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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Study group | Experimental | Children receiving exogenous ketone esters + standard of care |
|
| Control group | No Intervention | Children receiving only standard of care |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Exogenous ketone ester | Drug | 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. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of patients achieving electroclinical cessation of seizures | Proportions of patients who achieve cessation of BOTH clinical seizures (as observed clinically) AND electrical seizures (evaluated by electroencephalography [EEG]) | 60 minutes |
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of patients achieving electroclinical cessation of seizures | Proportions of patients who achieve cessation of BOTH clinical seizures (as observed clinically) AND electrical seizures (evaluated by electroencephalography [EEG]) | 12 hours |
| Time to electroclinical cessation of seizures |
| Measure | Description | Time Frame |
|---|---|---|
| Change in blood bicarbonates level | Change in blood bicarbonates level | From baseline to 30 minutes, 1 hour, 2 hours, 5 hours, 9 hours, and 12 hours study timepoints |
| Change in blood lactate level | Change in blood lactate level |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Elsayed M Abdelkreem, MD, PhD | Contact | 01114232126 | d.elsayedmohammed@med.sohag.edu.eg |
| Name | Affiliation | Role |
|---|---|---|
| Abdelrahim A Sadek, MD, PhD | Sohag University | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Pediatrics at Sohag University Hospital | Recruiting | Sohag | 82524 | Egypt |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29727818 | Background | 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. | |
| 35158320 |
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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
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| ID | Term |
|---|---|
| D013226 | Status Epilepticus |
| D012640 | Seizures |
| ID | Term |
|---|---|
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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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.
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Time to cessation of BOTH clinical seizures (as observed clinically) AND electrical seizures (evaluated by electroencephalography [EEG]) |
| 24 hours |
| Proportion of patients achieving electroclinical seizure freedom | Proportion of patients achieving freedom from BOTH clinical seizures (as observed clinically) AND electrical seizures (evaluated by electroencephalography [EEG]) | 24 hours |
| Proportion of patients with super-refractory status epilepticus | 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 | 24 hours |
| Proportion of patients with adverse gastrointestinal effects | Proportion of patients with adverse gastrointestinal effects (vomiting, diarrhea, abdominal pain) evaluated by direct observation and patient-reporting | 24 hours |
| Change in blood beta-hydroxybutyrate level | Change in blood level of beta-hydroxybutyrate | From baseline to 30 minutes, 1 hour, 2 hours, 5 hours, 9 hours, and 12 hours study timepoints |
| Change in blood glucose level | Change in blood level of glucose | From baseline to 30 minutes, 1 hour, 2 hours, 5 hours, 9 hours, and 12 hours study timepoints |
| Change in blood pH | Change in blood pH | From baseline to 30 minutes, 1 hour, 2 hours, 5 hours, 9 hours, and 12 hours study timepoints |
| From baseline to 30 minutes, 1 hour, 2 hours, 5 hours, 9 hours, and 12 hours study timepoints |
| Change in hemoglobin level | Change in hemoglobin level | From baseline to 1 hour and 12 hours study timepoints |
| Change in leukocyte count | Change in leukocyte count | From baseline to 1 hour and 12 hours study timepoints |
| Change in platelets count | Change in platelets count | From baseline to 1 hour and 12 hours study timepoints |
| Change in serum sodium level | Change in serum sodium level | From baseline to 1 hour and 12 hours study timepoints |
| Change in serum potassium level | Change in serum potassium level | From baseline to 1 hour and 12 hours study timepoints |
| Change in CRP level | Change in CRP level | From baseline to 1 hour and 12 hours study timepoints |
| Change in lipid profile | Change in lipid profile | From baseline to 1 hour and 12 hours study timepoints |
| Change in blood alanine transaminase level | Change in blood alanine transaminase (ALT) level | From baseline to 1 hour and 12 hours study timepoints |
| Change in serum creatinine level | Change in serum creatinine level | From baseline to 1 hour and 12 hours study timepoints |
| Background |
| 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. |
| 22561291 | Background | 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. |
| 11198492 | Background | 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. |
| 33776895 | Background | 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. |
| 33101467 | Background | 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. |
| 29163194 | Background | 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. |
| 34510212 | Background | 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. |
| 27475046 | Background | 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. |
| 26336950 | Background | 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. |