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Digitalis (cardiac glycoside) poisoning

Authors: Michael Levine, MD, Ayrn O'Connor, MD

Section Editors: Stephen J Traub, MD, Michele M Burns, MD, MPH
Deputy Editor: Jonathan Grayzel, MD, FAAEM

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2017. | This topic last updated: Feb 07, 2017.

INTRODUCTION — In 1785, Sir William Withering described the use of the foxglove plant, Digitalis
purpurea, for treatment of heart failure [1]. More than 200 years later, cardiac glycosides are still
prescribed for patients with atrial fibrillation and heart failure or left ventricular dysfunction.

While the overall use of digitalis has declined, the number of patients admitted with digitalis toxicity
has remained stable and the use of digitalis antibody fragments has increased [2]. In 2011, there were
2513 cases of cardiac glycoside exposures reported to United States poison control centers. Of these,
132 patients suffered major toxicity and 27 died [3].

In addition to digitalis, other cardiac glycosides exist and have been associated with toxicity. These
include: the xenobiotics ouabain and lanatoside C; various plants, including foxglove, dogbane, red
squill, lily of the valley, oleander, and henbane; and bufadienolides, cardioactive steroids found in the
skin of toads belonging to the Bufonidae family [4]. In 2011, there were an additional 1376 cases of
cardiac glycoside exposure from various plant species [3].

The pharmacology, diagnosis, and management of acute and chronic digitalis poisoning will be
reviewed here. The dosing of digoxin-specific antibody (Fab) fragments for the treatment of digoxin
toxicity and the therapeutic use of digoxin are discussed separately. (See "Dosing regimen for digoxin-
specific antibody (Fab) fragments in patients with digoxin toxicity" and "Use of digoxin in heart failure
with reduced ejection fraction" and "Control of ventricular rate in atrial fibrillation: Pharmacologic
therapy", section on 'Digoxin' and "Treatment with digoxin: Initial dosing, monitoring, and dose
modification".)

PHARMACOLOGY AND CELLULAR TOXICOLOGY — Cardiac glycosides all possess a steroid

nucleus with an unsaturated lactone at the C17 position, and at least one glycosidic residue at the C3
position (figure 1) [5]. Cardiac glycosides are used primarily to increase inotropy in cardiac myocytes
but also affect cells in the vascular smooth muscle and sympathetic nervous system [5-7].

Normal depolarization of the cardiac myocyte begins with the opening of the fast sodium channels.
The resulting increase in intracellular sodium, and subsequent change in the resting membrane
potential, opens voltage-gated calcium channels. The initial influx of calcium induces further release of
calcium from the sarcoplasmic reticulum, which results in muscle contraction [8]. Sodium is then
removed from the cell by, among several mechanisms, the sodium-potassium-ATPase. Some calcium
is removed from the cell by the sodium-calcium antiporter.

Cardiac glycosides reversibly inhibit the sodium-potassium-ATPase, causing an increase in

intracellular sodium and a decrease in intracellular potassium [1,5]. The increase in intracellular
sodium prevents the sodium-calcium antiporter from expelling calcium from the myocyte, which
increases intracellular calcium. The net increase in intracellular calcium augments inotropy [9,10].
Cardiac glycosides also increase vagal tone, which results in decreased conduction through the
sinoatrial and atrioventricular nodes [5].

Excessive intracellular calcium may cause delayed after-depolarizations, which may in turn lead to
premature contractions and trigger arrhythmias. Cardiac glycosides shorten repolarization of the atria
and ventricles, decreasing the refractory period of the myocardium, thereby increasing automaticity
and the risk for arrhythmias [11,12].

The effects of cardiac glycosides on vasoconstriction can vary [12-14]. Digitalis has been shown to
reduce plasma renin concentrations in patients with advanced decompensated heart failure, causing
peripheral vasodilation [12]. In patients without heart failure, digitalis can increase vasoconstriction.
This difference is likely due to enhanced responsiveness of the baroreceptors in patients with chronic
heart failure [13]. (See "Overview of the therapy of heart failure with reduced ejection fraction".)

KINETICS — Digoxin and digitoxin are the two cardiac glycosides available for clinical use. Important
pharmacokinetic properties of these agents are presented in the attached table (table 1).

While mechanistically equivalent, these drugs have several different pharmacologic properties.
Digitoxin is absorbed more readily and has a smaller volume of distribution, a longer half-life, and
greater protein binding. In addition, digitoxin is hepatically cleared while digoxin is cleared renally.

Both digoxin and digitoxin have a narrow therapeutic index and toxicity is common [15]. Furthermore,
dosing adjustments must be made whenever significant alterations occur in factors affecting
absorption, distribution, or elimination. Such factors are numerous and include changes in volume of
distribution due to age or increased adipose stores, diminished protein binding from conditions
causing hypoalbuminemia, and renal impairment resulting in decreased elimination.

