Nutritional management of high-output ileostomies in paediatric patients is vital and more evidence-based guidelines are needed.

AIM: Paediatric patients with high-output ileostomies (HOI) face an elevated risk of complications. This study aimed to comprehensively review the existing literature and offer nutritional management recommendations for paediatric patients with an HOI. METHODS: PubMed and Embase were searched for relevant English or French language papers up to 31 June 2022. The emphasis was placed on studies involving paediatric ileostomy patients, but insights were obtained from adult literature and other intestinal failure pathologies when these were lacking. RESULTS: We identified 16 papers that addressed nutritional issues in paediatric ileostomy patients. Currently, no evidence supports a safe paediatric HOI threshold exceeding 20 mL/kg/day on two consecutive days. Paediatric HOI patients were at risk of dehydration, electrolyte disturbances, micronutrient deficiencies and growth failure. The primary dietary choice for neonates is bolus feeding with breastmilk. In older children, an enteral fluid restriction should be installed favouring isotonic or slightly hypotonic glucose-electrolyte solutions. A diet that is high in calories, complex carbohydrates and proteins, low in insoluble fibre and simple carbohydrates, and moderate in fat is recommended. CONCLUSION: Adequate nutritional management is crucial to prevent complications in children with an HOI. Further research is needed to establish more evidence-based guidelines.

Population pharmacokinetics of lisinopril in hypertensive children and adolescents with normal to mildly reduced kidney function.

AIMS: Lisinopril, an angiotensin-converting enzyme inhibitor, is a frequently prescribed antihypertensive drug in the paediatric population, while being used off-label under the age of 6 years in the USA and for all paediatric patients globally. The SAFEPEDRUG project (IWT-130033) investigated lisinopril pharmacokinetics in hypertensive paediatric patients corresponding with the day-to-day clinical population. METHODS: The dose-escalation pilot study included 13 children with primary and secondary hypertension who received oral lisinopril once daily in the morning; doses ranged from 0.05 to 0.2 mg kg-1 . Patients were aged between 1.9 and 17.9 years (median 13.5 years) and weight ranged between 9.62 and 97.2 kg (median 53.2 kg). All data were analysed using Monolix version 2020R1 (Lixoft, France) and R version 3.6.2. RESULTS: A 1-compartment model with first-order absorption and first-order elimination optimally describes the data. Parameter estimates of absorption rate constant (0.075 h-1 [0.062, 0.088], typical value [95% confidence interval]), volume of distribution (31.38 L 70 kg-1 [10.5, 52.3]) and elimination clearance (24.2 L h-1 70 kg-1 [19.5, 28.9]) show good predictive ability. Significant covariate effects include total body weight on elimination clearance, and distribution volume and estimated glomerular filtration rate (eGFR) on elimination clearance. The effects of eGFR on the elimination clearance are optimally described by a linear effect centred around 105 mL min-1  1.73 m-2 . The effects of body weight were implemented using fixed allometric exponents centred around an adult weight of 70 kg. CONCLUSION: Lisinopril dose and regimen adjustments for paediatric patients should include eGFR on top of weight adjustments. An expanded model characterizing the pharmacodynamic effect is required to identify the optimal dose and dosing regimen.

Time Is Money in Case of a Button Battery Ingestion.

Button battery (BB) ingestion is a preventable pediatric health hazard with important morbidity and mortality due to complications. We present 3 pediatric patients with a complicated course after BB ingestion and discuss current guidelines. Urgent endoscopic removal is necessary for every BB impacted in the esophagus. A new strategy before endoscopic removal is the administration of honey or sucralfate. During endoscopy, rinsing the esophageal mucosae with acetic acid can neutralize the alkalic environment and prevent late complications. Prevention of ingestion needs to be pursued by increasing awareness and changing legislation of packaging of BB.

Successful liver transplantation in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: Case report.

