In the Netherlands, perinatal asphyxia (severe perinatal oxygen shortage) occurs in at least 200 out of 180–185.000 born infants/year. Term neonates experiencing a severe hypoxic-ischemic insult during birth may develop hypoxic ischemic encephalopathy (HIE) within hours. There is a high risk for long term neurological sequelae such as cerebral palsy, psychomotor retardation, and visual or auditory handicaps leading to long-term healthcare costs [1
Cerebral hypoxia and ischemia result in several adverse biochemical events such as increased levels of excitatory neurotransmitters, excessive free radical production, an increase in intracellular calcium, and secretion of inflammatory mediators and messengers by microglial cells in the central nervous system initiating neuronal cell death [3
Supportive treatment in the Neonatal Intensive Care Unit (NICU) comprises mechanical ventilation, cardiovascular support, and treatment of infections and seizures [6
Animal research on controlled hypothermia following perinatal asphyxia showed a reduction in cerebral free radical and inflammatory damage [4
]. Recent large randomized controlled trials and Meta analyses concerning the neuroprotective effects of hypothermia treatment in human asphyxiated neonates demonstrated a statistically significant and clinically important improvement of long term outcome [6
]. Since 2008, all ten NICUs in the Netherlands have adopted controlled hypothermia as the standard of care for newborns suffering perinatal asphyxia.
Unfortunately, the potential benefits of therapeutic hypothermia could potentially be offset by decreased responsiveness to drug therapy and the occurrence of side effects due to the altered pharmacokinetics (PK) and pharmacodynamics (PD) during hypothermia [14
]. Frequently used life-saving drugs in these newborns are sedatives, analgesics, antibiotics, and antiepileptic drugs (AED) and toxic side effects of these agents (e.g. cardiac arrhythmias from lidocaine; prolonged sedative effects from midazolam or morphine; nephrotoxicity –or ototoxicity for aminoglycosides) must be prevented.
There is evidence that the application of mild to moderate hypothermia decreases the systemic clearance of drugs metabolized by cytochrome P450 enzymes between approximately 7% and 22% per degree Celsius below 37°C [16
The effects of hypothermia on drug metabolism have been investigated in humans but few studies concern drug metabolism in asphyxiated newborns. Sedatives and AEDs are important drugs used in the care of asphyxiated newborns. A decreased elimination rate constant (Ke) and clearance (CL) of midazolam was demonstrated during hypothermia in adult volunteers [17
] but data on cooled neonatal patients are unknown. Recent findings suggest that phenytoin metabolism is inhibited by mild therapeutic hypothermia [18
]. The administration of phenobarbital to newborns under whole body hypothermia has been reported to result in higher plasma concentrations when compared to normothermic newborns [19
]. In non-cooled newborns an optimal lidocaine dosage schedule has been established [20
], but the PK during cooling are unknown.
Analgesia is of major importance in neonatal intensive care as inadequate analgesia causes stress, counterproductive to the neuroprotective actions of hypothermia. On the other hand, toxic analgesic levels may cause prolonged sedative effects interfering with clinical neurological evaluations. Experimental studies demonstrated a 25% increase in plasma concentration of fentanyl at core body temperatures of 32°C [21
]. Furthermore, Róka described elevated serum morphine concentrations and potentially toxic morphine levels in newborns with commonly used infusion rates of 10 μg/kg/hour during hypothermia [22
Almost all newborns undergoing hypothermia treatment receive multiple antibiotic courses. The PK/PD properties of aminogycoside and glycopeptide antibiotics in these patients are largely unknown. The toxicity risks of gentamicin (nephro- and ototoxicity) in hypothermic newborns have only been evaluated in one study by Thorensen and colleagues [23
]. A study in three adult cases concluded that induced hypothermia may result in impaired excretion of aminoglycosides [24
]. The pharmacokinetics of penicillin and beta-lactam during hypothermia have not been studied yet.
Interestingly, other drugs do not seem to be influenced by cooling. A recent report concerning infants treated with the AED topiramate, a drug not licensed for use in neonates in the Netherlands at present, in a dose of 5 mg/kg/day, demonstrated drug concentrations within the reference range for the entire cooling treatment duration [25
Altered pharmacokinetics during hypothermia may result in sub therapeutic as well as toxic drug concentrations Since many asphyxiated newborns will be exposed to controlled hypothermia evidence based guidelines for drug dosing (including loading and maintenance dose and dose interval) and therapeutic drug monitoring are urgently needed. The consequences of possible serious side effects or sub therapeutic dosing may have an unknown impact on survival or long term outcome of these infants.
In this Dutch multicenter study it will be investigated how controlled hypothermia influences the PK and PD time profiles of four major drug classes (i.e. analgesics, sedatives; antibiotic and antiepileptic drugs) used in the intensive care treatment of infants suffering perinatal asphyxia. Funding for this study has been received by the Dutch Government (ZonMw Grant number: 40-41500-98-9002).