bluuebunny/crossref_metadata_2025_split huggingface dataset:
P19 Drug use in adolescents attending the emergency department for mental health problems
Authors: Buttera M , Clavenna A , Maselli E , Tansini L , Canevini MP , Bonati M 
Published: May 2019

BackgroundScant evidence is available regarding the pharmacological management of acute episodes of mental disorders in children and adolescents attending emergency departments (ED). In this regard, we performed a retrospective study with the aim to evaluate the pattern of psychotropic drug use in an ED of a large hospital.MethodsA retrospective chart review of adolescents (13–17 years) visited in the ED of San Paolo University Hospital in Milan for a mental disorder between January and June 2018 was conducted. In particular, information concerning age, gender, type of mental disorder, psychotropic drugs administered in the ED and outcome of the visit were extracted and analysed, using an anonymous patient code.ResultsA total of 1,298 adolescents 13–17 years old were visited during the observation period, 56 (4%) of whom had a diagnosis of mental disorder (35 females and 21 males).The most common disorder was predominant psychomotor disturbance (International Classification of Diseases 9 (ICD9) revision code 308.2; 12 patients), followed by anxiety disorder in conditions classified elsewhere (293.84, 8 patients) and anxiety states (300.0, 7 patients).Ten adolescents were hospitalised, while 16 (29%) received a psychotropic drug in the ED: 14 patients received a benzodiapine (8 delorazepam, 3 lorazepam), and 2 an antipsychotic drug (risperidone+olanzapine; promazine). Five out of 12 adolescents with psychomotor disturbance received a psychotropic drug (3 delorazepam, 1 lorazepam, 1 risperidone+olanzapine).Although no randomized controlled trial has evaluated the safety and effectiveness of benzodiazepines in the paediatric population, delorazepam was identified as the first choice pharmacological treatment for agitation in children and adolescents in a local protocol.ConclusionNearly all children received drugs for which no controlled trials have been performed in the paediatric population and for which the appropriateness is debatable. More evidence is needed to guide the pharmacological management of acute episodes of mental disorders.Disclosure(s)Nothing to disclose
P24 Caffeine in preterm neonates: impact on sleep wake regulation
Authors: Datta AN , Koch G , Schönfeld N , Jost K , Atkinson A , Schulzke SM , Pfister M 
Published: May 2019

BackgroundSleep wake regulation undergoes distinctive maturational changes. Ultradian sleep wake rhythm predominates at preterm age and is mainly driven by the internal clock. Increased perinatal morbidity in preterm neonates often appears with breathing disorders, among which apnea of prematurity (AOP) is the most frequently observed. Pharmacological support with caffeine has been successfully employed in the treatment of AOP. Nowadays, caffeine citrate is administered to all preterm neonates suffering from AOP. Objective of our study was a quantitative investigation of whether caffeine citrate treatment for reduction of apnea and bradycardia of prematurity affects sleep-wake behavior in preterm neonates.MethodsObservational study of 64 preterm neonates during their first five days of life with gestational age (GA) < 32 weeks or very low birth weight of < 1500 g. Total of 52 patients treated with caffeine and 12 controls without caffeine were included. Sleep-wake behavior was scored in wakefulness (W), active sleep (AS), and quiet sleep (QS) associated with physical and cerebral regeneration. Individual caffeine concentration of every neonate was simulated with a pharmacokinetic model.ResultsFor increasing caffeine concentration, W increased, AS decreased, and QS was unchanged for GA > or = 28 weeks. No caffeine effect for GA < 28 weeks could be demonstrated. Maturational effects could be seen when comparing preterm neonates of GA >32 weeks with a birth weight of < 1500 g with very preterm neonates born of GA < 32: Neonates born >32 weeks had a significantly higher amount of W and lower percentage of AS.ConclusionsTreatment of apnea and bradycardia as well as stabilization of respiration with standard caffeine treatment is not at cost of QS, i.e. time for physical and cerebral regeneration during sleep remains unchanged. There is an increased fraction of W, alertness and most probably also arousability.Disclosure(s)Nothing to disclose
P26 Pilot on harmonising dosing recommendation for term and preterm neonates in the Netherlands (Neodose project)
Authors: de Hoop-Sommen MA , van der Zanden TM , Allegaert K , Flint RB , Simons SHP , de Wildt SN , Consortium NeoDose 
Published: May 2019

