Document Type : Original Article
Authors
1 Department of Pharmacology, Raiganj Government Medical College and Hospital, Raiganj, West Bengal, India
2 Department of Pediatrics, Burdwan Medical College and Hospital, Bardhaman, West Bengal, India
Abstract
BACKGROUND: Neonatal seizure (NS) reflects serious underlying brain injury, requiring immediate
evaluation and early treatment. In neonates, phenobarbitone and phenytoin are used primarily to
control the seizures. If uncontrolled, widespread off‑label use of midazolam and levetiracetam was
practiced. These drugs gained popularity though there are no such studies available on literature
search comparing them. The present study was designed to explore these lacunae using these two
drugs in refractory cases. To study the efficacy and adverse drug reactions (ADRs) of midazolam
and levetiracetam not responding to usual line of therapy.
MATERIALS AND METHODS: This was a prospective cross-sectional study conducted on 69
neonates in the NICU and Department of Pharmacology in Burdwan Medical College and Hospital,
West Bengal. Patients receiving midazolam or levetiracetam when uncontrolled with first line
antiepileptics, namely, phenobarbitone and phenytoin, were considered eligible. The study variables
were time to control seizure, seizure recurrence and frequency, and treatment-related adverse events.
analysis used Mann–Whitney U-test were applied Comparison with respect to time to control and
Chi-square test were applied to detect difference in proportion for ADRs. The SPSS Statistics 17.0
was used for analysis.
RESULTS: We compared the time periods to control neonatal seizure for effectiveness between
levetiracetam and midazolam showing no significant difference (P = 0.190). Comparing the portion
of recurrences in two groups gives statistically nonsignificant (P = 0.878) result. Only respiratory
depression was seen in the levetiracetam group (12.90%) and midazolam group (18.42%). All
adverse events were ‘probable’ as per the WHO‑UMC criteria, and there was no statistically significant
difference between the two drugs (P = 0.533).
CONCLUSIONS: Both midazolam and levetiracetam are equally effective and safe in NS not
responding to usual line of treatment.
Keywords
Philadelphia: WB Saunders; 2008.p. 203-44.
2. Tekgul H, Gauvreau K, Soul J, Murphy L, Robertson R, Stewart J,
et al. The current etiologic profile and neurodevelopmental
outcome of seizures in term newborn infants. Pediatrics
2006;117:1270-80.
3. Andreolli A, Turco E, C, Pedrazzi G, Beghi E, Pisani F: Incidence
of Epilepsy after Neonatal Seizures: A Population-Based Study.
Neuroepidemiology 2019;52:144-51.
4. Mizrahi EM, Clancy RR, Dunn JK, Hirtz D, McGuan S, Cuccaro P,
et al. Neurologic impairment, developmental delay and post-natal
seizures two-years after video-EEG documented seizures in
near-term and full-term neonates: report of the Clinical Research
Centers for Neonatal Seizures. Epilepsia 2001; 42(suppl 7):102-3.
5. Da Silva LF, Nunes ML, Da Costa JC. Risk factors for developing
epiliepsy after neonatal seizures. Pediatr Neurol 2004;30:271.
6. Vasudevan C, Levene M. Epidemiology and aetiology of neonatal
seizures. Semin Fetal Neonatal Med 2013;18:185-91.
7. Bassan H, Bental Y, Shany E, Berger I, Froom P, Levi L, Shiff Y.
Neonatal seizures: Dilemmas in workup and management. Pediatr
Neurol. 2008;38:415-21. doi: 10.1016/j.pediatrneurol.2008.03.003.
PMID: 18486824.
8. Bartha AI, Shen J, Katz KH, Mischel RE, Yap KR, Ivacko JA,
et al. Neonatal seizures: multicenter variability in current
treatment practices. Pediatr Neurol. 2007;37:85–90.
9. Baudou E, Cances C, Dimeglio C, Hachon Lecamus C. Etiology
of neonatal seizures and maintenance therapy use: A 10-year
retrospective study at Toulouse Children’s hospital. BMC Pediatr
2019;19:136.
10. Gupta P, Upadhyay A. Phenobarbitone in neonatal seizures:
Controversies. J Neonatal Biol 2016;5:226.
11. Donovan MD, Griffin BT, Kharoshankaya L, Cryan JF, Boylan GB.
Pharmacotherapy for Neonatal Seizures: Current Knowledge and
Future Perspectives. Drugs. 2016;76 (6):647-661. doi: 10.1007/
s40265-016-0554-7
12. Burman RJ, Ackermann S, Shapson-Coe A, Ndondo A, Buys H,
Wilmshurst JM. A Comparison of parenteral phenobarbital vs.
parenteral phenytoin as second-line management for pediatric
convulsive status epilepticus in a resource-limited setting. Front
Neurol 2019;10:506.
13. Neonatal Formulary. Sixth edition. John Wiley & Sons, Limited
European Distribution Centre New Era Estate, Oldlands Way
Bognor Regis, West Sussex, PO22 9NQ, UK. 2011. pp. 305.
14. Pacifici GM. Clinical pharmacology of midazolam in neonates and
children: Effect of disease-a review. Int J Pediatr 2014;2014:309342.
15. Mizrahi EM, Kellaway P. Diagnosis and Management of Neonatal
Seizures, Lippincott-Raven, Philadelphia 1998. p. 15-35.
