Clinical Pharmacokinetics

, Volume 51, Issue 10, pp 671–679

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

A Thermopharmacological Approach
  • M. P. H. van den Broek
  • F. Groenendaal
  • M. C. Toet
  • H. L. M. van Straaten
  • J. G. C. van Hasselt
  • A. D. R. Huitema
  • L. S. de Vries
  • A. C. G. Egberts
  • C. M. A. Rademaker
Original Research Article


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.


  1. 1.
    Edwards AD, Brocklehurst P, Gunn AJ, et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ. 2010;340:c363.PubMedCrossRefGoogle Scholar
  2. 2.
    Guillet R, Edwards AD, Thoresen M, et al. Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy. Pediatr Res. 2012;71(2):205–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Glass HC, Nash KB, Bonifacio SL, et al. Seizures and magnetic resonance imaging-detected brain injury in newborns cooled for hypoxic-ischemic encephalopathy. J Pediatr. 2011;159(5):731-5.e1.Google Scholar
  4. 4.
    McBride MC, Laroia N, Guillet R. Electrographic seizures in neonates correlate with poor neurodevelopmental outcome. Neurology. 2000;55(4):506–13.PubMedCrossRefGoogle Scholar
  5. 5.
    Miller SP, Weiss J, Barnwell A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology. 2002;58(4):542–8.PubMedCrossRefGoogle Scholar
  6. 6.
    van Rooij LG, Toet MC, van Huffelen AC, et al. Effect of treatment of subclinical neonatal seizures detected with aEEG: randomized, controlled trial. Pediatrics. 2010;125(2):e358–66.PubMedCrossRefGoogle Scholar
  7. 7.
    Hellstrom-Westas L, Rosén I, Svenningsen NW. Predictive value of early continuous amplitude integrated EEG recordings on outcome after severe birth asphyxia in full term infants. Arch Dis Child Fetal Neonatal Ed. 1995;72(1):F34–8.PubMedCrossRefGoogle Scholar
  8. 8.
    ter Horst HJ, Sommer C, Bergman KA, et al. Prognostic significance of amplitude-integrated EEG during the first 72 hours after birth in severely asphyxiated neonates. Pediatr Res. 2004;55(6):1026–33.PubMedCrossRefGoogle Scholar
  9. 9.
    Toet MC, van Rooij LG, de Vries LS. The use of amplitude integrated electroencephalography for assessing neonatal neurologic injury. Clin Perinatol. 2008;35(4):665-78, v.Google Scholar
  10. 10.
    Bassan H, Bental Y, Shany E, et al. Neonatal seizures: dilemmas in workup and management. Pediatr Neurol. 2008;38(6):415–21.PubMedCrossRefGoogle Scholar
  11. 11.
    Blume HK, Garrison MM, Christakis DA. Neonatal seizures: treatment and treatment variability in 31 United States pediatric hospitals. J Child Neurol. 2009;24(2):148–54.PubMedCrossRefGoogle Scholar
  12. 12.
    Clancy RR. Summary proceedings from the neurology group on neonatal seizures. Pediatrics. 2006;117(3 Pt 2):S23–7.PubMedGoogle Scholar
  13. 13.
    Smith MC, Riskin BJ. The clinical use of barbiturates in neurological disorders. Drugs. 1991;42(3):365–78.PubMedCrossRefGoogle Scholar
  14. 14.
    van den Broek MP, Groenendaal F, Egberts AC, et al. Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of preclinical and clinical studies. Clin Pharmacokinet. 2010;49(5):277–94.PubMedCrossRefGoogle Scholar
  15. 15.
    Azzopardi D, Brocklehurst P, Edwards D, et al. The TOBY study: whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial. BMC Pediatr. 2008;8:17.PubMedCrossRefGoogle Scholar
  16. 16.
    Toet MC, van der Meij W, de Vries LS, et al. Comparison between simultaneously recorded amplitude integrated electroencephalogram (cerebral function monitor) and standard electroencephalogram in neonates. Pediatrics. 2002;109(5):772–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Beal SL, Boeckman AJ, Sheiner LB. NONMEM: user’s guides. San Francisco: University of California at San Francisco; 1988–1992.Google Scholar
