Flecainide toxicity with high pacemaker capture thresholds and associated takotsubo syndrome

Abstract

We describe a case of a woman in her 80s with persistent atrial fibrillation (AF) despite being on flecainide who was admitted for AF with rapid ventricular response. Attempts with direct-current cardioversions were unsuccessful despite increased doses of the antiarrhythmic therapy. At atrioventricular (AV) nodal ablation, very high right ventricular capture thresholds resulted in abortion of the procedure as back-up ventricular pacing could not be assured with adequate margin for safety. Shortly following the electrophysiology (EP) study, the patient developed cardiogenic shock with new apical left ventricular regional wall motion abnormality suggestive of apical ballooning and a toxic-appearing wide QRS complex electrocardiogram (EKG). The patient was successfully treated with sodium bicarbonate infusion for presumed flecainide toxicity. The regional wall motion abnormality and EKG changes resolved along with normalisation of capture thresholds after 2 days of treatment. The patient underwent an uncomplicated successful AV nodal ablation several weeks later.

Background

Flecainide is the fourth most commonly prescribed antiarrhythmic drug to maintain sinus rhythm in patients with symptomatic atrial fibrillation (AF).¹ It has an increased risk of serious adverse reactions due to its narrow therapeutic index, decreased clearance in kidney or liver injury and interaction with other medications.² Toxic levels of flecainide have been associated with cardiac arrest, dysrhythmias and acute heart failure,³ which may be life-threatening if not recognised promptly. We present a case of a patient with flecainide toxicity who developed new regional wall motion abnormality, toxic EKG appearance and high pacemaker capture thresholds and recovered soon after starting sodium bicarbonate infusion.

This case illustrates that early recognition and prompt treatment of flecainide toxicity as the potential cause of cardiogenic shock can lead to good outcomes. Furthermore, it describes a case of flecainide toxicity with new regional wall motion abnormality with left ventricular ballooning suggestive of takotsubo syndrome (TTS).

Case presentation

Our patient is a woman in her 80s with hypertension, aortic stenosis, stage II chronic kidney disease and persistent AF. She presented to the emergency department with worsening cough, shortness of breath and chest tightness. Her AF has been symptomatic for the last 2 years. She had undergone multiple unsuccessful direct-current cardioversions (DCCVs) prior to admission. Her home medications are apixaban, furosemide, verapamil and flecainide 100 mg two times per day.

On presentation she was hypoxic, volume overloaded and in AF with rapid ventricular rate (RVR). Due to respiratory distress, she was initiated on non-invasive mechanical ventilation and admitted for further management.

Investigations

Initial chest X-ray showed significant bibasilar airspace opacities. B-type natriuretic peptide was elevated at 1008 pg/mL, consistent with a diagnosis of heart failure for which we started furosemide with good diuresis response. She had leukocytosis of 12.4 K/μL. Empiric treatment of community-acquired pneumonia was initiated. Transthoracic echocardiogram (TTE) showed an ejection fraction (EF) of 55%, severe left atrial dilation and moderate aortic valve stenosis.

On admission, flecainide dose was increased to 150 mg two times per day and her home verapamil was continued. Diltiazem drip was titrated in an attempt to achieve rate control of her AF. Apixaban was continued without interruption. Because her rates remained elevated, rhythm control strategy was pursued with DCCV. Two attempts resulted in recurrence of AF 5 min after the procedure. Our electrophysiology colleagues recommended AV nodal ablation with requisite back-up right ventricular (RV) pacing.

During the AV nodal ablation, 10 repositioning attempts of a Medtronic Micra leadless pacemaker resulted in extremely high capture thresholds of more than 5 mV. The first Micra device was removed. A second Micra device deployment was attempted, with five repositioning attempts revealing the same unacceptably high thresholds. The venous sheath and Micra device were removed. After that, a conventional left infraclavicular generator and transvenous permanent pacemaker (PPM) were implanted in the usual fashion. Potential RV lead positions were assessed in the RV septum, outflow tract and apex, but poor capture thresholds were once again seen. The best threshold of 2.25 V at 1 ms. Using an external analyser, the RV pacing threshold was 2.25 V at 1.0 ms with a pacing impedance of 708 Ω at 5 V pacing. RVR waves were still sensed at 8.6 mV and there was no diaphragmatic stimulation at 10 V pacing from any lead. The decision was made to abort the AV node ablation due to elevated capture thresholds and leave the PPM system in situ.

Within a couple of hours following the procedure, the patient became profoundly diaphoretic with altered mental status and hypotension. Her EKG showed AF with bizarre wide-complex rhythm with a change in the QRS axis and a morphology suggestive of toxic metabolic effect (figure 1) compared with her baseline EKG prior to the acute illness (figure 2). After stabilising the patient, emergent TTE showed a reduced left ventricular) LV EF of 28% and a large mid-to-apical regional wall motion abnormality (anterior, anteroseptal, anterolateral, inferior and inferolateral). There was no evidence of intracavitary thrombus (video 1). A sodium bicarbonate infusion was then started for suspicion of flecainide toxicity. Emergent left heart catheterisation showed patent coronary arteries.

Figure 1.

Abnormal electrocardiogram (EKG) shows a toxic bizarre wide QRS complex (red arrow), right bundle branch block (RBBB) (green arrow), long QT interval (blue interval) and a right axis.

Figure 2.

Baseline electrocardiogram (EKG) shows atrial fibrillation with normal QRS complex morphology prior to the acute illness.

Video 1.

