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| ORIGINAL ARTICLE |
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| Year : 2023 | Volume
: 10
| Issue : 1 | Page : 18-23 |
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Comparison of levetiracetam as second-line drug with fosphenytoin in convulsive status epilepticus among children: A single center, open-label randomized controlled trial
S Anupama1, V Poovazhagi2, R Nisha2, S Suresh Kumar3, J Sathya3
1 Department of Pediatrics, Government Medical College and Hospital, Tiruvallur, Tamil Nadu, India
2 Department of Pediatric Intensive Care, Institute of Child Health and Hospital for Children, Egmore, Chennai, Tamil Nadu, India
3 Department of Pediatrics, Chengalpattu Medical College and Hospital, Chengalpattu, Chennai, Tamil Nadu, India
| Date of Submission | 10-Jun-2022 |
| Date of Decision | 03-Nov-2022 |
| Date of Acceptance | 30-Nov-2022 |
| Date of Web Publication | 20-Jan-2023 |
Correspondence Address:
Dr. S Anupama
Flat No. 5, Kanakadhara, 20, Temple Avenue, Srinagar Colony, Saidapet, Chennai - 600 015, Tamil Nadu
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/jpcc.jpcc_52_22
Background: Status epilepticus (SE) is the most common neurologic emergency in the pediatric age group often serious and life-threatening. Although newer drugs were used, morbidity and mortality are still high. This study was done to compare the efficacy of levetiracetam with the existing second-line drug fosphenytoin in the treatment of SE.
Subjects and Methods: This was a prospective, randomized parallel group trial from Pediatric Intensive Care Unit of a Tertiary Care Institute. One hundred children were recruited according to the inclusion and exclusion criteria, 50 in fosphenytoin group and 50 in levetiracetam group. Two groups were compared with respect to clinical cessation of seizures, recurrence, adverse event, and outcome.
Results: Male-to-female ratio was 1.45:1. Seizure were controlled in 37 (74%) in fosphenytoin group and 28 (56%) in levetiracetam group) (P = 0.059). The mean time for cessation of seizures was 11.16 ± 3.58 min in fosphenytoin group as compared to was 12.78 ± 3.07 min in levetiracetam group (P = 0.059) The seizure recurrence in first 24 h (18 [36%] vs. 12 [24%]) (P = 0.643) and development of shock (14 [28%] vs. 11 [22%]) (P = 0.488) was comparable in two groups. Overall mortality was 10 (20%) in fosphenytoin group as compared to 7 (14%) levetiracetam group (P = 0.281).
Conclusions: Efficacy of intravenous levetiracetam is comparable to fosphenytoin as a second-line medication in the management of convulsive SE in children.
Keywords: Fosphenytoin, levetiracetam, status epilepticus
How to cite this article:
Anupama S, Poovazhagi V, Nisha R, Kumar S S, Sathya J. Comparison of levetiracetam as second-line drug with fosphenytoin in convulsive status epilepticus among children: A single center, open-label randomized controlled trial. J Pediatr Crit Care 2023;10:18-23 |
How to cite this URL:
Anupama S, Poovazhagi V, Nisha R, Kumar S S, Sathya J. Comparison of levetiracetam as second-line drug with fosphenytoin in convulsive status epilepticus among children: A single center, open-label randomized controlled trial. J Pediatr Crit Care [serial online] 2023 [cited 2023 Mar 24];10:18-23. Available from: http://www.jpcc.org.in/text.asp?2023/10/1/18/368232 |
| Introduction | |  |
Status epilepticus (SE) is the most common life-threatening childhood neurological emergency. The annual incidence of convulsive SE is higher in children <5 year of age with an incidence of 17–23 cases/100,000 children/year;[1] benzodiazepines are the first line anticonvulsant and second in line is phenytoin/fosphenytoin in SE.[2] The complication of phenytoin such as hypotension, arrhythmias, and phlebitis seen much lesser in fosphenytoin;[3] Newer broad-spectrum anticonvulsant such as levetiracetam is less likely to cause cardiovascular complications and is preferred over other drugs, although limited data were available regarding efficacy and safety of levetiracetam in children;[4] Recent Indian Academy of Pediatrics Guidelines on Evaluation and Management of SE-2022 is as follows-General Measures (airway, breathing, and circulation), quick history (if on any AED [anti-epileptic drugs]) and examination followed by antiepileptic drugs: 1st line – injection Benzodiazepenes, 2nd line – Intravenous (IV) phenytoin or fosphenytoin 20 mg/kg of phenytoin equivalent (PE) at 3 mg/kg/min, if seizure persist either IV levetiracetam 20–60 mg/kg at 5 mg/kg/min or IV phenobarbitone 20 mg/kg or IV valproate 20–40 mg/kg, followed by general anesthesia to achieve burst suppression.[5]
