Flecainide toxicity: ECG changes associated with supratherapeutic levels in milk-fed infants

Background

Flecainide is a class 1C antiarrhythmic predominantly used as a second-line treatment for a range of arrhythmias in children, usually following failure of beta-blocker monotherapy. Flecainide acts primarily on the fast sodium channels, slowing conduction throughout the cardiac conduction system, including the bundle of His and the specialised intraventricular conduction system.1

In the adult population, the use of flecainide to treat asymptomatic or mildly symptomatic ventricular arrhythmias in patients with left ventricular dysfunction was shown to increase mortality rates.2 In the paediatric population, flecainide has safely been used for a range of arrhythmias in children with structurally normal hearts.3 It should, however, be used with caution in children with structural heart disease, due to its myocardial depressant effects and proarrhythmic risk.4 Structural heart disease and systolic ventricular dysfunction are therefore relative contraindications for commencing treatment, although data in children are limited.2

The use of flecainide is contraindicated in patients with Brugada syndrome, but even in the absence of an underlying sodium channelopathy, supratherapeutic levels of flecainide can lead to a Brugada phenocopy by causing excessive sodium channel blockade.5 Considerations should be also taken of enzyme deficiencies due to genetic polymorphisms causing poor drug metabolism thus inadvertently causing toxicity.6

Pharmacokinetic studies indicate that oral preparations should be commenced at 2–6 mg/kg/day (median 4 mg/kg/day) to ensure plasma concentrations are within the therapeutic range.7

The target range for serum levels in paediatric patients is 200–800 µg/L. When supratherapeutic, flecainide’s action on conduction manifests on ECG with prolongation of PR interval, QRS duration and subsequently of the QT.8 9

Breast milk, infant formula and dairy products are thought to reduce the absorption of flecainide in children and infants. Flecainide binding is related to serum glycoprotein concentration, which is found in high concentrations in milk. Thus, significant changes in serum proteins secondary to intake alters the fraction of free drug in circulation.10 11

In milk-fed infants, regular feeding patterns and consistent timing of doses are therefore paramount to achieve a steady therapeutic state.

Despite appropriate dosing, a sudden cessation or reduction in milk intake may affect absorption, causing increase in plasma drug levels, which could lead to toxicity. Therefore, when concerned about poor oral intake, or acute gastroenteritis, it is recommended to reduce the flecainide dosage in order to prevent toxicity.

Case presentation

Case 1 is a term baby girl who was postnatally diagnosed with hypoplastic aortic arch with coarctation. She was recovering postoperatively in the cardiology ward following an aortic arch repair with a structurally normal heart and normal biventricular function. On day 17 of life, she had sustained episodes of narrow complex tachyarrhythmia at 230–280 beats per minute (bpm). The 12-lead ECG of the tachycardia was consistent with a diagnosis of atrial ectopic tachycardia with a variable ventricular rate and intermittent broadening of QRS due to aberrancy in the His-Purkinje system.

She was transferred to the paediatric intensive care unit (PICU). Due to a lack of response to esmolol, she required loading with intravenous (IV) flecainide which cardioverted her to sinus rhythm. She was given oral propranolol 2 mg/kg three times a day and flecainide 2 mg/kg three times a day. Once stable, she was again given regular formula feeds via a nasogastric tube.

Several days later, while being fasted for central line insertion, she was administered her regular dose of flecainide. This resulted in prolonged episodes of broad complex QRS changes on ECG consistent with flecainide toxicity (figure 1). The corresponding flecainide level was 1186 µg/L. Flecainide was consequently stopped, and her arrhythmia remained well controlled on propranolol monotherapy.

Figure 1

Baseline ECGs taken during flecainide treatment (left). ECGs taken during flecainide toxicity (right) illustrating characteristic PR prolongation and QRS broadening.

