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ObjectiveWe aimed to identify gestational-age corrected prenatal ultrasound markers of complex gastroschisis, and to compare physical growth and neurodevelopment between children with simple and complex gastroschisis.DesignWe included prenatally diagnosed gastroschisis patients from 2000 to 2012 who joined our longitudinal follow-up programme. Associations between complex gastroschisis and prenatal ultrasound markers collected at 30 weeks’ gestation and prior to delivery were tested using logistic regression. Physical growth (SD scores (SDS)), mental and psychomotor developmental index (MDI, PDI; Bayley Scales of Infant Development) were recorded at 12 and 24 months. Data were analysed using general linear models and compared with population norms.ResultsData of 61 children were analysed (82% of eligible cases). Extra-abdominal bowel dilatation at 30 weeks’ gestation was significantly associated with complex gastroschisis (OR (95% CI): 5.00 (1.09 to 22.98)), with a high negative (88%) but low positive (40%) predictive value. The mean (95% CI) height SDS at 12 months (−0.46 (–0.82 to –0.11)), and weight SDS at 12 and 24 months (−0.45 (–0.85 to –0.05), and −0.44 (−0.87 to –0.01), respectively) fell significantly below 0 SDS. MDI and PDI were significantly below 100 at 24 months; 93 (88 to 99) and 83 (78 to 87), respectively). Children with complex gastroschisis had a significantly lower PDI (76 (68 to 84)) than those with simple gastroschisis (94 (90 to 97), pConclusionsPrenatal ultrasound markers could not reliably distinguish between simple and complex gastroschisis. Children with complex gastroschisis may be at increased risk for delayed psychomotor development; they should be monitored more closely, and offered timely intervention.

To longitudinally evaluate motor development and predictive factors in school-age children with oesophageal atresia.Cohort study with prospective longitudinal follow-up.Outpatient clinic of a tertiary university paediatric hospital.Children with oesophageal atresia born between January 1999 and May 2006 were assessed at 5 and 8 years of age.None.Motor performance was evaluated at 5 and 8 years using the Movement Assessment Battery for Children (M-ABC). Additionally, we evaluated perinatal characteristics, duration of anaesthesia within the first 24 months, socioeconomic status, sports participation and school performance at time of follow-up and intelligence and sustained attention at the age of 8 years.In 5-year-olds (n=54), the mean (SD) z-score M-ABC was slightly, but significantly lower than age-predicted normative values (-0.75 (0.83), p0.001). In 8-year-olds (n=49), the z-score M-ABC was -0.53 (0.91) (p0.001), intelligence was normal, but sustained attention was impaired: z-score speed (-1.50 (1.73)) and raw score attentional fluctuation (3.99 (1.90)) (both p0.001). Motor problems mainly concerned gross motor performance. Duration of anaesthesia and sustained attention were negatively associated with motor development; sports participation was positively associated.Longer duration of anaesthesia and sustained attention problems were associated with gross motor problems in school-age patients with oesophageal atresia. Parental awareness of risks for motor problems may provide the opportunity to offer timely intervention.

BackgroundPostnatal developmental changes of human renal membrane transporters, which are key players of disposition of renally cleared drugs and endogenous substrates, are largely unknown. This study aimed to characterize the ontogeny of 11 human renal transporters to understand changes in the renal clearance of substrate drugs in children.Methods mRNA levels of known renal transporters: BCRP, MATE1, MATE2-K, MDR1, MRP2, MRP4, URAT1, GLUT2, OAT1, OAT3 and OCT2, and the transcription factor PXR were measured with RT-qPCR in 184 human postmortem frozen renal cortical tissues (preterm newborns - adults; 1 day-75 yrs old) from individuals of European and African descent. Protein expression of all but MRP2, MRP4 and PXR was quantified with LC-MS/MS SRM in 62 of those samples (term newborns - adults; 1 day-29 yrs old). Localization of MRP4 was tested with immunohistochemistry.ResultsExpression levels of MDR1, URAT1, OAT1, OAT3, and OCT2 increased with age, but levels of MATE1 and GLUT2 were stable from birth. Protein levels of MATE2-K and BCRP showed no difference from newborns to adults despite age-related changes in mRNA expression. MRP2, MRP4 and PXR expression levels were stable. MRP4 localization in pediatric samples was similar to that in adult samples.ConclusionRenal drug transporters exhibited different rates and patterns of maturation, suggesting that renal handling of both endogenous and exogenous compounds may change with age. It is important to consider ontogeny of renal transporters during pediatric drug development.Disclosure(s)The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Views expressed in this paper are those of authors and do not necessarily reflect the official views or policies of the FDA; nor does any mention of trade names, commercial practices, or organization imply endorsement by the U.S. Government.*Contributed equally,**Contributed equally

