Disposition of Midazolam in Asphyxiated Neonates Receiving Therapeutic Hypothermia – A Pilot Study

Abstract

Background:

Moderate hypothermia has become an established therapy for asphyxiated neonates. Midazolam is a frequently used sedative for this indication, although it has never been investigated how therapeutic hypothermia and asphyxia influence midazolam metabolism in neonates.

Patients and Methods:

9 asphyxiated newborns were treated with whole body hypothermia of 32–34°C for 72 h and all of them received continuous midazolam infusion for sedation. Serum concentrations of midazolam and its metabolites 1-hydroxy-midazolam and 4-hydroxy-midazolam were measured during hypothermia and the rewarming period. Renal and hepatic parameters were assessed to take into account the influence of asphyxia related renal or hepatic impairment.

Results:

We found a high interindividual variability of serum midazolam concentrations in asphyxiated neonates with therapeutic hypothermia; median midazolam concentration was 369.3 ng/ml (minimum 36.6; maximum 3 218.6 ng/ml). The population pharmacokinetic model revealed a midazolam clearance of 2.57 ml/kg/min, comparable to midazolam clearances observed in normothermic critically ill neonates. However, midazolam clearance was significantly decreased in patients with asphyxia related renal and hepatic impairment.

Conclusion:

It seems that isolated hypothermia does not significantly influence midazolam metabolism. However, neonates with asphyxia related hepatic and renal impairment are at risk of generating unexpectedly high serum midazolam concentrations. In addition pronounced interindividual variability of midazolam metabolism may contribute to dangerously high midazolam concentrations.

Zusammenfassung

Einleitung:

Die moderate Hypothermie ist in den letzten Jahren bei asphyktischen Neugeborenen zu einer etablierten Therapie geworden. Zur Sedierung wird den Kindern dabei häufig Midazolam verabreicht, obwohl es keine Daten darüber gibt, wie sich Hypothermie und Asphyxie bei Neugeborenen auf die Metabolisierung von Midazolam auswirken.

Patienten und Methode:

9 asphyktische Neugeborene wurden über 72 Stunden mit einer therapeutischen Hypothermie von 32–34°C und einer Midazolam-Dauerinfusion therapiert. ­Sowohl in der Hypothermie- als auch in der Aufwärmphase erfolgten regelmäßige Messungen der Serumkonzentration von Midazolam und seinen Metaboliten 1-Hydroxy-Midazolam und 4-Hydroxy-Midazolam. Zur Erfassung Asphyxie-bedingter Leber- und Nierenschädigungen wurden zusätzlich Leber- und Nierenparameter ­bestimmt.

Ergebnisse:

Die Midazolam-Serumkonzentrationen wiesen bei den gekühlten, asphyktischen Neugeborenen eine große interindividuelle Streubreite auf; die mittlere Midazolam-Konzentration betrug 369,3 ng/ml (Minimum 36,6; Maximum 3 218,6 ng/ml). Das Populationskinetische Modell ergab, ähnlich wie bei normothermen kranken Neugeborenen, eine Clearance von 2,57 ml/kg/min. Bei den Neugeborenen mit Asphyxie-bedingter Leber- und Nierenschädigung hingegen war die Clearance signifikant erniedrigt.

Schlussfolgerungen:

Die isolierte therapeutische Hypothermie scheint bei Neugeborenen zu keinen signifikanten Veränderungen im Metabolismus von Midazolam zu führen. Bei Neugeborenen mit Asphyxie-bedingter Leber- und Nierenschädigung hingegen können unerwartet hohe Midazolam-Konzentrationen auftreten.

Key words

neonate - asphyxia - midazolam - therapeutic hypothermia - population ­pharmacokinetics

Schlüsselwörter

Neugeborene - Asphyxie - Midazolam - therapeutische ­Hypothermie - Populationskinetik

^* L. Welzing and S. Junghaenel both serve as first author as they contributed equally to this work.

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