BackgroundMany drugs are used off-label in term and preterm neonates, and dosing recommendations for many drugs are lacking in the Dutch Paediatric Formulary (DPF). This results in widely varying dosing regimens used across neonatal intensive care units (NICUs) in the Netherlands. The Neodose pilot project aimed to develop best-evidence national dosing recommendations for (pre)term neonates. Because scientific evidence is scarce, a consensus-based approach was used.MethodsA priority drug list, containing the most frequently used drugs for neonates, was drafted. From this list 22 drugs were selected for further research within the Neodose pilot project. The pilot utilized a two-step approach: First, consensus was established with all Dutch NICUs for neonatal dosing recommendations. Local treatment protocols were retrieved, compared and discussed, leading to consensus-based dosing recommendations. Secondly, we aimed to develop best-evidence dosing recommendations for the following five drugs: acyclovir, ganciclovir, ibuprofen, hydrocortisone and dexamethasone.ResultsFor 21 of 22 drugs, local dosing guidelines differed significantly. Mostly concerning total daily dose, dosing frequency and route of administration. Little or no distinction is made between treatment of preterm and term neonates. Approximately half of the consensus-based dosing recommendations (45%) differ in some degree from all local protocols. Comparing the consensus-based dosing recommendations with the available evidence, almost half of the consensus doses were adjusted. The grounds on which dosing recommendations were adjusted differed. Acyclovir-dosing adjustment was based on pharmacokinetics. Hydrocortisone-dosing was adjusted due to new insights after the evidence has been put together. For dexamethasone-dosing, the consensus dose was eventually chosen, because every available trial used a different dosing regimen.ConclusionThis pilot showed that, when evidence is inconclusive, consensus on dosing regimens in neonates can be obtained by comparing local regimens and analysing the available evidence. For more uniform use, these new recommendations will be published in the DPF.Disclosure(s)This project was funded by the federation of medical specialists for qualitative improvement (Stichting Kwaliteitsgelden Medisch Specialisten (SKMS).
P27 The juvenile pig as animal model for unraveling renal drug elimination processes in children
Authors: Dhondt L , Croubels S , De Paepe P , De Cock P , Devreese M 
Published: May 2019

BackgroundOver the years pigs were promoted as potential animal model for humans due to their high degree of anatomical and physiological similarities with humans. Gasthuys et al. demonstrated that the maturation of the kidney function in terms of the glomerular filtration rate (GFR) in growing pigs was comparable to humans, but no data are currently available on renal plasma flow, renal tubular secretion and reabsorption.1 The aim of this pilot study was to unravel the contribution of distinct renal elimination processes in juvenile pigs and to compare with reported human values.MethodsEight seven-week-old pigs were intravenously administered a single bolus of a cocktail of following renal markers: iohexol (64.7 mg/kg body weight (BW), GFR), para-aminohippuric acid (PAH, 10 mg/kg BW, effective renal plasma flow (ERPF) and anion secretion), pindolol (0.05 mg/kg BW, cation secretion) and fluconazole (0.5 mg/kg, tubular reabsorption). Plasma and urinary concentrations were determined for PAH, pindolol and fluconazole at several time points. Only plasma concentrations were assessed for iohexol. PK modelling was performed with Phoenix® WinNonlin®.ResultsThe clearance of iohexol was 97.9 ± 16.1 ml/min/m² (mean ± SD). The ERPF, calculated as the renal clearance of PAH, was 9.5 ± 2.1 ml/min/kg. These GFR and ERPF values are approximately a factor 1.3 higher than the values observed in humans, namely 63.5–75.0 mL/min/m² and 6.5 ± 2.0 mL/min/kg.2,3 The net tubular secretion of PAH was 5.4 ± 1.8 mL/min/kg, which was comparable with the values obtained in humans (5.0 ± 1.8 mL/min/kg).3 Results for cation secretion and tubular reabsorption are not yet available (to be presented at the congress).ConclusionThe net tubular secretion of PAH was comparable between the juvenile pigs and humans. The GFR and ERPF were generally a factor 1.3 higher in juvenile pigs compared to humans.ReferencesGasthuys E., et al., Postnatal maturation of the glomerular filtration rate in conventional growing piglets as potential juvenile animal model for preclinical pharmaceutical research. Frontiers in Pharmacology 2017. 8.Schwartz GJ, Furth SL. Glomerular filtration rate measurement and estimation in chronic kidney disease. Pediatric Nephrology 2007;22(11):1839–1848.Gross AS, et al., Simultaneous administration of a cocktail of markers to measure renal drug elimination pathways: absence of a pharmacokinetic interaction between fluconazole and sinistrin, p-aminohippuric acid and pindolol. British Journal of Clinical Pharmacology 2001. 51(6):547–555.Disclosure(s)This study was funded by the Special Research Fund of Ghent University (BOF16/DOC/285).
P28 Pharmacokinetics and implications for drug dosing in children with sickle cell disease: a systematic review
Authors: Dia N , Autmizguine J , Pastore Y , Litalien C , Rémy A , Amélie M , Théorêt Y , Kleiber N 
Published: May 2019

