Predicting adverse long-term neurocognitive outcomes after pediatric intensive care unit admission.

BACKGROUND AND OBJECTIVE: Critically ill children may suffer from impaired neurocognitive functions years after ICU (intensive care unit) discharge. To assess neurocognitive functions, these children are subjected to a fixed sequence of tests. Undergoing all tests is, however, arduous for former pediatric ICU patients, resulting in interrupted evaluations where several neurocognitive deficiencies remain undetected. As a solution, we propose using machine learning to predict the optimal order of tests for each child, reducing the number of tests required to identify the most severe neurocognitive deficiencies. METHODS: We have compared the current clinical approach against several machine learning methods, mainly multi-target regression and label ranking methods. We have also proposed a new method that builds several multi-target predictive models and combines the outputs into a ranking that prioritizes the worse neurocognitive outcomes. We used data available at discharge, from children who participated in the PEPaNIC-RCT trial (ClinicalTrials.gov-NCT01536275), as well as data from a 2-year follow-up study. The institutional review boards at each participating site have also approved this follow-up study (ML8052; NL49708.078; Pro00038098). RESULTS: Our proposed method managed to outperform other machine learning methods and also the current clinical practice. Precisely, our method reaches approximately 80% precision when considering top-4 outcomes, in comparison to 65% and 78% obtained by the current clinical practice and the state-of-the-art method in label ranking, respectively. CONCLUSIONS: Our experiments demonstrated that machine learning can be competitive or even superior to the current testing order employed in clinical practice, suggesting that our model can be used to severely reduce the number of tests necessary for each child. Moreover, the results indicate that possible long-term adverse outcomes are already predictable as early as at ICU discharge. Thus, our work can be seen as the first step to allow more personalized follow-up after ICU discharge leading to preventive care rather than curative.

The efficacy of therapeutic interventions on paediatric burn patients' height, weight, body composition, and muscle strength: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy of therapeutic interventions on pediatric burn patients' height, weight, body composition, and muscle strength. METHODS: A systematic literature search was conducted in PubMed, Embase, and Web of Science up to March 2021. Eligible interventional studies reported metrics on the height, weight, body composition, or muscle strength of pediatric burn patients in a peer-reviewed journal. Meta-analyses were performed if ≥ 2 trials of clinical homogeneity reported on an outcome measure at the same time point post-burn. RESULTS: Twenty-six interventional studies were identified, including twenty-two randomised controlled trials and four non-randomised trials. Most studies were conducted by a single institution. On average, the burn covered 45.3% ( ± 9.9) of the total body surface area. Three categories of interventions could be distinguished: rehabilitative exercise programs, pharmacologic agents, and nutrition support. CONCLUSIONS: Each of the interventions had a positive effect on height, weight, body composition, or muscle strength. The decision to initiate an intervention should be made on a case-by-case basis following careful consideration of the benefits and risks. In future research, it is important to evaluate the heterogeneity of intervention effects and whether participation in an intervention allowed pediatric burn patients to reach the physical and functional status of healthy peers.

Severe obstructive sleep apnea in children with syndromic craniosynostosis: analysis of pulse transit time.

STUDY OBJECTIVES: We examined the association between pulse transit time (PTT) and obstructive sleep apnea (OSA) in children with syndromic craniosynostosis (SCS), where OSA is a common problem and may cause cardiorespiratory disturbance. METHODS: Retrospective study of children (age <18 years) with SCS and moderate-to-severe OSA (i.e., obstructive apnea-hypopnea index [oAHI] ≥ 5), or no OSA (oAHI < 1) who underwent overnight polysomnography (PSG). Children without SCS and normal PSG were included as controls. Reference intervals (RIs) for PTT were computed by non-parametric bootstrap analysis. Based on RIs of controls, the sensitivity and specificity of PTT to detect OSA were determined. In a linear mixed-model the explanatory variables assessed were sex, age, sleep stage, and time after obstructive events. RESULTS: In all 68 included children (19 SCS with OSA, 30 SCS without OSA, 19 controls), obstructive events occurred throughout all sleep stages, most prominently during rapid eye movement sleep (REM) and non-REM sleep stages N1 and N2, with evident PTT changes. Greatest reductions were observed 4 - 8 s after an event (p < 0.05). In SCS with OSA, PTT RIs were lower during all sleep stages compared to SCS without OSA. The highest sensitivity was observed during N1 (55.5%), and the highest specificity during REM (76.5%). Lowest PTT values were identified during N1. CONCLUSIONS: Obstructive events occur throughout all sleep stages with transient reductions in PTT. However, PTT as a variable for OSA detection is limited by its sensitivity and specificity.

