This pilot feasibility study aims to examine how the timing of ketamine introduction as a third-line anti-seizure medication infusion relates to seizure cessation in patients with refractory status epilepticus (RSE).

Patients admitted to the Jefferson Neurological Intensive Care Unit with seizures or status epilepticus will be screened for eligibility. Surrogate consent will be obtained from the participants legally authorized representative (LAR) by study personnel for eligible patients using remote e-consent process via RedCap. Participants will be randomized 1:1 to receive either early intravenous ketamine plus midazolam infusion or the current institutional protocol of midazolam followed by late ketamine infusion (Fernandez et al., 2018). Continuous video EEG monitoring will guide medication titration, increasing doses every 20 minutes for ongoing seizure activity. The primary goal of this study is to examine the feasibility of the protocol and obtain estimates of the timing of seizure cessation. The primary outcome is time to seizure cessation, defined as the time from initiation of anesthetic infusion (midazolam or midazolam plus ketamine) to the time of last electrographic seizure. The investigators will also collect preliminary data on other clinical measures that would serve as secondary outcomes for future trials. These clinical measures include progression to super refractory status epilepticus, intensive care unit and hospital length of stay, duration of mechanical ventilation, and functional outcomes assessed by the modified Rankin Scale at discharge, 3 months, and 6 months. This study does not evaluate ketamine as a novel therapy but rather assesses a minor modification in the timing of ketamine administration to optimize seizure control.

Inclusion Criteria:

1. Adults 18 years of age or older

2. Patients with refractory status epilepticus unresponsive to appropriately dosed first line agents administered intravenous or intraosseous and one second line agent

   1. First line agents: lorazepam, midazolam, or diazepam
   2. Second line agents: phenytoin (20 mg/kg), valproate (40 mg/kg), levetiracetam (60 mg/kg), lacosamide (400 mg)

3. All etiologies of status epilepticus will be included

Exclusion Criteria:

1. Exclusively psychogenic non epileptic seizures
2. Pregnant individuals
3. Incarcerated individuals
4. Patients with hypersensitivity to ketamine or any component of the formulation
5. Conditions in which an increase in blood pressure would be hazardous
6. Focal motor status epilepticus
7. Status epilepticus lasting > 24 hours prior to enrollment (SRSE)
8. Patients with EEG in the ictal-interictal continuum (IIC)