REVIEWED BY

Junjie Ning MD
PICU, First People’s Hospital of Zigong City, Sichuan Province，Zigong 643000，China

CORRESPONDING AUTHOR

Junjie Ning MD
PICU, First People’s Hospital of Zigong City, Sichuan Province，Zigong 643000，China
Email address：196425984@qq.com

MANUSCRIPT CITATION

Sharpe C, Reiner GE, Davis SL, Nespeca M, Gold JJ, Rasmussen M, Kuperman R, Harbert MJ, Michelson D, Joe P, Wang S, Rismanchi N, Le NM, Mower A, Kim J, Battin MR, Lane B, Honold J, Knodel E, Arnell K, Bridge R, Lee L, Ernstrom K, Raman R, Haas RH; NEOLEV2 INVESTIGATORS. Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial. Pediatrics. 2020 Jun;145(6):e20193182. PMID: 32385134

TYPE OF INVESTIGATION

Treatment

QUESTION

In neonates with seizures (P), phenobarbital as the control is more effective in controlling seizures (I) than (C) levetiracetam(O) as the intervention within 24 hours (T) ?

METHODS

Design: Prospective, randomised, multi-centre, blinded

Allocation: Patients were randomly assigned to the levetiracetam or control phenobarbital treatment group in a 60:40 allocation ratio by using a block randomization strategy and stratified by site.

Blinding: Blinded study drugs were provided to the NICUs. All study investigators, medical staff, neurophysiologists, and patient families were blinded to the treatment arm.

Follow-up period: 24 hours

Setting: Five hospitals in the US and one in New Zealand

Patients: 280 patients were enrolled, but only 30 patients were analyzed in the Phenobarbital arm and 53 patients were analyzed in the LEV arm, and the majority of patients with seizures were due to HIE and stroke.

Inclusion Criteria:
Infants at risk for developing seizures or suspected of having seizures were enrolled.
Patients were term infants of a corrected gestational age between 36 and 44 weeks (>2 weeks of age) with a weight of at least 2.2 kg.

Exclusion criteria:
 Patients had received any previous anticonvulsants.
The serum creatinine level was >1.6 mg/dL.
Seizures were due to correctable metabolic abnormalities (such as hypoglycemia or hypocalcemia).
Patients in whom death was imminent.

Intervention: Patients confirmed to have electrographic seizures received infusion levetiracetam vs infusion phenobarbital to control seizure.

Outcomes:

Primary outcomes:
The rate of achieving and maintaining electrographic seizure freedom for 24 hours.

Secondary outcomes:
The rate of achieving and maintaining seizure freedom for 1 hour.
Seizure cessation for 48 hours.

Analysis and sample size:
Power calculations were based on a 2-sided χ2 test for detecting a difference between 2 proportions, assuming a type 1 error of 0.05. With a sample size of 60 subjects receiving levetiracetam and 40 subjects receiving phenobarbital and assuming a seizure-cessation rate of 50% in the control arm, the study had 80% power to detect an absolute difference in seizure outcome rates of ≥28% in the levetiracetam group.

The primary outcome, which was a comparison of the 24-hour seizure termination rate between the two treatment arms, was calculated by using Fisher’s exact test. Secondary outcomes of 1- and 48-hour seizure termination rates were analyzed similarly.

Safety analyses were conducted on all randomly assigned participants. Fisher’s exact tests were used to compare rates of adverse events, serious adverse events, study discontinuations, and deaths.

Patient follow-up: 53 with follow-up data in levetiracetam (n = 64) and 30 with follow-up data in phenobarbital (n = 42).

MAIN RESULTS

The groups were well balanced at baseline on demographics, clinical variables, and pretreatment seizure severity. Ethnicity, race, pregnancy abnormality, delivery situation, mode of delivery, and anesthesia (not shown) were distributed evenly between randomization arms.

For the primary outcomes, 80% of patients (24 of 30) randomly assigned to phenobarbital remained seizure free for 24 hours, compared with 28% of patients (15 of 53) randomly assigned to levetiracetam (P < 0.001; relative risk 0.35 [95% confidence interval: 0.22-0.56]; modified intention-to-treat population).

For secondary outcomes, 64% of patients (18 of 28) randomly assigned to phenobarbital remained seizure free for 48 hours, compared with 17% of patients (8 of 47) randomly assigned to levetiracetam (P < 0.001; relative risk 0.26 [95% confidence interval: 0.13-0.53]). 93% of patients (28 of 30) randomly assigned to phenobarbital were seizure free for at least 1 hour, compared with 49% of patients (26 of 53)randomly assigned to levetiracetam (P < 0.001; relative risk 0.53 [95% confidence interval: 0.39–0.7]).

