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)

Abstract

IntroductionStatus 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 analysisA 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 disseminationThe 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 numberNCT02431663; Pre-results.

Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee

“…Most human studies on KET for the treatment of CRSE are small retrospective series or isolated cases focused on the late use of this drug when multiple ASMs have failed, making it difficult to formulate recommendations, but ongoing clinical trials may provide further information. 43 We identified no class I to III and 25 class IV references, including 14 case reports and 11 case series containing from 2 to less than 15 cases of CRSE in infants, children, and adults, with age ranging from a preterm neonate age 1 day of life to an 88-year-old patient. Variability in studies encompasses not only age but also SE etiology, timing of KET treatment, ranging from days to weeks after onset, number of continuous infusions tried prior to KET, and the number of concomitant ASMs.…”

How close is ketamine to routine use in refractory status epilepticus?

“…Due to the lack of large randomized controlled studies, the limitations of this approach have not been completely assessed. The results of two ongoing studies (ClinicalTrials.gov identification numbers NCT02431663 and NCT03115489) may provide new information that sheds light on these issues [6,23].…”

Pharmacotherapy for Pediatric Convulsive Status Epilepticus

“…A multicenter, randomized, controlled, sequentially designed study is planned to assess the efficacy of ketamine in the treatment of RSE in children aged 1 month to 18 years of age (KETASER01). This study will randomize patients to either a control arm receiving 12 µg/kg/min of midazolam or an experimental arm receiving 100 µg/kg/min of ketamine [55].…”