1. Topiramate plus Cooling for Hypoxic-Ischemic Encephalopathy: A Randomized, Controlled, Multicenter, Double-Blinded Trial
- Author
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Isabel Benavente-Fernández, Héctor Boix, Sheila Lorente-Pozo, Inés Tofé, Juan Martínez-Rodilla, David Hervás, Maria Teresa Moral-Pumarega, Fernando Cabañas, Remedios Marqués, Máximo Vento, Dorotea Blanco, Belén Fernández-Colomer, Ana García-Robles, Begoña Loureiro, Ángel Sánchez-Illana, José Ramón Fernández-Lorenzo, Antonio Núñez-Ramiro, Anna Parra-Llorca, Eva Valverde, Antonio Pavón, Mercedes Chaffanel, Roberto Llorens, Malaika Cordeiro, María Cernada, and Julia Kuligowski
- Subjects
Male ,Topiramate ,Encephalopathy ,Brain damage ,Placebo ,Hypoxic Ischemic Encephalopathy ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Pharmacokinetics ,Hypothermia, Induced ,030225 pediatrics ,Multicenter trial ,medicine ,Humans ,030212 general & internal medicine ,Dosing ,business.industry ,Infant, Newborn ,medicine.disease ,Combined Modality Therapy ,Magnetic Resonance Imaging ,Logistic Models ,Neuroprotective Agents ,Anesthesia ,Hypoxia-Ischemia, Brain ,Pediatrics, Perinatology and Child Health ,Female ,medicine.symptom ,business ,Developmental Biology ,medicine.drug - Abstract
Background and Objectives: Therapeutic interventions to improve the efficacy of whole-body cooling for hypoxic-ischemic encephalopathy (HIE) are desirable. Topiramate has been effective in reducing brain damage in experimental studies. However, in the clinical setting information is limited to a small number of feasibility trials. We launched a randomized controlled double-blinded topiramate/placebo multicenter trial with the primary objective being to reduce the antiepileptic activity in cooled neonates with HIE and assess if brain damage would be reduced as a consequence. Study Design: Neonates were randomly assigned to topiramate or placebo at the initiation of hypothermia. Topiramate was administered via a nasogastric tube. Brain electric activity was continuously monitored. Topiramate pharmacokinetics, energy-related and Krebs’ cycle intermediates, and lipid peroxidation biomarkers were determined using liquid chromatography-mass spectrometry and MRI for assessing brain damage. Results: Out of 180 eligible patients 110 were randomized, 57 (51.8%) to topiramate and 53 (48.2%) to placebo. No differences in the perinatal or postnatal variables were found. The topiramate group exhibited less seizure burden in the first 24 h of hypothermia (topiramate, n = 14 [25.9%] vs. placebo, n = 22 [42%]); needed less additional medication, and had lower mortality (topiramate, n = 5 [9.2%] vs. placebo, n = 10 [19.2%]); however, these results did not achieve statistical significance. Topiramate achieved a therapeutic range in 37.5 and 75.5% of the patients at 24 and 48 h, respectively. A significant association between serum topiramate levels and seizure activity (p < 0.016) was established. No differences for oxidative stress, energy-related metabolites, or MRI were found. Conclusions: Topiramate reduced seizures in patients achieving therapeutic levels in the first hours after treatment initiation; however, they represented only a part of the study population. Our results warrant further studies with higher loading and maintenance dosing of topiramate.
- Published
- 2019
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