Pharmacokinetics of melatonin as a neuroprotectant In preterm infants

Background and purpose: Advances in perinatal care have increased survival rates of infants but long-term neurodisability and social consequences have remained unchanged over the last decade. Preterm infants are deprived of the normal intrauterine exposure to maternal melatonin and experimental studies suggest that melatonin has a neuroprotective effect on cerebral white matter injury. However, pharmacokinetic data on melatonin in preterm infants are lacking, which hinders potential therapeutic trials. The aims of this study were to determine the pharmacokinetics of melatonin in the relevant preterm population, assess the tolerability of melatonin and determine a dose regime that would allow replication of adult melatonin levels. Methods: In a multi-centre, single dose escalation/de-escalation, open label study in preterm infants less than 31 weeks gestation, melatonin was administered to eighteen infants in doses ranging from 0.04-0.6 micrograms/kilograms, over 0.5-6 hours. Pharmacokinetic profiles were analysed individually and by population methods. Results: Baseline melatonin was largely undetectable. At the highest and lowest doses half-life could not be calculated due to blood concentrations not reaching a consistent steady state, but infants receiving melatonin at 0.1 micrograms/kilogram/hour for 2 hours showed a median half-life of 15.82 hours and median maximum plasma concentration of 203.3 picograms/millilitre. Population pharmacokinetic analysis showed that clearance was 0.045 litre/hour, volume of distribution 1.098 litres and elimination half-life 16.91 hours with gender (p=0.047) and race (p<0.0001) as significant covariates. Melatonin infusion appeared to be well tolerated in preterm infants. Conclusions: The pharmacokinetic profile of melatonin in preterm infants differs from that of adults. Slow clearance makes replication of adult and thus fetal concentrations of melatonin problematic. Further studies are needed to confirm these findings.Open acces

Quantitative Analysis of Ultrasound Images of the Preterm Brain

In this PhD new algorithms are proposed to better understand and diagnose white matter damage in the preterm Brain. Since Ultrasound imaging is the most suited modality for the inspection of brain pathologies in very low birth weight infants we propose multiple techniques to assist in what is called Computer-Aided Diagnosis. As a main result we are able to increase the qualitative diagnosis from a 70% detectability to a 98% quantitative detectability

STDMn+p0: a multidimensional patient oriented data mining framework for critical care research

In the neonatal intensive care unit (NICU) environment, critical care and treatment directly correlate to the multidimensional development of an infant and are influenced by attributes such as gender and gestational age (GA). Recent literature on guidelines developed for neonatal intensive care; do not take the gender or the GA of the infant into account. The exponential activity of a growing neonate in its early stages of life needs to be captured and embedded into algorithms designed to extract patterns of predictive temperament within the NICU domain. The STDMn+p0 framework presents an extended multidimensional approach with the ability to create patient characteristic clinical rules. Further defining NICU algorithms, through the extended use of attributes to include gender and GA, and using these new algorithms in clinical decision support systems increases the accuracy and thereby minimizes the risk of adverse events

Hilo Trial: A Comparative Study of High versus Low Tidal Volume in Very Low Birth Babies with Respiratory Distress Syndrome

Background  Preterm infants often require mechanical ventilation. Volume targeted ventilation has been shown to reduce both complications and the duration of required mechanical ventilation. The recommended tidal volumes vary from 4-8 mL/kg, but the optimal tidal volume remains elusive.  Aims and objectives  To compare volume ventilation at a lower (4-5 mL/kg) with a higher (7-8 mL/kg) tidal volume during volume guarantee ventilation (VG) of respiratory distress syndrome (RDS) in very preterm infants.  Methodology  The randomised trial was conducted at North Tees Hospital in North East England from 2013 to 2016. Babies <32 weeks’ gestation or <1500 grams birthweight requiring mechanical ventilation within 12 hours of life from RDS were included in the study. Babies were randomised to receive lower (4-5 mL/kg) or higher (7-8 mL/kg) tidal volume using Volume Guarantee (VG). The primary outcome was the time to achieve a 25% reduction from the initial peak inspiratory pressure (PIP). Secondary outcomes included the duration of mechanical ventilation, as well as respiratory and non-respiratory complications.  Results  Babies in both groups were similar at baseline with regard to maternal, demographic and clinical characteristics. There was no difference in the primary outcome of time difference to reach a 25% reduction in baseline peak pressure between the two groups. There were no differences in short term secondary outcomes (air leak, pulmonary haemorrhage, sepsis, IVH, NEC, PDA and ROP) or medium term complications (Bronchopulmonary Dysplasia at 28 days’ life and 36 weeks PMA, severity of Bronchopulmonary Dysplasia, amount of home oxygen, survival to discharge and survival without Bronchopulmonary Dysplasia at 36 weeks PMA). The minute volume, paCO2 or FIO2 requirements were not significantly different either.  Summary and conclusions  This trial did not find statistically significant differences between lower versus higher tidal volume delivery in a population of 70 infants with RDS. It is possible that both tidal volume ranges selected for study are at functional residual capacity and this might be one reason for negative results of the study.