Outcome measures in Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe intellectual disability, little to no expressive speech, visual and motor problems, emotional/behavioral challenges, and a tendency towards hyperphagia and weight gain. The characteristics of AS make it difficult to measure these children's functioning with standard clinical tests. Feasible outcome measures are needed to measure current functioning and change over time, in clinical practice and clinical trials. AIM: Our first aim is to assess the feasibility of several functional tests. We target domains of neurocognitive functioning and physical growth using the following measurement methods: eye-tracking, functional Near-Infrared Spectroscopy (fNIRS), indirect calorimetry, bio-impedance analysis (BIA), and BOD POD (air-displacement plethysmography). Our second aim is to explore the results of the above measures, in order to better understand the AS phenotype. METHODS: The study sample consisted of 28 children with AS aged 2-18 years. We defined an outcome measure as feasible when (1) at least 70% of participants successfully finished the measurement and (2) at least 60% of those participants had acceptable data quality. Adaptations to the test procedure and reasons for early termination were noted. Parents rated acceptability and importance and were invited to make recommendations to increase feasibility. The results of the measures were explored. RESULTS: Outcome measures obtained with eye-tracking and BOD POD met the definition of feasibility, while fNIRS, indirect calorimetry, and BIA did not. The most important reasons for early termination of measurements were showing signs of protest, inability to sit still and poor/no calibration (eye-tracking specific). Post-calibration was often applied to obtain valid eye-tracking results. Parents rated the BOD POD als most acceptable and fNIRS as least acceptable for their child. All outcome measures were rated to be important. Exploratory results indicated longer reaction times to high salient visual stimuli (eye-tracking) as well as high body fat percentage (BOD POD). CONCLUSIONS: Eye-tracking and BOD POD are feasible measurement methods for children with AS. Eye-tracking was successfully used to assess visual orienting functions in the current study and (with some practical adaptations) can potentially be used to assess other outcomes as well. BOD POD was successfully used to examine body composition. TRIAL REGISTRATION: Registered d.d. 23-04-2020 under number 'NL8550' in the Dutch Trial Register: https://onderzoekmetmensen.nl/en/trial/23075.

Prospective evaluation and follow-up of nutritional status of children hospitalized in secondary-care level hospitals: a multicentre study.

Although disease-associated undernutrition is still an important problem in hospitalized children that is often underrecognized, follow-up studies evaluating post-discharge nutritional status of children with undernutrition are lacking. The aim of this multicentre prospective observational cohort study was to assess the rate of acute undernutrition (AU) and/or having a high nutritional risk (HR) in children on admission to seven secondary-care level Dutch hospitals and to evaluate the nutritional course of AU/HR group during admission and post-discharge. STRONGkids was used to indicate HR, and AU was based on anthropometric data (z-score < -2 for weight-for-age (WFA; <1 year) or weight-for-height (WFH; ≥1 year)). In total, 1985 patients were screened for AU/HR over a 12-month period. On admission, AU was present in 9.9% of screened children and 6.2% were classified as HR; 266 (13.4%) children comprised the AU/HR group (median age 2.4 years, median length of stay 3 days). In this group, further nutritional assessment by a dietitian during hospitalization occurred in 44% of children, whereas 38% received nutritional support. At follow-up 4-8 weeks post-discharge, 101 out of orginal 266 children in the AU/HR group (38%) had available paired anthropometric measurements to re-assess nutrition status. Significant improvement of WFA/WFH compared to admission (-2.48 vs. -1.51 SD; p < 0.001) and significant decline in AU rate from admission to outpatient follow-up (69.3% vs. 35.6%; p < 0.001) were shown. In conclusion, post-discharge nutritional status of children with undernutrition and/or high nutritional risk on admission to secondary-care level pediatric wards showed significant improvement, but about one-third remained undernourished. Findings warrant the need for a tailored post-discharge nutritional follow-up.

Abnormal DNA methylation within HPA-axis genes years after paediatric critical illness.

