Drug disposition in neonatal Göttingen Minipigs: Exploring Effects of Perinatal Asphyxia and Therapeutic Hypothermia.

Asphyxiated neonates often undergo therapeutic hypothermia (TH) to reduce morbidity and mortality. Since both perinatal asphyxia (PA) and TH influence physiology, altered pharmacokinetics (PK) and pharmacodynamics (PD) are expected. Given that TH is the standard of care for PA with moderate to severe hypoxic-ischemic encephalopathy (HIE), disentangling the effect of PA versus TH on PK/PD is not possible in clinical settings. However, animal models can provide insights into this matter. The (neonatal) Göttingen Minipig, the recommended strain for nonclinical drug development, was selected as translational model. Four drugs - midazolam (MDZ), fentanyl (FNT), phenobarbital (PHB), and topiramate (TPM), were intravenously administered under four conditions: control (C), therapeutic hypothermia (TH), hypoxia (H), hypoxia + TH (H+TH). Each group included six healthy male neonatal Göttingen Minipigs anesthetized for 24 hours. Blood samples were drawn at 0 (pre-dose), and 0.5, 2, 2.5, 3, 4, 4.5, 6, 8, 12, 24 hours post-drug administration. Drug plasma concentrations were determined using validated bioanalytical assays. The PK parameters were estimated through compartmental and non-compartmental PK analysis (NCA). The study showed a statistically significant decrease in FNT clearance (CL, 66% decrease) with approximately 3-fold longer half-life (t1/2) in the TH group. The H+TH group showed a 17% reduction in FNT CL with a 62% longer t1/2 compared to the C group, however non-statistically significant. Trends towards lower CL and longer t1/2 were observed in the TH and H+TH groups for MDZ and PHB. Additionally, TPM demonstrated a 28% decrease in CL in the H group compared to controls. Significance Statement The overarching goal of this study using the neonatal Göttingen Minipig model was to disentangle the effects of systemic hypoxia and TH on PK, using four model drugs. Such insights can subsequently be used to inform and develop a physiologically-based pharmacokinetic (PBPK) model, which is useful for drug exposure prediction in human neonates.

Global cross-sectional survey on neonatal pharmacologic sedation and analgesia practices and pain assessment tools: impact of the sociodemographic index (SDI).

BACKGROUND: There is variability in the use of sedatives and analgesics in neonatal intensive care units (NICUs). We aimed to investigate the use of analgesics and sedatives and the management of neonatal pain and distress. METHODS: This was a global, prospective, cross-sectional study. A survey was distributed May-November 2022. The primary outcome of this research was to compare results between countries depending on their socio-sanitary level using the sociodemographic index (SDI). We organized results based on geographical location. RESULTS: The survey collected 1304 responses, but we analyzed 924 responses after database cleaning. Responses from 98 different countries were analyzed. More than 60% of NICUs reported having an analgosedation guideline, and one-third of respondents used neonatal pain scales in more than 80% of neonates. We found differences in the management of sedation and analgesia between NICUs on different continents, but especially between countries with different SDIs. Countries with a higher SDI had greater availability of and adherence to analgosedation guidelines, as well as higher rates of analgosedation for painful or distressing procedures. Countries with different SDIs reported differences in analgosedation for neonatal intubation, invasive ventilation, and therapeutic hypothermia, among others. CONCLUSIONS: Socio-economic status of countries impacts on neonatal analgosedation management. IMPACT: There is significant variability in the pain management practices in neonates. There is a lack of knowledge related to how neonatal pain management practices differ between regions. Sociodemographic index is a key factor associated with differences in neonatal pain management practices across global regions.

Publication Recommendations to Report Laboratory Data of Neonates - a Modified Delphi Approach.