BackgroundThe disposition of orally prescribed drugs in critically ill children may be affected critical illness in in addition to age, resulting in erratic effects and safety. We aimed to study oral drug prescribing in the neonatal and pediatric intensive care unit (NICU and PICU).MethodsA one-year retrospective cohort study of all drug prescriptions, including route of administration for all children admitted to the NICU and PICU of the Erasmus MC-Sophia’s children’s hospital.Results1723 children with 2091 unique admissions received per admission (median [IQR]) 5 (3–10) drugs; 1 (0–2) orally and 3 (1–7) intravenously (IV). During mechanical ventilation 15% and 75% of drugs were given orally and IV, respectively. In non-ventilated patients, 27% of drugs were given orally and 60% IV. The 5 most frequently orally prescribed drugs were: vitamin K, spironolactone, oral probiotics, amphotericin B (prophylaxis) and trimethoprim.DiscussionCritically ill infants receive a considerable proportion of drugs orally. Considering that critical illness may significantly impact intestinal drug absorption, this may expose them to an increased risk of ineffective or unsafe drug therapy.Disclosure(s)Nothing to disclose

BackgroundLittle is known about fetal acetaminophen (paracetamol) pharmacokinetics and its potential for toxicity, despite the frequent use of acetaminophen during pregnancy. The aim of this study was to develop a feto-maternal physiologically based pharmacokinetic model (f-m PBPK) to predict placental transfer and PK of acetaminophen and its metabolites in fetus at term pregnancy.MethodsPreviously, a pregnancy PBPK model was developed for prediction of maternal PK of acetaminophen and its metabolites. This model was structurally extended with the fetal liver, and quantitative information on the maturation of relevant enzymes was integrated. Three different approaches (ex vivo placenta perfusion experiments, scaling of passive diffusion transfer rates, and the Mobi® default method) to describe placental drug transfer were tested. Predicted maternal and fetal acetaminophen concentrations were compared with those observed in the literature. umbilical cord data at birth.ResultsThe 3 different approaches to predicted acetaminophen PK in the umiblical vein were found to yield broadly similar results. Acetaminophen exposure was similar in maternal blood compared to venous umbilical cord blood. Prediction of the median dose fraction of acetaminophen converted to its metabolites (fm) revealed higher maternal acetaminophen-glucuronide formation clearance and sulphate formation compared to that in the fetal liver (fm_glucuronide52.2 vs 0% and fm_sulphate30.4 vs 0.8%, respectively) and higher fraction of acetaminophen converted to the reactive metabolite N-acetyl-p-benzoquinone-imine (fm_NAPQI, 6.5 vs 0.06%) in pregnant women compared to their fetus.ConclusionNo differences were observed in the 3 approaches for integration of placental drug transfer. Differences in acetaminophen biotransformation to its metabolites between pregnant women and their fetuses were quantitatively predicted.Disclosure(s)Paola Mian received a Short term Minor (STM-2017) grant from the Stichting Sophia Kinderziekenhuis fonds to conduct this research.

BackgroundLittle is known about the pharmacokinetics (PK) of acetaminophen during different stages of pregnancy. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict acetaminophen PK throughout pregnancy.MethodsPBPK models for acetaminophen and its metabolites were developed in non-pregnant and pregnant women. Physiological and enzymatic changes in pregnant women expected to impact acetaminophen PK were considered. The models were evaluated using goodness-of-fit-plots and through comparison of predicted PK profiles with in-vivo PK data. Predictions were performed to illustrate the concentrations at steady state (Css-mean), used as indicator for efficacy of acetaminophen achieved following 1000 mg q6h. Furthermore, as measurement for potential hepatotoxicity, the molar dose fraction of acetaminophen converted to NAPQI was estimated.ResultsPBPK models successfully predicted the PK of acetaminophen and its metabolites in populations of non-pregnant and pregnant women. Predictions resulted in lowest Css-mean in the third trimester (4.5 mg/L), while Css-mean was 6.7, 5.6 and 4.9 mg/L in non-pregnant, first and second trimester populations, respectively. Assuming a constant increased activity of CYP2E1 throughout pregnancy, the molar dose fraction of acetaminophen converted to NAPQI was highest during the first (11.0%), followed by second (9.0%) and third trimester (8.2%), compared to non-pregnant women (7.1%).ConclusionRisk for drug related hepatotoxicity in pregnant women might be increased as more NAPQI is produced during pregnancy compared to non-pregnant women, especially during the first trimester. However, lack of information on the detoxifying capacity precludes any strong conclusions.Disclosure(s)Paola Mian received a Short term Minor (STM-2017) grant from the Stichting Sophia Kinderziekenhuis fonds to conduct this research.

