Keywords
cardiac dysfunction - antiseizure medication - preterm infant - lacosamide
Case Presentation
A 34 weeks' gestation female infant was born at a primary care hospital following
an emergency cesarean section for decreased fetal movement and poor biophysical profile.
Apgar scores were 0 at 1, 5, and 10 minutes, 1 at 15 minutes, 3 at 20 minutes, and
4 at 25 minutes. The modified SARNAT exam was consistent with severe hypoxic ischemic
encephalopathy (HIE) for which prompted transfer to a level IV neonatal intensive
care unit for therapeutic hypothermia. Laboratory evaluation showed no evidence of
renal impairment (serum creatinine 1 mg/dL with urine output 3.4 mL/kg/d).[1]
[2]
[3]
[4] Baseline electrocardiogram and renal ultrasound were unremarkable. On admission,
there was clinical and echocardiography evidence of acute pulmonary arterial hypertension
and severe right ventricular (RV) dysfunction. These findings had resolved by postnatal
day 2, after treatment with inhaled nitric oxide and myocardial inotropic support
([Table 1]).
Table 1
Clinical course and echocardiographic data
|
Day 1
|
Day 2
|
Day 7
|
Day 9
|
Day 12
|
Day 16
|
|
LV function
|
|
|
|
|
|
|
|
EF (%)
|
61
|
64
|
42
|
49
|
53
|
63
|
|
GLS (%)
|
N/A
|
N/A
|
−11.3
|
−10.4
|
−11.7
|
−11.9
|
|
LVO (mL/kg/min)
|
96
|
176
|
188
|
185
|
165
|
167
|
|
RV function
|
|
|
|
|
|
|
|
TAPSE (mm)
|
7.2
|
9.5
|
7.4
|
8.1
|
8.0
|
9.0
|
|
FAC
|
0.26
|
0.43
|
0.37
|
0.51
|
0.48
|
0.48
|
|
RVO (mL/kg/min)
|
60
|
102
|
215
|
214
|
203
|
188
|
|
RVSp using TR jet (mm Hg)
|
51 mm Hg + RAp
|
62 mm Hg + RAp
|
Incomplete TR jet
|
Incomplete TR jet
|
Incomplete TR jet
|
Incomplete TR jet
|
|
Eccentricity Index in systole
|
1.3
|
1.24
|
1.1
|
1.02
|
1.08
|
0.94
|
|
Ductal shunt
|
Bidirectional
|
Bidirectional
|
Closed
|
Closed
|
Closed
|
Closed
|
|
Atrial shunt
|
Bidirectional
|
Bidirectional
|
Bidirectional
|
Left to right
|
Left to right
|
Left to right
|
|
Cardiovascular medications
|
iNO 20 ppm
Epinephrine 0.05 µg/kg/min
Vasopressin 1.6 milliunits/kg/min
|
iNO 20 ppm
Epinephrine weaned off on day 2
|
None
|
Milrinone 0.66 µg/kg/min
|
Milrinone 0.66 µg/kg/min
|
Milrinone 0.66 µg/kg/min
|
|
Therapeutic hypothermia
|
Yes
|
Yes
|
No
|
No
|
No
|
No
|
|
Antiseizure medications
|
Single dose (20 mg/kg/dose) phenobarbital IV
|
Maintenance phenobarbital 5 mg/kg/day
Fosphenytoin 20 mg/kg/dose ×2 doses on DOL 1 and 2
Midazolam infusion 90 µg/kg/min
|
Lacosamide
Phenobarbital
Midazolam infusion weaning
|
Phenobarbital
Levetiracetam
|
Phenobarbital
Levetiracetam
|
Phenobarbital
Levetiracetam
|
EF, ejection fraction by Simpson's biplane; FAC, fractional area change; GLS, Global
longitudinal strain; IV, intravenous; LV, left ventricle; LVO, left ventricular output;
Rap, Right atrial pressure; RV, right ventricle; RVO, right ventricular output; RVSp,
right ventricular systolic pressure; TAPSE, tricuspid annular plane systolic excursion;
TR, tricuspid regurgitation.
Her hospital course, however, was complicated by refractory status epilepticus for
which lacosamide was added as adjunctive therapy. Thereafter, continuous electroencephalogram
monitoring showed improvement in frequency and duration of the seizure activity. Treatment
was gradually titrated to a maximum dose of 9 mg/kg/d over 72 hours. Within 24 hours
of reaching the maximum dose of lacosamide, the infant developed persistent systemic
hypertension (systolic blood pressure [SBP] 85–111 mm Hg, diastolic blood pressure
[DBP] 58–76 mm Hg [>95th percentile blood pressure for 34 weeks' postmenstrual age])[5] for which targeted neonatal echocardiography (TnECHO) was obtained. TnECHO revealed
impaired left ventricular (LV) systolic and diastolic performance ([Fig. 1]; [Table 1]). Continuous milrinone infusion was initiated for cardiovascular support; however,
48-hour follow-up assessment with TnECHO continued to demonstrate severe LV systolic
dysfunction.
Fig. 1 Echocardiography imaging on postnatal day 7 demonstrating decreased ejection fraction
(A) with a preserved left ventricular output (C). Echocardiographic strain imaging (myocardial deformation analysis) demonstrating
decreased systolic function (Global longitudinal strain [GLS] = −11.3%) (B, D).
Due to the temporal relationship of initiation/dose escalation of lacosamide and onset
of cardiac dysfunction, and lack of alternative explanatory cause, lacosamide was
discontinued and replaced with levetiracetam. Serial follow-up with TnECHOs were performed
24, 96, and 192 hours after discontinuation of lacosamide. There was a marginal improvement
in LV systolic function by 96 hours; however, by 192 hours, complete resolution was
noted. LV function remained normal following discontinuation of milrinone. The infant
remained hemodynamically stable without recurrence of systemic hypertension and was
discharged home with no cardiovascular medications.
Discussion
Recent evidence of a potential neuroprotective effect of lacosamide in animal experimental
models suggest it to be a candidate for seizure control in neonates with HIE.[6] Through blockage of voltage-gated sodium channels, lacosamide may predispose to
cardiac arrythmias. Moreover, it also has been shown that at the cellular level, alteration
of cardiac sodium current may play important roles in mechanical dysfunction of the
myocardium.[7] Case reports have also suggested impaired, but reversible, cardiac excitation, and
contraction in adults and a dose-dependent response with higher rates of toxicity
and mortality seen with dose escalation or when used in combination with other sodium
channel blockers.[8]
[9] Although there are currently no published data on the effect of lacosamide on neonatal
cardiac function, concomitant use with phenobarbital and fosphenytoin could also negatively
impact heart function.[10]
[11] Regardless, it is important to note that the temporal relationship between lacosamide
initiation and LV dysfunction was striking; however, it is not possible to exclude
a synergistic negative effect of concurrent anticonvulsant use. The impact on RV systolic
performance is unknown. In addition, normalization of LV function following cessation
of treatment lends supports to the possibility of causation. It is not clear whether
the mechanism relates to a direct effect on the myocardium or represents an independent
effect of increased LV afterload secondary to systemic hypertension and elevated systemic
vascular resistance.
Conclusion
This case highlights the susceptibility of premature infants to cardiac dysfunction
following lacosamide administration. While it is not possibly to assign causality
on the basis of a single case report, clinicians should consider a possible contributary
effect of lacosamide in patients with new-onset LV systolic dysfunction; therefore,
caution is advised using this medication and especially in patients with known LV
dysfunction. Cautious use, strict monitoring, and pharmacokinetic investigation are
warranted in neonates.