BACKGROUND: HHH syndrome is a rare autosomal recessive disorder of the urea cycle, caused by a deficient mitochondrial ornithine transporter. We report the first successful liver transplantation in HHH syndrome performed in a seven-year-old boy. The patient presented at 4 weeks of age with hyperammonemic coma. The plasma amino acid profile was suggestive of HHH syndrome, and the diagnosis was confirmed when sequencing of the SLC25A15 gene identified two mutations p.R275Q and p.A76D. Although immediate intervention resulted in normalization of plasma ammonia levels within 24 hours, he developed cerebral edema, coma, convulsions, and subsequent neurological sequelae. Metabolic control was difficult requiring severe protein restriction and continued treatment with sodium benzoate and L-arginine. Despite substantial developmental delay, he was referred to our center for liver transplantation because of poor metabolic control. Following cadaveric split liver transplantation, there was complete normalization of his plasma ammonia and plasma amino acid levels under a normal protein-containing diet. This excellent metabolic control was associated with a markedly improved general condition, mood and behavior, and small developmental achievements. Twelve years after liver transplantation, the patient has a stable cognitive impairment without progression of spastic diplegia. CONCLUSION: This first case of liver transplantation in HHH syndrome demonstrates that this procedure is a therapeutic option for HHH patients with difficult metabolic control.

Desmopressin oral lyophilisate in young children: new insights in pharmacokinetics and pharmacodynamics.

OBJECTIVE: To study the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of desmopressin (dDAVP) oral lyophilisate in children below the age of 8 years with special emphasis on age-related and size-related differences in bioavailability. DESIGN: Open label, non-randomised, interventional PK and PD trial. SETTING: Single-centre study. PATIENTS: Children (age: 6 months to 8 years) with nocturnal polyuria, including both children with uropathy or nephropathy (glomerular filtration rate >60 mL/min/1.73 m²) and children (age: 5-8 years) with severe monosymptomatic nocturnal enuresis, who were unresponsive to treatment with 400 µg of the dDAVP tablet for at least 1 month. INTERVENTIONS: After a water load, dDAVP was administered sublingually as a single dose of oral lyophilisate. Subsequently, blood and urine samples were collected until 7 hours post-administration. MAIN OUTCOME MEASURES: Non-compartmental analysis of PK parameters was performed based on dDAVP concentrations in both plasma and urine. To evaluate the effect of dDAVP lyophilisate (PD parameters), the urinary concentration capacity (urine osmolality (mOsm/kg)) and antidiuretic effect (diuresis rate (mL/kg/h)) were calculated. RESULTS: The PK data support the need for size-dependent dosing in children. Body weight was shown to be a significant covariate for apparent clearance (CL/F) and apparent volume of distribution (Vd/F). A double absorption peak of dDAVP lyophilisate in the first 2 hours post-administration was demonstrated. CONCLUSIONS: For the first time, a double absorption profile of dDAVP lyophilisate was found in children, questioning extrapolation of bioequivalence from adults towards children. Moreover, the need for size-adapted dosing regimens of dDAVP lyophilisate in young children is indicated. TRIAL REGISTRATION NUMBER: NTC02584231.

An Integrated Paediatric Population PK/PD Analysis of dDAVP: How do PK Differences Translate to Clinical Outcomes?

INTRODUCTION: The bioequivalence of two formulations of desmopressin (dDAVP), a vasopressin analogue prescribed for nocturnal enuresis treatment in children, has been previously confirmed in adults but not in children. In this study, we aimed to study the pharmacokinetics (PK) and pharmacodynamics (PD) of these two formulations, in both fasted and fed children, including patients younger than 6 years of age. METHODS: Previously published data from one PK study and one PK/PD study in children aged between 6 and 16 years were combined with a new PK/PD study in children aged between 6 months and 8 years, and analysed using population PK/PD modelling. Simulations were performed to further explore the relative bioavailability of both formulations and evaluate current dosing strategies. RESULTS: The complex absorption behaviour of the lyophilizate was modelled using a double input, linked to a one-compartmental model with linear elimination and an indirect response model linking dDAVP concentration to produced urine volume and osmolality. The final model described the observed data well and elucidated the complexity of bioequivalence and therapeutic equivalence of the two formulations. Simulations showed that current dosing regimens using a fixed dose of lyophilizate 120 µg is not adequate for children, assuming children to be in the fed state when taking dDAVP. A new age- and weight-based dosing regimen was suggested and was shown to lead to improved, better tailored effects. CONCLUSIONS: Bioequivalence and therapeutic equivalence data of two formulations of the same drug in adults cannot be readily extrapolated to children. This study shows the importance of well-designed paediatric clinical trials and how they can be analysed using mixed-effects modelling to make clinically relevant inferences. A follow-up clinical trial testing the proposed dDAVP dosing regimen should be performed. CLINICAL TRIAL REGISTRATION: This trial has been registered at www.clinicaltrials.gov (identifier NCT02584231; EudraCT 2014-005200-13).

