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Summary: Background: The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. Methods: Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. Findings: Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. Interpretation: Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. Funding: CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

Summary: Background: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. Methods: Exposure–response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. Findings: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13–15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13–15 and positive CT (1.21–2.81), GCS 9–12 (1.16–2.02), GCS 3–8 (1.09–1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51–1.80) percentages of unfavourable outcome were 37–51% in the lowest quintiles of biomarker levels and reached 90–94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83–3.79), the percentages were 2–4% and 19–28% in the lowest and highest biomarker quintiles, respectively. Interpretation: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. Funding: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.

ObjectiveApproximately 50% of adolescents who have undergone scoliosis surgery still experience severe pain one year postoperatively. We explored the postoperative pain trajectory and the potential value of preoperative Thermal Quantitative Sensory Testing (T-QST) as predictor of chronic postsurgical pain after scoliosis surgery.DesignSingle-center prospective cohort study in adolescents undergoing scoliosis surgery.OutcomesPrevalence of chronic postsurgical pain (CPSP) one year after scoliosis surgery and postsurgical pain course during this year. The need for rescue medication and the relationship between pre-operative T-QST, acute pain and CPSP.ResultsThirty-nine patients (mean age 13.9 years; SD 1.9 years) completed the study. One year postoperatively, ten patients (26%) self-reported pain [numeric rating scale (NRS) score ≥ 4]) when moving and two (5%) when in rest. Four of these patients (10.3%) experienced neuropathic pain. The pre-operative cold pain threshold was lower (p = 0.002) in patients with CPSP at 12 months. Preoperative cold and heat pain thresholds were correlated with the number of moderate or severe pain reports (NRS ≥ 4) in the first week postoperatively (r -.426; p = 0.009 and r.392; p = 0.016, respectively).ConclusionsOne year after scoliosis surgery, a significant part of patients (26%) still reported pain, some with neuropathic characteristics. Better diagnosis and treatment is needed; our study suggests that T-QST could be further explored to better understand and treat children with this negative outcome.

This study aimed to characterize the impact of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics (PK) of meropenem in neonates and children and to provide recommendations for meropenem dosing in this specific population of patients. Therapeutic drug monitoring (152 meropenem plasma concentrations) data from 45 patients (38 received ECMO) with a body weight (BW) of 7.88 (3.62–11.97) kg (median (interquartile range)) and postnatal age of 3 (0–465) days were collected. The population PK analysis was performed using NONMEM V7.3.0. Monte Carlo simulations were performed to assess the probability of target achievement (PTA) for 40% of time the free drug remained above the minimum inhibitory concentration (fT > MIC) and 100% fT > MIC. BW was found to be a significant covariate for the volume of distribution (Vd) and clearance (CL). Additionally, continuous renal replacement therapy (CRRT) was associated with a two-fold increase in Vd. In the final model, the CL and Vd for a typical patient with a median BW of 7.88 kg that was off CRRT were 1.09 L/h (RSE = 8%) and 3.98 L (14%), respectively. ECMO did not affect meropenem PK, while superimposed CRRT significantly increased Vd. We concluded that current dosing regimens provide acceptably high PTA for MIC ≤ 4 mg/L for 40% fT > MIC, but individual dose adjustments are needed for 100% fT > MIC.

Summary: Background: Limited evidence existed on the comparative effectiveness of decompressive craniectomy (DC) versus craniotomy for evacuation of traumatic acute subdural hematoma (ASDH) until the recently published randomised clinical trial RESCUE-ASDH. In this study, that ran concurrently, we aimed to determine current practice patterns and compare outcomes of primary DC versus craniotomy. Methods: We conducted an analysis of centre treatment preference within the prospective, multicentre, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (known as CENTER-TBI) and NeuroTraumatology Quality Registry (known as Net-QuRe) studies, which enrolled patients throughout Europe and Israel (2014–2020). We included patients with an ASDH who underwent acute neurosurgical evacuation. Patients with severe pre-existing neurological disorders were excluded. In an instrumental variable analysis, we compared outcomes between centres according to treatment preference, measured by the case-mix adjusted proportion DC per centre. The primary outcome was functional outcome rated by the 6-months Glasgow Outcome Scale Extended, estimated with ordinal regression as a common odds ratio (OR), adjusted for prespecified confounders. Variation in centre preference was quantified with the median odds ratio (MOR). CENTER-TBI is registered with ClinicalTrials.gov, number NCT02210221, and the Resource Identification Portal (Research Resource Identifier SCR_015582). Findings: Between December 19, 2014 and December 17, 2017, 4559 patients with traumatic brain injury were enrolled in CENTER-TBI of whom 336 (7%) underwent acute surgery for ASDH evacuation; 91 (27%) underwent DC and 245 (63%) craniotomy. The proportion primary DC within total acute surgery cases ranged from 6 to 67% with an interquartile range (IQR) of 12–26% among 46 centres; the odds of receiving a DC for prognostically similar patients in one centre versus another randomly selected centre were trebled (adjusted median odds ratio 2.7, p

IntroductionIn mechanically ventilated adults, thickening fraction of diaphragm (dTF) measured by ultrasound is used to predict extubation success. Whether dTF can also predict extubation success in children is unclear.AimTo investigate the association between dTF and extubation success in children. Second, to assess diaphragm thickness during ventilation and the correlation between dTF, diaphragm thickness (Tdi), age and body surface.MethodProspective observational cohort study in children aged 0–18 years old with expected invasive ventilation for >48 h. Ultrasound was performed on day 1 after intubation (baseline), day 4, day 7, day 10, at pre-extubation, and within 24 h after extubation. Primary outcome was the association between dTF pre-extubation and extubation success. Secondary outcome measures were Tdi end-inspiratory and Tdi end-expiratory and atrophy defined as

Abstract 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.

Introduction: This study reports on the translation, cultural adaptation, and validation of a Portuguese version of the Rotterdam Elderly Pain Observation Scale (REPOS), a Dutch scale to assess pain in patients who cannot communicate, with or without dementia. Methods: This is a multicenter study in pain and neurological units involving Brazil (clinical phase) and the Netherlands (training phase). We performed a retrospective cross-sectional, 2-staged analysis, translating and culturally adapting the REPOS to a Portuguese version (REPOS-P) and evaluating its psychometric properties. Eight health professionals were trained to observe patients with low back pain. REPOS consists of 10 behavioral items scored as present or absent after a 2-min observation. The REPOS score of ≥3 in combination with the Numerical Rating Scale (NRS) of ≥4 indicated pain. The Content Validity Index (CVI) in all items and instructions showed CVI values at their maximum. According to the higher correlation coefficient found between NRS and REPOS-P, it may be suggested that there was an adequate convergent validity. Results: The REPOS-P was administered to 80 patients with a mean age of 60 years (SD 11.5). Cronbach’s alpha coefficient showed a moderate internal consistency of REPOS-P (α = 0.62), which is compatible with the original study of REPOS. All health professionals reached high levels of interrater agreement within a median of 10 weeks of training, assuring reproducibility. Cohen’s kappa was 0.96 (SD 0.03), and the intraclass correlation coefficient was 0.98 (SD 0.02), showing high reliability of REPOS-P scores between the trainer (researcher) and the trainees (healthcare professionals). The Pearson correlation coefficient was 0.95 (95% confidence interval 0.94–0.97), showing a significant correlation between the total scores of REPOS-P and NRS. Conclusion: The REPOS-P was a valuable scale for assessing elderly patients with low back pain by different healthcare professionals. Short application time, ease of use, clear instructions, and the brief training required for application were essential characteristics of REPOS-P.

