31.7.6 Comparative Efficacy of Intravenous Levetiracetam Vs Phenobarbitone in Neonatal Seizures

Original Article

 

Levetiracetam Vs Phenobarbitone in Neonatal Seizures

Comparative Efficacy of Intravenous Levetiracetam Vs Phenobarbitone in Neonatal Seizures

Junaid Ghaffar1, Amna Riaz1, Uzair1, Ahmad Omair Virk3 and Akmal Bhatti2

ABSTRACT

Objective: to study the Comparative efficacy of intravenous levetiracetam vs phenobarbitone in neonatal seizures.

Study Design: Observational Study

Place and Duration of Study: This study was conducted at the Pediatric Department of Idris Teaching Hospital Sialkot from Jan2019 to Feb 2020.

Materials and Methods: A total of 60 neonates of both gender with Neonatal seizures of less than 24 hours were included in the study. Patients who were already receiving anticonvulsants, seizures were due to correctable metabolic abnormalities (i.e. hypoglycemia, hypocalcemia, hypomagnesaemia, hyponatremia), neonates with associated pulmonary, hepatic, renal, or cardiac dysfunction were excluded. The antibiotic administration was based on departmental policy as 1st,2nd& 3rd line antibiotics and other drugs like intravenous fluids, blood products were according to the need for the patients. For anticonvulsant therapy we divided patients randomly into two groups Group A and Group B via lottery method. Group A was given inj phenobarbitone loading dose maximum 40mg/kg (initial loading dose 20mg/kg reloading with 10 mg/kg for further 2 times) and maintenance dose 5mg/kg. Group B was given injection Levetiracetam loading maximum40mg/kg(initially with 30mg/kg then reloading with 10mg/kg) and maintenance dose 20mg/kg/day. Both Drugs were given in infusion form in dilution in 15 ml normal saline over 15 minutes. All the procedures were done under supervision of a consultant pediatrician of three years post fellowship experience. If seizures reoccur with maximum loading dose then the patient was switched to other drug. Patient was continuous monitoring & observed for reoccurrence of seizure within 24 hours. Efficacy was noted.

Results: Age range in this study was < 28 days with mean age of 15.200± 5.62 days in Group A while 14.900± 5.99 days in Group B. Mean duration of complain was 10.400±4.83 hours in Group A and 11.433±4.67 hours in Group B. Mean weight was 4.056±0.65 kg in Group A and 4.163±0.64 Kg in Group B. Male gender was dominant in both group (63.3% and 63.3%). In group A efficacy was seen in 9 (30%) patients as compare to 25 (83.3%) patients in group B, (P=0.000).

Conclusion: It is concluded that levetiracetam is more efficacious than phenobarbital in control of clinical seizures in treatment of neonatal seizures.

Key Words: Neonatal seizures, Levetiracetam, Phenobarbital, Efficacy

Citation of article: Ghaffar J, Riaz A, Uzair, Virk AO, Bhatti A. Comparative Efficacy of Intravenous Levetiracetam Vs Phenobarbitone in Neonatal Seizures. Med Forum 2020;31(7):25-28.

 

 

INTRODUCTION

Seizures are the most widely recognized neurological crises in the neonatal period and are related with poor neuro formative outcomes.1 Seizures happen in roughly 1–5 for every 1,000 live birth.

 

 

1. Department of Paediatrics, / Community Medicine2, Sialkot Medical College, Sialkot.

3. Department of Pediatrics Neurology, Children Complex Institute, Faisalabad.

 

 

Correspondence: Dr. Junaid Ghaffar, Senior Registrar Department of Paediatrics, Sialkot Medical College, Sialkot.

Contact No: 03348100633

Email: docjunaid156@gmail.com

 

 

Received:    March, 2020

Accepted:    April, 2020

Printed:        July, 2020

 

\

Neonatal seizures a few times are hard to control and unmanageable to treatment.2 Phenobarbital and phenytoin remain the antiepileptic drugs (AEDs) most generally used to treat neonatal seizures, in spite of their imperfect viability and wellbeing.

