BRIEF REPORT | doi:10.20944/preprints202004.0043.v1
Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: lactation; physiology-based lactation models; drug exposure prediction; fasting; drug safety; newborn; infant; human milk
Online: 6 April 2020 (09:11:05 CEST)
There are guidelines on lactation following maternal analgo-sedative exposure, but these do not consider the effect of maternal fasting, nor 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 6 papers and one abstract related to religious fasting (n=129 women) and observational studies in lactating women (n=23, healthy volunteers, fasting). These data reflect two different ‘fasting’ patterns: an acute (18-25h) model in 71 (healthy volunteers, Yom Kippur/Ninth of Av) women and a chronic fasting (Ramadan) model in 81 women. Changes were most related to electrolytes and were moderate, with almost no changes in macronutrients during acute fasting. We therefor conclude that neither short term fasting nor fluid abstention (18-25h) affect human milk macronutrient composition, so that women can be reassured when this topic were raised during consulting. Besides the nutritional relevance, this also matters as clinical research samples – especially to estimate analgo-sedative exposure by lactation - are commonly collected after maternal procedural sedation, associated with maternal fasting and physiology-based pharmacokinetic (PBPK) models assume stable human milk composition.
ARTICLE | doi:10.20944/preprints202001.0213.v1
Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: glomerular filtration rate; Brenner hypothesis; extreme low birth weight infants; renal outcome
Online: 19 January 2020 (05:12:19 CET)
Different cohort studies documented 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/kg/1.73m2) 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 mgl/kg/1.73m2). 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.
ARTICLE | doi:10.20944/preprints202110.0077.v1
Subject: Public Health And Healthcare, Nursing Keywords: questionnaire development; lactation; breastfeeding; analgesics; education; knowledge assessment; midwife; nurse
Online: 5 October 2021 (10:57:49 CEST)
There is a need to assess the knowledge of healthcare providers on the use of maternal analgesics during lactation, while a valid instrument is not yet available. This study aimed to develop a valid and reliable questionnaire on the knowledge of analgesics (acetaminophen, ibuprofen, aspirin, tramadol, codeine, oxycodone) during lactation, using a prospective, stepwise approach. To generate a pool of item subgroups, literature was assessed as first step. This preliminary version was subsequently reviewed in two focus groups [midwives (n=4), pediatric nurses (n=6)], followed by an expert panel (n=7, 2 rounds) to confirm content validity [item-level and scale content validity]. This resulted in a instrument consisting of 33 questions, and 5 clincial case descriptions specific for both disciplines. Based on known-groups validity between midwives and pediatric nurses (assuming an a priori difference related to their curricula), high construct validity was subsequently demonstrated in a pilot e-survey (86 midwives, 73 pediatric nurses). We therefore conclude that an instrument to assess knowledge on lactation-related exposure to analgesics was generated, that can be further developed and validated. Furthermore, pilot findings suggest suboptimal knowledge for both professions, so that adaptations in their curricula and postgraduate training are warranted.
ARTICLE | doi:10.20944/preprints202208.0135.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: physiologically based pharmacokinetic modelling; propofol; low cardiac output; pharmacokinetics; neonate; developmental pharmacology; asphyxia; hypothermia; pediatrics; pharmacokinetics
Online: 8 August 2022 (06:12:36 CEST)
Background: pathophysiological changes like low cardiac output (LCO) impact pharmacokinetics, but its extent may be different throughout pediatrics compared to adults. Physiologically based pharmacokinetic (PBPK) modelling enables further exploration. Methods: A validated propofol model was used to simulate the impact of LCO on propofol clearance across age groups using the PBPK platform, Simcyp® (version 19). The hepatic and renal extraction ratio of propofol was then determined in all age groups. Subsequently, dose explorations were conducted under LCO conditions, targeting a 3 µg/mL (80-125%) propofol concentration range. Results: Both hepatic and renal extraction ratios increased from neonates, infants, children to adolescents and adults. The relative change in clearance following CO reductions increased with age, with the least impact of LCO in neonates. The predicted concentration remained within the 3 µg/mL (80-125%) range under normal CO and LCO (up to 30%) conditions in all age groups. When CO was reduced by 40-50%, a dose reduction of 15% is warranted in neonates, infants and children, 25% in adolescents and adults. Conclusions: PBPK driven, the impact of reduced CO on propofol clearance is predicted to be age-dependent, proportionally greater in adults. Consequently, age group specific dose reductions for propofol are required in LCO conditions.
