Authors: Alexandra T. Geanacopoulos, Benjamin Zielonka, Miriam T. Fox, Sarah Kerr, Kristina D. Chambers, Robert Przybylski, Michele M. Burns
Categories: Pediatrics, antiarrhythmic ingestion, antiarrhythmics, pediatric electrophysiology, pediatrics, pharmacology, toxicology, Review Article
Source: Journal of the American College of Emergency Physicians Open
Doi: 10.1002/emp2.13090
Antiarrhythmic medications are fundamental in the acute and chronic management of pediatric arrhythmias. Particularly in the pediatric patient population, associated antiarrhythmic toxicities represent important potential adverse effects. Emergency medicine clinicians must be skilled in the detection, workup, and management of antiarrhythmic toxicity. This is a clinical review of the indications, pharmacology, adverse effects, and toxicologic treatment of antiarrhythmics commonly used in the pediatric patient population.
Keywords: antiarrhythmic ingestion, antiarrhythmics, pediatric electrophysiology, pediatrics, pharmacology, toxicology
Cardiac arrhythmias are observed in as many as 1 in 250 children. ^1^ , ^2^ These rhythm disturbances are frequently recurrent and occur in the presence or absence of structural heart disease, posing unique management challenges to clinicians. Antiarrhythmic medications are commonly used for the acute management and chronic therapy of pediatric arrhythmias. Intentional or exploratory ingestion of antiarrhythmics by children can be fatal at low doses and requires quick recognition and treatment to prevent mortality. ^3^ Knowledge of antiarrhythmic medications and associated toxicities is an important tool for health care practitioners in the emergency department.
The purpose of this review is to summarize the indications, pharmacology, and toxicologic considerations for antiarrhythmics in the pediatric patient population. We report on standard dosing, available preparations, drug–drug and food–drug interactions, and recommendations for therapeutic monitoring (Table 1). We also propose a generalized management approach to all antiarrhythmic toxicities (Table 2). In the following sections, we review commonly used antiarrhythmic agents according to Vaughan‐Williams classification.
Procainamide is a Class IA antiarrhythmic that is administered as an intravenous bolus and/or continuous infusion. An oral formulation of procainamide previously used for chronic arrhythmia management is no longer available in the United States. Procainamide is used for the acute treatment of a wide variety of supraventricular tachycardias (SVT) and monomorphic ventricular tachycardia (VT). Small series have suggested that procainamide may be superior to amiodarone in the management of refractory SVT in pediatric patients. ^4^ Procainamide is also an effective agent for rate control of junctional ectopic tachycardia in the postoperative setting, particularly when used in combination with hypothermia. ^5^ , ^6^
Procainamide binds and inhibits the open‐state fast inward sodium channel (Nav1.5) encoded by SCN5A resulting in reduced fast sodium current (INa). This slows depolarization and conduction velocity, corresponding to a blunted upstroke in phase 0 of the action potential in the atria, ventricular muscle fibers, and His‐Purkinje system.
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The main active metabolite of procainamide, N‐acetylprocainamide (NAPA), is a Class III antiarrhythmic that delays repolarization and contributes to increases in action potential duration and effective refractory period in the cardiomyocytes (Figure 1). Of note, there is genetic variation in the rate of acetylation and accumulation of NAPA, with patients exhibiting either a fast or slow acetylator phenotype.
FIGURE 1 Cardiac action potentials and effects of antiarrhythmics by Vaughan‐Williams classification. Left‐hand Cardiac myocyte action potential with corresponding electrocardiographic findings. Right‐hand Pacemaker cell action potential; Solid lines represent typical action potential and dotted lines represent expected changes with administration of each antiarrhythmic class. Abbreviations: APD, action potential duration; ERP, effective refractory period.
