{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T15:13:29Z","timestamp":1786720409077,"version":"build-2736575974"},"reference-count":75,"publisher":"National Institute for Health and Care Research","issue":"58","license":[{"start":{"date-parts":[[2020,11,1]],"date-time":"2020-11-01T00:00:00Z","timestamp":1604188800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.nationalarchives.gov.uk\/doc\/non-commercial-government-licence\/non-commercial-government-licence.htm"}],"funder":[{"DOI":"10.13039\/501100000664","name":"Health Technology Assessment programme","doi-asserted-by":"publisher","award":["12\/127\/134"],"award-info":[{"award-number":["12\/127\/134"]}],"id":[{"id":"10.13039\/501100000664","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journalslibrary.nihr.ac.uk"],"crossmark-restriction":false},"short-container-title":["Health Technol Assess"],"abstract":"\n Background<\/jats:title>\n Convulsive status epilepticus is the most common neurological emergency in children. Its management is important to avoid or minimise neurological morbidity and death. The current first-choice second-line drug is phenytoin (Epanutin, Pfizer Inc., New York, NY, USA), for which there is no robust scientific evidence.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To determine whether phenytoin or levetiracetam (Keppra, UCB Pharma, Brussels, Belgium) is the more clinically effective intravenous second-line treatment of paediatric convulsive status epilepticus and to help better inform its management.<\/jats:p>\n <\/jats:sec>\n \n Design<\/jats:title>\n A multicentre parallel-group randomised open-label superiority trial with a nested mixed-method study to assess recruitment and research without prior consent.<\/jats:p>\n <\/jats:sec>\n \n Setting<\/jats:title>\n Participants were recruited from 30 paediatric emergency departments in the UK.<\/jats:p>\n <\/jats:sec>\n \n Participants<\/jats:title>\n Participants aged 6 months to 17 years 11 months, who were presenting with convulsive status epilepticus and were failing to respond to first-line treatment.<\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n Intravenous levetiracetam (40\u2009mg\/kg) or intravenous phenytoin (20\u2009mg\/kg).<\/jats:p>\n <\/jats:sec>\n \n Main outcome measures<\/jats:title>\n Primary outcome \u2013 time from randomisation to cessation of all visible signs of convulsive status epilepticus. Secondary outcomes \u2013 further anticonvulsants to manage the convulsive status epilepticus after the initial agent, the need for rapid sequence induction owing to ongoing convulsive status epilepticus, admission to critical care and serious adverse reactions.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Between 17 July 2015 and 7 April 2018, 286 participants were randomised, treated and consented. A total of 152 participants were allocated to receive levetiracetam and 134 participants to receive phenytoin. Convulsive status epilepticus was terminated in 106 (70%) participants who were allocated to levetiracetam and 86 (64%) participants who were allocated to phenytoin. Median time from randomisation to convulsive status epilepticus cessation was 35 (interquartile range 20\u2013not assessable) minutes in the levetiracetam group and 45 (interquartile range 24\u2013not assessable) minutes in the phenytoin group (hazard ratio 1.20, 95% confidence interval 0.91 to 1.60; p<\/jats:italic>\u2009=\u20090.2). Results were robust to prespecified sensitivity analyses, including time from treatment commencement to convulsive status epilepticus termination and competing risks. One phenytoin-treated participant experienced serious adverse reactions.<\/jats:p>\n <\/jats:sec>\n \n Limitations<\/jats:title>\n First, this was an open-label trial. A blinded design was considered too complex, in part because of the markedly different infusion rates of the two drugs. Second, there was subjectivity in the assessment of \u2018cessation of all signs of continuous, rhythmic clonic activity\u2019 as the primary outcome, rather than fixed time points to assess convulsive status epilepticus termination. However, site training included simulated demonstration of seizure cessation. Third, the time point of randomisation resulted in convulsive status epilepticus termination prior to administration of trial treatment in some cases. This affected both treatment arms equally and had been prespecified at the design stage. Last, safety measures were a secondary outcome, but the trial was not powered to demonstrate difference in serious adverse reactions between treatment groups.