BackgroundChildren with sickle cell disease (SCD) are at high risk of intractable pain and severe infections despite early and aggressive drug treatment. SCD is a multisystemic disease potentially leading to liver and renal dysfunction. Altogether, those may lead to pharmacokinetic (PK) alterations, which may contribute to therapeutic failure or drug toxicity. We performed a systematic literature review to describe the current evidence on the effect of SCD on drug disposition in children.MethodsA systematic literature search was conducted by a librarian on 5 databases until 08.2018 and independently assessed by two reviewers. All full-text articles, containing PK data in children, were included. The reported differences in PK parameters between SCD and non-SCD children were examined.ResultsAmong 4213 retrieved abstracts, 50 full-text articles were assessed and 27 studies were included (13 exclusively children). Data on 15 drugs was available from which 5 were exclusively developed for SCD (impeding any comparison). From the remaining 10 drugs, a comparison of PK parameters was available in 8. Six were investigated in adults and children. Three (37.5%) showed significant PK alterations (morphine, cefotaxime,lidocaine) while 5 did not (hydroxyurea, sulfadoxine-pyrimethamine, methadone, rofecoxib,arginine butyrate). In children with SCD, clearance was higher by 42–61% for IV morphine, and by 24–62% for cefotaxime, compared with non-SCD controls. This difference led to a new dosing recommendation only for cefotaxime (400 mg/kg/day). Hepatic drug metabolism assessed by lidocaine was impaired in children with SCD compared to healthy controls.ConclusionSCD alters drug disposition of commonly used drugs but data is scarce. A significant increase in clearance of morphine and cefotaxime, two commonly used drugs in patients with SCD, suggests that recommended doses may not be sufficient to provide adequate analgesia and antimicrobial control. PK data is urgently needed to ensure adequate drug efficacy and safety in this high-risk population.ReferencesDong M, McGann PT, Mizuno T, et al. Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia. Brit J Clin Pharmacol. 2016;81:742–52.Gremse DA, et al. Hepatic function as assessed by lidocaine metabolism in sickle cell disease. J Pediatr 1998;132:989–93.Dampier CD, et al. Intravenous morphine pharmacokinetics in pediatric patients with sickle cell disease. J Pediatr 1995;126:461–7.Kopecky EA, et al. Systemic exposure to morphine and the risk of acute chest syndrome in sickle cell disease. Clin Pharmacol Ther 2004;75:140–6.Maksoud E, et al. Population Pharmacokinetics of Cefotaxime and Dosage Recommendations in Children with Sickle Cell Disease. Antimicrob Agents Chemother. 2018;62: e00637–1.Disclosure(s)Nothing to disclose
P36 What can be learnt from serious drug related medical errors in pediatric patients in Gothenburg 2015–2017?
Authors: Fjeldseth S 
Published: May 2019

Background2017 a rise in serious drug related medical errors in pediatric care at Sahlgrenska University hospital was discovered. 2018 a pediatric Clinical Decision Support System (CDSS) called ePed with weight based dose calculation, dosage control and easy access to pediatric drug information was integrated with the Electronic Medical Record.AimAnalyze causes and underlying factors to serious drug related medical errors, labeled Lex Maria, in children and further evaluate if these errors could be prevented within the framework of ePed.Method28 Lex Maria cases in children ≤16 years were registered during 2015–2017 at Sahlgrenska University hospital, Gothenburg. These were analyzed and summarized according to type of error, underlying cause and when during the drug managing process the error occurred. Finally, comparison between years was made.Results2015 and 2016 five Lex Maria cases occurred respectively. 2017 the number increased to 18 cases. Most commonly the patients received an incorrect dose. Errors divide equally between prescription, preparation and administration. Drugs requiring dilution were of certain risk especially when diluted in several steps. Midazolam was the most frequently involved drug. In 2017 especially one ward stands out in numbers and was responsible for 10 of the 18 cases.ConclusionsePed will help to avoid human calculation errors in prescription and provides easy access to pediatric drug information facilitating drug preparation and administration. Nurses are particularly exposed to medication incidents since they usually are the last link to the patient and need to be their own control. High-risk medicines need to be identified and made safe. A complex interplay between individual/human and systemic factors contribute to errors. However, to reduce serious drug related errors a CDSS is of great value but adequate education for medical staff, both pharmacologically and about the system is vital. Future follow up will be needed.Disclosure(s)Nothing to disclose
P40 Comparison of antibiotic consumption between pediatric hospitals
Authors: Gober H-J 
Published: May 2019