IntroductionKetorolac is a racemic drug with analgesic effects specific to its S-enantiomer. This study aimed to describe enantiomer-specific maturational pharmacokinetics (PK). Simulations were performed to describe how S-ketorolac exposure in infants differs from adults, and how this affects the adult racemic analgesic trough threshold EC50 (EC50thr-adult, 0.37 mg/L) in infants (EC50thr-infant)when the same S-target is applied.MethodsA population PK analysis (NONMEM 7.3) was performed based on 1020 plasma samples from 5 studies including 80 patients (adults, children, infants) following single intravenous ketorolac administration.ResultsS-ketorolac PK was best described with a 2-compartment model in infants and 3-compartment model in adults, while R-ketorolac PK was best described with a 2-compartment model in all. S-ketorolac clearance [mean population value: 3.45 L/h/56 kg] and central volume of distribution (V1) [4.27 L/56kg] increased exponentially with bodyweight (0.75, 0.59 respectively). R-ketorolac clearance [0.93 L/h/56kg], peripheral volume of distribution (V2) and inter-compartmental clearance (Q) increased exponentially with bodyweight (0.62, 1.20, 0.76 respectively), V1 [4.11 L/56kg] linearly with bodyweight. Simulations revealed EC50thr-adult (0.37 mg/L) contained 0.048 mg/L S-ketorolac as mean in typical adults (BW 48.6–99.6 kg), while EC50thr-adult contained 0.032–0.036 mg/L S-ketorolac in typical infants (BW 5.3–10.6 kg). To reach adult S-enantiomer concentration (0.048 mg/L) in typical infants (BW 5.3–10.6 kg), EC50thr-infant should be 0.49–0.46 mg/L, respectively.ConclusionEnantiomer-specific maturational PK of ketorolac were described. Subsequent simulations displayed differences in proportion of S- and R-ketorolac on the racemic threshold EC50. A The same S-ketorolac concentration necessitates a higher EC50thr-infant to EC50thr-adult.Disclosure(s)Nothing to disclose

BackgroundAlternative mRNA transcripts occur in >90% of human genes and may be triggered by developmental signals. The hepatic transporter OATP1B1 (gene name SLCO1B1) traffics substrates across the hepatic membrane, and shows age-related changes in protein expression. We aimed to predict novel isoforms of OATP1B1 by studying alternative splicing of SLCO1B1 in human paediatric post-mortem liver tissue, and the relationship of their mRNA expression with age.Methods mRNA expression of SLCO1B1 transcripts was determined using RNA sequencing (HISAT2/StringTie). Novel mRNA transcripts were considered of relevance when (1) the expression was >5% of the annotated isoform, (2) it was a SLCO1B7 and SCLO1B1 hybrid transcript, or (3) when the expression was associated with age. The software packages ORF-finder, TMpred and TOPO2 were used to predict the protein sequence and structure of the novel isoforms. Relationship of expression with age was studied with the Kruskal-Wallis test for age groups (fetal, 0–1.5 year, 1.5–6 year, 6–12 year and 12–18 year) and with Spearman correlation tests for age on continuous scale.ResultsIn 97 hepatic post-mortem tissues (gestational age median 16.4 [range 14.7–41.3] weeks, postnatal age 0.36 [0 - 17] years) 27 novel mRNA transcripts were detected. Of these, 13 were relevant: 2 isoforms are predicted to translate into amino acid sequences similar to the annotated isoform for OATP1B1, 9 isoforms may translate into truncated versions, and the expression of 8 isoforms was associated with age. None of the isoforms had an ORF that covered the SLCO1B7 region.ConclusionWe showed that novel SLCO1B1 mRNA isoforms potentially translate into OATP1B1 protein with unknown function, and that alternative splicing may well be a regulatory mechanism for SLCO1B1 expression during development. This data provides a better understanding of age-related changes in the expression of OATP1B1, and, with that, potentially improves prediction of disposition of endogenous and exogenous substrates.Disclosure(s)BG was supported, in part, by the Ter Meulen fund 2018 provided by the Royal Dutch Academy of Sciences. The National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders at the University of Maryland is funded by the National Institutes of Health (NIH) contract HHSN275200900011C, reference number, N01-HD-9-0011 and the Liver Tissue Cell Distribution System is funded by NIH contract number N01-DK-7-0004/HHSN267200700004C.

BackgroundProlonged treatment with analgesics and sedatives can result in iatrogenic withdrawal syndrome (IWS) in children being weaned from these drugs.1Personalized weaning strategies might lower the incidence of IWS, but this requires a quantitative understanding of withdrawal over time in individual patients.MethodsData from 81 children (aged 1 month to 17 years) collected during an observational clinical study on IWS2 were used, including a total of 1782 withdrawal assessments performed by PICU nurses, on a numerical rating scale (NRSwithdrawal) from 0 (no withdrawal) to 10 (worst withdrawal possible). Population pharmacokinetic models from literature were used to generate concentration-time profiles in each patient of all key analgesics and sedatives: morphine, fentanyl, methadone, midazolam, lorazepam, propofol, esketamine and clonidine. A mechanism-based withdrawal model was developed using NONMEM 7.3 to quantify IWS over time. The final model was used to perform simulations in which different weaning strategies were compared.ResultsA novel mechanism-based withdrawal model structure was developed with a hypothetical compartment, which equilibrates with the central pharmacokinetic compartment, and which characterizes the development and disappearance of drug dependence over time. With this model and available data, withdrawal dynamics could be established with statistical significance for fentanyl (p< 10-6), morphine (p=0.043) and esketamine (p=0.002), and not for any of the other drugs. Compared with fentanyl, development and disappearance of esketamine and morphine dependence is slower.ConclusionsGiven the patient‘s use of fentanyl, morphine and esketamine, the developed model can dynamically predict IWS from these substances under different weaning strategies. The results show that the optimal strategy for weaning of drug dependent children depends on both the type of drug and the drug levels prior to weaning. In this study, there was insufficient information to characterise midazolam withdrawal dynamics, potentially because of slow midazolam weaning with insufficiently high NRSwithdrawal scores.ReferencesBest KM, Boullata JI, Curley MAQ. Risk factors associated with iatrogenic opioid and benzodiazepine withdrawal in critically ill pediatric patients: A Systematic Review and Conceptual Model. Pediatr Crit Care Med ( 2015) 16(2): 175–183.Ista E, de Hoog M, Tibboel D, Duivenvoorden HJ, van Dijk M. Psychometric evaluation of the sophia observation withdrawal symptoms scale in critically ill children. Pediatr Crit Care Med ( 2013).14(8): 761–769.Disclosure(s)Nothing to disclose

