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Background: Recognizing a change in serum creatinine concentrations is useful to detect a renal adverse drug reaction signal. Assessing and characterizing the nephrotoxic side-effects of drugs in extremely low birth weight (ELBW, ≤1000 g) neonates remain challenging due to the high variability in creatinine in this population. This study aims to investigate and quantify the impact of ibuprofen treatment on kidney function, reflected by serum creatinine. Method: A recently developed dynamical model for serum creatinine was used to simulate creatinine profiles for typical, reference ELBW neonates with varying gestational and postnatal ages whilst being exposed to ibuprofen treatment. Results: The increase of serum creatinine concentrations due to ibuprofen treatment is most apparent during the first week of life. The difference in serum creatinine values between ibuprofen-exposed vs. non-exposed neonates decreases with increasing postnatal age, independent of gestational age. Conclusion: The difference in serum creatinine concentrations between ibuprofen-exposed vs. non-exposed neonates decreases with postnatal age, indicating an increased clearing capacity and resulting in a weak ibuprofen-related adverse drug reaction signal beyond early neonatal life.

Background: Disentangling renal adverse drug reactions from confounders remains a major challenge to assess causality and severity in neonates, with additional limitations related to the available tools (modified Kidney Disease Improving Global Outcome, or Division of Microbiology and Infectious Diseases pediatr

Pharmacotherapy in pediatric patients is challenging in view of the maturation of organ systems and processes that affect pharmacokinetics and pharmacodynamics. Especially for the youngest age groups and for pediatric-only indications, neonatal and juvenile animal models can be useful to assess drug safety and to better understand the mechanisms of diseases or conditions. In this respect, the use of neonatal and juvenile pigs in the field of pediatric drug discovery and development is promising, although still limited at this point. This review summarizes the comparative postnatal development of pigs and humans and discusses the advantages of the juvenile pig in view of developmental pharmacology, pediatric diseases, drug discovery and drug safety testing. Furthermore, limitations and unexplored aspects of this large animal model are covered. At this point in time, the potential of the neonatal and juvenile pig as nonclinical safety models for pediatric drug development is underexplored.

Breastfeeding plays a major role in the health and wellbeing of mother and infant. However, information on the safety of maternal medication during breastfeeding is lacking for most medications. This leads to discontinuation of either breastfeeding or maternal therapy, although many medications are likely to be safe. Since human lactation studies are costly and challenging, validated non-clinical methods would offer an attractive alternative. This review gives an extensive overview of the non-clinical methods (in vitro, in vivo and in silico) to study the transfer of maternal medication into the human breast milk, and subsequent neonatal systemic exposure. Several in vitro models are available, but model characterization, including quantitative medication transport data across the in vitro blood-milk barrier, remains rather limited. Furthermore, animal in vivo models have been used successfully in the past. However, these models don't always mimic human physiology due to species-specific differences. Several efforts have been made to predict medication transfer into the milk based on physicochemical characteristics. However, the role of transporter proteins and several physiological factors (e.g., variable milk lipid content) are not accounted for by these methods. Physiologically-based pharmacokinetic (PBPK) modelling offers a mechanism-oriented strategy with bio-relevance. Recently, lactation PBPK models have been reported for some medications, showing at least the feasibility and value of PBPK

COVID-19 also affects pregnant and breastfeeding women. Hence, clinicians and policymakers require reliable evidence on COVID-19 epidemiology and consequences in this population. We aimed to assess the susceptibility of pregnant women to SARS-CoV-2 and women’s perceived impact of the pandemic on their breastfeeding practices, medical counseling and social support. We performed a cross-sectional study using an online survey in primary care in Belgium. Pregnant and breastfeeding women and women who breastfed in the preceding four weeks were eligible to participate. The survey was distributed through social media in April 2020. In total, 6470 women participated (i.e., 2647 pregnant and 3823 breastfeeding women). Overall, 0.3% of all respondents reported to have tested positive for SARS-CoV-2, not indicating a higher susceptibility of pregnant women to contracting COVID-19. More than 90% refuted that the pandemic affected their breastfeeding practices, nor indicated that the coronavirus was responsible for breastfeeding cessation. Half of the women even considered giving longer breastmilk because of the coronavirus. In contrast, women’s medical counseling and social support were negatively affected by the lockdown. Women without previous breastfeeding experience and in the early postpartum period experienced a higher burden in terms of reduced medical counseling and support. In the future, more consideration and alternative supportive measures such as tele-visits by midwives or perinatal organizations are required for these women.

Background Neonatal hypoxic ischaemic encephalopathy due to perinatal asphyxia, can result in severe neurodevelopmental disability or mortality. Hypothermia is at present the only proven neuroprotective intervention. During hypothermia, the neonate may need a variety of drugs with their specific pharmacokinetic profile. The aim of this paper is to determine the effect that hypothermia for neonates suffering from hypoxic ischaemic encephalopathy has on the pharmacokinetics and to what extent dosing regimens need adjustments. Method A systematic search was performed on PubMed, Embase and Cochrane Library of literature (2000–2020) using a combination of the following search terms: therapeutic hypothermia, neonate, hypoxic ischemic encephalopathy and pharmacokinetics. Titles and abstracts were screened, and inclusion/exclusion criteria were applied. Finally, relevant full texts were read, and secondary inclusion was applied on the identified articles. Results A total of 380 articles were retrieved, and 34 articles included after application of inclusion/exclusion criteria and duplicate removal, two additional papers were included as suggested by the reviewers. Twelve out of 36 studies on 15 compounds demonstrated a significant decrease in clearance, be it that the extent differs between routes of elimination and compounds, most pronounced for renal elimination (phenobarbital no difference, midazolam metabolite −21%, lidocaine −24%; morphine −21% to −47%, gentamicin −25% to −35%, amikacin −40%) during hypothermia. The data as retrieved in literature were subsequent compared with the dosing regimen as stated in the Dutch paediatric formulary. Conclusion Depending on the drug-specific disposition characteristics, therapeutic hypothermia in neonates with hypoxic ischaemic encephalopathy affects pharmacokinetics.