Digoxin is a substrate of intestinal and renal p-glycoprotein. P-glycoprotein is an efflux pump that
excretes many drugs into the intestine or proximal renal tubule, thereby lowering serum
concentrations. Drugs that alter p-glycoprotein activity can increase serum digoxin concentrations
[16,17]. Examples of such drugs include verapamil, diltiazem, quinidine, and amiodarone (table 2)
[18,19].

The molecular weight of both digoxin and digitoxin is large, making extracorporeal elimination
ineffective for either agent. (See 'Extracorporeal removal' below.)

CLINICAL FEATURES AND DIAGNOSIS — Both pharmaceutical formulations and naturally

occurring sources of cardiac glycosides can cause toxicity. Critical clinical manifestations of toxicity
are usually cardiac but may include gastrointestinal and neurologic signs. The diagnosis of cardiac
glycoside toxicity is based upon clinical and electrocardiographic manifestations rather than isolated
elevated serum digoxin concentrations. Presentation can vary depending upon whether toxicity is
acute or chronic.

History — Determine the agent, amount taken, time of ingestion, and any coingestants whenever
possible. The time is especially important because the serum digoxin concentration ideally should be
measured at least six hours after ingestion to ensure accuracy. A level drawn prematurely may be
falsely elevated due to incomplete drug distribution. Determine also if the patient normally takes
digitalis or if it was someone else's prescription. (See 'Serum digoxin concentration' below.)

Ask about symptoms suggesting an acute illness, such as gastroenteritis, that may have caused
dehydration or acute renal insufficiency and contributed to the development of chronic toxicity [20].
Inquire carefully about gastrointestinal, cardiac, and neurologic manifestations, including visual
disturbances, because these are the most common findings associated with chronic toxicity.

Inquire also about symptoms that suggest hypoperfusion, such as confusion and abdominal pain,
which may stem from mesenteric ischemia [21]. (See "Overview of intestinal ischemia in adults",
section on 'Clinical features'.)

Obtain a thorough medication history to determine if any recent additions or dosing changes were
made. Several medications, including verapamil, amiodarone, and quinidine, can increase serum
digitalis concentrations (table 2).

Physical examination — After initial evaluation of the patient's airway and breathing, the clinician
should assess the patient's vital signs. Bradycardia is frequently encountered in digitalis toxicity.

Look for evidence of hypoperfusion and end organ dysfunction. Pay particular attention to mentation
and neurologic status, keeping in mind that such effects are often due to direct toxicity but may be
secondary to cerebral hypoperfusion. Look for symptoms and signs suggestive of acute mesenteric
ischemia, which is a rare complication. (See "Overview of intestinal ischemia in adults", section on
'Physical examination'.)

Clinical manifestations — In both acute and chronic digitalis toxicity, cardiac effects are of the
greatest concern. The cardiac manifestations of digitalis toxicity can include virtually any type of
arrhythmia with the exception of rapidly conducted atrial arrhythmias [11]. Digitalis-related arrhythmias
are discussed below and separately. (See 'Electrocardiogram' below and "Cardiac arrhythmias due to
digoxin toxicity".)

Other symptoms of acute and chronic digoxin toxicity may overlap, but a few important differences
should be noted. With an acute ingestion, the patient may remain asymptomatic for several hours then
develop significant gastrointestinal symptoms, such as anorexia, nausea, vomiting, and abdominal
pain. Neurologic manifestations such as confusion and weakness, independent of hemodynamic
parameters, are common. Electrolyte abnormalities occur with both acute and chronic toxicity and are
discussed further below. (See 'Electrolyte abnormalities' below.)

Chronic toxicity is often more difficult to diagnose, as symptom onset tends to be more insidious and
may occur over a period ranging from days to months. Gastrointestinal symptoms, such as anorexia,
nausea, and vomiting, can occur but may be less pronounced. Neurologic manifestations, such as
lethargy, fatigue, delirium, confusion, disorientation, and weakness, may be prominent in chronic
toxicity [22]. Often patients are brought to medical attention by family members who note a change in
mental status since their last visit, which may have been days, weeks, or even months prior.

Visual changes associated with digitalis toxicity are varied and may include alterations in color vision
(chromatopsia), diplopia, photophobia, decreased visual acuity, photopsia, scotomas, or blindness.
Chromatopsia, specifically xanthopsia (objects appear yellow), is classically associated with digitalis
toxicity but is frequently absent and not needed for diagnosis.

