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Analgosedation is a fundamental part of traumatic brain injury (TBI) treatment guidelines, encompassing both first and second tier supportive strategies. Worldwide analgosedation practices continue to be heterogeneous due to the low level of evidence in treatment guidelines (level III) and the choice of analgosedative drugs is made by the treating clinician. Current practice is thus empirical and may result in unfavourable (often hemodynamic) side effects. This article presents an overview of current analgosedation practices in the paediatric intensive care unit (PICU) and addresses pitfalls both in the short and long term. We discuss innovative (pre-)clinical research that can provide the framework for initiatives to improve our pharmacological understanding of analgesic and sedative drugs used in paediatric severe TBI and ultimately facilitate steps towards evidence-based and precision pharmacotherapy in this vulnerable patient group.

Purpose: Over 80% of the terminally ill patients experience delirium in their final days. In the treatment of delirium, haloperidol is the drug of choice. Very little is known about the pharmacokinetics of haloperidol in this patient population. We therefore designed a population pharmacokinetic study to gain more insight into the pharmacokinetics of haloperidol in terminally ill patients and to find clinically relevant covariates that may be used in developing an individualised dosing regimen. Methods: Using non-linear mixed effects modelling (NONMEM 7.2), a population pharmacokinetic analysis was conducted with 87 samples from 28 terminally ill patients who received haloperidol either orally or subcutaneously. The covariates analysed were patient and disease characteristics as well as co-medication. Results: The data were accurately described by a one-compartment model. The population mean estimates for oral bioavailability, clearance and volume of distribution for an average patient were 0.86 (IIV 55%), 29.3 L/h (IIV 43%) and 1260 L (IIV 70%), respectively. This resulted in an average terminal half-life of haloperidol of around 30 h. Conclusion: Our study showed that the pharmacokinetics of haloperidol could be adequately described by a one-compartment model. The pharmacokinetics in terminally ill patients was comparable to other patients. We were not able to explain the wide variability using covariates.

Contains fulltext : 168023.pdf (Publisher’s version ) (Closed access) Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.

Sedatives administered to critically ill children should be titrated to effect, because both under- and oversedation may have negative effects. We conducted a systematic review to examine reported incidences of under-, optimal, and oversedation in critically ill children receiving intensive care. A systematic literature search using predefined criteria was performed in PubMed and Embase to identify all articles evaluating level of sedation in PICU patients receiving continuous sedation. Two authors independently recorded: study objective, study design, sample size, age range, details of study intervention (if applicable), sedatives used, length of sedation, sedation scale used, and incidences of optimal, under-, and oversedation as defined in the studies. Twenty-five studies were included. Two studies evaluated sedation level as primary study outcome; the other 23 as secondary outcomes. Together, these studies investigated 1,163 children; age range, 0–18 years. Across studies, children received many different sedative agents and sedation level was assessed with 12 different sedation scales. Optimal sedation was ascertained in 57.6 % of the observations, under sedation in 10.6 %, and oversedation in 31.8 %. This study suggests that sedation in the PICU is often suboptimal and seldom systematically evaluated. Oversedation is more common than undersedation. As oversedation may lead to longer hospitalization, tolerance, and withdrawal, preventing oversedation in pediatric intensive care deserves greater attention.

Item does not contain fulltext PURPOSE: The optimal timing of ostomy closure is a matter of debate. We performed a systematic review of outcomes of early ostomy closure (EC, within 8 weeks) and late ostomy closure (LC, after 8 weeks) in infants with necrotizing enterocolitis. METHODS: PubMed, EMbase, Web-of-Science, and Cinahl were searched for studies that detailed time to ostomy closure, and time to full enteral nutrition (FEN) or complications after ostomy closure. Patients with Hirschsprung's disease or anorectal malformations were excluded. Analysis was performed using SPSS 17 and RevMan 5. RESULTS: Of 778 retrieved articles, 5 met the inclusion criteria. The median score for study quality was 9 [range 8-14 on a scale of 0 to 32 points (Downs and Black, J Epidemiol Community Health 52:377-384, 1998)]. One study described mean time to FEN: 19.1 days after EC (n = 13) versus 7.2 days after LC (n = 24; P = 0.027). Four studies reported complication rates after ostomy closure, complications occurred in 27% of the EC group versus 23% of the LC group. The combined odds ratio (LC vs. EC) was 1.1 [95% CI 0.5, 2.5]. CONCLUSION: Evidence that supports early or late closure is scarce and the published articles are of poor quality. There is no significant difference between EC versus LC in the complication rate. This systematic review supports neither early nor late ostomy closure.