BACKGROUND: Clinical and analytical information on laboratory data of neonates in scientific publications is sparse and incomplete. Furthermore, interpreting neonatal laboratory data can be complex due to their time-dependent and developmental physiology, and paucity of well-established age-appropriate reference ranges for neonates. This study aims to develop publication recommendations to report laboratory data of neonates to enhance the quality of these data in research and clinical care. METHODS: A modified Delphi approach was used to develop recommendations in cooperation with the International Neonatal Consortium. A Core Group, including different stakeholders, was responsible for developing the recommendations, in collaboration with a Reflection Group, responsible for providing additional input. RESULTS: The recommendations were classified into three categories: 'Clinical Characteristics', 'Bio-analytical Information' and 'Data-analytical Information'. These were each divided into 'Core Data' (always to be reported) and 'Supplemental Considerations' (to be reported when considered relevant to the study). CONCLUSION: Our recommendations provide guidance on standardization of neonatal laboratory data in publications. This will enhance the comparison, replication, and application of study results in research initiatives and clinical practice. Furthermore, these recommendations also serve as foundational work to develop reference ranges for neonatal laboratory values by standardizing the quality of information needed for such efforts. IMPACT: Standardized reporting of neonatal laboratory data in scientific publications will enhance the comparison, replication, and application of study results in research initiatives and clinical practice, as well as improve reporting to regulatory agencies. To integrate multistakeholder perspectives, a modified Delphi approach was used to develop publication recommendations which strengthens the applicability of the recommendations. Implementation of standardization will likely improve the overall quality of neonatal clinical research and neonatal healthcare. In addition, these recommendations are foundational to develop reference ranges for neonatal laboratory values by standardizing the quality of information needed for such efforts.

Grading the level of evidence of neonatal pharmacotherapy: midazolam and phenobarbital as examples.

BACKGROUND: Many drugs are used off-label or unlicensed in neonates. This does not mean they are used without evidence or knowledge. We aimed to apply and evaluate the Grading and Assessment of Pharmacokinetic-Pharmacodynamic Studies (GAPPS) scoring system for the level of evidence of two commonly used anti-epileptic drugs. METHODS: Midazolam and phenobarbital as anti-epileptics were evaluated with a systematic literature search on neonatal pharmacokinetic (PK) and/or pharmacodynamic [PD, (amplitude-integrated) electroencephalography effect] studies. With the GAPPS system, two evaluators graded the current level of evidence. Inter-rater agreement was assessed for dosing evidence score (DES), quality of evidence (QoE), and strength of recommendation (REC). RESULTS: Seventy-two studies were included. DES scores 4 and 9 were most frequently used for PK, and scores 0 and 1 for PD. Inter-rater agreements on DES, QoE, and REC ranged from moderate to very good. A final REC was provided for all PK studies, but only for 25% (midazolam) and 33% (phenobarbital) of PD studies. CONCLUSIONS: There is a reasonable level of evidence concerning midazolam and phenobarbital PK in neonates, although using a predefined target without integrated PK/PD evaluation. Further research is needed on midazolam use in term neonates with therapeutic hypothermia, and phenobarbital treatment in preterms. IMPACT: There is a reasonable level of evidence concerning pharmacotherapy of midazolam and phenobarbital in neonates. Most evidence is however based on PK studies, using a predefined target level or concentration range without integrated, combined PK/PD evaluation. Using the GAPPS system, final strength of recommendation could be provided for all PK studies, but only for 25% (midazolam) to 33% (phenobarbital) of PD studies. Due to the limited PK observations of midazolam in term neonates with therapeutic hypothermia, and of phenobarbital in preterm neonates these subgroups can be identified for further research.

A physiological approach to renal clearance: From premature neonates to adults.

AIMS: We propose using glomerular filtration rate (GFR) as the physiological basis for distinguishing components of renal clearance. METHODS: Gentamicin, amikacin and vancomycin are thought to be predominantly excreted by the kidneys. A mixed-effects joint model of the pharmacokinetics of these drugs was developed, with a wide dispersion of weight, age and serum creatinine. A dataset created from 18 sources resulted in 27,338 drug concentrations from 9,901 patients. Body size and composition, maturation and renal function were used to describe differences in drug clearance and volume of distribution. RESULTS: This study demonstrates that GFR is a predictor of two distinct components of renal elimination clearance: (1) GFR clearance associated with normal GFR and (2) non-GFR clearance not associated with normal GFR. All three drugs had GFR clearance estimated as a drug-specific percentage of normal GFR (gentamicin 39%, amikacin 90% and vancomycin 57%). The total clearance (sum of GFR and non-GFR clearance), standardized to 70 kg total body mass, 176 cm, male, renal function 1, was 5.58 L/h (95% confidence interval [CI] 5.50-5.69) (gentamicin), 7.77 L/h (95% CI 7.26-8.19) (amikacin) and 4.70 L/h (95% CI 4.61-4.80) (vancomycin). CONCLUSIONS: GFR provides a physiological basis for renal drug elimination. It has been used to distinguish two elimination components. This physiological approach has been applied to describe clearance and volume of distribution from premature neonates to elderly adults with a wide dispersion of size, body composition and renal function. Dose individualization has been implemented using target concentration intervention.