BackgroundDespite being the most commonly used analgesic and antipyretic, oral APAP bioavailability has not been determined in children. The aim of this study is to compare exposure after oral vs iv APAP using the PK data of the first pediatric oral bioavailability 14C microtracer study.MethodsDesignbioavailability microtracer population PK studyParticipantspatients < 6 yrs old in the pediatric ICU who received 15 mg/kg iv APAP q6hInterventiona single microdose of 14CAPAP (3µg/kg) given orally at the same time as a therapeutic iv doseData collectionBlood was sampled 8 times up to 24 h post-doseData analysispopulation PK analysis using NONMEM. Based on the model, exposure after oral vs iv was compared by simulating the concentration-time profiles and Css (targeted: 10 mg/L ± 20% deviation).3 doses were simulated: 15 mg/kg q6h oral and iv and 22.5 mg/kg oral q6h. 1000 simulations were performed and the percentage of patients reaching the targeted mean Css of 10 mg/L±20% were compared.ResultsOral bioavailibity was 72% (range:11–91%). After 15 mg/kg APAP, the median simulated oral Css was subtherapeutic (6.5 mg/L), but therapeutic (10 mg/L) for IV dosing (15 mg/kg). Patients were 2.5 times less likely to reach therapeutic plasma concentrations with 15 mg/kg oral vs iv APAP.With the maximal recommended oral doses of 22.5 mg/kg 6 h aimed to overcome the 72% bioavailability, median mean Css were therapeutic but overexposure and underexposure were more common than with iv (37 vs 32% Css< 8 mg/L and 30 vs 21% Css>12 mg/L).ConclusionCompared to IV, the usual (15 mg/kg) oral APAP doses result in low systemic exposure with subsequent risk of therapeutic failure. When oral doses are increased to overcome the low bioavailability, underdosing still occurs and overdosing was observed in patients with high bioavailability. IV APAP should therefore be preferred for acute pain management.Disclosure(s)Nothing to disclose

BackgroundDrug disposition in children may vary from adults due to age-related variation in drug metabolism, but paediatric pharmacokinetic (PK) studies are challenging. Microdose studies present an innovation to study PK in paediatrics, and can only be used when the PK of a microdose are dose-linear to a therapeutic dose. We aimed to assess dose-linearity of [14C]midazolam (MDZ), a marker for the activity of the developmentally regulated CYP3A enzyme, by comparing the PK of an intravenous (IV) [14C]MDZ microtracer given simultaneously with therapeutic MDZ, with the PK of a single IV [14C]MDZ microdose.MethodsPreterm to 2-year-old infants admitted to the intensive care unit received [14C]MDZ IV either as a microtracer during therapeutic MDZ infusion or as an isolated microdose. Dense blood sampling was done up to 36 hours after dosing. Plasma concentrations of [14C]MDZ and [14C]1-OH-MDZ were determined by accelerator mass spectrometry. A population PK model was developed with NONMEM 7.4 to study whether there was a difference in the PK of the microtracer versus those of a microdose [14C]MDZ.ResultsOf fifteen children (median gestational age 39.4 [range 23.9–41.4] weeks, postnatal age 11.4 [0.6–49.1] weeks), nine received a microdose and six a microtracer [14C]MDZ (111 Bq/kg; 37.6 ng/kg). In a two-compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the [14C]MDZ microdose or microtracer, suggesting the PK of MDZ to be linear within the range of the therapeutic doses and microdoses.ConclusionOur data supports the dose-linearity of an IV [14C]MDZ microdose in children, thus a [14C]MDZ microdosing approach can be used to study developmental changes in hepatic CYP3A activity.Disclosure(s)This project was funded by the ZonMw ERA-NET PRIOMEDCHILD programme (projectnumber 113205022). * both authors contributed equally