The lung is composed of a highly branched airway structure, which humidifies and warms the inhaled air before entering the alveolar compartment. In the alveoli, a thin layer of epithelium is in close proximity with the capillary endothelium, allowing for an efficient exchange of oxygen and carbon dioxide. During development proliferation and differentiation of progenitor cells generates the lung architecture, and in the adult lung a proper function of progenitor cells is needed to regenerate after injury. Malfunctioning of progenitors during development results in various congenital lung disorders, such as Congenital Diaphragmatic Hernia (CDH) and Congenital Pulmonary Adenomatoid Malformation (CPAM). In addition, many premature neonates experience continuous insults on the lung caused by artificial ventilation and supplemental oxygen, which requires a highly controlled mechanism of airway repair. Malfunctioning of airway progenitors during regeneration can result in reduction of respiratory function or (chronic) airway diseases. Pathways that are active during development are frequently re-activated upon damage. Understanding the basic mechanisms of lung development and the behavior of progenitor cell in the ontogeny and regeneration of the lung may help to better understand the underlying cause of lung diseases, especially those occurring in prenatal development or in the immediate postnatal period of life. This review provides an overview of lung development and the cell types involved in repair of lung damage with a focus on the airway.

ObjectiveSpine injury is highly prevalent in patients with poly-trauma, but data on the co-occurrence of spine trauma in patients with traumatic brain injury (TBI) are scarce. In this study, we used the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) database to assess the prevalence, characteristics, and outcomes of patients with TBI and a concurrent traumatic spinal injury (TSI).MethodsData from the European multi-center CENTER-TBI study were analyzed. Adult patients with TBI (≥18 years) presenting with a concomitant, isolated TSI of at least serious severity (Abbreviated Injury Scale; AIS ≥3) were included. For outcome analysis, comparison groups of TBI patients with TSI and systemic injuries (non-isolated TSI) and without TSI were created using propensity score matching. Rates of mortality, unfavorable outcomes (Glasgow Outcome Scale Extended; GOSe < 5), and full recovery (GOSe 7–8) of all patients and separately for patients with only mild TBI (mTBI) were compared between groups at 6-month follow-up.ResultsA total of 164 (4%) of the 4,254 CENTER-TBI core study patients suffered from a concomitant isolated TSI. The median age was 53 [interquartile range (IQR): 37–66] years and 71% of patients were men. mTBI was documented in 62% of cases, followed by severe TBI (26%), and spine injuries were mostly cervical (63%) or thoracic (31%). Surgical spine stabilization was performed in 19% of cases and 57% of patients were admitted to the ICU. Mortality at 6 months was 11% and only 36% of patients regained full recovery. There were no significant differences in the 6-month rates of mortality, unfavorable outcomes, or full recovery between TBI patients with and without concomitant isolated TSI. However, concomitant non-isolated TSI was associated with an unfavorable outcome and a higher mortality. In patients with mTBI, a negative association with full recovery could be observed for both concomitant isolated and non-isolated TSI.ConclusionRates of mortality, unfavorable outcomes, and full recovery in TBI patients with and without concomitant, isolated TSIs were comparable after 6 months. However, in patients with mTBI, concomitant TSI was a negative predictor for a full recovery. These findings might indicate that patients with moderate to severe TBI do not necessarily exhibit worse outcomes when having a concomitant TSI, whereas patients with mTBI might be more affected.

Congenital diaphragmatic hernia is a structural birth defect of the diaphragm, with lung hypoplasia and persistent pulmonary hypertension. Aside from vascular defects, the lungs show a disturbed balance of differentiated airway epithelial cells. The Sry related HMG box protein SOX2 is an important transcription factor for proper differentiation of the lung epithelium. The transcriptional activity of SOX2 depends on interaction with other proteins and the identification of SOX2-associating factors may reveal important complexes involved in the disturbed differentiation in CDH. To identify SOX2-associating proteins, we purified SOX2 complexes from embryonic mouse lungs at 18.5 days of gestation. Mass spectrometry analysis of SOX2-associated proteins identified several potential candidates, among which were the Chromodomain Helicase DNA binding protein 4 (CHD4), Cut-Like Homeobox1 (CUX1), and the Forkhead box proteins FOXP2 and FOXP4. We analyzed the expression patterns of FOXP2, FOXP4, CHD4, and CUX1 in lung during development and showed co-localization with SOX2. Co-immunoprecipitations validated the interactions of these four transcription factors with SOX2, and large-scale chromatin immunoprecipitation (ChIP) data indicated that SOX2 and CHD4 bound to unique sites in the genome, but also co-occupied identical regions, suggesting that these complexes could be involved in co-regulation of genes involved in the respiratory system.

ObjectiveTo evaluate possible negative long-term effects of neonatal exposure to pain, opioids and anesthetics in children and adolescents.Study DesignWe studied five unique groups of children recruited from well-documented neonatal cohorts with a history of neonatal exposure to pain, opioids or anesthetics at different points along the continuum from no pain to intense pain and from no opioid exposure to very high opioid exposure in the presence or absence of anesthetics. We evaluated children who underwent major surgery (group 1 and 2), extracorporeal membrane oxygenation (group 3), preterm birth (group 4) and prenatal opioid exposure (group 5) in comparison to healthy controls. Neuropsychological functioning, thermal detection and pain thresholds and high-resolution structural and task-based functional magnetic resonance imaging during pain were assessed. In total 94 cases were included and compared to their own control groups.ResultsChildren and adolescents in groups 3 and 5 showed worse neuropsychological functioning after high opioid exposure. A thicker cortex was found in group 1 (pain, opioid and anesthetic exposure) in only the left rostral-middle-frontal-cortex compared to controls. We found no differences in other brain volumes, pain thresholds or brain activity during pain in pain related brain regions between the other groups and their controls.ConclusionsNo major effects of neonatal pain, opioid or anesthetic exposure were observed in humans 8–19 years after exposure in early life, apart from neuropsychological effects in the groups with the highest opioid exposure that warrants further investigation. Studies with larger sample sizes are needed to confirm our findings and test for less pronounced differences between exposed and unexposed children.

Congenital diaphragmatic hernia (CDH) is a rare developmental defect of the lungs and diaphragm, with substantial morbidity and mortality. Although internationally established treatment guidelines have been developed, most recommendations are still expert opinions. Trials in patients with CDH, more in particular randomized controlled trials, are rare. Only three multicenter trials in patients with CDH have been completed, which focused on fetoscopic tracheal occlusion and ventilation mode. Another four are currently recruiting, two with a focus on perinatal transition and two on the treatment of pulmonary hypertension. Herein, we discuss major challenges and pitfalls when performing a clinical trial in infants with CDH. It is essential to select the correct intervention and dose, select the appropriate population of CDH patients, and also define a relevant endpoint that allows a realistic duration and sample size. New statistical approaches might increase the feasibility of randomized controlled trials in patients with CDH. One should also timely perform the trial when there is still equipoise. But above all, awareness of policymakers for the relevance of investigator-initiated trials is essential for future clinical research in this rare disease.

