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Abstract
Flecainide is a medication used to treat supraventricular and ventricular tachyarrhythmias. Cases of overdoses are rare, however, can lead to significant cardiac effects. In previous cases of flecainide toxicity, treatment with sodium bicarbonate, intravenous lipid emulsion and amiodarone have been reported to be effective in preventing cardiovascular collapse and reestablishing baseline rhythm. Here, we present a case of a man in his 40s presented with flecainide overdose with wide-complex tachycardia that was treated with intravenous sodium bicarbonate following failure of amiodarone to normalise QRS interval.
- cardiovascular medicine
- arrhythmias
- pacing and electrophysiology
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Background
Flecainide is a class 1C antiarrhythmic medication, with a narrow therapeutic index, that is used to treat supraventricular and ventricular tachyarrhythmias.1 In cases of overdose with flecainide, both systemic effects and cardiac aberrancy can result.2 Significant cardiac effects include reduced ionotropy, increased conduction delay and potential to develop ventricular arrhythmias.2 The first diagnostic clue is ECG abnormalities. Flecainide’s action on conduction pathways is manifested as a prolonged PR interval and QRS duration.3 When diagnosed, prompt treatment for toxicity must be initiated to prevent life-threatening haemodynamic collapse. A number of treatments have been used but no large studies or guidelines exist. Currently, sodium bicarbonate infusion and supportive therapy is the standard method.4 Other modalities such as lipid emulsion therapy has conflicting evidence.5–7 Amiodarone has also been reported as effective, though evidence is limited and the mechanism is not understood.8
Case presentation
A man in his 40s with a history of seizures, sick sinus syndrome status-post dual chamber pacemaker and atrial fibrillation presented to the hospital after having a seizure episode. The seizure was aborted with intravenous benzodiazepine administration in the emergency department. Following his seizure he complained of mild chest discomfort, palpitations and diaphoresis. His home medications included brivaracetam, divalproate, diltiazem and flecainide. Further review of medications showed he had been taking 225 mg of flecainide two times a day, exceeding the maximum dosing of 400 mg daily. The patient was taking this dose of flecainide due to a misunderstanding where he thought it was the dose he was prescribed. The last dose was taken 4 hours prior to his presentation to the hospital. The patient had started flecainide on directive of an outside cardiologist within the past year, as it was not included in a previous admission’s medical reconciliation at 14 months prior to this incident. ECG at that time revealed sinus rhythm with QRS interval 110 ms and QT interval 428 ms.
His heart rate was initially 141 beats per minute while in the emergency department (ED), though he was otherwise haemodynamically stable. His laboratory testing revealed non-anion gap metabolic acidosis and normal electrolytes. Troponin levels were elevated with a peak of 0.31 ng/mL with a flat trend.
Divalproate serum levels were within normal limits. His ECG showed wide-complex tachycardia (figure 1A).
(A) Initial ECG showing wide-complex tachycardia and QRS duration 0.17 s. (B) ECG 6 hours after arrival with QRS duration 0.14 s. (C) ECG after 8 hours of hospitalisation. (D) ECG after 23 hours showing normalised QRS interval.
He remained in a wide-complex tachycardia and was given a 150 mg intravenous amiodarone bolus and started on an amiodarone infusion at 1 mg/min (for a total of 7 hours) with minimal improvement to his ECG findings. Heart rate normalised, though evidence of conduction abnormalities were still present at 6 hours as QRS duration was still found to be prolonged (figure 1B). QRS interval continued to be prolonged to 198 ms at 8 hours (figure 1C). He was then started on a sodium bicarbonate therapy with sustained normalisation of QRS interval near the end of day 1 of hospitalisation (figure 1D). Sodium bicarbonate was initiated at hour 12, after recommendations were received from the electrophysiology team, with a 150 mEq intravenous bolus followed by 150 mEq infusion at 15 mEq/hour.
Interrogation of his pacemaker was unremarkable and demonstrated low pacing requirements at baseline (right atrium 4% and right ventricle 6%). It is worth noting that the patient’s rhythm had high level of pacing requirement over his hospitalisation prior to sodium bicarbonate infusion (figure 1C, others not shown). Following infusion his tracings demonstrated intrinsic rhythm (figure 1D).
Echocardiogram showed left ventricular ejection fraction of 35%–40% with global hypokinesis. Cardiac catheterisation showed normal cardiac pressures and widely patent coronary arteries. Unfortunately, no serum flecainide levels were obtained. His calculated Naranjo score following stabilisation was 5. There are documented previous cases, the presentation correlated with drug administration, his condition improved with discontinuation and sodium bicarbonate, and the diagnosis was confirmed through electrophysiological monitoring and treatment effect. He was discharged on hospital day 5 with instructions not to take flecainide again.
Outcome and follow-up
The patient was discharged from the hospital with instructions to no longer take flecainide. He was ultimately started on bisoprolol 10 mg daily for rate control of atrial fibrillation and lisinopril 2.5 mg daily for his newly diagnosed non-ischaemic cardiomyopathy. The patient remains alive though has had multiple hospitalisations for his seizure disorder. On outpatient follow-up with primary care he had no complaints of symptoms such as palpitations, chest pain, diaphoresis. ECGs from his subsequent ED visits were without evidence of conduction abnormalities and QRS interval was maintained within normal limits.
