title: Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia: a thermopharmacological approach.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Laboratory Medicine and Pharmacy, Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: M P H
authors.initials: MP
authors.lastname: van den Broek
authors.forename: F
authors.initials: F
authors.lastname: Groenendaal
authors.forename: M C
authors.initials: MC
authors.lastname: Toet
authors.forename: H L M
authors.initials: HL
authors.lastname: van Straaten
authors.forename: J G C
authors.initials: JG
authors.lastname: van Hasselt
authors.forename: A D R
authors.initials: AD
authors.lastname: Huitema
authors.forename: L S
authors.initials: LS
authors.lastname: de Vries
authors.forename: A C G
authors.initials: AC
authors.lastname: Egberts
authors.forename: C M A
authors.initials: CM
authors.lastname: Rademaker
mesh_terms: D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D001238:Asphyxia Neonatorum / Q000097:blood* / Q000150:complications / Q000628:therapy; D004334:Drug Administration Schedule; D004569:Electroencephalography; D016231:Fluorescence Polarization Immunoassay; D006801:Humans; D007036:Hypothermia, Induced; D002534:Hypoxia, Brain / Q000097:blood* / Q000150:complications / Q000628:therapy; D007231:Infant, Newborn; D007275:Injections, Intravenous; D007363:Intensive Care Units, Neonatal; D015931:Intensive Care, Neonatal; D008390:Markov Chains; D008954:Models, Biological; D009426:Netherlands; D010634:Phenobarbital / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D011446:Prospective Studies; D012640:Seizures / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D010634:Phenobarbital