Ketogenic Emergency Treatment Of Status Epilepticus In SIREN 

Status epilepticus (SE) is the second most common neurologic emergency worldwide, second only to stroke, and time is brain when treating patients with SE as well as stroke. Over one-half of patients with SE are resistant to one first- and one second-line anti-seizure drug, defined as refractory status epilepticus (RSE). Patients with RSE receive mechanical ventilation and intravenous anesthetic drugs to suppress seizures which may otherwise cause life-threatening complications. In patients with RSE, one third to nearly half die in the hospital, and only approximately 20%-30% of patients who survive return to their neurologic baseline. There is a critical need for prospective, randomized clinical trials establishing safe and effective treatments for RSE. Among interventions that have shown promise, ketogenic diet therapies (high fat, low carbohydrate diets designed to induce ketone body production or ketosis) have been shown to suppress seizures and status epilepticus in preclinical studies and in patients of all ages. Recent small studies showed resolution of status epilepticus in 71-73% of patients receiving a ketogenic enteral formula (tube feed) as an adjunct to standard medical care for super-refractory status epilepticus (RSE that does not resolve with treatment with general anesthesia or returns after 24 hours of aggressive therapy), compared to approximately 45% in studies of other therapies. However, interventions for status epilepticus are most effective when administered early and aggressively, before seizures cause permanent brain injury and death. Recent retrospective studies have demonstrated safe and effective use of a ketogenic enteral formula during established RSE (defined as RSE requiring mechanical ventilation during treatment with a medically-induced coma using general anesthesia to suppress seizures), before progressing to super-refractory status epilepticus. The primary aim of this proposal is to determine whether a ketogenic enteral formula will improve clinical outcomes in patients with established RSE. We will compare a 4:1 ratio ketogenic enteral formula to a standard of care enteral formula as adjunctive interventions in the management of patients with established RSE. We hypothesize that patients receiving a ketogenic formula will require fewer days of mechanical ventilation compared to patients receiving a standard enteral formula combined with routine medical care. The secondary aims of this study are to confirm the safety and feasibility of administering a ketogenic formula in an emergent setting and to explore the potential mechanisms of action of ketosis in suppressing status epilepticus in humans. The study leverages the robust collaborative infrastructure of the SIREN Network.

An NIH grant application for KETOSIS has been reviewed is being revised for resubmission in March 2021.