Background: In the Netherlands, perinatal asphyxia (severe perinatal oxygen shortage) necessitating newborn\r\nresuscitation occurs in at least 200 of the 180ââ?¬â??185.000 newly born infants per year. International randomized controlled\r\ntrials have demonstrated an improved neurological outcome with therapeutic hypothermia. During hypothermia\r\nneonates receive sedative, analgesic, anti-epileptic and antibiotic drugs. So far little information is available how the\r\npharmacokinetics (PK) and pharmacodynamics (PD) of these drugs are influenced by post resuscitation multi organ\r\nfailure and the metabolic effects of the cooling treatment itself. As a result, evidence based dosing guidelines are\r\nlacking. This multicenter observational cohort study was designed to answer the question how hypothermia influences\r\nthe distribution, metabolism and elimination of commonly used drugs in neonatal intensive care.\r\nMethods/Design: Multicenter cohort study. All term neonates treated with hypothermia for Hypoxic Ischemic\r\nEncephalopathy (HIE) resulting from perinatal asphyxia in all ten Dutch Neonatal Intensive Care Units (NICUs) will be\r\neligible for this study. During hypothermia and rewarming blood samples will be taken from indwelling catheters to\r\ninvestigate blood concentrations of several antibiotics, analgesics, sedatives and anti-epileptic drugs. For each individual\r\ndrug the population PK will be characterized using Nonlinear Mixed Effects Modelling (NONMEM). It will be investigated\r\nhow clearance and volume of distribution are influenced by hypothermia also taking maturation of neonate into\r\naccount. Similarly, integrated PK-PD models will be developed relating the time course of drug concentration to\r\npharmacodynamic parameters such as successful seizure treatment; pain assessment and infection clearance.\r\nDiscussion: On basis of the derived population PK-PD models dosing guidelines will be developed for the application\r\nof drugs during neonatal hypothermia treatment. The results of this study will lead to an evidence based drug\r\ntreatment of hypothermic neonatal patients. Results will be published in a national web based evidence based\r\npaediatric formulary, peer reviewed journals and international paediatric drug references
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