BackgroundSufentanil is a potent synthetic opioid increasingly used as an analgesic drug for pain treatment in critically ill neonates. Clinical studies concerning the pharmacokinetics (PK) of sufentanil administered as a bolus or continuous infusion in neonates are sparse and a population model has been developed for critically ill children beyond the newborn period. The aim of our study was to determine the PK of sufentanil in critically ill neonates treated with continuous sufentanil infusion for pain management (prophylactic and therapeutic use).MethodsEight term neonates (birth weight 2.60–4.30 kg; postnatal age 2–96 h) were treated with sufentanil (initial bolus 0.1–0.5 µg/kg i.v. administered for 5 minutes followed by continuous infusion 0.1–0.5 µg/kg per hour i.v.). Sufentanil plasma concentrations were determined using a UPLC-MS/MS assay. Totally 159 sufentanil concentrations were measured (8–27 measurements per patient). Individual sufentanil PK parameters were calculated in a two-compartmental PK model with first-order elimination kinetics based on individual demographic and clinical data and observed sufentanil plasma levels using MWPharm++ software (MediWare, Prague, Czech Republic). The sufentanil population PK model was individualized to maximize fitting of the simulated PK profile curve with observed concentration points. The fitting was performed using Bayesian method.ResultsMedian (IQR) sufentanil central and total volume of distribution, clearance, and distribution and elimination half-life were 4.7 (4.2–5.2) L/kg and 11.8 (9.9–14.2) L/kg, 0.552 (0.415- 0.671) L/h/kg, and 0.0264 (0.0260–0.0264) h and 15.7 (13.4–19.2) h, respectively.ConclusionWe observed similar sufentanil PK parameters (preliminary results) as described previously in literature. However, further studies with more patients are needed.FundingThis study is supported by a Charles University project Progres Q25, SVV 260373 and a project MH CZ-DRO - VFN64165, and by an unrestricted research grant of the Intensive Care of the ErasmusMC-Sophia Children’s Hospital.Disclosure(s)Nothing to disclose

ObjectivesTo study the effect of organ failure and inflammation on midazolam clearance in critically ill children, using population pharmacokinetic modeling.MethodsA total of 83 critically ill children (median age 5 months (range 1 day-17 years), n=523 samples) receiving intravenous midazolam for continuous sedation during mechanical ventilation were included. Disease severity was described using the validated and clinically used scores PELOD, PIM2 and PRISM II. Cytokines (IL-1, IL-2, IL-6, TNF-a) and C-reactive protein (CRP) were used as markers for inflammation. A population pharmacokinetic model for midazolam was developed using NONMEM 7.3. Body weight, age, severity of organ failure and inflammatory markers were considered as potential covariates.ResultsIn a two-compartmental PK model, body weight was found as most significant covariate for clearance and volume of distribution. Moreover, both severity of organ failure (PELOD) and inflammation (IL6 and CRP) were significant determinants of clearance (pConclusionFor midazolam clearance, apart from body weight, we found organ failure reflected by the PELOD score, and inflammation reflected by IL6 and CRP, as significant covariates. Most likely this effect is due to reduced activity of CYP3A in critically ill mechanically ventilated children. Both CRP concentration and organ failure should be considered when dosing midazolam and potentially other CYP3A substrates in critically ill children.

BackgroundTransporters are membrane-bound proteins involved in trafficking substrates (e.g. drugs) across membranes of among others hepatocytes. Limited data exists on the developmental expression. We aim to study protein expression of transporters in fetal, neonatal and infantile liver.MethodsTransporter protein expression (ABCB1, ABCG2, ABCC2, ABCC3, BSEP, GLUT1, MCT1, OATP1B1, OATP2B1, OCTN2) was quantified using UPLC-MS-MS, on snap-frozen post mortem livers (Erasmus MC tissuebank) and adult control livers (UMC-Groningen). Protein expression was determined in isolated crude membrane and quantified using stable-isotope-labelled peptides. Age groups were compared with Mann-Whitney test and post hoc Bonferroni-correction (significance pResults25 liver samples were studied. 10 fetal [median gestational age 23.2 weeks (range 16.4–37.9)], 12 pediatric [postnatal age 1 week (0–11.4) and gestational age at birth 35.1 weeks (27.1–41.0)], and 3 adult liver samples. ABCB1, ABCC2, OATP1B1, OATP2B1 expressions appeared similar in fetuses, pediatrics and adults. MCT1 expression was similar in fetuses and adults, but higher in pediatrics. BSEP expression was lower in fetuses and pediatrics than in adults. ABCC3 expression was lower level in fetuses than in adults, but not in pediatrics compared to adults. ABCG2, GLUT1, OCTN2 expressions were higher in fetuses than in adults, but similar in pediatrics and adults.ConclusionHepatic transporters appear in different developmental expression profiles. ABCB1, ABCC2, OATP1B1 protein expression appears stable. This contrast previous mRNA expression data, which showed lower expression in fetus/neonate. The age-related differences in transporter expression may result in age-dependent pharmacokinetics of substrates.