When will the Glomerular Filtration Rate in Former Preterm Neonates Catch up with Their Term Peers?

AIMS: Whether and when glomerular filtration rate (GFR) in preterms catches up with term peers is unknown. This study aims to develop a GFR maturation model for (pre)term-born individuals from birth to 18 years of age. Secondarily, the function is applied to data of different renally excreted drugs. METHODS: We combined published inulin clearance values and serum creatinine (Scr) concentrations in (pre)term born individuals throughout childhood. Inulin clearance was assumed to be equal to GFR, and Scr to reflect creatinine synthesis rate/GFR. We developed a GFR function consisting of GFRbirth (GFR at birth), and an Emax model dependent on PNA (with GFRmax, PNA50 (PNA at which half of GFR max is reached) and Hill coefficient). The final GFR model was applied to predict gentamicin, tobramycin and vancomycin concentrations. RESULT: In the GFR model, GFRbirth varied with birthweight linearly while in the PNA-based Emax equation, GA was the best covariate for PNA50, and current weight for GFRmax. The final model showed that for a child born at 26 weeks GA, absolute GFR is 18%, 63%, 80%, 92% and 96% of the GFR of a child born at 40 weeks GA at 1 month, 6 months, 1 year, 3 years and 12 years, respectively. PopPK models with the GFR maturation equations predicted concentrations of renally cleared antibiotics across (pre)term-born neonates until 18 years well. CONCLUSIONS: GFR of preterm individuals catches up with term peers at around three years of age, implying reduced dosages of renally cleared drugs should be considered below this age.

Pharmacovigilance of nephrotoxic drugs in neonates: the Pottel method for acute kidney injury detection in ELBW neonates.

BACKGROUND: Extremely low birth weight (ELBW) neonates (birth weight ≤ 1000 g) are at high risk to develop drug-induced acute kidney injury (AKI). However, we lack a pragmatic detection tool to capture their time-dependent (patho)physiologic serum creatinine (Scr) patterns. Pottel et al. suggested rescaling Scr by dividing Scr with the mean Scr value of the age- and sex-specific reference population. We explored if this Pottel method can detect drug-related nephrotoxicity in ELBW neonates. METHODS: A previously reported dataset on Scr changes in ELBW neonates exposed to ibuprofen, amikacin, or vancomycin was updated to calculate Pottel scores for every available Scr value in the first 28 postnatal days. We hereby used previously published postnatal age-specific 50th centile values in an ELBW population. Linear mixed models were applied, analyzing Pottel scores as response variable and continuous time (day), drug exposure, and interaction thereof in the explanatory model. RESULTS: Serum creatinine (n = 3231) observations in 201 ELBW neonates were collected. A statistically significant rise of Pottel scores was observed with ibuprofen starting from postnatal day 4. In addition, a cumulative effect of treatment with mean Pottel scores on day 0 of 1.020 and on day 3 during treatment of 1.106 (95% CI 1.068-1.145, p < 0.001) was observed, corrected for effect of antibiotics. Antibiotic administrations showed a small but statistically significant difference up to postnatal day 5. CONCLUSIONS: As rescaled Scr biomarker, the Pottel method showed a clear association with ibuprofen-exposed ELBW neonates, suggesting its applicability as a pragmatic bedside alternative tool to assess nephrotoxicity.

Favipiravir pharmacokinetics in COVID-19 patients with moderate to severe kidney dysfunction: Lessons learned for future use.