Background Prematurity disrupts the perinatal maturation of the microvasculature and macrovasculature and confers high risk of vascular dysfun

Background: Preterm infants commonly present with oral feeding problems. The role of maturation of esophageal bolus transport mechanisms herein remains unclear. Objectives: To characterize esophageal motility and function of esophagogastric junction (EGJ) during deglutitive swallowing in healthy preterm infants and to describe maturational changes. Methods: Four consecutive high-resolution manometry studies with impedance studies were performed weekly to investigate esophageal motility and EGJ function. Esophageal pressure topography and pressure-impedance metrics were derived. Mixed models with repeated measures were used for statistical analysis. Results: We analyzed 137 nutritive swallows from 36 motility studies in 10 preterm infants. The mean gestational age was 30.17 ± 0.94 weeks; the mean postmenstrual age at time point 1 and 4 was 34.42 ± 0.86 and 37.45 ± 1.16 weeks, respectively. Esophageal peristaltic wave patterns in response to nutritive swallows were observed in all patients. At later time points, esophageal body peristalsis became more rapid, evidenced by a faster distal contractile velocity and shorter distal latency (p = 0.002 and p < 0.0001, respectively). In addition, 4-s integrated relaxation pressures increased and distal contractile integral decreased at later time points (p = 0.003 and p = 0.021, respectively). Bolus clearance also improved at later age (p = 0.008). Conclusions: Preterm infants demonstrate peristaltic esophageal motility following nutritive swallows. However, alterations in esophageal bolus transport in relation to peristalsis are demonstrated. Peristaltic progression becomes more rapid, while deglutitive relaxation pressures increase with increasing age. These maturational changes may suggest further development of the enteric

Background: To characterize esophageal motility and function of the esophagogastric junction (EGJ) in preterm infants with bronchopulmonary dysplasia (BPD). Methods: High-resolution manometry with impedance was used to investigate esophageal motility and EGJ function in 28 tube-fed preterm infants with BPD. Patients with BPD were studied at term age during oral feeding. Thirteen healthy term-aged infants were included as controls. Esophageal analysis derived objective measures to evaluate esophageal contractile vigor, bolus distension pressure, EGJ relaxation, and EGJ barrier function (in rest and during respiration). In addition, we investigated the effect of BPD severity on these measures. Key results: A total of 140 nutritive swallows were analyzed (BPD, n = 92; controls, n = 48). Normal esophageal peristaltic wave patterns were observed in all infants. BPD patients had higher distal contractile esophageal strength compared with controls (Kruskal-Wallis (KW) P =.048), and their deglutitive EGJ relaxation was comparable to controls. Severe BPD patients showed higher bolus distension pressures, higher EGJ resting pressures, and increased EGJ contractile integrals compared with mild BPD patients (Mann-Whitney U P =.009, KW P =.012 and KW P =.028, respectively). Conclusions and Inferences: Preterm infants with BPD consistently present with normal peristaltic esophageal patterns following nutritive liquid swallows. The EGJ barrier tone and relaxation pressure appeared normal. In general, infants with BPD do not have altered esophageal motor function. There is however evidence for increased flow resistance at the EGJ in severe BPD patients possibly related to an increased contractility of the diaphragm.

Renal precision medicine in neonates is useful to support decision making on pharmacotherapy, signal detection of adverse (drug) events, and individual prediction of short- and long-term prognosis. To estimate kidney function or glomerular filtration rate (GFR), the most commonly measured and readily accessible biomarker is serum creatinine (Scr). However, there is extensive variability in Scr observations and GFR estimates within the neonatal population, because of developmental physiology and superimposed pathology. Furthermore, assay related differences still matter for Scr, but also exist for Cystatin C. Observations in extreme low birth weight (ELBW) and term asphyxiated neonates will illustrate how renal precision medicine contributes to neonatal precision medicine. When the Kidney Disease Improving Global Outcome (KDIGO) definition of acute kidney injury (AKI) is used, this results in an incidence up to 50% in ELBW neonates, associated with increased mortality and morbidity. However, urine output criteria needed adaptations to broader time intervals or weight trends, while Scr and its trends do not provide sufficient detail on kidney function between ELBW neonates. Instead, we suggest to use assay-specific centile Scr values to better describe postnatal trends and have illustrated its relevance by quantifying an adverse drug event (ibuprofen) and by explaining individual amikacin clearance. Term asphyxiated neonates also commonly display AKI. While oliguria is a specific AKI indicator, the majority of term asphyxiated cases are non-oliguric. Asphyxia results in a clinical significant—commonly transient—mean GFR decrease (−50%) with a lower renal drug elimination. But there is still major (unexplained) inter-individual variability in GFR and subsequent renal drug elimination between these asphyxiated neonates. Recently, the Baby-NINJA (nephrotoxic injury negated by just-in-time action) study provided evidence on the concept that a focus on nephrotoxic injury n

Health-care professionals who prescribe medicines have the professional duty to choose medicines that are in the best interest of their individual patient, irrespective if that patient is an adult or a child. However, the availability of medicines with an appropriate label for pediatric use is lagging behind those for adults, and even available pediatric drugs are sometimes not suitable to administer to children. Consequently, health-care professionals often have no other option than to prescribe off-label medicines to children. An important reason for use of off-label medicines is to improve access to (innovative) treatments or to address medical needs and preferences of patients, especially when no other options are available. However, off-label use of medicines is in general not supported by the same level of evidence as medicines licensed for pediatric use. This may result in increased uncertainty on efficacy as well as the risk for toxicity and other side effects. In addition, liability may also be of concern, counterbalanced by professional guidelines. Conclusion: The purpose of this joint EAP/ESDPPP policy statement is to offer guidance for HCPs on when and how to prescribe off-label medicines to children and to provide recommendations for future European policy.

Antimicrobial prophylaxis during surgery aims to prevent post-operative site infections. For fetal surgery, this includes the fetal and amniotic compartments. Both are deep compartments as drug equilibrium with maternal blood is achieved relatively late. Despite prophylaxis, chorio-amnionitis or endometritis following ex utero intrapartum treatment or fetoscopy occur in 4.13% and 1.45% respectively of the interventions. This review summarizes the observations on two commonly administered antimicrobials (cefazolin, clindamycin) for surgical prophylaxis during pregnancy, with emphasis on the deep compartments. For both compounds, antimicrobial exposure is on target when we consider the maternal and fetal plasma compartment. In contrast, amniotic fluid concentrations-time profiles display a delayed and much more blunted pattern, behaving as deep compartment. For cefazolin, there are data that document further dilution in the setting of polyhydramnios. Along this deep compartment concept, there is some accumulation during repeated administration, modeled for cefazolin and observed for clindamycin. The relative underexposure to antimicrobials in amniotic fluid may be reflected in the pattern of maternal-fetal complications after fetal surgery, and suggest that antimicrobial prophylaxis practices for fetal surgery should be reconsidered. Further studies should be designed by a multidisciplinary team (fetal surgeons, clinical pharmacologists and microbiologists) to facilitate efficient evaluation of antimicrobial prophylaxis.