Neonatal painful procedures causes acute pain and trigger long-term changes in nociceptive processing and anxiety behavior, highlighting the need for adequate analgesia during this critical time. Spinal serotonergic receptors 5-HT1a and 5-HT3 play an important role in modulating incoming nociceptive signals in neonates. The current study aims to attenuate acute and long-term hypersensitivity associated with neonatal procedural pain using ondansetron (a 5-HT3 antagonist) and buspirone (a 5-HT1a agonist) in a well-established rat model of repetitive needle pricking. Sprague-Dawley rat pups of both sexes received ondansetron (3 mg/kg), buspirone (3 mg/kg) or saline prior to repetitive needle pricks into the left hind-paw from postnatal day 0–7. Control animals received tactile stimulation or were left undisturbed. Acute, long-term, and post-operative mechanical sensitivity as well as adult anxiety were assessed. Neonatal 5-HT1a receptor agonism completely reverses acute hypersensitivity from P0-7. The increased duration of postoperative hypersensitivity after re-injury in adulthood is abolished by 5-HT3 receptor antagonism during neonatal repetitive needle pricking, without affecting baseline sensitivity. Moreover, 5-HT1a and 5-HT3 receptor modulation decreases adult state anxiety. Altogether, our data suggests that targeted pharmacological treatment based on the modulation of spinal serotonergic network via the 5-HT1a and 5-HT3 receptors in neonates may be of use in treatment of neonatal procedural pain and its long-term consequences. This may result in a new mechanism-based therapeutic venue in treatment of procedural pain in human neonates.

Summary: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 × 10−8; odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10–5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 × 10−10; OR = 1.47; 95% CI, 1.38–1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 × 10−16; OR = 1.75; 95% CI, 1.64–1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% ± 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes.

The hepatic influx transporter OATP1B1 (SLCO1B1) plays an important role in the disposition of endogenous substrates and drugs prescribed to children. Alternative splicing increases the diversity of protein products from > 90% of human genes and may be triggered by developmental signals. As concentrations of several endogenous OATP1B1 substrates change during growth and development, with this exploratory study we investigated age‐dependent alternative splicing of SLCO1B1 mRNA in 97 postmortem livers (fetus‐adolescents). Twenty‐seven splice variants were detected; 10 were confirmed by additional bioinformatic analyses and verified by quantitative polymerase chain reaction, and selected for detailed analysis based on relative abundance, association with age, and overlap with an adjacent gene. Two splice variants code for reference OATP1B1 protein, and eight code for truncated proteins. The expression of eight isoforms was associated with age. We conclude that alternative splicing of SLCO1B1 occurs frequently in children; although the functional consequences remain unknown, the data raise the possibility of a regulatory role for alternative splicing in mediating developmental changes in drug disposition.

Congenital diaphragmatic hernia (CDH) is a congenital structural anomaly in which the diaphragm has not developed properly. It may occur either as an isolated anomaly or with additional anomalies. It is thought to be a multifactorial disease in which genetic factors could either substantially contribute to or directly result in the developmental defect. Patients with aneuploidies, pathogenic variants or de novo Copy Number Variations (CNVs) impacting specific genes and loci develop CDH typically in the form of a monogenetic syndrome. These patients often have other associated anatomical malformations. In patients without a known monogenetic syndrome, an increased genetic burden of de novo coding variants contributes to disease development. In early years, genetic evaluation was based on karyotyping and SNP-array. Today, genomes are commonly analyzed with next generation sequencing (NGS) based approaches. While more potential pathogenic variants are being detected, analysis of the data presents a bottleneck—largely due to the lack of full appreciation of the functional consequence and/or relevance of the detected variant. The exact heritability of CDH is still unknown. Damaging de novo alterations are associated with the more severe and complex phenotypes and worse clinical outcome. Phenotypic, genetic—and likely mechanistic—variability hampers individualpatient diagnosis, short and long-term morbidity prediction and subsequent care strategies. Detailed phenotyping, clinical follow-up at regular intervals and detailed registries are needed to find associations between long-term morbidity, genetic alterations, and clinical parameters. Since CDH is a relatively rare disorder with only a few recurrent changes large cohorts of patients are needed to identify genetic associations. Retrospective whole genome sequencing of historical patient cohorts using will yield valuable data from which today's patients and parents will profit Trio whole genome sequencing has an excellent potential for future re-analysis and data-sharing increasing the chance to provide a genetic diagnosis and predict clinical prognosis. In this review, we explore the pitfalls and challenges in the analysis and interpretation of genetic information, present what is currently known and what still needs further study, and propose strategies to reap the benefits of genetic screening.

Introduction: Neurocognitive problems associated with posttraumatic stress disorder (PTSD) can interact with impairment resulting from traumatic brain injury (TBI). Research question: We aimed to identify neurocognitive problems associated with probable PTSD following TBI in a civilian sample. Material and methods: The study is part of the CENTER-TBI project (Collaborative European Neurotrauma Effectiveness Research) that aims to better characterize TBI. For this cross-sectional study, we included patients of all severities aged over 15, and a Glasgow Outcome Score Extended (GOSE) above 3. Participants were assessed at six months post-injury on the PTSD Checklist-5 (PCL-5), the Trail Making Test (TMT), the Rey Auditory Verbal Learning Test (RAVLT) and the Cambridge Neuropsychological Test Automated Battery (CANTAB). Primary analysis was a complete case analysis. Regression analyses were performed to investigate the association between the PCL-5 and cognition. Results: Of the 1134 participants included in the complete case analysis, 13.5% screened positive for PTSD. Probable PTSD was significantly associated with higher TMT-(B-A) (OR ​= ​1.35, 95% CI: 1.14–1.60, p ​

Item‐level data from composite scales can be analyzed with pharmacometric item response theory (IRT) models to improve the quantification of disease severity compared with the use of total composite scores. However, regular IRT models assume unidimensionality, which is violated in the scale measuring iatrogenic withdrawal in children because some items are also affected by pain, undersedation, or delirium. Here, we compare regular IRT modelling of pediatric iatrogenic withdrawal symptom data with two new analysis approaches in which the latent variable is guided towards the condition of interest using numerical withdrawal severity scored by nurses as a “supervising variable:” supervised IRT (sIRT) and supervised multi‐dimensional (smIRT) modelling. In this example, in which the items scores are affected by multiple conditions, regular IRT modeling is worse to quantify disease severity than the total composite score, whereas improved performance compared with the composite score is observed for the sIRT and smIRT models.

Background and aim: Neonatal brain monitoring is increasingly used due to reports of brain injury perioperatively. Little is known about the effect of sedatives (midazolam) and anesthetics (sevoflurane) on cerebral oxygenation (rScO2) and cerebral activity. This study aims to determine these effects in the perioperative period.Methods: This is an observational, prospective study in two tertiary pediatric surgical centers. All neonates with a congenital diaphragmatic hernia received perioperative cerebral oxygenation and activity measurements. Patients were stratified based on intraoperatively administrated medication: the sevoflurane group (continuous sevoflurane, bolus fentanyl, bolus rocuronium) and the midazolam group (continuous midazolam, continuous fentanyl, and continuous vecuronium).Results: Intraoperatively, rScO2 was higher in the sevoflurane compared to the midazolam group (84%, IQR 77–95 vs. 65%, IQR 59–76, p = < 0.001), fractional tissue oxygen extraction was lower (14%, IQR 5–21 vs. 31%, IQR 29–40, p = < 0.001), the duration of hypoxia was shorter (2%, IQR 0.4–9.6 vs. 38.6%, IQR 4.9–70, p = 0.023), and cerebral activity decreased more: slow delta: 2.16 vs. 4.35 μV2 (p = 0.0049), fast delta: 0.73 vs. 1.37 μV2 (p = < 0.001). In the first 30 min of the surgical procedure, a 3-fold increase in fast delta (10.48–31.22 μV2) and a 5-fold increase in gamma (1.42–7.58 μV2) were observed in the midazolam group.Conclusion: Sevoflurane-based anesthesia resulted in increased cerebral oxygenation and decreased cerebral activity, suggesting adequate anesthesia. Midazolam-based anesthesia in neonates with a more severe CDH led to alarmingly low rScO2 values, below hypoxia threshold, and increased values of EEG power during the first 30 min of surgery. This might indicate conscious experience of pain. Integrating population-pharmacokinetic models and multimodal neuromonitoring are needed for personalized pharmacotherapy in these vulnerable patients.Trial Registration:https://www.trialregister.nl/trial/6972, identifier: NL6972.