LABORATORY AND ECG EVALUATION

Approach to testing — In the patient with suspected digoxin toxicity, the following studies should be
obtained:

● Serum digoxin concentration: For an acute overdose, obtain a serum concentration measurement
on presentation and approximately six hours after the ingestion; for chronic toxicity, obtain a
concentration on presentation.
● Serum potassium concentration
● Creatinine and BUN to assess renal function
● Serial electrocardiograms (ECGs)

In the setting of an intentional ingestion, the following studies should also be obtained:

● Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status
● Acetaminophen and salicylate levels, to rule out these common coingestants
● Pregnancy test in women of childbearing age

Electrolyte abnormalities — Inhibition of the sodium-potassium-ATPase, in both heart and skeletal

muscle, leads to an increase in extracellular potassium. Thus, hyperkalemia is an important marker of
acute digitalis toxicity, and a predictor of mortality. Other electrolyte abnormalities may also occur in
the setting of digitalis poisoning. (See 'Pharmacology and cellular toxicology' above.)

In acute toxicity, the degree of hyperkalemia correlates with mortality. This was first shown in a classic
study performed before the advent of antidotal therapy using digoxin-specific antibody (Fab)
fragments. In this study of 91 patients primarily with acute digoxin poisoning from intentional overdose,
researchers noted that no patient with an initial potassium concentration above 5.5 mEq/L (or mmol/L)
survived, while no patient with a potassium concentration below 5 mEq/L died [23]. This correlation
has also been demonstrated in plant cardiac glycoside ingestions [24,25].

In the setting of chronic toxicity, hypokalemia is of greater concern. Several electrolyte abnormalities,
including hypokalemia, hypomagnesemia, and hypercalcemia, increase patient susceptibility to the
toxic effects of digoxin [15]. Loop diuretics to treat heart failure are the most common cause of
hypokalemia in these patients, but other causes of hypokalemia (eg, diarrhea or vomiting) do occur.

Renal dysfunction is commonly encountered in the setting of chronic digoxin toxicity and is often what
precipitates the rise in the digoxin concentration. Therefore, assessment of renal function is essential
and should include measurements of BUN and creatinine, as well as urine output to assess renal
perfusion. The adjustments needed for digoxin dosing in the setting of renal insufficiency are
described separately. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification",
section on 'Dose adjustments'.)

Serum digoxin concentration — The therapeutic window of digoxin is narrow, with substantial
overlap between “therapeutic” and “toxic” serum concentrations (or levels), and the concentration can
be affected by many factors (eg, impaired renal function, other medications). Therefore, determining
an appropriate therapeutic serum digoxin concentration can be difficult. Issues related to the
therapeutic serum concentration of digoxin are reviewed in detail separately. (See "Treatment with
digoxin: Initial dosing, monitoring, and dose modification", section on 'Monitoring serum digoxin'.)

A quantitative serum digoxin concentration is readily measured in most hospital laboratories, which
use a standard radioimmunoassay. The approximate therapeutic range for patients in heart failure is
0.5 to 0.8 ng/mL (0.65 to 1 nmol/L), with a typical immunoassay reference range being 0.8 to 2.0
ng/mL (1 to 2.6 nmol/L). Ideally, blood samples should be collected four hours after an intravenous
dose or six hours after an oral dose in order to account for drug distribution and obtain an accurate
measurement. The serum digoxin concentration is likely to be falsely elevated if the sample is
obtained soon after administration or ingestion because of the time required to equilibrate through the
large volume of distribution.

The serum digoxin concentration does not necessarily correlate with toxicity. Numerous reports have
described asymptomatic patients with a "toxic" level, while others described patients with significant
toxicity despite a serum digoxin concentration in the therapeutic range [22,26-28].

Although they may not correlate with clinical manifestations of toxicity, serum digoxin levels are used
in some cases to determine the dosing of antidotal therapy with Fab fragments. (See 'Antidotal
therapy with antibody (Fab) fragments' below.)

Although the digoxin immunoassay is specifically designed to measure digoxin, cross reactivity with
other cardiac glycosides does occur. Consequently, patients poisoned with another cardiac glycoside,
such as those found in various plant species, may have an elevated initial digoxin concentration.
However, because cross reactivity is incomplete, an elevated digoxin concentration only confirms
exposure in such instances and there is NO correlation between the numerical measurement and the
degree of toxicity. Therefore, in this setting digoxin concentration should not be used to calculate
antidotal therapy with Fab fragments.

Following the administration of Fab fragments, serum immunoassays of digoxin are unreliable, as they
measure both bound and unbound drug. Fab treatment frequently causes an elevation in the
measured digoxin concentration despite a free digoxin level approaching zero [29,30]. Consequently,
total digoxin levels should not be obtained or used clinically following Fab fragment administration.
The measurement of "free" digoxin concentrations may be helpful in determining when a patient can
restart digoxin, if desired. However, the free digoxin level may not be routinely available in some
centers.

