KD Treatment for Super-refractory Status Epilepticus

Официальное название

Ketogenic Diet Treatment for Super-refractory Status Epilepticus: a Multicenter, Prospective, Randomized, Controlled Trial

Обзор

The purpose of the study is to investigate to evaluate the efficacy and safety of ketogenic diet (KD) as an adjunctive therapy in patients with Super Refractory Status Epilepticus (SRSE) in the intensive care unit (ICU).

Подробное описание

This is a multicenter, prospective, randomized, controlled, open-label clinical study to evaluate the efficacy and safety of ketogenic diet (KD) as an adjunctive therapy in patients with Super Refractory Status Epilepticus (SRSE).

The study plans to enroll eligible SRSE patients. Participants will be randomly assigned in a 1:1 ratio to one of two groups:

1. Control Group: Receives standard medical therapy according to current guideline recommendations for SRSE management. 2. Intervention Group: Receives standard medical therapy plus a ketogenic diet intervention.

The KD intervention will be administered via a nasogastric tube using a ketogenic formula. The nutritional goal is 25-30 kcal/kg, initiated at half-strength and advanced to the full caloric target within 72 hours. If no clinical improvement is observed within 2 weeks of initiating the KD, it will be discontinued. For responders, continuation is recommended. All patients in the KD group will receive concomitant daily nutritional supplements.

The primary outcome measure is the efficacy of controlling SRSE within 2 weeks after randomization. Efficacy is defined as the cessation of both clinical and electrographic status epilepticus, as confirmed by continuous EEG monitoring.

Key secondary outcomes include:

* Safety evaluation, including all KD-related adverse events and in-hospital mortality. * Feasibility of KD (time to achieve ketosis, defined as blood beta-hydroxybutyrate level ≥1.2 mmol/L or urine ketones 1+). * Neurological and functional outcomes assessed by the modified Rankin Scale (mRS), Glasgow Outcome Scale-Extended (GOS-E), and quality of life (QOLIE-31) at discharge, 3 months, and 6 months. * Cognitive function (MMSE, MoCA) at 3 and 6 months. Statistical analysis will be performed on both the Full Analysis Set (FAS) and the Per-Protocol Set (PPS).

Вмешательства

• Другое the ketogenic diet
  First, ketogenic formulation was initiated continuously via naso-enteric tube at 50% of goal and increase to goal (25-30 kcal/kg/day) within 72h. The KD regimen was continued according to seizure control and tolerance before discharge. If the patient was receiving oral nutrition, the modified MAD-KD regimen (carbohydrate 10-20 g/d) was initiated. In addition, if weaning off the diet after discharge, the reduction was 0.5:1 per week.
• Препарат Standard Medical Therapy
  Standard Medical Therapy include continuous intravenous infusion of an anesthetic agent, such as midazolam (starting regimen: 0.2 mg/kg IV bolus followed by continuous infusion of 0.1-0.6 mg/kg/h), titrated to seizure termination

Первичные конечные точки

• Time to cessation of SRSE [Срок оценки: 2 weeks]

Критерии участия

Критерии включения

• Patients diagnosed with super-refractory status epilepticus (SRSE), in whom status epilepticus (SE) persists or recurs after the initial treatment for SE-including intravenous benzodiazepines, an anti-seizure medication (ASM, such as valproate, levetiracetam, or phenobarbital), and an anesthetic (e.g., propofol) administered continuously for 24 hours-fails to terminate the episode, or when SE recurs upon reduction of the anesthetic.
• Age between 14 and 80 years, regardless of gender.
• The patient's legal guardian has provided signed informed consent.

