Exogenous Ketone Esters for Refractory Status Epileptics (EKERSE)

This study aims to investigate the efficacy of add-on exogenous ketone esters for the treatment of children with refractory generalized convulsive status epilepticus

Generalized convulsive status epilepticus (GCSE) is a common neurological emergency in children with significant morbidity and mortality. Benzodiazepines (Bzs) are the initial anti-seizure medications (ASMs) for children with GCSE, but nearly a third of cases are not controlled by (Bzs). Moreover, about 40% of cases not responding to BZs are not controlled by second-line ASMs. Ketogenic diet (KD) has been classically used for treating children with drug resistant epilepsy. Recently, KD has been used for refractory and super refractory status epilepticus. However, KD takes time to achieve ketosis and may be practically challenging in emergency situations and critically ill patients. Exogenous ketone esters (EKE) could be a more convenient and rapid way to achieve ketosis in acute settings.

Status epilepticus, Refractory status epilepticus, Generalized convulsive status epilepticus, Exogenous ketone esters, Children, Seizures

Eligible children will be randomized into two equal-sized groups. Study group: will receive exogenous ketone esters plus standard of care. Control group: will receive only standard of care.

500 mg/kg over 5 min administered by nasogastric tube, followed after 1 hr by repeated hourly doses of 125 mg/kg for 8 hrs.

Proportions of patients who achieve cessation of BOTH clinical seizures (as observed clinically) AND electrical seizures (evaluated by electroencephalography [EEG])

Proportions of patients who achieve cessation of BOTH clinical seizures (as observed clinically) AND electrical seizures (evaluated by electroencephalography [EEG])

Time to cessation of BOTH clinical seizures (as observed clinically) AND electrical seizures (evaluated by electroencephalography [EEG])

Proportion of patients achieving freedom from BOTH clinical seizures (as observed clinically) AND electrical seizures (evaluated by electroencephalography [EEG])

Proportion of patients with persistent seizures for 24 hours or more after initiation of 3rd line medications (anesthetics) or recurrence of seizure during withdrawal of the anesthetics

Proportion of patients with adverse gastrointestinal effects (vomiting, diarrhea, abdominal pain) evaluated by direct observation and patient-reporting

Inclusion Criteria: Refractory Generalized convulsive status epilepticus. Exclusion Criteria: Failure to obtain informed consent. Recent intake of exogenous ketones, ketogenic diet, or any dietary restrictions/modifications. Hemodynamic or cardio-respiratory instability. Traumatic brain injury. Hypo-/hyperglycemia. Metabolic acidosis. Ketosis (βHB > 2 mmol/L). Associated severe disease condition, including hepatic, renal, respiratory, cardiac, gastrointestinal, endocrinal, and immune systems. Malnutrition/obesity. Limitations to nasogastric tube feeding. Inborn errors of metabolism. Allergies or any other contraindication to exogenous ketone esters. Current or recent (within the last 24 hours) propofol therapy. Intake of carbonic-anhydrase inhibitors.

Unidentified individual participant data (IPD) underlying study results will be available upon reasonable request

Unidentified individual participant data (IPD) underlying study results will be available upon reasonable request 6-months after publication

Arya R, Peariso K, Gainza-Lein M, Harvey J, Bergin A, Brenton JN, Burrows BT, Glauser T, Goodkin HP, Lai YC, Mikati MA, Fernandez IS, Tchapyjnikov D, Wilfong AA, Williams K, Loddenkemper T; pediatric Status Epilepticus Research Group (pSERG). Efficacy and safety of ketogenic diet for treatment of pediatric convulsive refractory status epilepticus. Epilepsy Res. 2018 Aug;144:1-6. doi: 10.1016/j.eplepsyres.2018.04.012. Epub 2018 Apr 27.

Chomtho S, Uaariyapanichkul J, Chomtho K. Outcomes of parenteral vs enteral ketogenic diet in pediatric super-refractory status epilepticus. Seizure. 2022 Mar;96:79-85. doi: 10.1016/j.seizure.2022.01.019. Epub 2022 Feb 5.

Clarke K, Tchabanenko K, Pawlosky R, Carter E, Todd King M, Musa-Veloso K, Ho M, Roberts A, Robertson J, Vanitallie TB, Veech RL. Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul Toxicol Pharmacol. 2012 Aug;63(3):401-8. doi: 10.1016/j.yrtph.2012.04.008. Epub 2012 May 3.

Gilbert DL, Pyzik PL, Freeman JM. The ketogenic diet: seizure control correlates better with serum beta-hydroxybutyrate than with urine ketones. J Child Neurol. 2000 Dec;15(12):787-90. doi: 10.1177/088307380001501203.

Schoeler NE, Simpson Z, Zhou R, Pujar S, Eltze C, Cross JH. Dietary Management of Children With Super-Refractory Status Epilepticus: A Systematic Review and Experience in a Single UK Tertiary Centre. Front Neurol. 2021 Mar 12;12:643105. doi: 10.3389/fneur.2021.643105. eCollection 2021.

Si J, Wang Y, Xu J, Wang J. Antiepileptic effects of exogenous beta-hydroxybutyrate on kainic acid-induced epilepsy. Exp Ther Med. 2020 Dec;20(6):177. doi: 10.3892/etm.2020.9307. Epub 2020 Oct 9.

Stubbs BJ, Cox PJ, Evans RD, Santer P, Miller JJ, Faull OK, Magor-Elliott S, Hiyama S, Stirling M, Clarke K. On the Metabolism of Exogenous Ketones in Humans. Front Physiol. 2017 Oct 30;8:848. doi: 10.3389/fphys.2017.00848. eCollection 2017.

Carson RP, Herber DL, Pan Z, Phibbs F, Key AP, Gouelle A, Ergish P, Armour EA, Patel S, Duis J. Nutritional Formulation for Patients with Angelman Syndrome: A Randomized, Double-Blind, Placebo-Controlled Study of Exogenous Ketones. J Nutr. 2021 Dec 3;151(12):3628-3636. doi: 10.1093/jn/nxab284.

Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, King MT, Dodd MS, Holloway C, Neubauer S, Drawer S, Veech RL, Griffin JL, Clarke K. Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metab. 2016 Aug 9;24(2):256-68. doi: 10.1016/j.cmet.2016.07.010. Epub 2016 Jul 27.

Trinka E, Cock H, Hesdorffer D, Rossetti AO, Scheffer IE, Shinnar S, Shorvon S, Lowenstein DH. A definition and classification of status epilepticus--Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015 Oct;56(10):1515-23. doi: 10.1111/epi.13121. Epub 2015 Sep 4.