Ketamine as advanced second‐line treatment in benzodiazepine‐refractory convulsive status epilepticus in children

Abstract

Status epilepticus (SE) is one of the most common neurological emergencies in children. To date, there is no definitive evidence to guide treatment of SE refractory to benzodiazepines. The main objectives of treatment protocols are to expedite therapeutic decisions and to use fast-and short-acting medications without significant adverse effects. Protocols differ among institutions, and most frequently valproate, phenytoin, and levetiracetam are used as second-line treatment. After failure of first-and second-line medications, admission to the intensive care unit and continuous infusion of anesthetics are usually indicated. Ketamine is a noncompetitive N-methyl-D-aspartate receptor antagonist that has been safely used for the treatment of refractory SE in adults and children. In animal models of SE, ketamine demonstrated antiepileptic and neuroprotective properties and synergistic effects with other antiseizure medications. We reviewed the literature to demonstrate the potential role of ketamine as an advanced second-line agent in the treatment of SE. Pharmacological targets, pathophysiology of SE, and the receptor trafficking hypothesis are reviewed and presented. The pharmacology of ketamine is outlined with related properties, advantages, and side effects. We summarize the most recent and relevant publications on experimental and clinical studies on ketamine in SE. Key expert opinion is also reported. Considering the current knowledge on SE pathophysiology, early sequential polytherapy should include ketamine for its wide range of positive assets. Future research and clinical trials on SE pharmacotherapy should focus on the role of ketamine as second-line medication. K E Y W O R D S ketamine, pediatric, pharmacotherapy, seizures F I G U R E 5 Dual therapy in a model of lithium-pilocarpine-induced convulsive status epilepticus (SE) in rats. The left panels show the compressed electroencephalogram (EEG) from SE control (Cont), midazolam (Mz), ketamine (Ket), or midazolam-ketamine animals up to 75 min following treatment (tr.). The right panels show the magnified 6-s EEG traces prior to SE or following SE (marked by vertical lines a-c). Vertical bar = .5 mV; horizontal bar = 1 s. From Niquet et al. 46 Reproduced with permission provided by John Wiley and Sons and the Copyright Clearance Center.

Behavioral and Cognitive Outcomes of Rhesus Macaques Following Neonatal Exposure to Antiseizure Medications

“…In the operant test battery, ketamine‐exposed animals performed significantly worse than controls in learning, color and position discriminations, accuracy, and speed of task performance. This is highly relevant for seizure management, as ketamine is increasingly being used in the treatment of refractory seizures and status epilepticus 42 . The present results in the PbM‐treated animals conform with those of Paule et al and strongly argue that treatment duration is critical for neurocognitive outcomes.…”

“…This is highly relevant for seizure management, as ketamine is increasingly being used in the treatment of refractory seizures and status epilepticus. 42 The present results in the PbM-treated animals conform with those of Paule et al and strongly argue that treatment duration is critical for neurocognitive outcomes. Notably, we have reported that 5-hour sevoflurane or 8-hour PbM treatment cause significantly less brain injury than 24 hours of PbM treatment.…”

Ketamine: Pro or antiepileptic agent? A systematic review

“…In this regard, various studies have shown that ketamine has anticonvulsant and neuroprotective characteristics [ 21 ]. Recent research has demonstrated that ketamine can be utilized to effectively control refractory status epilepticus [ 22 ]. McCarthy et al 23 published the first evidence that ketamine exerts an anticonvulsant effect in animal models in 1965.…”

Midazolam, Ketamine, and Propofol: While We Slept, Others Worked on Anesthetizing Infusions for Refractory Status Epilepticus

“…The second study 10 adds important data in neonates and younger children to the world literature to suggest that ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, can be effectively and safely used to treat adults and children with RSE as the first CIV ASM. 1,2 Unfortunately, long-term patient outcomes were not reported in either study.…”

“…1 To reduce complications from RSE, clinicians often select a continuous intravenous anesthetizing ASM (CIV ASM) as the third drug. 2 Continuous intravenous anesthetizing ASMs in current use are midazolam, pentobarbital, and propofol, but there have been several newer reports on the use of ketamine. The desire to quickly stop RSE is understandable, but there are 2 questions to consider when considering a CIV ASM.…”