Comparision between phenobarbitone and levetiracetam as the intial anti convulsant in preterm neonatal seizures-a randomized control trail

INTRODUCTION:

Neonatal seizures is defined clinically as a paroxysmal alterationin neurologic function, i.e.motor, behavior and/or autonomic function.According to National Neonatal Perinatal Database (NNPD; 2002-03)- incidence ofneonatal seizure is  10.3 per 1000 live-births. The incidence wasfound to increase with decreasing gestation and birth weight. Seizure incidencein preterm infants is 20.8  per 1000 live-births and very low birthweight infants have 36.1 per 1000 live-births. Based on EEG ,neonatal seizureclassified into  Epileptic seizures, Non-epileptic seizuresand  EEG seizures. Phenobarbitone(PB) is the usual  initialanticonvulsant  for neonatal seizures treatmentwith  efficacy of 33 and 77%  .PB can cause neuronalapoptosis in animal model  and have highly variable pharmacokineticsin neonates. CNSdepression and respiratory depression are the common side effect  ofPB. Levetiracetam (LEV) may have a better safety profile and seizure cessationwas achieved in 77% and 86% in various studies.In recent stud Sharpe C et.alduring EEG based seizure free at 24 hour PB was better than LEV, but more sideeffects.The efficacy of AED depends on study population, dose ,etiology ofseizure,definition of seizure control,which are widely varied in clinicalstudies. we want tocompare  PB vs LEV  as first line antiepileptic in pretermneonatal seizure AIMS AND OBJECTIVES

Hypothesis- Leveteracetam will be equal efficacious to    phenobarbitone in treatment  pretermneonatal seizure.

Primary objective-

Evaluate  theefficacy of PB  and LEV as the initial anti convulsant in preterm neonatalseizure

Secondary objective**-**

Adverse effect of PB andLEV in preterm neonates

Clinical response basedon the etiology of seizure.

MATERIALS AND METHODOLOGY:

**PLACE OF STUDY:**kalinga institute ofMedical sciences, Bhubaneswar

STUDY DURATION: From OCTOBER 2020to OCTOBER 2022

**STUDY DESIGN:**Interventional study  - A Randomised, non blinded, parallel trial.

Patients will be of allocated -computergenerated randomlist .

Allocation concealment- opaque sealed envelop.

STUDY POPULATION: preterm neonatesadmitted in the NICU  in the paediatrics department of pradyumna bal memorial hospital,kims will be enrolled into this  study after taking informedconsent .

Sample size

No of Cases(expected/calculated): 53

No of Controls:53

Inclusion criteria**-**

Neonate with gestationalage <37 week with diagnosis of clinical seizure admitted within 28 days oflife in NICU.

Exclusion criteria**-**

Multiple congenital malformation

Seizure secondary tohypoglycemia and hypocalcemia controlled with glucose or calcium bolusrespectively.

Arm of the trial**-**

Onearm will receive  iv inj  PB

Otherarm   will receive iv inj LEV.

METHODOLOGY

Allpreterm  neonates with  clinical diagnosis of seizure will beassessed to ensure patency of the airway, breathing  &circulation. Random blood sugar will be checked by glucometer  blood sample will be collected for serum electrolytes  and inj calciumgluconate  will be given.

Afterexcluding hypoglycaemia and inj cal.gluconate bolus, if seizure persist,babies  will be randomized  to receive either LEV (40mg/kg/dose) orPB (15mg/kg/dose) intravenously.Levetiracetam(40 mg/kg) will be  dilutedin 10 ml normal saline and administered intravenously under cardiorespiratorymonitoring  over 10 min.

Ifseizure persisitent another loading dose of levetiracetam  20mg/kg will begiven.If seizure terminated  LEV was maintained at 20mg/kg/dose  intwice daily.If seizure still persisited, neonate will be switched over to PB(15 mg/kg).

Phenobarbitalwill be administrated in the dose of 15 mg/kg/dose diluted in normal saline andgiven intravenously over 20 min .If seizure persist, another loading dose of10mg/kg of phenobarbital will be over 10 min.

Ifseizure subsided it will be continued as mantainance dose 3-5mg/kg/day in twodivided doses. If seizure still persist after 2 loading doses PB, neonatewill be  switched over to LEV(40mg/kg).

P- Pre term neonates with seizures

I- IV inj leveteracetam

C-IV  inj phenobarbitone

O-Clinical cessation of seizure for 24hours

T- Till nicu discharge

Data lnclusion

Clinical details- antenatal, intrapartum,neonatal course,clinicalsymptoms, seizure types and antiepileptic administration,  sequence ofdrugs with dosage, timing and duration of therapy were recorded. Investigations– random blood glucose, serum calcium, electrolytes ,complete blood counts,Creactive protein, blood culture, csf analysis,liver function tests, renalfunction tests, arterial blood gas, cranial ultrasonography,MRI Imaging, IEMscreening, serum ammonia & lactate  EEG  based on clinician adv.

Hemodynamic instability ,Apnoea, respiratory depression, increasedventilator support requirement, arrhythmias, , Heart rate fluctuations morethan 10 %  compared to previous two hours, if vasopressors were intiatedor increased, blood pressure, increased  ventilator requirement wasconsidered.

Statistical analysis:

Continous variables willbe compared between the two groups using independent samples t-test . seizurescontrol and occurrence of adverse effect in each in each anti epileptic drugwill be compared with chi-square test. Effect size and its 95% CI will becomputed for the primary and secondary outcomes. P value of less than 0.05 willbe considered as significant. The analyses will be carried out using stat 1.5software.

REFERENCES

1)     Maitre NL, Smolinsky C,Slaughter JC, et al. Adverse neurodevelopmental outcomes after exposure tophenobarbital and               levetiracetam for the treatment of neonatalseizures. Journal of Perinatology. 2013. 33, 841- 846.

2)     Ramantani G, IkonomidouC, Walter B, et al. Levetiracetam: safety and efficacy in neonatal seizures.European Journal of              Paediatric Neurology. 2011; 1-7. 14

3)     Gowda, V.K., Romana, A.,Shivanna, N.H. et al. Levetiracetam versus Phenobarbitone in Neonatal Seizures— A Randomized        Controlled Trial. Indian Pediatr 56,643–646 (2019). https://doi.org/10.1007/s13312-019-1586-3

4)      Mruk AL, GarlitzKL, Leung NR. Levetiracetam in neonatal seizures: A review.  J PediatrPharmacol Ther. 2015;20:76-89. 10. McHugh DC, Lancaster S, Manganas LN. Asystematic review of the efficacy of levetiracetam in neonataL seizures.Neuropediatrics.2018;49:12-17

5)     Falsaperla R, Vialiti G, Mauceri L, et al.Levetiracetam in neonatal seizures as first line treatment: a prospectivestudy.

6)     Journal of Pediatric Neurosciences. 2017; 12:24-28. 15.

7) Mruk AL, Garlitz KL, Leung NR, et al. Levetiracetam in neonatalseizures: a review. Journal of Pediatric Pharmacology and Therapeutics.2015; 20(2): 76-89 Granelli SP, McGrath JM. Neonatal seizures: diagnosis,pharmacologic interventions, and outcomes.