Data-sharing can help to successfully develop and validate population pharmacokinetic models in neonates. From the results it seems that both PNA and bodyweight are required to guide dosing of phenobarbital in term and preterm neonates.

Adequate postoperative analgesia in pediatric patients in the intensive care unit (ICU) matters, since untreated pain is associated with negative outcomes. Compared to routine postoperative patients, children undergoing hypothermia (HT) or extracorporeal membrane oxygenation (ECMO), or recovering after cardiac surgery likely display non-maturational differences in pharmacokinetics (PK) and pharmacodynamics (PD). These differences warrant additional dosing recommendations to optimize pain treatment. Areas covered: Specific populations within the ICU will be discussed with respect to expected variations in PK and PD for various analgesics. We hereby move beyond maturational changes and focus on why PK/PD may be different in children undergoing HT, ECMO or cardiac surgery. We provide a stepwise manner to develop PK-based dosing regimens using population PK approaches in these populations. Expert opinion: A one-dose to size-fits-all for analgesia is suboptimal, but for several commonly used analgesics the impact of HT, ECMO or cardiac surgery on average PK parameters in children is not yet sufficiently known. Parameters considering both maturational and non-maturational covariates are important to develop population PK-based dosing advices as part of a strategy to optimize pain treatment.

On behalf of the Innovative Medicines Initiative conect4children (IMI c4c) Expert group on Developmental Pharmacology and the European Society for Developmental, Perinatal and Paediatric Pharmacology (ESDPPP)

Background Management and monitoring of pain and sedation to reduce discomfort as well as side effects, such as over- and under-sedation, withdrawal syndrome and delirium, is an integral part of pediatric intensive care practice. However, the current state of management and monitoring of analgosedation across European pediatric intensive care units (PICUs) remains unknown. The aim of this survey was to describe current practices across European PICUs regarding the management and monitoring of pain and sedation. Methods An online survey was distributed among 357 European PICUs assessing demographic features, drug choices and dosing, as well as usage of instruments for monitoring pain and sedation. We also compared low- and high-volume PICUs practices. Responses were collected from January to April 2021. Results A total of 215 (60% response rate) PICUs from 27 European countries responded. Seventy-one percent of PICUs stated to use protocols for analgosedation management, more frequently in high-volume PICUs (77% vs 63%, p = 0.028). First-choice drug combination was an opioid with a benzodiazepine, namely fentanyl (51%) and midazolam (71%) being the preferred drugs. The starting doses differed between PICUs from 0.1 to 5 mcg/kg/h for fentanyl, and 0.01 to 0.5 mg/kg/h for midazolam. Daily assessment and documentation for pain (81%) and sedation (87%) was reported by most of the PICUs, using the preferred validated FLACC scale (54%) and the COMFORT Behavioural scale (48%), respectively. Both analgesia and sedation were mainly monitored by nurses (92% and 84%, respectively). Eighty-six percent of the responding PICUs stated to use neuromuscular blocking agents in some scenarios. Monitoring of paralysed patients was preferably done by observation of vital signs with electronic devices support. Conclusions This survey provides an overview of current analgosedation practices among European PICUs. Drugs of choice, dosing and assessment strategies were shown to differ widely. Further research and development of evidence-based guidelines for optimal drug dosing and analgosedation assessment are needed.

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Phenobarbital is an anticonvulsive drug widely used in newborns with hypoxic-ischemic encephalopathy. The objective of our study was to describe possible effect of frequently co-administered medications (dopamine, dobutamine, norepinephrine, furosemide, phenytoin, and analgesics) on the phenobarbital pharmacokinetics in full term newborns with hypoxic-ischemic encephalopathy. Phenobarbital pharmacokinetic parameters (standardized intravenous loading dose was 10-20 mg/kg, maintenance dose 2-6 mg/kg/day) were computed using non-compartmental analysis. Co-medication was evaluated throughout the whole treatment period up to 5 days. Volume of distribution, clearance, and half-life median values (95 % CI) for phenobarbital in the whole study population (n=37) were 0.48 (0.41-0.56) l/kg, 0.0034 (0.0028-0.0040) l/h/kg, and 93.7 (88.1-99.2) h, respectively. Phenobarbital pharmacokinetic parameters were not significantly affected by vasoactive drugs (dopamine, dobutamine, and norepinephrine), furosemide, phenytoin, or analgesics. Furthermore, no dose-dependent alteration of phenobarbital pharmacokinetic parameters was noted for vasoactive medication at doses equivalent to cumulative vasoactive-inotropic score (area under the curve in a plot of vasoactive-inotropic score against time) 143.2-8473.6, furosemide at cumulative doses of 0.2-42.9 mg/kg, or phenytoin at cumulative doses of 10.3-46.2 mg/kg. Phenobarbital pharmacokinetics was not affected by investigated co-administered drugs used in newborns with hypoxic-ischemic encephalopathy in real clinical settings.

IntroductionAnalgesia and sedation are essential for the care of children in the pediatric intensive care unit (PICU); however, when prolonged, they may be associated with iatrogenic withdrawal syndrome (IWS) and delirium. We sought to evaluate current practices on IWS and delirium assessment and management (including non‐pharmacologic strategies as early mobilization) and to investigate associations between the presence of an analgosedation protocol and IWS and delirium monitoring, analgosedation weaning, and early mobilization.MethodsWe conducted a multicenter cross‐sectional survey‐based study collecting data from one experienced physician or nurse per PICU in Europe from January to April 2021. We then investigated differences among PICUs that did or did not follow an analgosedation protocol.ResultsAmong 357 PICUs, 215 (60%) responded across 27 countries. IWS was systematically monitored with a validated scale in 62% of PICUs, mostly using the Withdrawal Assessment Tool‐1 (53%). The main first‐line treatment for IWS was a rescue bolus with interruption of weaning (41%). Delirium was systematically monitored in 58% of PICUs, mostly with the Cornell Assessment of Pediatric Delirium scale (48%) and the Sophia Observation Scale for Pediatric Delirium (34%). The main reported first‐line treatment for delirium was dexmedetomidine (45%) or antipsychotic drugs (40%). Seventy‐one percent of PICUs reported to follow an analgosedation protocol. Multivariate analyses adjusted for PICU characteristics showed that PICUs using a protocol were significantly more likely to systematically monitor IWS (odds ratio [OR] 1.92, 95% confidence interval [CI] 1.01–3.67) and delirium (OR 2.00, 95% CI 1.07–3.72), use a protocol for analgosedation weaning (OR 6.38, 95% CI 3.20–12.71) and promote mobilization (OR 3.38, 95% CI 1.63–7.03).ConclusionsMonitoring and management of IWS and delirium are highly variable among European PICUs. The use of an analgosedation protocol was associated with an increased likelihood of monitoring IWS and delirium, performing a structured analgosedation weaning and promoting mobilization. Education on this topic and interprofessional collaborations are highly needed to help reduce the burden of analgosedation‐associated adverse outcomes.

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