Elevated digoxin levels have been identified in pregnant women, newborns, and patients with
acromegaly, subarachnoid hemorrhage, liver disease, and renal failure due to endogenous digoxin-
like substances [31]. The clinical significance of endogenous digoxin-like substances remains
unknown.
Electrocardiogram — Digitalis toxicity can produce a range of cardiac arrhythmias, and rhythm
disturbances may evolve and change rapidly. Thus, performing continuous cardiac monitoring and
obtaining serial electrocardiograms (ECG) is important in the setting of toxicity. An ECG should be
obtained upon presentation and repeated with any change in the patient's clinical condition or any
significant alteration in the rhythm or waveform on the cardiac monitor.

Premature ventricular contractions are the most common rhythm disturbance caused by digitalis
toxicity [9]. Others include bradycardia, atrial tachyarrhythmias with AV block, ventricular bigeminy,
junctional rhythms, various degrees of AV nodal blockade, ventricular tachycardia, and ventricular
fibrillation. Bidirectional ventricular tachycardia, while not pathognomonic for digoxin toxicity, is
encountered in rare instances; digoxin is one of only a few xenobiotics known to produce this
arrhythmia (waveform 1).

Ventricular arrhythmias are reportedly more common in chronic toxicity and in patients with chronic
heart disease [26]. A detailed description of the arrhythmias caused by digitalis is found separately.
(See "Cardiac arrhythmias due to digoxin toxicity".)

The so-called "digitalis effect" on the ECG consists of T wave changes (flattening or inversion), QT
interval shortening, scooped ST segments with ST depression in the lateral leads, and increased
amplitude of the U waves. It is often seen with chronic digoxin use and does not correlate well with
clinical manifestations of toxicity (waveform 2) [11].

DIAGNOSIS — The diagnosis of digitalis (cardiac glycoside) toxicity is made clinically based upon a
combination of a history of exposure, suggestive clinical features, and/or electrocardiographic
manifestations. Isolated elevated serum digoxin concentrations may confirm exposure but do not
correlate consistently with clinical manifestations of toxicity. Following an acute overdose, the patient
may remain asymptomatic for several hours and then manifest a number of symptoms and signs,
including cardiac (arrhythmia), gastrointestinal (anorexia, nausea, vomiting, and abdominal pain), and
neurologic findings (confusion, weakness, delirium). The cardiac manifestations of digitalis toxicity can
include virtually any type of arrhythmia, with the exception of rapidly conducted atrial arrhythmias.
Hyperkalemia is an important marker of and prognostic indicator for acute toxicity. Chronic toxicity is
often more difficult to diagnose, as symptom onset tends to be more insidious and digoxin
concentrations may be minimally elevated.

DIFFERENTIAL DIAGNOSIS — Poisoning with beta blockers, calcium channel blockers, and alpha
agonists (eg, clonidine) can present in a similar fashion to digitalis toxicity, with bradycardia and
hypotension being prominent features. An elevated serum digoxin concentration distinguishes digitalis
poisoning. In addition, significant toxicity from calcium channel blockers generally produces
hyperglycemia. Clonidine poisoning leads to greater CNS depression, respiratory depression, and
miosis than is seen with digoxin poisoning.

Nontoxicologic etiologies may also present with symptoms and signs similar to digitalis poisoning.
These may include sick-sinus syndrome, hypothermia, hypothyroidism, myocardial infarction, and
hyperkalemia from other causes.

MANAGEMENT

Basic measures and arrhythmias — When digitalis toxicity is suspected, the following measures
should be performed:

● Assess airway, breathing, and circulation; stabilize as necessary

● Place the patient on continuous cardiac and pulse oximetry monitors
● Establish intravenous (IV) access
● Obtain an electrocardiogram (ECG)
● Obtain a fingerstick glucose measurement if there is any alteration in mental status (see
'Approach to testing' above)

The treatment for any clinically significant arrhythmia from digitalis toxicity, such as those producing
hypotension, is digoxin-specific antibody (Fab) fragments. Treatment decisions must be made on an
individual basis and are often made in conjunction with a medical toxicologist or a poison control
center. (See 'Additional resources' below.)

As temporizing measures or if Fab fragments are not immediately available, symptomatic bradycardia
or bradyarrhythmia can be treated with atropine (0.5 mg IV in adults; 0.02 mg/kg IV in children,
minimum dose 0.1 mg) and hypotension with IV boluses of isotonic crystalloid. In patients with history
of decompensated heart failure, judicious use of fluids may be required. Life-threatening ventricular
arrhythmias are treated according to the algorithms of advanced cardiac life support. (See "Advanced
cardiac life support (ACLS) in adults".)