OBJECTIVE: There is limited information on favipiravir pharmacokinetics in critically ill patients and no studies on pharmacokinetics in patients with moderate and severe kidney dysfunction. The aim was to determine favipiravir pharmacokinetics (oral, 1,600 mg, q12h on day 1, then 600 mg, q12h for 4 days) in critically ill COVID-19 patients with kidney dysfunction and to compare those with observations reported in healthy adults. MATERIALS AND METHODS: In a descriptive study, blood samples taken from patients meeting the relevant criteria (estimated glomerular filtration rate < 60 mL/min) were collected and analyzed. Analysis of blood samples was done by high performance liquid chromatography (HPLC), and the maximal concentration (Cmax), the time of maximal concentration (tmax), half-life (T1/2) and area under the curve (AUC0-12h) of favipiravir were calculated (WinNonlin) and compared to reported data in healthy subjects after first administration. RESULTS: Based on analysis of samples collected in 7 patients, the Cmax (29.99 vs. 64.5 µg/mL) of favipiravir was decreased, T1/2 (5.8 vs. 4.8 hours) longer, tmax delayed, while total exposure was lower (AUC0-12: 192.53 vs. 446.09 µg/mL) compared to reported data in healthy subjects after first administration. Exposure remained lower up to day 5. CONCLUSION: In patients with kidney dysfunction related to COVID-19, favipiravir did not reach the expected exposure. This may be due to poorer and delayed absorption, and subsequent altered disposition. Population pharmacokinetic and mechanistic studies are needed to better explore the relevant covariates and to determine the optimal dose in these patients, as this drug is likely of relevance for other indications.

Modulation of engineered nanomaterial interactions with organ barriers for enhanced drug transport.

The biomedical use of nanoparticles (NPs) has been the focus of intense research for over a decade. As most NPs are explored as carriers to alter the biodistribution, pharmacokinetics and bioavailability of associated drugs, the delivery of these NPs to the tissues of interest remains an important topic. To date, the majority of NP delivery studies have used tumor models as their tool of interest, and the limitations concerning tumor targeting of systemically administered NPs have been well studied. In recent years, the focus has also shifted to other organs, each presenting their own unique delivery challenges to overcome. In this review, we discuss the recent advances in leveraging NPs to overcome four major biological barriers including the lung mucus, the gastrointestinal mucus, the placental barrier, and the blood-brain barrier. We define the specific properties of these biological barriers, discuss the challenges related to NP transport across them, and provide an overview of recent advances in the field. We discuss the strengths and shortcomings of different strategies to facilitate NP transport across the barriers and highlight some key findings that can stimulate further advances in this field.

Applied pharmacokinetics to improve pharmacotherapy in neonatal and paediatric intensive care units: focus on correct dose selection.

Drug dosing and exposure throughout childhood are constantly affected by maturational changes like weight, age or body surface area. In neonatal and paediatric intensive care units (NICU and PICU, respectively), drug dosing and exposure are further impacted by non-maturational changes. These changes are related to factors such as sepsis, cardiac failure, acute kidney injury, extracorporeal circuits or drug-drug interactions (DDIs) resulting from polypharmacy.This potentially complex situation may alter drug pharmacokinetics to result in greater-than-usual intrapatient and interpatient drug exposure variability. These effects may call for individual dosage adjustments. Dosage adjustments may apply to both loading doses or maintenance doses, which should be used as appropriate, depending on the specific characteristics of a given drug. Phenobarbital and vancomycin dosing are hereby used as illustrations.To optimise dose selection in NICU/PICU settings, we suggest to consider therapeutic drug monitoring integrated in model-informed precision dosing, and to familiarise oneself with existing paediatric drug formularies as well as DDI databases/search engines. Paediatric clinical pharmacologists and pharmacists can hereby guide clinicians with no prior experience on how to properly apply these data sources to day-to-day practice in individual patients or specific subpopulations of NICU or PICU patients.

Oral and Intravenous Amoxicillin Dosing Recommendations in Neonates: A Pooled Population Pharmacokinetic Study.

