Background This position statement provides clinical recommendations for the assessment of pain, level of sedation, iatrogenic withdrawal syndrome and delirium in critically ill infants and children. Admission to a neonatal or paediatric intensive care unit (NICU, PICU) exposes a child to a series of painful and stressful events. Accurate assessment of the presence of pain and non-pain-related distress (adequacy of sedation, iatrogenic withdrawal syndrome and delirium) is essential to good clinical management and to monitoring the effectiveness of interventions to relieve or prevent pain and distress in the individual patient. Methods A multidisciplinary group of experts was recruited from the members of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC). The group formulated clinical questions regarding assessment of pain and non-pain-related distress in critically ill and nonverbal children, and searched the PubMed/Medline, CINAHL and Embase databases for studies describing the psychometric properties of assessment instruments. Furthermore, level of evidence of selected studies was assigned and recommendations were formulated, and grade or recommendations were added on the basis of the level of evidence. Results An ESPNIC position statement was drafted which provides clinical recommendations on assessment of pain (n = 5), distress and/or level of sedation (n = 4), iatrogenic withdrawal syndrome (n = 3) and delirium (n = 3). These recommendations were based on the available evidence and consensus amongst the experts and other members of ESPNIC. Conclusions This multidisciplinary ESPNIC position statement guides professionals in the assessment and reassessment of the effectiveness of treatment interventions for pain, distress, inadequate sedation, withdrawal syndrome and delirium.

We studied meropenem in 23 pre-term (gestational age, 29 to 36 weeks) and 15 full-term (gestational age, 37 to 42 weeks) neonates. Meropenem doses of 10, 20, and 40 mg/kg were administered as single doses (30-min intravenous infusion) on a random basis. Blood was obtained for determining the meropenem concentration nine times. Each child required other antimicrobials for proven/suspected bacterial infections. Samples were assayed by high-performance liquid chromatography analysis. Population pharmacokinetic parameter values were obtained by employing the BigNPAG program. Model building was performed by the likelihood ratio test. The final model included estimated creatinine clearance (CL _cr ) (Schwartz formula) and weight (Wt) in the calculation of clearance (meropenem clearance = 0.00112 × CL _cr + 0.0925 × Wt + 0.156 liter/hr). The overall fit of the model to the data was good (observed = 1.037 × predicted − 0.096; r ² = 0.977). Given the distributions of estimated creatinine clearance and weight between pre-term and full-term neonates, meropenem clearance was substantially higher in the full-term group. A Monte Carlo simulation was performed using the creatinine clearance and weight distributions for pre-term and full-term populations separately, examining 20- and 40-mg/kg doses, 8- and 12-h dosing intervals, and 0.5-h and 4-h infusion times. The 8-h interval produced robust target attainments (both populations). If more resistant organisms were to be treated (MIC of 4 to 8 mg/liter), the 40-mg/kg dose and a prolonged infusion was favored. Treating clinicians need to balance dose choices for optimizing target attainment against potential toxicity. These findings require validation in clinical circumstances.

Therapeutic hypothermia (HT) is frequently used in neonates with hypoxic-ischemic encephalopathy and young infants during cardiopulmonary bypass (CPB). Hypothermia and CPB result in physiological changes contributing to pharmacokinetic (PK) and pharmacodynamic (PD) changes. Changes in the absorption, the volume of distribution (Vd) and the total body clearance (CL) of drugs used during hypothermia and CPB might lead to the interindividual PK variability resulting in either insufficient or toxic plasma concentrations and have an impact on the biodisposition and action of drugs. Both under- or overdosing of medicines in these critically ill patients may contribute to a worse overall outcome. Overall, hypothermia decreases CL but may decrease or increase Vd by changing intravascular blood volume, organ perfusion and enzymatic metabolic processes. In addition, maturational as well as organ specific changes may occur during hypothermia superimposed on the underlying disease and/or procedures such as extracorporeal membrane oxygenation (ECMO) or CPB. This paper will provide an overview of variables and potential covariates (e.g., asphyxia, sepsis, multiorgan dysfunction syndrome, cardiac arrest) determining the PK of frequently used drugs. In addition, the effects of hypothermia on individual drugs are described as well as alternative ways for future study designs such as the use of population PK-PD and opportunistic sampling. Ultimately, these investigations are warranted to obtain specific dosing nomograms of medicines for use in clinical practice and to improve the treatment results of this vulnerable group of pediatric patients.

ECMO support is an established life saving therapy for potentially reversible respiratory and/or cardiac failure. Improvement of outcome depends on effective treatment of the primary diagnosis and complications. Adequate drug therapy is important in reaching these goals. Pharmacokinetic and pharmacodynamic data in neonates and older children on ECMO are sparse. Most studies show altered volume of distribution and clearance for the drugs studied. This article gives an overview of the available PK and PD studies in neonates and children on ECMO, suggests possible mechanisms of altered PK and PD and identifies areas of interest for further research.

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. 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. 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. 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.