Open Access Study protocol

Pharmacokinetics and pharmacodynamics of medication in asphyxiated newborns during controlled hypothermia. The PharmaCool multicenter study

Timo R de Haan115*, Yuma A Bijleveld12, Johanna H van der Lee2, Floris Groenendaal3, Marcel PH van den Broek14, Carin MA Rademaker14, Henrica LM van Straaten9, Mirjam M van Weissenbruch11, Jeroen R Vermeulen13, Peter H Dijk4, Jeroen Dudink7, Monique Rijken10, Arno van Heijst5, Koen P Dijkman8, Danilo Gavilanes6, Anton H van Kaam1, Martin Offringa12 and Ron AA Mathôt12

Author Affiliations

1 Department of Neonatology, Emma Children’s Hospital, Academic Medical Center, Amsterdam, The Netherlands

2 Department of Paediatric Clinical Epidemiology, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

3 Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands

4 Department of Neonatology, University Medical Center Groningen, Groningen, The Netherlands

5 Department of Neonatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

6 Department of Neonatology, Maastricht University Medical Center, Maastricht, The Netherlands

7 Department of Neonatology and Radiology, Erasmus MC-Sophia, Rotterdam, The Netherlands

8 Department of Neonatology, Maxima Medical Center Veldhoven, Veldhoven, The Netherlands

9 Department of Neonatology, Isala Clinics, Zwolle, the Netherlands

10 Department of Neonatology, Leiden University Medical Center, Leiden, the Netherlands

11 Department of Neonatology, VU University Medical Center, Amsterdam, The Netherlands

12 Department of Hospital Pharmacy, Clinical Pharmacology Unit, Academic Medical Center, Amsterdam, The Netherlands

13 Department of Pediatric Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands

14 Department of Clinical Pharmacy, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands

15 Academic Medical Center, Meibergdreef 9, 1100 DD, Amsterdam, the Netherlands

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BMC Pediatrics 2012, 12:45  doi:10.1186/1471-2431-12-45

Published: 19 April 2012

Abstract

Background

In the Netherlands, perinatal asphyxia (severe perinatal oxygen shortage) necessitating newborn resuscitation occurs in at least 200 of the 180–185.000 newly born infants per year. International randomized controlled trials have demonstrated an improved neurological outcome with therapeutic hypothermia. During hypothermia neonates receive sedative, analgesic, anti-epileptic and antibiotic drugs. So far little information is available how the pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs are influenced by post resuscitation multi organ failure and the metabolic effects of the cooling treatment itself. As a result, evidence based dosing guidelines are lacking. This multicenter observational cohort study was designed to answer the question how hypothermia influences the distribution, metabolism and elimination of commonly used drugs in neonatal intensive care.

Methods/Design

Multicenter cohort study. All term neonates treated with hypothermia for Hypoxic Ischemic Encephalopathy (HIE) resulting from perinatal asphyxia in all ten Dutch Neonatal Intensive Care Units (NICUs) will be eligible for this study. During hypothermia and rewarming blood samples will be taken from indwelling catheters to investigate blood concentrations of several antibiotics, analgesics, sedatives and anti-epileptic drugs. For each individual drug the population PK will be characterized using Nonlinear Mixed Effects Modelling (NONMEM). It will be investigated how clearance and volume of distribution are influenced by hypothermia also taking maturation of neonate into account. Similarly, integrated PK-PD models will be developed relating the time course of drug concentration to pharmacodynamic parameters such as successful seizure treatment; pain assessment and infection clearance.

Discussion

On basis of the derived population PK-PD models dosing guidelines will be developed for the application of drugs during neonatal hypothermia treatment. The results of this study will lead to an evidence based drug treatment of hypothermic neonatal patients. Results will be published in a national web based evidence based paediatric formulary, peer reviewed journals and international paediatric drug references.

Trial registration

NTR2529.

Keywords:
Perinatal asphyxia, Therapeutic hypothermia; Pharmacokinetic research; Drug monitoring; Evidence based; Drug dosing; Guideline