Current knowledge, challenges and innovations in developmental pharmacology: A combined conect4children Expert Group and European Society for Developmental, Perinatal and Paediatric Pharmacology White Paper.

Developmental pharmacology describes the impact of maturation on drug disposition (pharmacokinetics, PK) and drug effects (pharmacodynamics, PD) throughout the paediatric age range. This paper, written by a multidisciplinary group of experts, summarizes current knowledge, and provides suggestions to pharmaceutical companies, regulatory agencies and academicians on how to incorporate the latest knowledge regarding developmental pharmacology and innovative techniques into neonatal and paediatric drug development. Biological aspects of drug absorption, distribution, metabolism and excretion throughout development are summarized. Although this area made enormous progress during the last two decades, remaining knowledge gaps were identified. Minimal risk and burden designs allow for optimally informative but minimally invasive PK sampling, while concomitant profiling of drug metabolites may provide additional insight in the unique PK behaviour in children. Furthermore, developmental PD needs to be considered during drug development, which is illustrated by disease- and/or target organ-specific examples. Identifying and testing PD targets and effects in special populations, and application of age- and/or population-specific assessment tools are discussed. Drug development plans also need to incorporate innovative techniques such as preclinical models to study therapeutic strategies, and shift from sequential enrolment of subgroups, to more rational designs. To stimulate appropriate research plans, illustrations of specific PK/PD-related as well as drug safety-related challenges during drug development are provided. The suggestions made in this joint paper of the Innovative Medicines Initiative conect4children Expert group on Developmental Pharmacology and the European Society for Developmental, Perinatal and Paediatric Pharmacology, should facilitate all those involved in drug development.

Pain and sedation management and monitoring in pediatric intensive care units across Europe: an ESPNIC survey.

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.

Assessment and management of iatrogenic withdrawal syndrome and delirium in pediatric intensive care units across Europe: An ESPNIC survey.

INTRODUCTION: Analgesia 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. METHODS: We 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. RESULTS: Among 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). CONCLUSIONS: Monitoring 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.

Pharmacokinetic considerations for pediatric patients receiving analgesia in the intensive care unit; targeting postoperative, ECMO and hypothermia patients.

INTRODUCTION: 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.

Model-based clinical dose optimization for phenobarbital in neonates: An illustration of the importance of data sharing and external validation.

BACKGROUND: Particularly in the pediatric clinical pharmacology field, data-sharing offers the possibility of making the most of all available data. In this study, we utilize previously collected therapeutic drug monitoring (TDM) data of term and preterm newborns to develop a population pharmacokinetic model for phenobarbital. We externally validate the model using prospective phenobarbital data from an ongoing pharmacokinetic study in preterm neonates. METHODS: TDM data from 53 neonates (gestational age (GA): 37 (24-42) weeks, bodyweight: 2.7 (0.45-4.5) kg; postnatal age (PNA): 4.5 (0-22) days) contained information on dosage histories, concentration and covariate data (including birth weight, actual weight, post-natal age (PNA), postmenstrual age, GA, sex, liver and kidney function, APGAR-score). Model development was carried out using NONMEM® 7.3. After assessment of model fit, the model was validated using data of 17 neonates included in the DINO (Drug dosage Improvement in NeOnates)-study. RESULTS: Modelling of 229 plasma concentrations, ranging from 3.2 to 75.2mg/L, resulted in a one compartment model for phenobarbital. Clearance (CL) and volume (Vd) for a child with a birthweight of 2.6kg at PNA day 4.5 was 0.0091L/h (9%) and 2.38L (5%), respectively. Birthweight and PNA were the best predictors for CL maturation, increasing CL by 36.7% per kg birthweight and 5.3% per postnatal day of living, respectively. The best predictor for the increase in Vd was actual bodyweight (0.31L/kg). External validation showed that the model can adequately predict the pharmacokinetics in a prospective study. CONCLUSION: 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.