Early Use of the NMDA Receptor Antagonist Ketamine in Refractory and Superrefractory Status Epilepticus

Abstract

Refractory status epilepticus (RSE) and superrefractory status epilepticus (SRSE) pose a difficult clinical challenge. Multiple cerebral receptor and transporter changes occur with prolonged status epilepticus leading to pharmacoresistance patterns unfavorable for conventional antiepileptics. In particular, n-methyl-d-aspartate (NMDA) receptor upregulation leads to glutamate mediated excitotoxicity. Targeting these NMDA receptors may provide a novel approach to otherwise refractory seizures. Ketamine has been utilized in RSE. Recent systematic review indicates 56.5% and 63.5% cessation in seizures in adults and pediatrics, respectively. No complications were described. We should consider earlier implementation of ketamine or other NMDA receptor antagonists, for RSE. Prospective study of early implementation of ketamine should shed light on the role of such medications in RSE.

Starting ketamine for neuroprotection earlier than its current use as an anesthetic/antiepileptic drug late in refractory status epilepticus

“…It has been known for >20 years that NMDA-receptor antagonists such as ketamine are remarkably neuroprotective when given before 16,41 or after the onset of SE. 17,18 This information has not been used in treatment protocols for SE; rather, in recent years ketamine has been proposed as an antiepileptic drug in refractory SE in rodents, 32,33 and in humans, 1,[34][35][36][37] despite the early evidence that it is neuroprotective despite ongoing epileptic discharges. [16][17][18]41 Data in rats indicate that widespread neuronal necrosis occurs after 60 minutes of continuous SE and that it becomes worse as the duration of SE increases 21 (Figures 2 and 3).…”

“…1,2 Two prospective clinical trials referred to later in this commentary are studying the effect of ketamine on refractory SE, which I describe in detail later. However, it has a long history, first being used as a "dissociative" anesthetic (see below), and then as a neuroprotective drug in animal studies of status epilepticus.…”

“…Others have also suggested that ketamine should be started early in SE for neuroprotection. 1,2 Two prospective clinical trials referred to later in this commentary are studying the effect of ketamine on refractory SE, which I describe in detail later.…”

Treatment of drug‐induced seizures

“…Further studies are needed to verify these findings. During status epilepticus, GABA A receptors become less responsive while NMDA receptors become more responsive and there may be a role for NMDA/glutamate antagonists . Ketamine proved useful in at least one case report of refractory status epilepticus and in two cases of tetramine poisoning in which seizures were refractory to benzodiazepines and thiopental .…”

Ketamine for the treatment of (super) refractory status epilepticus? Not quite yet

“…introduction after a median time of 3 [17] or 9 days of SE [15]) with very variable protocols, it is very difficult to draw firm conclusions. Earlier administration is probably a key to success [12,18], at least by limiting the uncontrolled adverse effects and interactions related to polypharmacy. Concerns about possible developmental neurotoxicity might limit its pediatric use although reports suggest its benefits, notably by avoiding endotracheal intubation, a negative prognostic factor of morbidity and mortality [19].…”