The cardiotoxic effects of procainamide are closely related to serum procainamide and/or NAPA levels and primarily occur in the setting of hepatic or renal dysfunction. Electrocardiographic signs of toxicity include PR interval prolongation, QRS widening, and QTc prolongation that can predispose to torsades de pointes (TdP). Procainamide can cause bradycardia and hypotension, the latter of which is largely secondary to vasodilation. It may have weak negative inotropic effects but has a more neutral impact on cardiac contractility than other intravenous antiarrhythmic agents. ^8^ Oral procainamide can result in positive antinuclear antibody titers that can manifest as a drug‐induced lupus syndrome. ^9^ Blood dyscrasias including pancytopenia or agranulocytosis are a rare complication of oral procainamide. ^10^
The generalized management approach for all antiarrhythmic toxicities in Table 2 is recommended for acute procainamide toxicity, including treatment of TdP. Sodium bicarbonate or lidocaine (Class IB) may reverse fast sodium channel blockade and result in QRS narrowing. There are case reports of hemodialysis in the treatment of procainamide toxicity. ^11^
Lidocaine is a Class IB antiarrhythmic administered as an intravenous bolus and/or continuous infusion in the acute treatment of ventricular arrhythmias. Current Pediatric Advanced Life Support guidelines recommend either amiodarone or lidocaine for the treatment of shock refractory ventricular fibrillation or pulseless VT. ^12^ Historically, lidocaine was also used for the treatment of arrhythmias resulting from digoxin toxicity. ^13^
Lidocaine primarily binds to inactivated state fast inward sodium channels, which decreases the duration of the action potential in the His‐Purkinje system and ventricular muscle fibers via reduction of the late INa. Thus, lidocaine's major effect is to reduce the action potential duration and effective refractory period.
^14^
Lidocaine may also decrease the slope of phase 0 via reduction of INa, though to a much lesser extent than Class IA or Class IC antiarrhythmics, and decreases the slope of phase 4, the spontaneous depolarization (Figure 1).
^15^
Compared to Class IC antiarrhythmic, lidocaine dissociates comparatively quickly from sodium channels, particularly during diastole. As a result, lidocaine demonstrates use‐dependence with a more pronounced sodium channel blockade at faster heart rates.
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Due to its affinity for binding inactivated sodium channels in depolarized cells, lidocaine is particularly efficacious in treating ventricular arrhythmias arising from myocardial ischemia.
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Severe lidocaine toxicity may result in respiratory depression, hypotension, myocardial depression, arrhythmias, or cardiorespiratory arrest. ^15^ , ^19^ , ^20^ Due to the risk of bradycardia, lidocaine should be used with caution in patients with abnormal atrioventricular or intraventricular conduction. ^14^ , ^21^ Central nervous system effects include tremors, confusion, twitching, vision changes, and loss of consciousness, with seizure activity and central nervous system depression resulting from more severe toxicity. The central nervous system effects typically manifest before cardiorespiratory effects, which occur at higher levels of toxicity.
Management of lidocaine toxicity includes targeted supportive care and discontinuing lidocaine administration. Antiseizure medications should be provided for prolonged seizure activity. Hemodynamic support should be initiated as clinically indicated. Toxic effects are generally short lived once the medication is discontinued, though effects may be prolonged in patients with hepatic insufficiency or low cardiac output due to impaired lidocaine clearance. ^15^ , ^20^ Sodium bicarbonate and intralipid are used early in resuscitation to prevent potentiation of cardiac toxicity, with extracorporeal membrane oxygenation reserved for severe or refractory cases. ^22^
Flecainide is an oral Class IC antiarrhythmic most commonly used for the maintenance of sinus rhythm in children and infants with a history of SVT. There is also a limited role for flecainide in the management of VT. ^23^ Flecainide can be used as monotherapy or in combination with other oral antiarrhythmics for refractory arrhythmias. ^24^ Although the findings of the Cardiac Arrhythmia Suppression Trial have historically limited the use of flecainide in the adult population to patients without structural heart disease, flecainide is used in pediatric patients with structurally normal hearts as well as those with congenital heart disease. ^25^ , ^26^
Flecainide selectively binds and inhibits the open‐state fast inward sodium channel, which causes blunting of the depolarization upstroke corresponding to phase 0 of the cardiac action potential (Figure 1) in the ventricular muscle fibers and His‐Purkinje system.