Medical devices that look like medicines: safety and regulatory concerns for children in Europe.

INTRODUCTION: Medical devices (MedDevs) and medicines are assessed (and monitored) differently before and after launch. There are products for repeated oral ingestion that are marketed in the European Union as MedDevs. OBJECTIVES AND METHODS: To illustrate the consequences of these differences in assessment, we compared the leaflet information of three MedDevs with the standards for medicines and with published evidence at launch. As examples, gelatin tannate (GT), its combination with tyndalised probiotics (TP) (GTTP) for diarrhoea and a gel containing hyaluronic acid (HA)/chondroitin sulfate (CS)/poloxamer (Pol407) (HACSPol) for gastro-oesophageal reflux disease were examined. RESULTS: Applying standards for medicines, product composition is insufficiently defined in the MedDev leaflet (eg, plant origin, polymerisation grade, dose and ratio of the relevant constituents). As no age limit is mentioned in the leaflets, all 3 products allow use in children from birth onwards, although published clinical documentation in children was poor (GT) or lacking (GTTP and HACSPol). MedDev leaflets do not mention adverse events (AEs), while literature search suggests safety concerns such as tannic acid (TA) cytotoxicity, potentially more diarrhoea/AEs with TP, use of doses higher than established safe (TA and HA) and lack of chronic toxicity studies for oral Pol407. None refers to interactions with medicines, although some ingredients may affect medicine absorption. CONCLUSION: Although these MedDevs require repeated oral intake as do medicines, their assessment and monitoring differ significantly from the standards for medicines. Compared with medicines, MedDevs for repeated oral use are poorly labelled and rely on very limited clinical information at market release.

The perspectives of parents, general practitioners, and community pharmacists about treating an ill child in primary care: a comparative study.

As children are unable to make health-related decisions themselves, parents play a central role in consultations with healthcare providers. Parents' perspectives are therefore the focus of this study. Our first aim was to determine parents' expectations of a healthcare visit with a general practitioner and a community pharmacist. The second aim was to determine the general practitioners' and community pharmacists' perspectives about consultations with children. An observational cross-sectional study was conducted in April and May 2018. We developed three questionnaires: one for parents, one for general practitioners, and one for community pharmacists. The questionnaire for parents was only available through an online platform. The healthcare providers were questioned face-to-face and through an online platform. The study included 380 respondents. Parents considered prescribing or proposing medication the least important action by a general practitioner or community pharmacist, respectively. As well, parents expect information in most cases from both healthcare providers. The questionnaire for general practitioners and community pharmacists revealed that prescribing or proposing medication was regarded the least important action.Conclusion: Considering parents' expectations for a consultation with a general practitioner or community pharmacist, there is a substantial resemblance with the healthcare providers' perspective.What is Known:• The previous studies focusing on parents' perspectives were carried out in a hospital setting or focused on a specific disorder.• Parents consider reassurance and advice from their general practitioner to be very important; the treatment is considered less important.What is New:• Parents considered for both general practitioners' and community pharmacists' verbal information, answers to their questions, and reassurance as more important than receiving pharmacological treatment, while general practitioners and community pharmacists consider prescribing/proposing medication and providing written information as less important.• The expectations of the different groups (parents in relation to not only the healthcare providers but also the general practitioners and community pharmacists compared to each other) know a great resemblance.