Discussion
Flecainide has a narrow therapeutic index of 0.2–1.0 µcg/mL1 which increases the potential for toxicity. Despite this finding, cases of overdose are not often reported, with a PubMed search through December 2023 yielding 84 results. The major cardiac effects of flecainide toxicity are related to reduced sodium conduction through ion channels.2 This leads to negative inotropy, conduction blocks, arrhythmias and potentially asystole.2 Toxicity is suggested when ECG shows a 50% increase in QRS duration (0.18 s) or 30% prolongation in PR interval (0.26 s).3 In severe cases cardiovascular collapse necessitating haemodynamic support can occur.4 5 The patient’s Nanjaro score was calculated to be 5, which corresponds to probable likelihood of drug adverse event.6
When diagnosed, therapeutics must be administered rapidly to prevent haemodynamic collapse from ventricular arrhythmias. The current treatment approach is not standardised. Most successful cases have used sodium bicarbonate infusion, as sodium ions are thought to compete with flecainide at the molecular level of the sodium channel.7 Cases with successful treatment typically used an initial 50–100 mEq bolus of sodium bicarbonate with subsequent infusion to reach pH>7.5 and sodium concentration greater than 150 mEq/L.5 7 Interestingly, the effect of sodium bicarbonate in isolation of other pharmacological agents is illustrated by ECG changes between figure 1B and D.
Other medical therapies have been proposed, though evidence is currently limited. One popular modality is lipid emulsion therapy, which is thought to act via sequestration of flecainide through its lipophilicity.9 The efficacy of this medication has been questioned as it has not been shown to alter the elimination half-life of flecainide.9 Additionally, the potential side effects of lipid emulsion are not few, and include acute pancreatitis, lipid embolus, acute kidney injury, cardiac arrest and acute lung injury.8
Amiodarone has also been suggested, however many of these cases occurred in cases where patients progressed to cardiac arrest.10 In our case, the patient’s rhythm did improve following initiation of amiodarone though evidence of conduction abnormalities persisted as QRS remained prolonged. It is unclear if any effect seen was due to the medication or metabolism of flecainide. The half-life of flecainide is 12–27 hours when taken at therapeutic levels11 and our patient was reportedly taking the excess dosage consistently. Furthermore, the patient’s QRS interval did not improve until receiving a sodium bicarbonate infusion (figure 2). Figure 2 demonstrates the QRS interval on ECG over time with a non-linear regression curve to represent the trend.
QRS duration recorded on ECG over time. Figure created by James Boris.
It is worth noting that amiodarone itself is known to cause prolongation of QRS and QT intervals. In our patient, the QRS interval prolongation was not exacerbated by infusion of amiodarone, and there was no worsening of the QT interval after starting intravenous amiodarone. In addition, it is reasonable to expect amiodarone-induced electrophysiological changes to persist as peak levels are reached in 1–3 hours and amiodarone is known to have a long half-life.12 In our case, the conduction abnormalities were rapidly improved following sodium bicarbonate infusion despite any anticipated effects of amiodarone on ECG intervals.
Furthermore, the interrogation of the dual chamber pacemaker showed no evidence of malfunction as well as a relatively low burden of baseline pacing requirement (right atrial 4% and right ventricle 6%). The patient’s multiple cardiac tracings throughout hospitalisation showed persistent dependency on pacemaker activity that is postulated to be in the context of flecainide toxicity. The mechanism of which is due to flecainide increasing pacemaker capture threshold, which will increase pacing output as the leads fail to sense inherent activity.13 In some cases, conduction abnormality can be so severe that pacemakers fail to capture, and the patient’s condition can progress to cardiac arrest.13 Conduction abnormalities, in this case, did lead to the higher necessity for pacemaker intervention though thankfully capture mechanisms were not affected. After a sodium bicarbonate infusion, the patient’s inherent rhythm was predominant.
Finally, flecainide is metabolised through hepatic CYP enzymes, thus medication interactions must be considered in cases of suspected toxicity. In our case, the patient was on divalproate which is a known inhibitor of CYP2C9. Flecainide is metabolised through a different subset of cytochrome enzymes14 so interaction between flecainide and divalproate was not thought to be significant.
This case exemplifies the challenge in identifying and treating flecainide toxicity based on ECG patterns and patient history. A sodium bicarbonate infusion can be used to reverse acute toxicity and prevent or treat life-threatening arrhythmias. Treatment protocols for flecainide toxicity do not currently exist and more research is needed in this area.
Learning points
Flecainide toxicity is rare but can present as life-threatening arrhythmias that require prompt recognition and treatment.
Flecainide is metabolised by hepatic cytochrome enzymes, thus medication interactions need to be considered.
Common findings of flecainide toxicity include conduction delays and occasionally visual effects.
Sodium bicarbonate infusion has been shown to normalise conduction abnormalities due to flecainide toxicity.
Ethics statements
Patient consent for publication
Footnotes
Contributors JB, HA-S and AB were responsible for drafting this text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content. JB, HA-S and AB gave final approval of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.