Stuart R Dalziel1, Meredith L Borland2, Jeremy Furyk3, Megan Bonisch4, Jocelyn Neutze5, Susan Donath6, Kate L Francis7, Cynthia Sharpe4, A Simon Harvey8, Andrew Davidson9, Simon Craig10, Natalie Phillips11, Shane George12, Arjun Rao13, Nicholas Cheng14, Michael Zhang15, Amit Kochar16, Christine Brabyn17, Ed Oakley8, Franz E Babl8. 1. Children's Emergency Department, Starship Children's Hospital, Auckland, New Zealand; Departments of Surgery, University of Auckland, Auckland, New Zealand; Paediatrics: Child and Youth Health, University of Auckland, Auckland, New Zealand. Electronic address: sdalziel@adhb.govt.nz. 2. Perth Children's Hospital, Perth, WA, Australia; Division of Emergency Medicine, School of Medicine, University of Western Australia, Perth, WA, Australia; Division of Paediatrics, School of Medicine, University of Western Australia, Perth, WA, Australia. 3. Emergency Department, The Townsville Hospital, Townsville, QLD, Australia; College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD, Australia. 4. Children's Emergency Department, Starship Children's Hospital, Auckland, New Zealand. 5. Kidz First Hospital, Auckland, New Zealand. 6. Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia. 7. Murdoch Children's Research Institute, Parkville, VIC, Australia. 8. Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia; Royal Children's Hospital, Melbourne, VIC, Australia. 9. Murdoch Children's Research Institute, Parkville, VIC, Australia; Royal Children's Hospital, Melbourne, VIC, Australia. 10. Monash Medical Centre, Melbourne, VIC, Australia; Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, VIC, Australia. 11. Queensland Children's Hospital, Brisbane, QLD, Australia; Child Health Research Centre, University of Queensland, Brisbane, QLD, Australia. 12. Child Health Research Centre, University of Queensland, Brisbane, QLD, Australia; Department of Emergency Medicine, Gold Coast University Hospital, Southport, QLD, Australia; School of Medicine, Griffith University, Gold Coast, QLD, Australia. 13. Sydney Children's Hospital, Randwick, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia. 14. Children's Hospital at Westmead, Sydney, NSW, Australia. 15. Emergency Department, John Hunter Hospital, Newcastle, NSW, Australia. 16. Emergency Department, Women's and Children's Hospital, Adelaide, SA, Australia. 17. Emergency Department, Waikato Hospital, Hamilton, New Zealand.
Abstract
BACKGROUND:Phenytoin is the current standard of care for second-line treatment of paediatric convulsive status epilepticus after failure of first-line benzodiazepines, but is only effective in 60% of cases and is associated with considerable adverse effects. A newer anticonvulsant, levetiracetam, can be given more quickly, is potentially more efficacious, and has a more tolerable adverse effect profile. We aimed to determine whether phenytoin or levetiracetam is the superior second-line treatment for paediatric convulsive status epilepticus. METHODS:ConSEPT was an open-label, multicentre, randomised controlled trial conducted in 13 emergency departments in Australia and New Zealand. Children aged between 3 months and 16 years, with convulsive status epilepticus that failed first-line benzodiazepine treatment, were randomly assigned (1:1) using a computer-generated permuted block (block sizes 2 and 4) randomisation sequence, stratified by site and age (≤5 years, >5 years), to receive 20 mg/kg phenytoin (intravenous or intraosseous infusion over 20 min) or 40 mg/kg levetiracetam (intravenous or intraosseous infusion over 5 min). The primary outcome was clinical cessation of seizure activity 5 min after the completion of infusion of the study drug. Analysis was by intention to treat. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12615000129583. FINDINGS:Between March 19, 2015, and Nov 29, 2017, 639 children presented to participating emergency departments with convulsive status epilepticus; 127 were missed, and 278 did not meet eligibility criteria. The parents of one child declined to give consent, leaving 233 children (114 assigned tophenytoin and 119 assigned to levetiracetam) in the intention-to-treat population. Clinical cessation of seizure activity 5 min after completion of infusion of study drug occurred in 68 (60%) patients in the phenytoin group and 60 (50%) patients in the levetiracetam group (risk difference -9·2% [95% CI -21·9 to 3·5]; p=0·16). One participant in the phenytoin group died at 27 days because of haemorrhagic encephalitis; this death was not thought to be due to the study drug. There were no other serious adverse events. INTERPRETATION:Levetiracetam is not superior to phenytoin for second-line management of paediatric convulsive status epilepticus. FUNDING: Health Research Council of New Zealand, A+ Trust, Emergency Medicine Foundation, Townsville Hospital Private Practice Fund, Eric Ormond Baker Charitable Fund, and Princess Margaret Hospital Foundation.
RCT Entities:
BACKGROUND:Phenytoin is the current standard of care for second-line treatment of paediatric convulsive status epilepticus after failure of first-line benzodiazepines, but is only effective in 60% of cases and is associated with considerable adverse effects. A newer anticonvulsant, levetiracetam, can be given more quickly, is potentially more efficacious, and has a more tolerable adverse effect profile. We aimed to determine whether phenytoin or levetiracetam is the superior second-line treatment for paediatric convulsive status epilepticus. METHODS: ConSEPT was an open-label, multicentre, randomised controlled trial conducted in 13 emergency departments in Australia and New Zealand. Children aged between 3 months and 16 years, with convulsive status epilepticus that failed first-line benzodiazepine treatment, were randomly assigned (1:1) using a computer-generated permuted block (block sizes 2 and 4) randomisation sequence, stratified by site and age (≤5 years, >5 years), to receive 20 mg/kg phenytoin (intravenous or intraosseous infusion over 20 min) or 40 mg/kg levetiracetam (intravenous or intraosseous infusion over 5 min). The primary outcome was clinical cessation of seizure activity 5 min after the completion of infusion of the study drug. Analysis was by intention to treat. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12615000129583. FINDINGS: Between March 19, 2015, and Nov 29, 2017, 639 children presented to participating emergency departments with convulsive status epilepticus; 127 were missed, and 278 did not meet eligibility criteria. The parents of one child declined to give consent, leaving 233 children (114 assigned to phenytoin and 119 assigned to levetiracetam) in the intention-to-treat population. Clinical cessation of seizure activity 5 min after completion of infusion of study drug occurred in 68 (60%) patients in the phenytoin group and 60 (50%) patients in the levetiracetam group (risk difference -9·2% [95% CI -21·9 to 3·5]; p=0·16). One participant in the phenytoin group died at 27 days because of haemorrhagic encephalitis; this death was not thought to be due to the study drug. There were no other serious adverse events. INTERPRETATION:Levetiracetam is not superior to phenytoin for second-line management of paediatric convulsive status epilepticus. FUNDING: Health Research Council of New Zealand, A+ Trust, Emergency Medicine Foundation, Townsville Hospital Private Practice Fund, Eric Ormond Baker Charitable Fund, and Princess Margaret Hospital Foundation.
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