Karel Allegaert

Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe

Congenital diaphragmatic hernia (CDH) is associated with high mortality and morbidity. To date, there are no standardized protocols for the treatment of infants with this anomaly. However, protocols based on the literature and expert opinion might improve outcome. This paper is a consensus statement from the CDH EURO Consortium prepared with the aim of achieving standardized postnatal treatment in European countries. During a consensus meeting between high-volume centers with expertise in the treatment of CDH in Europe (CDH EURO Consortium), the most recent literature on CDH was discussed. Thereafter, 5 experts graded the studies according to the Scottish Intercollegiate Guidelines Network (SIGN) Criteria. Differences in opinion were discussed until full consensus was reached. The final consensus statement, therefore, represents the opinion of all consortium members. Multicenter randomized controlled trials on CDH are lacking. Use of a standardized protocol, however, may contribute to more valid comparisons of patient data in multicenter studies and identification of areas for further research.

Urine of Preterm Neonates as a Novel Source of Kidney Progenitor Cells

In humans, nephrogenesis is completed prenatally, with nephrons formed until 34 weeks of gestational age. We hypothesized that urine of preterm neonates born before the completion of nephrogenesis is a noninvasive source of highly potent stem/progenitor cells. To test this hypothesis, we collected freshly voided urine at day 1 after birth from neonates born at 31-36 weeks of gestational age and characterized isolated cells using a single-cell RT-PCR strategy for gene expression analysis and flow cytometry and immunofluorescence for protein expression analysis. Neonatal stem/progenitor cells expressed markers of nephron progenitors but also, stromal progenitors, with many single cells coexpressing these markers. Furthermore, these cells presented mesenchymal stem cell features and protected cocultured tubule cells from cisplatin-induced apoptosis. Podocytes differentiated from the neonatal stem/progenitor cells showed upregulation of podocyte-specific genes and proteins, albumin endocytosis, and calcium influx via podocyte-specific transient receptor potential cation channel, subfamily C, member 6. Differentiated proximal tubule cells showed upregulation of specific genes and significantly elevated p-glycoprotein activity. We conclude that urine of preterm neonates is a novel noninvasive source of kidney progenitors that are capable of differentiation into mature kidney cells and have high potential for regenerative kidney repair.

The Clinical Relevance of Pediatric Formulations

Extensive variability in dose and dosing regimens used to treat pediatric patients, based on maturational and non-maturational differences between individuals, is part of the essence of pediatric clinical pharmacology today. Consequently, the pediatric community is in need of drug formulations tailored to the specific needs of neonates, infants, children, and adolescents. This must include valid data on product stability, palatability, and compatibility. Most of the time, children are still treated with medicines that were neither designed, developed nor evaluated specifically for use by children. As a consequence, there is a risk of suboptimal (too low, too high, or too variable) dosing and side effects from potentially toxic ingredients, including excipients.

Is hyperbilirubinaemia a clinical useful indicator of reduced drug clearance capacity in neonates

Background: There is extensive variability in clearance between neonates, mainly explained by age or size. We aimed to assess if hyperbilirubinaemia also contributes as covariate, using reported paracetamol [1] and propofol datasets [2] since both compounds undergo glucuronidation.Methods: Population pharmacokinetic analysis of 943 paracetamol observations in 158 neonates was undertaken (NONMEM, two-compartment linear disposition). A similar approach (three-compartment) was performed on a dataset of 235 propofol concentration-time points in 25 neonates. Covariates were postmenstrual and postnatal age (PMA, PNA), weight and indirect hyperbilirubinaemia (dichotomous, PNA adapted fixed cut-off values [3])Results: For the paracetamol clearance, covariate information predicted 60.9% of variance [weight 57.5, PMA 2.2, unconjugated bilirubin 1.2 %]. For propofol, the age (PMA+PNA) model described the data most accurately. The covariates PMA+PNA explained 67% of the interindividual variability compared to 45% with PMA+bilirubin. Introduction of bilirubin into the PMA+PNA model did not improved this model.Conclusions: Ontogeny itself, reflected by age (PMA, PNA) or size are the dominant covariates of drug clearance in neonates. Hyperbilirubinaemia appears to be only a very modest clinical indicator of (reduced) drug clearance in neonates for drugs that undergo glucuronidation.

478 Haemodynamics Following Intravenous Paracetamol Administration in (PRE) Term Neonates

Introduction: There are recent observations on the haemodynamics of intravenous paracetamol (hypotension) in adult IC setting (1). We therefore evaluated the haemodynamics following iv paracetamol loading dose (20 mg.kg-1) in (pre)term neonates. Methods: Pooled analysis of observations on heart rate and blood pressure (mean, systolic, diastolic) collected during iv paracetamol pharmacokinetic studies in neonates already reported (2,3) or collected during the ongoing PK/PD iv paracetamol study (PARANEO, NCT 00969176). Heart rate and blood pressure (arterial access) were recorded just before and 30, 60, 120, 180, 240, 300 and 360 minutes afterwards. Data by median, paired analysis (Wilcoxon). Results: Data in 64 neonates (GA 35 weeks, PNA 2 days, weight 2.425 kg) were available. Heart rate decreased from (pre) 143 bpm to 137 (p< 0.01), 140 (p< 0.05), 137 (p< 0.01), 133 (p< 0.01), and 140 (p< 0.05) bpm at 30, 60, 120, 180, 240-360 min. Mean blood pressure decreased (pre = 46 mmHg) to 43 at 60 min, 300 and 360 minutes (p< 0.05), while there were no significant changes in systolic or diastolic blood pressure. Conclusions: Statistical significant, clinical minor effects on heart rate (-6 to -8) and blood pressure (-3 mmHg) were documented following iv paracetamol. These changes may reflect improved analgesia, but it seems cautious to consider impaired haemodynamics to be a relative contra-indication for intravenous paracetamol.

144 Incidence, Risk Factors and Severity of Pulmonary Morbidity in Infants with Congenital Diaphragmatic Hernia Born in High-Volume Centres in Europe

Background and aims: Newborns with congenital diaphragmatic hernia (CDH) may develop chronic lung disease (CLD). Our aim was to determine the incidence, severity and risk factors of CLD in infants with CDH. Methods: Data were collected about 426 CDH patients born between 2005 and 2008 at 8 high-volume centres (> 10 admissions of infants with CDH per year) in Europe. The primary endpoint was CLD, defined as oxygen dependency at day 28. The severity of CLD (mild: FiO2 0.21; moderate: FiO2 0.22-0.29; severe: FiO2 ≥ 0.30 or CPAP/mechanical ventilation) was determined at day 56 or at discharge, whichever came first. Results: At day 28, the mortality rate was 28% and the CLD incidence was 31%. Of all patients with CLD, 31% had severe CLD, 15% moderate CLD and 54% had mild CLD. Compared to patients without CLD, patients with CLD had a lower lung-to-head ratio (p< 0.001), more often had an intrathoracic liver position (p< 0.001), required treatment for pulmonary hypertension (p< 0.001), had a patch repair (p< 0.001), developed a pneumothorax (p< 0.001) and required ECMO (p< 0.001). Independent risk factors for CLD were an intrathoracic liver position (OR 5.9, 95% CI 3.9-10.4) and a lower gestational age at birth (OR 0.86, 95% CI 0.73-0.97). Patients with severe CLD more often had a pneumothorax (p< 0.001), patch repair (p=0.035) and ECMO treatment (p< 0.001) than patients with mild to moderate CLD. Conclusion: Pulmonary morbidity, which is a major problem in infants with CDH, can be identified antenatally.