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Levetiracetam was not statistically superior to phenytoin in convulsive status epilepticus termination rate, time taken to terminate convulsive status epilepticus or frequency of serious adverse reactions. The results suggest that it may be an alternative to phenytoin in the second-line management of paediatric convulsive status epilepticus. Simple trial design, bespoke site training and effective leadership were found to facilitate practitioner commitment to the trial and its success. We provide a framework to optimise recruitment discussions in paediatric emergency medicine trials.<\/jats:p>\n <\/jats:sec>\n \n Future work<\/jats:title>\n Future work should include a meta-analysis of published studies and the possible sequential use of levetiracetam and phenytoin or sodium valproate in the second-line treatment of paediatric convulsive status epilepticus.<\/jats:p>\n <\/jats:sec>\n \n Trial registration<\/jats:title>\n Current Controlled Trials ISRCTN22567894 and European Clinical Trials Database EudraCT number 2014-002188-13.<\/jats:p>\n <\/jats:sec>\n \n Funding<\/jats:title>\n This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment<\/jats:italic>; Vol. 24, No. 58. See the NIHR Journals Library website for further project information.<\/jats:p>\n <\/jats:sec>","DOI":"10.3310\/hta24580","type":"journal-article","created":{"date-parts":[[2020,11,16]],"date-time":"2020-11-16T09:17:36Z","timestamp":1605518256000},"page":"1-96","update-policy":"https:\/\/doi.org\/10.3310\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":19,"title":["Levetiracetam as an alternative to phenytoin for second-line emergency treatment of children with convulsive status epilepticus: the EcLiPSE RCT"],"prefix":"10.3310","volume":"24","clinical-trial-number":[{"clinical-trial-number":"isrctn22567894","registry":"10.18810\/isrctn","type":"results"},{"clinical-trial-number":"2014-002188-13","registry":"10.18810\/euctr","type":"results"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0742-2113","authenticated-orcid":true,"given":"Richard E","family":"Appleton","sequence":"first","affiliation":[{"name":"The Roald Dahl Neurophysiology Department, Alder Hey Children\u2019s Hospital, Liverpool, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5876-3946","authenticated-orcid":true,"given":"Naomi EA","family":"Rainford","sequence":"additional","affiliation":[{"name":"Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3021-1955","authenticated-orcid":true,"given":"Carrol","family":"Gamble","sequence":"additional","affiliation":[{"name":"Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0645-3070","authenticated-orcid":true,"given":"Shrouk","family":"Messahel","sequence":"additional","affiliation":[{"name":"Emergency Department, Alder Hey Children\u2019s Hospital, Liverpool, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5996-2613","authenticated-orcid":true,"given":"Amy","family":"Humphreys","sequence":"additional","affiliation":[{"name":"Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0467-0362","authenticated-orcid":true,"given":"Helen","family":"Hickey","sequence":"additional","affiliation":[{"name":"Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5726-5304","authenticated-orcid":true,"given":"Kerry","family":"Woolfall","sequence":"additional","affiliation":[{"name":"Institute of Population Health, University of Liverpool, Liverpool, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2918-7628","authenticated-orcid":true,"given":"Louise","family":"Roper","sequence":"additional","affiliation":[{"name":"Institute of Population Health, University of Liverpool, Liverpool, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5232-8495","authenticated-orcid":true,"given":"Joanne","family":"Noblet","sequence":"additional","affiliation":[{"name":"Emergency Department, Alder Hey Children\u2019s