Flecainide toxicity: a presentation to the emergency department with literature review

Abstract

Flecainide toxicity can result in increased cardiovascular instability which can significantly alter patient outcome if not recognised early. In this case report, the management of a 68-year-old woman who took an unintentional overdose of flecainide is detailed. We look at the management she received in the emergency department and her successful recovery and follow-up since the admission. In addition, the case report outlines the ECG changes that are most commonly documented in flecainide overdose and reviews the frequently used treatment methods for the overdose as summarised in current literature.

Background

The therapeutic window for flecainide is narrow: 200–800 μg/L,¹ and toxicity can occur with a few extra pills. Flecainide has no specific antidote and there is no way of rapidly eliminating the drug from the body.² Severe toxicity due to flecainide has a reported mortality of 22.5%.³ The management of flecainide toxicity is primarily dependent on recognising the ECG pattern which goes with it. Standard treatment for managing the rhythms seen on ECG is futile in most cases. Prompt recognition of flecainide toxicity and administration of medication will help achieve cardiovascular stability and improve patient outcomes. In some cases, the use of extracorporeal membrane oxygenation (ECMO) or cardiopulmonary bypass can achieve good outcomes. It is a diagnosis which is often mismanaged because there is scarce evidence or guidance on how to appropriately recognise (and manage) the toxicity.

Case presentation

A 68-year-old women presented to a district general hospital with intermittent, irregular palpitations that started in the morning after blowing her nose aggressively. She had known paroxysmal atrial fibrillation (pAF) with a history of previous cardioversion many years ago. She had taken her own morning flecainide dose of 100 mg at 09:00 to resolve the symptoms, as well as an extra 300 mg between 10:00 and 11:00, as the symptoms were not settling. She therefore attended the emergency department and walked into triage. There was no associated shortness of breath, chest pain or fevers with the palpitations. While being assessed by the triage nurse, she had an episode of lightheadedness, sweating and further palpitations and so she was brought into the resuscitation room. Her blood pressure had dropped to 91/56 and she was tachycardic at 148. Her Glasgow Coma Score was 15/15. Her medical history included type 2 diabetes mellitus and hypertension as well as pAF.

Investigations

Her initial ECG showed a wide complex right bundle branch block (RBBB) with a run of ventricular tachycardia (VT) in the rhythm strip (figure 1). This was compared with an ECG on her records from 2017 which showed normal sinus rhythm (figure 2). Her lactate was 3.9 on the initial venous gas with pH 7.34. Her temperature was 36.1°C. Initial impressions were that this could be acute coronary syndrome or a pulmonary embolism with new onset RBBB, but the history did not fit with the differential diagnosis.

Figure 1.

ECG on arrival into resus: right bundle branch block with a run of ventricular tachycardia in the rhythm strip.

Figure 2.

ECG from previous hospital attendance from patients records: sinus rhythm.

Treatment

She was initially treated with a 500 mL 0.9% saline intravenous fluid bolus to manage her low blood pressure and 4 mg of intravenous metoprolol for pharmacological management of her tachycardia. This brought her heart rate down to 108 and she reverted into a sinus tachycardia. Her blood pressure improved to 113/68 with another 500 mL 0.9% saline intravenous bolus, but her heart rate continued to fluctuate between 120 and 180 beats/min with variable complexes seen on telemetry. Her ECG morphology improved with her QRS complexes narrowing and no further runs of VT captured (figure 3). Her systolic blood pressure did not drop below 100 mm Hg again.

Figure 3.

ECG showing narrower QRS complexes following initial treatment.

Cardiology advice was sought and after reviewing the first ECG a diagnosis of flecainide overdose was made, as she had taken a total of 400 mg within the space of 2 hours. The cardiologist recognised the widened QRS complexes on the initial ECG which he noted was extremely common in flecainide overdoses. The cardiologist recommended giving her sodium bicarbonate should she develop ventricular fibrillation/VT again.

Outcome and follow-up

The remainder of her hospital stay was uneventful. She was admitted into the acute assessment unit for observations. Approximately 8 hours after her first ingestion of flecainide, her heart rate stabilised at 80 beats/min and ECG showed an irregular rhythm with normalisation of QRS complexes (figure 4).

Figure 4.

ECG showing normalisation of QRS complexes and an irregular rhythm, 8 hours after ingesting flecainide.

The following day she was reviewed by cardiologists. They counselled the patient to take 1 pill of flecainide if palpitations were to occur again and to attend the emergency department if palpitations did not resolve within 30 min. She was to continue her bisoprolol and apixaban as normal. She was booked in as an outpatient for cardiology where the discharge advise was reiterated. The flecainide level taken at the time of clinical suspicion returned at a result of 1256 μg/L. Following her discharge for intermittent, irregular palpitations and flecainide toxicity, she has not had any further episodes and has not needed to take any flecainide medication.

Discussion

Flecainide is a Vaughan-Williams class 1C antiarrhythmic agent which is licenced to be used in supraventricular and ventricular arrhythmias. It is especially effective in the conversion of atrial fibrillation to sinus rhythm in patients without structural heart disease. Its mechanism of action focuses on phase 0 of the action potential, by blocking the fast sodium channel and thus depolarisation of the myocyte. This results in marked depression in all major conduction pathways—it is a negative inotrope.⁴

The general management of flecainide toxicity is unclear and there is a lack of cohesive guidance to support or refute the use of many of the current management strategies.

This review focuses on the ECG changes seen in flecainide overdose and outlines the main areas of management which have been documented through case reports.

ECGs

The ECG has an important diagnostic value in the identification of flecainide overdoses.