BACKGROUND: There is a lack of evidence on oral amoxicillin pharmacokinetics and exposure in neonates with possible serious bacterial infection (pSBI). We aimed to describe amoxicillin disposition following oral and intravenous administration and to provide dosing recommendations for preterm and term neonates treated for pSBI. METHODS: In this pooled-population pharmacokinetic study, 3 datasets were combined for nonlinear mixed-effects modeling. In order to evaluate amoxicillin exposure following oral and intravenous administration, pharmacokinetic profiles for different dosing regimens were simulated with the developed population pharmacokinetic model. A target of 50% time of the free fraction above the minimal inhibitory concentration (MIC) with an MICECOFF of 8 mg/L (to cover gram-negative bacteria such as Escherichia coli) was used. RESULTS: The cohort consisted of 261 (79 oral, 182 intravenous) neonates with a median (range) gestational age of 35.8 weeks (range, 24.9-42.4) and bodyweight of 2.6 kg (range, 0.5-5). A 1-compartment model with first-order absorption best described amoxicillin pharmacokinetics. Clearance (L/h/kg) in neonates born after 30 weeks' gestation increased with increasing postnatal age (PNA day 10, 1.25-fold; PNA day 20, 1.43-fold vs PNA day 3). Oral bioavailability was 87%. We found that a twice-daily regimen of 50 mg/kg/day is superior to a 3- or 4-times daily schedule in the first week of life for both oral and intravenous administration. CONCLUSIONS: This pooled population pharmacokinetic description of intravenous and oral amoxicillin in neonates provides age-specific dosing recommendations. We conclude that neonates treated with oral amoxicillin in the first weeks of life reach adequate amoxicillin levels following a twice-daily dosing regimen. Oral amoxicillin therapy could therefore be an adequate, cost-effective, and more patient-friendly alternative for neonates worldwide.

The publication quality of laboratory values in clinical studies in neonates.

BACKGROUND: There are no generally accepted age-appropriate reference ranges for laboratory values in neonates. This also matters for drug development. The International Neonatal Consortium (INC) is engaged to define actionable reference ranges of commonly used laboratory values in neonates. METHODS: A structured literature search was performed to identify standards or recommendations for publications that present neonatal laboratory data to assess the publication quality of laboratory values in neonates. Using a modified Delphi approach, an assessment and data extraction instrument to screen on completeness of information was developed. RESULTS: On 2908 hits, 281 papers were retained for full reading and 257 for data extraction. None of the papers reported a publication standard. Using the extraction instrument, most papers presented single country or unit findings. The median number of neonates was 120, with uncertainty on single or repeated measurements. Clinically meaningful information on age, sex, and medical conditions was commonly provided. Information on pharmacotherapy, equipment, analytical method, or laboratory location was rarely mentioned. CONCLUSIONS: Published information on laboratory values for neonates is sparse, not systematic, and incomplete. This undermines efforts to compare treatments, safety monitoring, or clinical management. Furthermore, there appears to be no standard yet to report laboratory values in neonates. IMPACT: There are no generally accepted age-appropriate reference ranges for laboratory values in neonates, leading to a significant knowledge gap, also for safety reporting and drug development in neonates. We performed a literature search to identify standards or recommendations for publications on neonatal laboratory data and to assess the publication quality of laboratory values in clinical studies involving neonates. Standards or recommendations for publications that present neonatal laboratory data were not identified, while published information on laboratory values for neonates is sparse, not systematic, and incomplete.

Perfused boundary region as biomarker for endothelial integrity in former preterms in adolescence.

INTRODUCTION: Extremely low birth weight (ELBW) survivors have microvascular structural differences already described in kidney and retina, suggesting changes in endothelial integrity. A biomarker of endothelial integrity is perfused boundary region (PBR), which measures glycocalycal thickness. The endothelial glycocalyx is a complex, highly versatile structure with essential roles in vascular integrity and function. We explored PBR patterns together with other microvascular markers in healthy controls and former ELBW children. METHODS: In the PREMATCH cohort (87 healthy controls, 93 ELBW survivors), we assessed endothelial integrity by calculating PBR (sidestream dark-field imaging), several microvascular markers (blood pressure, estimated glomerular filtration rate (eGFRcysC)), and retinal imaging in early adolescence. We explored differences between both groups, and searched for perinatal determinants of PBR and correlations between different microvascular markers. RESULTS: We provided reference values for PBR (average 1.90 µm, SD 0.30) in children. PBR was not different from ELBW survivors during early adolescence, despite their higher blood pressure, lower eGFRcysC, and different retinal vessel width and tortuosity. CONCLUSIONS: We generated reference values for PBR in early adolescence. Despite some correlations between microvascular parameters, there seem to be numerous confounders to propose PBR as a marker for endothelial integrity in ELBW survivors. IMPACT: The endothelial glycocalyx is a complex and versatile structure. Changes in blood pressure and retinal and renal vascularization suggest a disturbance of its integrity in extremely low birth weight (ELBW) survivors. Its thickness can be measured by calculating perfused boundary region (PBR) using sidestream dark-field imaging, with a higher PBR indicating a thinner glycocalyx. We generated reference values for PBR in healthy adolescents. These values were not different in former ELBW children. Despite some correlations of PBR with other microvascular biomarkers, these are not strong enough to describe endothelial integrity and its covariates in former ELBW children.