  18. 18.
    Keizer RJ, van Benten M, Beijnen JH, et al. Piraña and PCluster: a modeling environment and cluster infrastructure for NONMEM. Comput Methods Programs Biomed. 2011;101(1):72–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Comets E, Brendel K, Mentré F. Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: the npde add-on package for R. Comput Methods Programs Biomed. 2008;90(2):154–66.PubMedCrossRefGoogle Scholar
  20. 20.
    Buchthal F, Svensmark O, Simonsen H. Relation of eeg and seizures to phenobarbital in serum. Arch Neurol. 1968;19(6):567–72.PubMedCrossRefGoogle Scholar
  21. 21.
    Gilman JT, Gal P, Duchowny MS, et al. Rapid sequential phenobarbital treatment of neonatal seizures. Pediatrics. 1989;83(5):674–8.PubMedGoogle Scholar
  22. 22.
    Painter MJ, Pippenger C, MacDonald H, et al. Phenobarbital and diphenylhydantoin levels in neonates with seizures. J Pediatr. 1978;92(2):315–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Van Orman CB, Darwish HZ. Efficacy of phenobarbital in neonatal seizures. Can J Neurol Sci. 1985;12(2):95–9.PubMedGoogle Scholar
  24. 24.
    Farwell JR, Lee YJ, Hirtz DG, et al. Phenobarbital for febrile seizures: effects on intelligence and on seizure recurrence. N Engl J Med. 1990;322(6):364–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Gal P, Toback J, Erkan NV, et al. The influence of asphyxia on phenobarbital dosing requirements in neonates. Dev Pharmacol Ther. 1984;7(3):145–52.PubMedGoogle Scholar
  26. 26.
    Filippi L, la Marca G, Cavallaro G, et al. Phenobarbital for neonatal seizures in hypoxic ischemic encephalopathy: a pharmacokinetic study during whole body hypothermia. Epilepsia. 2011;52(4):794–801.PubMedCrossRefGoogle Scholar
  27. 27.
    Hall RT, Hall FK, Daily DK. High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: a randomized, prospective study with three-year follow-up. J Pediatr. 1998;132(2):345–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Barks JD, Liu YQ, Shangguan Y, et al. Phenobarbital augments hypothermic neuroprotection. Pediatr Res. 2010;67(5):532–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Sarkar S, Barks JD, Bapuraj JR, et al. Does phenobarbital improve the effectiveness of therapeutic hypothermia in infants with hypoxic-ischemic encephalopathy? J Perinatol. 2012;32(1):15–20.Google Scholar
  30. 30.
    Hellström-Westas L, Rosén I, de Vries LS, et al. Amplitude-integrated EEG classification and interpretation in preterm and term infants. NeoReviews. 2006;7:76–87.CrossRefGoogle Scholar
  31. 31.
    Singh D, Kumar P, Narang A. A randomized controlled trial of phenobarbital in neonates with hypoxic ischemic encephalopathy. J Matern Fetal Neonatal Med. 2005;18(6):391–5.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2012

Authors and Affiliations

  • M. P. H. van den Broek
    • 1
  • F. Groenendaal
    • 2
  • M. C. Toet
    • 2
  • H. L. M. van Straaten
    • 3
  • J. G. C. van Hasselt
    • 4
  • A. D. R. Huitema
    • 4
  • L. S. de Vries
    • 2
  • A. C. G. Egberts
    • 1
    • 5
  • C. M. A. Rademaker
    • 1
  1. 1.Division of Laboratory Medicine and Pharmacy, Department of Clinical PharmacyUniversity Medical Center UtrechtUtrechtThe Netherlands
  2. 2.Department of NeonatologyWilhelmina Children’s Hospital, University Medical Centre Utrecht (UMCU)Utrechtthe Netherlands
  3. 3.Department of NeonatologyIsala ClinicsZwollethe Netherlands
  4. 4.Department of Pharmacy and Pharmacology, Slotervaart HospitalThe Netherlands Cancer InstituteAmsterdamthe Netherlands
  5. 5.Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtthe Netherlands

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