Congenital diaphragmatic hernia (CDH) is a structural birth defect characterized by a diaphragmatic defect, lung hypoplasia and structural vascular defects. In spite of recent developments, the pathogenesis of CDH is still poorly understood. CDH is a complex congenital disorder with multifactorial etiology consisting of genetic, cellular and mechanical factors. This review explores the cellular origin of CDH pathogenesis in the diaphragm and lungs and describes recent developments in basic and translational CDH research.

Corticosteroids have been used to decrease the inflammatory response to cardiac surgery and cardiopulmonary bypass in children for decades. Sparse information is present concerning the pharmacokinetics and pharmacodynamics of corticosteroids in the context of pediatric cardiac surgery. There is large interindividual variability in plasma concentrations, with indications for a larger volume of distribution in neonates compared to other age groups. There is ample evidence that perioperative use of MP leads to a decrease in pro-inflammatory mediators and an increase in anti-inflammatory mediators, with no difference in effect between doses of 2 and 30 mg/kg. No differences in inflammatory mediators have been shown between different times of administration relative to the start of surgery in various studies. MP has been shown to have a beneficial effect in certain subgroups of patients but is also associated with side effects. In lower risk categories, the balance between risk and benefit may be shifted toward risk. There is limited information on short- to medium-term outcome (mortality, low cardiac output syndrome, duration of mechanical ventilation, length of stay in the intensive care unit or the hospital), mostly from underpowered studies. No information on long-term outcome, such as neurodevelopmental outcome, is available. MP may provide a small benefit that is easily abolished by patient characteristics, surgical techniques, and perfusion management. The lack of evidence leads to large differences in practice between and within countries, and even within hospitals, so there is a need for adequately powered randomized studies.

Introduction: To our knowledge, methylprednisolone pharmacokinetics and plasma concentrations have not been comprehensively investigated in children with congenital heart disease undergoing cardiac surgery with cardiopulmonary bypass. It is unknown whether there is a significant influence of cardiopulmonary bypass on the plasma concentrations of methylprednisolone and whether this may be an explanation for the limited reported efficacy of steroid administration in cardiac surgery with cardiopulmonary bypass.Methods: The study was registered in the Dutch Trial Register (NTR3579; https://www.trialregister.nl/trial/3428). Methylprednisolone 30 mg/kg was administered as an intravenous bolus after induction of anesthesia. Methylprednisolone concentration was measured with liquid chromatography tandem mass spectrometry and analyzed using linear mixed-effects modeling.Results: Thirty-nine patients were included in the study, of which three were excluded. There was an acute decrease in observed methylprednisolone plasma concentration on initiation of cardiopulmonary bypass (median = 26.8%, range = 13.9–48.14%, p < 0.001). We found a lower intercept (p = 0.02), as well as a less steep slope of the model predicted methylprednisolone concentration vs. time curve for neonates (p = 0.048). A lower intercept (p = 0.01) and a less steep slope (p = 0.0024) if the volume of cell saver blood processed was larger than 91 ml/kg were also found.Discussion: We report similar methylprednisolone plasma concentrations as earlier studies performed in children undergoing cardiopulmonary bypass, and we confirmed the large interindividual variability in achieved methylprednisolone plasma concentrations with weight-based methylprednisolone administration. A larger volume of distribution and a lower clearance of methylprednisolone for neonates were suggested. The half-life of methylprednisolone in our study was calculated to be longer than 6 h for neonates, 4.7 h for infants, 3.6 h for preschool children and 4.7 h for school children. The possible influence of treatment of pulmonary hypertension with sildenafil and temperature needs to be investigated further.

Hirschsprung disease (HSCR) is a complex genetic disease characterized by absence of ganglia in the intestine. HSCR etiology can be explained by a unique combination of genetic alterations: rare coding variants, predisposing haplotypes and Copy Number Variation (CNV). Approximately 18% of patients have additional anatomical malformations or neurological symptoms (HSCR-AAM). Pinpointing the responsible culprits within a CNV is challenging as often many genes are affected. Therefore, we selected candidate genes based on gene enrichment strategies using mouse enteric nervous system transcriptomes and constraint metrics. Next, we used a zebrafish model to investigate whether loss of these genes affects enteric neuron development in vivo. This study included three groups of patients, two groups without coding variants in disease associated genes: HSCR-AAM and HSCR patients without associated anomalies (HSCR-isolated). The third group consisted of all HSCR patients in which a confirmed pathogenic rare coding variant was identified. We compared these patient groups to unaffected controls. Predisposing haplotypes were determined, confirming that every HSCR subgroup had increased contributions of predisposing haplotypes, but their contribution was highest in isolated HSCR patients without RET coding variants. CNV profiling proved that specifically HSCR-AAM patients had larger Copy Number (CN) losses. Gene enrichment strategies using mouse enteric nervous system transcriptomes and constraint metrics were used to determine plausible candidate genes located within CN losses. Validation in zebrafish using CRISPR/Cas9 targeting confirmed the contribution of UFD1L, TBX2, SLC8A1, and MAPK8 to ENS development. In addition, we revealed epistasis between reduced Ret and Gnl1 expression and between reduced Ret and Tubb5 expression in vivo. Rare large CN losses-often de novo-contribute to HSCR in HSCR-AAM patients. We proved the involvement of six genes in enteric nervous system development and Hirschsprung disease.

SOX2 expression levels are crucial for the balance between maintenance and differentiation of airway progenitor cells during development and regeneration. Here, we describe patterning of the mouse proximal airway epithelium by SOX21, which coincides with high levels of SOX2 during development. Airway progenitor cells in this SOX2+/SOX21+ zone show differentiation to basal cells, specifying cells for the extrapulmonary airways. Loss of SOX21 showed an increased differentiation of SOX2+ progenitor cells to basal and ciliated cells during mouse lung development. We propose a mechanism where SOX21 inhibits differentiation of airway progenitors by antagonizing SOX2-induced expression of specific genes involved in airway differentiation. Additionally, in the adult tracheal epithelium, SOX21 inhibits basal to ciliated cell differentiation. This suppressing function of SOX21 on differentiation contrasts SOX2, which mainly drives differentiation of epithelial cells during development and regeneration after injury. Furthermore, using human fetal lung organoids and adult bronchial epithelial cells, we show that SOX2+/SOX21+ regionalization is conserved. Lastly, we show that the interplay between SOX2 and SOX21 is context and concentration dependent leading to regulation of differentiation of the airway epithelium.

Abstract Background In adolescents limited data are available on the pharmacokinetics (PK) and pharmacodynamics (PD) of propofol. In this study we derived a PK-PD model for propofol in adolescents undergoing idiopathic scoliosis surgery with an intraoperative wake-up test with reinduction of anesthesia using both Bispectral Index (BIS) and composite A-line ARX index (cAAI) as endpoints. Methods Fourteen adolescents (9.8–20.1 years) were evaluated during standardized propofol-remifentanil anesthesia for idiopathic scoliosis surgery with an intraoperative wake-up test with reinduction of anesthesia. BIS and cAAI were continuously measured and blood samples collected. A propofol PKPD model was developed using NONMEM. Results The time courses of propofol concentrations, BIS and cAAI values during anesthesia, intra-operative wakeup and reduction of anesthesia were best described by a two-compartment PK model linked to an inhibitory sigmoidal Emax PD model. For the sigmoidal Emax model, the propofol concentration at half maximum effect (EC50) was 3.51 and 2.14 mg/L and Hill coefficient 1.43 and 6.85 for BIS and cAAI, respectively. The delay in PD effect in relation to plasma concentration was best described by a two compartment effect-site model with a keo of 0.102 min− 1, ke12 of 0.121 min− 1 and ke21 of 0.172 min− 1. Conclusions A population PKPD model for propofol in adolescents was developed that successfully described the time course of propofol concentration, BIS and cAAI in individuals upon undergoing scoliosis surgery with intraoperative wake-up test and reinduction of anesthesia. Large differences were demonstrated between both monitors. This may imply that BIS and cAAI measure fundamentally different endpoints in the brain.