Preterm infants are obviously born lighter and shorter, with smaller head circumferences than normal birth weight term born neonates. They also have a different body composition. Compromised growth is associated with adverse health outcomes. Both growth retardation and accelerated growth are suggested to cause metabolic, cardiovascular, and renal complications. Reviews regarding growth and body composition in preterm infants often do not differentiate between birth weight and gestational age. The purpose of this systematic review is to assemble growth data, specific in extremely low birth weight children. Different databases were searched for studies regarding growth and body composition in former extremely low birth weight infants until adulthood. We compared height, weight, head circumference, body mass index, fat mass, lean mass, fat distribution, and body water to matched normal birth weight co

Background: Bacterial and fungal infections are common and often contribute to death in patients undergoing extracorporeal membrane oxygenation (ECMO). Drug disposition is altered during ECMO, and adsorption in the circuit is an established causative factor. Vancomycin and voriconazole are widely used, despite the lack of evidence-based prescription guidelines. Objective: The objective of this study was to determine the extraction of voriconazole and vancomycin by the Xenios/Novalung ECMO circuits. Methods: We have set up nine closed-loop ECMO circuits, consisting of four different iLAActivve® kits for neonatal, pediatric, and adult support: three iLA-ActivveMiniLung® petite kits, two iLA-ActivveMiniLung® kits, two iLA-ActivveiLA® kits, and two iLA-Activve X-lung® kits. The circuits were primed with whole blood and maintained at physiologic conditions for 24 h. Voriconazole and vancomycin were injected as a single-bolus age-related dose into the circuits. Pre-membrane (P2) blood samples were obtained at baseline and after drug injection at 2, 10, 30, 180, 360 min, and 24 h. A control sample at 2 min was collected for spontaneous drug degradation testing at 24 h. Results: Seventy-two samples were analyzed in triplicate. The mean percentage of drug recovery at 24 h was 20% for voriconazole and 62% for vancomycin. Conclusions: The extraction of voriconazole and vancomycin by contemporary ECMO circuits is clinically relevant across all age-related circuit sizes and may result in reduced drug exposure in vivo.

There are guidelines on lactation following maternal analgo-sedative exposure, but these do not consider the effect of maternal fasting or fluid abstention on human milk macronutrient composition. We therefore performed a structured search (PubMed) on ‘human milk composition’ and screened title, abstract and full paper on ‘fasting’ or ‘abstention’ and ‘macronutrient composition’ (lactose, protein, fat, solids, triglycerides, cholesterol). This resulted in six papers and one abstract related to

Glomerular filtration (GF) and active tubular secretion (ATS) contribute to renal drug elimination, with the latter remaining understudied across the pediatric age range. Therefore, we systematically analyzed the influence of transporter ontogeny on the relative contribution of GF and ATS to renal clearance CLR for drugs with different properties in children. A physiology-based model for CLR in adults was extrapolated to the pediatric population by including maturation functions for the system-specific parameters. This model was used to predict GF and ATS for hy

Drug dosing in neonates should be based on integrated knowledge concerning the disease to be treated, the physiological characteristics of the neonate, and the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. It is critically important that all sources of information be leveraged to optimize dose selection for neonates. Sources may include data from adult studies, pediatric studies, non-clinical (juvenile) animal models, in vitro studies, and in silico models. Depending on the drug development program, each of these modalities could be used to varying degrees and with varying levels of confidence to guide dosing. This paper aims to illustrate the variability between neonatal drug development programs for neonatal diseases that are similar to those seen in other populations (meropenem), neonatal diseases related but not similar to pediatric or adult populations (clopidogrel, thyroid hormone), and diseases unique to neonates (caffeine, surfactant). Extrapolation of efficacy from older children or adults to neonates is infrequently used. Even if a disease process is similar between neonates and children or adults, such as with anti-infectives, additional dosing and safety information will be necessary for labeling, recognizing that dosing in neonates is confounded by maturational PK in addition to body size.

Therapeutic hypothermia (TH) is standard treatment for neonates (≥36 weeks) with perinatal asphyxia (PA) and hypoxic–ischemic encephalopathy. TH reduces mortality and neurodevelopmental disability due to reduced metabolic rate and decreased neuronal apoptosis. Since both hypothermia and PA influence physiology, they are expected to alter pharmacokinetics (PK). Tools for personalized dosing in this setting are lacking. A neonatal hypothermia physiology-based PK (PBPK) framework would enable precision dosing in the clinic. In this literature review, the stepwise approach, benefits and challenges to develop such a PBPK framework are covered. It hereby contributes to explore the impact of non-maturational PK covariates. First, the current evidence as well as knowledge gaps on the impact of PA and TH on drug absorption, distribution, metabolism and excretion in neonates is summarized. While reduced renal drug elimination is well-documented in neonates with PA undergoing hypothermia, knowledge of the impact on drug metabolism is limited. Second, a multidisciplinary approach to develop a neonatal hypothermia PBPK framework is presented. Insights on the effect of hypothermia on hepatic drug elimination can partly be generated from in vitro (human/animal) profiling of hepatic drug metabolizing enzymes and transporters. Also, endogenous biomarkers may be evaluated as surrogate for metabolic activity. To distinguish the impact of PA versus hypothermia on drug metabolism, in vivo neonatal animal data are needed. The conventional pig is a well-established model for PA and the neonatal Göttingen minipig should be further explored for PA under hypothermia conditions, as it is the most commonly used pig strain in nonclinical drug development. Finally, a strategy is proposed for establishing and fine-tuning compound-specific PBPK models for this application. Besides improvement of clinical exposure predictions of drugs used during hypothermia, the developed PBPK models can be applie