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In addition, flecainide inhibits the delayed rectifier potassium current (IKr) encoded by the KCNH2 gene and prolongs repolarization in atrial and ventricular myocytes.
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This results in increased action potential duration and effective refractory period in atrial and ventricular myocytes and increased refractoriness in the His‐Purkinje system. Flecainide exhibits use‐dependence, with increased sodium channel blockade with increasing heart rate.
Children are particularly susceptible to flecainide toxicity given its narrow therapeutic window and the frequent need among younger patients for extemporaneous compounding of a liquid formulation, increasing the risk for medication dosing errors. ^29^ Flecainide has proarrhythmic properties that are characterized by a prolonged PR interval, widening of the QRS duration, bundle branch block, and a Brugada‐like pattern on ECG with the potential to progress to sinus bradycardia, sinus arrest, or TdP. ^30^ Flecainide also exerts a negative inotropic effect and may cause or worsen myocardial dysfunction. These effects may present clinically with palpitations, chest pain, dizziness, and syncope. Extracardiac effects may include dyspnea, abdominal pain, nausea, vomiting, constipation, visual changes, and seizures.
The mainstay of therapy for flecainide toxicity in children is administration of intravenous sodium bicarbonate in 1 mEq/kg aliquots given over 1–2 minutes and repeated as needed until the QRS duration remains <100 milliseconds. ^31^ , ^32^ Case reports have demonstrated success in using intravenous lipid emulsion therapy. ^33^
Propranolol is an oral Class II antiarrhythmic commonly used for the treatment of SVT and the prevention of recurrence in infants and children. ^34^ It is also prescribed for symptom management in children with palpitations secondary to premature ventricular complexes. ^35^ Propranolol is associated with reduced risk of cardiac arrest among patients with cardiac channelopathies including long QT syndrome and catecholaminergic polymorphic VT. ^35^ Apart from its antiarrhythmic effects, propranolol is also used for the treatment of pediatric hypertension, infantile hemangioma, migraine prophylaxis, and thyrotoxicosis.
Propranolol is a non‐selective beta‐adrenergic antagonist with equal affinity for ß1 and ß2 receptors. At the cardiomyocyte ß1 receptors, binding of propranolol results in reduced intracellular calcium influx through the cyclic AMP pathway. This results in reduced automaticity and slowing of conduction velocity in nodal tissue, thereby prolonging the PR interval. Additionally, propranolol has sodium‐channel blocking effects, which may enhance its antiarrhythmic properties. ^36^
The majority of pediatric propranolol and other beta‐blocker toxicities are associated with small‐dose exploratory ingestions in young children after ingestion of a caregiver's prescription medication. ^37^ Clinical symptoms and signs secondary to these exploratory ingestions are rare. ^38^ The most common cardiac side effects are bradycardia and hypotension, though significant ingestions can result in atrioventricular block (Figure 1) and heart failure. Extracardiac effects include lethargy, seizures, dizziness, bronchospasms, diarrhea, and hypoglycemia. ^35^ Propranolol is more lipophilic than other beta‐blockers and can more easily penetrate the blood–brain barrier, leading to more significant neurologic toxicity. ^37^
Preliminary management of beta blocker toxicity involves stabilization and support of bradycardia and hypotension with intravenous isotonic fluids and atropine if bradycardia is symptomatic. ^39^ Despite limited evidence to support its efficacy, glucagon is commonly administered as an intravenous bolus and continuous infusion with the goal of increasing cardiac contractility through the cyclic AMP pathway. ^40^ Similarly, intravenous calcium, administered either as calcium gluconate or calcium chloride, may be used to augment inotropy. ^41^ More recently, high‐dose insulin therapy is used with greater frequency for the treatment of beta blocker and calcium channel toxicity with the theory that insulin increases inotropy and vasodilation and minimizes insulin resistance. ^42^ Common protocols involve a bolus insulin dose of 0.5–1.0 U/kg followed by continuous infusion with concurrent dextrose containing fluids to maintain euglycemia. ^43^ Finally, lipid emulsion therapy may be considered in situations where more traditional therapies are unsuccessful though experience is limited primarily to adults. ^44^ Propranolol may be particularly susceptible to lipid emulsion therapy given its highly lipophilic properties. In asymptomatic cases of propranolol ingestion, children may be safely discharged from care 6 hours after ingestion. Ingestion of extended‐release preparations may warrant up to 24 hours of observation. ^38^
