Topiramate plus Cooling for Hypoxic-Ischemic Encephalopathy: A Randomized, Controlled, Multicenter, Double-Blinded Trial

• Published in: Neonatology (Basel, Switzerland) Vol. 116; no. 1; p. 76
• Main Authors: Nuñez-Ramiro, Antonio, Benavente-Fernández, Isabel, Valverde, Eva, Cordeiro, Malaika, Blanco, Dorotea, Boix, Hector, Cabañas, Fernando, Chaffanel, Mercedes, Fernández-Colomer, Belén, Fernández-Lorenzo, Jose Ramón, Kuligowski, Julia, Loureiro, Begoña, Moral-Pumarega, Maria Teresa, Pavón, Antonio, Sánchez-Illana, Angel, Tofé, Inés, Hervás, David, García-Robles, Ana, Parra-Llorca, Anna, Cernada, Maria, Martinez-Rodilla, Juan, Lorente-Pozo, Sheila, Llorens, Roberto, Marqués, Remedios, Vento, Máximo
• Format: Journal Article
• Language: English
• Published: Switzerland 01.07.2019
• Subjects: Combined Modality Therapy; Double-Blind Method; Female; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain - diagnostic imaging; Hypoxia-Ischemia, Brain - therapy; Infant, Newborn; Logistic Models; Magnetic Resonance Imaging; Male; Neuroprotective Agents - adverse effects; Neuroprotective Agents - therapeutic use; Topiramate - adverse effects; Topiramate - therapeutic use; Anaerobic metabolism; Hypoxic-ischemic encephalopathy; Oxidative stress biomarkers; Hyperexcitability; Seizures
• ISSN: 1661-7819
• DOI: 10.1159/000499084

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. 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. 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. 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.