Abstract Background Gabapentin has shown efficacy in the treatment of chronic neuropathic or mixed pain in adults. Although pediatric pain specialists have extensive experience with gabapentin for the treatment of neuropathic pain, its use is off-label. Its efficacy and safety in this context have never been shown. The aim of this trial is to compare gabapentin with placebo as add-on to morphine for the treatment of severe chronic mixed or neuropathic pain in children. This trial is part of the European Union Seventh Framework Programme project Gabapentin in Paediatric Pain (GAPP) to develop a pediatric use marketing authorization for a new gabapentin suspension. Methods/design The GAPP-2 study is a randomized, double-blind, placebo-controlled, multicenter superiority phase II study in children with severe chronic neuropathic or mixed pain. Its primary objective is to evaluate the efficacy of a gabapentin liquid formulation as adjunctive therapy to morphine. Sixty-six eligible children 3 months to 18 years of age with severe pain (pain scores ≥ 7), stratified in three age groups, will be randomized to receive gabapentin (to an accumulating dose of 45 to 63 mg/kg/day, dependent on age) or placebo, both in addition to morphine, for 12 weeks. Randomization will be preceded by a short washout period, and treatment will be initiated by a titration period of 3 weeks. After the treatment period, medication will be tapered during 4 weeks. The primary endpoint is the average pain scores in the two treatment groups (average of two measures each day for 3 days before the end-of-study visit [V10] assessed by age-appropriate pain scales (Face, Legs, Activity, Cry, Consolability scale; Faces Pain Scale–Revised; Numeric Rating Scale). Secondary outcomes include percentage responders to treatment (subjects with 30% reduction in pain scale), number of episodes of breakthrough pain, number of rescue interventions, number of pain-free days, participant dropouts, quality of life (Pediatric Quality of Life Inventory), and acceptability of treatment. Outcomes will be measured at the end-of-study visit after 12 weeks of treatment at the optimal gabapentin dose. Groups will be compared on an intention-to-treat basis. Discussion We hope to provide evidence that the combination of morphine and gabapentin will provide better analgesia than morphine alone and will be safe. We also aim to obtain confirmation of the recommended pediatric dose. Trial registration EudractCT, 2014-004897-40. Registered on 7 September 2017. ClinicalTrials.gov, NCT03275012. Registered on 7 September 2017.

Aim of Study: The use of extracorporeal membrane oxygenation (ECMO) has increased as a result of technological developments and the expansion of indications. Relatedly, the number of patients undergoing surgery during ECMO is also rising, at least in the adult population. Little is known on surgery in children during ECMO-therapy. We therefore aimed to assess the frequencies and types of surgical interventions in neonatal and pediatric patients on ECMO and to analyze surgery-related morbidity and mortality.Methods: We retrospectively collected information of all patients on ECMO over a 10-year period in a single tertiary and designated ECMO-center, excluding patients undergoing cardiac surgery, and correction of congenital diaphragmatic hernia. Chi-squared test and Mann-Whitney U test were used to analyze data.Main Results: Thirty-two of 221 patients (14%) required surgery when on ECMO. Common interventions were thoracotomy (32%), laparotomy (23%), fasciotomy (17%), and surgical revision of ECMO (15%). Complications occurred in 28 cases (88%), resulting in a 50% in-hospital mortality rate. Surgical patients had a longer ICU stay and longer total hospital stay compared to those not receiving surgery during ECMO. No significant difference in mortality was found when comparing surgical to non-surgical patients (50 vs. 41%).Conclusions: Approximately one in seven neonatal or pediatric patients required surgical intervention during ECMO, of whom almost 90% developed a complication, resulting in a 50% mortality rate. These results should be taken into account in counseling.

Background: Pulmonary hypertension is the major cause of morbidity and mortality in congenital diaphragmatic hernia (CDH). Mutations in several genes that encode signaling molecules of the transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) pathways have previously been associated with CDH. Since studies on the activation of these pathways in CDH are scarce, and have yielded inconsistent conclusions, the downstream activity of both pathways was assessed in the nitrofen-CDH rat model.Methods and Results: Pregnant Sprague-Dawley rats were treated with nitrofen at embryonic day (E) 9.5 to induce CDH in offspring. At E21, lungs were screened for the expression of key factors of both signaling pathways, at both the mRNA transcript and protein levels. Subsequently, paying particular attention to the pulmonary vasculature, increased phosphorylation of SMAD2, and decreased phosphorylation of Smad5 was noted in the muscular walls of small pulmonary vessels, by immunohistochemistry. This was accompanied by increased proliferation of constituent cells of the smooth muscle layer of these vessels.Conclusions: Increased activation of the TGFβ pathway and decreased activation of the BMP pathway in the pulmonary vasculature of rats with experimentally-induced CDH, suggesting that the deregulated of these important signaling pathways may underlie the development of pulmonary hypertension in CDH.

Background and Aim: Newborns needing major surgical intervention are at risk of brain injury and impaired neurodevelopment later in life. Disturbance of cerebral perfusion might be an underlying factor. This study investigates the feasibility of serial transfontanellar ultrasound measurements of the pial arteries during neonatal surgery, and whether perioperative changes in cerebral perfusion can be observed and related to changes in the perioperative management.Methods: In this prospective, observational feasibility study, neonates with congenital diaphragmatic hernia and esophageal atresia scheduled for surgical treatment within the first 28 days of life were eligible for inclusion. We performed transfontanellar directional power Doppler and pulsed wave Doppler ultrasound during major high-risk non-cardiac neonatal surgery. Pial arteries were of interest for the measurements. Extracted Doppler ultrasound parameters were: peak systolic velocity, end diastolic velocity, the resistivity index and pulsatility index.Results: In 10 out of 14 patients it was possible to perform perioperative measurements; the others failed for logistic and technical reasons. In 6 out of 10 patients, it was feasible to perform serial intraoperative transfontanellar ultrasound measurements with directional power Doppler and pulsed wave Doppler of the same pial artery during neonatal surgery. Median peak systolic velocity was ranging between 5.7 and 7.0 cm s−1 and end diastolic velocity between 1.9 and 3.2 cm s−1. In patients with a vasoactive-inotropic score below 12 the trend of peak systolic velocity and end diastolic velocity corresponded with the mean arterial blood pressure trend.Conclusion: Perioperative transfontanellar ultrasound Doppler measurements of the pial arteries are feasible and provide new longitudinal data about perioperative cortical cerebral blood flow velocity.Trial Registration:https://www.trialregister.nl/trial/6972, identifier: NL6972.