Studies comparing levetiracetam and fosphenytoin among children with SE is scarce. A recent study done by Nalisetty et al.,[6] comparing the clinical effectiveness of levetiracetam with fosphenytoin revealed levetiracetam is an effective alternative to fosphenytoin in the management of benzodiazepine refractory SE. Levetiracetam is a newer anticonvulsant which has a good safety profile and no known severe life-threatening complications among children. With this background, this study was planned to compare the effectiveness and complications of levetiracetam with the existing second-line drug fosphenytoin.
| Materials and Methods | | |
This was an open-label randomized parallel group trial, conducted in the Pediatric Intensive Care Unit (PICU) of a Semi-Urban Tertiary Care Referral Institute from Tamil Nadu, India, between August 2016 and September 2017. The study was undertaken after Institutional Ethical Committee approval and with Clinical Trials Registry-India (CTRI) registration, CTRI/2017/07/008980. Study group includes children aged between 1 month and 12 years. Children from 1 month to 12 years of age with SE refractory to 2 doses of midazolam were included and children who received drugs other than 2 doses of midazolam, who received prehospital treatment with medications for seizures, children who presented with shock and parents or guardians denying consent were excluded.
Study protocol
One hundred and eighty children were admitted with SE of which 100 were recruited according to the inclusion and exclusion criteria. Study parameters such as age, sex, weight, detailed history, febrile or afebrile episode, onset of seizures, family history of seizures, history of asphyxia, neonatal intensive care unit admission, neurological development, previous oral intake of any anti-convulsant, comorbid conditions, clinical features of type of seizures, heart rate, blood pressure, capillary blood glucose, signs of raised intra cranial pressure (hypertension, bradycardia, and abnormal breathing), lab parameters of sodium, potassium, total count, hemoglobin, neuro-imaging, lumbar puncture, and electroencephalography (EEG) were documented.
Allocation by randomization
Children fulfilling the inclusion criteria were randomly allocated into two groups, by computer-generated random number table. Concealment of allocation was ensured by serially numbered opaque envelope under the supervision of in-charge staff nurse. Once the child satisfied inclusion criteria, treatment modality was decided as per randomization.
Intervention (drugs, dose and frequency)
All children diagnosed as SE at the Emergency room/PICU after meeting the inclusion criteria were recruited into one of the two groups. Children in Group 1 received injection fosphenytoin at a dose of 20 mg PE/kg over 20 min at the rate of 3 mg/kg/min and those in Group 2 received injection levetiracetam at a dose of 20 mg/kg over 20 min of 1 mg/kg/min.
Outcome measures
Primary outcome
For the next 20 min, children were observed for clinical cessation of seizures, time to control seizures, recurrence of seizures within 24 h, and mean time for recurrence of seizures.
Secondary outcome
Adverse effect (shock) following drug administration, time required to regain Glasgow Coma Scale (GCS) 15/15, need of mechanical ventilation, etiology of SE, duration of hospital stay, and mortality were assessed. Children whose seizures did not get controlled at the end of the either infusion were managed further according to the unit protocol and management was similar in both the study groups. Subsequent drugs used included sodium valproate, phenobarbitone, and midazolam infusion. All children were followed up till outcome defined as discharge from the hospital or death.
