Early NMDA Antagonism in Pediatric Status Epilepticus: From Pathophysiological Rationale to Clinical Application of Ketamine

Status epilepticus (SE) is one of the most severe neurological emergencies in childhood and is associated with significant morbidity, mortality, and long-term neurodevelopmental consequences. Timely seizure termination is crucial, as prolonged seizure activity promotes pharmacoresistance through dynamic alterations in inhibitory and excitatory neurotransmission. Experimental evidence demonstrates that sustained seizures are characterized by internalization of GABA-A receptors and increased expression of NMDA receptors, providing a pathophysiological rationale for targeting glutamate-mediated excitotoxicity through NMDA receptor antagonism. This thesis explores the role of ketamine, a non-competitive NMDA receptor antagonist, in the management of pediatric SE, integrating pharmachologic insights, experimental and clinical evidence, and healthcare organization strategies. A comprehensive review of preclinical and clinical literature was conducted, highlighting ketamine’s anticonvulsant, neuroprotective, and potentially disease-modifying properties. Available data suggests that earlier administration may improve seizure control while maintaining a favorable safety profile, particularly regarding respiratory and hemodynamic stability. To translate these concepts into clinical practice, the thesis describes the development and implementation of institutional and national initiatives aimed at improving SE management. Particular attention is given to the IRCCS Istituto Giannina Gaslini treatment protocol, which incorporates early ketamine administration after benzodiazepine failure, and to the activities of the Italian Pediatric Status Epilepticus (IPSE) network, dedicated to harmonizing hospital and prehospital care pathways across Italy. Original clinical data are presented through the KETA DEA study, a retrospective observational analysis of children with benzodiazepine-refractory convulsive SE treated with early intravenous ketamine in the emergency department. Preliminary findings support the feasibility, safety, and potential effectiveness of this strategy, with the aim of reducing progression to refractory SE, minimizing the need for invasive respiratory support, and improving adherence to time-sensitive treatment pathways. Overall, this work supports a paradigm shift toward earlier mechanism-based interventions in pediatric SE and provides the scientific rationale for further prospective studies evaluating ketamine as an integral component of standardized treatment algorithms in both hospital and prehospital settings.