Current pain management practices for preterm infants with necrotizing enterocolitis: a European survey.

BACKGROUND: Necrotizing enterocolitis (NEC) is a highly painful intestinal complication in preterm infants that requires adequate pain management to prevent short- and long-term effects of neonatal pain. There is a lack of international guidelines for pain management in NEC patients. Therefore, this study aims to describe current pain management for NEC patients in European neonatal intensive care units (NICUs). METHODS: An online survey was designed and conducted to assess current practices in pain management for NEC patients in European NICUs. The survey was distributed via neonatal societies, digital platforms, and professional contacts. RESULTS: Out of the 259 responding unique European NICUs from 36 countries, 61% had a standard protocol for analgesic therapy, 73% assessed pain during NEC, and 92% treated NEC patients with intravenous analgosedatives. There was strong heterogeneity in the used pain scales and initial analgesic therapy, which mainly included acetaminophen (70%), fentanyl (56%), and/or morphine (49%). A third of NICU representatives considered their pain assessment adequate, and half considered their analgesic therapy adequate for NEC patients. CONCLUSIONS: Various pain scales and analgesics are used to treat NEC patients in European NICUs. Our results provide the first step towards an international guideline to improve pain management for NEC patients. IMPACT: This study provides an overview of current pain management practices for infants with necrotizing enterocolitis (NEC) in European neonatal intensive care units. Choice of pain assessment tools, analgosedatives, and dosages vary considerably among NICUs and countries. A third of NICU representatives were satisfied with their current pain assessment practices and half of NICU representatives with their analgesic therapy practices in NEC patients in their NICU. The results of this survey may provide a first step towards developing a European pain management consensus guideline for patients with NEC.

Low agreement between various eGFR formulae in pediatric and young adult ADPKD patients.

BACKGROUND: Young autosomal dominant polycystic kidney disease (ADPKD) patients are becoming the new target population for the development of new treatment options. Determination of a reliable equation for estimated glomerular filtration rate (eGFR) from early stages is needed with the promising potential interventional therapies. METHODS: Prospective and longitudinal study on a cohort of 68 genotyped ADPKD patients (age range 0-23 years) with long-term follow-up. Commonly used equations for eGFR were compared for their relative performance. RESULTS: The revised Schwartz formula (CKiD) showed a highly significant decline in eGFR with aging (- 3.31 mL/min/1.73 m2/year, P < 0.0001). The recently updated equation by the Schwartz group (CKiDU25) showed a smaller (- 0.90 mL/min/1.73 m2/year) but significant (P = 0.001) decline in eGFR with aging and also showed a significant sex difference (P < 0.0001), not observed by the other equations. In contrast, the full age spectrum (FAS) equations (FAS-SCr, FAS-CysC, and the combined) showed no age and sex dependency. The prevalence of hyperfiltration is highly dependent on the formula used, and the highest prevalence was observed with the CKiD Equation (35%). CONCLUSIONS: The most widely used methods to calculate eGFR in ADPKD children (CKiD and CKiDU25 equations) were associated with unexpected age or sex differences. The FAS equations were age- and sex-independent in our cohort. Hence, the switch from the CKiD to CKD-EPI equation at the transition from pediatric to adult care causes implausible jumps in eGFR, which could be misinterpreted. Having reliable methods to calculate eGFR is indispensable for clinical follow-up and clinical trials. A higher resolution version of the Graphical abstract is available as Supplementary information.

Nurse-driven intranasal dexmedetomidine administration as sedation for non-invasive procedures in children: a single centre audit.

