Digitalis Toxicity
Continuing Education Activity
Digoxin is a well-known cardiac
glycoside and one of the oldest drugs
used today in cardiovascular medicine.
It has wide-ranging beneficial effects
and continues to play an important role
in the contemporary management of
appropriately selected patients with heart failure and atrial
fibrillation. Although considered safe, digoxin has a narrow
therapeutic window, and its proper dosing requires the clinician to
be mindful of various patient characteristics including age, gender,
kidney function and concomitant use of other drugs to avoid
potentially life-threatening toxicity. This activity reviews digitalis
toxicity, its pathophysiology, presentation and highlights the role
of the interprofessional team in its management.
Objectives:
• Identify the pathophysiology of digitalis toxicity.
• Discuss the history and physical findings expected in a
patient with digitalis toxicity.
• List the treatment and management options available for
digitalis toxicity.
• Discuss interprofessional team strategies for improving care
in patients with digitalis toxicity.
Introduction
Digoxin is a well-known cardiac glycoside and one of the oldest
drugs used today in cardiovascular medicine. It has wide-ranging
beneficial effects and continues to play an important role in the
contemporary management of appropriately selected patients with
heart failure and atrial fibrillation. Although considered safe,
digoxin has a narrow therapeutic window, and its proper dosing
requires the clinician to be mindful of various patient
characteristics including age, gender, kidney function and
concomitant use of other drugs to avoid potentially
life-threatening toxicity.
Over the past two decades, the use of digoxin has declined
significantly and toxicity cases cases are rare. The few sporadic
cases are often managed with digoxin specific antigen binding
antibody.
What are the side effects of digitalis toxicity?
These are symptoms of digitalis toxicity:
• Confusion.
• Irregular pulse.
• Loss of appetite.
• Nausea, vomiting, diarrhea.
• Fast heartbeat.
• Vision changes (unusual), including blind spots, blurred
vision, changes in how colors look, or seeing spots.
What causes digitalis toxicity?
The most common trigger of digoxin toxicity is hypokalemia,
which may occur as a result of diuretic therapy. Dosing errors are
also a common cause of toxicity in the younger population.
Etiology
Digitalis use was first described in 1785 and was derived from the
foxglove plant. Poisoning with digitalis can occur with acute over-
ingestion of medication or as chronic toxicity most commonly due
to decreased renal clearance. Some metabolic disturbances such as
hypokalemia and hypercalcemia can make one more prone to
toxicity as well as some drug interactions. Chronic toxicity is
more common than acute intoxication.[3]
The most common trigger of digoxin toxicity is hypokalemia,
which may occur as a result of diuretic therapy. Dosing errors are
also a common cause of toxicity in the younger population.
Factors that increase the risk of digoxin toxicity include:
• Hypothyroidism/hyperthyroidism
• Advanced age
• MI
• Renal insufficiency
• Hypercalcemia
• Alkalosis
• Hypoxemia
• Acidosis
Medications that are associated with digoxin toxicity include?
• Diuretics
• Amiodarone
• Beta-blockers
• Benzodiazepines
• Calcium channel blockers
• Macrolide antibiotics
• Propylthiouracil
• Amphotericin
Pathophysiology
The main mechanism of action of digitalis is on the sodium-
potassium ATPase of the myocyte. It reversibly inhibits the
ATPase resulting in increased intracellular sodium levels. The
build-up of intracellular sodium leads to a shift of sodium
extracellularly through another channel in exchange for calcium
ions. This influx of intracellular calcium assists with myocyte
contractility. Digoxin also has direct effects on conduction through
increased vagal tone. Digoxin stimulates the vagus nerve leading
to prolonged conduction through the sinuatrial (SA) and
atrioventricular (AV) nodes. Overall, digoxin slows the conduction
and increases the refractory period in cardiac tissue by enhancing
vagal tone. These actions of digoxin can result in almost every
type of arrhythmia possible such as:
• Extrasystole
• Nonparoxysmal junctional tachycardia
• Ventricular fibrillation
• Premature ventricular contractions
• Atrial fibrillation and flutter
• Bidirectional ventricular tachycardia
• SA and AV node block
The major electrolyte complication in acute digoxin toxicity is
hyperkalemia
.
What are the nursing consideration for digoxin?
