Aims: Evidence for drug use in newborns is sparse, which may cause large differences in drug prescriptions. We aimed to investigate the differences between neonatal intensive care units (NICUs) in the Netherlands in currently prescribed drugs.Methods: This multicentre study included neonates admitted during 12 months to four different NICUs. Drugs were classified in accordance with the Anatomical Therapeutic Chemical (ATC) classification system and assessed for on/off‐label status in relation to neonatal age. The treatment protocols for four common indications for drug use were compared: pain, intubation, convulsions and hypotension.Results: A total of 1491 neonates (GA range 23⁺⁶–42⁺² weeks) were included with a total of 32 182 patient days, 181 different drugs and 10 895 prescriptions of which 23% was off‐label in relation to neonatal age. Overall, anti‐infective drugs were most frequently used with a total of 3161 prescriptions, of which 4% was off‐label in relation to neonatal age. Nervous system drugs included 2500 prescriptions of which 31% was off‐label in relation to neonatal age. Nervous system drugs, blood and blood forming organs, and cardiovascular drugs showed the largest differences between NICUs with ranges of 919–2278, 554–1465, and 238–952 total prescriptions per 1000 patients per ATC class, respectively.Conclusions: We showed that drug use varies widely in neonatal clinical practice. The drug classes with the highest proportion of off‐label drugs in relation to neonatal age showed the largest differences between NICUs, i.e. cardiovascular and nervous system drugs. Drug research in neonates should receive high priority to guarantee safe and appropriate medicines and optimal treatment.

Purpose: The purpose of this international study was to investigate prescribing practices of dexmedetomidine by paediatric anaesthesiologists. Methods: We performed an online survey on the prescription rate of dexmedetomidine, route of administration and dosage, adverse drug reactions, education on the drug and overall experience. Members of specialist paediatric anaesthesia societies of Europe (ESPA), New Zealand and Australia (SPANZA), Great Britain and Ireland (APAGBI) and the USA (SPA) were consulted. Responses were collected in July and August 2019. Results: Data from 791 responders (17% of 5171 invitees) were included in the analyses. Dexmedetomidine was prescribed by 70% of the respondents (ESPA 53%; SPANZA 69%; APAGBI 34% and SPA 96%), mostly for procedural sedation (68%), premedication (46%) and/or ICU sedation (46%). Seventy-three percent had access to local or national protocols, although lack of education was the main reason cited by 26% of the respondents not to prescribe dexmedetomidine. The main difference in dexmedetomidine use concerned the age of patients (SPA primarily < 1 year, others primarily > 1 year). The dosage varied widely ranging from 0.2–5 μg kg⁻¹ for nasal premedication, 0.2–8 μg kg⁻¹ for nasal procedural sedation and 0–4 μg kg⁻¹ intravenously as adjuvant for anaesthesia. Only ESPA members (61%) had noted an adverse drug reaction, namely bradycardia. Conclusion: The majority of anaesthesiologists use dexmedetomidine in paediatrics for premedication, procedural sedation, ICU sedation and anaesthesia, despite the off-label use and sparse evidence. The large intercontinental differences in prescribing dexmedetomidine call for consensus and worldwide education on the optimal use in paediatric practice.

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. 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 MIC_ECOFF of 8 mg/L (to cover gram-negative bacteria such as Escherichia coli) was used. 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. 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.

Beta-blockers are often used during pregnancy to treat cardiovascular diseases. The described neonatal side effects of maternal beta-blocker use are hypoglycemia and bradycardia, but the evidence base for these is yet to be evaluated comprehensively. Hence, this systematic review and meta-analysis was performed to evaluate the potential increased risk for hypoglycemia and bradycardia in neonates exposed to beta-blockers in utero or during lactation. A systematic search of English-language human studies was conducted until 21 April 2021. Both observational studies and randomized controlled trials investigating hypoglycemia and/or bradycardia in neonates following beta-blocker exposure during pregnancy and lactation were included. All articles were screened by two authors independently and eligible studies were included. Pair-wise and proportion-based meta-analysis was conducted and the certainty of evidence (CoE) was performed by standard methodologies. Of the 1.043 screened articles, 55 were included in this systematic review. Our meta-analysis showed a probable risk of hypoglycemia (CoE—Moderate) and possible risk of bradycardia (CoE—Low) in neonates upon fetal beta-blocker exposure. Therefore, we suggest the monitoring of glucose levels in exposed neonates until 24 h after birth. Due to the limited clinical implication, monitoring of the heart rate could be considered for 24 h. We call for future studies to substantiate our findings.

Aims: Racemic ibuprofen is widely used for the treatment of preterm neonates with patent ductus arteriosus. Currently used bodyweight‐based dosing guidelines are based on total ibuprofen, while only the S‐enantiomer of ibuprofen is pharmacologically active. We aimed to optimize ibuprofen dosing for preterm neonates of different ages based on an enantiomer‐specific population pharmacokinetic model.Methods: We prospectively collected 210 plasma samples of 67 preterm neonates treated with ibuprofen for patent ductus arteriosus (median gestational age [GA] 26 [range 24–30] weeks, median body weight 0.83 [0.45–1.59] kg, median postnatal age [PNA] 3 [1–12] days), and developed a population pharmacokinetic model for S‐ and R‐ibuprofen.Results: We found that S‐ibuprofen clearance (CL_S, 3.98 mL/h [relative standard error {RSE} 8%]) increases with PNA and GA, with exponents of 2.25 (RSE 6%) and 5.81 (RSE 15%), respectively. Additionally, a 3.11‐fold higher CL_S was estimated for preterm neonates born small for GA (RSE 34%). Clearance of R‐ibuprofen was found to be high compared to CL_S (18 mL/h [RSE 24%]), resulting in a low contribution of R‐ibuprofen to total ibuprofen exposure. Current body weight was identified as covariate on both volume of distribution of S‐ibuprofen and R‐ibuprofen.Conclusion: S‐ibuprofen clearance shows important maturation, especially with PNA, resulting in an up to 3‐fold increase in CL_S during a 3‐day treatment regimen. This rapid increase in clearance needs to be incorporated in dosing guidelines by adjusting the dose for every day after birth to achieve equal ibuprofen exposure.