Introduction
Key Teaching Points
•
A clinical presentation of flecainide toxicity can occur at normal serum levels in
the setting of electrolyte disturbances, namely hyponatremia.
•
Caution should be used when initiating flecainide in patients on diuretics, and serum
electrolytes should be monitored. Use of diuretics may predispose patients to electrolyte
abnormalities that can result in flecainide toxicity.
•
The combination of hyponatremia with the use of class Ic sodium channel blocking antiarrhythmics,
like flecainide, can result in clinically significant pacemaker failure.
Flecainide is a class Ic antiarrhythmic agent that depresses the rate of depolarization
of action potentials by blocking sodium channels.1, 2 It is used commonly in the treatment
of supraventricular arrhythmias, atrial fibrillation, and atrial flutter, and less
commonly in ventricular tachycardias, in patients with normal cardiac structure.3,
4 Flecainide has a narrow therapeutic window. Severe effects in cases of toxicity
and overdose include negative inotropy, bradyarrhythmias, atrioventricular nodal block,
ventricular tachycardia or fibrillation, and asystole, with overdose mortality rate
at approximately 22%.
5
There is sparse literature describing precipitating events for flecainide toxicity.6,
7 We report a case with hyponatremia as a precipitating event for flecainide toxicity
manifest by severe bradycardia with normal flecainide serum levels in a patient with
a pacemaker.
Case report
A 78-year-old African-American woman with sinus node dysfunction requiring pacemaker
implantation, chronic kidney disease stage IV, and recent ischemic stroke was admitted
directly to the cardiac intensive care unit from a subacute rehabilitation facility
owing to symptomatic bradycardia with pacemaker malfunction and prolonged QRS complexes
concerning for flecainide toxicity.
She had been on flecainide at a low dose of 50 mg twice daily for the treatment of
paroxysmal atrial fibrillation. A recent echocardiogram had shown normal left ventricular
function (ejection fraction 60%) without structural heart disease. A myocardial perfusion
stress test showed no evidence for coronary ischemia. On the fourth day of rehabilitation,
serum creatinine had risen from baseline 1.3–1.5 mg/dL to 2.0 mg/dL and sodium dropped
to 128 mmol/L from 133 mmol/L. Renal function and hyponatremia continued to worsen,
with creatinine rising to a peak of 3.53 mg/dL and sodium to 121 mmol/L. She then
developed symptomatic bradycardia with heart rate to 32 beats per minute with loss
of pacemaker capture. Her blood pressure dropped to the 70s systolic with intact respiratory
and mental status and the patient was transferred to our tertiary care academic medical
center. Potassium (4.2 mmol/L), magnesium (2.3 mg/dL), and lactate (1.5 mmol/L) levels
were normal.
The initial electrocardiogram (ECG) showed severe sinus bradycardia and pacing spikes
without capture, with a wide QRS of 190 ms and a heart rate of 47 beats per minute
(Figure 1). An ECG just 1 month prior to presentation notes a narrow QRS complex,
without V pacing at that time (Figure 2). Pacemaker interrogation demonstrated a programmed
mode of DDDR with outputs set at 4 V @ 1 ms and 3.5 V @ 0.5 ms in the right atrial
(RA) and right ventricular (RV) leads, respectively. Documented sensing and capture
thresholds from 1 week prior to this encounter were 2.5 mV and 1.1 V @ 1 ms, respectively,
in the RA lead and 5.8 mV and 0.6 V @ 0.5 ms in the RV lead. After the current admission,
the atrial lead demonstrated no sensing and no ability to capture with stable impedance.
The RV lead sensing was 11 mV with increased capture threshold to 3.4 mV @ 1 ms, with
stable impedance. The pacemaker was reprogrammed to VVI with lower rate limit of 70
and RV output set to 6 mV @ 1 ms. An ECG obtained following these changes showed ventricular
paced rhythm with a markedly prolonged QRS interval of approximately 320 ms (Figure 3).
Interrogation of the patient’s device 1 week prior to presentation showed underlying
inconsistent severe sinus bradycardia to the 30s or slower with some long pauses and
first-degree atrioventricular nodal block with a PR interval of approximately 340
ms. A repeat echocardiogram showed no significant change or wall motion abnormality,
with left ventricular ejection fraction remaining at 60%.
Figure 1
Admission electrocardiogram.
Figure 2
Electrocardiogram 1 month prior to admission.
Figure 3
Electrocardiogram after pacemaker adjustments.
Further urine studies suggested a largely prerenal etiology of renal injury. The precipitating
insult likely dated back to workup of the stroke with a computed tomography study
with intravenous contrast in the setting of hydrochlorothiazide 25 mg daily, which
had been given continuously up until the day of transfer. The patient also remained
on enalapril 20 mg by mouth 2 times daily, up until the day of transfer to our institution.
She was treated with sodium bicarbonate intravenous injections at a weight-based dosing
of 1 mEq/kg, which for our patient resulted in 89 mEq of sodium bicarbonate per injection.
An ECG was completed and electrolytes were drawn 3 hours after each dose. A serum
flecainide level was drawn before initiation of treatment.
After the administration of 2 doses of sodium bicarbonate 3 hours apart, the ECGs
minimally changed, with the QRS complexes still at approximately 320 ms. Serum sodium
rose from 121 mmol/L to 127 mmol/L, and serum creatinine improved with each dose.
Further sodium bicarbonate injections and diuretics were held in addition to flecainide.