Case 2 is a boy born at 37 weeks following induction of labour due to detection of fetal tachycardia with a structurally normal heart on a routine antenatal scan. He was transferred to Evelina London Children's Hospital on day 2 of life in cardiogenic shock secondary to an atrial tachycardia which was not responsive to adenosine and direct current (DC) cardioversion. His ECGs showed a multifocal atrial ectopic tachycardia with variable atrio-ventricular (AV) conduction and intermittent aberrant conduction. The tachyarrhythmia had caused severely impaired systolic function and he was commenced on milrinone. The atrial tachycardia remained difficult to control, despite multiple different combinations of antiarrhythmics; including beta-blockers, flecainide, amiodarone and a trial of ivabradine. Eventually a combination of propranolol 2 mg/kg three times a day and 2 mg/kg three times a day of flecainide achieved stabilisation. Once arrhythmia control was achieved, his cardiac function normalised. Following a period of stability at home on regularly expressed breast milk, he presented again to the outpatient clinic having had daily vomits and increasing lethargy. His ECG at the time showed an irregular atrial rhythm with PR prolongation and broad complex QRS consistent with flecainide toxicity (figure 1). Flecainide level taken at the time was 901 µg/L. He was admitted in order to support feeding and monitor heart rhythm on a reduced flecainide dose. He was discharged on a reduced dose of flecainide 1.5 mg/kg two times per day and higher dose of propranolol 3 mg/kg three times a day, which have since slowly been weaned over time due to improving burden of arrhythmias.

Case 3 is a boy postnatally diagnosed with Noonan syndrome after being born at term.

He had syndromic cardiac associations with ventricular hypertrophy, normal biventricular function, mitral valve dysplasia and supravalvular pulmonary stenosis. During the neonatal period, he also had a high burden of atrial ectopics with runs of sustained atrial ectopic tachycardia, which were initially well controlled with propranolol monotherapy.

At 5 months of age, he was found floppy at home and admitted with suspected aspiration pneumonia. Due to the severity of his illness, he required intubation, ventilation and a long PICU stay. During this admission, he again developed frequent atrial ectopics and occasional episodes of sustained atrial tachycardia for which flecainide was introduced at a dose of 2 mg/kg three times a day in addition to a high dose of propranolol at 3 mg/kg four times a day. He was discharged on continuous nasojejunal (NJ) feeds due to an unsafe swallow.

A few months later, he was electively admitted again for a percutaneous endoscopic transgastric jejunostomy insertion for his feed intolerance. He was fasted before this procedure but continued to have regular administration of his antiarrhythmics. Postprocedurally he became floppy, hypotensive and bradycardic with broad-complex QRS changes on ECG (figure 1). This episode was deemed to be secondary to inadvertent flecainide toxicity requiring a cessation of treatment. This diagnosis was supported by his corresponding flecainide level being 1664 µg/L. He was discharged on propranolol and amiodarone dual therapy and has since been converted to atenolol as a monotherapy.

Case 4 is a boy delivered by emergency caesarean section at 35⁺⁴ weeks’ gestation due to fetal tachycardia. Following delivery he was tachycardic at 180–200 bpm with ECGs showing a broad complex tachycardia (BCT) with retrograde P waves following each QRS complex consistent with either ventricular tachycardia (VT), or supraventricular tachycardia (SVT) with rate-related aberrancy. Adenosine failed to cardiovert the BCT, but demonstrated transient ventriculoatrial dissociation, proving VT as the mechanism. He had a structurally normal heart with normal biventricular function. He was commenced on IV esmolol, then oral propranolol which helped gain rate control, but continued to have recurrences of VT. Flecainide was added to maintain him in sinus rhythm.

Following a period of monitoring, he was discharged home on demand breast feeds and oral propranolol 1 mg/kg three times a day and flecainide 2 mg/kg three times a day.

At 5 months of age, he presented to his local hospital with 1 day of reduced feeding followed by episodes of distressed crying and an episode of sudden pallor and lethargy. An ECG performed in the emergency department showed QRS broadening and AV Wenckebach pattern (figure 1), consistent with flecainide toxicity. The level taken at the time was 2427 µg/L. The flecainide was promptly stopped and he was admitted in a monitored bed. Once the acute gastroenteritis had resolved, he was given omeprazole and regular feeding patterns were started. He continued propranolol and was then started again on a reduced dose of flecainide. Since discharge he has since been weaned off flecainide and remains on propranolol 2 mg/kg three times a day as monotherapy.