Phenobarbitone has been utilized since 1914 as the favored first-line anticonvulsant in quite a while3. Phenobarbitone and phenytoin during neonatal period impedes physiological development of neurotransmitters in neurons after the underlying medication affront. Phenobarbitone is related with more regrettable neuro formative results than levetiracetam.4 Levetiracetam was found not to have impact on synaptic development.4

Levetiracetam was seen as generally safe in treating neonatal seizures.5 Levetiracetam is a wide range anticonvulsant. Its digestion does exclude CYP P450 framework and quick intravenous organization isn't related with cardiovascular unfavorable impacts. Intravenous Levetiracetam has indicated potential advantage in controlling seizures when recalcitrant seizures didn't react to at least two traditional anticonvulsants. Levetiracetam is viewed as protected in light of its straight pharmacokinetics, non hepatic end, absence of protein authoritative and no known communications with other antiepileptic prescriptions. Because of the restricted symptom profile and medication cooperations of levetiracetam, routine observing isn't necessary.6

Current medications for the cerebrum harming inconveniences of neonatal seizures are unsuitable. Levetiracetam as mono treatment in neonatal seizures and its utilization in patients explicitly giving seizures optional to HIE are warranted.7 Recent examinations on this medication demonstrate that Levetiracetam was seen as generally sheltered and adequate in treating neonatal seizures.3

In an examination by Perveen S, et al has demonstrated the viability of 23.3% with intravenous levetiracetam when contrasted with 86.7% with Phenobarbital for the treatment of neonatal seizures.7

In another investigation by Daoud A has indicated the viability of half with intravenous levetiracetam for the treatment of neonatal seizures.8

No such examination has been done before in our overall public. In addition just one randomized examination has been found so far globally, which outcomes can't be summed up on all populace. In this way I have wanted to contrast the adequacy of intravenous Levetiracetam and Phenobarbital in treatment of neonatal seizures in our overall public. The aftereffect of this examination will include additional proof with respect to adequacy of Levetiracetam and Phenobarbital in treatment of neonatal seizures. It will likewise add to the information that assists with changing past rules in the executives of neonatal seizure.

MATERIALS AND METHODS

Randomized controlled trail study conducted at the Pediatric Department of Idris Teaching Hospital Sialkot from Jan2019 to Feb 2020.

Sample size: (n= 60 sample size)

Total sample size was divided into two groups. n1=30 patients for Phenobarbital group or group A while n2=30 patients for intravenous Levetiracetam group or group B.

Sampling technique: Non-probability Consecutive Sampling

After getting permission from the concerned authorities and ethical committee, total of 60 patients presenting to emergency department of neonatal unit with seizures were included after fulfilling the inclusion criteria. The Informed consent was taken from all the patients care takers. All neonates with clinically identifiable seizure were included in the study. The blood sample for secondary causes of seizures was sent to laboratory these include blood sugar, serum calcium, magnesium, sodium, potassium. Other disease specific investigation was sent. The antibiotic administration was based on departmental policy as 1st,2nd & 3rd line antibiotics and other drugs like intravenous fluids, blood products were according to the need for the patients. For anticonvulsant therapy we divided patients randomly into two groups Group A and Group B via lottery method. Group A was given inj phenobarbitone loading dose maximum 40mg/kg (initial loading dose 20mg/kg reloading with 10 mg/kg for further 2 times) and maintenance dose 5mg/kg. Group B was given injection Levetiracetam loading maximum40mg/kg(initially with 30mg/kg then reloading with 10mg/kg) and maintenance dose 20mg/kg/day. Both Drugs were given in infusion form in dilution in 15 ml normal saline over 15 minutes. If seizures reoccur with maximum loading dose then the patient was switched to other drug. Patient was continuous monitoring & observed for reoccurrence of seizure within 24 hours.  Efficacy as per operational definition was noted after 24 hours by the researcher himself. All data was recorded on the specially designed Proforma.

Data was analyzed with statistical analysis program (SPSS version 22).

Inclusion criteria:

1.      Age < 28 days

2.      Both gender

3.      Neonatal seizures as per operational definition for < 24 hours

Exclusion criteria:

1.      Who were already receiving anticonvulsants

2.      If seizures were due to correctable metabolic abnormalities (i.e. hypoglycemia, hypocalcemia, hypomagnesaemia, hyponatremia)

3.      Neonates with associated pulmonary, hepatic, renal, or cardiac dysfunction.

RESULTS

Age range in this study was < 28 days with mean age of 15.200± 5.62 days in Group A while 14.900± 5.99 days in Group B. Mean duration of complain was 10.400±4.83 hours in Group A and 11.433±4.67 hours in Group B.

Table No. I: Mean±SD of patients according to age, gestational age and BMI in both groups (n=60)

Demographics

Mean±SD

Case Group

n=30

Mean±SD

Control Group

n=30

Age(days)

15.200± 5.62

14.900± 5.99

Duration of Complain (hours)

10.400±4.83

11.433±4.67

Weight (Kg)

4.056±0.65

4.163±0.64

Mean weight was 4.056±0.65 kg in Group A and 4.163±0.64 Kg in Group B as shown in Table-I. 

Male gender was dominant in both group (63.3% and 63.3%) as shown in Table-2.