Antidotal therapy with antibody (Fab) fragments

Indications and general approach — Early recognition of digitalis toxicity and prompt
administration of Fab fragments is essential for the successful treatment of severe poisoning [13,32].
Fab fragments are highly effective and safe and have transformed the management of cardiac
glycoside poisoning [32,33].

The dosing of Fab fragments is based upon the clinical setting (eg, agent and amount ingested; serum
digoxin concentration) and is discussed in detail separately. Following the acute ingestion of an
unknown amount of digitalis, empiric treatment consists of 10 vials of digoxin Fab fragments for adults
or 5 vials for children [34]. One vial binds approximately 0.5 mg of digoxin. The indications for
treatment are described below. (See "Dosing regimen for digoxin-specific antibody (Fab) fragments in
patients with digoxin toxicity".)

Fab fragments should be given in all cases of severe digitalis poisoning, as there is no alternative
therapy with comparable efficacy and safety. We suggest Fab fragments be given to patients with
digitalis toxicity and any of the following:

● Life-threatening or hemodynamically unstable arrhythmia (eg, ventricular tachycardia; ventricular

fibrillation; asystole; complete heart block; Mobitz II heart block; symptomatic bradycardia)
● Hyperkalemia (serum potassium >5 to 5.5 meq/L [>5 to 5.5 mmol/L])
● Evidence of end-organ dysfunction from hypoperfusion (eg, renal failure, altered mental status)

We generally do not advocate treatment with Fab fragments based solely upon the serum digoxin
concentration or the amount ingested; treatment is predicated on the clinical manifestations described
above. However, some advocate giving Fab fragments if the serum digoxin concentration is greater
than 10 ng/mL (13 nmol/L) at steady state in acute ingestions, or greater than 4 ng/mL (5.1 nmol/L) in
chronic ingestions, or when an adult ingests more than 10 mg or a child more than 4 mg acutely.

Cross reactivity exists between digoxin and other cardiac glycosides. Therefore, digoxin-specific
antibodies can be used to treat poisoning involving cardiac glycosides from both plants and animals
[24,35,36]. However, the dosing of Fab fragments should be done empirically in such cases because
the degree of toxicity in naturally occurring cardiac glycosides does not correlate with the serum
digoxin concentration. (See 'Serum digoxin concentration' above.)

The advent of digoxin-specific antibody (Fab) fragments occurred in 1976 [26,37]. Evidence for the
benefit of Fab fragments is found in the many case series that have appeared since that time [33,38].
Prior to the development of this treatment, the management of digitalis overdose was difficult and
often resulted in life-threatening arrhythmias.

Patients with pacemakers — It may be impossible to determine the underlying cardiac rhythm
and thereby detect early signs of digitalis toxicity in patients with pacemakers. The ECG in such
patients may demonstrate a paced rhythm without ventricular ectopy or bradyarrhythmia despite the
presence of moderate to severe digitalis toxicity. We suggest treating these patients with digoxin-
specific antibody fragments if the serum potassium concentration is above 5 to 5.5 meq/L [>5 to 5.5
mmol/L] or clinical symptoms are significant (eg, encephalopathy) or progressing. (See 'Clinical
manifestations' above.)

GI decontamination — The administration of activated charcoal (AC) or cholestyramine for

gastrointestinal decontamination should be viewed as adjunctive and not primary therapy in patients
with digitalis poisoning.

Patients suspected of having an acute digitalis intoxication who present to the emergency department
within one to two hours of ingestion may benefit from the administration of AC. The standard dose is 1
g/kg (maximum 50 g). The decision to administer AC should be made after ensuring that the patient is
alert and adequately protecting their airway. We do not advocate insertion of a nasogastric tube in a
nonintubated patient solely for the purpose of administering AC. AC is unlikely to benefit patients with
chronic digitalis toxicity.

Cardiac glycosides undergo some degree of enterohepatic or enteroenteric recirculation and are
adsorbed to activated charcoal. However, there are mixed clinical data regarding the efficacy of AC or
multi-dose AC (MDAC) in the setting of yellow oleander poisoning: One randomized trial found a
reduction in mortality with AC administration [39], while another did not [40].

When Fab fragments are not readily available, AC or MDAC are reasonable interventions in patients
with yellow oleander poisoning, although their efficacy remains unclear. The extrapolation of data from
studies of yellow oleander poisoning to poisonings with other glycosides (eg, digoxin) should be made
with caution. Most importantly, neither AC nor MDAC should ever be considered an alternative to Fab
fragment therapy for any cardiac glycoside poisoning when Fab fragments are available. Fab fragment
therapy remains the essential treatment for digitalis poisoning. (See 'Antidotal therapy with antibody
(Fab) fragments' above.)

Cholestyramine may interrupt enterohepatic recirculation and its use has been reported in patients
with acute digitalis intoxication and renal failure for whom Fab fragments were not available [41,42]. If
used, the dose is 4 g by mouth, given twice daily.

