Combined Ketamine and Midazolam for Generalized Convulsive Status Epilepticus

Generalized convulsive status epilepticus (GCSE) is a common neurological emergency in children, which is associated with significant morbidity and mortality. This condition is defined as > 5 minutes of continuous or recurrent generalized tonic-clonic seizure activity without regaining consciousness. GCSE requires immediate evaluation and management in order to control ongoing seizures.

According to most guidelines, benzodiazepines are the recommended first line antiseizure medication (ASMs). Second-line ASMs for benzodiazepines-refractory GCSE include multiple options, such as fosphenytoin/phenytoin, valproic acid, or levetiracetam. Last, refractory GCSE requires treatment with third-line ASMs, such as another second-line ASMs or infusion with thiopental, midazolam, pentobarbital, propofol, or ketamine.

However, about 35% of cases with GCSE are not controlled by benzodiazepines, and up to 40% of benzodiazepines-refractory GCSE don't respond to second-line ASMs. As GCSE persists for a longer time, it becomes more difficult to control with worse prognosis. Indeed, the effectiveness of benzodiazepines to control seizures decreases by 50% when given after 10-15 minutes of continuous seizures. Therefore, new ASMs or combinations are required for earlier control of seizures, which will contribute to better outcome. Combination of benzodiazepines with another ASM that has a different mechanism of action may be a promising option for faster control of GCSE. One of the potential drugs for such combination is ketamine.

Several adult and pediatric studies have shown effectiveness of ketamine in refractory and super-refractory GCSE. Unlike benzodiazepines that act through inhibitory Gamma-aminobutyric acid (GABA), ketamine is a non-competitive antagonist for N- methyl- d- aspartate (NMDA) receptors, which mediates excitatory glutamate action. Continuous seizure activity is associated with internalization of GABA receptors and upregulation of NMDA receptors.

A number of animal studies have demonstrated synergistic action of combined ketamine and benzodiazepines for status epilepticus. While combined ketamine and benzodiazepines have been used in pediatric sedation/analgesia, there are limited studies on such combination for children with GCSE.

In this study, the investigators aim to evaluate the efficacy and safety of ketamine plus midazolam versus midazolam alone as first-line therapy of pediatric GCSE.

Inclusion criteria

• Age from 6 month to 16 years.
• Generalized convulsive status epilepticus, defined as > 5 minutes of clinically observed continuous or recurrent generalized, tonic-clonic seizure activity without regaining of consciousness.

Exclusion criteria

• Failure to obtain informed consent.
• Previous treatment with any antiseizure medication for the presenting seizure episode.
• Hypertension
• Alcohol intake
• Conditions associated with increased intracranial pressure (e.g., central nervous system mass lesions, hydrocephalus)
• Glaucoma
• Known allergy or contraindications to any of the study drugs.
• End-stage kidney disease.
• End stage liver disease
• Arrhythmia, severe heart disease, or pulmonary hypertension.
• Hyperthyroidism
• Pheochromocytoma
• Hypoglycemia or hyperglycemia.
• Inborn errors of metabolism.
• Known or suspected psychiatric disorder.
• Failure to obtain intravenous access in the first 5 minutes of stabilization phase.
• Cessation of seizures during the stabilization phase (0 - 5 minutes).
• Traumatic brain injury.