Statistical analysis
Sample size
Based on the article in children, Senthil Kumar et al.[7] mean time to control seizure in fosphenytoin 2.5 ± 1.4, levetiracetam − 3.3 ± 1.16, with mean difference of (−0.8) sample size in each group was n = 44. Based on this, sample size taken as 50 in levetiracetem group and 50 in fosphenytoin group with a power of 80% (beta = 0.20) and at 95% confidence limits (Type 1 error Alpha = 0.05).
Data were analyzed using the SPSS software version 21. The comparison was done between the two groups with respect to the study parameters for any statistically significance using Student's t-test for the continuous variable and Chi-square for the discrete variable. P < 0.05 was considered for statistical significance. Children were recruited for the study after informed written consent from the parents or caregivers.
| Results | | |
[Figure 1] gives CONSORT flow diagram of the entire study. Out of 180 children admitted with SE, 100 children were recruited according to the inclusion and exclusion criteria. | Figure 1: Consolidated standards of reporting of trials chart of the entire study
Click here to view |
Baseline characteristics
Gender distribution in either of the group was 1.45:1, of which 33 (66%) male and 17 (34%) female in fosphenytoin group and 26 (54%) male and 24 (46%) female in levetiracetam group, (P = 0.309). Median age in fosphenytoin group was 30 months with 25th to 75th interquartile percentile of 13 and 104 months respectively and median age in the levetiracetam group was 26 months with 25th to 75th interquartile percentile of 13.5 and 84 months respectively, (P = 0.730). The comparison of study parameters among the two groups is given in [Table 1]. The comparison of mean values of the lab parameters among the two groups is given in [Table 2].
Primary outcome
Thirty-seven children in fosphenytoin group had their seizures controlled, while 28 in levetiracetam group had their seizure controlled (P = 0.059). Mean time of seizure control from the initiation of the infusion in fosphenytoin group was 11.16 ± 3.58 min and in levetiracetam group was 12.78 ± 3.07 min (P = 0.059). Seizure recurrence within 24 h was found in 30 children. Eighteen (36%) children from fosphenytoin group and 12 (24%) levetiracetam group had recurrence of seizures (P = 0.643). Median time for seizure recurrence in fosphenytoin group was 60 min (30–150 min) and for levetiracetam group it was 65 min (22.5 to 320 min) (P = 0.966). Primary outcome is summarized in [Table 3].
Secondary outcome
Adverse effect encountered in the study group was shock 14 (28%) among fosphenytoin group and 11 (22%) in levetiracetam group (P = 0.488). Median time to regain GCS 15/15 in fosphenytoin group was 12 h (6–24 h) and in levetiracetam group was 18 h (6–48 h), P = 0.164 not significant.
Among fosphenytoin group, 11 (22%) children needed mechanical ventilation and in levetiracetam group 8 (16%) needed mechanical ventilation (P = 0.444). The need for mechanical ventilation was refractory seizures, hemodynamic instability, hypoxic posturing, and poor GCS. When the etiology of SE were analyzed, overall, the most common was drug withdrawal seizures 27 (54%), (children were on single or multiple drugs including sodium valproate or phenobarbitone, phenytoin or levetiracetam) with 14 (28%) in fosphenytoin group and 13 (26%) in levetiracetam group, second common etiology were acute meningoencephalitis 17 (34%), with 10 (20%) in fosphenytoin group and 7 (14%) in levetiracetam group. Secondary outcome is summarized in [Table 4].
Other outcomes
Duration of stay at the PICU for fosphenytoin group was 89 h (55.50–150.50) as compared to levetiracetam group was 83 h (52 to 180), (P = 0.907). Of 100 children, 81 children discharged and 17 children died. Out of 10 deaths in the fosphenytoin group, 4 children had of acute meningoencephalitis, 2 had intracranial tumor, 1 had due to tuberculosis (TB) meningitis, 1 had to Intracranial bleed, and 2 had drug withdrawal seizures. There were seven deaths among levetiracetam group, of which 2 had TB meningitis, 1 had acute central nervous system infection, 1 was metabolic (refractory hypocalcemic seizures and 2 had seizure disorder with breakthrough seizure), and 1 had mitochondrial disorder with refractory seizure. Overall mortality was 10 (20%) in fosphenytoin group as compared to 7 (14%) levetiracetam group (P = 0.281).