Effective and safe pain relief in neonates matters. This is not only because of ethical constraints or human empathy, but even more because pain treatment is an important and crucial part of contemporary medical, paramedical, and nursing care to improve the outcome in neonatal intensive care graduates. Paracetamol (acetaminophen) is likely one of the pharmacological tools to attain this, with data on prescription practices suggesting that paracetamol is somehow the “rising star” in neonatal pain management. Besides very rare topical clinical scenarios like peripartal asphyxia and subsequent whole body hypothermia or the use of cardiorespiratory support devices, data on paracetamol pharmacokinetics and metabolism were reported throughout neonatal age or weight ranges, and we have summarized these data. In this review, we subsequently aimed to provide the reader with the currently available observations on the use of paracetamol as analgesic for different pain syndromes (major surgery, minor surgery or trauma, and procedural pain), with focus on the limitations of paracetamol when prescribed for neonatal procedural pain

Various cohort studies document a lower glomerular filtration rate (GFR) in former extremely low birth weight (ELBW, <1000 g) neonates throughout childhood when compared to term controls. The current aim is to pool these studies to describe the GFR pattern over the pediatric age range. To do so, we conducted a systematic review on studies reporting on GFR measurements in former ELBW cases while GFR data of healthy age-matched controls included in these studies were co-collected. Based on 248 hits, 6 case-control and 3 cohort studies were identified, with 444 GFR measurements in 380 former ELBW cases (median age 5.3-20.7 years). The majority were small (17-78 cases) single center studies, with heterogeneity in GFR measurement (inulin, cystatin C or creatinine estimated GFR formulae) tools. Despite this, the median GFR (mL/min/1.73 m2) within case-control studies was consistently lower (-13%, range -8% to -25%) in cases, so that a relevant minority (15-30%) has a eGFR<90 mL/min/1.73 m2). Consequently, this pooled analysis describes a consistent pattern of reduced eGFR in former ELBW cases throughout childhood. Research should focus on perinatal risk factors for impaired GFR and long-term outcome, but is hampered by single center cohorts, study size and heterogeneity of GFR assessment tools.

Background: Neonatal withdrawal secondary to in utero opioid exposure is a growing global concern stressing the psychosocial well-being of affected families and scarce hospital resources. In the ongoing search for the most effective treatment, randomized controlled trials are indispensable. Consistent outcome selection and measurement across randomized controlled trials enables synthesis of results, fostering the translation of research into practice. Currently, there is no core outcome set to standardize outcome selection, definition and reporting. This study identifies the outcomes currently reported in the literature for neonates experiencing withdrawal following opioid exposure during pregnancy. Methods: A comprehensive literature search of MEDLINE, EMBASE and Cochrane Central was conducted to identify all primary research studies (randomized controlled trials, clinical trials, case-controlled studies, uncontrolled trials, observational cohort studies, clinical practice guidelines and case reports) reporting outcomes for interventions used to manage neonatal abstinence syndrome between July 2007 and July 2017. All "primary" and "secondary" neonatal outcomes were extracted by two independent reviewers and were assigned to one of OMERACT's core areas of "pathophysiological manifestation", "life impact", "resource use", "adverse events", or "death". Results: Forty-seven primary research articles reporting 107 "primary" and 127 "secondary" outcomes were included. The most frequently reported outcomes were "duration of pharmacotherapy" (68% of studies, N = 32), "duration of hospital stay" (66% of studies, N = 31) and "withdrawal symptoms" (51% of studies, N = 24). The discrepancy between the number of times an outcome was reported and the number of articles was secondary to the use of composite outcomes. Frequently reported outcomes had heterogeneous definitions or were not defined by the study and were measured at dif

Background and Objective: Although acetaminophen is frequently used during pregnancy, little is known about fetal acetaminophen pharmacokinetics. Acetaminophen safety evaluation has typically focused on hepatotoxicity, while other events (fetal ductal closure/constriction) are also relevant. We aimed to develop a fetal–maternal physiologically based pharmacokinetic (PBPK) model (f-m PBPK) to quantitatively predict placental acetaminophen transfer, characterize fetal acetaminophen exposure, and quantify the contributions of specific clearance pathways in the term fetus. Methods: An acetaminophen pregnancy PBPK model was extended with a compartment representing the fetal liver, which included maturation of relevant enzymes. Different approaches to describe placental transfer were evaluated (ex vivo cotyledon perfusion experiments, placental transfer prediction based on Caco-2 cell permeability or physicochemical properties [MoBi®]). Predicted maternal and fetal acetaminophen profiles were compared with in vivo observations. Results: Tested approaches to predict placental tr

The clinical management and subsequent outcome of pediatric and neonatal patients can improve significantly with the availability of effective and safe medicines if appropriately investigated in the relevant population [1]. This is also the case for neonates treated with hypothermia for perinatal asphyxia. However, the vast majority of medicines are developed with adult pathophysiology in mind and are not guided by neonatal (patho)physiology. Drug development is mainly driven by adult indications, subsequently tailored or repurposed for use in neonates, with exogenous surfactant as the latest but hopefully not last example of drug discovery specific to neonates [2].

The clinical management and subsequent outcome of pediatric and neonatal patients can improve significantly with the availability of effective and safe medicines if appropriately investigated in the relevant population [1]. This is also the case for neonates treated with hypothermia for perinatal asphyxia. However, the vast majority of medicines are developed with adult pathophysiology in mind and are not guided by neonatal (patho)physiology. Drug development is mainly driven by adult indications, subsequently tailored or repurposed for use in neonates, with exogenous surfactant as the latest but hopefully not last example of drug discovery specific to neonates [2].

