DESCRIPTION

Cardiac glycoside is a term used to describe a group of naturally occurring plants that produce toxicity similar to digoxin.

FORMS AND USES

Plants that contain cardiac glycosides include:

• Common oleander (Nerium oleander).
• Yellow oleander (Thevetia peruviana).
• Lily-of-the-valley (Convallaria majalis).
• Types of foxglove (Digitalis purpurea, Digitalis lantana).
• Henbane (Helleborus niger).
• Sea onion (Urginea maritima) and squill (Urginea indica).
• Milkweed family, African arrow poisons, wintersweet, bushman's poison, frangipani, sea-mango, balloon cotton, redheaded cottonbush, king's crown, and rubber vine.
• Historically, plant glycosides were used as heart remedies.

TOXIC DOSE

• Toxicity varies widely depending on plant and preparation.
• An extract (e.g., tea made from plant) is generally the most toxic preparation.

PATHOPHYSIOLOGY

• The therapeutic mechanism is inhibition of the myocardial Na⁺/K⁺ exchange pump, increasing intracellular Na⁺, decreasing Ca²⁺ excretion, and causing a net increase in intracellular Ca²⁺, which augments myocardial contractility.
• Cardiac glycosides also increases vagal tone by decreasing baroreceptor sensitivity; the increased vagal tone results in decreased conduction velocity of the electrical impulse through the myocardium and atrioventricular (AV) node and increased AV node refractoriness.

EPIDEMIOLOGY

• Poisoning is rare.
• Toxic effects are typically mild.
• Death occurs following suicidal ingestion or consumption of brewed teas.

CAUSES

• Cardiac glycoside poisoning is usually an unintentional ingestion.
• Child neglect or abuse should be considered if the patient is less than 1 year of age; suicide if the patient is over 6 years of age.

DRUG AND DISEASE INTERACTIONS

• Any drug that inhibits myocardial conduction (beta-receptor blocker, calcium channel blocker) may enhance cardiac glycoside toxicity.
• Underlying cardiac disease may predispose to dysrhythmia.
• Renal failure decreases digitalis elimination.
• Hypokalemia, hypercalcemia, hypomagnesemia, increased sympathetic nervous system activity, and hypothyroidism may exacerbate digitalis toxicity by different mechanisms.
• Nifedipine, spironolactone, triamterene, and amiloride decrease renal clearance of digoxin.
• Quinidine, quinine, verapamil, and amiodarone may increase digitalis levels.
• Warfarin can increase digoxin levels by displacement from protein binding sites.

PREGNANCY AND LACTATION

Digoxin. US FDA Pregnancy Category C. The drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• TOXIC DOSE
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

DIFFERENTIAL DIAGNOSIS

• Other toxic agents that cause depression of cardiac conduction include beta-receptor or calcium channel blockers and type 1 antidysrhythmics, among others.
• Nontoxic causes of cardiovascular depressant effects include myocardial ischemia and electrolyte abnormalities.

SIGNS AND SYMPTOMS

• Early signs of plant cardiac glycoside toxicity may be nonspecific, such as malaise, nausea and vomiting.
• As toxicity increases, cardiac conduction abnormalities emerge.

Vital Signs

Bradycardia, tachycardia, or hypotension may occur.

HEENT

Visual complaints, blurred vision, amblyopia, and colored halos may be present.

Cardiovascular

• Severe bradycardia, AV blocks, conduction delays, supraventricular and ventricular dysrhythmias, and congestive heart failure may occur.
• Cardiac arrest may develop suddenly.

Gastrointestinal

Nausea, vomiting, and abdominal pain may develop within a few hours and precede cardiac effects.

Fluids and Electrolytes

• Hyperkalemia is common with acute overdose.
• Hypokalemia is associated with chronic toxicity and use of diuretics.

Neurologic

Headache, lightheadedness, weakness, drowsiness, hallucinations, and confusion may develop in severe cases.

PROCEDURES AND LABORATORY TESTS

Essential Tests

• Serum digitalis level
  • Some plant cardiac glycosides will cross-react with the standard digoxin assay, especially foxglove and oleander.
  • The absolute level is not meaningful, but a positive result helps to confirm the diagnosis.
  • The absence of detectable digoxin level does not rule out plant cardiac glycoside toxicity.
• ECG and continuous cardiac monitoring
  • Prolonged PR interval and shortened QTc interval are common with cardiac glycoside toxicity.
  • Atrial or junctional tachydysrhythmias, sinus bradycardia, and AV block are characteristic.
  • Bidirectional ventricular tachycardia, atrial flutter with 2:1 block, and regularized atrial fibrillation are highly suggestive of cardiac glycoside toxicity.
  • Peaked T waves, PR prolongation, and QRS prolongation may suggest hyperkalemia.
• Serum electrolytes, glucose, calcium, magnesium, BUN, and creatinine
  • Hyperkalemia is an indication for digoxin-specific antibodies.
  • Hypokalemia, hypercalcemia, or hypomagnesemia may predispose patients to dysrhythmias.
  • Renal insufficiency impairs cardiac glycoside clearance.