Download video file ^{(858.4KB, mp4)}

DOI: 10.1136/bcr-2021-243326.video01

Treatment

Flecainide, diltiazem and verapamil were discontinued. Metoprolol and digoxin were instituted instead for rate control. Given suspected flecainide toxicity, sodium bicarbonate was infused for 48 hours resulting in improvement of the patient’s clinical status. Furthermore, we performed a pacemaker interrogation which showed a capture threshold of 0.5 mV at 1 s significantly improved from before. A repeat TTE showed a dramatic improvement in her ventricular function (video 2), and her QRS morphology also normalised (figure 3).

Video 2.

Download video file ^{(936.9KB, mp4)}

DOI: 10.1136/bcr-2021-243326.video02

Figure 3.

Atrial flutter with normal QRS complex morphology after treatment.

Differential diagnosis

We initially attributed the high capture threshold to device malfunction or position; thus, another Micra device was chosen for a repeat attempt. However, it was clear that there was a secondary aetiology for the high capture thresholds after a standard RV lead was placed. The results were confirmed via the external analyser. Eventually, the high capture thresholds were attributed to flecainide toxicity that was subsequently discontinued.

Ischaemic heart disease was initially considered given new systolic dysfunction, hypokinesia and ST depression. However, when the coronary angiography showed patent coronaries, TTS was diagnosed.

Septic shock was initially considered given new onset fever. However, a thorough infectious workup did not elucidate any evidence of infection. Antibiotics were stopped at day 2 of her hospital stay and the fever resolved after dexmedetomidine was discontinued making drug-induced fever the most plausible diagnosis.

Outcome and follow-up

The patient was discharged on metoprolol and digoxin for rate control. Despite her regimen, she remained with elevated heart rates. She underwent successful AV nodal ablation 2 months after her hospitalisation. TTE after the AV nodal ablation shows a normal left ventricle cavity size with normal left ventricular systolic function and EF of 55% without regional wall motion abnormalities. The patient continues to follow with cardiology and remains free of heart failure symptoms.

Discussion

The current American and European guidelines recommend flecainide as the first-line choice to restore and maintain sinus rhythm in patients with AF without structural heart disease.^{4 5} Despite these recommendations, there is a general concern for its potential proarrhythmic effect and increased risk of adverse effects due to its narrow therapeutic index.^{2 6} In fact, intoxication with class 1C antiarrhythmic drugs is also associated with mean mortality of 22.5%. Conduction disturbances begin with widening the QRS complex, which can rapidly progress to ventricular tachycardia, electromechanical dissociation and asystole.⁷ Toxic effects appear to correlate closely with plasma drug levels, which is more common in overdose and liver and renal failure.⁸

Despite the lack of diagnostic criteria for flecainide toxicity, early recognition of abnormal EKG morphology remains the key in identifying it. It should be suspected with a wide QRS, RBBB morphology with QRS<200 ms, RBBB or left bundle brach block (LBBB) morphology with QRS>200 ms and a heart rate out of proportion to the degree of haemodynamic instability.^{9 10} In fact, mechanical circulatory support requirement and death are more frequently associated with QRS>200 ms.¹⁰ Additionally, flecainide accumulation can also cause prolonged PR interval, resulting in sinus bradycardia that can convert to monomorphic wide-complex tachycardia.¹¹

In patients with PPMs, flecainide toxicity can cause a ventricular capture latency failure by increasing the capture thresholds. This complication can evolve into syncope and haemodynamic collapse. The intermittent failure to capture is thought to be secondary to the device attempting to pace, while the myocardium is in an extended refractory period due to the slowing of the action potential in the conduction system.^{12 13} These increased capture thresholds have been described in atrial, ventricular and permanent His-bundle pacing.¹⁴

Flecainide toxicity may present as cardiogenic shock, which can be a life-threatening adverse effect. Typically, this manifests as severe global systolic dysfunction with marked interventricular dyssynchrony.^{15 16} Refractory shock has been successfully treated with sodium bicarbonate, sequestration of flecainide with intravenous fat emulsion (IFE) and extracorporeal life support with continued heamofiltration.¹⁵ Both sodium bicarbonate and IFE therapies have been compared in rabbit models and no difference was found for the primary endpoint of median arterial pressure at 15 min from initiation of therapy or QRS duration at any time.¹⁷

Most of the cases of flecainide toxicity have occurred in the setting of severe acute kidney injury (AKI) causing accumulation of the drug.3 8–12 14–16 18 19 However, our patient developed a mild AKI on chronic kidney disease stage II and her creatine went from 0.87 at baseline to 1.20 which represents a creatine clearance drop from 28 mL/min to 20 mL/min. It is also important to note that verapamil decreases the plasma clearance of flecainide,¹⁸ and diltiazem can increase the effects of flecainide and decrease its clearance as well. There have been cases of cardiogenic shock, asystole and death reported in patients receiving flecainide and verapamil and since diltiazem may interact with flecainide in a similar manner.^{19 20} The combination of these three medications should be closely monitored to avoid potential side effects.

Learning points.

• Flecainide levels and signs of toxicity should be closely monitored in patients when increasing flecainide doses. Careful consideration and monitoring should be used when initiating flecainide, especially in patients with renal impairment and those on multiple antiarrhythmic medications.

• Combination of antiarrhythmic medications can cause dangerous side effects and thus also requires close monitoring.

• Takotsubo has never been described in flecainide toxicity and should be suspected in the appropriate clinical setting.

• Prompt recognition leads to better outcomes. Physicians should be familiar with EKG changes, such as the bizarre morphology of the QRS complex. Similarly, cardiogenic shock and increased pacemaker capture thresholds should increase suspicion of flecainide toxicity.

• Sodium bicarbonate infusion should be initiated promptly and used to maintain an alkalotic state to help narrow the QRS on EKG, normalise the capture threshold and improve cardiogenic shock.

Ethics statements

Patient consent for publication

Obtained.