Treatment with digoxin: Initial dosing, monitoring, and dose modification

For maximal early benefits, digoxin requires loading doses, which can be administered
intravenously or orally. The electrolyte and renal status of each patient should be ascertained
prior to initiating treatment and periodically thereafter. Hypokalemia or hypomagnesemia
may promote digoxin-induced arrhythmias. Patients receiving digoxin for ventricular rate
control in atrial fibrillation or flutter will usually require more rapid loading than those
treated with digoxin for heart failure, in whom a loading dose is typically not required.

Slow digoxin loading — Slow oral digitalization, generally preferred for most patients, can
be achieved by starting a maintenance dose of 0.125 to 0.25 mg daily. A steady state will be
achieved after five cycles of the drug half-life which is approximately 7 to 10 days

Rapid digoxin loading — Rapid intravenous and oral digitalization can be used to control the
ventricular response in atrial fibrillation and flutter. The total loading dose with digoxin
varies from patient to patient but is usually between 0.75 to 1.5 mg with intravenous
administration and 1 to 1.5 mg with oral administration.

●Intravenous loading –initial intravenous dose of 0.25 to 0.5 mg of digoxin is given over
several minutes, followed by 0.25 mg every 6 hours for a total loading dose of 0.75 to 1.5 mg
(10 to 12 mcg/kg lean body weight) . Intravenous digoxin begins to act in 15 to 30 minutes
with a peak effect in 1 to 5 hours.

●Oral loading – Rapid oral digitalization can be accomplished by giving 0.5 mg initially
followed by 0.25 mg every six hours for a total loading dose of 0.75 to 1.5 mg.

Loading dose adjustments — Patients who are hypokalemic, hypomagnesemic,

hypercalcemic, hypoxic, or with hypothyroidism are more sensitive to the effects of digoxin.
If these issues persist at the time of digoxin loading, an initial loading dose in the lower range
(eg, 0.75 mg or less) should be considered.

Digoxin distributes widely to skeletal muscle, cardiac, and other lean tissue and has a large
volume of distribution in normal subjects, which is decreased in patients who are older, have
low skeletal muscle mass, or severe renal impairment. Digoxin serum concentrations relative
to the administered loading dose may be proportionally increased among persons with low
muscle mass and/or renal impairment, and a reduced loading dose should be considered.

Renal impairment — The digoxin loading dose should be reduced by approximately one-third
to one-half in the setting of severe chronic renal insufficiency, including hemodialysis. The
reduced loading dose may be supplemented after six hours if clinical response is inadequate,
in absence of toxicity.

Lean body weight — In general, it is reasonable to select an initial loading dose in the lower
range (ie, 0.75 to 1 mg) for patients of low to average lean body weight (eg, 45 to 70 kg) and
in the upper part of the dose range (ie, 1 to 1.5 mg) for patients of average to above average
lean body weight (eg, 71 to 90 kg)

Patients with low body weight — Patients with body weight of less than 45 kg should receive
50 percent of the normal loading dose.
Patients who are obese — Compared with normal weight subjects, neither volume of
distribution nor clearance of digoxin are consistently altered by changes in body composition
associated with obesity. Therefore, normal (non-weight based) loading doses should be used.
However, if a weight based dose is used, it should be based upon estimated lean body weight

Maintenance digoxin dosing — For most patients, the maintenance dose of digoxin will be
between 0.125 mg and 0.25 mg daily. The daily maintenance dose will vary depending on the
indication for digoxin therapy, with patients receiving digoxin for heart failure often
requiring lower doses than those who are taking digoxin for ventricular rate control.
Additionally, the maintenance dose is affected by renal function, body weight, and the
presence or absence of other medications which are known to alter the metabolism of digoxin
●Ventricular rate control – For patients taking digoxin for ventricular rate control in the
setting of atrial arrhythmias, the typical maintenance dose is between 0.125 and 0.25 mg
daily. In contrast to digoxin use for heart failure, there is no particular serum digoxin level
which is targeted, as the medication should be adjusted to maintain optimal ventricular rate
control. However, serum digoxin levels higher than 1 ng/mL (1.3 nmol/L) should be avoided
to reduce the risk of digoxin toxicity.

Dose adjustments — Bioavailability is between 70 and 80 percent for conventional digoxin

tablets and the half life of of digoxin ranges from 33 to 50 hours when renal function is
normal. Unlike certain other drugs (eg, furosemide), the bioavailability of the oral dose forms
of digoxin does not appear to be affected by heart failure. Dose adjustments of digoxin are
necessary in patients with renal dysfunction, patients with low body weight, and with the
concomitant use of certain medications.