Ethical considerations of researchers conducting pediatric clinical drug trials: a qualitative survey in two Belgian university children's hospitals.

There is a general consensus about the underlying theoretical ethical principles that ground the practice of pediatric clinical trials: scientific necessity, good risk/benefit ratio, minimized burden, and parental consent/child assent. However, these principles are so broadly construed that it is not always clear how they should be applied in clinical practice. We conducted a qualitative study at Ghent University Hospital and the hospital of the Dutch-speaking university of Brussels on how researchers weigh ethical principles, assess the risk/benefit balance, estimate patient experience, and experience informed consent procedures in pediatric drug studies. Based on our assessment of the burden and risk versus benefit ratio in 62 pediatric drug research protocols, we selected 21 studies for further study to maximize diversity. Twenty-seven researchers (17 physicians, 10 study nurses) completed a qualitative survey about their study. We compared their responses to our assessments. The risk benefit assessment of our participants about their own research projects resembled our assessment almost perfectly. Assessing burden appeared to be more subjective. The researchers were confident in their ability to obtain valid consent. However, we question whether this confidence is warranted. CONCLUSION: We argue for constant ethical reflexivity in pediatric clinical trials, because broad ethical principles are not always easy to apply to specific situations. What is Known: • Several international guidelines and a large body of scientific literature indicate a broad consensus about the basic ethical framework for pediatric clinical trials, based on risk benefit assessment and respect for autonomy. • Little is known about how researchers implement these broad principles in practice. What is New: • Researchers' risk/benefit assessments about their own studies resembled the assessment of neutral peers, assessing burden was more subjective. • Researchers were very confident in their ability to obtain valid informed consent.

Systemic fluoroquinolone prescriptions for hospitalized children in Belgium, results of a multicenter retrospective drug utilization study.

BACKGROUND: Fluoroquinolones (FQ) are increasingly prescribed for children, despite being labeled for only a limited number of labeled pediatric indications. In this multicenter retrospective drug utilization study, we analyzed indications for systemic FQ prescriptions in hospitalized children and the appropriateness of the prescribed dose. METHODS: Using data obtained from electronic medical files, the study included all children who received a systemic FQ prescription in two Belgian university children's hospitals between 2010 and 2013. Two authors reviewed prescribed daily doses. Univariate and multivariate logistic regression models were used to analyze risk factors for inadequately dosing. Results262 FQ prescriptions for individual patients were included for analysis. 16.8% of these prescriptions were for labeled indications, and 35.1% were guided by bacteriological findings. Prescribed daily dose was considered to be inappropriate in 79 prescriptions (30.2%). Other FQ than ciprofloxacin accounted for 9 prescriptions (3.4%), of which 8 were correctly dosed. Underdosing represented 45 (56.9%) dosing errors. Infants and preschool children were at particular risk for dosing errors, with associated adjusted OR of 0.263 (0.097-0.701) and 0.254 (0.106-0.588) respectively. CONCLUSIONS: FQ were often prescribed off-label and not guided by bacteriological findings in our study population. Dosing errors were common, particularly in infants and preschool children. FQ prescriptions for children should be improved by specific pediatric antimicrobial stewardship teams. Furthermore, pharmacokinetic studies should optimise dosing recommendations for children.

Population Pharmacokinetic Modeling of a Desmopressin Oral Lyophilisate in Growing Piglets as a Model for the Pediatric Population.

Desmopressin is used to treat primary nocturnal enuresis in children. Over the years, various formulations of desmopressin were commercialized of which the sublingual melt tablet is preferred in the pediatric population, despite the lack of full PK studies in this population. A full PK study was performed in growing conventional piglets to evaluate if this juvenile animal model can provide supplementary information to complement the information gap in the pediatric population. A desmopressin sublingual melt tablet (120 µg) was administered to 32 male piglets aged 8 days, 4 weeks, 7 weeks, and 6 months (each group n = 8). Population PK (pop-PK) analysis was performed to derive the PK parameters, the between- and within-subject variabilities and the effects of covariates. Desmopressin demonstrated two-compartmental PK, with a dual, sequential absorption process, and linear elimination. Body weight was the only significant covariate on clearance and on apparent volume of distribution of the central compartment. In human pediatric trials, no double peak in the absorption phase was observed in the plasma concentration-time curves, possibly due to the sparse sampling strategy applied in those pediatric studies. Therefore, it is recommended to perform additional studies, based on the sampling protocol applied in the current study.