BACKGROUND: Critically ill children suffer from impaired physical/neurocognitive development 2 years later. Glucocorticoid treatment alters DNA methylation within the hypothalamus-pituitary-adrenal (HPA) axis which may impair normal brain development, cognition and behaviour. We tested the hypothesis that paediatric-intensive-care-unit (PICU) patients, sex- and age-dependently, show long-term abnormal DNA methylation within the HPA-axis layers, possibly aggravated by glucocorticoid treatment in the PICU, which may contribute to the long-term developmental impairments. RESULTS: In a pre-planned secondary analysis of the multicentre PEPaNIC-RCT and its 2-year follow-up, we identified differentially methylated positions and differentially methylated regions within HPA-axis genes in buccal mucosa DNA from 818 former PICU patients 2 years after PICU admission (n = 608 no glucocorticoid treatment; n = 210 glucocorticoid treatment) versus 392 healthy children and assessed interaction with sex and age, role of glucocorticoid treatment in the PICU and associations with long-term developmental impairments. Adjusting for technical variation and baseline risk factors and correcting for multiple testing (false discovery rate < 0.05), former PICU patients showed abnormal DNA methylation of 26 CpG sites (within CRHR1, POMC, MC2R, NR3C1, FKBP5, HSD11B1, SRD5A1, AKR1D1, DUSP1, TSC22D3 and TNF) and three DNA regions (within AVP, TSC22D3 and TNF) that were mostly hypomethylated. These abnormalities were sex-independent and only partially age-dependent. Abnormal methylation of three CpG sites within FKBP5 and one CpG site within SRD5A1 and AKR1D1 was partly attributable to glucocorticoid treatment during PICU stay. Finally, abnormal methylation within FKBP5 and AKR1D1 was most robustly associated with long-term impaired development. CONCLUSIONS: Two years after critical illness in children, abnormal methylation within HPA-axis genes was present, predominantly within FKBP5 and AKR1D1, partly attributable to glucocorticoid treatment in the PICU, and explaining part of the long-term developmental impairments. These data call for caution regarding liberal glucocorticoid use in the PICU.

Association between fat-free mass and survival in critically ill patients with COVID-19: A prospective cohort study.

BACKGROUND: Most critically ill patients with COVID-19 experience malnutrition and weight loss associated with negative clinical outcomes. Our primary aim was to assess body composition during acute and late phase of illness in these patients in relation to clinical outcome and secondary to tailored nutrition support. METHODS: This prospective cohort study included adult critically ill patients with COVID-19. Body composition (fat-free mass [FFM] [exposure of interest], fat mass [FM], skeletal muscle mass [SMM], and phase angle [PA]) was determined with multifrequency bioelectrical impedance analyses in the acute and late phase. Nutrition support data were collected simultaneously. Clinical outcome was defined as intensive care unit (ICU) survival (primary outcome) and 30-90 days thereafter, duration of mechanical ventilation, and length of ICU stay and length of hospital stay (LOS). Nonparametric tests and regression analyses were performed. RESULTS: We included 70 patients (73% male, median age 60 years). Upon admission, median BMI was 30 kg/m2 , 54% had obesity (BMI > 30 kg/m2 ). Median weight change during ICU stay was -3 kg: +3 kg FM and -6 kg FFM (-4 kg SMM). Body composition changed significantly (P < 0.001). Regarding clinical outcome, only low PA was associated with prolonged LOS (odds ratio = 0.83, 95% CI = 0.72-0.96; P = 0.015). Patients with optimal protein intake (>80%) during acute phase maintained significantly more FFM (2.7 kg, P = 0.047) in the late phase compared with patients who received <80%. CONCLUSION: FFM decreased significantly during acute and late phase of illness, but we observed no association with ICU survival. Only low PA was associated with prolonged LOS. FFM wasting likely occurred because of disease severity and immobility.

Non-Surgical Respiratory Management in Relation to Feeding and Growth in Patients with Robin Sequence; a Prospective Longitudinal Study.

OBJECTIVE: To reflect upon our non-surgical respiratory management by evaluating clinical outcomes regarding airway, feeding, and growth during the first year of life in patients with Robin Sequence. DESIGN: Prospective study. SETTING: Sophia Children's Hospital, Rotterdam, the Netherlands. PATIENTS/ PARTICIPANTS: 36 patients with Robin Sequence who were treated between 2011 and 2021. INTERVENTIONS: Positional therapy and respiratory support. MAIN OUTCOME MEASURE(S): Data on respiratory outcomes included polysomnography characteristics and capillary blood gas values. Feeding outcomes were based on the requirement of additional tube feeding. Outcomes on growth were expressed as standard-deviation-scores (SDS) for weight-for-age (WFA) and height-for-age (HFA). RESULTS: Twenty patients were treated with positional therapy (PT), whilst the other 16 patients required respiratory support. Twenty-two patients presented with non-isolated Robin Sequence (RS). During the first year of life, obstructive apnea hypopnea index decreased, oxygen levels enhanced, and capillary blood gas values improved. Eighty-six percent (31/36) experienced feeding difficulties, which completely resolved in 71% (22/31) during their first year of life. From start treatment, to stop treatment, to the age of 1 year, the SDS WFA worsened from -0.40 to -0.33 to -1.03, respectively. CONCLUSIONS: Non-surgical respiratory treatment resulted in an improvement of respiratory outcomes to near normal during the first year of life in patients with RS. These patients often experience feeding difficulties and endure impaired weight gain up to 1 year of age, despite near normalization of breathing. The high prevalence of feeding difficulties and impaired weight for age indicate the urgency for early recognition and adequate treatment to support optimal growth.