Electrolyte abnormalities — Hyperkalemia is common in acute digitalis intoxication and accurately

reflects the degree of toxicity and risk of death. However, hyperkalemia itself does not cause death,
and treatment with potassium-lowering agents such as insulin and dextrose, sodium bicarbonate, or
ion exchange resins does not reduce mortality [23].

Once treatment with digoxin-specific antibody (Fab) fragments is instituted, hyperkalemia is rapidly
corrected as the regenerated sodium-potassium ATPase pumps potassium back into cells. Thus,
aggressive treatment with potassium-lowering agents could cause significant hypokalemia following
antidotal therapy.

If a patient with digitalis poisoning is hypokalemic, potassium should be administered since

hypokalemia exacerbates digitalis toxicity [22]. The need for potassium repletion is particularly
important for patients who are to be treated with Fab fragments, because this treatment leads to a
further reduction in the serum potassium. Many hypokalemic patients are simultaneously
hypomagnesemic and should be given magnesium as well. (See "Clinical manifestations and
treatment of hypokalemia in adults".)

It has been taught that calcium should not be given to patients with digitalis toxicity for the treatment of
hyperkalemia. This teaching is based primarily upon five published cases dating back to 1933. Of
these five cases, only three patients had a temporal association between calcium administration and
digoxin toxicity [43-45]. Some studies have shown that hypercalcemic animals given digoxin
developed adverse effects with lower doses than normocalcemic animals [46,47]. However, the serum
calcium levels in these studies exceeded 20 mg/dL (5 mmol/L) before increased toxicity occurred.
Other animal experiments involving lower, more physiologic, serum calcium concentrations did not
show increased toxicity [48].

There are several case reports of patients receiving calcium for treatment of digoxin-induced
hyperkalemia without adverse effects [49,50]. In addition, a large retrospective series of patients with
digoxin toxicity found no ill effects attributable to the administration of calcium [51].

Nonetheless, because hyperkalemia is not the cause of death and excessive intracellular calcium is
present in digitalis poisoning, we do not recommend routine administration of calcium in hyperkalemic
patients with recognized digoxin toxicity. In this setting, hyperkalemia is best treated with digoxin-
specific antibody fragments. (See 'Antidotal therapy with antibody (Fab) fragments' above.)

Renal failure

General care — Volume depletion from diuretics or gastrointestinal losses can cause prerenal
disease, contributing to digitalis toxicity. Appropriate fluid resuscitation is necessary in such cases.
(See "Etiology, clinical manifestations, and diagnosis of volume depletion in adults".)

Fab fragment dosing — The dose of digoxin-specific antibody (Fab) fragments does not need to
be adjusted in patients with renal failure, but the elimination of both digoxin and Fab fragments is
markedly prolonged in this setting [52-54]. Cases of recurrent digoxin toxicity, including ventricular
arrhythmias, have been reported 72 to 90 hours after antidotal therapy [29]. Thus, any patient with
significant renal dysfunction who receives Fab fragments should be observed in a closely monitored
setting for a minimum of 72 hours.

Extracorporeal removal — Because of digoxin's large volume of distribution and molecular

weight, extracorporeal removal is not beneficial. Neither hemoperfusion nor hemodialysis has been
shown to be helpful in the management of digoxin toxicity [55-57].

The combination of Fab fragments and plasmapheresis has been used with apparent success in a few
patients with renal failure [58,59]. Nevertheless, we do not routinely recommend this approach.
Instead, we administer Fab fragments for the usual indications and observe the patient with renal
failure in a closely monitored setting over several days. Additional Fab fragments are given if signs of
toxicity recur.

Disposition — All patients with signs of digitalis toxicity should be admitted to the hospital with
continuous cardiac monitoring. Patients who have displayed unstable cardiac rhythms and those with
underlying cardiac disease or major comorbidities are admitted to an intensive care setting.

Patients with less severe signs of digitalis toxicity who do not receive antidotal therapy with Fab
fragments are admitted for monitoring, which should include serial measurements of their serum
potassium and digoxin concentrations. Serial electrocardiograms (ECG) should be obtained. Although
the time interval for obtaining ECGs will vary depending on the patient's clinical condition, a new ECG
should be obtained if any significant changes are noted on the cardiac monitor.

Patients with suspected digitalis toxicity but without significant manifestations or renal disease are
placed on cardiac monitoring and observed for approximately six hours. If they remain asymptomatic
and a repeat serum digoxin concentration is not increasing, they may be discharged.

PEDIATRIC CONSIDERATIONS — While less common, pediatric ingestions of digitalis are potentially
life threatening [60]. Toxicity among children generally presents with signs and symptoms similar to
adults, but with a few important exceptions. Children are more likely to present with bradyarrhythmias
and heart block, rather than ventricular arrhythmias [61]. In addition, children may be more resistant to
digoxin's cardiotoxic effects than adults at an equivalent serum concentration [26].