Table No.2: Frequency and %age of patients according to gender in both groups

Gender

n=30

n=30

Group A

Group B

Male

19 (63.3%)

19 (63.3%)

Female

11 (36.7%)

11 (36.7%)

Table No.3: Comparison of Efficacy in both groups (n=60)

Efficacy

n=30

n=30

 

P Value

Group A

Group B

Yes

9 (30%)

25 (83.3%)

 

0.000

No

21 (70%)

5 (16.7%)

Total

30 (100%)

30 (100%)

Table No.4: Stratification of Efficacy with respect to age in Group A and Group B

For Age group 1-15 days

 

Efficacy

 

P Value

Group

Yes

No

A

3(17.6%)

14(82.4%)

 

0.000

B

14(82.4%)

3(17.6%)

For Age group 16-27 days

Group

Yes

No

 

0.039

A

6(46.2%)

7(53.8%)

B

11(84.6%)

2(15.4%)

Table No.5: Stratification of Efficacy with respect to gender in Group A and Group B

For Male

 

Efficacy

 

P Value

Group

Yes

No

A

5(26.3%)

14(73.7%)

 

0.000

B

16(84.2%)

3(15.8%)

For Female

Group

Yes

No

 

0.030

A

4(36.4%)

7(63.6%)

B

9(81.8%)

2(18.2%)

Table No.6: Stratification of Efficacy with respect to duration of complain in Group A and Group B

For 1-12 hours

 

Efficacy

 

P Value

Group

Yes

No

A

7(38.9%)

11(61.1%)

 

0.000

B

16(100%)

0(0%)

For 13-23 hours

Group

Yes

No

 

0.014

A

2(16.7%)

10(83.3%)

B

9(64.3%)

5(35.7%)

Table No.7: Stratification of Efficacy with respect to weight in Group A and Group B

For ≤3.5 Kg

 

Efficacy

 

P Value

Group

Yes

No

A

5(62.5%)

3(37.5%)

 

0.310

B

6(85.7%)

1(14.3%)

For > 3.5 Kg

Group

Yes

No

 

0.000

A

4(18.2%)

18(81.8%)

B

19(82.6%)

4(17.4%)

In group A efficacy was seen in 9 (30%) patients as compare to 25 (83.3%) patients in group B, (P=0.000) as shown in Table-3. Stratification of efficacy with regard to age, gender, duration of complain and weight are shown in Table-4, 5, 6 and 7 respectively.

DISCUSSION

Levetiracetam has been reported to be a promising new drug for neonatal seizures. In two separate case series, Shoemaker and Rotenberg reported 80% seizure control in 10 infants aged 1 day to 3 months, treated with oral levetiracetam for seizures refractory to phenobarbital, phenytoin and benzodiazepines.9,10 Furwentsches A et al did prospective pilot feasibility study of oral levetiracetam for 3 days on newborns with seizures but they permitted additional treatment with single daily doses of phenobarbitone. So, which drug contributed more to this seizure control would be difficult to say. A recently published case series of 22 neonates by Khan O et al reported clinical control of seizures in 32%, in babies who had not responded to phenobarbitone.6 Similarly, Abend NS et al reported effective seizure control in 35% neonates.11 Most studies have used levetiracetam as second line drug after phenobarbitone failure. Our study is the first study to test levetiracetam as a first line drug in treatment of neonatal seizures in Pakistan.

In my study efficacy was seen in 9 (30%) patients with phenobarbitone as compare to 25 (83.3%) patients with Levetiracetam, (P=0.000).

In a study by Daoud A has showed the efficacy of 50% with intravenous levetiracetam for the treatment of neonatal seizures.8

In another study, Perveen S, et al has showed the efficacy of 23.3% with intravenous levetiracetam as compared to 86.7% with Phenobarbital for the treatment of neonatal seizures.7

There was not enough data on pharmacokinetics of levetiracetam at time of onset of our trial. We used a loading dose of 60 mg /kg followed by maintenance dose of 30 mg/kg/day based on dose used in a study. Though subsequent study on pharmecokinetics of levetiracetam were done using 40 mg/kg, Ramantani G et al have reported safety and efficacy of LVR with 60 mg/kg as well.12 Higher dose may be required in neonates due to (i) higher volume of distribution (ii) greater than predicted clearance in first week of life (iii) intractability of neonatal seizures in neonates and (iv) safety demonstrated in children even with dose up to 275 mg/kg and up to 1800 mg/kg in animals (no death, organ failure or irreversible toxicities were noted).

