Topiramate plus Cooling for Hypoxic-Ischemic Encephalopathy: A Randomized, Controlled, Multicenter, Double-Blinded Trial.
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.
['Nuñez-Ramiro|Antonio|A|', 'Benavente-Fernández|Isabel|I|', 'Valverde|Eva|E|', 'Cordeiro|Malaika|M|', 'Blanco|Dorotea|D|', 'Boix|Hector|H|', 'Cabañas|Fernando|F|', 'Chaffanel|Mercedes|M|', 'Fernández-Colomer|Belén|B|', 'Fernández-Lorenzo|Jose Ramón|JR|', 'Kuligowski|Julia|J|', 'Loureiro|Begoña|B|', 'Moral-Pumarega|Maria Teresa|MT|', 'Pavón|Antonio|A|', 'Sánchez-Illana|Angel|A|', 'Tofé|Inés|I|', 'Hervás|David|D|', 'García-Robles|Ana|A|', 'Parra-Llorca|Anna|A|', 'Cernada|Maria|M|', 'Martinez-Rodilla|Juan|J|', 'Lorente-Pozo|Sheila|S|', 'Llorens|Roberto|R|', 'Marqués|Remedios|R|', 'Vento|Máximo|M|', '|||']
D003131:Combined Modality Therapy D004311:Double-Blind Method D005260:Female D006801:Humans D007036:Hypothermia, Induced D020925:Hypoxia-Ischemia, Brain D007231:Infant, Newborn D016015:Logistic Models D008279:Magnetic Resonance Imaging D008297:Male D018696:Neuroprotective Agents D000077236:Topiramate
Hypoxic-ischemic encephalopathy Seizures Anaerobic metabolism Hyperexcitability Oxidative stress biomarkers