BackgroundAntibiotic exposure and reduced microbiome diversity in early childhood are associated with the incidence of inflammatory bowel disease,1 asthma2 and type-1 diabetes3 later in life. Together with the emergence of microbial resistance, those adverse effects of antibiotics impacting on the individual and population levels.Periodic monitoring of therapeutically used antibiotics in the framework of antimicrobial stewardship is required for their effective and restricted use in hospitals.Children´s hospitals face two challenges for a meaningful quantification of antibiotic consumption:§ Firstly, the algorithm DDD/inpatient days used in adult patients do not take into account the heterogeneity of the pediatric population. Up to date there is no global consensus on how to calculate and interpret the antibiotic consumption of wards and hospitals for children.§ Second challenge is the relative scarcity of suitable pediatric hospitals as basis for comparison.This study deals with the comparison and interpretation of antibiotic consumption between two similarly structured children´s hospitals in Austria.MethodologyThe annual use of antibiotics was assessed in two large pediatric clinical settings at geographically distinct locations in Austria, encompassing all relevant wards, such as neonatology, internal medicine, surgery, pediatric oncology and PICU´s. The analysis discriminates among the wards and classes of antibiotics.In addition to DDD and inpatient days, alternative parameters such as number of patient-admittances and number of used vials were included in the calculation.ResultPediatric-specific pitfalls affecting the quantification and comparability were identified:Hospital guidelines concerning the multiple usage of dissolved and diluted antibiotics.Regional composition of the pediatric patient population in terms of pathology.Intramural allocations of wards sharing the drug deposit.ConclusionUnexpected factors have severe impact on the reliability of annual antibiotic quantification and interpretation. Those factors need to be taken into account when comparing pediatric hospitals.ReferencesAm J Gastroenterol 2010 Dec;105(12):2687–92.Nat Commun 2018 Jan;9(1):141.Cell 2016 May;165(4):842–53.Disclosure(s)Nothing to disclose
P41 Prenatal exposure to antibiotics and development of epilepsy in children
Authors: Gorodischer R , Sassonker- Joseph N , Atar-Vardi M , Noyman I , Novak L 
Published: May 2019

BackgroundStudies reported that prenatal exposure to antibiotics in general represents a risk factor for development of epilepsy and/or cerebral palsy in children. A pathophysiological relationship seemed improbable and required adjustment to possible confounders.MethodsIn a retrospective cohort investigation, we enrolled children aged 3 to 18 years born between 1998 and 2012 at the single regional hospital, and their mothers, members of ‘Clalit’ (the largest Health Service Organization in the region). Computerized medications database was linked with hospital records of mothers and their children. The exposed group included all children whose mothers purchased one or more antibiotic medications during their pregnancy. Epilepsy was defined by Epilepsy diagnosis and/or by chronic dispensing of antiepileptic drugs. After applying inclusion and exclusion criteria for mothers and children, 88,899 children and their 74,416 mothers were selected for the study.ResultsThe group exposed prenatally to antibiotics comprised 36,622 (or 41.2%) children. Of them, 326 (0.9%) developed epilepsy compared to 370 (0.7%) in the unexposed group (p=0.002); Number Needed to Harm 500. Exposure during the first, second and third trimester was characterized by incidence of epilepsy in 0.8% (p= 0.928), 0.9% (p= 0.270) and 0.9% (p=0.094) of exposed children, respectively, compared to unexposed group Based on Poisson regression analysis, epilepsy was associated with male sex, maternal smoking and delivery by cesarean section. The possibility of confounding by indication was refuted by sensitivity analysis.ConclusionWe found an association of intrauterine exposure to antibiotics (particularly in late pregnancy) and development of epilepsy in children. Possible pathophysiological mechanisms are discussed. The effect of some undetermined confounder(s) cannot be ruled out.Disclosure(s)Nothing to disclose
O08 Pharmacokinetics of prophylactic and therapeutic fluconazole in preterm neonates
Authors: Engbers A , Flint RB , Völler S , Reiss IKM , Liem KD , Degraeuwe PLJ , Andriessen P , Alffenaar JWC , Koch BCP , Simons SHP , Knibbe CAJ , Brüggemann R 
Published: May 2019

