Original articleEfficacy and safety of intravenous sodium valproate versus phenobarbital in controlling convulsive status epilepticus and acute prolonged convulsive seizures in children: A randomised trial
Introduction
Status epilepticus and acute prolonged seizures are the most commonly occurring neurological emergencies in children. Unlike brief seizures, such events have high morbidity and mortality rates, along with poor long-term outcomes depending on their duration, causes, and co-morbidities. Therefore, such seizures warrant urgent treatment using appropriate doses of rapidly acting anticonvulsants. An ideal anticonvulsant for treating status epilepticus should be effective, reach the brain rapidly, lack serious adverse effects, and should have a formulation appropriate for rapid administration to a patient experiencing convulsions.1, 2, 3
Traditionally, benzodiazepines administered via the rectal, buccal, and intravenous routes have been relied upon as the first line of treatment by emergency room physicians. Caregivers at home generally prefer to administer rectal, nasal, and buccal benzodiazepines as seizure-aborting agents.1 When benzodiazepines, particularly intravenous forms, either fail to terminate the convulsion or successfully stop the convulsion, a long-acting anticonvulsant should be administered, the selection of which depends on the circumstances specific to each case. Such long-acting anticonvulsants include phenytoin or phenobarbital.2, 3 In our country and most other developing countries, phenobarbital and phenytoin are the most commonly used second-line anticonvulsants for controlling status epilepticus and acute prolonged seizures. However, these medications have several well-known and potentially serious adverse effects. Respiratory depression, sedation, and hypotension are the primary adverse effects resulting from phenobarbital rapid infusion, especially when the patient has previously received a high dose of intravenous benzodiazepine as the first-line treatment. Cardiac dysrhythmias and hypotension have frequently been reported following rapid infusion of phenytoin; local irritation, phlebitis, and dizziness are also commonly observed adverse effects.4
Recently, an intravenous formulation of sodium valproate has become available in our country. The pharmacokinetics of intravenous valproate have been elucidated in both adults and children,5, 6, 7, 8 with several studies on adults and a small number on children demonstrating the efficacy and safety of rapid infusion of sodium valproate in controlling status epilepticus and acute prolonged seizures.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 However, most of these studies have used relatively small sample sizes or have major methodological shortcomings. Besides, very few well-designed randomised trials have been conducted in children specifically, and there remains a paucity of data regarding intravenous sodium valproate use in children at standard or rapid infusion rates.5, 20 To the best of our knowledge, no study has been performed to compare the efficacy of rapid loading of sodium valproate versus phenobarbital in children with status epilepticus and acute prolonged seizures. Therefore, we carried out a randomised controlled trial with the aim of comparing the efficacy and safety of rapid infusion of intravenous sodium valproate with those of intravenous phenobarbital in children with convulsive status epilepticus and acute prolonged convulsive seizures.
Section snippets
Study location, sample, and design
Our study was conducted between May 2008 and May 2010 in 2 major university paediatric hospitals in Tehran, Iran. We enrolled children aged 2 years and older presenting with convulsive status epilepticus or acute prolonged convulsive seizures.
Our definition of status epilepticus was based on the practical definition of status epilepticus proposed by Lowenstein et al., who defined status epilepticus as a continuous, generalised, convulsive seizure lasting longer than 5 min9, 30 Based on this
Baseline characteristics
In the present study, 60 children were enrolled (30 in each trial group) and were randomly allocated to receive either sodium valproate or phenobarbital. The valproate group consisted of 16 boys and 14 girls, with a median age of 5 years and a range from 3 to 16 years. The phenobarbital group consisted of 21 boys and 9 girls with a median age of 4 years and a range of 3–11 years. In the valproate group, 21 children had remote symptomatic epilepsy, 4 had idiopathic epilepsy, and 5 had prolonged
Discussion
Convulsive status epilepticus and acute prolonged convulsive seizures require prompt treatment using an anticonvulsant that should be effective, readily available in emergency rooms, lacking any serious adverse effects, and ideally available in intravenous form so that therapeutic serum concentrations can be established rapidly.1, 2 In addition, in developing countries, the expenditure on anticonvulsants is a practical and potentially limiting factor that could limit the use of some of the
Conflicts of interest
The authors declare no conflicts of interest.
Acknowledgements
The authors are grateful to all parents and patients for their participation in this study. Our special thanks to Dr. Sadjad Bakhtiar and the Sanofi Company for providing the Depakine used in this study.
References (30)
- et al.
Efficacy and usability of buccal midazolam in controlling acute prolonged convulsive seizures in children
Eur J Paediatr Neurol
(2010) - et al.
Pharmacokinetics and clinical application of intravenous valproate in Thai epileptic children
Brain Dev
(2011) - et al.
Randomized study of intravenous valproate and phenytoin in status epilepticus
Seizure
(2007) - et al.
Intravenous sodium valproate in mainland China for the treatment of diazepam refractory convulsive status epilepticus
J Clin Neurosci
(2009) - et al.
Safety of rapid intravenous valproate infusion in pediatric patients
Pediatr Neurol
(2007) - et al.
Intravenous valproate as an innovative therapy in seizure emergency situations including status epilepticus–experience in 102 adult patients
Seizure
(2005) Status epilepticus and acute repetitive seizures in children, adolescents, and young adults: etiology, outcome, and treatment
Epilepsia
(1996)- et al.
A comparison of four treatments for generalized convulsive status epilepticus. Veterans affairs status epilepticus cooperative study group
New Engl J Medicine
(1998) The use of valproate and new antiepileptic drugs in status epilepticus
Epilepsia
(2007)The pharmacology of parenteral valproate
Epilepsy Curr
(2003)
Intravenous loading of valproate for epilepsy
Clin Neuropharmacol
Clinical utility of a continuous intravenous infusion of valproic acid in pediatric patients
Pharmacotherapy
Treatment of absence status with intravenous valproate
Neurology
Intravenous valproate for seizures in 137 Taiwanese children – valproate naive and non-naive
Acta Neurol Taiwan
Safety of intravenous valproate
Ann Neurol
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