Objective To study whether new pharmacological and non-pharmacological guidelines lowered numbers of painful procedures in neonates and changed the amount and frequency of analgesic therapy as compared to the results of our previous study in 2001. Design A prospective observational study.Setting: Level III NICU of the Erasmus MC-Sophia Children’s Hospital, Rotterdam. Participants Neonates admitted at postnatal ages less than 3 days with length of stay at least 72 hours. Main outcome measures Number of all potentially painful procedures and analgesic therapy recorded at the bedside during the first 14 days of NICU stay. Results A total number of 21076 procedures were performed in the 175 neonates studied during 1730 patient-days (mean 12.2). The mean number of painful procedures per neonate per day was 11.4 (SD 5.7), significantly lower than the number of 14.3 (SD 4.0) in 2001 (p Conclusions The mean number of painful procedures per NICU patient per day declined and analgesic treatment changed to a more tailored or individualized approach. Non-pharmacological pain- or stress reducing strategies like NIDCAP and sucrose were fully embedded in our pain management. As further reduction of the number of painful procedures is unlikely we should explore newer pharmacological agents and apply non-pharmacological interventions more frequently.

Background Ongoing advances in paediatric intensive care led to increased survival, with increased morbidity and long-lasting sequelae. This increases parental burden and impedes quality of life of both child and parents. A poll amongst parents of children with congenital anatomical anomalies showed a need to better prepare parents for hospital discharge with their chronically ill child. Besides, parents needed a ward providing a more structured environment for child and parents rather than the hectic PICU. Aim Evaluation of a high dependence transitional care unit (HDTCU) as part of PICU care. Methods A 6 bedded HDTCU for chronically ill children in need of intensive nursing care was built, managed under full (medical and nursing) responsibility of our PICU. Increasingly during admission, parents take responsibility of caring for the child. We calculated duration of admission and bed occupancy rate. Furthermore a survey was held evaluating satisfaction among parents. Results Pallieterburght is an extramural HDTCU providing care between PICU and home for children dependent on medical appliances. From January 2010 until April 2012, 33 children were admitted with a median length of stay of 50 days (range 4–345). Bed occupancy was 67%. Main appliances were: tracheal cannula 16 (48%), mechanical home-ventilation 3 (1%) and home parenteral nutrition 12 (36%). Parental satisfaction and parental confidence at discharge were high. Conclusions Although the number of patients is too small to draw definitive conclusions, occupancy rates are high and parents seemed better prepared to accept full responsibility in home-care for their child.

Rationale Microdosing is a promising new method to obtain pharmacokinetic data in children with minimal burden and minimal risk. The use of a labelled oral microdose offers the added benefit to study intestinal and hepatic drug disposition in children already receiving an intravenous therapeutic drug dose for clinical reasons. Objective To present pilot data of an oral [ 14 C]paracetamol (AAP) microdosing study as proof of concept for this method to study developmental pharmacokinetics in children. Methods In an open microdose pharmacokinetic pilot study, infants (0–6 yrs of age) received a single oral [ 14 C]AAP microdose (3.3 ng/kg, 60 Bq/kg) in addition to intravenous therapeutic doses of AAP (15 mg/kg IV q6 h) prescribed by the treating physician to provide analgesia. Blood samples were taken from an indwelling catheter at multiple time points. AAP blood levels were measured by LC-MS/MS and [ 14 C]AAP and metabolites ([ 14 C]AAP-Glu and [ 14 C]AAP-4Sul) were measured by accelerator mass spectrometry. Results Ten infants (ranging from 0.1 to 83.1 months of age) were included, one patient was excluded from PK analysis, as he vomited shortly after administration. In all 9 patients, [ 14 C]AAP and metabolites in blood samples were detectable at expected concentrations. Dose normalised [ 14 C]AAP C max concentrations approached median C av intravenous concentrations: median 8.41 mg/L (range 3.75 to 23.78 mg/L) and 8.87 mg/L (range 3.45 to 12.9 mg/L), respectively. Conclusions We demonstrate the practical and ethical feasibility to use a [ 14 C]labelled microdose to study paracetamol pharmacokinetics, including metabolite disposition, in young children.

Background Since mortality in congenital diaphragmatic hernia (CDH) is decreasing, morbidity such as neurodevelopmental delay receives increased attention. We evaluated neurodevelopmental outcome in high-risk CDH patients treated according to the Euroconsortium standardised neonatal treatment protocol (Reiss, 2010). Methods Observational, prospective cohort study in CDH patients treated in two level-III university hospitals (Rotterdam (ECMO available) and Rome (no ECMO available)) between January 2009–April 2011. Sixty-three patients underwent standardised neurodevelopmental assessment at corrected age of 12 and 24 months by using Bayley Scales of Infant Development (BSID)-II-NL (Rotterdam; Dutch reference data) or BSID-III (Rome; US reference data). Both centres were analysed separately due to differences in assessment instruments. Results are presented as n (%), mean (SD) or median (range). Results Mortality was 24.1% and 20.5% in Rotterdam and Rome, respectively. Baseline characteristics were for Rotterdam (n = 36)/Rome (n = 27): observed to expected lung-to-head ratio 53.8% (19.1)/55.4% (15.8), p = 0.67; SNAP-II score (19 (0–40)/7 (0–25), p Conclusions At two years, the majority of CDH patients have normal cognition, but they are at risk for motor function delay. Future multicenter collaboration should focus on continuation of standardisation of treatment and follow-up to identify risk factors and reduce morbidity.