BACKGROUND and OBJECTIVE Paracetamol is the most used analgesic in older people. The physiological changes occurring with ageing influence the pharmacokinetics of paracetamol and its variability. A population pharmacokinetic analysis to describe the pharmacokinetics of intravenous paracetamol in fit older people was performed. Thereafter, simulations were conducted to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg q6h, q8h) using steady-state concentration (Css-mean) of 10 mg/L as target for effective analgesia. DESIGN and METHODS A population pharmacokinetic-analysis, using NONMEM 7.2, was performed based on 601 concentrations of paracetamol from 30 fit

Rational medicine use in neonates implies the prescription and administration of age-appropriate drug formulations, selecting the most efficacious and safe dose, all based on accurate information on the drug and its indications in neonates. This review illustrates that important uncertainties still exist concerning the different aspects (when, what, how) of rational antibiotic use in neonates. Decisions when to prescribe antibiotics are still not based on robust decision tools. Choices (what) on empiric antibiotic regimens should depend on the anticipated pathogens, and the available information on the efficacy and safety of these drugs. Major progress has been made on how (beta-lactam antibiotics, aminoglycosides, vancomycin, route and duration) to dose. Progress to improve rational antibiotic use necessitates further understanding of neonatal pharmacology (short- and long-term safety, pharmacokinetics, duration and route) and the use of tailored tools and smarter practices (biomarkers, screening for colonization, and advanced therapeutic drug monitoring techniques). Implementation strategies should not only facilitate access to knowledge and guidelines, but should also consider the most effective strategies (‘skills’) and psychosocial aspects involved in the prescription process: we should be aware that both the decision not to prescribe as well as the decision to prescribe antibiotics is associated with risks and benefits.

Background: Increasing numbers of children undergo ambulatory surgery each year and a significant proportion experiences substantial preoperative anxiety and postoperative pain. The management of perioperative anxiety and pain remains challenging in children and is inadequate, which negatively impacts physical, psychosocial, and economic outcomes. Existing non-pharmacological interventions are costly, time consuming, vary in availability, and lack benefits. Therefore, there is a need for an evidence-based, accessible, non-pharmacological intervention as an adjunct to existing pharmacological alternatives to reduce perioperative anxiety and pain in children undergoing ambulatory surgery. Technology-enabled interventions have been proposed as a method to address the unmet need in this setting. In particular, serious games for health (SGHs) hold unique potential to change health beliefs and behaviors in children. Objective: The objective of this research was to describe the rationale, scientific evidence, design aspects, and features of CliniPup, an SGH aimed at reducing perioperative anxiety and pain in children undergoing ambulatory surgery. Methods: The SERES framework for SGH development was used to create the SGH, CliniPup. In particular, a mixed-methods approach was applied that consisted of a structured literature review supplemented with ethnographic research, such as expert interviews and a time-motion exercise. The resulting scientific evidence base was leveraged to ensure that the resulting SGH was relevant, realistic, and theory-driven. A participatory design approach was applied wherein clinical experts qualitatively reviewed several versions of the SGH and an iterative creative process was used to integrate the applicable feedback. Results: CliniPup, an SGH, was developed to incorporate (1) scientific evidence base from a structured literature review, (2) realistic content collected during ethnographic research such as expert interviews, (3) explicit peda

Purpose There is a need for alternative analgosedatives such as dexmedetomidine in neonates. Given the ethical and practical difficulties, protocol design for clinical trials in neonates should be carefully considered before implementation. Our objective was to identify a protocol design suitable for subsequent evaluation of the dosing requirements for dexmedetomidine in mechanically ventilated neonates. Methods A published paediatric pharmacokinetic model was used to derive the dosing regimen for dexmedetomidine in a firstin-neonate study. Optimality criteria were applied to optimise the blood sampling schedule. The impact of sampling schedule optimisation on model parameter estimation was assessed by simulation and re-estimation procedures for different simulation scenarios. The optimised schedule was then implemented in a neonatal pilot study. Results Parameter estimates were more precise and similarly accurate in the optimised scenarios, as compared to empirical sampling (normalised root mean square error: 1673.1% vs. 13,229.4% and relative error: 46.4% vs. 9.1%). Most importantly, protocol deviations from the optimal design still allowed reasonable parameter estimation. Data analysis from the pilot group (n = 6) confirmed the adequacy of the optimised trial protocol. Dexmedetomidine pharmacokinetics in term neonates was scaled using allometry and maturation, but results showed a 20% higher clearance in this population compared to initial estimates obtained by extrapolation from a slightly older paediatric population. Clearance for a typical neonate, with a post-menstrual age (PMA) of 40 weeks and weight 3.4 kg, was 2.92 L/h. Extension of the study with 11 additional subjects showed a further increased clearance in pre-term subjects with lower PMA. Conclusions The use of optimal design in conjunction with simulation scenarios improved the accuracy and precision of the estimates of the parameters of interest, taking into account protocol deviations, whic

Background: A number of studies examined the association between preterm delivery and kidney size and function later in life. However, the number of cases in published cohort studies is low. This study was aimed at performing a multicenter collaboration to pool data to obtain more accurate results to quantify the extent of renal impairment in former extremely low birth weight (ELBW; <1,000 g) children. Methodology: We performed a subject-level metaanalysis to pool data from Cracow (64 cases/34 controls) and Leuven (93 cases/87 controls). We assessed and analyzed cystatin C, estimated glomerular filtration rate (eGFR), ultrasound kidney length, and blood pressure (BP) in 11-year-old ELBW children compared with controls born at term. The prevalence of hypertension (HT) and prehypertension (preHT) in both groups was also analyzed. Results: The study group comprised 157 former ELBW children (gestational age 23–33 weeks and birth weight 430–1,000 g) and 123 children born at term. Former ELBW children had lower mean eGFR (100.62 ± 16.53 vs. 111.89 ± 15.26 mL/min/1.73 m2; p < 0.001), smaller absolute kidney length (8.56 ± 0.78 vs. 9.008 ± 0.73 cm; <0.001), and higher systolic (111.8 ± 9.8 vs. 107.2 ± 9.07 mm Hg; p = 0.01) and diastolic (68.6 ± 6.8 vs. 66.3 ± 7.7 mm Hg; p = 0.03) BP. Smaller renal size in former ELBW children was positively associated with lower birth weight, shorter gestational age, and severity of perinatal complications (intraventricular hemorrhage, length of stay, mechanical ventilation, and oxygen therapy). Conclusion: ELBW is associated with lower eGFR and a high frequency of preHT and HT.