Gastrointestinal Biomarkers and Their Association with Feeding in the First Five Days of Pediatric Critical Illness.

OBJECTIVES: Predicting the patients' tolerance to enteral nutrition (EN) would help clinicians optimize individual nutritional intake. This study investigated the course of several gastrointestinal (GI) biomarkers and their association with EN advancement (ENA) longitudinally during pediatric intensive care unit (PICU) admission. METHODS: This is a secondary analysis of the Early versus Late Parenteral Nutrition in the Pediatric Intensive Care Unit randomized controlled trial. EN was started early and increased gradually. The cholecystokinin (CCK), leptin, glucagon, intestinal fatty acid-binding protein 2 (I-FABP2), and citrulline plasma concentrations were measured upon PICU admission, day 3 and day 5. ENA was defined as kcal EN provided as % of predicted resting energy expenditure. The course of the biomarkers and ENA was examined in patients with samples on all time points using Friedman and Wilcoxon signed-rank tests. The association of ENA with the biomarkers was examined using a 2-part mixed-effects model with data of the complete population, adjusted for possible confounders. RESULTS: For 172 patients, median age 8.6 years (first quartile; third quartile: 4.2; 13.4), samples were available, of which 55 had samples on all time points. The median ENA was 0 (0; 0) on admission, 14.5 (0.0; 43.8) on day 3, and 28.0 (7.6; 94.8) on day 5. During PICU stay, CCK and I-FABP2 concentrations decreased significantly, whereas glucagon concentrations increased significantly, and leptin and citrulline remained stable. None of the biomarkers was longitudinally associated with ENA. CONCLUSIONS: Based on the current evidence, CCK, leptin, glucagon, I-FABP2, and citrulline appear to have no added value in predicting ENA in the first 5 days of pediatric critical illness.

Characteristics of Long-Stay Patients in a PICU and Healthcare Resource Utilization After Discharge.

OBJECTIVES: To examine the characteristics of long-stay patients (LSPs) admitted to a PICU and to investigate discharge characteristics of medical complexity among discharged LSP. DESIGN: We performed a retrospective cohort study where clinical data were collected on all children admitted to our PICU between July 1, 2017, and January 1, 2020. SETTING: A single-center study based at Erasmus MC Sophia Children's Hospital, a level III interdisciplinary PICU in The Netherlands, providing all pediatric and surgical subspecialties. PATIENTS: LSP was defined as those admitted for at least 28 consecutive days. INTERVENTIONS: None. MEASUREMENTS: Length of PICU stay, diagnosis at admission, length of mechanical ventilation, need for extracorporeal membrane oxygenation, mortality, discharge location after PICU and hospital admission, medical technical support, medication use, and involvement of allied healthcare professionals after hospital discharge. MAIN RESULTS: LSP represented a small proportion of total PICU patients (108 patients; 3.2%) but consumed 33% of the total admission days, 47% of all days on extracorporeal membrane oxygenation, and 38% of all days on mechanical ventilation. After discharge, most LSP could be classified as children with medical complexity (CMC) (76%); all patients received discharge medications (median 5.5; range 2-19), most patients suffered from a chronic disease (89%), leaving the hospital with one or more technological devices (82%) and required allied healthcare professional involvement after discharge (93%). CONCLUSIONS: LSP consumes a considerable amount of resources in the PICU and its impact extends beyond the point of PICU discharge since the majority are CMC. This indicates complex care needs at home, high family needs, and a high burden on the healthcare system across hospital borders.

What We Know About Intracranial Hypertension in Children With Syndromic Craniosynostosis.

OBJECTIVE: A scoping review of literature about mechanisms leading to intracranial hypertension (ICH) in syndromic craniosynostosis (sCS) patients, followed by a narrative synopsis of whether cognitive and behavioral outcome in sCS is more related to genetic origins, rather than the result of ICH. METHODS: The scoping review comprised of a search of keywords in EMBASE, MEDLINE, Web of science, Cochrane Central Register of Trials, and Google scholar databases. Abstracts were read and clinical articles were selected for full-text review and data were extracted using a structured template. A priori, the authors planned to analyze mechanistic questions about ICH in sCS by focusing on 2 key aspects, including (1) the criteria for determining ICH and (2) the role of component factors in the Monro-Kellie hypothesis/doctrine leading to ICH, that is, cerebral blood volume, cerebrospinal fluid (CSF), and the intracranial volume. RESULTS: Of 1893 search results, 90 full-text articles met criteria for further analysis. (1) Invasive intracranial pressure measurements are the gold standard for determining ICH. Of noninvasive alternatives to determine ICH, ophthalmologic ones like fundoscopy and retinal thickness scans are the most researched. (2) The narrative review shows how the findings relate to ICH using the Monro-Kellie doctrine. CONCLUSIONS: Development of ICH is influenced by different aspects of sCS: deflection of skull growth, obstructive sleep apnea, venous hypertension, obstruction of CSF flow, and possibly reduced CSF absorption. Problems in cognition and behavior are more likely because of genetic origin. Cortical thinning and problems in visual function are likely the result of ICH.