The eight hourly dosing is required to ensure that 95% of infants maintain trough concentration >10 microgram/ml and above 20 microgram/ml for 1st 3 days when seizure frequency is maximum. The 12 hourly dosing schedule used in our study was supported by a subsequent pharmacokinetic study by Merher SL et al who reported that 12 hourly interval is acceptable due to reduced renal clearance until the glomerular filtration matures over first few weeks.13

Our study does not report any significant effect of levetiracetam on hemodynamic, cardiovascular or renal status. Merher SL et al also reported no change in vital sign or laboratory parameters with its use.13 Levetiracetam is reported to cause only minor side effects like sedation, behavior abnormalities and depression in older children and somnolence in neonates. Occasional reports of reversible thrombocytopenia and possible liver failure and anaphylactic shock because of levetiracetam have also been reported.14 Though levetiracetam has predominantly renal excretion, like us, other studies has also not reported derangements in renal parameters with its use. Boylan GB et al had reported that only about 35% neonates with electrical seizures display clinical seizures.15 In other two-third babies, clinical manifestations were unrecognized even by experienced neonatal staff. They therefore concluded that clinical diagnosis may not be enough in recognition and management of neonatal seizures. However, more trials, with larger sample size are required. Further studies are required to evaluate role of LVR in neonatal seizure both as first line and 2nd line therapy. Role of higher first dose and repeated loading doses in non-responders to 1st dose also needs to be evaluated in further studies. More studies on pharmacokinetics with larger sample size are also required.

CONCLUSION

It is concluded that levetiracetam is more efficacious than phenobarbital in control of clinical seizures in treatment of neonatal seizures. Phenobarbitone is often ineffective as a first line anticonvulsant in neonates with seizures in whom the background EEG is significantly abnormal. Levetiracetam has been tried for the treatment of seizures refractory to phenobarbitone in children and neonates.

Author’s Contribution:

Concept & Design of Study:

Junaid Ghaffar

Drafting:

Amna Riaz, Uzair

Data Analysis:

Ahmad Omair Virk, Akmal Bhatti

Revisiting Critically:

Junaid Ghaffar,
Amna Riaz

Final Approval of version:

Junaid Ghaffar

Conflict of Interest: The study has no conflict of interest to declare by any author.

 

REFERENCES

1.       Donovan MD, Griffin BT, Kharoshankaya L, Cryan JF, Boylan GB. Pharmacotherapy for neonatal seizures: current knowledge and future perspectives. Drugs 2016;76(6):647-61. 

2.       Murty YVSS, Patel MR. Role of levetiracetam in neonatal seizure. J Clin Neonatol 2012;1(3): 168. 

3.       Yau ML, Fung EL, Ng PC. Response of levetiracetam in neonatal seizures. World J Clin Pediatr 2015;4(3):45-9. 

4.       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):841-6.

5.       Mruk AL, Garlitz KL, Leung NR. Levetiracetam in neonatal seizures: a review. J Pediatr Pharmacol Ther 2015;20(2):76-89. 

6.       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(4):265-9.

7.       Perveen S, Singh A, Upadhyay A, Singh N, Chauhan R. A randomized controlled trial on comparison of phenobarbitone and levetiracetam for the treatment of neonatal seizures: pilot study. Int J Res Med Sci 2016;4:2073-8.

8.       Daoud A, Al-Hamouri F. The efficacy of levetiracetam for the treatment of neonatal seizures. Eur J Paediatr Neurol 2015;19(1):S97.

9.       Shoemaker MT, Rotenberg JS. Levetiracetam for the Treatment of Neonatal Seizures. J Child Neurol 2007;22:95-8.

10.    Shoemaker MT, Rotenberg JS. Safety and tolerability of levetiracetam in infants. Epilepsia 2005;46:160.

11.    Abend NS, Gutierrez-Colina AM, Monk HM, Dlugos DJ, Clancy RR. Levetiracetam for treatment of neonatal seizures. J Child Neurol 2011;26:465-70.

12.    Ramantani G, Ikonomidou C, Walter B, t al. Levetiracetam: safety and efficacy in neonatal seizures. Eur J Paediatr Neurol 2011;15:1-7.

13.    Merhar SL, Schibler KR, Sherwin CM, Meinzen-Derr J, Shi J, Balmakund T, et al. Pharma-cokinetics of levetiracetam in neonates with seizures. J Pediatr 2011;159:152-4. 

14.    Sahaya K, Goyal MK, Sarwal A, Singh NN. Levetiracetam-induced thrombocytopenia among inpatients: a retrospective study. Epilepsia 2010; 51:2492-5.

15.    Boylan GB, Rennie JM, Pressler M, Wilson G, Morton M, Binnie CD. Phenobarbitone, neonatal seizures, and video-EEG. Arch Dis Child. Fetal Neonatal Ed 2002; 86:F165-70.