Background Congenital diaphragmatic hernia (CDH) is a life-threatening anomaly with significant mortality and morbidity. The lungs have a high susceptibility for oxygen and ventilation damage resulting in a high incidence of chronic lung disease (CLD). Aim To establish the optimal initial ventilation strategy in CDH. Methods In a prospective, randomised international multicenter trial initiated by the CDH Euroconsortium (VICI-trial, NTR 1310), prenatally diagnosed CDH neonates born between November 2008 and December 2013, were randomised for either conventional mechanical ventilation (CMV) or high-frequency oscillation ventilation (HFO) as initial ventilation mode. Primary outcome measure was death or CLD (Jobe and Bancalari, 2001) at day 28 analysed by multiple logistic regression analysis corrected for centre, lung-to-head ratio, liver position and side of defect. Secondary outcome was corrected for centre. Results Of the 171 included patients, 91 (53.2%) initially received CMV (median gestational age 38.1 weeks) and 80 (46.8%) HFO (median gestational age 38.0 weeks). In total, 21 (23.1%) patients ventilated by CMV died and 25 (31.3%) in HFO. Of the survivors, 21 (23.1%) had CLD in CMV and 18 (22.5%) in HFO. Primary outcome measure showed that in CMV 41 (45.1%) died or had CLD at day 28 and in HFO 43 (53.8%), OR 0.6, 95% CI [0.12–2.54]. Results of secondary outcome are shown in Table 1. Conclusions Although the primary outcome was statistically not significant, CDH patients initially ventilated by CMV were ventilated less days, received inotropics less days, and received less often nitric oxide, sildenafil and ECMO compared to HFO.

Introduction Early screening of paediatric delirium (PD) allows for early intervention if necessary. The aim of this study was to determine if early screening with the SOS-PD scale led to higher prevalence of PD in ICU patients. Methods A prospective before-after study design was applied in a population of children aged >3 months and admitted for ≥48 h to the PICU. In the before-period the prevalence of PD was estimated in terms of the number of children with PD confirmed by the consulting psychiatrist. During the after-period nurses systematically assessed the children with the SOS-PD scale three times a day in addition to the psychiatric consultation (SOS-PD score ≥4). Results 148 and 150 children were included in the before and after period, respectively. The prevalence of PD was 6.1% and 8.7% for the before and after period respectively (see Table). The relative risk of PD with early screening was 1:43 (95% CI 0.63 to 3.23). In 33 patients (22%) the SOS-PD score was ≥4 on one or more occasions. In 14 of these patients, the child psychiatrist was consulted. In the remaining patients the child psychiatrist was not consulted for the following reasons: only once a high score (n = 9), adverse effects of sedatives (n = 4), and underlying disease/motor restlessness (n = 6). Conclusions Systematic early screening of PD resulted in a higher incidence of PD and could contribute to timely start of treatment.

Background and aims Treatment of critically ill and preterm neonates includes the use of multiple drugs. Many drugs are unlicensed for children or used off-label. Recent changes of drug legislation by FDA and EMA should encourage more drug research in children. We aimed to study the current drugs used in a neonatal intensive care unit. Methods All drug prescriptions at the level III NICU of Erasmus MC from January 2007 till June 2013 were retrieved from the patient data management system. The product license of each drug was used to judge the label for use in neonatal age. Results A total of 4,054 neonates (2,240 males) with a median gestational age of 32+0 (range 23+6–42+2) weeks and a bodyweight at admission of median 1.8 (range 0.36–5.4) kg, were included. Most frequently administered drugs were benzyl-penicillin, gentamycin, caffeine, morphine and surfactant. Of the 24,903 prescriptions, 7,948 (32%) were off-label for neonatal age, and 1,932 (8%) were unlicensed for children. Conclusion The availability of adequately licensed drugs still shows important shortcomings. Almost all CNS drugs were off-label for neonatal age (93%) although few unlicensed for use in children (7%). On the other hand most antimicrobial drugs were on label (7%). We believe that drug research in neonates should have high priority to access safe and appropriate medicines.