Abnormal DNA methylation within genes of the steroidogenesis pathway two years after paediatric critical illness and association with stunted growth in height further in time.

BACKGROUND: Former critically ill children show an epigenetic age deceleration 2 years after paediatric intensive care unit (PICU) admission as compared with normally developing healthy children, with stunted growth in height 2 years further in time as physical correlate. This was particularly pronounced in children who were 6 years or older at the time of critical illness. As this age roughly corresponds to the onset of adrenarche and further pubertal development, a relation with altered activation of endocrine pathways is plausible. We hypothesised that children who have been admitted to the PICU, sex- and age-dependently show long-term abnormal DNA methylation within genes involved in steroid hormone synthesis or steroid sulphation/desulphation, possibly aggravated by in-PICU glucocorticoid treatment, which may contribute to stunted growth in height further in time after critical illness. RESULTS: In this preplanned secondary analysis of the multicentre PEPaNIC-RCT and its follow-up, we compared the methylation status of genes involved in the biosynthesis of steroid hormones (aldosterone, cortisol and sex hormones) and steroid sulphation/desulphation in buccal mucosa DNA (Infinium HumanMethylation EPIC BeadChip) from former PICU patients at 2-year follow-up (n = 818) and healthy children with comparable sex and age (n = 392). Adjusting for technical variation and baseline risk factors and corrected for multiple testing (false discovery rate < 0.05), former PICU patients showed abnormal DNA methylation of 23 CpG sites (within CYP11A1, POR, CYB5A, HSD17B1, HSD17B2, HSD17B3, HSD17B6, HSD17B10, HSD17B12, CYP19A1, CYP21A2, and CYP11B2) and 4 DNA regions (within HSD17B2, HSD17B8, and HSD17B10) that were mostly hypomethylated. These abnormalities were partially sex- (1 CpG site) or age-dependent (7 CpG sites) and affected by glucocorticoid treatment (3 CpG sites). Finally, multivariable linear models identified robust associations of abnormal methylation of steroidogenic genes with shorter height further in time, at 4-year follow-up. CONCLUSIONS: Children who have been critically ill show abnormal methylation within steroidogenic genes 2 years after PICU admission, which explained part of the stunted growth in height at 4-year follow-up. The abnormalities in DNA methylation may point to a long-term disturbance in the balance between active sex steroids and mineralocorticoids/glucocorticoids after paediatric critical illness, which requires further investigation.

Intermittent feeding with an overnight fast versus 24-h feeding in critically ill neonates, infants, and children: An open-label, single-centre, randomised controlled trial.

BACKGROUND & AIMS: Critically ill children are fed day and night, assuming this improves enteral tolerance and the probability of achieving nutritional goals. It was previously shown that a fasting response, reflected by increased ketosis, at least partly explained the beneficial outcome of delayed initiation of supplemental parenteral nutrition. This study aims to investigate whether an overnight fast increases ketosis and is feasible and safe in critically ill children. METHODS: The Continuousversus Intermittent Nutrition in Paediatric Intensive Care (ContInNuPIC) study is a randomised controlled trial in a tertiary referral Paediatric Intensive Care Unit (PICU) in the Netherlands. Critically ill children (term newborn-18 years) with an expected PICU stay ≥48 h, dependent on artificial nutrition, were eligible. Participants were randomly assigned (1:1, stratified for age group) to intermittent feeding, with interruption of feedings during an age-dependent overnight period of eight to 12 h, or to continuous feeding, with the administration of feedings day and night. In both groups, similar daily caloric targets were pursued. For children younger than one year, mandatory minor glucose infusions were provided during fasting. The primary outcome was the feasibility, defined as two conditions (1): a significant difference in the patients' highest daily ketone (3-ß-hydroxybutyrate, BHB) levels during each overnight period, and (2): non-inferiority regarding daily caloric intake, examined using a two-part mixed-effects model with a predefined non-inferiority margin of 33%, in an intention-to-treat analysis. The study is registered in the Netherlands Trial Register (NL7877). RESULTS: Between May 19, 2020, and July 13, 2022, 140 critically ill children, median (first quartile; third quartile) age 0.3 (0.1; 2.7) years, were randomised to intermittent (n = 67) or continuous feeding (n = 73). In the intermittent feeding group, BHB levels were significantly higher (median 0.4 (0.2; 1.0) vs. 0.3 (0.1; 0.7) mmol/L, p < 0.001). The ratio of total caloric intake in the intermittent feeding group to the intake in the continuous feeding group was not consistently significantly more than 0.67, thus not proving non-inferiority. No severe, resistant hypoglycaemic events, nor severe gastrointestinal complications related to the intervention occurred, and feeding intolerance did not occur more often in the intermittent than in the continuous feeding group. CONCLUSION: Compared with day and night feeding, intermittent feeding with an overnight fast and mandatory glucose infusion for children younger than one year marginally increased ketosis and did not lead to more hypoglycaemic incidents in critically ill children. Because non-inferiority regarding daily caloric intake was not proven, the feasibility of an overnight fast could not be shown in the current study. However, as feeding intolerance did not increase during the condensed feeding periods, the nutritional intake was probably limited by the prescription of nutrition and interruptions. More research is needed to determine the optimal level and duration of clinically relevant ketosis and the best method to achieve this.