Esmolol is a short‐acting, rapid‐onset Class II antiarrhythmic used as a continuous intravenous infusion in acute care and surgical settings for the treatment of tachycardia and hypertension in the setting of cardiac surgery. ^45^ , ^46^ , ^47^ , ^48^ Among infants with SVT, esmolol is commonly used, along with other adjunctive therapies, as an abortive medication in the acute care setting. ^45^ It has also been used as an adjunct to anesthesia during cardiac surgeries in children requiring cardiopulmonary bypass. ^49^
Esmolol is a cardioselective beta‐adrenergic antagonist with binding only to ß1 receptors. At the ß1 receptors on cardiac myocytes, esmolol binds and works by the same mechanism of action as propranolol. ^50^
Similar to other beta blockers, esmolol can be associated with symptomatic bradycardia and hypotension. Extracardiac effects include dizziness, fatigue, headache, nausea, vomiting, and local infusion site reactions.
Given its short half‐life, the first step in the treatment of esmolol toxicity in the acute care setting should be discontinuation of the infusion. For ongoing symptomatic management, similar treatment strategies to those discussed for toxicologic treatment for propranolol toxicity may be employed.
Sotalol is a non‐cardioselective beta blocker with Class III antiarrhythmic properties that can be administered orally or as an intravenous infusion. Sotalol is commonly used for the treatment of reentrant tachyarrhythmias, including atrial flutter and intra‐atrial reentrant tachycardia, in the postoperative setting in patients with congenital heart disease. ^51^ , ^52^ More recently, intravenous sotalol has emerged as an option for termination of acute arrhythmias or for more rapidly achieving steady‐state concentrations during sotalol initiation in pediatric patients. ^53^ , ^54^
Sotalol comprises a racemic mixture of d‐ and *l‐*sotalol isomers, with l‐sotalol having more pronounced beta‐blockade activity. At lower doses, beta blocker activity predominates and results in inhibitory binding of ß1‐ and ß2‐adrenergic receptors with a corresponding increase in the effective refractory period in the atrioventricular node (Figure 1). At higher doses, sotalol inhibits the rapid component of the delayed‐rectifier potassium current potassium current (IKr) encoded by the KCHN2 gene. This increases the action potential duration and effective refractory period in the atria, ventricles, and His‐Purkinje system.
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Sotalol exhibits reverse use dependence with more potent potassium channel blockade and prolongation of the action potential at lower heart rates.
The cardiovascular toxicities of sotalol overlap with those of other Class II and Class III antiarrhythmics. Sotalol is associated with bradycardia and hypotension and exerts negative inotropic effects. In addition, sotalol can be proarrhythmic and exhibits dose‐dependent QTc prolongation that can progress to ventricular arrhythmias such as TdP. Extracardiac effects include dyspnea, fatigue, dizziness, and nausea/vomiting and sotalol may cause bronchospasm in patients with reactive airway disease or asthma. Toxicity related to sotalol in the adult population has been most often reported within the first 3 days of initiation; therefore, it is recommended that sotalol initiation or upward titration occur in the inpatient setting. ^56^
Management of sotalol toxicity including TdP is primarily supportive (Table 2) with an emphasis on electrolyte optimization in the setting of QTc prolongation. Sotalol is not protein bound and hemodialysis can be used to reduce plasma concentrations of sotalol. ^57^
Amiodarone is an intravenous Class III antiarrhythmic approved in pediatric patients to control SVT (including postoperative junctional ectopic tachycardia) and VT and for use during pediatric resuscitation in shock resistant ventricular fibrillation and pulseless VT. ^58^ , ^59^ , ^60^ Given its extensive side effect profile, amiodarone is typically used in refractory cases. As described previously (see Section 3.1 Lidocaine, Pediatric Indications), amiodarone and lidocaine are recommended in patients with shock‐refractory ventricular fibrillation or pulseless VT.