Hospital, Liverpool, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2846-2448","authenticated-orcid":true,"given":"Elizabeth","family":"Lee","sequence":"additional","affiliation":[{"name":"Emergency Department, Alder Hey Children\u2019s Hospital, Liverpool, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1463-279X","authenticated-orcid":true,"given":"Sarah","family":"Potter","sequence":"additional","affiliation":[{"name":"Faculty of Health and Applied Sciences, University of the West of England, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4246-1409","authenticated-orcid":true,"given":"Paul","family":"Tate","sequence":"additional","affiliation":[{"name":"Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2851-0913","authenticated-orcid":true,"given":"Nadia","family":"Al Najjar","sequence":"additional","affiliation":[{"name":"Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3932-4729","authenticated-orcid":true,"given":"Anand","family":"Iyer","sequence":"additional","affiliation":[{"name":"The Roald Dahl Neurophysiology Department, Alder Hey Children\u2019s Hospital, Liverpool, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicki","family":"Evans","sequence":"additional","affiliation":[{"name":"Patient and public involvement representative, Wrexham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8634-7210","authenticated-orcid":true,"given":"Mark D","family":"Lyttle","sequence":"additional","affiliation":[{"name":"Faculty of Health and Applied Sciences, University of the West of England, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"6221","published-online":{"date-parts":[[2020,11]]},"reference":[{"key":"key20201112094717809_ref1-bib1","doi-asserted-by":"publisher","first-page":"2125","DOI":"10.1016\/S0140-6736(19)30724-X","article-title":"Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial","volume":"393","author":"Lyttle","year":"2019","journal-title":"Lancet"},{"key":"key20201112094717809_ref1-bib2","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1186\/s13063-017-2010-8","article-title":"Emergency treatment with levetiracetam or phenytoin in status epilepticus in children-the EcLiPSE study: study protocol for a randomised controlled trial","volume":"18","author":"Lyttle","year":"2017","journal-title":"Trials"},{"key":"key20201112094717809_ref1-bib3","volume-title":"Emergency Treatment with Levetiracetam or Phenytoin in Status Epilepticus","author":"ISRCTN registry"},{"key":"key20201112094717809_ref1-bib4","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1136\/adc.2006.107516","article-title":"Outcome of convulsive status epilepticus: a review","volume":"92","author":"Novorol","year":"2007","journal-title":"Arch Dis Child"},{"key":"key20201112094717809_ref1-bib5","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/S0140-6736(06)69043-0","article-title":"Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study","volume":"368","author":"Chin","year":"2006","journal-title":"Lancet"},{"key":"key20201112094717809_ref1-bib6","volume-title":"Annual Report 2010","author":"PICANet"},{"key":"key20201112094717809_ref1-bib7","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1017\/s0012162204000027","article-title":"Outcome after prolonged convulsive seizures in 186 children: low morbidity, no mortality","volume":"46","author":"Mets\u00e4ranta","year":"2004","journal-title":"Dev Med Child Neurol"},{"key":"key20201112094717809_ref1-bib8","doi-asserted-by":"publisher","first-page":"1584","DOI":"10.1136\/jnnp.2003.032797","article-title":"Inappropriate emergency management of status epilepticus in children contributes to need for intensive care","volume":"75","author":"Chin","year":"2004","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"key20201112094717809_ref1-bib9","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/j.seizure.2007.01.007","article-title":"Aetiology, course and outcome of children admitted to paediatric intensive care with convulsive status epilepticus: a retrospective 5-year review","volume":"16","author":"Hussain","year":"2007","journal-title":"Seizure"},{"key":"key20201112094717809_ref1-bib10","doi-asserted-by":"publisher","first-page":"1316","DOI":"10.1212\/01.wnl.0000180959.31355.92","article-title":"Treatment delay and the risk of prolonged status