Challenges in body composition assessment using air-displacement plethysmography by BOD POD in pediatric and young adult patients.

BACKGROUND & AIMS: Air-Displacement-Plethysmography (ADP) by BOD POD is widely used for body fat assessment in children. Although validated in healthy subjects, studies about use in pediatric patients are lacking. We evaluated user experience and usability of ADP measurements with the BOD POD system in healthy children and pediatric and young adult patients. METHODS: Using the experiences of seven cohort studies, which included healthy children and patients aged 2-22 years, we retrospectively evaluated the user experience with the User Experience Questionnaire (UEQ) (n = 13) and interviews (n = 7). Technical performance was studied using the quality control data collected by the ADP-system. RESULTS: From 2016 to 2022, 1606 measurements were scheduled. BOD POD was mostly rated 'user-friendly', with a generally neutral evaluation on all scales of the UEQ. However, questionable reliability and validity of the results were frequently (86%) reported. We found a high technical failure-rate of the device, predominantly in stability (17%) and accuracy of the measurement (12%), especially in the 'pediatric option' for children aged <6 years. Measurement failure-rate was 38%, mostly due to subject's fear or device failure, especially in young and lean children, and in children with physical and/or intellectual disabilities. CONCLUSION: We conclude that ADP by BOD POD in children and young adults is non-invasive and user-friendly. However, in specific pediatric populations, BOD POD has several limitations and high (technical) failure-rates, especially in young children with aberrant body composition. We recommend caution when interpreting body composition results of pediatric patients as assessed with BOD POD using the current default settings.

The association of hypoglycemia with outcome of critically ill children in relation to nutritional and blood glucose control strategies.

BACKGROUND: Withholding parenteral nutrition (PN) until one week after PICU admission facilitated recovery from critical illness and protected against emotional and behavioral problems 4 years later. However, the intervention increased the risk of hypoglycemia, which may have counteracted part of the benefit. Previously, hypoglycemia occurring under tight glucose control in critically ill children receiving early PN did not associate with long-term harm. We investigated whether hypoglycemia in PICU differentially associates with outcome in the context of withholding early PN, and whether any potential association with outcome may depend on the applied glucose control protocol. METHODS: In this secondary analysis of the multicenter PEPaNIC RCT, we studied whether hypoglycemia in PICU associated with mortality (N = 1440) and 4-years neurodevelopmental outcome (N = 674) through univariable comparison and multivariable regression analyses adjusting for potential confounders. In patients with available blood samples (N = 556), multivariable models were additionally adjusted for baseline serum NSE and S100B concentrations as biomarkers of neuronal, respectively, astrocytic damage. To study whether an association of hypoglycemia with outcome may be affected by the nutritional strategy or center-specific glucose control protocol, we further adjusted the models for the interaction between hypoglycemia and the randomized nutritional strategy, respectively, treatment center. In sensitivity analyses, we studied whether any association with outcome was different in patients with iatrogenic or spontaneous/recurrent hypoglycemia. RESULTS: Hypoglycemia univariably associated with higher mortality in PICU, at 90 days and 4 years after randomization, but not when adjusted for risk factors. After 4 years, critically ill children with hypoglycemia scored significantly worse for certain parent/caregiver-reported executive functions (working memory, planning and organization, metacognition) than patients without hypoglycemia, also when adjusted for risk factors including baseline NSE and S100B. Further adjustment for the interaction of hypoglycemia with the randomized intervention or treatment center revealed a potential interaction, whereby tight glucose control and withholding early PN may be protective. Impaired executive functions were most pronounced in patients with spontaneous or recurrent hypoglycemia. CONCLUSION: Critically ill children exposed to hypoglycemia in PICU were at higher risk of impaired executive functions after 4 years, especially in cases of spontaneous/recurrent hypoglycemia.

