Many anti-arrhythmic drugs are used in both acute and maintenance treatment of re-entry and automatic tachycardias in the first year of life; however, to date no consensus exists regarding the most effective drug, and there is still a wide variability in the treatments. According to the European guidelines, in case of re-entry tachycardias the first antiarrhythmic choice should be a Class 1A, Class 1C or Class 3 antiarrhythmic agent, except for amiodarone that should only be used if other drugs fail to control the arrhythmia. In case of automatic tachycardias, the first choice should be digoxin, with a Class 1C agent or beta-blocker added in case of failure, and using amiodarone as a third-line drug [
4]. Our data demonstrate the effectiveness of flecainide and beta-blockers for a long-term follow up, starting from neonatal age up to childhood. In re-entry tachycardias we focused on the antiarrhythmic properties of oral flecainide as maintenance therapy. Flecainide, an IC anti-arrhythmic drug, has optimal pharmacodynamic properties, namely, the ability to slow the rate of diastolic depolarization plus it is highly effective in inducing anterograde and retrograde conduction block on accessory pathways. It also presents good pharmacokinetic properties, including relatively fast oral absorption and a long half-life elimination of about 11–12 h [
13,
14]. Thanks to these properties, this drug showed high efficacy in 73–100% of supraventricular tachycardias [
15]. Unlike in adulthood, where a significant incidence of pro-arrhythmic effects was reported in the CAST study, flecainide-induced arrhythmias were documented in less than 7% of the paediatric population [
15,
16]. Propafenone, another IC anti-arrhythmic drug, demonstrated good results in clinical trials [
17]. In a prospective study comparing four anti-arrhythmic drugs in long-term prophylaxis of SVT, it appeared to be less effective than flecainide [
10]. Few studies are reported with sotalol, a Class III anti-arrhythmic agent with beta-blocking properties; although high effectiveness has been reported with elevated doses in paediatric SVTs, we decided to use it in combination with flecainide, given the encouraging results of this combination [
18]. Beta-blockers in monotherapy might be an alternative choice, both in re-entry and automatic tachycardias. In the SAMIS trial, one of the first prospective studies in infants, long-term treatment with propranolol in monotherapy demonstrated non-inferiority when compared with digoxin in monotherapy [
19]. In automatic atrial tachycardia, beta-blockers were used in monotherapy or combined mostly with digoxin or flecainide [
20]. Finally, amiodarone, a third-class anti-arrhythmic agent, can only be considered an alternative for infants with resistant supraventricular tachycardias due to its well-known adverse events: in a recent cohort of 150 paediatric patients receiving amiodarone in acute and long-term treatment, 50.8% developed thyroid dysfunction, especially the newborns (66.7%) [
12]. Furthermore, a recent comparative study between flecainide and amiodarone for the treatment of paediatric supraventricular tachycardias demonstrated the non-inferiority of the former, both in patients with congenital heart disease and those with structurally normal hearts. Lastly, in all the patients in whom amiodarone was ineffective, the shift to flecainide allowed for controlling the arrhythmia [
11]. Perry et al. [
14] observed 45 patients with supraventricular tachycardias (both re-entries and automatics) and showed that flecainide controlled about 81% of cases. O’Sullivan et al. [
21] reported that 39 infants with sustained atrioventricular re-entry tachycardias non-responsive to digoxin were treated with flecainide, with about 96% of success. Ferlini et al. [
9] showed that neonates could be treated with this drug both in acute and mid-term therapy with an effectiveness of approximately 85%. Our data showed an efficacy of about 51.1% in re-entry tachycardias as monotherapy; however, when we combined it with beta-blockers or digoxin, a stable cardioversion was achieved in up to 95.5% of cases. Digoxin has been reported to be successful when combined with flecainide both in fetal and neonatal supraventricular tachycardias [
20,
22]. The effectiveness of combined treatment compared to monotherapy may be related to the enhanced adrenergic tone of the neonate, representing a trigger for re-entry arrhythmias
. In order to achieve stable rhythm control, automatic tachycardias, known to be more resistant to incessant antiarrhythmic treatment, require a pharmacological combination more frequently than re-entry forms [
20].
Price et al. [
23] considered 10 patients with supraventricular tachycardias (eight re-entry and two automatic) in the first year of life who were unresponsive to at least two anti-arrhythmic agents: the combination of flecainide and sotalol was effective in all patients in an average of twelve days. Also in our experience, although sotalol is scarcely effective in monotherapy, when combined with flecainide, even at beta-blocking doses, it was able to obtain a stable cardioversion in resistant forms without prolonging the QTc interval [
24]. Von Alvensleben et al. [
25] considered 28 patients with supraventricular tachycardias (27 with re-entries and 1 with focal atrial tachycardia) under 2 years of age; nadolol alone resolved arrhythmia in 20/28 (71.4%) cases, and for the other six this result was achieved when combined with flecainide. Perry et al. [
14] obtained stable cardioversion with flecainide alone for 9/13 (69.2%) patients with ectopic atrial tachycardias. In our study, beta-blockers proved to be effective in monotherapy in a minority (30%), but again, the combination with flecainide allowed for controlling almost all resistant tachycardias. Therefore, a substantial number of infants with re-entry supraventricular tachycardias and the majority with automatic forms, required the combination of two antiarrhythmic agents for a stable cardioversion. Flecainide and nadolol or sotalol seemed to be the most effective choice. The time to sustained sinus rhythm was significantly longer in automatic tachycardias than in re-entry forms [
20,
26]. In one case, after obtaining a satisfactory rate control, we discharged the patient, and in the end observed stable conversion to sinus rhythm in all patients. In two cases a stable cardioversion was obtained when anti-arrhythmic drugs were administered more frequently than two or three times a day, with the strict recommendation to monitor ECG and blood flecainide concentration continuously in order to prevent toxicity [
5,
27]. This different administration rate may be related to the variability of the drug’s pharmacokinetics, often reported in infants [
14,
15]. Measuring flecainide blood concentration helped us to quantify the correct doses of the drug. Therefore, we strongly recommend this approach in clinical practice when possible in order to avoid life-threatening complications due to overdosage.
With flecainide treatment we observed two major ventricular arrhythmias. As for the patient coming from another hospital who died, flecainide toxicity could indeed have been the cause of death, possibly owing to a poor metabolizing mechanism, as also potentially reported in a recent Japanese study [
28]. Incessant supraventricular tachyarrhythmias, ventricular tachycardias and severe bradycardias have been reported during flecainide treatment, therefore it is recommended to start therapy during hospitalization and to closely monitor the ECG and plasma concentration [
15,
29]. Pro-arrhythmic effects and cardiac arrest seem to be more common among patients with underlying heart diseases or impaired systemic ventricular function than in those with a normal heart [
30]. However, in a recent study, a comparison between the use of flecainide and other drugs in patients with cardiomyopathy or structural heart diseases showed that there were no differences in the incidence of cardiac arrest or death [
31].
In our work, the gestational age at birth, birth weight and perinatal age were not predisposing factors influencing a different antiarrhythmic approach. Moreover, the efficacy of antiarrhythmic agents was not influenced by the presence of CHD defects, most of which were well-tolerated.