Current monitoring techniques in neonates lack sensitivity for hypoxia at cellular level. The recent introduction of the non-invasive Cellular Oxygen METabolism (COMET) monitor enables measuring in vivo mitochondrial oxygen tension (mitoPO2), based on oxygen-dependent quenching of delayed fluorescence of 5-aminolevulinic acid (ALA)-enhanced protoporphyrin IX. The aim is to determine the feasibility and safety of non-invasive mitoPO2 monitoring in surgical newborns. MitoPO2 measurements were conducted in a tertiary pediatric center during surgical repair of congenital diaphragmatic hernia or esophageal atresia. Intraoperative mitoPO2 monitoring was performed with a COMET monitor in 11 congenital diaphragmatic hernia and four esophageal atresia neonates with the median age at surgery being 2 days (IQR 1.25–5.75). Measurements were done at the skin and oxygen-dependent delayed fluorescence was measurable after at least 4 h application of an ALA plaster. Pathophysiological disturbances led to perturbations in mitoPO2 and were not observed with standard monitoring modalities. The technique did not cause damage to the skin, and seemed safe in this respect in all patients, and in 12 cases intraoperative monitoring was successfully completed. Some external and potentially preventable factors—the measurement site being exposed to the disinfectant chlorohexidine, purple skin marker, or infrared light—seemed responsible for the inability to detect an adequate delayed fluorescence signal. In conclusion, this is the first study showing it is possible to measure mitoPO2 in neonates and that the cutaneous administration of ALA to neonates in the described situation can be safely applied. Preliminary data suggests that mitoPO2 in neonates responds to perturbations in physiological status.

Background: Bacterial and fungal infections are common and often contribute to death in patients undergoing extracorporeal membrane oxygenation (ECMO). Drug disposition is altered during ECMO, and adsorption in the circuit is an established causative factor. Vancomycin and voriconazole are widely used, despite the lack of evidence-based prescription guidelines.Objective: The objective of this study was to determine the extraction of voriconazole and vancomycin by the Xenios/Novalung ECMO circuits.Methods: We have set up nine closed-loop ECMO circuits, consisting of four different iLAActivve® kits for neonatal, pediatric, and adult support: three iLA-ActivveMiniLung®petite kits, two iLA-ActivveMiniLung® kits, two iLA-ActivveiLA® kits, and two iLA-Activve X-lung® kits. The circuits were primed with whole blood and maintained at physiologic conditions for 24 h. Voriconazole and vancomycin were injected as a single-bolus age-related dose into the circuits. Pre-membrane (P2) blood samples were obtained at baseline and after drug injection at 2, 10, 30, 180, 360 min, and 24 h. A control sample at 2 min was collected for spontaneous drug degradation testing at 24 h.Results: Seventy-two samples were analyzed in triplicate. The mean percentage of drug recovery at 24 h was 20% for voriconazole and 62% for vancomycin.Conclusions: The extraction of voriconazole and vancomycin by contemporary ECMO circuits is clinically relevant across all age-related circuit sizes and may result in reduced drug exposure in vivo.

Background: The VATER/VACTERL association (VACTERL) is defined as the non-random occurrence of the following congenital anomalies: Vertebral, Anal, Cardiac, Tracheal-Esophageal, Renal, and Limb anomalies. As no unequivocal candidate gene has been identified yet, patients are diagnosed phenotypically. The aims of this study were to identify patients with monogenic disorders using a genetics-first approach, and to study whether variants in candidate genes are involved in the etiology of VACTERL or the individual features of VACTERL: Anorectal malformation (ARM) or esophageal atresia with or without trachea-esophageal fistula (EA/TEF).Methods: Using molecular inversion probes, a candidate gene panel of 56 genes was sequenced in three patient groups: VACTERL (n = 211), ARM (n = 204), and EA/TEF (n = 95). Loss-of-function (LoF) and additional likely pathogenic missense variants, were prioritized and validated using Sanger sequencing. Validated variants were tested for segregation and patients were clinically re-evaluated.Results: In 7 out of the 510 patients (1.4%), pathogenic or likely pathogenic variants were identified in SALL1, SALL4, and MID1, genes that are associated with Townes-Brocks, Duane-radial-ray, and Opitz-G/BBB syndrome. These syndromes always include ARM or EA/TEF, in combination with at least two other VACTERL features. We did not identify LoF variants in the remaining candidate genes.Conclusions: None of the other candidate genes were identified as novel unequivocal disease genes for VACTERL. However, a genetics-first approach allowed refinement of the clinical diagnosis in seven patients, in whom an alternative molecular-based diagnosis was found with important implications for the counseling of the families.

Esophageal atresia (EA) and tracheoesophageal fistula (TEF) are relatively frequently occurring foregut malformations. EA/TEF is thought to have a strong genetic component. Not much is known regarding the biological processes disturbed or which cell type is affected in patients. This hampers the detection of the responsible culprits (genetic or environmental) for the origin of these congenital anatomical malformations. Therefore, we examined gene expression patterns in the TEF and compared them to the patterns in esophageal, tracheal and lung control samples. We studied tissue organization and key proteins using immunohistochemistry. There were clear differences between TEF and control samples. Based on the number of differentially expressed genes as well as histological characteristics, TEFs were most similar to normal esophagus. The BMP-signaling pathway, actin cytoskeleton and extracellular matrix pathways are downregulated in TEF. Genes involved in smooth muscle contraction are overexpressed in TEF compared to esophagus as well as trachea. These enriched pathways indicate myofibroblast activated fibrosis. TEF represents a specific tissue type with large contributions of intestinal smooth muscle cells and neurons. All major cell types present in esophagus are present-albeit often structurally disorganized-in TEF, indicating that its etiology should not be sought in cell fate specification.

Abstract Backgrounds Reports of increasing incidence rates of delirium in critically ill children are reason for concern. We evaluated the measurement properties of the pediatric delirium component (PD-scale) of the Sophia Observation Withdrawal Symptoms scale Pediatric Delirium scale (SOS-PD scale). Methods In a multicenter prospective observational study in four Dutch pediatric ICUs (PICUs), patients aged ≥ 3 months and admitted for ≥ 48 h were assessed with the PD-scale thrice daily. Criterion validity was assessed: if the PD-scale score was ≥ 4, a child psychiatrist clinically assessed the presence or absence of PD according to the Diagnostic and statistical manual of mental disorders (DSM)-IV. In addition, the child psychiatrist assessed a randomly selected group to establish the false-negative rate. The construct validity was assessed by calculating the Pearson coefficient (rp) for correlation between the PD-scale and Cornell Assessment Pediatric Delirium (CAP-D) scores. Interrater reliability was determined by comparing paired nurse-researcher PD-scale assessments and calculating the intraclass correlation coefficient (ICC). Results Four hundred eighty-five patients with a median age of 27.0 months (IQR 8–102) were included, of whom 48 patients were diagnosed with delirium by the child psychiatrist. The PD-scale had overall sensitivity of 92.3% and specificity of 96.5% compared to the psychiatrist diagnosis for a cutoff score ≥4 points. The rp between the PD-scale and the CAP-D was 0.89 (CI 95%, 0.82–0.93; p