ECGs in cases presenting with flecainide overdose can be broadly split into two categories based on the QRS duration, depending on whether it is <200 ms or >200 ms. It is interesting to see that the length of QRS duration can also determine the type of bundle branch morphology.⁵

If the patient has a QRS duration <200 ms, there is likely to be an associated RBBB morphology. Patients are more likely to experience a rapid recovery without the need for mechanical circulatory support. In patients who have a QRS>200 ms, the ECGs are more likely to show a left bundle branch block morphology. The need for mechanical ventilatory support is more prevalent with patients with a QRS duration >200 ms and there is also an associated increase in chance of mortality.⁵

Along with the QRS durations, p waves can also be examined. Those who have a QRS<200 ms are more likely to have p waves, compared with those who have a QRS>200 ms. The QT and QTc intervals are also shorter in those who have a QRS duration <200 ms.⁵

It has also been demonstrated that the duration of QRS interval and morphology of the rhythm does not relate to the amount of flecainide consumed, the serum flecainide level or heart rate. Therefore, a very light suspicion can lead to the diagnosis and treatment of flecainide toxicity.⁶

Brugada type ECG patterns have also been reported⁶ in severe flecainide toxicity, even if individuals have no clinical suggestion of the congenital abnormality. Sodium channel blockers may unmask the Brugada sign in patients with the hereditary form of the Brugada syndrome and it can also induce it in asymptomatic individuals.⁷

In patients without a hereditary form of Brugada syndrome, significant amounts of flecainide in overdose can sufficiently suppress cardiac sodium ion channels because of mutations on these channels. The ECG abnormality seen is a result of abnormalities to action potentials in the right ventricular epicardium.^{8 9}

In worst case scenarios, VT and or ventricular fibrillation should be managed as per standard resuscitation guidelines.

Sodium bicarbonate

From the case reports which have been documented and published, the majority promote the use of sodium bicarbonate as the first-line management of flecainide toxicity. While the precise mechanism of action is unclear, it is thought that sodium bicarbonate reverses sodium channel blockade and narrows the QRS interval by a combination of sodium loading and alkalinisation. By narrowing the QRS interval, sodium bicarbonate manages the cardiovascular instability. There has been a documented need for giving further boluses of sodium bicarbonate following repeat ECG derangements through the clinical course. In the UK, the National Poisons Information Service recommends 50–100 mL 8.4% intravenous sodium bicarbonate.¹⁰ Most of this evidence is case based and depends on blood gas analysis, an ECG trend and analysis of the overall patient clinical picture.

Lipid emulsion therapy

The traditional use of lipid emulsion therapy is in the management of local anaesthetic toxicity. In recent years, this has extended to the treatment of severe cardiovascular toxicity as the result of other lipid soluble drugs, such as flecainide.¹¹ A systematic review of animal and human studies has shown that intravenous lipid emulsion therapy can be used in the treatment of acute poisoning.¹¹

The mechanisms via which intravenous lipid emulsions work are not yet fully understood. A hypothesis is that intravenous lipid emulsion works as a lipid sink, recruiting and isolating lipophilic medications (like flecainide) from the receptor sites where they mediate their toxicity.^{3 12} A second hypothesis suggests that intravenous lipid emulsion exerts a positive ionotropic effect with more efficient metabolism of fatty acids.¹³ It has been shown to open voltage-gated calcium channels, which can lead to increased contractility of cardiac myocytes.¹⁴

In the management of flecainide toxicity, lipid emulsion therapy is often used as an adjunct to the initial boluses of sodium bicarbonate. In one case report of deliberate flecainide ingestion, the effect of a lipid emulsion infusion showed dramatic improvement to cardiovascular stability and QRS duration after 30 min of starting the treatment, and in another report after 1 hour.^{3 15} In the UK, the dose of 20% lipid emulsion is 1.5 mL/kg as an initial bolus, followed by an infusion of 15 mL/kg/hour.¹⁶

Extracorporeal membrane oxygenation

A novel method for stabilising patients is through the initiation of invasive haemodynamic support, although this is restricted to cases where conventional treatment options have been exhausted and cardiovascular compromise remains. ECMO is a temporising measure to allow for cardiac recovery and drug elimination.¹⁷ A case report documented the use of ECMO for 26 hours in a patient with a deliberate flecainide overdose, to maintain cardiac output and vital organ perfusion while allowing time for drug metabolism and clearance. The patient was successfully discharged from intensive care 12 days after admission and had no documented complications from ECMO following discharge.⁴ The main short-term complication of ECMO is major bleeding; late deaths are due to multiorgan system failure. In a separate study of deliberate flecainide overdose, the patient remained on cardiopulmonary bypass for a total of 30 hours. In that time, she had developed coagulopathy requiring transfusions of fresh frozen plasma, platelets and packed red cells. She also developed an irretractable femoral nerve palsy and an early femoral deep vein thrombosis on the side used for access.¹⁸ This shows that the use of ECMO or cardiopulmonary bypass is not without its risks. However, it is a useful intervention in the resuscitation of patients with flecainide overdose with cardiovascular instability, without compromising vital organ perfusion and thus allowing for excellent drug clearance in a short space of time. Its use so far has therefore only been reserved for exceptional circumstances.

Learning points.

• Patients with suspected flecainide toxicity can present with cardiovascular instability; early recognition with a 12 lead ECG can help facilitate correct management.

• The 12 lead ECG often has a widened QRS giving rise to either right bundle or left bundle branch block depending on the duration of QRS interval.

• The pharmacological treatment of flecainide toxicity is based on case-by-case documented scenarios.

• In scenarios where pharmacological management has failed, ECMO should be considered for resuscitation.