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Pharmacokinetic-pharmacodynamic study reveals low anticonvulsant efficacy and frequent hypotension from midazolam in hypothermic neonates, suggesting it is unsuitable as second-line therapy.
BACKGROUND: Midazolam is used as an anticonvulsant in neonatology, including newborns with perinatal asphyxia treated with hypothermia. Hypothermia may affect the safety and effectiveness of midazolam in these patients. OBJECTIVES: The objective was to evaluate the anticonvulsant effectiveness and hemodynamic safety of midazolam in hypothermic newborns and to provide dosing guidance. METHODS: Hypothermic newborns with perinatal asphyxia and treated with midazolam were included. Effectiveness was studied using continuous amplitude-integrated electroencephalography. Hemodynamic safety was assessed using pharmacokinetic-pharmacodynamic modeling with plasma samples and blood pressure recordings (mean arterial blood pressure) under hypothermia. RESULTS: No effect of therapeutic hypothermia on pharmacokinetics could be identified. Add-on seizure control with midazolam was limited (23% seizure control). An inverse relationship between the midazolam plasma concentration and mean arterial blood pressure could be identified. At least one hypotensive episode was experienced in 64%. The concomitant use of inotropes decreased midazolam clearance by 33%. CONCLUSIONS: Under therapeutic hypothermia, midazolam has limited add-on clinical anticonvulsant effectiveness after phenobarbital administration. Due to occurrence of hypotension requiring inotropic support, midazolam is less suitable as a second-line anticonvulsant drug under hypothermia.
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Broek et al. (2015) studied this question.
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