Background In congenital diaphragmatic hernia (CDH) reliable postnatal predictors of outcome are scarce. Score for Neonatal Acute Physiology-II (SNAP-II) (Richardson, 2001) has been validated to predict mortality in newborns. We hypothesised that higher SNAP-II scores are found in non-survivors, those who need extracorporeal membrane oxygenation (ECMO), and those who develop chronic lung disease (CLD), defined as oxygen dependency at day 28. Methods In a prospective, randomised controlled multicenter trial initiated by the Euroconsortium (VICI-trial, NTR 1310), neonates born between November 2008 and December 2013, were randomised for initial ventilation strategy (either high-frequency oscillation or conventional mechanical ventilation). Prenatal, perinatal and postnatal data including SNAP-II scores were collected. Mann-Whitney U test was used for analyses. Data were presented as n (%) and median (IQR). Results Of the 173 included patients, 46 patients (26.6%) died, 39 (22.5%) underwent ECMO, and 38 patients (29.9%) of the survivors developed CLD. Overall, the SNAP-II score was 22.5 (10 to 37). In non-survivors SNAPP-II score was 40.0 (32.0 to 54.5) and 16.5 (7.8 to 26.5) in survivors (p Conclusions In this prospective multicenter study, we showed that in CDH patients SNAP-II scores may not only be useful to predict mortality but also to identify patients who need ECMO or are at risk for development of CLD.

Background and aims Health professionals in the PICU support both child and parents when the death of a child is imminent. The aim of this contribution is to emphasise that parents can suffer from the altered physical appearance of their child (e.g. severe oedema, bruises and cuts) but physical proximity in the final hours can help them cope. Methods Parents of 24 children who died 4 to 5 years ago in the ICU were invited for a semi-structured interview. Qualitative analysis was applied with Atlas-ti 7.0. Results Parents of 14 children (response rate 58.3%) participated. The children (aged 2 weeks to 13 years) were admitted in PICU from 2 h up to 7 months. The importance of the integrity of their child’s physical appearance stood out in their narratives. Parents spoke of the ‘damaged’ body as a result of necessary medical interventions, quote: “It was terrible, after the reanimation his ribs were broken. He was looking black. It was awful, really awful.” However, getting physically close to the child in the hour of death helped, quote: “We actually crept into bed with her bed, to hold her.” Caring for the body afterwards also helped parents, quote: “After she had died I brushed her teeth like I always did when the kids were smaller. That was so good to do.” Conclusions End-of-life care asks for awareness that the child’s damaged body deeply affects parents. Yet, being able to stay physically close helps them to be the parent they want to be.

Background and Aims Pediatric intensive care units (PICU) worldwide use different ventilators with a wide variety of ventilation modes. As an unambiguous international ventilation guideline, we developed one. After implementation we evaluated to what extent physicians adhered to the new guideline. Method We developed a ventilation guideline accounting for two groups: 1) heterogeneous lung disease, in which pressure control is the preferred mode; 2) homogeneous lung disease, in which pressure-regulated volume control is preferred. The guideline was implemented in October 2008. We performed an uncontrolled, retrospective before-after design with a pre-test from January to July 2008 (T0) and two post-tests: May-November 2009 (T1); May-November 2010 (T2). All patients on conventional invasive mechanical ventilation during these periods were included. Outcome measure was the percentage of physicians’ adherence to the ventilation protocol. We measured this by describing the ventilation mode on the first hour on the day of admission and the cause of respiratory failure, to distinguish in which group this patient belonged. Results In group 1, the T0 adherence percentage was 79% (67/85). Adherence percentages after implementation of the guideline were 71% (51/72) and 84% (46/55) for respectively T1 and T2. For group 1, adherence in period T2 was slightly better (p=0.092) than that in period T1. In group 2, adherence percentages rose statistically significantly from 66% at T0 (62/93) to 78% (79/101) and 84% (85/101) (p=0.015). Conclusion Implementation of a new ventilation guideline increased guideline adherence over time. Selection of the appropriate ventilation mode seems now clearer for physicians.

Over the last decade increasingly RCT’s have been published about optimal dosing of opioids and benzodiazepines in critically ill children of different age groups. In this way progress is made about optimal dosing as well as combination of therapies against the background of the use of novel ways of trial design. To this effect the application of population pharmacokinetics-pharmacodynamics (NON-MEM) using spare data have guided the design of trials preceded by in vitro simulation and prediction of dose effect responses. Both in the premature infant as well as in the so-called surgical newborn, dosages have been adjusted based on solid observational and experimental data sets for which the results should be evaluated. Apart from short term pharmacodynamic parameters such as validated pain scores, and eventually pharmacokinetic data analysis potentially equally important is the evaluation of long term consequences both of neonatal pain and the use of opioids. Experimental data have revealed increased neuro apoptosis in the developing brain. The data of a number of RCT’s conducted by our group will be combined with prospective longitudinal data recently acquired combining quantitative sensory testing (QST) under conditions of fMRI. In this way the question whether neonatal pain and/or opioid use results in altered pain response and long term negative sequelae can be answered.

A prospective study of 10 neonates with congenital diaphragmatic hernia and five controls to determine the importance of prostanoid concentrations perioperatively and the relation with persistent pulmonary hypertension (PPH) is reported. In neonates with congenital diaphragmatic hernia postoperative concentrations of the vasoconstrictor thromboxane B2 rose significantly and were higher during episodes of PPH; this rise may provoke PPH and subsequent right to left shunting.