By Padmaja Kandula, MD
Assistant Professor of Neurology and Neuroscience, Comprehensive Epilepsy Center, Weill Cornell Medical College
Dr. Kandula reports no financial relationships relevant to this field of study.
SYNOPSIS: In this retrospective paper, the authors review the efficacy and safety of ketamine infusion in patients with status epilepticus who have failed benzodiazepine, standard anticonvulsant, and at least one other anesthetic drip.
SOURCE: Alkhachroum A, Der-Nigoghossian CA, Mathews E, et al. Ketamine to treat super-refractory status epilepticus. Neurology 2020; Sept. 1. doi: 10.1212/WNL.0000000000010611. [Online ahead of print].
Status epilepticus, defined as an emergent enduring ictal state, has nearly tripled in the last three decades, with an annual mortality of nearly 20%. The treatment of super-refractory status epilepticus (SRSE), or failure of benzodiazepine, one standard anticonvulsant, and anesthetic use, defines a population of patients with potentially increased mortality and morbidity. Despite the increased armamentarium of treatment options, standardized, high-quality data for SRSE are absent in the literature. Predictably, there is great variability across the nation and worldwide regarding management.
Animal models of self-sustaining status epilepticus suggest that drugs with gamma-aminobutyric acid (GABA) mediated inhibition, such as benzodiazepines, may become less effective over time because of receptor trafficking. As status epilepticus continues, GABAA receptors undergo endocytosis with upregulation of N-methyl-D-aspartate (NMDA) receptors.
This relative GABA pharmacoresistance has led to renewed interest in exploring agents with alternative mechanisms of action. Although ketamine has been in widespread clinical use since the 1970s, secondary to the agent’s combined hypnotic, analgesic, and amnestic qualities, recent interest for use in status epilepticus has emerged only over the last two decades as a result of the agent’s unique role as an NMDA receptor antagonist. The authors presented a retrospective single-center series of patients treated with adjunctive ketamine infusion for SRSE.
Nearly 261 adult patients were retrospectively identified as meeting SRSE at New York Presbyterian Hospital, Columbia University Medical Center in New York. Nearly one-quarter of patients were treated with adjunctive ketamine. All 68 patients treated with ketamine received prior midazolam anesthetic infusion. Concurrent electroencephalographic (EEG) recording, mean arterial pressure (MAP), arterial blood pressure (ABP), intracranial pressure (ICP), cerebral perfusion pressure (CPP), and cerebral blood flow (CBF) were measured. The main outcome was seizure control (complete seizure cessation or more than 50% reductive burden) within 24 hours of ketamine initiation. Seizure control post-ketamine discontinuation, in-house mortality, discharge status, and modified Rankin and Glasgow outcome scales extended at discharge also were incorporated into the analysis. Practical measures, such as hospital length of stay, withdrawal of life support, resuscitation status, and need for tracheostomy and percutaneous endoscopic gastrostomy, also were recorded. Ketamine was started at the discretion of the treating physician after midazolam failure.
The study cohort was composed of cardiac arrest (27%) and new onset refractory status epilepticus (18%). Seizures were noted as either focal or generalized. Roughly 80% of patients had 50% reduction in seizure burden within 24 hours of ketamine initiation. Nearly 65% of patients had seizure cessation. Forty percent of patients with seizure cessation eventually died. Of those without seizure cessation, nearly 55% of patients died. On average, ketamine was started two days after admission, with an average rate of 1.8 mg/kg/hr to 2.2 mg/kg/hr. MAP and ICP remained stable, along with a decrease in vasodepressor requirements over time, irrespective of dosage or duration of ketamine use.
Mechanistically, ketamine NMDA antagonism may help offset GABA-mediated pharmacoresistance in refractory status epilepticus. In addition, the lack of profound vasodepressor effect also is appealing in the critically ill population where treatment may carry equal or higher morbidity than the underlying condition.
However, the study is not without several limitations. All data were retrospective, unblinded, and without a control group. Treatment dose and titration schedule also were variable, complicating the independent vs. cumulative effects of concurrent anesthetic agents. The electrographic endpoint also was binary (seizure vs. no seizure), not reflecting the often “gray” zone of ictal equivalents, including periodic discharges. However, despite the aforementioned limitations, the overall rationale for earlier use in status epilepticus is interesting and warrants further prospective investigation.