| Discussion | | |
Baseline characteristics were comparable between both the groups. Primary outcome: Seizures controlled at the end of administration of the drug among both the groups, were not significant (P = 0.059) and is similar to a study done by Senthil Kumar et al.[7] comparing levetiracetam and fosphenytoin in SE in children 84% in fosphenytoin and 92% in levetiracetam group had their seizure controlled (P = 0.6671). Another study done by Nakamura et al.[8] comparing levetiracetam and fosphenytoin in SE in adults 81% in fosphenytoin group and 85.1% in levetiracetam group had control of seizures with P = 0.69, which is similar to our study. A study done by Nalisetty et al.,[6] comparing clinical effectiveness of levetiracetam with fosphenytoin in the treatment of benzodiazepine refractory SE, response latency (time for seizure termination) in fosphenytoin were 16.2 ± 7.8 and in levetiracetam were 13.3 ± 4.5, P = 0.07, this is similar to our study. However, study done by Sharma et al.,[9] comparing levetiracetam and phenytoin in 250 pediatric patients in 6 months to 18 years of age with SE, seizure terminated in 107 (85.6%) in phenytoin group and 114 (91.2%) in levetiracetam group with P value statistically significant. The difference in results may be due to the large number of subjects enrolled and inclusion of children in wider age group for the study.
In this study, seizure recurrence within 24 h was found in 30 children. Eighteen (36%) children from fosphenytoin group and 12 (24%) levetiracetam group had recurrence of seizures (P = 0.643). This is similar to a study done by Anusha et al.,[10] in SE, 13 (22.4%) and 10 (17.2%) in levetiracetam and fosphenytoin had their seizure recurrence, respectively, (P = 0.485). Another study done by Alvarez et al.,[11] comparing IV valproate and phenytoin in adult patients with SE showed 6 in valproate group and 8 in phenytoin group had seizure recurrence within 12 h which was also not statistically significant.
Secondary outcome
In this study, adverse effect encountered in the study group was shock 14 (28%) among fosphenytoin group and 11 (22%) in levetiracetam group (P = 0.488), which is similar to a study done by Anusha et al.,[10] where 2 (3.4%) in fosphenytoin group and one (1.7%) in levetiracetam group developed shock which was statistically not significant. Children who required mechanical ventilation were similar in both the groups (P = 0.444) and is similar to a study done by Chakravarthi et al.,[12] comparing phenytoin and levetiracetam in adults in SE 6 out of 22 adults in phenytoin group and 4 out of 22 in levetiracetam group needed mechanical ventilation which was not statistically significant. When the etiology of SE was analyzed, overall most common was drug withdrawal seizures, which is similar to a study done by Bassin et al.,[13] on clinical review of SE in which most common etiology were drug withdrawal seizures (25%). Overall mortality was 17% of which 30% of the mortality were due to acute meningoencephalitis which is similar to a study done by Aicardi and Chevrie[14] on convulsive SE in infants and children, in which mortality due to acute meningoencephalitis was 28%.
Strength
Levetiracetam, a more recent anticonvulsant, was evaluated for efficacy with fosphenytoin (second line in SE) in ideal conditions, and this study's strengths include randomization to minimize bias and secondary outcomes such as adverse effects, etiology, and mortality were also analyzed.
Limitations
First, this is a single-centered open-label comparative randomized controlled trial with small sample size. Double-blind study would have been more ideal. Second, in this trial, a lower-than-recommended dose of levetiracetam was administered for a longer period of time, with the possibility of increasing the amount if seizures continued. Third, EEG confirmation of cessation of seizures could be more scientific.
| Conclusions | | |
Efficacy of IV levetiracetam is comparable to fosphenytoin as a second-line medication in the management of convulsive SE in children after benzodiazepine failure.
Recommendation
Levetiracetam can therefore be used as a second-line medication in place of fosphenytoin in children with SE.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1]
[Table 1], [Table 2], [Table 3], [Table 4]
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