Dose adjustment in renal disease — Approximately 70 to 80 percent of digoxin is eliminated

unchanged in the urine, leading to prolongation of the half-life in patients with renal
insufficiency. Renal insufficiency also decreases the extravascular volume of distribution of
digoxin, another effect that can elevate plasma drug levels. As a result, both the initial
loading dose and the maintenance dose must be reduced in patients with underlying
renal disease. In end-stage renal disease, for example, the loading dose should be one-
half to two-thirds normal.

Hepatic disease has little influence on digoxin metabolism or clearance; therefore, no dose
adjustment is necessary.

Dose adjustment with concomitant medications — There are a number of important drug
interactions: ●Inhibitors of P-glycoprotein efflux transporters (eg, amiodarone, dronedarone,
propafenone, quinidine, and verapamil) can increase serum digoxin levels. With concurrent
dronedarone administration, for example, the digoxin dose should be reduced by one-half if
digoxin cannot be discontinued ●Inducers of P-glycoprotein (eg, phenytoin, rifampin, etc),
on the other hand, can decrease serum digoxin levels.

●Cholestyramine and antacids can decrease the intestinal absorption of digoxin by 20 to 35

percent, necessitating an increase in the daily dose. To avoid these interactions, digoxin
should be dosed one hour before or two to three hours after the administration of the antacids
or cholestyramine.

●Bupropion, an antidepressant that is also frequently prescribed to aid in smoking cessation,

can decrease digoxin levels by 60 percent ●Diuretics may increase digitalis toxicity as a
result of a decrease in the glomerular filtration rate and the development of electrolyte
abnormalities, especially hypokalemia.

●Tetracycline and erythromycin can interfere with the sequential hydrolysis pathway of
digoxin metabolism (which begins in the stomach and is responsible for less than 15 percent
of the metabolism in most patients but which can be significantly more active in a minority of
patients). As such, these drugs increase digoxin levels in approximately 10 percent of patients
in whom this pathway is a significant component of the drug's metabolism.

Digoxin crosses the placenta and has been used for both fetal and maternal cardiac
indications without report of fetal harm or teratogenicity . As such, there is no
contraindication for using digoxin during pregnancy or during lactation.

Digoxin in patients with amyloidosis — The inotropic effects of digoxin are not generally
beneficial in patients with amyloidosis. Moreover, because digoxin binds avidly to amyloid
fibrils, patients with amyloidosis who take digoxin may be at an increased risk of digoxin
toxicity .Additionally, as a result of the binding of digoxin to myocardial amyloid fibrils,
cardiac digoxin concentration may be higher than serum digoxin concentration, leading to
toxicity in the setting of "therapeutic" serum digoxin levels. However, in a patient with atrial
fibrillation with a rapid ventricular response, careful digoxin administration is usually safe
and effective for reducing the ventricular rate

Monitoring — Given the relatively narrow therapeutic window of digoxin, with substantial
overlap between so-called therapeutic and toxic levels, the "optimal" level varying with the
clinical setting. Monitoring the serum digoxin level is particularly important in persons with
chronic renal dysfunction or rapidly changing renal function. Additionally, patients with
electrolyte disturbances, particularly hypokalemia and hypomagnesemia should undergo
monitoring of the serum digoxin level until serum potassium level and magnesium
concentration return to the normal range

Monitoring the serum digoxin concentration is most important when digoxin is used in the
treatment of heart failure with systolic dysfunction, whereas levels are only checked when
used in patients with atrial fibrillation if toxicity is suspected. Blood samples should be
obtained at least 6 hours, but optimally 12 hours, after administration of digoxin to ensure
completion of distribution from the blood to the tissues. In patients with advanced kidney
disease or who are on hemodialysis, the digoxin level should be checked at least 12 to 24
hours after the prior dose. Serum digoxin concentrations measured prior to these times may
be falsely elevated.

Adjusting the digoxin dose — Assuming that the digoxin level was drawn at the correct time,
at steady state, and under conditions of stable renal function, there is a linear relationship
between digoxin dose and serum concentration. As an example, a steady state concentration
is measured and returns at 1.6 ng/mL (2.05 nmol/L) in a patient taking a daily maintenance
dose (for this example, 0.25 mg daily). Assuming the desired serum concentration is 0.8
ng/mL (1.0 nmol/L), the dose should be reduced by 50 percent (to 0.125 mg daily in this
example). The same linear relationship is true for patients whose serum concentration is
lower than desired in whom a dose increase is needed.