Introduction Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that impairs normal lung development, causing pulmonary hypertension (PH). PH in CDH newborns is the main determinant for morbidity and mortality. Different therapies are still mainly based on trial and error'. Inhaled nitric oxide (iNO) is often the drug of first choice. However, iNO does not seem to improve mortality. Intravenous sildenafil has reduced mortality in newborns with PH without CDH, but prospective data in CDH patients are lacking. Methods and analysis In an open label, multicentre, international randomised controlled trial in Europe, Canada and Australia, 330 newborns with CDH and PH are recruited over a 4-year period (2018-2022). Patients are randomised for intravenous sildenafil or iNO. Sildenafil is given in a loading dose of 0.4 mg/kg in 3 hours; followed by continuous infusion of 1.6 mg/kg/day, iNO is dosed at 20 ppm. Primary outcome is absence of PH on day 14 without pulmonary vasodilator therapy and/or absence of death within the first 28 days of life. Secondary outcome measures include clinical and echocardiographic markers of PH in the first year of life. We hypothesise that sildenafil gives a 25% reduction in the primary outcome from 68% to 48% on day 14, for which a sample size of 330 patients is needed. An intention-to-treat analysis will be performed. A p-value (two-sided) <0.05 is considered significant in all analyses. Ethics and dissemination Ethics approval has been granted by the ethics committee in Rotterdam (MEC-2017-324) and the central Committee on Research Involving Human Subjects (NL60229.078.17) in the Netherlands. The principles of the Declaration of Helsinki, the Medical Research Involving Human Subjects Act and the national rules and regulations on personal data protection will be used. Parental informed consent will be obtained.

BACKGROUND and OBJECTIVE: Paracetamol is the most used analgesic in older people. The physiological changes occurring with ageing influence the pharmacokinetics of paracetamol and its variability. A population pharmacokinetic analysis to describe the pharmacokinetics of intravenous paracetamol in fit older people was performed. Thereafter, simulations were conducted to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg q6h, q8h) using steady-state concentration [Css-mean] of 10 mg/L as target for effective analgesia. DESIGN and METHODS: A population pharmacokinetic-analysis. using N0NMEM 7.2. was performed based on 601 concentrations of paracetamol from 30 fit older people (median age = 77.3 years [61.8-88.5], body weight = 79 kg 160-107)1. All had received an intravenous paracetamol dose of 1000 mg - over 15 min - after elective knee surgery. RESULTS: A two-compartment pharmacokinetic-model best described the data. Volume of distribution of paracetamol increased exponentially with body weight. Clearance was not influenced by any covariate. Simulations of the standardized dosing regimens resulted in a Css-mean of 9.2 mg/L Iq6h) and 7.2 mg/L Iq8h|. Variability in paracetamol pharmacokinetics resulted in a Css-mean above 5.4 (q6h| and 4.1 mg/L (q8h) in 90%. and above 15.5 Iq6h) and 11.7 mg/L Iq8h) in 10% of the population. CONCLUSION: The target concentration was achieved in the average patient with 1000 mg q6h, while q8h resulted in underdosing for the majority of the population. Due to large unexplained interindividual variability in paracetamol pharmacokinetics a relevant proportion of the fit older people remained either under- or overexposed.

Background and Objectives Uncertainty exists regarding the optimal dosing regimen for vancomycin in diferent patient populations, leading to a plethora of subgroup-specifc pharmacokinetic models and derived dosing regimens. We aimed to investigate whether a single model for vancomycin could be developed based on a broad dataset covering the extremes of patient characteristics. Furthermore, as a benchmark for current dosing recommendations, we evaluated and optimised the expected vancomycin exposure throughout life and for specifc patient subgroups. Methods A pooled population-pharmacokinetic model was built in NONMEM based on data from 14 diferent studies in diferent patient populations. Steady-state exposure was simulated and compared across patient subgro

__Introduction__ High morbidity and mortality rates of proven bacterial infection are the main reason for substantial use of intravenous antibiotics in neonates during the first week of life. In older children, intravenous-to-oral switch after 48 hours of intravenous therapy has been shown to have many advantages and is nowadays commonly practised. We, therefore, aim to evaluate the effectiveness, safety and cost-effectiveness of an early intravenous-to-oral switch in neonates with a probable bacterial infection. __Methods and analysis__ We present a protocol for a multicentre randomised controlled trial assessing the non-inferiority of an early intravenous-to-oral antibiotic switch compared with a full course of intravenous antibiotics in neonates (0-28 days of age) with a probable bacterial infection. Five hundred and fifty patients will be recruited in 17 hospitals in the Netherlands. After 48 hours of intravenous treatment, they will be assigned to either continue with intravenous therapy for another 5 days (control) or switch to amoxicillin/clavulanic acid suspension (intervention). Both groups will be treated for a total of 7 days. The primary outcome will be bacterial (re)infection within 28 days after treatment completion. Secondary outcomes are the pharmacokinetic profile of oral amoxicillin/clavulanic acid, the impact on quality of life, cost-effectiveness, impact on microbiome development and additional yield of molecular techniques in diagnosis of probable bacterial infection. __Ethics and dissemination__ This study has been approved by the Medical Ethics Committee of the Erasmus Medical Centre. Results will be presented in peer-reviewed journals and at international conferences.

Children undergoing cardiac surgery often receive acetaminophen (paracetamol) as part of their postoperative pain treatment. To date, there is no information on the pharmacokinetics (PK) of acetaminophen in this special population, even though differences, as a result of altered hemodynamics and/or use of cardiopulmonary bypass, may be anticipated. Therefore, the aim of this study was to investigate the PK of intravenous acetaminophen in children after cardiac surgery with cardiopulmonary bypass. In the study, both children with and without Down syndrome were included. A population PK analysis, using NONMEM 7.2, was performed based on 161 concentrations of acetaminophen, acetaminophen sulfate, acetaminophen glucuronide, and oxidative metabolites from 17 children with Down syndrome and 13 children without Down syndrome of a previously published study (median age, 177 days [range, 92–944], body weight, 6.1 kg [4.0–12.9]). All children received 3 intravenous acetaminophen doses of 7.5 mg/kg (<10 kg) or 15 mg/kg (10 kg) at 8–hour intervals after cardiac surgery. For acetaminophen and its metabolites, 1-compartment models were identified. Clearance of acetaminophen and metabolites increased linearly with body weight. Acetaminophen clearance in a typical child of 6.1 kg is 0.96 L/h and volume of distribution 7.96 L. Down syndrome did not statistically significantly impact any of the PK parameters for acetaminophen, nor did any other remaining covariate.When comparing the PK parameters of acetaminophen in children after cardiac surgery with cardiopulmonary bypass with those from children of the same age following noncardiac surgery reported in the literature, clearance of acetaminophen was lower and volume of distribution higher.

