Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns : impact of design optimisation

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

Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns: impact of design optimisation

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

Environmental contaminants of emerging concern in seafood - European database on contaminant levels

Marine pollution gives rise to concern not only about the environment itself but also about the impact on food safety and consequently on public health. European authorities and consumers have therefore become increasingly worried about the transfer of contaminants from the marine environment to seafood. So-called "contaminants of emerging concern" are chemical substances for which no maximum levels have been laid down in EU legislation, or substances for which maximum levels have been provided but which require revision. Adequate information on their presence in seafood is often lacking and thus potential risks cannot be excluded. Assessment of food safety issues related to these contaminants has thus become urgent and imperative. A database (www.ecsafeseafooddbase.eu), containing available information on the levels of contaminants of emerging concern in seafood and providing the most recent data to scientists and regulatory authorities, was developed. The present paper reviews a selection of contaminants of emerging concern in seafood including toxic elements, endocrine disruptors, brominated flame retardants, pharmaceuticals and personal care products, polycyclic aromatic hydrocarbons and derivatives, microplastics and marine toxins. Current status on the knowledge of human exposure, toxicity and legislation are briefly presented and the outcome from scientific publications reporting on the levels of these compounds in seafood is presented and discussed.</p

Belgian consensus recommendations to prevent vitamin k deficiency bleeding in the term and preterm infant

Neonatal vitamin K prophylaxis is essential to prevent vitamin K deficiency bleeding (VKDB) with a clear benefit compared to placebo. Various routes (intramuscular (IM), oral, intravenous (IV)) and dosing regimens were explored. A literature review was conducted to compare vitamin K regimens on VKDB incidence. Simultaneously, information on practices was collected from Belgian pediatric and neonatal departments. Based on the review and these practices, a consensus was developed and voted on by all co-authors and heads of pediatric departments. Today, practices vary. In line with literature, the advised prophylactic regimen is 1 or 2 mg IM vitamin K once at birth. In the case of parental refusal, healthcare providers should inform parents of the slightly inferior alternative (2 mg oral vitamin K at birth, followed by 1 or 2 mg oral weekly for 3 months when breastfed). We recommend 1 mg IM in preterm <32 weeks, and the same alternative in the case of parental refusal. When IM is perceived impossible in preterm <32 weeks, 0.5 mg IV once is recommended, with a single additional IM 1 mg dose when IV lipids are discontinued. This recommendation is a step towards harmonizing vitamin K prophylaxis in all newborns