Monitor BP periodically in patients
receiving IV digoxin. Monitor ECG during
IV administration and 6 hr after each dose.
Notify health care professional if
bradycardia or new arrhythmias occur.
Observe IV site for redness or infiltration;
extravasation can lead to tissue irritation and sloughing
How do nurses assess for digoxin toxicity?
An additional nursing intervention to guard against digoxin
toxicity is to assess the apical pulse for one full minute before
administering digoxin. Hold the next dose and contact the
physician if the apical pulse is less than 60 or more than 120 beats
per minute
Toxicokinetics
Distribution of digoxin to various tissues normally takes several
hours; therefore, levels of digoxin should me measured six hours
after last ingestion for the most accurate measurement. A steady-
state of dioxin can take up to seven days with a half-life of digoxin
being anywhere between 36 to 48 hours. Increased intracellular
calcium seen with digitalis use may lead to premature contractions
of the myocytes. Repolarization time for both the atria and
ventricles are reduced. This decreased refractory period leads to
increased automaticity and makes the myocytes more prone to the
induction of arrhythmias. Digoxin is primarily renally excreted
with chronic toxicity commonly seen in those with renal
impairment. Many drug interactions lead to decreased clearance of
digoxin. Well-known offenders include verapamil, macrolides, and
antifungals. There is very little difference between sub-therapeutic
and toxic levels of digoxin. The therapeutic window for digoxin is
narrow and difficult to determine. The accepted range is between
0.5 ng/mL to 0.9 ng/mL. What is important to consider is that
concentration does not necessarily correlate with toxicity. There
have been documented cases of clinical toxicity with digoxin
levels in the therapeutic range. Electrolyte disturbances such as
hypomagnesemia, hypercalcemia, and hypokalemia lead to
increased sensitivity to digoxin making toxicity more likely even
with a lower concentration of serum digoxin. This makes
diagnosis difficult and has led to the declining use of digoxin over
the last several years. Diagnosis is primarily based on clinical
presentation in the setting of suspected digoxin intoxication.
History and Physical
History of exposure is necessary to determine if poisoning is acute
or chronic. Most reported poisonings result from chronic toxicity.
Clinical signs of toxicity include gastrointestinal, neurological and
the most concerning cardiac. Most symptoms are non-specific
findings and include a headache, malaise, insomnia, altered mental
status, abdominal pain, nausea, and vomiting.
Of note visual changes especially changes involving colors such
as seeing a yellow hue are better known and specifically seen in
digitalis toxicity. Cardiac manifestations include arrhythmias and
rhythm disturbances. Other visual problems include photophobia,
photopsia and diminished visual acuity. There is no specific
arrhythmia for digoxin toxicity rather a range of arrhythmias can
be present such as various degrees of AV block, premature
ventricular contractions, bradycardia, and even ventricular
tachycardia. Cardiac arrhythmias are the main cause of death for
those with digoxin toxicity.
Some patients may have hemodynamic instability depending on
the type of arrhythmia and others may have dyspnea and altered
mental status.
Evaluation
The difference between toxicity and therapeutic range is small for
digoxin and is determined to be between 0.5-2 ng/mL. Diagnosis
is difficult and usually made clinically, as levels of digoxin in the
blood do not necessarily correlate with toxicity. Digoxin is
primarily cleared by the kidneys and declining renal function is a
common cause of chronic toxicity. Therefore, renal function must
be assessed. Electrolytes must also be evaluated; hypokalemia,
hypercalcemia, and hypomagnesemia are known to worsen the
effects of toxicity. The inhibition of the sodium-potassium ATPase
leads to hyperkalemia and can be used as a marker of toxicity
severity. Serial electrocardiograms should be performed and the
use of continuous cardiac monitoring may be considered as
fluctuation in rhythms is commonly seen. EKG findings
sometimes referred to as the digitalis effect may be seen. These
changes commonly involve the T wave and include flattening,
inversion, scooped appearance of ST-segment and ST depression
in the lateral leads.
It is important to know that endogenous digoxin like
immunoreactive proteins can result in a false-positive result.
This is more likely to occur in patients with:
• Liver or renal disease
• Chronic heart failure
• Subarachnoid hemorrhage
• Acromegaly
• Diabetes
• Pregnancy
The other problem is that there are several types of assays to
measure digoxin and its metabolites, but these assays do vary in
sensitivity. Further, the tests are hampered by cross-reaction with
steroids and cholesterol-like substances.