When digoxin is used strictly for ventricular rate control in AF, serum digoxin levels should
be monitored periodically, although the drug concentration often does not correlate with
ventricular rate control and is used more as a guide to toxicity than to therapy. Junctional
escape beats (as detected by the equality of all the longest observed R-R intervals on the
electrocardiogram) are common when digitalis has successfully slowed the ventricular rate.
Giving more digoxin in this setting will increase the degree of AV nodal block and produce
periods of regular junctional rhythm. The change from single junctional escapes to periodic
junctional rhythm usually signifies the development of digoxin toxicity.

Digoxin-related cardiac arrhythmias and extracardiac symptoms can occur when the serum
digoxin concentration is in the therapeutic or even subtherapeutic range; as a result, the
presence of digoxin toxicity or excess is often a clinical diagnosis irrespective of circulating
levels (unless of course the value is zero).

DiGOXIN IN HFrEF

We recommend use of digoxin in the following clinical settings:

●For most patients with heart failure with reduced ejection fraction (HFrEF), we suggest not
routinely using digoxin. We reserve use of digoxin for patients with HFrEF on optimal
evidence-based therapy with NYHA functional class III or IV; some experts also require a
left ventricular ejection fraction (LVEF) <25 percent). Optimal evidence-based therapy for
HFrEF includes (ACE) inhibitor, angiotensin II receptor blocker (ARB), or angiotensin
receptor-neprilysin inhibitor (ARNI); beta blocker; mineralocorticoid receptor antagonist
(MRA) as indicated; and a diuretic as needed for fluid control.

digoxin may be added during initial therapy for HF with severe symptoms or may be used
only in patients with persistent symptoms despite guideline-directed therapy for HFrEF.
●Some patients in sinus rhythm with HFrEF present for care while taking digoxin but are not
yet optimally treated with other evidence-based therapies . In such patients, we may continue
digoxin while initiating and/or titrating these other agents. The decision on whether or not to
continue digoxin therapy while initiating and/or titrating other therapy is based upon
weighing the potential risks and benefits for each patient, including consideration of the
patient's renal function and risk of digoxin toxicity. If the patient is asymptomatic, in sinus
rhythm, and has improved systolic function after these medications (including at least an
ACE inhibitor, ARB, or ARNI; and a beta blocker) have been initiated and titrated, we
attempt a trial of discontinuation of digoxin

digoxin improved clinical symptoms, quality of life, and exercise tolerance while lowering
rates of hospitalization for HF, but did not improve survival

Digoxin is not indicated for primary stabilization of patients with an acute exacerbation of
HF. Long-term therapy (including digoxin, if needed) is initiated after stabilization. Digoxin
may be initiated in the early treatment of such patients if it is anticipated to be part of a long-
term treatment strategy in those who were already treated with appropriate medical therapy
prior to decompensation.

Digoxin is not indicated for patients with HF with preserved ejection fraction (HFpEF).

Patients with HFrEF who are candidates for digoxin therapy should be evaluated for
contraindications and cautions and should undergo baseline electrolyte and renal function
testing. Digoxin dose is individualized based upon renal function, ideal body weight, and
concomitant medications that may alter serum digoxin concentrations (SDCs).

Digoxin is contraindicated in patients with significant sinus or atrioventricular (AV) block

(unless the block has been addressed with a permanent pacemaker).

Digoxin possesses a narrow toxic to therapeutic window. Toxic effects include the induction
of arrhythmias, conduction disturbances, and, in severe cases, constitutional symptoms such
as nausea, vomiting, and visual disturbances. We suggest avoiding digoxin use in the setting
of acute or subacute kidney injury.

Digoxin dose adjustment is based upon renal function Hypothyroidism is a risk factor for
digoxin toxicity, so thyroid function tests should be checked before initiating digoxin
Standard initial dosing is commonly used. A nomogram may be helpful, particularly for
patients with large body size and/or renal dysfunction.

The target serum digoxin level for treatment of HFrEF is between 0.5 and 0.8 ng/mL (0.65 to
1 nmol/L). The typical daily dose to achieve this target level typically ranges from 0.0625 mg
(given as 0.125 mg every other day) to 0.25 mg per day . In patients with normal renal
function, 0.125 mg daily is the typical dose.

Digoxin dosing should be adjusted when digoxin is used concomitantly with drugs that alter
SDCs. Of note, loading doses of digoxin (as may be used for rate control in patients with
atrial fibrillation) are not indicated in patients with HF. Some clinicians obtain a follow-up
trough digoxin level at steady state to guide dose adjustment

Standard initial dose — A common strategy is to use standard initial dosing (particularly for
individuals with ideal body weight, 61 to 80 kg) as follows: ●0.125 mg per day for
individuals with a creatinine clearance ≥30 mL/min. ●0.0625 mg per day (which can be
given as 0.125 mg every other day) for individuals with a creatinine clearance <30 mL/min.