Abstract Background Morphine is worldwide the analgesic of first choice after cardiac surgery in children. Morphine has unwanted hemodynamic and respiratory side effects. Therefore, post–cardiac surgery patients may potentially benefit from a non-opioid drug for pain relief. A previous study has shown that intravenous (IV) paracetamol is effective and opioid-sparing in children after major non-cardiac surgery. The aim of the study is to test the hypothesis that intermittent IV paracetamol administration in children after cardiac surgery will result in a reduction of at least 30% of the cumulative morphine requirement. Methods This is a prospective, multi-center, randomized controlled trial at four level-3 pediatric intensive care units (ICUs) in the Netherlands and Belgium. Children who are 0–36 months old will be randomly assigned to receive either intermittent IV paracetamol or continuous IV morphine up to 48 h post-operatively. Morphine will be available as rescue medication for both groups. Validated pain and sedation assessment tools will be used to monitor patients. The sample size (n = 208, 104 per arm) was calculated in order to detect a 30% reduction in morphine dose; two-sided significance level was 5% and power was 95%. Discussion This study will focus on the reduction, or replacement, of morphine by IV paracetamol in children (0–36 months old) after cardiac surgery. The results of this study will form the basis of a new pain management algorithm and will be implemented at the participating ICUs, resulting in an evidence-based guideline on post-operative pain after cardiac surgery in infants who are 0–36 months old. Trial registration Dutch Trial Registry (www.trialregister.nl): NTR5448 on September 1, 2015. Institutional review board approval (MEC2015–646), current protocol version: July 3, 2017

Abstract Background Use of donor blood in congenital cardiac surgery increases the risk for post-operative morbidity and mortality. To reduce the need for allogenic blood transfusion a technique for peri-operative mechanical red cell salvage is applied. Blood from the operation site is collected in a reservoir, processed, passed through a lipophilic filter and returned to the patient. Influence of this cellsaver system on coagulation, fibrinolysis and inflammatory markers is known. To our knowledge no studies have been performed on the effects of autotransfusion on drug concentrations. A clinically relevant drug dose could potentially be returned to the patient through the auto-transfused blood, leading to unwanted drug reactions post-operatively. We aimed to measure drug concentrations in blood salvaged from the operation site and in the auto-transfused blood to determine if a clinically relevant drug dose is returned to the patient. Methods The study was performed at the Department of Cardiothoracic Surgery of a tertiary university hospital. Blood samples were taken from the reservoir, after processing before the lipophilic filter, the auto-transfused blood, and the waste fluid. Samples were stored at − 80 C and drug concentration for sufentanil, propofol, midazolam and cefazolin were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Drug concentrations measured in the reservoir and the auto-transfused blood were compared and the relative reduction was calculated for each patient. Results Blood samples were taken from 18 cellsaver runs in 18 patients, age 0–13 years. Drug concentrations in the reservoir were comparable to concomitant concentrations in the patient. For sufentanil 34% (median, IQR 27–50) of drug concentration was retained from the reservoir in the auto-transfused blood, for midazolam 6% (median, IQR 4–10), for cefazolin 5% (median, IQR 2–6) and for propofol 0% (median, IQR 0–0) respectively. Conclusion Depending on the drug, up to 34% of the drug concentration salvaged from the operation site is returned to the patient through autotransfusion, potentially causing unwanted drug reactions post-operatively. Additionally, influence of a cellsaver system should be considered in pharmacological research during and after congenital cardiac surgery and could result in dose adjustments in the postoperative phase. Trial registration Registration at the Dutch Trial Registry (NTR3579) at August 14 2012.

Abstract Background In palliative care, administration of opioids is often indispensable for pain treatment. Pain assessment may help recognize pain and guide treatment in non-communicative patients. In the Netherlands the Rotterdam Elderly Pain Observation Scale (REPOS) is recommended to this aim, but not yet validated. Therefore the objective of this study was to validate the REPOS in non-communicative or unconscious end-of-life patients. Methods In this observational study, the primary researcher applied the REPOS, while both the researcher and a nurse applied the Numeric Rating Scale (NRS). If possible, the patient in question applied the NRS as well. The NRS scores were compared with the REPOS scores to determine concurrent validity. REPOS scores obtained before and after a pain-reducing intervention were analysed to establish the scale’s sensitivity to change. Results A total of 183 REPOS observations in 100 patients were analysed. Almost 90% of patients had an advanced malignancy; observations were done a median of 3 days (IQR 1 to 13) before death. Internal consistency of the REPOS was 0.73. The Pearson product moment correlation coefficient ranged from 0.64 to 0.80 between REPOS and NRS scores. REPOS scores declined with median 2 points (IQR 1 to 4) after a pain-reducing intervention (p

Abstract Background Patients with congenital diaphragmatic hernia (CDH) have structural and functional different pulmonary vessels, leading to pulmonary hypertension. They often fail to respond to standard vasodilator therapy targeting the major vasoactive pathways, causing a high morbidity and mortality. We analyzed whether the expression of crucial members of these vasoactive pathways could explain the lack of responsiveness to therapy in CDH patients. Methods The expression of direct targets of current vasodilator therapy in the endothelin and prostacyclin pathway was analyzed in human lung specimens of control and CDH patients. Results CDH lungs showed increased expression of both ETA and ETB endothelin receptors and the rate-limiting Endothelin Converting Enzyme (ECE-1), and a decreased expression of the prostaglandin-I2 receptor (PTGIR). These data were supported by increased expression of both endothelin receptors and ECE-1, endothelial nitric oxide synthase and PTGIR in the well-established nitrofen-CDH rodent model. Conclusions Together, these data demonstrate aberrant expression of targeted receptors in the endothelin and prostacyclin pathway in CDH already early during development. The analysis of this unique patient material may explain why a significant number of patients do not respond to vasodilator therapy. This knowledge could have important implications for the choice of drugs and the design of future clinical trials internationally.

Over the years, it has become clear that children growing up after neonatal critical illness are at high risk of long-term neurocognitive deficits that impact their school performance and daily life activities. Although the pathophysiological mechanisms remain largely unknown, emerging evidence seems to suggest that long-term neuropsychological deficits following neonatal critical illness are not associated with the type of treatment, such as extracorporeal membrane oxygenation (ECMO), but rather with underlying disease processes. In this review, neurocognitive outcome and brain pathology following neonatal critical respiratory and cardiac illness, either treated with or without ECMO, are described and compared in order to gain insight into potential underlying pathophysiological mechanisms. Putting these findings together, it becomes apparent that both children with complex congenital heart disease and children who survived severe respiratory failure are at risk of neurocognitive deficits later in life. Neurorehabilitation strategies, such as Cogmed working-memory training, are discussed. While prevention of neurocognitive deficits altogether should be strived for in the future, this is not realistic at this moment. It is therefore of great importance that children growing up after neonatal critical illness receive long-term care that includes psychoeducation and personalized practical tools that can be used to improve their daily life activities.

Extracorporeal membrane oxygenation (ECMO) is a lifesaving support technology for potentially reversible neonatal cardiac and/or respiratory failure. As the survival and the overall outcome of patients rely on the treatment and reversal of the underlying disease, effective and preferentially evidence-based pharmacotherapy is crucial to target recovery. Currently limited data exist to support the clinicians in their every-day intensive care prescribing practice with the contemporary ECMO technology. Indeed, drug dosing to optimize pharmacotherapy during neonatal ECMO is a major challenge. The impact of the maturational changes of the organ function on both pharmacokinetics (PK) and pharmacodynamics (PD) has been widely established over the last decades. Next to the developmental pharmacology, additional non-maturational factors have been recognized as key-determinants of PK/PD variability. The dynamically changing state of critical illness during the ECMO course impairs the achievement of optimal drug exposure, as a result of single or multi-organ failure, capillary leak, altered protein binding, and sometimes a hyperdynamic state, with a variable effect on both the volume of distribution (Vd) and the clearance (Cl) of drugs. Extracorporeal membrane oxygenation introduces further PK/PD perturbation due to drug sequestration and hemodilution, thus increasing the Vd and clearance (sequestration). Drug disposition depends on the characteristics of the compounds (hydrophilic vs. lipophilic, protein binding), patients (age, comorbidities, surgery, co-medications, genetic variations), and circuits (roller vs. centrifugal-based systems; silicone vs. hollow-fiber oxygenators; renal replacement therapy). Based on the potential combination of the above-mentioned drug PK/PD determinants, an integrated approach in clinical drug prescription is pivotal to limit the risks of over- and under-dosing. The understanding of the dose-exposure-response relationship in critically-ill neonates on ECMO will enable the optimization of dosing strategies to ensure safety and efficacy for the individual patient. Next to in vitro and clinical PK data collection, physiologically-based pharmacokinetic modeling (PBPK) are emerging as alternative approaches to provide bedside dosing guidance. This article provides an overview of the available evidence in the field of neonatal pharmacology during ECMO. We will identify the main determinants of altered PK and PD, elaborate on evidence-based recommendations on pharmacotherapy and highlight areas for further research.