ARTICLE | doi:10.20944/preprints202012.0534.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: creatinine; vancomycin; amikacin; renal impairment; acute kidney injury; adverse drug reaction
Online: 21 December 2020 (15:42:59 CET)
Background: Disentangling adverse drug reactions from confounders remains a major challenge to assess causality and severity in neonates. Vancomycin and amikacin are perceived as nephrotoxic and often prescribed in neonates. We selected these compounds to assess their impact on creatinine dynamics as sensitive tool to detect a renal impairment signal. Methods: A recently developed dynamical model that characterized serum creatinine concentrations of 217 ELBW neonates (4036 serum creatinine observations) was enhanced with data on individual administration of vancomycin and/or amikacin to identify a potential effect of antibiotic exposure by nonlinear mixed-effects modelling analysis. Results: Of our ELBW patients, 77% were exposed to either vancomycin or amikacin. Antibiotic exposure resulted in transient lower overall creatinine clearance and a modest increase in serum creatinine. Dependency on gestational age was observed in the difference in serum creatinine when exposed to antibiotics during the third week after birth (difference in creatinine for a neonate at 24 weeks gestation decreased with 56% for a 32-week-old neonate). Conclusions: A previously described model on creatinine dynamics was used to explore and quantify the impact amikacin or vancomycin exposure on creatinine dynamics. Such tools can be used to explore minor changes, or compare minor differences between treatment modalities.
REVIEW | doi:10.20944/preprints202208.0312.v1
Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: procedural sedation; children; dexmedetomidine; imaging
Online: 17 August 2022 (09:44:28 CEST)
There is an increasing need for effective anxiety and pain reduction during medical imaging procedures in children. This is a complex issue, addressed by both non-pharmacological or pharmacological approaches. Dexmedetomidine is a fairly recently marketed, selective α2-adrenergic agonist, and can be administered intranasally. To develop an evidence-guided clinical protocol, we investigated its (side)-effects, preconditions and safety aspects following intranasal dexmedetomidine in children (1 month-5 years) for procedural sedation during medical imaging. To do so, a systematic search (PubMed, Embase, CINAHL (12/2021)) was performed to identify clinical studies on intranasal dexmedetomidine for procedural sedation for medical imaging (Computer Tomography, Magnetic Resonance Imaging). Following screening and quality assessment, 8 studies were retained. Nasal nebulization was considered the best administration method, dosing varied between 2 to 4 µg/kg (age-dependent) 30-45 minutes prior to imaging, and contra-indications or restrictions on oral intake were somewhat consistent across studies. Valid sedation scores were routinely used to assess sedation and the need for rescue dosing, while discharge was generally based on the Aldrete score (score ≥9). Heart rate, blood pressure and saturation were routinely monitored, with commonly observed bradycardia or hypotension (decrease by 20%). Based on these findings, a roadmap for evidence-guided clinical protocol was generated.
ARTICLE | doi:10.20944/preprints202105.0062.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: creatinine; cystatin C; asphyxia; whole body hypothermia; acute kidney injury; renal clearance; kidney function.
Online: 5 May 2021 (13:27:42 CEST)
Many neonates undergoing whole body hypothermia (WBH) following moderate to severe perinatal asphyxia suffer from renal impairment. While recent data suggest a WBH-related reno-protection, the differences in serum creatinine (Scr) patterns to reference patterns were not yet reported. We therefore aimed to document Scr trends and patterns in asphyxiated neonates undergoing WBH, and compared these to centiles reference Scr dataset of non-asphyia neonates. Using a systematic review strategy, reports on Scr trends (mean ± SD, or median and range) were collected (day 1-7) in WBH cohorts, and compared to centiles of an earlier reported reference cohort of non-asphyxia cases. Based on 13 papers on asphyxia+WBH cases, a pattern on postnatal Scr trends in asphyxia+WBH cases was constructed. Compared to the reference cohort, mean or median Scr values at birth (>90th centile) and the first two days of WBH (>75th centile) remained clinical relevantly higher in asphyxia+WBH cases, with a subsequent decline to reach at best high or high normal creatinine values (all >50th centile, but mainly >75th centile) from day 4 onwards. Such patterns are valuable to anticipate average changes in renal clearance capacity relevant for pharmacotherapy, but do not yet cover the relevant inter-patient variability observed in WBH cases.
ARTICLE | doi:10.20944/preprints202308.1823.v1
Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: newborn blood screening; Guthrie; knowledge; consent; mother; parent
Online: 28 August 2023 (08:24:05 CEST)
To learn what mothers know on newborn bloodspot screening (NBS), the procedure, and sources used, a pilot study was performed. An online questionnaire was developed, with a first part fo-cused on characteristics and the NBS procedure, a second on knowledge, information sources, and health care providers (HCP). This questionnaire was accessible until 200 answers were received. Characteristics of respondents were representative for the population. Mothers recalled verbal consent in 69.5%, 12.5% did not, 18% stated that no consent was requested. The ‘knowledge’ part contained 12 closed questions, 5 multiple-choice questions on sources, and assessment (5-point Likert) of the information transfer. The mean knowledge level was 7.2/12. Screening concepts (consequences, likelihood, sensitivity, carrier) and absence of notification of normal findings were well known. The fact that NBS is not compulsory and post-analysis sample handling were poorly known. Key HCPs were midwifes (80.5%) and nurses (38.5%). When the leaflet (44%) was pro-vided, the majority read it. Mean Likert scores were 3.36, 3.38, 3.11 and 3.35 (clarity, timing ap-propriateness, sufficiency, usefulness). The knowledge level and consent practices were reasonable well. Key HCP were midwives and nurses, leaflets were supporting. This should enable a quality improvement program to a sustainable NBS program in Flanders.