Hospital-to-home transitions for children with medical complexity: part 2-a core outcome set.

Appropriate outcome measures as part of high-quality intervention trials are critical to advancing hospital-to-home transitions for Children with Medical Complexity (CMC). Our aim was to conduct a Delphi study and focus groups to identify a Core Outcome Set (COS) that healthcare professionals and parents consider essential outcomes for future intervention research. The development process consisted of two phases: (1) a three-round Delphi study in which different professionals rated outcomes, previously described in a systematic review, for inclusion in the COS and (2) focus groups with parents of CMC to validate the results of the Delphi study. Forty-five professionals participated in the Delphi study. The response rates were 55%, 57%, and 58% in the three rounds, respectively. In addition to the 24 outcomes from the literature, the participants suggested 12 additional outcomes. The Delphi rounds resulted in the following core outcomes: (1) disease management, (2) child's quality of life, and (3) impact on the life of families. Two focus groups with seven parents highlighted another core outcome: (4) self-efficacy of parents.   Conclusion: An evidence-informed COS has been developed based on consensus among healthcare professionals and parents. These core outcomes could facilitate standard reporting in future CMC hospital to home transition research. This study facilitated the next step of COS development: selecting the appropriate measurement instruments for every outcome. What is Known: • Hospital-to-home transition for Children with Medical Complexity is a challenging process. • The use of core outcome sets could improve the quality and consistency of research reporting, ultimately leading to better outcomes for children and families. What is New: • The Core Outcome Set for transitional care for Children with Medical Complexity includes four outcomes: disease management, children's quality of life, impact on the life of families, and self-efficacy of parents.

Early brain magnetic resonance imaging findings and neurodevelopmental outcome in children with congenital heart disease: A systematic review.

AIM: To investigate the association between early brain magnetic resonance imaging (MRI) findings and neurodevelopmental outcome (NDO) in children with congenital heart disease (CHD). METHOD: A search for studies was conducted in Embase, Medline, Web of Science, Cochrane Central, PsycINFO, and Google Scholar. Observational and interventional studies were included, in which patients with CHD underwent surgery before 2 months of age, a brain MRI scan in the first year of life, and neurodevelopmental assessment beyond the age of 1 year. RESULTS: Eighteen studies were included. Thirteen found an association between either quantitative or qualitative brain metrics and NDO: 5 out of 7 studies showed decreased brain volume was significantly associated with worse NDO, as did 7 out of 10 studies on brain injury. Scanning protocols and neurodevelopmental tests varied strongly. INTERPRETATION: Reduced brain volume and brain injury in patients with CHD can be associated with impaired NDO, yet standardized scanning protocols and neurodevelopmental assessment are needed to further unravel trajectories of impaired brain development and its effects on outcome.

Sleep, 24-hour activity rhythms, and cardiometabolic risk factors in school-age children.

STUDY OBJECTIVES: Disturbed sleep and 24-hour activity rhythms are linked to adverse cardiometabolic profiles in adults and adolescents, and these associations may originate in early life. We aimed to study associations of sleep and 24-hour rhythms with cardiometabolic risk factors in school-age children. METHODS: This cross-sectional population-based study comprised 894 children aged 8-11 years from the Generation R Study. Sleep (duration, efficiency, number of awakenings, and time awake after sleep onset) and 24-hour activity rhythms (social jet lag, interdaily stability, and intradaily variability) were assessed using triaxial wrist actigraphy for 9 consecutive nights. Cardiometabolic risk factors included adiposity (body mass index Z-score, fat mass index using dual-energy X-ray absorptiometry, and visceral fat mass and liver fat fraction using magnetic resonance imaging), blood pressure, and blood markers (glucose, insulin, and lipids). We adjusted for season, age, sociodemographics, and lifestyle factors. RESULTS: Each increase in interquartile range of nightly awakenings (2 times) was associated with -0.12 standard deviation (95% confidence interval: -0.21, -0.04) lower body mass index and 0.15 mmol/L (0.10, 0.21) higher glucose. Among boys, an increase in interquartile range of intradaily variability (0.12) was associated with higher fat mass index (+0.07 kg/m2; 95% confidence interval: 0.03, 0.11) and visceral FM (+0.08 g; 95% confidence interval: 0.02, 0.15). We observed no associations with blood pressure or clustering of cardiometabolic risk factors. CONCLUSIONS: Already at school age, greater fragmentation of the 24-hour activity rhythm is associated with general and organ adiposity. In contrast, more nightly awakenings were associated with lower body mass index. Future research should bring clarity to these disparate observations in order to create potential targets for obesity prevention programs. CITATION: Beunders VAA, Koopman-Verhoeff ME, Vermeulen MJ, et al. Sleep, 24-hour activity rhythms, and cardiometabolic risk factors in school-age children. J Clin Sleep Med. 2023;19(7):1219-1229.