epilepticus","volume":"65","author":"Eriksson","year":"2005","journal-title":"Neurology"},{"key":"key20201112094717809_ref1-bib11","volume-title":"A Practical Approach to Emergencies (APLS) 6th Edition","author":"Advanced Life Support Group"},{"key":"key20201112094717809_ref1-bib12","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD001905.pub3","article-title":"Drug management for acute tonic\u2013clonic convulsions including convulsive status epilepticus in children","volume":"1","author":"McTague","year":"2018","journal-title":"Cochrane Database Syst Rev"},{"key":"key20201112094717809_ref1-bib13","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.yebeh.2016.09.030","article-title":"Direct and indirect comparison meta-analysis of levetiracetam versus phenytoin or valproate for convulsive status epilepticus","volume":"64","author":"Brigo","year":"2016","journal-title":"Epilepsy Behav"},{"key":"key20201112094717809_ref1-bib14","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1097\/PEC.0b013e318196ea6e","article-title":"Emergency management of pediatric convulsive status epilepticus: a multicenter study of 542 patients","volume":"25","author":"Lewena","year":"2009","journal-title":"Pediatr Emerg Care"},{"key":"key20201112094717809_ref1-bib15","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/S1059-1311(02)00338-2","article-title":"Adverse events associated with intravenous phenytoin in children: a prospective study","volume":"12","author":"Appleton","year":"2003","journal-title":"Seizure"},{"key":"key20201112094717809_ref1-bib16","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1385\/NCC:3:2:161","article-title":"Phenytoin poisoning","volume":"3","author":"Craig","year":"2005","journal-title":"Neurocrit Care"},{"key":"key20201112094717809_ref1-bib17","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1111\/j.1742-6723.2010.01269.x","article-title":"Review article: phenytoin use and efficacy in the ED","volume":"22","author":"Gallop","year":"2010","journal-title":"Emerg Med Australas"},{"key":"key20201112094717809_ref1-bib18","volume-title":"Risk of Death and Severe Harm From Error With Injectable Phenytoin","author":"NHS Improvement"},{"key":"key20201112094717809_ref1-bib19","doi-asserted-by":"publisher","first-page":"1634","DOI":"10.1007\/s00415-009-5166-7","article-title":"Intravenous levetiracetam as treatment for status epilepticus","volume":"256","author":"Berning","year":"2009","journal-title":"J Neurol"},{"key":"key20201112094717809_ref1-bib20","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1177\/1756285608100460","article-title":"New treatment options in status epilepticus: a critical review on intravenous levetiracetam","volume":"2","author":"Trinka","year":"2009","journal-title":"Ther Adv Neurol Disord"},{"key":"key20201112094717809_ref1-bib21","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1136\/jnnp.2007.130260","article-title":"Intravenous levetiracetam in the treatment of benzodiazepine refractory status epilepticus","volume":"79","author":"Knake","year":"2008","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"key20201112094717809_ref1-bib22","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.eplepsyres.2008.05.004","article-title":"Tolerability and dosing experience of intravenous levetiracetam in children and infants","volume":"81","author":"Michaelides","year":"2008","journal-title":"Epilepsy Res"},{"key":"key20201112094717809_ref1-bib23","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.yebeh.2008.01.004","article-title":"Intravenous levetiracetam: treatment experience with the first 50 critically ill patients","volume":"12","author":"R\u00fcegg","year":"2008","journal-title":"Epilepsy Behav"},{"key":"key20201112094717809_ref1-bib24","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1177\/0883073808331351","article-title":"Rapid infusion of a loading dose of intravenous levetiracetam with minimal dilution: a safety study","volume":"24","author":"Wheless","year":"2009","journal-title":"J Child Neurol"},{"key":"key20201112094717809_ref1-bib25","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.pediatrneurol.2009.02.016","article-title":"Role of intravenous levetiracetam in acute seizure management of children","volume":"41","author":"Kirmani","year":"2009","journal-title":"Pediatr