REVIEW | doi:10.20944/preprints202210.0225.v1
Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: QTc interval; Torsades de Pointes; neonates; infants; maturational changes; pharmacovigilance
Online: 17 October 2022 (04:09:55 CEST)
QTc interval measurement is a widely used screening tool to assess the risk of cardiac diseases, arrhythmias, and is a useful biomarker for pharmacovigilance. However, interpretation of QTc is difficult in neonates due to hemodynamic maturational changes and uncertainties on reference values. To describe trends in QTc values throughout infancy (1 year of life), and to explore the impact of (non)-maturational changes and medicines exposure, a structured systematic review (PROSPERO CRD42022302296) was performed. In term neonates, a decrease was observed over the first week of life, whereafter values increased until two months of age, followed by a progressive decrease until six months. A similar pattern, with longer QTc values was observed in preterms. QTc is influenced by cord clamping, hemodynamic changes, therapeutic hypothermia, illnesses and sleep, not by sex. Cisapride, domperidone and doxapram result in QTc prolongation in neo-nates. Further research in this age category is needed to improve primary screening practices, earlier detection of risk factors and precision pharmacovigilance.
ARTICLE | doi:10.20944/preprints202111.0336.v1
Subject: Medicine And Pharmacology, Cardiac And Cardiovascular Systems Keywords: therapeutic hypothermia; newborn; QTc interval; QTc prolongation; pharmacovigilance.
Online: 18 November 2021 (17:26:05 CET)
Background: There are anecdotal reports on reversible QTc prolongation during therapeutic hypothermia (TH) for moderate to severe neonatal encephalopathy after asphyxia. As the QTc interval is a relevant biomarker to assess safety during medication development, a structured search and review on published neonatal QTc values to generate reference values is warranted to facilate medication development in this specific population. Methods: A structured search and literature assessment (PubMed, Embase, Google Scholar) with ‘Newborn/Infant, QT and hypothermia’ was conducted (October 2021). Retrieved individual values were converted to QTc (Bazett) over postnatal age (day 1-7). Results: We retrieved 94 QTc intervals [during TH (n=50, until day 3) or subsequent normothermia (n=44, day 4-7)] in 33 neonates from 6 publications. The median (range) of QTc intervals during TH was 508 (430-678), and 410 (317-540) ms afterwards (difference 98 ms, or +28 ms/°C decrease). Four additional cohorts (without individual QTc intervals) confirmed the pattern and magnitude of the effect of body temperature on the QTc interval. Conclusions: We added a relevant non-maturational covariate (TH, °C dependent) and generated reference values for the QTc interval in this specific neonatal subpopulation. This knowledge on QTc during TH should be considered and integrated in neonatal medication development.
REVIEW | doi:10.20944/preprints202010.0047.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: children; adolescents; burns; dressing changes; virtual reality; pain.
Online: 2 October 2020 (15:29:05 CEST)
Children and adolescents with severe burns require dressing changes, associated with pain. As immersive virtual reality (VR) gained prominence as non-pharmacological adjuvant analgesia, we conducted a systematic review and meta-analysis on the efficacy of full immersive VR on pain experienced during dressing changes in hospitalized children and adolescents with severe burns. This exercise included quality and risk of bias assessment. The systematic reviewsearch resulted in eight studies and 142 patients. This exercise included quality and risk of bias assessment. Due to missing data, four studies were excluded from the meta-analysis. Fixed effects meta-analysis of the four included studies (n = 104) revealed a large effect size (ES) (SMD=0.94; 95% CI=0.62, 1.27; Z=5.70; p<0.00001) for adjuvant full immersive VR compared to standard care. In conclusion, adjuvant full immersive VR significantly reduces pain experienced during dressing changes in children and adolescents with burns. We therefore recommend implementing full immersive VR as an adjuvant in this specific setting and population. However, this requires further research into the hygienic use of VR appliances in health institutions. Furthermore, due to the high cost of the hardware, a cost-benefit analysis is required. Finally, research should also verify the long term physical and psychological benefits of VR.
ARTICLE | doi:10.20944/preprints202304.0265.v1
Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: Drug information; drug database; drug formulary; neonatal; pediatric
Online: 12 April 2023 (09:32:12 CEST)
Neonatal drug information (DI) is essential for safe and effective pharmacotherapy in (pre)term neonates. Such information is usually absent from drug labels, making formularies a crucial part of the neonatal clinician’s toolbox. Several formularies exist worldwide, but they have never been fully mapped nor compared for content, structure and workflow. The objective of this review was to identify neonatal formularies, explore (dis)similarities, and raise awareness of their existence.Neonatal formularies were identified through self-acquaintance, experts and structured search. A questionnaire was sent to all identified formularies to provide details on formulary function. An original extraction tool was employed to collect DI from the formularies on the 10 most commonly used drugs in pre(term) neonates.Eight different neonatal formularies were identified worldwide (Europe, USA, Australia-New Zealand, Middle East). Six responded to the questionnaire and were compared for structure and content. Each formulary has its own workflow, monograph template and style, and update routine. Focus on certain aspects of DI also varies, as well as the type of initiative and funding.Clinicians should be aware of the various formularies available and their differences in characteristics and content to use them properly for the benefit of their patients.