Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI)

Luca Filippi,Giancarlo La Marca,Claudio Fonda,Giovanni Cioni,Paola Papoff,Renzo Guerrini,Maria Luisa Della Bona,Tiziana Pisano,Sabrina Malvagia,Gianpaolo Donzelli,Melania Falchi,Patrizio Fiorini,Francesca Del Balzo,Alberto Spalice,Matteo Giampietri,Serena Catarzi,Francesca Tinelli,Antonio Boldrini,Marta Daniotti,Laura Bartalena,Rosa Teresa Scaramuzzo ,Sara Savelli

doi:10.1186/1471-2431-12-144

Abstract

BackgroundDespite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements. In countries with a high level of perinatal care, the incidence of asphyxia responsible for moderate or severe encephalopathy is still 2–3 per 1000 term newborns. Recent trials have demonstrated that moderate hypothermia, started within 6 hours after birth and protracted for 72 hours, can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy. It is not currently known whether neuroprotective drugs can further improve the beneficial effects of hypothermia. Topiramate has been proven to reduce brain injury in animal models of neonatal hypoxic ischemic encephalopathy. However, the association of mild hypothermia and topiramate treatment has never been studied in human newborns. The objective of this research project is to evaluate, through a multicenter randomized controlled trial, whether the efficacy of moderate hypothermia can be increased by concomitant topiramate treatment.Methods/DesignTerm newborns (gestational age ≥ 36 weeks and birth weight ≥ 1800 g) with precocious metabolic, clinical and electroencephalographic (EEG) signs of hypoxic-ischemic encephalopathy will be randomized, according to their EEG pattern, to receive topiramate added to standard treatment with moderate hypothermia or standard treatment alone. Topiramate will be administered at 10 mg/kg once a day for the first 3 days of life. Topiramate concentrations will be measured on serial dried blood spots. 64 participants will be recruited in the study. To evaluate the safety of topiramate administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of topiramate, the neurologic outcome of enrolled newborns will be evaluated by serial neurologic and neuroradiologic examinations. Visual function will be evaluated by means of behavioural standardized tests.DiscussionThis pilot study will explore the possible therapeutic role of topiramate in combination with moderate hypothermia. Any favourable results of this research might open new perspectives about the reduction of cerebral damage in asphyxiated newborns.Trial registrationCurrent Controlled Trials ISRCTN62175998; ClinicalTrials.gov Identifier NCT01241019; EudraCT Number 2010-018627-25

Highlights

Despite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements
We found no signs of metabolic acidosis in newborns co-treated with moderate hypothermia and TPM; abdomen ultrasound scanning did not show kidney stones and ophthalmological evaluation was normal in all treated newborns [104]
Study population-setting Term newborns delivered at gestational age higher than 36 weeks and with birth weight higher than 1800 g admitted for Hypoxic ischemic encephalopathy (HIE) to the Neonatal Intensive Care Units (NICUs) of A

Summary

Introduction

Despite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements. Recent trials have demonstrated that moderate hypothermia, started within 6 hours after birth and protracted for 72 hours, can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy. After a few hours, cerebral energy metabolism recovers, but a cascading series of biochemical events triggers neuronal apoptosis and leads to severe brain damage. These events include an increased release of excitatory neurotransmitters, especially glutamate [5]. High glutamate concentrations can over-excite nervous cells and lead to their death (excito-toxicity) [7] This excitotoxicity contributes to neuronal damage in various neurodegenerative disorders

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