The objectives of this study are to describe the number and nature of adverse events occurring in general pediatric practice, to describe factors contributing to the occurrence of these adverse events, and to report on the experience of pediatricians with reporting adverse events. It is a prospective study on 11 pediatric units in a 3-month period; adverse events were registered for all newly admitted patients. Ninety-four adverse events were registered in 88 of 5,669 patients, amounting to a 1.6 per 100 admissions rate and a 0.4 per 100 patient days rate. Ninety percent of the adverse events did not cause serious harm. Failed diagnostic procedures were most common. Conclusion: Adverse event registration in general pediatric practice is a first step in assessing quality and safety of care. It yields a considerable number of adverse events. Compliance to adverse event registration in daily practice is difficult but also key to optimal monitoring of quality of care.

Purpose In most extracorporeal membrane oxygenation (ECMO) centers patients are heavily sedated to prevent accidental decannulation and bleeding complications. In ventilated adults not on ECMO, daily sedation interruption protocols improve short- and long-term outcome. This study aims to evaluate safety and feasibility of sedation interruption following cannulation in neonates on ECMO. Methods Prospective observational study in 20 neonates (0.17–5.8 days of age) admitted for ECMO treatment. Midazolam (n = 20) and morphine (n = 18) infusions were discontinued within 30 min after cannulation. Pain and sedation were regularly assessed using COMFORT-B and visual analog scale (VAS) scores. Midazolam and/or morphine were restarted and titrated according to protocolized treatment algorithms. Results Median (interquartile range, IQR) time without any sedatives was 10.3 h (5.0–24.1 h). Median interruption duration for midazolam was 16.5 h (6.6–29.6 h), and for morphine was 11.2 h (6.7–39.4 h). During this period no accidental extubations, decannulations or bleeding complications occurred. Conclusions This is the first study to show that interruption of sedatives and analgesics following cannulation in neonates on ECMO is safe and feasible. Interruption times are 2–3 times longer than reported for adult ICU patients not on ECMO. Further trials are needed to substantiate these findings and evaluate short- and long-term outcomes.

This review gives an overview of the disease spectrum of congenital diaphragmatic hernia (CDH). Etiological factors, prenatal predictors of survival, new treatment strategies and long-term morbidity are described. Early recognition of problems and improvement of treatment strategies in CDH patients may increase survival and prevent secondary morbidity. Multidisciplinary healthcare is necessary to improve healthcare for CDH patients. Absence of international therapy guidelines, lack of evidence of many therapeutic modalities and the relative low number of CDH patients calls for cooperation between centers with an expertise in the treatment of CDH patients. The international CDH Euro-Consortium is an example of such a collaborative network, which enhances exchange of knowledge, future research and development of treatment protocols.

To construct a reliable and clinically practical instrument for monitoring opioids and benzodiazepine withdrawal symptoms in pediatric ICU patients. Instrument development. Intensive care unit in an academic children's hospital. 79 patients up to age 16 years on intravenous midazolam and/or opioids for a parts per thousand yen5 days. An expert panel of 85 physicians and nurses rated clinical relevance of withdrawal symptoms. During drug weaning repeated observations were performed with a checklist of 24 withdrawal symptoms described in the literature. For 76 children, 932 observations were obtained within 24 h after decrease and/or discontinuation of midazolam or opioids. Most frequent symptoms were tachypnea, agitation, motor disturbance, diarrhea, fever, anxiety, sleep disturbance and hypertension (14.6-29.6%). Multidimensional scaling (MDS) was performed to detect the underlying empirical structure of co-occurrences of symptoms. An expert panel judged clinical relevance of each withdrawal symptom on a four-point scale ranging from 'definitively so' to 'definitively not'. Agitation, anxiety, inconsolable crying, increased muscle tension, tremors, tachycardia and sweating were considered relevant by 85-95% of the experts. On the basis of the MDS results and the experts' opinions, 15 symptoms were included in the final instrument. We are the first to develop an assessment tool for withdrawal symptoms in pediatric ICU patients on the basis of the underlying empirical structure of co-occurrences of withdrawal symptoms that experts considered relevant. Future studies need to define cut-off points and clarify psychometric issues.

Objective: Research in child subjects requires parental permission. We examined whether parental authorization of involvement in a clinical study is influenced by the child's severity of illness at the time of the consent decision. Design and setting: Observational study in a multidisciplinary tertiary pediatric and neonatal intensive care. Patients and participants: Parents of 421 children (age range from preterm to 18 years) were asked to consent for participation in a study focusing on measuring their child's nutritional status within 24 h after admission to the ICU. Over 20% of the parents (n=88) refused consent, most of them because they expected the study to be too burdensome for their child. Measurements and results: Patient and disease characteristics were comparable in the children for whom consent had or had not been obtained. A higher illness severity score did not decrease the probability of obtaining informed consent, but parents of children with a history of disease were 3.2 times less likely to consent. Conclusions: Parents of children with higher illness severity scores are not more likely to decline permission to include their child in clinical observational research on the ICU. History of disease and subjectively perceived burden to the child are important factors that must be considered.

