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Pharmacokinetics and Clinical Efficacy of Phenobarbital in Asphyxiated Newborns Treated with Hypothermia

A Thermopharmacological Approach

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Abstract

Background and Objectives

Therapeutic hypothermia can influence the pharmacokinetics and pharmacodynamics of drugs, the discipline which is called thermopharmacology. We studied the effect of therapeutic hypothermia on the pharmacokinetics of phenobarbital in asphyxiated neonates, and the clinical efficacy and the effect of phenobarbital on the continuous amplitude-integrated electroencephalography (aEEG) in a prospective study.

Patients and Methods

Data were obtained from the prospective SHIVER study, performed in two of the ten Dutch level III neonatal intensive care units. Phenobarbital data were collected between 2008 and 2010. Newborns were eligible for inclusion if they had a gestational age of at least 36 weeks and presented with perinatal asphyxia and encephalopathy. According to protocol in both hospitals an intravenous (repeated) loading dose of phenobarbital 20 mg/kg divided in 1–2 doses was administered if seizures occurred or were suspected before or during the hypothermic phase. Phenobarbital plasma concentrations were measured in plasma using a fluorescence polarization immunoassay. aEEG was monitored continuously.

Results and Conclusion

A one-compartmental population pharmacokinetic/pharmacodynamic model was developed using a multi-level Markov transition model. No (clinically relevant) effect of moderate therapeutic hypothermia on phenobarbital pharmacokinetics could be identified. The observed responsiveness was 66 %. While we still advise an initial loading dose of 20 mg/kg, clinicians should not be reluctant to administer an additional dose of 10–20 mg/kg. An additional dose should be given before switching to a second-line anticonvulsant drug. Based on our pharmacokinetic/pharmacodynamic model, administration of phenobarbital under hypothermia seems to reduce the transition rate from a continuous normal voltage (CNV) to discontinuous normal voltage aEEG background level in hypothermic asphyxiated newborns, which may be attributed to the additional neuroprotection of phenobarbital in infants with a CNV pattern.

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Acknowledgments

The authors thank the doctors and nurses of the neonatal intensive care units at the Wilhelmina Children’s Hospital/University Medical Centre Utrecht (Utrecht, the Netherlands) and the Isala Clinics (Zwolle, the Netherlands) for their enthusiastic collaboration, and the parents of the patients for their cooperation in difficult times. No sources of funding were used to conduct this study or prepare this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this study.

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Authors and Affiliations

  1. Division of Laboratory Medicine and Pharmacy, Department of Clinical Pharmacy, University Medical Center Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands

    M. P. H. van den Broek, A. C. G. Egberts & C. M. A. Rademaker

  2. Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht (UMCU), Utrecht, the Netherlands

    F. Groenendaal, M. C. Toet & L. S. de Vries

  3. Department of Neonatology, Isala Clinics, Zwolle, the Netherlands

    H. L. M. van Straaten

  4. Department of Pharmacy and Pharmacology, Slotervaart Hospital, The Netherlands Cancer Institute, Amsterdam, the Netherlands

    J. G. C. van Hasselt & A. D. R. Huitema

  5. Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands

    A. C. G. Egberts

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  1. M. P. H. van den Broek
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  2. F. Groenendaal
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  3. M. C. Toet
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  4. H. L. M. van Straaten
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  5. J. G. C. van Hasselt
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  6. A. D. R. Huitema
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  7. L. S. de Vries
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  8. A. C. G. Egberts
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  9. C. M. A. Rademaker
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van den Broek, M.P.H., Groenendaal, F., Toet, M.C. et al. Pharmacokinetics and Clinical Efficacy of Phenobarbital in Asphyxiated Newborns Treated with Hypothermia. Clin Pharmacokinet 51, 671–679 (2012). https://doi.org/10.1007/s40262-012-0004-y

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  • DOI: https://doi.org/10.1007/s40262-012-0004-y

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