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Purpose The aim of this in vitro study was to evaluate potential determinants of drug loss in different ECMO circuits. Methods Midazolam, morphine, fentanyl, paracetamol, cefazolin, meropenem and vancomycin were injected into three neonatal roller pump, two paediatric roller pump and two clinically used neonatal roller pump circuits, all with a silicone membrane, and two neonatal centrifugal pump circuits with polypropylene hollow-fibre membranes. Serial blood samples were taken from a post-oxygenator site. Drug recovery was calculated as the ratio between the determined and the theoretical maximum concentration. The latter was obtained by dividing dose by theoretical circuit volume. Results Average drug recoveries at 180 min in three neonatal silicone membrane roller pump circuits were midazolam 0.62%, morphine 23.9%, fentanyl 0.35%, paracetamol 34.0%, cefazolin 84.3%, meropenem 82.9% and vancomycin 67.8%. There was a significant correlation between the lipophilicity of the drug expressed as log P and the extent of drug absorption, p  < 0.001. The recovery of midazolam and fentanyl in centrifugal pump circuits with hollow-fibre membrane oxygenator was significantly higher compared to neonatal roller pump circuits with silicone membranes: midazolam 63.4 versus 0.62%, fentanyl 33.8 versus 0.35%, p  < 0.001. Oxygenator size and used circuits do not significantly affect drug losses. Conclusions Significant absorption of drugs occurs in the ECMO circuit, correlating with increased lipophilicity of the drug. Centrifugal pump circuits with hollow-fibre membrane oxygenators show less absorption for all drugs, most pronounced for lipophilic drugs. These results suggest that pharmacokinetics and hence optimal doses of these drugs may be altered during ECMO.

[...]there is a need for alternative treatments that result in better closure rates or fewer adverse effects. [...]the peripheral PGH2 inhibition of PGH2 production is very limited and the pharmacological link between paracetamol exposure and systemic PG reduction related PDA closure is very weak.

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.

Introduction Propylene glycol (PG) is an unintentional frequently administered solvent in neonates despite the fact that PG accumulation potentially results in hyperosmolarity, lactic acidosis and renal/hepatic toxicity. Methods Prospective evaluation of renal (diuresis, creatinaemia, sodium), metabolic (base excess, anion gap, lactate, bicarbonate) and hepatic (alanine transaminase, aspartate aminotransferase, direct bilirubinaemia) tolerance to PG in (pre)term neonates following intravenous administration of formulations (paracetamol, phenobarbital, digoxin) that contain PG. Observations from 48 h before up to 48 after the last PG administration were described and compared (paired analysis). Clinical characteristics and observations collected following intravenous PG-paracetamol administration were compared with a historical cohort of neonates in whom similar (renal, hepatic) observations during exposure to a mannitol-containing paracetamol formulation were collected. Results 5566 observations were collected in 69 neonates before, during and following median PG exposure of 34 mg/kg/24 h (range 14–252). Progressive postnatal adaptation in renal, metabolic and hepatic function was documented, unrelated to the PG exposure. In the subgroup of 40 cases treated with intravenous PG-paracetamol, observations on renal and hepatic function were similar to a historical cohort of published observations following exposure to intravenous mannitol-paracetamol. Conclusions Unintended PG administration (34 mg/kg/24 h) for a maximum of 48 h seems to be tolerated in (pre)term neonates and does not affect short-term postnatal adaptations. Further studies on PG disposition and the level of safe exposure to PG, including long-term safety data in neonates are needed.