In a nationwide randomized controlled trial, white matter microstructure was assessed before and immediately after Cogmed Working-Memory Training (CWMT) in school-age neonatal critical illness survivors. Eligible participants were survivors (8–12 years) with an IQ ≥ 80 and a z-score of ≤ −1.5 on (working)memory test at first assessment. Diffusion Tensor Imaging was used to assess white matter microstructure. Associations between any training-induced changes and improved neuropsychological outcome immediately and one year post-CWMT were evaluated as well. The trial was conducted between October 2014–June 2017 at Erasmus MC-Sophia, Rotterdam, Netherlands. Researchers involved were blinded to group allocation. Participants were randomized to CWMT(n = 14) or no-intervention(n = 20). All children completed the CWMT. Global fractional anisotropy(FA) increased significantly post-CWMT compared to no-intervention(estimated-coefficient = .007, p = .015). Increased FA(estimated coefficient = .009, p = .033) and decreased mean diffusivity(estimated-coefficient = −.010, p = .018) were found in the left superior longitudinal fasciculus(SFL) post-CWMT compared no-intervention. Children after CWMT who improved with >1SD on verbal working-memory had significantly higher FA in the left SLF post-CWMT(n = 6; improvement = .408 ± .01) than children without this improvement post-CWMT(n = 6; no-improvement = .384 ± .02), F(1,12) = 6.22, p = .041, ηp2 = .47. No other structure-function relationships were found post-CWMT. Our findings demonstrate that white matter microstructure and associated cognitive outcomes are malleable by CWMT in survivors of neonatal critical illness. Keywords: Neurodevelopmental disorders, Neuropsychology, Cognitive remediation, Critical care outcomes, Neuroimaging, Diffusion tensor imaging, Memory

Background: Extracorporeal membrane oxygenation (ECMO) treatment alleviates systemic cardiorespiratory failure. However, it is unclear whether ECMO also improves microcirculatory function, as the microcirculation can be disturbed despite normal systemic hemodynamics. We therefore aimed to study the sublingual microcirculation (SMC) throughout neonatal and pediatric ECMO treatment. We hypothesized that the SMC improves after starting ECMO, that the SMC differs between venovenous (VV) and venoarterial (VA) ECMO, and that insufficient recovery of microcirculatory disturbances during ECMO predicts mortality.Methods: This single-center prospective longitudinal observational study included 34 consecutive children (April 2016—September 2018). The SMC was assessed daily with a handheld vital microscope (integrated with incident dark field illumination) before, during, and after ECMO. Validated parameters of vessel density, perfusion, and flow quality were assessed for all vessels (diameter 2.6) increased with higher MAP (OR: 1.050, 95%CI: 1.008–1.094). Microcirculatory parameters did not significantly differ between VV and VA ECMO or between survivors and non-survivors. None of the microcirculatory parameters could predict mortality on ECMO or overall mortality.Conclusion: In this heterogeneous study population, we were not able to demonstrate an effect of ECMO on the sublingual microcirculation. Microcirculatory parameters did not change throughout ECMO treatment and did not differ between VV and VA ECMO or between survivors and non-survivors. Future research should focus on determining which neonatal and pediatric ECMO patients would benefit from microcirculatory monitoring and how.

Assuring adequate tissue oxygenation in the critically ill, but still developing child is challenging. Conventional hemodynamic monitoring techniques fall short in assessing tissue oxygenation as these are directed at the macrocirculation and indirect surrogates of tissue oxygenation. The introduction of handheld vital microscopy (HVM) has allowed for the direct visualization of the microcirculation and with this has offered insight into tissue oxygenation on a microcirculatory level. Since its introduction, technical improvements have been made to HVM, to both hardware and software, and guidelines have been developed through expert consensus on image assessment and analysis. Using HVM, the microcirculation of the skin, the buccal mucosa, and the sublingual mucosa of healthy and (critically) ill neonates and children have been visualized and investigated. Yet, integration of HVM in hemodynamic monitoring has been limited due to technical shortcomings. Only superficial microcirculatory beds can be visualized, inter-observer and intra-observer variabilities are not accounted for and image analysis happens offline and is semi-automated and time-consuming. More importantly, patients need to be cooperative or fully sedated to prevent pressure and movement artifacts, which is often not the case in children. Despite these shortcomings, observational research with HVM in neonates and children has revealed the following: (1) age-related developmental changes in the microcirculation, (2) loss of hemodynamic coherence, i.e., microcirculatory disturbances in the presence of a normal macrocirculation and, (3) microcirculatory disturbances which were independently associated with increased mortality risk. Although these observations underline the importance of microcirculatory monitoring, several steps have to be taken before integration in the decision process during critical care can happen. These steps include technological innovations to ease the use of HVM in the pediatric age group, measuring additional functional parameters of microvascular blood flow and integrated automated analysis software. As a next step, reference values for microcirculatory parameters need to be established, while also accounting for developmental changes. Finally, studies on microcirculatory guided therapies are necessary to assess whether the integration of microcirculatory monitoring will actually improve patient outcome. Nevertheless, HVM remains a promising, non-invasive tool to help physicians assure tissue oxygenation in the critically ill child.

Validated diagnostic tools to diagnose chronic neuropathic and mixed pain in children are missing. Therapeutic options are often derived from therapeutics for adults. To investigate the international practice amongst practitioners for the diagnosis and treatment of chronic, neuropathic pain in children and adolescents, we performed a survey study among members of learned societies or groups whose members are known to treat pediatric pain. The survey included questions concerning practitioners and practice characteristics, assessment and diagnosis, treatment and medication. We analyzed 117 returned questionnaires, of which 41 (35%) were fully completed and 76 (65%) were partially completed. Most respondents based the diagnosis of neuropathic pain on physical examination (68 (58.1%)), patient history (67 (57.3%)), and underlying disease (59 (50.4%)) combined. Gabapentin, amitriptyline, and pregabalin were the first-choice treatments for moderate neuropathic pain. Tramadol, ibuprofen, amitriptyline, and paracetamol were the first-choice treatments for moderate mixed pain. Consensus on the diagnostic process of neuropathic pain in children and adolescents is lacking. Drug treatment varies widely for moderate, severe neuropathic, and mixed pain. Hence, diagnostic tools and therapy need to be harmonized and validated for use in children.

Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare and lethal disorder mainly involving the vascular development of the lungs. Since its first description, significant achievements in research have led to a better understanding of the underlying molecular mechanism of ACD/MPV and genetic studies have identified associations with genomic alterations in the locus of the transcription factor FOXF1 . This in turn has increased the awareness among clinicians resulting in over 200 cases reported so far, including genotyping of patients in most recent reports. Collectively, this promoted a better stratification of the patient group, leading to new perspectives in research on the pathogenesis. Here, we provide an overview of the clinical aspects of ACD/MPV, including guidance for clinicians, and review the ongoing research into the complex molecular mechanism causing this severe lung disorder.