Efficacy of ketamine in refractory convulsive status epilepticus in children: a protocol for a sequential design, multicentre, randomised, controlled, open-label, non-profit trial (KETASER01)

Anna Rosati, Lucrezia Ilvento, Manuela L'Erario, Salvatore De Masi, Annibale Biggeri, Giancarlo Fabbro, Roberto Bianchi, Francesca Stoppa, Lucia Fusco, Silvia Pulitanò, Domenica Battaglia, Andrea Pettenazzo, Stefano Sartori, Paolo Biban, Elena Fontana, Elisabetta Cesaroni, Donatella Mora, Paola Costa, Rosanna Meleleo, Roberta Vittorini, Alessandra Conio, Andrea Wolfler, Massimo Mastrangelo, Maria Cristina Mondardini, Emilio Franzoni, Kathleen S McGreevy, Lorena Di Simone, Alessandra Pugi, Lorenzo Mirabile, Federico Vigevano, Renzo Guerrini, Anna Rosati, Lucrezia Ilvento, Manuela L'Erario, Salvatore De Masi, Annibale Biggeri, Giancarlo Fabbro, Roberto Bianchi, Francesca Stoppa, Lucia Fusco, Silvia Pulitanò, Domenica Battaglia, Andrea Pettenazzo, Stefano Sartori, Paolo Biban, Elena Fontana, Elisabetta Cesaroni, Donatella Mora, Paola Costa, Rosanna Meleleo, Roberta Vittorini, Alessandra Conio, Andrea Wolfler, Massimo Mastrangelo, Maria Cristina Mondardini, Emilio Franzoni, Kathleen S McGreevy, Lorena Di Simone, Alessandra Pugi, Lorenzo Mirabile, Federico Vigevano, Renzo Guerrini

Abstract

Introduction: Status epilepticus (SE) is a life-threatening neurological emergency. SE lasting longer than 120 min and not responding to first-line and second-line antiepileptic drugs is defined as 'refractory' (RCSE) and requires intensive care unit treatment. There is currently neither evidence nor consensus to guide either the optimal choice of therapy or treatment goals for RCSE, which is generally treated with coma induction using conventional anaesthetics (high dose midazolam, thiopental and/or propofol). Increasing evidence indicates that ketamine (KE), a strong N-methyl-d-aspartate glutamate receptor antagonist, may be effective in treating RCSE. We hypothesised that intravenous KE is more efficacious and safer than conventional anaesthetics in treating RCSE.

Methods and analysis: A multicentre, randomised, controlled, open-label, non-profit, sequentially designed study will be conducted to assess the efficacy of KE compared with conventional anaesthetics in the treatment of RCSE in children. 10 Italian centres/hospitals are involved in enrolling 57 patients aged 1 month to 18 years with RCSE. Primary outcome is the resolution of SE up to 24 hours after withdrawal of therapy and is updated for each patient treated according to the sequential method.

Ethics and dissemination: The study received ethical approval from the Tuscan Paediatric Ethics Committee (12/2015). The results of this study will be published in peer-reviewed journals and presented at international conferences.

Trial registration number: NCT02431663; Pre-results.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Figures

Figure 1
Figure 1
Flow chart. MDZ, midazolam; KE, ketamine; PR, propofol; TPS, thiopental.

References

    1. Proposal for revised clinical and electrographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1981;22:489–501. 10.1111/j.1528-1157.1981.tb06159.x
    1. Brophy GM, Bell R, Claassen J et al. . Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;17:3–23. 10.1007/s12028-012-9695-z
    1. Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011;134:2802–18. 10.1093/brain/awr215
    1. Raspall-Chaure M, Chin RF, Neville BG et al. . Outcome of pediatric convulsive status epilepticus: a systematic review. Lancet Neurol 2006;5:769–79. 10.1016/S1474-4422(06)70546-4
    1. Chin RF, Neville BG, Peckham C et al. . Incidence, cause and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet 2006;368:222–31. 10.1016/S0140-6736(06)69043-0
    1. Abend NS, Duglas DT. Treatment of refractory status epilepticus. Literature review and a proposed protocol. Pediatr Neurol 2008;38:377–80. 10.1016/j.pediatrneurol.2008.01.001
    1. Sofou K, Kristjansdòttir R, Papachatzakis NE et al. . Management of prolonged seizures and status epilepticus in childhood: a systematic review. J Child Neurol 2009;24:918–26. 10.1177/0883073809332768
    1. Fernandez A, Claassen J. Refractory status epilepticus. Curr Opin Crit Care 2012;18:127–31. 10.1097/MCC.0b013e32835132cc
    1. Griesdale DE, Bosma TL, Kurth T et al. . Complications of endotracheal intubation in the critically ill. Int Care Med 2008;34:1835–42. 10.1007/s00134-008-1205-6
    1. Carroll CL, Spinella PC, Corsi JM et al. . Emergent endotracheal intubations in children: be careful if it's late when you intubate. Pediatr Crit Care Med 2010;11:343–8. 10.1097/PCC.0b013e3181ce6d19
    1. Schmutzhard E, Pfausler B. Complications of the management of status epilepticus in the intensive care unit . Epilepsia 2011;52:39–41. 10.1111/j.1528-1167.2011.03233.x
    1. Wasterlain CG, Chen JW. Mechanistic and pharmacologic aspects of status epilepticus and its treatment with new antiepileptic drugs. Epilepsia 2008;49:63–73. 10.1111/j.1528-1167.2008.01928.x
    1. Naylor DE. Glutamate and GABA in the balance: convergent pathways sustain seizures during status epilepticus. Epilepsia 2010;5l:106–9.
    1. Zeiler FA, Teitelbaum J, Gillman LM et al. . NMDA Antagonists for refractory seizures. Neurocrit Care 2014;20:502–13. 10.1007/s12028-013-9939-6
    1. Craven R. Ketamine. Anaesthesia 2007;62:48–53. 10.1111/j.1365-2044.2007.05298.x
    1. Shibuta S, Varathan S, Mashimo T. Ketamine and thiopental sodium: individual and combined neuroprotective effects on cortical cultures exposed to NMDA or nitric oxide. Br J Anaesth 2006;97:517–24. 10.1093/bja/ael192
    1. Rosati A, L'Erario M, Ilvento L et al. . Efficacy and safety of ketamine in refractory status epilepticus children. Neurology 2012;79:2355–8. 10.1212/WNL.0b013e318278b685
    1. Ilvento L, Rosati A, Marini C et al. . Ketamine in refractory convulsive status epilepticus in children avoids endotracheal intubation. Epilepsy Behav 2015;49:343–6. 10.1016/j.yebeh.2015.06.019
    1. Franck LS, Naughton I, Winter I. Opioid and benzodiazepine withdrawal symptoms in paediatric intensive care patients. Intensive Crit Care Nurs 2004;20:344–51. 10.1016/j.iccn.2004.07.008
    1. Straney L, Clements A, Parslow RC et al. . Paediatric index of mortality 3: an updated model for predicting mortality in pediatric intensive care. Pediatr Crit Care Med 2013;14:673–81. 10.1097/PCC.0b013e31829760cf
    1. Rossetti AO, Logroscino G, Milligan TA et al. . Status Epilepticus Severity Score (STESS): a tool to orient early treatment strategy. J Neurol 2008;255:1561–6. 10.1007/s00415-008-0989-1
    1. Whiteheand J, Stratton I. Group sequential clinical trials whit triangular continuation regions. Biometrics 1983;39:227–36. 10.2307/2530822
    1. Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS 31 March 2003. , Publish Date: 9 August 2006.

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