Treatment of status epilepticus: Too low, too slow

This review of the treatment of convulsive status epilepticus (SE) in adults examines why, with so many new tools, we have made so little progress. Major advances in basic mechanisms and increased number of available drugs, clinical trials, and publications have not led to a commensurate improvement in clinical outcomes. The central role of N-methyl-D-aspartate (NMDA) receptors in initiation and maintenance of SE is now understood, but its therapeutic implications have not been translated into clinical trials or clinical practice. Failure of inhibition from inactivation of synaptic γ-aminobutyric acid type A receptors (GABA_ARs) and KCC2 chloride transporters and runaway excitation from increases in NMDA receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are all under NMDAR control, yet no current guidelines recommend early treatment with NMDAR antagonists. Time plays a critical role in SE-associated morbidity and mortality, and in the response to benzodiazepines and antiseizure medications, yet most patients are treated after time t2 and are often underdosed. Traditional SE treatment leaves too much time for NMDAR-dependent pharmacoresistance to develop. There is a gap between the therapeutic strategies suggested by preclinical studies and the design of clinical trials, and between therapeutic recommendations from clinical trials and their real-life application (too low, too slow). Prehospital treatment should be standardized, home treatment should be encouraged, and underdosing is not acceptable. "Time-to-needle" must become an integral part of SE treatment. In untreated SE, if treatment delay (stage "1 plus") predicts failure of benzodiazepine monotherapy, more vigorous initial treatment should be considered. A recent double-blind pediatric SE study showed that initial treatment with midazolam plus ketamine was superior to and better tolerated than midazolam alone; we need a similar clinical trial in adults. When benzodiazepines fail, time to the next agent should be minimized, and we need a prehospital trial of ketamine as second agent. We have the tools to improve the outcome of SE; let us use them.