Long-term impact of paediatric critical illness on the difference between epigenetic and chronological age in relation to physical growth.

BACKGROUND: Altered DNA-methylation affects biological ageing in adults and developmental processes in children. DNA-methylation is altered by environmental factors, trauma and illnesses. We hypothesised that paediatric critical illness, and the nutritional management in the paediatric intensive care unit (PICU), affects DNA-methylation changes that underly the developmental processes of childhood ageing. RESULTS: We studied the impact of critical illness, and of the early use of parenteral nutrition (early-PN) versus late-PN, on "epigenetic age-deviation" in buccal mucosa of 818 former PICU-patients (406 early-PN, 412 late-PN) who participated in the 2-year follow-up of the multicentre PEPaNIC-RCT (ClinicalTrials.gov-NCT01536275), as compared with 392 matched healthy children, and assessed whether this relates to their impaired growth. The epigenetic age-deviation (difference between PedBE clock-estimated epigenetic age and chronological age) was calculated. Using bootstrapped multivariable linear regression models, we assessed the impact hereon of critical illness, and of early-PN versus late-PN. As compared with healthy children, epigenetic age of patients assessed 2 years after PICU-admission deviated negatively from chronological age (p < 0.05 in 51% of bootstrapped replicates), similarly in early-PN and late-PN groups. Next, we identified vulnerable subgroups for epigenetic age-deviation using interaction analysis. We revealed that DNA-methylation age-deceleration in former PICU-patients was dependent on age at time of illness (p < 0.05 for 83% of bootstrapped replicates), with vulnerability starting from 6 years onwards. Finally, we assessed whether vulnerability to epigenetic age-deviation could be related to impaired growth from PICU-admission to follow-up at 2 and 4 years. Multivariable repeated measures ANOVA showed that former PICU-patients, as compared with healthy children, grew less in height (p = 0.0002) and transiently gained weight (p = 0.0003) over the 4-year time course. Growth in height was more stunted in former PICU-patients aged ≥ 6-years at time of critical illness (p = 0.002) than in the younger patients. CONCLUSIONS: As compared with healthy children, former PICU-patients, in particular those aged ≥ 6-years at time of illness, revealed epigenetic age-deceleration, with a physical correlate revealing stunted growth in height. Whether this vulnerability around the age of 6 years for epigenetic age-deceleration and stunted growth years later relates to altered endocrine pathways activated at the time of adrenarche requires further investigation.

Sleep and 24-hour rhythm characteristics in preschool children born very preterm and full term.

STUDY OBJECTIVES: Sleep impacts the quality of life and is associated with cardiometabolic and neurocognitive outcomes. Little is known about the sleep of preterm-born children at preschool age. We, therefore, studied sleep and 24-hour rhythms of preschool children born very preterm compared with full-term children. METHODS: This was a prospective cohort study comparing sleep quality and quantity of children born very preterm (gestational age [GA] < 30 weeks) with full-term children at the (corrected) age of 3 years, using (1) 2 parent-reported questionnaires (Brief Infant Sleep Questionnaire and The Munich Chronotype Questionnaire) and (2) at least 3 days of triaxial wrist actigraphy combined with sleep diary. We performed regression analyses with adjustment for sex (corrected), age, and birth weight standard deviation (SD) score. RESULTS: Ninety-seven very-preterm-born (median GA 27+5; interquartile range 26 + 3;29 + 0 weeks) and 92 full-term children (GA 39 + 3; 38 + 4;40 + 4 weeks) were included. Sleep problems and other reported sleep parameters were not different between groups. As measured with actigraphy, sleep and 24-hour rhythm were similar between groups, except for very-preterm born children waking up 21 minutes (4;38) minutes later than full-term children (adjusted P = .001). CONCLUSIONS: Based on parent reports and actigraphy, very-preterm-born children sleep quite similar to full-term controls at the corrected age of 3 years. Reported sleep problems were not different between groups. Actigraphy data suggest that preterm-born children may wake up later than children born full term. Further studies are needed to explore how sleep relates to cardiometabolic and neurodevelopmental outcomes after preterm birth and whether early interventions are useful to optimize 24-hour rhythm and sleep. CITATION: Bijlsma A, Beunders VAA, Dorrepaal DJ, et al. Sleep and 24-hour rhythm characteristics in preschool children born very preterm and full term. J Clin Sleep Med. 2023;19(4):685-693.