Neurol"},{"key":"key20201112094717809_ref1-bib26","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/j.seizure.2012.05.010","article-title":"Intravenous levetiracetam in acute repetitive seizures and status epilepticus in children: experience from a children\u2019s hospital","volume":"21","author":"McTague","year":"2012","journal-title":"Seizure"},{"key":"key20201112094717809_ref1-bib27","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD003723.pub2","article-title":"Anticonvulsant therapy for status epilepticus","volume":"4","author":"Prasad","year":"2005","journal-title":"Cochrane Database Syst Rev"},{"key":"key20201112094717809_ref1-bib28","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1007\/s00415-011-6227-2","article-title":"Levetiracetam versus lorazepam in status epilepticus: a randomized, open labeled pilot study","volume":"259","author":"Misra","year":"2012","journal-title":"J Neurol"},{"key":"key20201112094717809_ref1-bib29","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.seizure.2012.01.008","article-title":"Levetiracetam as alternative stage two antiepileptic drug in status epilepticus: a systematic review","volume":"21","author":"Zelano","year":"2012","journal-title":"Seizure"},{"key":"key20201112094717809_ref1-bib30","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1016\/j.jocn.2014.12.013","article-title":"Levetiracetam versus phenytoin in management of status epilepticus","volume":"22","author":"Chakravarthi","year":"2015","journal-title":"J Clin Neurosci"},{"key":"key20201112094717809_ref1-bib31","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.eplepsyres.2015.04.013","article-title":"Management of generalised convulsive status epilepticus (SE): a prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam \u2013 pilot study","volume":"114","author":"Mundlamuri","year":"2015","journal-title":"Epilepsy Res"},{"key":"key20201112094717809_ref1-bib32","doi-asserted-by":"publisher","first-page":"192","DOI":"10.3389\/fneur.2013.00192","article-title":"Clinical pharmacology and pharmacokinetics of levetiracetam","volume":"4","author":"Wright","year":"2013","journal-title":"Front Neurol"},{"key":"key20201112094717809_ref1-bib33","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1111\/j.1528-1167.2006.00586.x","article-title":"Levetiracetam intravenous infusion: a randomized, placebo-controlled safety and pharmacokinetic study","volume":"47","author":"Ramael","year":"2006","journal-title":"Epilepsia"},{"key":"key20201112094717809_ref1-bib34","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1007\/s12028-009-9304-y","article-title":"Prospective, randomized, single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis","volume":"12","author":"Szaflarski","year":"2010","journal-title":"Neurocrit Care"},{"key":"key20201112094717809_ref1-bib35","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1111\/j.1535-7511.2008.00266.x","article-title":"Levitating levetiracetam\u2019s status for status epilepticus","volume":"8","author":"Hirsch","year":"2008","journal-title":"Epilepsy Curr"},{"key":"key20201112094717809_ref1-bib36","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.seizure.2013.12.007","article-title":"The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: a meta-analysis of published studies","volume":"23","author":"Yasiry","year":"2014","journal-title":"Seizure"},{"key":"key20201112094717809_ref1-bib37","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1136\/archdischild-2013-304998","article-title":"Pediatric Emergency Research in the UK and Ireland (PERUKI): developing a collaborative for multicentre research","volume":"99","author":"Lyttle","year":"2014","journal-title":"Arch Dis Child"},{"key":"key20201112094717809_ref1-bib38","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1136\/emermed-2014-204484","article-title":"Establishing the research priorities of paediatric emergency medicine clinicians in the UK and Ireland","volume":"32","author":"Hartshorn","year":"2015","journal-title":"Emerg Med J"},{"key":"key20201112094717809_ref1-bib39","volume-title":"Epilepsies: Diagnosis and Management","author":"National Institute for Health and Care Excellence"},{"key":"key20201112094717809_ref1-bib40","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1186\/s12887-017-0887-8","article-title":"A