Toxicity of long-term use of proton pump inhibitors in children.

Proton pump inhibitor (PPI) use is becoming increasingly common. Although the toxicity profiles of PPIs are not well understood particularly in children, PPIs have been associated with increased risks of gastrointestinal and respiratory tract infection, vitamin B12 deficiency, hypomagnesaemia, bone fractures, and rebound hyperacidity after discontinuation. Prescribers should take into account that PPI uses pose toxicity risks, which remain to be fully characterised in infants and children.

Confirmation of an ARID2 defect in SWI/SNF-related intellectual disability.

We present a 4-year-old girl with delayed neuromotor development, short stature of prenatal onset, and specific behavioral and craniofacial features harboring an intragenic deletion in the ARID2 gene. The phenotype confirmed the major features of the recently described ARID2-related intellectual disability syndrome. However, our patient showed overlapping features with Nicolaides-Baraitser syndrome and Coffin-Siris syndrome, providing further arguments to reclassify these disorders as "SWI/SNF-related intellectual disability syndromes."

Are antihistamines effective in children? A review of the evidence.

BACKGROUND AND AIMS: During the last decades, much attention has been paid to off-label and unlicensed prescriptions in paediatrics. However, on-label prescribing can also cause health issues. In this paper, the case of first-generation H1-antihistamines is investigated, notably the range of indications for which products are licensed in different European countries and the evidence base (or lack thereof) for each indication, as well as reported adverse drug reactions. METHODS: Review of the Summary of Product Characteristics of first-generation H1-antihistamines with a focus on paediatric use. This is plotted against the evidence available in the literature. RESULTS: This investigation shows a large variability in labelled indications and licensing ages when compared in five different European countries. Moreover, most of the indications are not based on clinical trials evaluating efficacy and safety of these drugs in children. CONCLUSIONS: Many of the licensed indications of first-generation antihistamines do not appear to be evidence based.

Therapeutic efficacy and safety of ACE inhibitors in the hypertensive paediatric population: a review.

PURPOSE: Since 1997, strong incentives have been introduced worldwide to improve access to safe and effective medicines addressing the therapeutic needs of children. ACE inhibitors, the most prescribed antihypertensive drugs in the paediatric population, are one of the prototype drugs targeted by the legislation initiatives. Our purpose in assembling this review is to evaluate and describe the current evidence for the efficacy and safety profile of ACE inhibitors in the paediatric population. METHODS: The authors made a descriptive review of the literature from 1980 to 2015 using the following search terms: hypertension, child, paediatric, ACE (inhibitors), renin-angiotensin aldosterone system, captopril, lisinopril, enalapril, ramipril and fosinopril. RESULTS: A total of 16 studies evaluating efficacy and safety of ACE inhibitors were included in this review. The included studies demonstrate that ACE inhibitors have the potency to decrease the systolic and/or diastolic blood pressure with an overall favourable safety profile in a short-term period. More importantly, the incentives resulted in an improvement of the overall availability of paediatric labelling, dosing and safety information for ACE inhibitors. However, they failed to fulfil several of paediatric needs: absence of long-term safety data on growth and maturation, absence of commercially available child-friendly formulations and incomplete evaluation of the entire paediatric hypertension population. CONCLUSION: Additional efforts are needed to close the gap between the availability of drugs that are labelled and indicated for paediatric use and the actual drug usage in children, especially in young children, neonates and children with severe hypertension, renal transplantation or severe renal impairment.

Effects of Food and Pharmaceutical Formulation on Desmopressin Pharmacokinetics in Children.