The treatment of digoxin toxicity, including the indications for antidotal therapy with digoxin-specific
antibody (Fab) fragments, remains unchanged. The dosing of Fab fragments is based upon the
clinical setting (eg, agent and amount ingested; serum digoxin concentration) and is discussed in
detail separately. The indications for treatment are described above. (See "Dosing regimen for
digoxin-specific antibody (Fab) fragments in patients with digoxin toxicity" and 'Antidotal therapy with
antibody (Fab) fragments' above.)

In addition to ingesting digitalis medications, children may ingest plants with toxic effects similar to
cardiac glycosides. The diagnosis and management of such ingestions is reviewed separately. (See
"Potentially toxic plant ingestions in children: Clinical manifestations and evaluation", section on
'Cardiac glycosides (eg, oleander, foxglove)' and "Toxic plant ingestions and nicotine poisoning in
children: Management".)

ADDITIONAL RESOURCES — Regional poison control centers in the United States are available at
all times for consultation on patients who are critically ill, require admission, or have clinical pictures
that are unclear (1-800-222-1222). In addition, some hospitals have clinical and/or medical
toxicologists available for bedside consultation and/or inpatient care. Whenever available, these are
invaluable resources to help in the diagnosis and management of ingestions or overdoses. The World
Health Organization provides a listing of international poison centers at its website:
www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from

selected countries and regions around the world are provided separately. (See "Society guideline
links: General measures for acute poisoning treatment".)

SUMMARY AND RECOMMENDATIONS

● Arrhythmia is the most dangerous manifestation of digitalis (cardiac glycoside) poisoning.

Arrhythmias occur through several mechanisms, which are described in the text. (See
'Pharmacology and cellular toxicology' above and 'Kinetics' above.)

● The cardiac manifestations of digitalis toxicity can include virtually any type of arrhythmia with the
exception of rapidly conducted atrial arrhythmias. Gastrointestinal (anorexia, nausea, vomiting,
and abdominal pain) and neurologic signs (confusion and weakness) may be present. Chronic
toxicity is more difficult to diagnose, as symptom onset tends to be more insidious. In addition to
gastrointestinal symptoms, visual changes may occur, including alterations in color vision, the
development of scotomas, or blindness. (See 'Clinical features and diagnosis' above.)

● The differential diagnosis for digitalis intoxication includes poisoning with beta blockers, calcium
channel blockers, or alpha agonists (eg, clonidine), as well as nontoxicologic etiologies such as
sick-sinus syndrome, hypothermia, hypothyroidism, myocardial infarction, and hyperkalemia
unrelated to digitalis. (See 'Differential diagnosis' above.)

● In the patient with suspected digoxin toxicity, a serum digoxin concentration, serum potassium
concentration, creatinine and BUN, and serial electrocardiograms (ECG) should be obtained.
(See 'Laboratory and ECG evaluation' above.)

● A quantitative serum digoxin concentration is readily determined in most hospital laboratories.

The therapeutic range is 0.8 to 2 ng/mL (1 to 2.6 nmol/L). The serum digoxin concentration does
not necessarily correlate with toxicity. (See 'Serum digoxin concentration' above.)

● We recommend that any patient with clinically significant manifestations of digitalis poisoning be
treated with digoxin-specific antibody (Fab) fragments (Grade 1B). Significant findings include:

• Life-threatening arrhythmia (eg, ventricular tachycardia; ventricular fibrillation; asystole;

complete heart block; Mobitz II heart block; symptomatic bradycardia)

• Evidence of end-organ dysfunction (eg, renal failure, altered mental status)

• Hyperkalemia (serum potassium >5 to 5.5 meq/L [>5 to 5.5 mmol/L]) (see 'Antidotal therapy
with antibody (Fab) fragments' above)

● As temporizing measures or if Fab fragments are not immediately available, bradycardia can be
treated with atropine (0.5 mg IV in adults; 0.02 mg/kg IV in children, minimum dose 0.1 mg) and
hypotension with IV boluses of isotonic crystalloid. (See 'Basic measures and arrhythmias'
 above.)

● Hyperkalemia is common in acute digitalis intoxication and accurately reflects the degree of
toxicity and risk of death. However, hyperkalemia itself does not cause death and treatment of
hyperkalemia does not reduce mortality, but does increase the risk of hypokalemia following
treatment with Fab fragments. As treatment with Fab fragments causes a reduction in the serum
potassium concentration, aggressive management of hyperkalemia is typically not warranted.
(See 'Electrolyte abnormalities' above.)