multicentre randomised controlled trial of levetiracetam versus phenytoin for convulsive status epilepticus in children (protocol): Convulsive Status Epilepticus Paediatric Trial (ConSEPT) \u2013 a PREDICT study","volume":"17","author":"Dalziel","year":"2017","journal-title":"BMC Pediatr"},{"key":"key20201112094717809_ref1-bib41","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.1016\/S0140-6736(19)30722-6","article-title":"Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial","volume":"393","author":"Dalziel","year":"2019","journal-title":"Lancet"},{"key":"key20201112094717809_ref1-bib42","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1111\/epi.12288","article-title":"The established status epilepticus trial 2013","volume":"54","author":"Bleck","year":"2013","journal-title":"Epilepsia"},{"key":"key20201112094717809_ref1-bib43","doi-asserted-by":"publisher","first-page":"e005045","DOI":"10.1136\/bmjopen-2014-005045","article-title":"Doing challenging research studies in a patient-centred way: a qualitative study to inform a randomised controlled trial in the paediatric emergency care setting","volume":"4","author":"Woolfall","year":"2014","journal-title":"BMJ Open"},{"key":"key20201112094717809_ref1-bib44","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1186\/s13063-019-3273-z","article-title":"Enhancing practitioners\u2019 confidence in recruitment and consent in the EcLiPSE trial: a mixed-method evaluation of site training \u2013 a Paediatric Emergency Research in the United Kingdom and Ireland (PERUKI) study","volume":"20","author":"Woolfall","year":"2019","journal-title":"Trials"},{"key":"key20201112094717809_ref1-bib45","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1136\/archdischild-2013-305093","article-title":"Phenytoin dosing and serum concentrations in paediatric patients requiring 20\u2009mg\/kg intravenous loading","volume":"99","author":"Piper","year":"2014","journal-title":"Arch Dis Child"},{"key":"key20201112094717809_ref1-bib46","volume-title":"Research Without Prior Consent (Deferred Consent) in Trials Investigating the Emergency Treatment of Critically Ill Children: CONNECT Study Guidance Version 2.0","author":"Woolfall"},{"key":"key20201112094717809_ref1-bib47","doi-asserted-by":"publisher","first-page":"e008522","DOI":"10.1136\/bmjopen-2015-008522","article-title":"How parents and practitioners experience research without prior consent (deferred consent) for emergency research involving children with life threatening conditions: a mixed method study","volume":"5","author":"Woolfall","year":"2015","journal-title":"BMJ Open"},{"key":"key20201112094717809_ref1-bib48","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1136\/archdischild-2015-309245","article-title":"15 minute consultation: an evidence-based approach to research without prior consent (deferred consent) in neonatal and paediatric critical care trials","volume":"101","author":"Woolfall","year":"2015","journal-title":"Arch Dis Child Educ Pract Ed"},{"key":"key20201112094717809_ref1-bib49","volume-title":"Research Without Prior Consent (Deferred Consent) in Trials Investigating the Emergency Treatment of Critically Ill Children: CONNECT Study Guidance","author":"Woolfall","year":"2015"},{"key":"key20201112094717809_ref1-bib50","volume-title":"Designing and Conducting Mixed Methods Research","author":"Cresswell","year":"2007"},{"key":"key20201112094717809_ref1-bib51","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1177\/1049732303260610","article-title":"Mixed methods, mixed methodology health services research in practice","volume":"14","author":"Johnstone","year":"2004","journal-title":"Qual Health Res"},{"key":"key20201112094717809_ref1-bib52","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1097\/ACM.0000000000000388","article-title":"Standards for reporting qualitative research: a synthesis of recommendations","volume":"89","author":"O\u2019Brien","year":"2014","journal-title":"Acad Med"},{"key":"key20201112094717809_ref1-bib53","volume-title":"Basics of Qualitative Research: Techniques and Procedures for Developing Grounded Theory","author":"Strauss","year":"1998","edition":"2nd"},{"key":"key20201112094717809_ref1-bib54","doi-asserted-by":"publisher","first-page":"436","DOI":"10.2307\/798843","article-title":"The