The hyponatremia improved with intravenous hydration with 0.9% normal saline at 83
cc/hour. Serum sodium returned to baseline at 134 mmol/L and creatinine to 1.24 mg/dL.
Pacemaker function showed improved thresholds daily, with progressive narrowing of
the QRS to 110 ms. The previously drawn flecainide level was determined to be within
normal therapeutic range (0.2–1.0 mcg/mL) at 0.66 mcg/mL. Approximately 3 days after
admission, the patient’s ECGs normalized and the long latency period resolved. The
underlying rhythm after recovery was not immediately recorded, but a couple of weeks
later it was the same as her preadmission rhythm. Her postrecovery thresholds noted
an atrial threshold of 0.9 V @ 1.5 ms with atrial sensing amplitude of 3.2 mV, and
a ventricular threshold of 1.2 V @ 0.6 ms with ventricular sensing amplitude of 5.9
mV.
Discussion
Flecainide is a class Ic antiarrhythmic agent used in patients with symptomatic atrial
arrhythmias with structurally normal hearts. To our knowledge, there are no prior
documented cases of hyponatremia-induced flecainide toxicity with documented normal
therapeutic serum flecainide levels.
Previous reports have associated electrolyte abnormalities with flecainide toxicity.
Ahmed and colleagues
6
described a case of flecainide toxicity as a cause of hyponatremia. When flecainide
was discontinued, serum sodium normalized and symptoms resolved. Khavandi and Walker
7
demonstrated a presentation of flecainide toxicity with hyponatremia and hypokalemia.
The suspected reason for metabolic derangements was from thiazide diuretics, with
flecainide toxicity as a result of hyponatremia rather than a definite cause of it.
7
In both, no serum flecainide level was drawn. To our knowledge, there are no cases
showing hyponatremia-induced flecainide toxicity with a documented normal flecainide
level, nor any presenting with pacemaker malfunction. In our patient, renal injury
along with use of a diuretic and angiotensin-converting enzyme inhibitor while on
flecainide led to cardiotoxic effects due to hyponatremia despite normal (therapeutic)
serum flecainide levels.
Flecainide can affect pacing thresholds,
8
particularly at supratherapeutic levels. In our case, we also see documentation of
pacemaker device malfunction in the setting of flecainide toxicity triggered acutely
by hyponatremia rather than supratherapeutic flecainide levels. Pacing thresholds
were previously unremarkable on flecainide in this patient. Now, severe QRS widening
was seen, and the device had temporary abnormalities in capture and sensing, involving
both atrial and ventricular leads—signs typical of flecainide toxicity rather than
a pacemaker lead abnormality. Normal pacemaker function recovered with discontinuation
of flecainide and resolution of hyponatremia, and the QRS duration began to appropriately
decrease.
Flecainide can lead to metabolic abnormalities that lead to toxicity, specifically
as it pertains to sodium. However, it appears that hyponatremia can be both a cause
and an effect of flecainide toxicity. Being cognizant of medications with potential
for sodium disturbances is crucial. Nephrotoxic medications should be monitored in
particular—especially diuretics, given their impact on the electrolyte transmembrane
channels present in the nephron.
Sodium channels in the myocardium are voltage-gated and generate current to overcome
membrane capacitance and resistance, and are the target sites of flecainide. It is
possible that the effects of flecainide were potentiated by the hyponatremia through
their effects on the myocardium and on other sodium channels in the body. Antiarrhythmics
have been shown in animal models to play a role on the sodium channel in locations
other than the myocardium, namely the nephron.9, 10 The nephron is responsible for
maintenance of total body water and sodium balance. With flecainide also blocking
sodium channels on the distal nephron and cortical collecting duct, sodium would not
be reabsorbed and thus further potentiate flecainide’s effects on the myocardium.
6
The concurrent use of a thiazide diuretic may have further augmented this outcome.
In the myocardium, the hyponatremia, possibly augmented through effects on the nephron—as
in the case of our patient—may have led to further sodium channel capacitance and
blockade, leading to exacerbated effects of flecainide even at therapeutic serum levels.
This case shows that flecainide toxicity can occur even at normal flecainide serum
levels in the setting of hyponatremia. Previous cases did not document serum flecainide
levels in similar cases of flecainide toxicity with hyponatremia, which may or may
not have been attributable to elevated flecainide levels. Hyponatremia alone has not
been documented as a cause of pacemaker failure.
Further study would be required to determine at what sodium and flecainide levels
these effects take place, and when they precipitate cardiotoxic effects.
Additional studies are also needed to define optimal acute therapy for flecainide
toxicity. Limited reports exist on the use of sodium bicarbonate and fat emulsion.11,
12, 13, 14 With use of sodium bicarbonate in this patient, the cardiotoxic effects
did not reverse immediately, as the QRS duration on the ECG initially remained prolonged
and the pacemaker malfunction persisted. Only with normalization of serum sodium and
withholding of flecainide did cardiotoxic changes abate. Further evaluation may need
to be performed to determine if the weight-based dosing of 1 mEq/kg is a sufficient
dose with which to achieve a desired effect. One case report of neonatal flecainide
toxicity documents success with the use of the 1 mEq/kg weight-based dosing, with
successful resolution of ECG and electrolyte abnormalities with its use.
15
However, this may not be entirely applicable to adult patients.
Flecainide toxicity from hyponatremia has the potential to cause life-threatening
arrhythmias, including loss of pacemaker capture, even with therapeutic flecainide
levels. Based on our experience from this case, we recommend regular sodium monitoring
in patients on flecainide and particular caution with concomitant diuretic use.