Digoxin is used for the treatment of congestive heart failure and supraventricular dysrhythmias. There are several plants that contain cardiac glycosides (digoxin-like substances), including foxglove, oleander, lily of the valley, and red squill. The introduction of digoxin-immune Fab fragments as a specific antidote has reduced the morbidity and mortality of this poisoning. In 2011, the American Association of Poison Control Centers documented 190 cardiac glycoside exposures in children aged less than 5 years and 26 in children between the ages of 6 and 19 years. The incidence of pediatric cardiac glycoside exposures have been declining in recent years; in fact, no pediatric deaths solely due to cardiac glycoside exposure reported to Poison Centers in 2011.1
Pharmacology and Pathophysiology
Digoxin is a positive inotrope that increases the force and velocity of myocardial contractions. In the failing heart, it can increase the cardiac output and decrease elevated end-diastolic pressures.
On the cellular level, digoxin presumably functions by binding to and inactivating the alpha subunit of the Na+-K+ ATPase pump in the membrane of myocardial cells. This results in increased intracellular sodium concentration. In addition, enhanced contractility depends on intracellular ionized calcium concentrations during systole. At toxic concentrations, it is felt that intracellular calcium concentrations are markedly increased, and that the membrane potential is unstable, which leads to dysrhythmias. Enhancement of vagal activity and decreased AV nodal conduction also occur. Due to automaticity and conduction disturbances, re-entrant tachydysrhythmias are common.
There are numerous factors that predispose the patient to digoxin toxicity, the most common of which is electrolyte imbalance.57 Both hypokalemia and hyperkalemia can increase the likelihood of developing digoxin toxicity. Hyperkalemia, due to an egress of potassium can result in significant conduction delays. Hypokalemia is common in patients on diuretic therapy and can predispose patients to the effects of chronic digoxin toxicity. Hypomagnesemia, hypercalcemia, renal insufficiency, and underlying heart disease all predispose to digoxin toxicity.58
Oral digoxin is well absorbed by passive diffusion in the upper small intestine.35 The onset of action is within 1 to 2 hours. The elimination half-life in full-term neonates, infants, and children are approximately 40, 20, and 35 hours, respectively. The volume of distribution also varies with age; in neonates, the volume of distribution is 7.5 to 10 L/kg, whereas in older children it is approximately 16 L/kg. Excretion is primarily renal for digoxin.35
The presentation of digoxin toxicity is highly varied and depends largely on whether it results from an acute overdose or is a manifestation of chronic toxicity.58
In the acute setting, patients tend to have more dramatic, clinical, and laboratory parameters than in chronic toxicity. Symptoms can be abrupt, with marked nausea, vomiting, and diarrhea. Associated complaints include weakness, headache, paresthesias, and altered color perception. Cardiovascular symptoms include palpitations and dizziness that may be secondary to hypotension. Movement disorders may also be present.59
As a substrate of CYP3A4, several medications administered concurrently with digoxin may result in digoxin toxicity. These include macrolide antibiotics (especially clarithromycin), propafenone, quinidine, famciclovir, fluoxetine, and cimetidine.60
Patients with chronic toxicity tend to have more vague complaints although many of the symptoms of acute overdose also occur. Malaise, anorexia, and low-grade nausea and vomiting are common. Patients with chronic toxicity tend to be more symptomatic at lower levels than those with acute overdoses.61
Cardiovascular toxicity is the most important factor in determining morbidity and mortality. There are multiple dysrhythmias associated with digoxin toxicity, the most common being frequent premature ventricular beats. Other dysrhythmias can be supraventricular, nodal, or ventricular. Common disturbances are junctional escape beats and accelerated junctional rhythm, paroxysmal atrial tachycardia with AV block, and AV block of varying degrees. Other than bidirectional ventricular tachycardia, there is no single pathognomonic rhythm. Lethal cardiac disturbances rarely occur in children with normal hearts, but serious AV conduction disturbances can occur.62
A history of the exact amount of digoxin ingested is extremely helpful. An exposure greater than 0.1 mg/kg is an indication that serious consequences can occur.
A serum digoxin level is indicated whenever there is clinical suspicion of toxicity.58–63 In an overdose situation, the level is most helpful if obtained ≥6 hours after the ingestion. The therapeutic serum digoxin range is between 0.8 and 1.8 ng/mL. However, there is poor correlation between the digoxin level and clinical manifestations. In an acute overdose, a level as high as 2.6 ng/mL may not correlate with toxicity. In a chronic overdose, toxicity can occur at lower levels. The fatality rate approaches 50% when the serum digoxin level exceeds 6 ng/mL.
Other laboratory studies include a complete blood count, serum electrolytes, calcium, magnesium, blood urea nitrogen, and creatinine. Cardiac monitoring is essential, as is a 12-lead ECG.
Digoxin-intoxicated patients can be highly unstable. All patients require a secure airway, intravenous access, and cardiac monitoring. If the patient has ingested a potentially toxic dose less than 1 hour before being assessed, administer activated charcoal. Indications for digoxin-specific Fab antibody fragments include an acute ingestion of greater than 0.1 mg/kg (or over 4 mg total), a digoxin level of greater than 10.0 ng/mL following acute ingestion, potassium greater than 5 mEq/L in adults or over 6 mEq/L in children, or the presence of a life-threatening dysrhythmia. In chronic digoxin poisoning, significant toxicity may occur at much lower serum concentrations; thus, antidotal therapy should be considered in chronic ingestions resulting in steady state serum digoxin levels of over 6 ng/mL in adults, or over 4 ng/mL in children. Standard modalities to treat hyperkalemia may also be used, with the exception of calcium salts. In the face of digoxin toxicity the administration of calcium may exacerbate the development of dysrhythmias.