constant comparative method of qualitative analysis","volume":"12","author":"Glaser","year":"1965","journal-title":"Soc Probl"},{"key":"key20201112094717809_ref1-bib55","doi-asserted-by":"publisher","first-page":"1893","DOI":"10.1007\/s11135-017-0574-8","article-title":"Saturation in qualitative research: exploring its conceptualization and operationalization","volume":"52","author":"Saunders","year":"2018","journal-title":"Qual Quant"},{"key":"key20201112094717809_ref1-bib56","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1136\/archdischild-2018-314924","article-title":"Restricted fluid bolus volume in early septic shock: results of the Fluids in Shock pilot trial","volume":"104","author":"Inwald","year":"2019","journal-title":"Arch Dis Child"},{"key":"key20201112094717809_ref1-bib57","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.jclinepi.2016.02.002","article-title":"A new simple six-step model to promote recruitment to RCTs was developed and successfully implemented","volume":"76","author":"Realpe","year":"2016","journal-title":"J Clin Epidemiol"},{"key":"key20201112094717809_ref1-bib58","doi-asserted-by":"publisher","first-page":"e21604","DOI":"10.1371\/journal.pone.0021604","article-title":"Communication about children\u2019s clinical trials as observed and experienced: qualitative study of parents and practitioners","volume":"6","author":"Shilling","year":"2011","journal-title":"PLOS ONE"},{"key":"key20201112094717809_ref1-bib59","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1136\/jme.2010.035485","article-title":"What do our patients understand about their trial participation? Assessing patients\u2019 understanding of their informed consent consultation about randomised clinical trials","volume":"37","author":"Behrendt","year":"2011","journal-title":"J Med Ethics"},{"key":"key20201112094717809_ref1-bib60","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/s0277-9536(01)00197-6","article-title":"\u2018Why don\u2019t they just tell me straight, why allocate it?\u2019 The struggle to make sense of participating in a randomised controlled trial","volume":"55","author":"Featherstone","year":"2002","journal-title":"Soc Sci Med"},{"key":"key20201112094717809_ref1-bib61","doi-asserted-by":"publisher","first-page":"20","DOI":"10.2307\/3562038","article-title":"False hopes and best data: consent to research and the therapeutic misconception","volume":"17","author":"Appelbaum","year":"1987","journal-title":"Hastings Cent Rep"},{"key":"key20201112094717809_ref1-bib62","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.breast.2013.11.009","article-title":"Communication skills training for breast cancer teams talking about trials","volume":"23","author":"Fallowfield","year":"2014","journal-title":"Breast"},{"key":"key20201112094717809_ref1-bib63","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1136\/bmj.38366.562685.8F","article-title":"Discussing randomised clinical trials of cancer therapy: evaluation of a Cancer Research UK training programme","volume":"330","author":"Jenkins","year":"2005","journal-title":"BMJ"},{"key":"key20201112094717809_ref1-bib64","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1177\/175114371401500405","article-title":"Priorities for future intensive care research in the UK: results of a James Lind Alliance priority setting partnership","volume":"15","author":"Reay","year":"2014","journal-title":"J Intensive Care Soc"},{"key":"key20201112094717809_ref1-bib65","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1016\/S0140-6736(10)60712-X","article-title":"The James Lind Alliance: tackling research mismatches","volume":"376","author":"Petit-Zeman","year":"2010","journal-title":"Lancet"},{"key":"key20201112094717809_ref1-bib66","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/s13054-019-2354-4","article-title":"Permissive versus restrictive temperature thresholds in critically ill children with fever and infection: a multicentre randomized clinical pilot trial","volume":"23","author":"Peters","year":"2019","journal-title":"Crit Care"},{"key":"key20201112094717809_ref1-bib67","doi-asserted-by":"publisher","first-page":"2018","DOI":"10.1016\/j.socscimed.2009.02.023","article-title":"It\u2019s