Introduction Paracetamol pharmacokinetics (PK) is highly variable in older fit adults after intravenous administration. Frailty and oral administration likely result in additional variability. The aim was to determine oral paracetamol PK and variability in geriatric inpatients. Methods A population PK analysis, using NONMEM 7.2, was performed on 245 paracetamol samples in 40 geriatric inpatients (median age 87 [range 80–95] years, bodyweight 66.4 [49.3–110] kg, 92.5% frail [Edmonton Frail Scale]). All subjects received paracetamol 1000 mg as tablet (72.5%) or granulate (27.5%) three times daily. Simulations of dosing regimens (1000 mg every 6 hours [q6h] or q8h) were performed to determine target attainment, using mean steady-state concentration (C ss-mean ) of 10 mg/L as target. Results A one-compartment model with first order absorption and lag time best described the data. The inter-individual variability was high, with absorption rate constant containing the highest variability. The inter-individual variability could not be explained by covariates. Simulations of 1000 mg q6h and q8h resulted in a C ss-mean of 10.8 [25–75th percentiles 8.2–12.7] and 8.13 [6.3–9.6] mg/L, respectively, for the average geriatric inpatient. The majority of the population remained off-target (22.2% [q6h] and 52.2% [q8h] <8 mg/L; 31.3 [q6h] and 7.6% [q8h] >12 mg/L). Conclusion A population of average geriatric inpatients achieved target C ss-mean with paracetamol 1000 mg q6h, while q8h resulted in underexposure for the majority of them. Due to high unexplained variability, a relevant proportion remained either above or below the target concentration of 10 mg/L. Research focusing on PK, efficacy and safety is needed to recommend dosing regimens.

Cefazolin (CFZ) is highly and saturably bound to human serum albumin (HSA) in adults. We aim to describe CFZ protein binding and its covariates in neonates. In neonates to whom intravenous CFZ (50 mg/kg) was administered prior to a surgical procedure, total and unbound CFZ plasma concentrations (mg/l) were determined at 0.5, 2, 4 and 8 h after CFZ administration. Linear and multiple regression analyses were used to document covariates of unbound CFZ fraction. The Wilcoxon signed-rank test was used for the paired analysis of unbound CFZ fractions. In 40 patients with a median weight of 2,767 (range 830–4,200) g and a postmenstrual age (PMA) of 39 (25–45) weeks, 131 samples were collected. The median unbound CFZ fraction was 0.39 (0.10–0.73). Linear regression of unbound CFZ fraction versus unbound CFZ plasma concentration ( R 2  = 0.39) had a slope significantly different from zero ( p  < 0.001). In a multiple regression analysis, albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA resulted in an R 2 value of 0.496. The median unbound CFZ fraction at the peak concentration (0.46, range 0.28–0.69) was significantly higher compared to the trough level (0.36, range 0.17–0.73) ( p  < 0.001). The between- and within-patient saturability of CFZ plasma protein binding were documented in neonates. The median unbound CFZ fraction in neonates is higher than in adults and depends partly on albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA. Integration of CFZ protein binding in future pharmacokinetic/pharmacodynamic research is warranted in order to optimise neonatal CFZ dosing. We recommend protein binding assessment in the neonatal pharmacokinetic evaluation of highly protein-bound or clinically relevant drugs.

Ibuprofen is used for treatment and prevention of patent ductus arteriosus in low-birthweight infants. Its effects on regional circulations differ from those of indometacin. Because prophylactic indometacin reduces the frequency of severe intraventricular haemorrhage and patent ductus arteriosus, we aimed to study the efficacy of early ibuprofen in reducing these outcomes in a double-blind, multicentre trial. Within 6 h after birth, 415 low-birthweight infants (gestational age <31 weeks) were randomly allocated ibuprofen-lysine (10 mg/kg then two doses of 5 mg/kg after 24 h and 48 h) or placebo intravenously. The primary outcome was occurrence of severe intraventricular haemorrhage; secondary outcomes were occurrence of patent ductus arteriosus and possible adverse effects of ibuprofen. Analysis was by intention to treat. 17 (8%) of 205 infants assigned ibuprofen and 18 (9%) of 210 assigned placebo developed severe intraventricular haemorrhage (relative risk 0·97 95% CI 0·51–1·82). In 172 (84%) infants of the ibuprofen group, the ductus was closed on day 3 compared with 126 (60%) of the placebo group (relative risk 1·40 [1·23–1·59]). No important differences in other outcomes or side-effects were noted; however, urine production was significantly lower on day 1 and concentration of creatinine in serum was significantly higher on day 3 after ibuprofen. Ibuprofen prophylaxis in preterm infants does not reduce the frequency of intraventricular haemorrhage, but does decrease occurrence of patent ductus arteriosus.