16. Dao K, Giannoni E, Diezi M, Roulet-Perez E, Lebon S. Midazolam
as a first-line treatment for neonatal seizures: Retrospective study.
Pediat Int 2018;60:498-500.
17. Abend NS, Gutierrez-Colina AM, Monk HM, Dlugos DJ,
Clancy RR. Levetiracetam for treatment of neonatal seizures.
J Child Neurol 2011;26:465-70.
18. Cormier J, Chu CJ. Safety and efficacy of levetiracetam for the
treatment of partial onset seizures in children from one month
of age. Neuropsychiatr Dis Treat 2013;9:295-306.
19. Silverstein FS, Ferriero DM. Off-label use of antiepileptic drugs for
the treatment of neonatal seizures. Pediatr Neurol 2008;39:77-9.
20. All India Institute of Medical Sciences (AIIMS) New Delhi, AIIMS
PROTOCOL 2014. Management of Neonatal Seizures. Available
from: https://www.newbornwhocc.org/2014_pdf/Neonatal%20 seizures%202014.pdf. [Last accessed on 2020 Jul 25].
21. Northern Devon Healthcare, Neonates Guideline V 2.0 FINAL
V2 Sept 2018 Seizures in Neonates Guideline. Available
from: https://www.northdevonhealth.nhs.uk/wp-content/
uploads/2018/10/Seizures-in-Neonates-Guidelines-V-2-0Sept-18.pdf. [Last accessed on 2020 Jul 25].
22. World Health Organization. Uppsala Monitoring Centre.
The use of the WHO-UMC System for Standardised Case
Causality Assessment. Available from: https://www.who.int/
medicines/areas/quality_safety/safety_efficacy/WHOcausality_
assessment.pdf. [Last accessed on 2020 Jul 20].
23. van Rooij LG, Hellström-Westas L, de Vries LS. Treatment of
neonatal seizures. Semin Fetal Neonatal Med 2013;18:209-15.
24. Sirsi D, Nangia S, LaMothe J, Kosofsky BE, Solomon GE.
Successful management of refractory neonatal seizures with
Midazolam. J Child Neurol 2008;23:706-9.
25. Shtull-Leber E, Silbergleit R, Meurer WJ. Pre-hospital midazolam
for benzodiazepine-treated seizures before and after the Rapid
Anticonvulsant Medication Prior to Arrival Trial: A national
observational cohort study. PLoS One 2017;12:e0173539.
26. Silbergleit R, Lowenstein D, Durkalski V, Conwit R;
Neurological Emergency Treatment Trials (NETT) Investigators.
RAMPART (Rapid Anticonvulsant Medication Prior to Arrival
Trial): A double-blind randomized clinical trial of the efficacy
of intramuscular midazolam versus intravenous lorazepam in
the prehospital treatment of status epilepticus by paramedics.
Epilepsia 2011;52 Suppl 8:45-7.
27. Kawaguchi N, Imataka G, Suzumura H, Yamanouchi H. Etiology
and management of neonatal seizures-successful treatment by
midazolam. No To Hattatsu 2006;38:5-9.
28. Hu KC, Chiu NC, Ho CS, Lee ST, Shen EY. Continuous midazolam
infusion in the treatment of uncontrollable neonatal seizures. Acta
Paediatr Taiwan 2003;44:279-81.
29. Castro Conde JR, Hernández Borges AA, Doménech Martínez E,
González CampoC, Perera SolerR. Midazolam in neonatal seizures
with no response to phenobarbital. Neurology 2005;64:876-9.
30. Khan O, Chang E, Cipriani C, Wright C, Crisp E, Kirmani B. Use
of intravenous levetiracetam for management of acute seizures
in neonates. Pediatr Neurol 2011;44:265-9.
31. Rao LM, Hussain SA, Zaki T, Cho A, Chanlaw T, Garg M,
et al. A comparison of levetiracetam and phenobarbital for the
treatment of neonatal seizures associated with hypoxic-ischemic
encephalopathy. Epilepsy Behav 2018;88:212-7.
32. Falsaperla R, Mauceri L, Pavone P, Barbagallo M, Vitaliti G,
Ruggieri M, et al. Short-term neurodevelopmental outcome in
term neonates treated with phenobarbital versus levetiracetam:
A single-center experience. Behav Neurol 2019;2019:3683548.
33. Fürwentsches A, Bussmann C, Ramantani G, Ebinger F,
Philippi H, Pöschl J, et al. Levetiracetam in the treatment of
neonatal seizures: A pilot study. Seizure 2010;19:185-9.
34. Trinka E, Dobesberger J. New treatment options in status
epilepticus: A critical review on intravenous levetiracetam. Ther
Adv Neurol Disord 2009;2:79-91.
35. Maitre NL, Smolinsky C, Slaughter JC, Stark AR. Adverse
neurodevelopmental outcomes after exposure to phenobarbital
and levetiracetam for the treatment of neonatal seizures. J
Perinatol. 2013;33 (11):841-846. doi: 10.1038/jp. 2013.116
36. Falsaperla R, Vitaliti G, Mauceri L, Romano C, Pavon P,
Motamed-Gorji N, et al. Levetiracetam in neonatal seizures as
first-line treatment: A prospective study. J Pediatr Neurosci
2017;12:24‑8.
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