The purpose of this study is to audit the efficacy and safety of intranasal dexmedetomidine sedation for non-invasive procedural sedation in children provided by nurses of the procedural sedation (PROSA) team in the University Hospitals Leuven. Efficacy (successful sedation as sole sedative) and safety (cardiorespiratory monitoring, saturation) were assessed. In this audit, prospectively recorded data were extracted from the medical files in 772 patients between 4 weeks to 18 years old, who underwent sedation with intranasal dexmedetomidine (2-4 µg/kg) by the nurse-driven PROSA team, following pre-screening on risk factors. Ninety-one percent of the patients were successfully sedated (single dose, monotherapy), 60 patients (7.8%) needed an additional intervention during sedation, 37 (4.8%) needed an extra dose of intranasal dexmedetomidine, and 14 (1.8%) received an additional other sedative. Successful sedation rates were higher in younger children, and medical imaging was the most common indication. Sedation failed in 12 (1.6%) patients, with 10 of them failed to fall asleep. Adverse events were limited in number (n = 13, 1.7%) and severity: 4 patients had a low heart rate (one received atropine), one had an irregular heart rate, and 7 desaturation events were described. Hypotension was treated with normal saline in one case. CONCLUSIONS: In this nurse-driven PROSA setting, intranasal dexmedetomidine is effective and safe for non-invasive procedural sedation in an a priori low risk group of paediatric patients. WHAT IS KNOWN: • Procedural sedation outside the operating theatre or intensive care units is increasingly used, including sedation performed by non-anaesthesiologists or nurses. This resulted in the development of procedural sedation and analgesia (PROSA) teams. • Off-label use of intranasal dexmedetomidine in children is increasing, with a limited number of audits on this practice, its safety and efficacy. WHAT IS NEW: • In an audit on 772 procedures, nurse-driven intranasal dexmedetomidine administration as sedation for non-invasive procedures in children within a structured framework was safe and effective. • Imaging (CT, MRI) was the most common procedural indication in our study, but also nuclear imaging techniques were included.

Neonatal pain score after use of paracetamol: Is there a relationship with serum trough concentration at steady state in preterm and term neonates?

OBJECTIVE: An easy to establish and patient-friendly biomarker to guide dosing of paracetamol in neonates is currently not available. The aim of this study was to determine the potential association between the serum trough concentration and area under the curve (AUC) of paracetamol at steady state and differences in pain scores in preterm and term neonates. MATERIALS AND METHODS: A retrospective observational study was performed, using an academic hospital database to identify neonates treated with intravenous or rectal paracetamol for at least 48 hours. At steady state, serum trough concentrations and the 24-hour AUC were determined. Pain was measured by COMFORTneo scores, before the 1st and 6th dose. Linear regression was performed to assess the association between serum trough concentration and 24-hour AUC and differences in pain scores. Subgroup analyses were performed for patients who received paracetamol due to a COMFORTneo score ≥ 14 (group 1) or who received prophylactic paracetamol because of upcoming surgery (group 2). RESULTS: 21 neonates were included. The median (interquartile range (IQR)) serum trough concentration of paracetamol before the 6th dose was 4.5 mg/L (2.7 - 8.5 mg/L). In subgroup 1, the median (IQR) COMFORTneo scores before the 1st and 6th dose were 17 (16.5 - 20) and 12 (11 - 16.5), respectively. In subgroup 2, the median (IQR) scores were 9 (8 - 10) and 11 (9 - 12), respectively. The serum trough concentration and 24-hour AUC were not associated with reduced pain scores (p = 0.12 and p = 0.67, respectively). CONCLUSION: No association was found between the serum trough concentration and 24-hour AUC of paracetamol at steady state and differences in pain scores in preterm and term neonates. Future research is needed to prospectively determine a patient-friendly biomarker to optimize the treatment with paracetamol.

QTc intervals are not prolonged in former ELBW infants at pre-adolescent age.