The aim of this study was to document the pharmacodynamics of chloral hydrate in former preterm infants at term post-conception age. The degree of sedation (COMFORT), feeding behaviour and cardiorespiratory events (bradycardic events, apnoeas) before and after administration of chloral hydrate (oral, 30 mg/kg) were prospectively evaluated in former preterm infants during procedural sedation. Characteristics at birth, during neonatal stay and at inclusion were collected. Paired Wilcoxon and McNemar tests were used to study the impact of chloral hydrate. Characteristics of infants who displayed severe bradycardic events were compared to infants in whom no bradycardic events were recorded (Mann Whitney U, Fischer’s exact). A significant increase in sedation (decrease COMFORT scale) was observed up to 12 h after administration. There was a minor but significant decrease in oral intake (161 to 156 ml/kg/day, P

Data concerning metabolism of paracetamol in infants are scant. Previous studies have examined urinary metabolite recovery rates after a single dose of paracetamol in either neonates (6 weeks) or children (3-9 years). There are no studies investigating infants.Infants ( n=47) undergoing major craniofacial surgery were given paracetamol 19-45 mg/kg 6-, 8-, or 12-hourly as either elixir or suppository formulation for postoperative analgesia, after a loading dose of 33-59 mg/kg rectally during the operation. Serum was assayed for paracetamol concentration in 40 of these infants at 5, 8, 11, 14, 17 and 20 h postoperatively. Urine samples were collected every 3 h for 24 h in 15 of these infants. The clearances of paracetamol to glucuronide and sulphate metabolites as well as the urinary clearance of unmetabolised paracetamol were estimated using non-linear, mixed-effects models.Mean (+/-SD) age and weight of the patients were 11.8+/-2.5 months and 9.1+/-1.9 kg. Clearances of paracetamol to paracetamol-glucuronide (%CV) and to paracetamol-sulphate were 6.6 (11.5) l/h and 7.5 (11.5) l/h respectively, standardised to a 70-kg person using allometric "1/4 power" models. Glucuronide formation clearance, but not sulphate formation, was related to age and increased with age from a predicted value in a neonate of 2.73 l/h/70 kg to a mature value of 6.6 l/h/70 kg with a maturation half-life of 8.09 months. Urine clearance of paracetamol-glucuronide, paracetamol-sulphate and unchanged paracetamol (%CV) were, respectively, 2.65, 3.03 and 0.55 (28) l/h/70 kg. The urine clearance of unchanged paracetamol and metabolites was related to urine volume flow rate. Clearance attributable to pathways other than these measured in urine was not identifiable. The glucuronide/sulphate formation clearance ratio was 0.69 at 12 months of age. Sulphate metabolism contributed 50% towards paracetamol clearance.Glucuronide formation clearance increases with age in the infant age range but sulphate formation does not. Renal clearance of paracetamol and its metabolites increases with urine flow rate. This and other studies show that paracetamol metabolism to glucuronide appears to be similar in infants and children, but in adults is increased in comparison with children. Oxidative pathways were undetectable in this infant study and may explain, in part, the reduced incidence of hepatotoxicity in infants.

An experimental study was conducted to determine the end-results of two different defects on the anterior abdominal wall: an abdominal wall defect (AWD) versus an umbilical cord defect (UCD) using chick embryos. The AWD was created by leaving an intact skin bridge between the defect and the umbilical cord in group l; the UCD was created on the umbilical cord near the junction of the skin in group 2. At the end of incubation, the intestines appeared hemorrhagic in the AWD group, but not in the UCD group. During microscopic examination, hemorrhagic areas were observed in the bowel wall and mucosal villi in the AWD group but not in the UCD group. The end-result of the defect causing the physiological umbilical hernia resulted in bowel damage resembling the classic picture of gastroschisis (GS). We conclude that the site of the defect in GS is not the abdominal wall itself, but the physiological umbilical hernia.

Based on blood and cerebrospinal fluid samples collected in a full-term neonate, the penetration of tramadol in the central nervous system is described. Following intravenous administration of tramadol, a lag time of about 4 h was observed until full blood-brain equilibration was achieved. This pharmacokinetic observation is in line with a recent pharmacodynamic evaluation of the central opioid effects of tramadol in adults.