A nomogram (with target serum concentration 0.7 ng/mL) may be helpful in determining an
initial dose based upon ideal body weight and renal function, particularly for patients with
small or large body size and/or renal dysfunction

When to check digoxin levels ●Some experts do not routinely measure digoxin levels if low
doses are used and there is no clinical evidence of toxicity. ●Alternatively, some experts
routinely check a digoxin level after steady state is reached.

Clinical settings in which a digoxin level may be helpful: ●Suspicion of digoxin toxicity in
the setting of new onset anorexia, nausea, or vomiting, or development of arrhythmias
characteristic of digoxin toxicity (eg, AV junctional rhythms or ventricular bigeminy).
●Fluctuating or worsening renal function (including development of acute kidney injury).
●Initiation of an interacting medication such as amiodarone. ●Worsening of HF symptoms
with suspicion of low medication adherence/compliance.

For patients with HFrEF, the target serum digoxin level for maximal efficacy and minimal
risk of toxicity is between 0.5 and 0.8 ng/mL (0.65 to 1 nmol/L). Higher serum levels should
be avoided since they are associated with an increased risk of toxicity without evidence of
enhanced efficacy.
How to monitor levels and adjust digoxin dose — When digoxin levels are monitored, the
serum digoxin level should be measured when steady state is achieved, which is 7 to 10 days
for most patients (and up to three weeks in patients with severe renal impairment) after
starting digoxin or changing the dose of digoxin. For patients with HF, the target serum
digoxin level for maximal efficacy and minimal risk of toxicity is between 0.5 and 0.8 ng/mL
(0.65 to 1 nmol/L). Monitoring may be repeated yearly if the patient is subsequently stable
The digoxin level is best determined as a trough concentration obtained immediately before
administering the daily (or every other day) dose. Otherwise, blood samples should be
obtained at least six hours, but optimally at least 12 hours, after administration of digoxin to
ensure completion of distribution from the blood to the tissues. In patients with advanced
kidney disease or who are on hemodialysis, the digoxin level should be checked at least 12 to
24 hours after the prior dose. SDCs measured prior to these times may be falsely elevated.

Assuming that a patient is receiving the prescribed dose, the digoxin level was drawn at the
correct time, at steady state, and under conditions of stable renal function, there is a linear
relationship between digoxin dose and serum concentration. As an example, a steady state
concentration is measured and returns at 1.6 ng/mL (2.05 nmol/L) in a patient taking a daily
maintenance dose (for this example, 0.25 mg daily). Assuming the desired serum
concentration is 0.8 ng/mL (1 nmol/L), the dose should be reduced by 50 percent (to 0.125
mg daily in this example). When a low digoxin level is detected, inadequate compliance
should be excluded before the digoxin dose is raised.

Digoxin dosing should be adjusted when used concomitantly with drugs that alter SDCs.

pharmacology, diagnosis, and management of acute and chronic digitalis poisoning

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,

Cardiac glycosides reversibly augments inotropy , increase vagal tone, which results in
decreased conduction through the sinoatrial and atrioventricular nodes .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

Both pharmaceuticals 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 varies if toxicity is acute or chronic.

History — Determine the agent, amount taken, time of ingestion, and any coingestants. 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.
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 & gastrointestinal, cardiac, and neurologic manifestations, including visual
disturbances, because these are the most common findings associated with chronic toxicity. 7
symptoms that suggest hypoperfusion, such as confusion and abdominal pain, which may
stem from mesenteric ischemia
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

Bradycardia is frequently encountered in digitalis toxicity./f hypoperfusion and end organ

dysfunction/ mentation and neurologic status, keeping in mind that such effects are often due
to direct toxicity but may be secondary to cerebral hypoperfusion/acute mesenteric ischemia,
which is a rare complication.

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

. 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

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. 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.

Approach to testing

●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●Fingerstick glucose●Acetaminophen and salicylate

levels, ●Pregnancy test
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.

In acute toxicity, the degree of hyperkalemia correlates with mortality. 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 . Renal dysfunction is commonly encountered in the setting of
chronic digoxin toxicity and is often what precipitates the rise in the digoxin concentration.

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 . 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 . The serum
digoxin concentration does not necessarily correlate with toxicity. 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. 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 . 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.