Similar to other Class III antiarrhythmics, amiodarone inhibits efflux through potassium rectifier channels to prolong phase 3 of the action potential. ^61^ This delays repolarization and prolongs the effective refractory period (Figure 1). Amiodarone also displays characteristics of other antiarrhythmics including those in Class I, II, and IV. ^62^ , ^63^
In the acute setting, intravenous amiodarone administration is associated with hypotension (secondary to the vasodilatory effects of the drug itself or its cosolvents), bradycardia, and heart block. ^64^ In young children, particularly those under 3 months of age and with ventricular dysfunction, intravenous amiodarone can be associated with cardiovascular collapse, necessitating slow infusion and close cardiorespiratory monitoring. ^65^ Acute respiratory distress syndrome after intravenous administration in children is rare but is associated with high mortality. ^66^ , ^67^ Organ dysfunction typically occurs after long‐term oral therapy and can include pulmonary toxicity (the leading cause of death), transaminitis, hypo‐ and hyperthyroidism, optic neuropathy, corneal deposits, skin discoloration, bradycardia, and QT prolongation (although resultant TdP is rare).
Treatment of amiodarone toxicity includes dose reduction or drug cessation; however, symptoms may persist for months because of the drug's long half‐life. In the acute setting, bradycardia is treated with beta‐adrenergic agonists, transcutaneous pacing, or temporary transvenous pacing. Hypotension is treated with fluid resuscitation or vasopressors. Although animal studies of amiodarone‐induced hypotension show efficacy with lipid emulsion therapy, there are no case reports indicating success in humans with amiodarone toxicity. ^68^ Chronic pulmonary toxicity, the most fatal complication, is treated with drug cessation, steroids for at least 4–12 months, and in severe cases, mechanical ventilation.
Diltiazem is a Class IV intravenous antiarrhythmic effective for ventricular rate control in those with primary atrial tachyarrhythmias. ^69^ Intravenous diltiazem can be used in children with hemodynamically stable SVT unresponsive to initial vagal maneuvers or adenosine and in patients with bronchospasm for whom adenosine is contraindicated. ^70^ It may also be effective for patients with fascicular VT. ^71^ As an antihypertensive, oral diltiazem is not first line in pediatrics. In transplant patients, however, it can be doubly advantageous in providing blood pressure control and increasing immunosuppressive concentrations. ^72^ , ^73^
Diltiazem is a non‐dihydropyridine calcium channel blocker that inhibits calcium influx in cardiac tissue and smooth muscle vasculature. In cardiac tissue, diltiazem exhibits dose‐dependent prolongation of intranodal conduction time and delays the atrioventricular node refractory period (Figure 1). ^74^ In smooth muscle vasculature, diltiazem is a potent vasodilator with minimal inotropic effects but with dose‐dependent decreases in blood pressure. ^75^
Diltiazem overdose causes cardiovascular compromise with bradycardia, atrioventricular block, hypotension, and in severe cases, cardiogenic shock and heart failure. Diltiazem causes insulin resistance with resultant hyperglycemia. ^76^ Lactic acidosis is also noted secondary to cardiogenic shock and hyperglycemia.