CONCLUSION

The authors conclude that phenobarbital was more effective than levetiracetam for treating neonatal seizures.

COMMENTARY

This prospective multicenter randomized controlled trial compared the efficacy and safety of levetiracetam (40mg/Kg) with phenobarbital as the first-line treatment for neonatal epilepsy, which showed that phenobarbital was more effective than levetiracetam for the treatment of neonatal seizures.¹ This study differs from others in that it is one of the first prospective studies using cEEG in neonates, and the use of cEEG to confirm the presence of electrographic epilepsy is a strength of this study. Because not all electrographic seizures can be accurately identified by clinicians only by visual assessment. However, Methodological biases may render a clinical study underpowered. While it is true that 280 patients were enrolled, only 30 patients were analyzed in the Phenobarbital arm and 53 patients were analyzed in the LEV arm, which is a small phase IIb study rather than a large phase III randomized control trial. When power calculations are calculated on a predicted response and the measured response is considerably different, it is difficult to interpret the study’s validity. This has probably been one of the more controversial aspects of this publication, being that the efficacy of the phenobarbital was so high in this small population.

Compared with older children and adults, the pharmacokinetics of levetiracetam in neonates has a wider volume of distribution and faster clearance, and tends to be administered in higher doses², but the appropriate dose has not been determined. In addition, the study found that only 26% of premature infants less than 28 weeks could be controlled by LEV (80mg/kg/day), suggesting that small gestational age is a risk factor for LEV treatment failure.³ A retrospective study showed that LEV at an initial dose of 50-100mg/Kg was as effective as PB in controlling neonatal epilepsy（gestational age ≥35weeks）.⁴ Liu BK et al. found that there was no significant difference in the short-term efficacy (3 days) between the phenobarbital and levetiracetam group (8-54mg/kg/d) in the treatment of neonatal epilepsy (gestational age: 38 (38,40) weeks).⁵ The gestational age of newborns in the study by et al. was 36 to 44 weeks, and LEV (40 mg/Kg) was less effective than PB.¹ Neonatal gestational age and dosing range of levetiracetam were inconsistent across the three studies, so definite conclusions were ultimately unable to make.

Based on the above studies, it is highly controversial whether LEV or PB should be used as a first-line drug to treat neonatal seizures. However, because levetiracetam has a neuroprotective effect with fewer adverse reactions, ^6-7 it is of great significance to further study whether LEV is stronger than phenobarbital and whether it can be used as a first-line drug for the treatment of neonatal seizures. I am eagerly looking forward to determining the optimal dose and dosing schedule of levetiracetam with uniform observational metrics and criteria, which need to include the effect of gestational age on the drug.

 

CONFLICTS OF INTEREST

The authors have no conflicts of interest to declare.

 

FUNDING INFORMATION

This review did not have a funding source.

 

REFERENCES

1. Sharpe C, Reiner GE, Davis SL, Nespeca M, Gold JJ, Rasmussen M, et al. Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial. Pediatrics. 2020;145(6):e20193182. doi:10.1542/peds.2019-3182

2. Lima-Rogel V, López-López EJ, Medellín-Garibay SE, Gómez-Ruiz LM, Romero-Méndez C, Milán-Segovia RC, et al. Population pharmacokinetics of levetiracetam in neonates with seizures. J Clin Pharm Ther. 2018;43(3):422-429.

3. Kurtom W, Courchia B, Pensirikul A, Sosenko I, Del-Moral T. Lack of response to treatment with levetiracetam in extreme preterm infants with seizures. J Perinatol. 2019;39(11):1480-1484.

4. Verwoerd C, Limjoco J, Rajamanickam V, Knox A. Efficacy of Levetiracetam and Phenobarbital as First-Line Treatment for Neonatal Seizures. J Child Neurol. 2022 Apr;37(5):401-409.

5. Liu BK, Jiang L, Li XJ, Hong SQ, Chen W, Hu Y. Efficacy and safety of levetiracetam in the off-label treatment of neonatal seizures. Int J Neurosci. 2020;130(4):336-342.

6. Komur M, Okuyaz C, Celik Y, et al. Neuroprotective effect of levetiracetam on hypoxic ischemic brain injury in neonatal rats. Child’s Nervous System, 2014, 30(6): 1001-1009.

7. Qiao MY, Cui HT, Zhao LZ, Miao JK, Chen QX. Efficacy and Safety of Levetiracetam vs. Phenobarbital for Neonatal Seizures: A Systematic Review and Meta-Analysis. Front Neurol. 2021 Nov 18;12:747745.