The dose of Fab fragments is based either on the amount ingested or on the serum level. Specific guidelines for dosing Fab fragments are available on the package insert.
Allergic reactions to Fab fragments are rare with a pruritic rash or facial swelling most often reported.64 In cases where Fab fragments have been effective, results have been achieved 30 minutes to 4 hours after administration. After administration of Fab fragments, subsequent digoxin levels will be elevated for several days, because the bound digoxin is measured along with the free drug.65,66 Certain laboratories can assay-free digoxin levels which avoids this problem.
In addition to the administration of Fab fragments, standard treatment of hyperkalemia, dysrhythmias, or AV blocks is indicated.
Atropine (0.02 mg/kg with a maximum single intravenous dose of 0.5 mg in young children or 1 mg in adolescents) or temporary pacing may be necessary while awaiting Fab fragment effects. Cardioversion and lidocaine are appropriate in the event of ventricular tachycardia or fibrillation. Treatment with intravenous phenytoin or magnesium sulfate has been shown to be useful in digoxin-induced tachydysrhythmias. Drugs to avoid in the treatment of digoxin-induced cardiac toxicity include calcium, bretylium tosylate, sotalol, isoproterenol, and quinidine. Direct-current cardioversion should be used only as a last resort for unstable, life-threatening arrhythmias. If utilized, it should be dosed at the lowest energy possible.
Diuresis, hemodialysis, and hemoperfusion do not aid in the removal of digoxin or digitoxin. Plasma exchange is also not expected to be useful.
Children with trivial ingestions (<0.05 mg/kg), who are asymptomatic and have no detectable levels of digoxin 4 hours after the ingestion, can be discharged from the emergency department after 6 hours of observation. Any child with signs or symptoms of toxicity is admitted to a pediatric intensive care unit.
In 2011, the American Association of Poison Control Centers documented 1926 clonidine exposures in children younger than 5 years and 1646 in 6- to 19-year-olds. Use of clonidine has been increasing, especially in children.1 Traditionally, clonidine hydrochloride has been used to treat mild-to-moderate hypertension. Over the past several years it has been utilized to treat opiate withdrawal (especially in neonatal abstinence syndrome), adjunctive therapy for pain control, migraine prophylaxis, impulse control disorder, and attention-deficit/hyperactivity disorder.67 It is also used as a chemical submissive agent, especially in Russia.35
Clonidine stimulates α2-adrenergic receptors in the brainstem, thus, activating neural inhibition, which results in decreasing sympathetic outflow. The cardiovascular effects of such inhibition include a decrease in vasomotor tone and bradycardia. Formulations include tablets (both immediate release and extended release), injection for epidural use and transdermal patch. An oral solution for use in neonatal abstinence syndrome or pediatric use can be compounded.68,69
The onset of action after the ingestion of conventional tablets is usually within 1 hour while the duration can last 6 to 10 hours. Symptom development following ingestion of extended-release tablets may not occur until approximately 5 hours after ingestion.70 Clonidine is lipid soluble and distributes readily into extravascular sites with a volume of distribution of 2.1 L/kg. Protein binding is 20% to 40%. It is metabolized in the liver to inactive metabolites. The half-life elimination in individuals with normal renal function is 6 to 20 hours; in renal impairment half-life can be as long as 40 hours. This is due to the fact that elimination is primarily urinary with 32% of the drug being excreted as unchanged. The usual therapeutic serum reference range is approximately 1 to 2 ng/mL.35 Serum clonidine levels in excess of 67 ng/mL have been associated with serious toxicity.69
The signs and symptoms of acute clonidine poisoning mirror those of opiate overdose. Central nervous system depression may be quite pronounced and can be associated with respiratory depression including intermittent apneic episodes. Sinus bradycardia is often present and may be associated with a first-degree AV block along with hypotension, which may be profound. Hypertension can be an initial manifestation in ingestions over 7 mg. Pupils are usually pinpoint.70 The patient may also exhibit hyporeflexia, and hypothermia can occur in severe cases; however, these signs usually resolve within 8 hours. Xerostomia may occur. Visual hallucinations may occur in patients with chronic toxicity. Onset of symptoms is typically within 30 minutes of ingestion and usually peaks at 2 to 4 hours. As little as a single dose of clonidine (0.1 mg or 0.01 mg/kg) may cause toxic effects on a toddler.35,70,71,72
If the patient has ingested a potentially toxic dose less than 1 hour before being assessed, administer activated charcoal. If extended-release tablets or multiple clonidine patches are ingested, whole bowel irrigation may be considered.73 Manage airway, breathing and circulation as per PALS protocols. Monitor vital signs and oxygen saturation. If symptomatic bradycardia develops, then atropine at 15 μg/kg intravenously may be given. Administer crystalloid for hypotension. If the patient does not respond then vasopressor support is indicated, norepinephrine 0.1 to 0.2 μg/kg/min intravenously titrated to response. Hemodialysis would not be expected to be of benefit.
Naloxone has been reported to reverse clonidine toxicity; however, these effects are inconsistent. It can be considered for the treatment of clonidine-induced hypotension, central nervous system depression, or apnea. It appears that naloxone is approximately 31% effective in this regard, and rebound hypertension would not be expected to occur following its admission.35 The dose of naloxone is 0.01 to 0.1 mg/kg intravenously titrated to effect.35
Symptomatic patients should be admitted to an intensive care unit. Asymptomatic patients should be observed for 4 to 6 hours after the ingestion of conventional tablets and up to 24 hours after the ingestion of modified-release tablets or patches.