Fatal lacosamide poisoning in relation to cardiac conduction impairment and cardiovascular failure

To the Editor:

Lacosamide, a third-generation anticonvulsive drug producing slow inactivation of voltage-gated sodium channels, has been recently licensed as an adjunctive treatment for partial-onset seizures.¹ Lacosamide's side effects are mainly gastro-intestinal and neurological including headaches, dizziness, diplopia, and confusion.¹ Cardiac side effects are rare but may occur either at therapeutic doses or following accidental and suicidal overdose.^2–8 However, they were mostly limited to ST-wave and T-wave abnormalities⁶ and slight lengthening in PR interval^2,3,7 and QRS duration^4,5 on electrocardiogram, although high-degree atrioventricular blocks^3,5 and collapse^2,3,5,8 have been described. Here, we report a fatal case of self-harm overdose with documented lacosamide concentration.

A 56-year-old man was admitted to our intensive care unit (ICU) for lacosamide poisoning. His medical history included depression, hypertension, hypercholesterolemia, and epilepsy in relation to an ischemic stroke ten years previously. His treatment consisted of lacosamide, lamotrigine, carbamazepine, gabapentin, phenobarbital, clonazepam, atorvastatin, amlodipine, and valsartan. The patient ingested 7.0 g lacosamide in a suicide attempt. He called a member of his family, was found unconscious ˜10 min later, and was presented with cardiac arrest on the arrival of the pre-hospital medical service ˜8 min later. Initial rhythm was asystole. No-flow duration was unknown. A return of spontaneous cardiac rhythm was obtained 57 min after intravenous injection of 8 mg epinephrine, 50 ml 8.4% sodium bicarbonate, and 1,000 mL 0.9% NaCl. He further required 2 mg/h-epinephrine infusion. On admission, the electrocardiogram showed junctional rhythm, with 0.206-s QRS, hemi-left anterior bundle, and complete right bundle branch block. Echocardiography displayed normal left ventricular systolic function (ejection fraction, 60%). Serum potassium was 3.6 mmol/L; serum bicarbonate, 33.0 mmol/L; and arterial pH, 7.46. Serum lacosamide concentration was 27.7 μg/mL (therapeutic range, 6.6–18.3; high-performance liquid chromatography–diode array detector); serum carbamazepine concentration, 6.6 mg/L (therapeutic range, 4.7–9.4; homogeneous enzyme multiplied immunoassay test); and serum phenobarbital concentration, 5.3 mg/L (therapeutic range, 11.6–23.2; enzymatic assay). Routine colorimetric and immunoassay-based toxicological screenings (including benzodiazepines, tricyclic antidepressants, phenothiazines, opioids, amphetamines, and cocaine) as well as ethanol, acetaminophen, and aspirin concentrations were negative. Sustained reduction in QRS width (0.132 s) was observed immediately after 750 mL of 8.4% sodium bicarbonate infusion. However, the patient's condition rapidly worsened with refractory distributive shock and multiorgan failure, leading to death 14 h after admission.

Here, we report a case of fatal overdose related to cardiovascular toxicity of lacosamide. The association on the post-resuscitation ECG of junctional rhythm, bi-bundle branch block, and enlarged QRS narrowed with hypertonic sodium bicarbonate infusion supported this hypothesis, additionally strengthened by the absence of evidence for any other etiology of asystole, that is, no witnessed seizures and no aspiration pneumonia.

Lacosamide's cardiovascular safety profile was evaluated in different clinical trials.¹ No changes in heart rate or prolongation of QTc interval were reported, while only slight, dose-related, but not clinically relevant increase in PR interval and slight increase in QRS duration with bundle branch block aspects were observed.¹ Third-degree atrioventricular block has been described in rare neuropathic diabetic patients.¹

Rare symptomatic cases including bradycardia, syncope, atrial fibrillation, and ventricular extrasystole were reported.^2–5,7,8 Cardiac side effects often occur at doses above the approved dosage range and in patients with heart disease.⁴ Decline in systolic blood pressure was reported in ICU patients treated with lacosamide for status epilepticus.⁸

Our patient died while the patient who self-ingested 12 g lacosamide survived but presented first-degree atrioventricular block (PR interval, 0.265 s) and collapse (blood pressure, 60/30 mmHg) requiring norepinephrine.² Moreover, his plasma lacosamide concentration was slightly above the therapeutic range. Several factors may explain our patient's vulnerability, including (i) his underlying hypertensive cardiopathy, (ii) a possible drug-drug interaction involving lacosamide-mediated enhanced slow inactivation and carbamazepine- and lamotrigine-mediated enhanced fast inactivation of voltage-gated sodium channels, both resulting in sodium influx and potassium efflux blockade explaining the junctional rhythm with a bifascicular infra-Hisian block, and (iii) a possible competition with cytochrome P450 (CYP)-mediated metabolism of lacosamide by phenobarbital (at the level of CYP2C9), clonazepam, atorvastatin, and amlodipine (CYP3A4), and carbamazepine (both CYPs). However, due to the occurrence of cardiac arrest in our patient, interpretation of serum lacosamide concentration in regard to the supposed ingested dose should be cautious.

We conclude that the physicians should be aware that overdose of lacosamide in the context of taking other sodium-channel blocking medications may cause widened QRS, shock, and death. Based on its mechanism of toxicity, sodium bicarbonate should be administered as first-line treatment in lacosamide-overdosed patient if QRS enlargement is observed.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.