INTRODUCTION: Desmopressin is used for treatment of nocturnal enuresis in children. In this study, we investigated the pharmacokinetics of two formulations-a tablet and a lyophilisate-in both fasted and fed children. METHODS: Previously published data from two studies (one in 22 children aged 6-16 years, and the other in 25 children aged 6-13 years) were analyzed using population pharmacokinetic modeling. A one-compartment model with first-order absorption was fitted to the data. Covariates were selected using a forward selection procedure. The final model was evaluated, and sensitivity analysis was performed to improve future sampling designs. Simulations were subsequently performed to further explore the relative bioavailability of both formulations and the food effect. RESULTS: The final model described the plasma desmopressin concentrations adequately. The formulation and the fed state were included as covariates on the relative bioavailability. The lyophilisate was, on average, 32.1 % more available than the tablet, and fasted children exhibited an average increase in the relative bioavailability of 101 % in comparison with fed children. Body weight was included as a covariate on distribution volume, using a power function with an exponent of 0.402. Simulations suggested that both the formulation and the food effect were clinically relevant. CONCLUSION: Bioequivalence data on two formulations of the same drug in adults cannot be readily extrapolated to children. This was the first study in children suggesting that the two desmopressin formulations are not bioequivalent in children at the currently approved dose levels. Furthermore, the effect of food intake was found to be clinically relevant. Sampling times for a future study were suggested. This sampling design should result in more informative data and consequently generate a more robust model.

The Potential Use of Piglets as Human Pediatric Surrogate for Preclinical Pharmacokinetic and Pharmacodynamic Drug Testing.

Pediatric drug research is still substandard, not reaching the same quality level as adult drug research. Despite the efforts made by the Food and Drug Administration and European Medicines Agency to reduce off-label use in children, the lack of clinical studies involving the pediatric population still stands. Pharmacokinetic and pharmacodynamics studies (PK/PD) taking growth and maturation into account are necessary to rationalize dosing strategies in children. Currently, traditional animal models such as rats, mice, dogs and primates are used to conduct pharmacokinetic and pharmacodynamic studies, however age-related trials are rather uncommon. Moreover, these species have several shortcomings as animal models, such as a different physiology and anatomy of the gastrointestinal tract in dogs or the ethical aspects for the use of primates. In contrast, piglets might be potential biomedical pediatric animal models because of the good resemblance with humans, anatomically, physiologically and biochemically. This review summarizes the comparative anatomy and physiology and postnatal development of piglets and infants, focusing on six major topics, namely growth, cardiovascular system, gastrointestinal tract, liver, kidney and integument. Furthermore, the application of piglets as animal model in pediatric PK/PD research is discussed.

Challenging factors for enuresis treatment: Psychological problems and non-adherence.

The evidence for organic pathogenetic factors in enuresis and the discovery of effective therapies targeting the bladder and/or nocturnal diuresis have overwhelmed every potential role of psychological factors in pathogenesis and treatment. However, psychopathology is still important in enuresis because according to the document of the International Children's Continence Society (ICCS) 20-30% of the children with enuresis have at least one psychological/psychiatric disorder at rates two times higher than non-wetting children. The most common comorbid disorder with enuresis is attention deficit hyperactivity disorder. The aim of this review is to translate the existing evidence on the importance of a psychological screening into daily clinical practice of the medical practitioner. The use of the minimal psychological screening tool should be considered mandatory in each primary setting. If psychological problems are indicated, referral of the patient to a multidisciplinary setting should be considered, not only to allow psychological assessment to screen for a possible psychopathology, but also since therapy resistance might be expected. This review concentrates on two items from psychopathology/psychotherapy that might predict insufficient treatment response: the psychological comorbidities as described according to the DSM-5 criteria and the underestimated importance of therapy adherence. Adherence is a cornerstone of effective therapy in enuresis. It is a problem involving the doctor, the patient, and the parents. Increasing adherence takes effort and is time-consuming. But it is worthwhile knowing that several studies have demonstrated that high adherence is associated with high therapy success of enuresis. Eventually, this is the ultimate goal of treatment.