Recommended Tests

• Liver function tests. Decreased hepatic function increases digitoxin levels.
• Serum acetaminophen and aspirin levels should be obtained in overdose setting to detect occult ingestion.
• Disorders that may alter laboratory results. Serum digoxin levels after administration of digoxin antibodies may be elevated because both free cardiac glycoside and bound glycoside may be measured by most laboratories.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • HEENT
  • Cardiovascular
  • Gastrointestinal
  • Fluids and Electrolytes
  • Neurologic
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests

• Therapy should focus on appropriate airway management and rapid assessment of need for digoxin immune Fab.
• Dose and time of exposure should be determined for all substances involved.

DIRECTING PATIENT COURSE

The health-care provider should call the poison control center when:

• Severe or persistent effects develop.
• Signs and symptoms are not consistent with cardiac glycoside poisoning.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

The patient should be referred to a health-care facility when:

• Toxic effects develop.
• Attempted suicide or homicide is possible.
• The patient or caregiver seems unreliable.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

Admission Considerations

Inpatient management in the intensive care unit is warranted for symptomatic patients and patients with ECG abnormalities.

DECONTAMINATION

Out of Hospital

Emesis should be induced with ipecac within 1 hour of ingestion for alert patients if health-care evaluation will be delayed.

In Hospital

• Ipecac-induced emesis should be considered because plant material is often not removed well by lavage, especially in children (due to small tube size).
• Gastric lavage should be performed in adult (tube size 36-42 French) patients presenting within 1 hour of a large ingestion or if serious effects are present.
• One dose of activated charcoal (1-2 g/kg) should be administered without a cathartic if a substantial ingestion has occurred within the previous few hours.

ANTIDOTES

Digoxin immune Fab is the antidote for cardiac glycoside poisoning.

Indications

• Any sign of cardiovascular instability should prompt administration of digoxin immune Fab.
• Rapid progression of toxicity, including gastrointestinal symptoms, is also an indication for digoxin immune Fab.
• Serum K⁺ higher than 5.5 mEq/L indicates a poor prognosis and is an indication for Fab administration.

Dosage and Method of Administration

• If the patient is critically ill and cardiac glycoside toxicity is possible, 10 to 20 vials of Fab should be administered intravenously.
• In symptomatic but relatively stable patients, there are no data on empiric dosing; a typical initial empiric dose would be five vials intravenously, repeated if necessary.
• A digoxin level should not be used to calculate the dose because the toxin measured is from the plant, not from pure medication.
• See SECTION III, Digoxin Immune Fab for details of administration.

ADJUNCTIVE TREATMENT

• Atropine, isoproterenol, and cardiac pacing have been used for bradycardia or heart block if digoxin Fab is not available.
• Lidocaine and phenytoin have been used successfully for managing ventricular dysrhythmias.
• Phenytoin has been used for supraventricular tachydysrhythmias.
• Vasopressors may be helpful during initial stabilization or until digoxin Fab is available.
• Procainamide, quinidine, disopyramide and propranolol are not recommended because they may decrease conduction and worsen AV nodal block.
• Calcium is contraindicated because of the risk of cardiac tetany.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In Hospital
• ANTIDOTES
  • Indications
  • Dosage and Method of Administration
• ADJUNCTIVE TREATMENT

PATIENT MONITORING

ECG should be obtained and continuous respiratory and hemodynamic monitoring should be instituted in all patients with cardiac glycoside toxicity.

EXPECTED COURSE AND PROGNOSIS

• Sequelae of hypotension or hypoxia may develop in some patients.
• Clinical improvement after administration of digoxin immune Fab is expected.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department. Patients who are asymptomatic, have an undetectable digoxin level, and normal ECG and electrolytes may be discharged following gastrointestinal decontamination, 6 hours of observation, and psychiatric evaluation, if needed.
• From the hospital. Patients may be discharged following gastrointestinal decontamination, resolution of cardiac effects, and psychiatric evaluation, if needed.

Section Outline:

• PATIENT MONITORING
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA/INSTRUCTIONS

DIAGNOSIS

• The symptoms of cardiac glycoside toxicity may be nonspecific, and a high index of suspicion is essential in arriving at the diagnosis.
• Patients may exhibit cardiac glycoside toxicity from plant ingestion despite undetectable serum digoxin levels.

TREATMENT

• Digoxin immune Fab should be administered even in the presence of cardiac arrest of short duration; survival rates of up to 50% for patients in cardiac arrest have been reported.
• Delay in treatment is dangerous because of rapid acute deterioration.
• Hospital pharmacies are often inadequately stocked with digoxin immune Fab.

Section Outline:

• DIAGNOSIS
• TREATMENT

Poisoning by agents primarily affecting the cardiovascular system.

See Also: SECTION II, Ventricular Dysrhythmias; SECTION III, Digoxin Immune Fab chapter.

RECOMMENDED READING

Lewin N. Digitalis. In: Goldfrank LR, Flomenbaum NE, Lewin NA, et al., eds. Goldfrank's toxicologic emergencies, 6^th ed. Norwalk, CT: Appleton & Lange, 1998.

Author: Edwin K. Kuffner

Reviewer: Gerald F. O'Malley