● Patients suspected of having acute digitalis intoxication who present to the emergency
department within one to two hours of ingestion may benefit from the administration of activated
charcoal. The standard dose is 1 g/kg (maximum 50 g). The decision to administer activated
charcoal should be made after ensuring that the patient is alert and adequately protecting their
airway. (See 'GI decontamination' above.)

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Topic 319 Version 27.0

GRAPHICS

Structure of digoxin

Graphic 65821 Version 1.0

Pharmacokinetic comparison of digoxin and digitoxin

Digoxin Digitoxin

Bioavailability (percent) 70 90

Plasma binding (percent) 25 95

VD (L/kg) 5.6 L/kg 0.56 L/kg

Half life (hours)* 50 161

Desired therapeutic concentrations 0.5 to 0.8 ng/mL ----

* Assumes normal renal function.

Data from:
1. Lapostolle F, Baud FJ, Borron SW, Mégarbane B. Digitalis glycosides. In: Critical Care Toxicology:
Diagnosis and Management of the Critically Poisoned Patient, Brent J, Wallace KL, Burkhart K, et al
(Eds), Elsevier Mosby, Philadelphia 2004. p.393.
2. Holford NHG. Pharmacokinetics and pharmacodynamics: Rational dosing and the time course of drug
action. In: Basic and Clinical Pharmacology, 8th ed, Katzung BG (Ed), McGraw Hill, New York 2001.
p.35.

Graphic 60113 Version 5.0

Inhibitors and inducers of P-glycoprotein (P-gp) drug efflux pump

Inhibitors of P-gp Inducers of P-gp

Amiodarone Lopinavir-ritonavir Fosphenytoin

Azithromycin Neratinib Phenobarbital*

(systemic)
Phenytoin
Carvedilol Ombitasvir-
Rifampin (rifampicin)
paritaprevir-ritonavir
(Technivie) ¶ St. John's wort

Clarithromycin Propafenone

Cobicistat and Quinidine

cobicistat-containing
coformulations*

Cyclosporine Quinine
(systemic)

Daclatasvir Ranolazine

Dronedarone Ritonavir and ritonavir

-containing
coformulations ¶

Eliglustat Rolapitant

Erythromycin Simeprevir
(systemic)

Flibanserin Tacrolimus (systemic)*

Glecaprevir- Tamoxifen*
pibrentasvir

Itraconazole Telaprevir

Ivacaftor Ticagrelor*

Ketoconazole Velpatasvir
(systemic)

Lapatinib Vemurafenib

Ledipasvir Verapamil

Inhibitors of the P-gp drug efflux pump listed above may increase serum concentrations of
drugs that are substrates of P-gp, whereas inducers of P-gp drug efflux may decrease serum
concentrations of substrates of P-gp. Examples of drugs that are substrates of P-gp efflux pump
include: Apixaban, cyclosporine, dabigatran, digoxin, rivaroxaban, and tacrolimus.
The degree of effect on P-gp substrate serum concentration may be altered by dose and timing
of orally administered P-gp inhibitor or inducer.
Specific drug interaction effects may be determined by using Lexi-Interact, the drug interactions
program included with UpToDate. Refer to UpToDate clinical topics on specific agents and
conditions for further details.

* Minor clinical effect or supportive data are limited to in-vitro effects (ie, clinical effect is unknown).
¶ The combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (Viekira Pak) is not a significant
inhibitor of P-gp efflux pump [1].

Reference:​
 1. Menon RM, Badri PS, Wang T, et al. Drug-drug interaction profile of the all-oral anti-hepatitis C virus
regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol 2015; 63:20.
​ Lexicomp Online (Lexi-Interact). Copyright © 1978-2017 Lexicomp, Inc. All Rights Reserved.

Graphic 73326 Version 32.0

Single-lead electrocardiogram (ECG) showing bidirectional
ventricular tachycardia (VT)

Rhythm strip showing bidirectional ventricular tachycardia (VT) which may be a

manifestation of digoxin toxicity. This rare, life-threatening tachyarrhythmia is
characterized by beat-to-beat changes in the polarity of consecutive premature
ventricular complexes.

Courtesy of Ary Goldberger, MD.

Graphic 71796 Version 3.0

Normal rhythm strip

Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS
duration is 0.08 sec. Both the P and T waves are upright.

Courtesy of Morton F Arnsdorf, MD.

Graphic 59022 Version 3.0

Digitalis effect

The ST segment is depressed and concave upward.

Graphic 56737 Version 4.0

Contributor Disclosures
Michael Levine, MD Nothing to disclose Ayrn O'Connor, MD Nothing to disclose Stephen J
Traub, MD Nothing to disclose Michele M Burns, MD, MPH Nothing to disclose Jonathan
Grayzel, MD, FAAEM Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found,
these are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
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