not just what you say, it\u2019s also how you say it: opening the \u2018black box\u2019 of informed consent appointments in randomised controlled trials","volume":"68","author":"Wade","year":"2009","journal-title":"Soc Sci Med"},{"key":"key20201112094717809_ref1-bib68","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1016\/j.jclinepi.2010.12.017","article-title":"Exploring treatment preferences facilitated recruitment to randomized controlled trials","volume":"64","author":"Mills","year":"2011","journal-title":"J Clin Epidemiol"},{"key":"key20201112094717809_ref1-bib69","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1093\/intqhc\/mzm042","article-title":"Consolidated criteria for reporting qualitative research (COREQ): a 32-item checklist for interviews and focus groups","volume":"19","author":"Tong","year":"2007","journal-title":"Int J Qual Health Care"},{"key":"key20201112094717809_ref1-bib70","doi-asserted-by":"publisher","first-page":"2103","DOI":"10.1056\/NEJMoa1905795","article-title":"Randomized trial of three anticonvulsant medications for status epilepticus","volume":"381","author":"Kapur","year":"2019","journal-title":"N Engl J Med"},{"key":"key20201112094717809_ref1-bib71","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1016\/S0140-6736(20)30611-5","article-title":"Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial","volume":"395","author":"Chamberlain","year":"2020","journal-title":"Lancet"},{"key":"key20201112094717809_ref1-bib72","doi-asserted-by":"publisher","first-page":"158","DOI":"10.4103\/jpn.JPN_126_17","article-title":"IV Levetiracetam versus IV phenytoin in childhood seizures: a randomized controlled trial","volume":"13","author":"Singh","year":"2018","journal-title":"J Pediatr Neurosci"},{"key":"key20201112094717809_ref1-bib73","doi-asserted-by":"publisher","first-page":"e7206","DOI":"10.1097\/MD.0000000000007206","article-title":"Efficacy of levetiracetam versus fosphenytoin for the recurrence of seizures after status epilepticus","volume":"96","author":"Nakamura","year":"2017","journal-title":"Medicine"},{"key":"key20201112094717809_ref1-bib74","doi-asserted-by":"publisher","first-page":"237","DOI":"10.17511\/ijpr.2018.i04.13","article-title":"Randomized controlled trial of levetiracetam versus fosphenytoin for convulsive status epilepticus in children","volume":"5","author":"Senthilkumar","year":"2018","journal-title":"Int J Pediatr Res"},{"key":"key20201112094717809_ref1-bib75","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/S0140-6736(05)66909-7","article-title":"Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial","volume":"366","author":"McIntyre","year":"2005","journal-title":"Lancet"}],"container-title":["Health Technology Assessment"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/njl-admin.nihr.ac.uk\/document\/download\/2034837","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.journalslibrary.nihr.ac.uk\/publications\/hta24580\/hta24580.xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/njl-admin.nihr.ac.uk\/document\/download\/2034837","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,15]],"date-time":"2023-08-15T15:36:54Z","timestamp":1692113814000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.journalslibrary.nihr.ac.uk\/hta\/hta24580"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11]]},"references-count":75,"journal-issue":{"issue":"58","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["10.3310\/hta24580"],"URL":"https:\/\/doi.org\/10.3310\/hta24580","relation":{},"ISSN":["1366-5278","2046-4924"],"issn-type":[{"value":"1366-5278","type":"print"},{"value":"2046-4924","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11]]},"assertion":[{"value":"This content has been made freely available to all.","name":"free","label":"Free to read"},{"value":"6-2014","name":"contractual_start_date","label":"Contractual start date","group":{"name":"article_history","label":"Article History"}},{"value":"11-2019","name":"editorial_review_begun","label":"Editorial review begun","group":{"name":"article_history","label":"Article History"}},{"value":"7-2020","name":"accepted_for_publication","label":"Accepted for publication","group":{"name":"article_history","label":"Article History"}}]}}