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. 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

.Premature ventricular contractions are the most common rhythm disturbance caused by
digitalis toxicity . 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 . Ventricular arrhythmias are reportedly
more common in chronic toxicity and in patients with chronic heart disease

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

DIFFERENTIAL DIAGNOSIS — beta blockers, calcium channel blockers, and alpha

agonists (eg, clonidine) .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

The treatment for any clinically significant arrhythmia from digitalis toxicity, such as those
producing hypotension, is digoxin-specific antibody (Fab) fragments.

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; minimum
dose 0.1 mg) and hypotension with IV boluses of isotonic crystalloid.

Antidotal therapy with antibody (Fab) fragments Early recognition of digitalis toxicity and
prompt administration of Fab fragments is essential for the successful treatment of severe
poisoning. Fab fragments are highly effective and safe . The dosing of Fab fragments is based
upon the clinical setting (eg, agent and amount ingested; serum digoxin concentration) .
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. One vial binds
approximately 0.5 mg of digoxin. Fab fragments should be given in all cases of severe
digitalis poisoning, as there is no alternative therapy with comparable efficacy and safety.

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
●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. 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.

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.

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

gastrointestinal decontamination should be viewed as adjunctive and not primary therapy
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. 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.

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. 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

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 . 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.

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

Volume depletion from diuretics or gastrointestinal losses can cause prerenal disease,
contributing to digitalis toxicity. Appropriate fluid resuscitation is necessary

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 . Cases of recurrent digoxin toxicity,
including ventricular arrhythmias, have been reported 72 to 90 hours after antidotal therapy.
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

The combination of Fab fragments and plasmapheresis has been used with apparent success
in a few patients with renal failure. 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.

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. 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 . 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. In
addition, children may be more resistant to digoxin's cardiotoxic effects than adults at an
equivalent serum concentration The treatment of digoxin toxicity remains unchanged.

Digitalis effect The ST segment is depressed and concave upward.

Dosing regimen for digoxin-specific antibody (Fab) fragments

Fab fragments are commercially available as DigiFab . Each vial of DigiFab contains 40 mg
of Fab fragments and binds approximately 0.5 mg of digoxin. DigiFab has an elimination
half-life of approximately 15 to 20 hours. However, the half-life may be up to 10 times longer
with renal impairment. Adverse effects of DigiFab include anaphylactic and anaphylactoid
reactions, which are uncommon, However, patients with known allergies to sheep or
sensitivity to papain or other papaya extracts used to cleave the antibody are at risk.

CALCULATING THE DOSE

Neither the digoxin level nor amount ingested is known — Empiric treatment in
severe cases of toxicity consists of 10 vials of Fab fragments which should be repeated if
clinical response is inadequate. Often small children can be adequately treated with smaller
empiric doses and it is reasonable to start with 5 vials and escalate dose based on clinical
response.
Amount of digoxin ingested is known but concentration is unknown — ●Step 1 –
Calculate the total body load (TBL): •TBL for digoxin = Dose (in mg) ingested x 0.8
●Step 2 – Number of vials = TBL/0.5

Steady state digoxin concentration is known — ●Number of vials = [(serum

digoxin concentration in ng/mL) (patient's weight in kg)]/ 100

Note that the formula for calculating the number of Fab fragment vials needed based upon the
serum concentration of digitoxin (which remains in use outside the United States) is not the
same as that used for digoxin.

Cardiac glycoside poisoning other than digoxin or digitoxin — Quantitative

serum levels obtained in poisonings from cardiac glycosides other than digoxin or digitoxin
do not correlate with measurements of these drugs and cannot be used to calculate the Fab
fragment dose. Therefore, empiric treatment is provided as if neither the amount ingested nor
the concentration was known (10 vials initially). These are starting doses; they may be
repeated if clinical response is inadequate after 30 minutes.

Fab fragments should be given over 30 minutes in all patients except those in cardiac arrest
or in whom arrest is imminent. In such patients, the Fab fragments can be given as a slow IV
push. It is important to emphasize that after Fab fragments are administered total serum
digoxin concentrations will be unreliable; only free or unbound digoxin levels will be
clinically useful.

Chronic toxicity without severe signs — In individuals with chronic toxicity who do not
manifest immediately life-threatening arrhythmias (eg, AV nodal blockade present on ECG,
but patient maintains normal blood pressure and clear mentation), half the recommended dose
can be given initially in order to avoid unmasking the condition for which the patient is
taking digoxin. Giving a full dose can elicit acute decompensated heart failure or atrial
fibrillation with rapid ventricular response.