Критерии исключения

• Patients with lipid metabolism disorders, including defects in fatty acid transport and beta-oxidation, such as carnitine deficiency (primary) and carnitine-related enzyme deficiencies (including carnitine palmitoyltransferase \[CPT\] I and II deficiency, carnitine translocase deficiency), fatty acid oxidation disorders (including beta-oxidation defects), short-chain acyl-CoA dehydrogenase deficiency (SCAD), medium-chain acyl-CoA dehydrogenase deficiency (MCAD), long-chain acyl-CoA dehydrogenase deficiency (LCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, medium-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, pyruvate carboxylase deficiency, and porphyria.
• Intolerance to enteral feeding (e.g., intestinal obstruction).
• Receipt of propofol infusion within 24 hours.
• Hemodynamic instability (systolic blood pressure <90 mmHg or diastolic blood pressure <60 mmHg, requiring high-dose vasopressors for maintenance).
• Liver failure (aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], blood ammonia >5 times the upper limit of normal; total bilirubin >10 mg/dL \[171 μmol/L\]).
• Pancreatitis.
• Pregnancy.
• Metabolic instability (blood glucose <3.1 mmol/L, arterial blood pH <7.2, serum sodium <120 or >160 mmol/L).
• Septic shock.
• Complicated by diabetes insipidus.
• Status epilepticus caused by hypoxic-ischemic brain injury.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 14 центров

• The First Affiliated Hospital of Anhui Medical University — Хэфэй
• Department of Neurology, Xuanwu Hospital Capital Medical University — Пекин
• Fujian Medical University Union Hospital — Фучжоу
• The First Affiliated Hospital of Guangxi Medical University — Nanning
• Guizhou Provincial People's Hospital — Guiyang
• The Second Affiliated Hospital of Hainan Medical University — Haikou
• The First Hospital of Hebei Medical University — Shijiazhuang
• The First Affiliated Hospital of Harbin Medical University — Харбин
• … и ещё 6 центров

Публикации

• Singh RK, Joshi SM, Potter DM, Leber SM, Carlson MD, Shellhaas RA. Cognitive outcomes in febrile infection-related epilepsy syndrome treated with the ketogenic diet. Pediatrics. 2014 Nov;134(5):e1431-5. doi: 10.1542/peds.2013-3106. PMID 25332495
• Li Y, Yang X, Zhang J, Jiang T, Zhang Z, Wang Z, Gong M, Zhao L, Zhang C. Ketogenic Diets Induced Glucose Intolerance and Lipid Accumulation in Mice with Alterations in Gut Microbiota and Metabolites. mBio. 2021 Mar 30;12(2):e03601-20. doi: 10.1128/mBio.03601-20. PMID 33785628
• Nabbout R, Mazzuca M, Hubert P, Peudennier S, Allaire C, Flurin V, Aberastury M, Silva W, Dulac O. Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia. 2010 Oct;51(10):2033-7. doi: 10.1111/j.1528-1167.2010.02703.x. Epub 2010 Aug 31. PMID 20813015
• Wusthoff CJ, Kranick SM, Morley JF, Christina Bergqvist AG. The ketogenic diet in treatment of two adults with prolonged nonconvulsive status epilepticus. Epilepsia. 2010 Jun;51(6):1083-5. doi: 10.1111/j.1528-1167.2009.02388.x. Epub 2009 Oct 20. PMID 19845731
• Mahmoud SH, Ho-Huang E, Buhler J. Systematic review of ketogenic diet use in adult patients with status epilepticus. Epilepsia Open. 2019 Nov 24;5(1):10-21. doi: 10.1002/epi4.12370. eCollection 2020 Mar. PMID 32140640
• Yudkoff M, Daikhin Y, Horyn O, Nissim I, Nissim I. Ketosis and brain handling of glutamate, glutamine, and GABA. Epilepsia. 2008 Nov;49 Suppl 8(Suppl 8):73-5. doi: 10.1111/j.1528-1167.2008.01841.x. PMID 19049594
• Lowe H, Keller AE, Tanzini E, Aimola S, Liu YMC, Zak M, Chan V, Kobayashi J, Donner EJ. Ketonuria and Seizure Control in the Medium Chain Triglyceride and Classic Ketogenic Diets. Can J Neurol Sci. 2022 May;49(3):433-436. doi: 10.1017/cjn.2021.122. Epub 2021 Jun 2. PMID 34075859
• Kaul N, Nation J, Laing J, Nicolo JP, Deane AM, Udy AA, Kwan P, O'Brien TJ. Modified low ratio ketogenic therapy in the treatment of adults with super-refractory status epilepticus. JPEN J Parenter Enteral Nutr. 2022 Nov;46(8):1819-1827. doi: 10.1002/jpen.2373. Epub 2022 Apr 7. PMID 35285036

Идентификаторы

NCT: NCT07496749 · KS2025230-001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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