Supportive measures are used for the treatment of bradycardia, atrioventricular block, hypotension, and cardiac shock (Table 2). ^77^ Evidence for intravenous calcium and high‐dose insulin in mitigating toxicity in pediatric patients is variable but should be considered (see Section 5.4 Propranolol, Toxicologic Treatment). Use of intravenous lipid emulsion therapy in pediatric patients with diltiazem overdose is limited to case reports with varied success and is often considered in treatment‐resistant cases. ^42^
Adenosine is a Class V (miscellaneous) intravenous antiarrhythmic drug used in the diagnosis and treatment of paroxysmal SVT whose substrate is a reentrant circuit that involves the atrioventricular node. In addition to treating SVT, adenosine can also be a diagnostic tool for unmasking primary atrial tachycardias (atrial flutter, atrial fibrillation) by inducing atrioventricular block. It also has utility in myocardial perfusion stress imaging as it has vasodilatory effects. Although most VT is unresponsive to adenosine, adenosine may aid in terminating outflow tract VT caused by catecholamines or exercise by inhibiting the production of intracellular cyclic AMP. ^78^
Adenosine functions as a pharmacologic drug by binding the purinergic adenosine receptors (A1, A2a, A2b, A3) found throughout the body. ^79^ It exerts transient negative dromotropic effects on the atrioventricular node, as well as transient negative chronotropic effects on the sinoatrial node via A1 receptors. ^80^ Adenosine increases potassium conductance in myocardial tissue, which results in hyperpolarization of the cell membrane and an increase in the threshold for triggering an action potential; this leads to transient slowing or block of spontaneous cell activity. ^81^ Adenosine is quickly metabolized by endothelial cells and erythrocytes via adenosine deaminase, hence why a rapid bolus in a vein close to the heart is required. ^82^
Adverse effects of adenosine are typically transient (<60 seconds) due to the medication's short half life. Common side effects include facial flushing, hyperpnea, headache, lightheadedness, nervousness, and chest pain secondary to peripheral vasodilation. Less common but more severe side effects include bradycardia, prolonged sinus arrest, complete atrioventricular block, atrial fibrillation, acceleration of VT, and apnea. ^83^ , ^84^ There are case reports of bronchospasm after administration of adenosine, and it should be used with caution in patients with asthma. ^85^ It has also been previously demonstrated that transplanted hearts exhibit hypersensitivity to adenosine and thus use in these patients requires caution and consideration of dose‐reduction. ^86^
Given the short half‐life of adenosine, side effects are typically transient and usually do not require intervention. Treatment is primarily supportive, although theophylline, an adenosine antagonist, has been used to attenuate more severe or prolonged adverse reactions.
Cardiac antiarrhythmics are commonly used in the treatment of pediatric arrhythmias. Antiarrhythmics have distinct pharmacokinetics, potential interactions, and dosing and formulation considerations in the pediatric population that represent important sources of medication error and toxicity. An understanding of the mechanisms of action and potential associated toxicities of these medications is essential to ensure the appropriate management and monitoring of patients with rhythm disturbances as well as those presenting with accidental or intentional antiarrhythmic ingestion. Prompt recognition of antiarrhythmic toxicity is required to prevent significant morbidity and mortality.
There are several important gaps in the literature regarding antiarrhythmics and toxicity in the pediatric population. Epidemiologic data regarding the incidence of ingestions are limited to the cardiovascular drug classification and information surrounding the rate of accidental and/or intentional ingestion of individual antiarrhythmics is lacking. There is limited evidence regarding antiarrhythmic toxicity management in the children, and management strategy continues to be guided by case series and expert consensus. The toxicologic profile and management strategy in pediatrics for newer medications, such as ivabradine, a voltage‐regulated inward funny current (If) anatagonist used in the management of heart failure and automatic atrial arrhythmias, merits further study.
The authors have no conflicts of interest relevant to this article to disclose.
Geanacopoulos AT, Zielonka B, Fox MT, et al. Pediatric antiarrhythmics and A clinical review. JACEP Open. 2024;5:11111. 10.1002/emp2.13090