Treatment / Management
Treatment involves early recognition and the administration of
antibodies specifically against digoxin also known as Fab
fragments. Digoxin concentration does not necessarily correlate
with clinical symptoms of toxicity however digoxin
concentrations may be used for calculating the amount of antidote
therapy. Although guidelines are unclear, treatment with digoxin
immune Fab is also known by the trade name Digibind, is
considered first-line therapy for dysrhythmias including AV block
and ventricular tachycardia caused by suspected digoxin toxicity.
Fab fragments are highly effective in binding the digoxin
molecule with minimal detrimental side effects. The antibody
fragments form complexes and are secreted via the urine. Empiric
treatment consists of 10 vials of Fab fragments for adults and five
vials for children. Treatment with digoxin-specific antibodies will
lead to hypokalemia, and serum potassium should be monitored
frequently. Activated charcoal can be considered in the treatment
of acute ingestion within two hours. Further treatment is
supportive. More research is needed for optimal dosing and
whether or not the use of digoxin-specific antibodies are cost-
effective for use in non-life threatening toxicities.
Hydration, oxygenation, and close monitoring are necessary. The
ECG has to be continuously monitored for dysrhythmias. All
electrolyte disturbances need to be corrected.
One should remember that if digoxin is neutralized with
antibodies, the patient may develop heart failure and lead to
worsening of the arrhythmias. Other issues related to the antibody
include serum sickness and anaphylaxis.
Supraventricular need to be managed with short-acting beta-
blockers. Phenytoin as been shown to suppress digoxin induced
tachyarrhythmias. Another option is lidocaine when managing
ventricular arrhythmias. Atropine may be used to managed
bradycardia. The use of magnesium is not recommended as it can
worsen bradycardia or an AV block. Cardioversion is not
recommended as it can precipitate ventricular arrhythmias;
instead, defibrillation may be used according to ACLS protocol
Differential Diagnosis
• Acute kidney injury
• Beta-blocker toxicity
• Calcium channel blocker toxicity
• Hypercalcemia
• Hyperkalemia
• Hypernatremia
• Hypoglycemia
• Hypokalemia
• Hyponatremia
Prognosis
The prognosis depends on the time of presentation, age and
associated comorbidity. The mortality is usually increased when
the toxicity is associated with a heart block or a new arrhythmia.
Deaths may occur in 1-5% of patients despite optimal care.
Complications
• Heart failure
• Nodal block
• Anaphylaxis associated with digibind
Consultations
• Toxicologist
• Nephrologist
• Cardiologist
• Poison control
Deterrence and Patient Education
• Avoid drug interaction
• Assess renal function
• Monitor Digoxin levels
• Avoid use of digoxin when possible
• Check electrolyte levels regularly
Enhancing Healthcare Team Outcomes
Even though the use of digoxin has declined over the past 2
decades, toxicity from this medication still is quite common.
Because of the numerous risk factors and varied presentation of
digoxin toxicity, the management is best done by an
interprofessional team that includes a cardiologist, emergency
department physician, intensivist, nephrologist, neurologist, ICU
nurses, and a toxicologist. Most patients with digoxin toxicity are
at risk for arrhythmias and need ICU monitoring. Nurses looking
after these patients need to be fully aware of the potential
problems associated with digoxin toxicity and notify the team
when there is a deviation from normal parameters. More
important, the pharmacist needs to educate the patient on the
prevention of another episode by knowing the dose he or she is
supposed to take. In addition, the pharmacist has to ensure that the
correct dose of digoxin has been prescribed by the physician.
Patients should be warned not to start or change the dose of any
medication without first consulting with the primary care provider.
The parent should store the medication safely away from the reach
of children. For patients with an intentional overdose, a mental
health nurse consult is recommended before discharge. Only
through an interprofessional team approach with open
communication can the morbidity of the disorder be lowered.
Outcomes
The outcome following digoxin toxicity depends on the patient
age and other comorbidities. Seniors tend to have worse outcomes
as they often develop recalcitrant arrhythmias and advanced
degree heart block. While death rates have started to decline,
digoxin toxicity is also associated with high morbidity. The key to
preventing digoxin toxicity is patient education. Patients need to
be educated about the signs and symptoms of toxicity and when to
return to the ED.
