children.

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. A response is
typically observed within 20-30 minutes; the elimination half-life of the drug-antibody
complex is about 16 hours.

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.
Activated charcoal (Kerr Insta-Char, Actidose-Aqua, EZ-Char)
Activated charcoal prevents absorption by adsorbing drug in intestine. A network of pores
present in activated charcoal absorbs 100-1000mg 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 AV node conduction by inhibiting vagal activity. They
are used as an alternative to digoxin immune Fab.

Atropine sulfate

Atropine sulfate increases the heart rate through vagolytic effects, causing an increase in
cardiac output.
Anticonvulsants, Hydantoins
Class Summary
Anticonvulsants that shorten the action potential in the heart may be effective.
Phenytoin (Dilantin, Phenytek)
Phenytoin prolongs effective refractory period and depresses spontaneous depolarization in
ventricular tissues. Antidysrhythmics, Ib
Class Summary
Antidysrhythmics 1b increase electrical stimulation threshold of ventricle by suppressing
automaticity of conduction
Lidocaine hydrochloride (Xylocaine)
Lidocaine hydrochloride is a class IB antiarrhythmic that increases the electrical stimulation
threshold of the ventricle, suppressing the automaticity of conduction through the tissue.
Electrolyte Supplements, Parenteral
Class Summary
Magnesium is useful as a temporizing antiarrhythmic agent until digoxin Fab fragments are
available.
Magnesium sulfate
Magnesium sulfate possesses antiarrhythmic properties that are beneficial with treatment of
digoxin toxicity. It may be a lifesaving adjunct in the treatment of digoxin-induced ventricular
tachycardia or ventricular fibrillation.