Ketamine and Levetiracetam as Second-line Antiseizure Medication for Status Epilepticus in Children

Efficacy of Combined Ketamine and Levetiracetam as a Second-line Anti-seizure Medication for Generalized Convulsive Status Epilepticus in Children

About 40% of children with generalized convulsive status epilepticus (GCSE) are not terminated by first-line benzodiazepines (BDZs), and approximately 50% of BDZ-refractory GCSE are not controlled by second-line antiseizure medications. This study investigates the efficacy of ketamine-levetiracetam combination vs. levetiracetam alone for treating children with BDZ-refractory GCSE.

Generalized convulsive status epilepticus (GCSE) is the most common pediatric neurological emergency. Benzodiazepines (BDZs) are the recommended first-line anti-seizure medication (ASM) for GCSE, but they fail to halt seizures in about 40% of cases. Moreover, approximately 50% of BDZ-refractory GCSE are not terminated by second-line ASMs, including levetiracetam, valproate, and phenytoin. Continuous GCSE for a longer duration is associated with progressive brain injury and a higher risk of mortality, epilepsy, and permanent neurodevelopmental impairment. Therefore, early control of GCSE is pivotal for improving patients' outcomes.

A potential approach for early control of GCSE is the use of early ASM polytherapy. Ketamine is a promising option to be combined with standard ASMs for more rapid control of seizures. Ketamine has been used for decades for pediatric procedural analgosedation due to its excellent safety profile and wide therapeutic index. Ketamine works as a noncompetitive antagonist for N-methyl-D-aspartate (NMDA) receptors, which are progressively upregulated by way of receptor trafficking during ongoing seizure activity. Ketamine administration is associated with termination or attenuation of refractory SE (RSE) and super-refractory SE (SRSE). Multiple observational studies have reported the efficacy of ketamine in the pre-hospital emergency treatment of BZD-refractory status epilepticus. Furthermore, the recently published Ket-Mid study demonstrated that the ketamine-midazolam combination was more effective than midazolam alone in the initial treatment of pediatric GCSE. However, the value of combining ketamine with levetiracetam for the treatment of BZD-refractory status epilepticus has not been well investigated.

The present study (Ketamine and Levetiracetam as Second-line antiseizure medication for Status Epilepticus in Children, KLaSSEC) aims to investigate the efficacy of ketamine-levetiracetam combination vs. levetiracetam alone for treating children with BDZ-refractory GCSE. The findings could help earlier control of seizures and better clinical outcomes for children with status epilepticus

Inclusion Criteria:

• Age from 1 year to 16 years.
• Generalized convulsive status epilepticus (GCSE), defined as clinically observed generalized tonic-clonic convulsions that continue or recur without complete regaining of consciousness in between for longer than 5 minutes.
• Benzodiazepine-refractory, defined as continuous or recurrent GCSE in the emergency room after receiving an adequate benzodiazepine dose, with the last dose administered within 5 to 30 minutes.

Exclusion Criteria:

• Failure to obtain informed consent.
• Prior treatment with antiseizure medication or anticonvulsant sedatives other than benzodiazepines for the presenting GCSE episode.
• Endotracheal intubation before enrollment.
• Acute traumatic brain injury.
• Cardiac arrest/post-anoxic seizures
• Hypoglycemia or hyperglycemia.
• Known allergies or contraindications to ketamine or levetiracetam
• Failure to obtain intravenous access.