Studies addressing the role of somatic copy number variation (CNV) in the genesis of congenital heart defects (CHDs) are scarce, as cardiac tissue is difficult to obtain, especially in non-affected individuals. We explored the occurrence of copy number differences in monozygotic (MZ) twins discordant for the presence of a CHD, as an illustrative model for chromosomal mosaicism in CHDs. Array comparative genomic hybridization was performed on peripheral blood-derived DNA obtained from 6 discordant MZ twin pairs and on sex-matched reference samples. To identify CNV differences between both twin members as well as potential CNVs in both twins contributing to the phenotype, DNA from each twin was hybridized against its co-twin, and against a normal control. Three copy number differences in 1 out of 6 MZ twin pairs were detected, confirming the occurrence of somatic CNV events in MZ twins. Further investigation by copy number and (epi)genome sequencing analyses in MZ twins, discordant for the presence of CHDs, is required to improve our knowledge on how postzygotic genetic, environmental and stochastic factors can affect human heart development.

*presenting author, supported by ERAWEB II scholarship for postdoctoral program at the KU Leuven, Belgium (2014-2015)IntroductionVancomycin, a glycopeptide antibiotic, is frequently used for late onset sepsis (LOS) and catheter-related infection. Larger inter- and intra-patient variability, combined with a narrow therapeutic index, warrants therapeutic drug monitoring (TDM). However, large inter-individual variability in PK parameters in neonates is documented, only partly explained by covariates such as weight, age or serum creatinine (1,2). In the current study, we focus on the potential impact of between assay differences for vancomycin (3) on the variability in its concentration in a single neonatal intensive care unit (NICU).MethodsVancomycin TDM observations of neonates and young infants treated with intravenous vancomycin, mainly for (suspected) LOS (ie, >72hours after birth), in the Leuven NICU, Belgium, between June 2011 and December 2014. Our patient population, consists of (pre)term neonates, inborn or transferred, in need of specialized care related to prematurity, infections, perinatal asphyxia, congenital diseases (eg, surgery for cardiopathy, congenital diaphragmatic hernia, or esophageal atresia), or other diseases. Clinical characteristics at birth, as well as characteristics at the moment of TDM were extracted from the patient files. We aimed to document early vancomycin exposure, therefore only first trough levels were included. Serum vancomycin assay was performed either with a particle-enhanced turbidimetric inhibitionimmunoassay method (Siemens Dimension; Dade Behring, Deerfield, Illinois-PETINIA) or with an enzyme multiplied immunoassay technique (Cobas c702; Roche Diagnostics, Basel, Germany-COBAS). The data were analyzed by Chi-square test, t test and Mann-Whitney U test. Linear Mix Model was used to assess significant differences between groups, when adjusting for confounding factors. Data were analyzed in SPSS 20.0 (IBM corp.), p-value <0.05 was significant.ResultsIn total, 564 vancomycin TDM observations, 311 assayed with PETINIA and 253 with COBAS, were included. Both cohorts had comparable clinical characteristics (median [min-max] current weight 2150 [420-5000] grams for PETINIA vs. 2120 [500-5840] grams for COBAS, and median postmenstrual age 35 [25-58] weeks for PETINIA vs. 35 [25-51] weeks for COBAS). We determined the significant difference between the vancomycin concentrations using two different immunoassays: PETINIA vs. COBAS (F=17.971; p<0.001). When adjusting for current body weight and postmenstrual age, the major covariates associated with vancomycin serum trough levels in neonates, the difference in vancomycin concentration between cohorts was statistically significant (F=17.076, p<0.001, F=18.951, p<0.001, respectively). Overall, immunoassays PETINIA and COBAS significantly differed by vancomycin concentrations when adjusting for covariates, and the mean difference for vancomycin concentration was 2.167mg/l.ConclusionThe present study confirms the impact of assays on the variability in vancomycin concentration in neonates in a single NICU. Comparison between these two immunoassays showed a mean proportional differences >20%. Therefore, it is important to know how the vancomycin is measured when interpreting results, and particularly the transferability of vancomycin results between the laboratories has to be interpreted with caution.