Background and Objective: Little is known about acetaminophen (paracetamol) pharmacokinetics during pregnancy. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict acetaminophen pharmacokinetics throughout pregnancy. Methods: PBPK 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 pharmacokinetics were considered. Models were evaluated using goodness-of-fit plots and by comparing predicted pharmacokinetic profiles with in vivo pharmacokinetic data. Predictions were performed to illustrate the average concentration at steady state (Css,avg) values, used as an indicator for efficacy, of acetaminophen achieved following administration of 1000 mg every 6 h. Furthermore, as a measurement of potential hepatotoxicity, the molar dose fraction of acetaminophen converted to N-acetyl-p-benzoquinone imine (NAPQI) was estimated. Results: PBPK models successfully predicted the pharmacokinetics of acetaminophen and its metabolites in non-pregnant and pregnant women. Predictions resulted in the lowest Css,avg in the third trimester (median [interquartile range]: 4.5 [3.8–5.1] mg/L), while Css,avg was 6.7 [5.9–7.4], 5.6 [4.7–6.3], and 4.9 [4.1–5.5] mg/L in non-pregnant, first trimester, and second trimester populations, respectively. Assuming a constant raised cytochrome P450 2E1 activity throughout pregnancy, the molar dose fraction of acetaminophen converted to NAPQI was highest during the first trimester (median [interquartile range]: 11.0% [9.1–13.4%]), followed by the second (9.0% [7.5–11.0%]) and third trimester (8.2% [6.8–10.1%]), compared with non-pregnant women (7.7% [6.4–9.4%]). Conclusion: Acetaminophen exposure is lower in pregnant than in non-pregnant women, and is related to pregnancy duration. Despite these findings, higher dose adjustments cannot be advised yet as it is unknown whether preg

Background: Esophageal atresia is a major congenital foregut anomaly. Affected patients often suffer from respiratory and gastro-intestinal morbidity. The objective of this study is to identify possible neonatal predictive factors contributing to a long-term complicated clinical course in patients after repair of esophageal atresia. Methods: A total of 93 patients born between 1993 and 2013, with esophageal atresia and surviving the neonatal period were included in this retrospective study. A complicated clinical course was defined as the occurrence of 1 of these complications: severe gastroesophageal reflux, esophageal stricture requiring dilatations, need for tube feeding for >100 days, severe tracheomalacia, severe chronic respiratory disease and death. We used linear models with a binomial distribution to determine risk factors for gastro-intestinal or respiratory complicated evolution and a backward stepwise elimination procedure to reduce models until only significant variables remained in the model. Multinomial logistic regression was used to assess risk factors for different evolutions of complication. Model parameter estimates were used to calculate odds ratios for significant risk factors. Results: Fifty-seven patients (61%) had a complicated clinical course in the first year of life and 47 (51%) had a complicated evolution during years 1e6. In the first year, prematurity was a significant factor for complicated gastro-intestinal (OR 2.84) and respiratory evolution (OR 2.93). After 1 year, gastro-intestinal morbidity in childhood was associated with VACTERL association (OR 12.2) and a complicated first year (OR 36.1). Respiratory morbidity was associated with congenital heart disease (OR 12.9) and a complicated first year (OR 86.9). Multinomial logistic regression showed that prematu

Retinal microvascular traits predict adverse health outcomes. The Singapore I Vessel Assessment (SIVA) software improved automated postprocessing of retinal photographs. In addition to microvessel caliber, it generates measures

Background--No longitudinal study compared associations of echocardiographic indexes of diastolic left ventricular function studies with conventional (CBP) and daytime ambulatory (ABP) blood pressure in the general population. Methods and Results--In 780 Flemish (mean age, 50.2 years; 51.7% women), we measured left atrial volume index (LAVI), peak velocities of the transmitral blood flow (E) and mitral annular movement (e0) in early diastole and E/e0 9.6 years (median) after CBP and ABP. In adjusted models including CBP and ABP, we expressed associations per 10/5-mm Hg systolic/diastolic blood pressure increments. LAVI and E/e0 were 0.65/0.40 mL/m2 and 0.17/0.09 greater with higher systolic/diastolic ABP (P≤0.028), but not with higher baseline CBP (P≤0.086). e0 was lower (P≤0.032) with higher diastolic CBP (-0.09 cm/s) and ABP (-0.19 cm/s). When we substituted baseline CBP by CBP recorded concurrently with echocardiography, LAVI and E/e0 remained 0.45/0.38 mL/m2 and 0.15/0.08 greater with baseline ABP (P≤0.036), while LAVI (+0.53 mL/m2) and E/e0 (+0.19) were also greater (P < 0.001) in relation to concurrent systolic CBP. In categorized analyses of baseline data, sustained hypertension or masked hypertension compared with normotension or white-c

To attain effective and safe pharmacotherapy, formulations in (pre)term neonates should enable extensive dose flexibility. During product development and subsequent authorization and clinical use of such formulations, there is also a need for informed decisions on excipient exposure: in addition to the need to improve the knowledge on active compounds, there is a similar need to improve the knowledge on excipients in neonates. Excipients are added to formulations as co-solvent, surfactant, preservative, colorant and/or sweetener as vehicle(s) to result in a suitable (e.g. taste, shelf life, stability) product. Progress has been made in the awareness, knowledge and access to this knowledge on the clinical pharmacology of excipients in neonates. This is thanks to different initiatives focussing on epidemiological data, excipient pharmacokinetics, or building datasets to create this knowledge. We highlight the Safe Excipient Exposure in Neonates and Small Children (SEEN) and propylene glycol project to illustrate the feasibility to build knowledge, and discuss the methods applied and problems observed during these studies. The information generated in these and other studies (European Study on Neonatal Exposure to Excipients, ESNEE) should be integrated in repositories like the Safety and Toxicity of Excipients for Paediatrics (STEP) to facilitate access to all stakeholders. This merged knowledge should have impact and assist in improving the quality of risk assessment and decision making during drug development, applying a risk-benefit framework (explicit justification of excipients, plan product development early and engage all stakeholders, data sharing and modeling, challenges related to new excipients, context sensitive risk-benefit analysis).