IntroductionFluconazole is a first choice drug for neonatal cerebral candidiasis and for prevention of candidemia/invasive candidiasis in neonates. Selection of the optimal neonatal dose is difficult and requires solid multiple dose pharmacokinetic (PK) research to guide dosing decisions. We performed a pharmacokinetic study in preterm neonates who received fluconazole prophylactically or as treatment.MethodsPreterm neonates received fluconazole according to local protocol for either prophylaxis or treatment in 5 different hospitals. Samples were collected on multiple occasions with an opportunistic sampling scheme. Patient characteristics were bodyweight, birthweight, postnatal age (PNA), gestational age (GA), postmenstrual age, gender and weight for age. Population PK modelling was performed using NONMEM V.7.3.ResultsIn 44 preterm neonates (median (range) GA 25.3 (24.0–31.3) weeks), 153 plasma samples were collected. Median PNA at treatment initiation was 1 (0–59) day, treatment duration 11 (2–67) days and median PNA during treatment 15 (4–60) days. A one-compartment model described the data best, with an estimated clearance (CL) for a neonate of 0.84 kg and PNA of 15 days of 0.0147 L/h (RSE 4.3%, interindividual variability 21.4%) and volume of distribution (Vd) of 0.815 L (RSE 5.9%). Bodyweight was found to influence both CL and V­d, with exponents of 1.05 (RSE 13.4%) and 1.19 (RSE 22.4%), respectively. Maturation of CL was best described by an exponent of 0.184 on PNA (RSE 34.3%).ConclusionIn this pharmacokinetic study on fluconazole in preterm neonates, CL was influenced by both bodyweight and PNA while Vd was influenced by bodyweight only. These findings imply that initial dosing of fluconazole in preterm neonates should be based on bodyweight and that an increase of the dose with 32% during the first week and with 47% during the first month of life could be necessary because of increasing clearance with PNA.Disclosure(s)Nothing to disclose
P44 Type 2 diabetes mellitus in children: non-insulin medication, where are we up to?
Authors: Austin R , Paul P , Hawcutt D 
Published: May 2019

BackgroundChildhood type 2 diabetes mellitus (T2DM) is a relatively rare condition but is an important health concern as its prevalence continues to rise. Current management consists of lifestyle modification, metformin and insulin. Several new pharmacological classes are currently used in adult medicine but are not yet available in paediatric care.In this review we will look at the current evidence for use of these newer medications in the paediatric population.MethodsA literature search (EMBASE, Medline, Pubmed, CINHAL) was performed for papers studying the use of non-insulin medications in children; including a separate search of ´clinicaltrials.gov´ to identify any ongoing trials in paediatric T2DM.ResultsNewer classes of medications include incretin mimetics, dipeptidyl peptidase-4-inhibitors, sodium/glucose-cotransporter-2-inhibitors, and thiazolidinediones. There have been a small number of pharmacokinetic/pharmacodynamic studies carried out in small cohorts of paediatric participants, but larger long-term efficacy and safety trials are lacking. These studies and individual case-reports have shown good tolerability but are unable to identify any long-term effects associated with these medications.Randomised controlled trials studying rosiglitazone and glimepiride use in children have been performed. However, safety concerns in adults and notable side-effects including weight gain, mean their future use is uncertain.Currently many relevant trials involving paediatric patients listed on ´clinicaltrials.gov´ are awaiting completion.ConclusionMedical management for T2DM in children remains limited. Ongoing studies are aiming to equip practitioners with wider treatment options in the future. However, there are concerns regarding the long-term safety of these medications due to the increased risk of pancreatitis, gallbladder conditions and bladder malignancy in adult patients.Paediatric T2DM patients suffer from complications earlier and more severely compared with adults, making this is a pressing issue. Long-term surveillance studies to identify adverse effects and a framework for highlighting research gaps are required to enable improvements in paediatric T2DM management.Disclosure(s)Nothing to disclose