BACKGROUND: Whether preterm birth is associated with cardiac conduction or repolarization abnormalities in later life is still poorly explored, with conflicting data on QTc prolongation in former extreme low birth weight (ELBW, <1000 g) infants. METHODS: Twelve lead electrocardiograms (ECG) at rest, collected in the PREMATurity as predictor of children's Cardiovascular-renal Health (PREMATCH) study in former ELBW cases and term controls during pre-adolescence (8-14 years) were analyzed on corrected QT time (QTc, Bazett) and QT dispersion (QTd). ECG findings were compared between groups (Mann-Whitney), and associations with clinical and biochemical findings were explored (Spearman). In ELBW cases, associations between QTc and perinatal characteristics (at birth, neonatal stay) were explored (Mann-Whitney, Spearman). RESULTS: QTc and QTd were similar between 93 ELBW cases and 87 controls [409 (range 360-465) versus 409 (337-460); 40 (0-100) versus 39 (0-110)] ms. Age, height, weight, or body mass index were not associated with the QTc interval, while female sex (median difference 11.4 ms) and lower potassium (r = -0.26) were associated with longer QTc interval. We could not observe any significant association between QTc interval and perinatal characteristics. CONCLUSIONS: There were no differences in QTc or QTd between ELBW and term controls in ECGs at rest in pre-adolescents. IMPACT: This study aimed to assess the differences in QTc and QTd intervals between extreme low birth weight infants (ELBW) and term controls in electrocardiographic measurements at rest during pre-adolescence. This analysis confirmed the absence of significant differences in QTc or QTd findings between ELBW cases and term controls, while female sex and lower potassium were associated with a prolonged QTc interval. These data suggest that QTc screening strategies-including for pharmacovigilance-should not differentiate between former ELBW cases and term controls. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02147457.

Innovative approaches and recent advances in the study of ontogeny of drug metabolism and transport.

The disposition of a drug is driven by various processes, such as drug metabolism, drug transport, glomerular filtration and body composition. These processes are subject to developmental changes reflecting growth and maturation along the paediatric continuum. However, knowledge gaps exist on these changes and their clinical impact. Filling these gaps may aid better prediction of drug disposition and creation of age-appropriate dosing guidelines. We present innovative approaches to study these developmental changes in relation to drug metabolism and transport. First, analytical methods such as including liquid chromatography-mass spectrometry for proteomic analyses allow quantitation of the expressions of a wide variety of proteins, e.g. membrane transporters, in a small piece of organ tissue. The latter is specifically important for paediatric research, where tissues are scarcely available. Second, innovative study designs using radioactive labelled microtracers allowed study-without risk for the child-of the oral bioavailability of compounds used as markers for certain drug metabolism pathways. Third, the use of modelling and simulation to support dosing recommendations for children is supported by both the European Medicines Agency and the US Food and Drug Administration. This may even do away with the need for a paediatric trial. Physiologically based pharmacokinetics models, which include age-specific physiological information are, therefore, increasingly being used, not only to aid paediatric drug development but also to improve existing drug therapies.

Pharmacokinetics of 2 oral paracetamol formulations in hospitalized octogenarians.

AIMS: It is currently unclear how paracetamol should be dosed in order to increase its efficacy while warranting safety in very old adults. The objective was to evaluate the pharmacokinetics of 2 oral paracetamol formulations and its metabolites in hospitalized octogenarians. METHODS: Geriatric inpatients aged 80 years and older received a 1000-mg paracetamol tablet or granulate at 08.00, 14.00 and 20.00. After at least 4 consecutive gifts, plasma samples were collected around the 08.00 dose (trough, +0.5, +1, +2, +4, +5 and +6 h). Plasma concentrations of paracetamol and its metabolites were determined and individual pharmacokinetic parameters were derived. The Edmonton Frail Scale was used to assess frailty. An analgesic plasma target was defined as an average plasma concentration (Cavg ) of 10 mg/L. RESULTS: The mean (±standard deviation) age was 86.78 (±4.20) years. The majority (n = 26/36, 72%) received the tablet, 10 (28%) the granulate. Thirty patients (85%) were classified with moderate to severe frailty. Seven (21%) patients had a Cavg above 10 mg/L. The median [interquartile range] time to reach the peak concentration was 50.5 [31.50-92.50] and 42.50 [33.75-106.75] min for the tablet and granulate, respectively. The coefficient of variation was 95% for time to reach the peak concentration and 30% for Cavg of paracetamol. A correlation of Cavg of paracetamol was observed with female sex and total serum bilirubin. CONCLUSION: Large interindividual differences were found for pharmacokinetic parameters of oral paracetamol in frail inpatients after multiple dosing. Female sex and higher total serum bilirubin concentrations were associated with paracetamol exposure. No significant differences were observed between the tablet and granulate.