Background: Congenital diaphragmatic hernia is an orphan disease with high neonatal mortality and significant morbidity. An important cause for this is pulmonary hypertension, for which no effective postnatal therapy is available to date. An innovative strategy aiming at treating or preventing pulmonary hypertension more effectively is urgently needed. Prenatal sildenafil administration to expectant mothers prevented fetal and neonatal vascular changes leading to pulmonary hypertension in several animal models, and is, therefore, a promising approach. Before transferring this antenatal medical approach to the clinic, more information is needed on transplacental transfer and safety of sildenafil in humans. Methods: This is a randomized, investigator-blinded, double-armed, parallel-group, phase I/II

Purpose: Ibuprofen is the drug of choice for treatment of patent ductus arteriosus (PDA). There is accumulating evidence that current ibuprofen-dosing regimens for PDA treatment are inadequate. We aimed to propose an improved dosing regimen, based on all current knowledge. Methods: We performed a literature search on the clinical pharmacology and effectiveness of ibuprofen. (R)- and (S)-ibuprofen plasma concentration-time profiles of different dosing regimens were simulated using a population pharmacokinetic model and evaluated to obtain a safe, yet likely more efficacious ibuprofen exposure. Results: The most effective intravenous ibuprofen dosing in previous clinical trials included a first dose of 20 mg kg−1 followed by 10 mg kg−1 every 24 h. Simulations of this dosing regimen show an (S)-ibuprofen trough concentration of 43 mg L−1 is reached at 48 h, which we assumed the target through concentration. We show that this target can be reached with a first dose of 18 mg kg−1, followed by 4 mg kg−1 every 12 h. After 96 h postnatal age, the dose should be increased to 5 mg kg−1 every 12 h due to maturation of clearance. This twice-daily dosing has the advantage over once-daily dosing that an effective trough level may be maintained, while peak concentrations are substantially (22%) lower. Conclusions: We propose to improve intermittent ibuprofen-dosing regimens by starting with a high first dose followed by a twice-daily maintenance dosing regimen that requires increase over time and should be continued until sufficient effect has been achieved.

Paracetamol is the most commonly used analgesic in older people, and is mainly dosed according to empirical dosing guidelines. However, the pharmacokinetics and thereby the effects of paracetamol can be influenced by physiological changes occurring with ageing. To investigate the steps needed to reach more evidence-based paracetamol dosing regimens in older people, we applied the concepts used in the paediatric study decision tree. A search was performed to retrieve studies on paracetamol pharmacokinetics and safety in older people (> 60 years) or studies that performed a (sub) analysis of pharmacokinetics and/or safety in older people. Of 6088 articles identified, 259 articles were retained after title and abstract screening. Further abstract and full-text screening identified 27 studies, of which 20 described pharmacokinetics and seven safety. These studies revealed no changes in absorption with ageing. A decreased (3.9–22.9%) volume of distribution (Vd) in robust older subjects and a further decreased Vd (20.3%) in frail older compared with younger subjects was apparent. Like Vd, age and frailty decreased paracetamol clearance (29–45.7 and 37.5%) compared with younger subjects. Due to limited and heterogeneous evidence, it was difficult to draw firm and meaningful conclusions on changed risk for paracetamol safety in older people. This review is a first step towards bridging knowledge gaps to move to evidence-based paracetamol dosing in older subjects. Remaining knowledge gaps are safety when using therapeutic dosages, pharmacokinetics changes in frail older people, and to what extent changes in paracetamol pharmacokinetics should lead to a change in dosage in frail and robust older people.

Objectives: A novel paradigm of diastolic left ventricular (LV) dysfunction proposes involvement of the cardiac microvasculature. Vitamin K dependent matrix Gla protein (MGP) plays a role in preserving microcirculatory integrity. We hypothesized that LV filling pressure–a measure of diastolic LV dysfunction–increases with higher plasma level of inactive desphospho-uncarboxylated MGP (dp-ucMGP). We also studied the dist

Hypertension and chronic kidney disease (CKD) have a significant impact on global morbidity and mortality. The Low Birth Weight and Nephron Number Working Group has prepared a consensus document aimed to address the relatively neglected issue for the developmental programming of hypertension and CKD. It emerged from a workshop held on April 2, 2016, including eminent internationally recognized experts in the field of obstetrics, neonatology, and nephrology. Through multidisciplinary engagement, the goal of the workshop was to highlight the association between fetal and childhood development and an increased risk of adult diseases, focusing on hypertension and CKD, and to suggest possible practical solutions for the future. The recommendations for action of the consensus workshop are the results of combined clinical experience, shared research expertise, and a review of the literature. They highlight the need to act early to prevent CKD and other related noncommunicable diseases later in life by reducing low birth weight, small for gestational age, prematurity, and low nephron numbers at birth through coordinated interventions. Meeting the current unmet needs would help to define the most cost-effective strategies and to optimize interventions to limit or interrupt the developmental programming cycle of CKD later in life, especially in the poorest part of the world.

Because the highest rates of morbidity and mortality in neonates are seen in those born at <32 weeks’ gestation, this group has the most urgent need for novel therapies to improve survival and outcome. Legislative efforts in the United States and Europe have attempted to address this issue by requiring the study of drugs, biological and nutritional products, devices, and other therapies in this population through a combination of high-quality regulatory and clinical trials, quality improvement initiatives, and observational studies. Because there are relatively small numbers of very preterm neonates born each year in any 1 country or continent, and because a significant number of clinical trials are recruiting at any 1 time, a neonate may meet enrollment criteria for >1 clinical trial. Neonatal units that have the infrastructure and resources to engage in research frequently face the question of whether it is permissible to enroll a neonate in >1 trial. This article examines the pertinent scientific, ethical, regulatory, and industry issues that should be taken into account when considering enrolling neonates in multiple clinical studies.

Objective: This review addresses sedation management on paediatric intensive care units and possible gaps in the knowledge of optimal sedation strategies. We present an overview of the commonly used sedatives and their pharmacokinetic and pharmacodynamic considerations in children, as well as the ongoing studies in this field. Also, sedation guidelines and current sedation strategies and assessment methods are addressed. Key findings: This review shows that evidence and pharmacokinetic data are scarce, but fortunately, there is an active research scene with promising new PK and PD data of sedatives in children using new study designs with application of advanced laboratory methods and modelling. The l