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Background: Concerns are raised about the influence of rapid growth on excessive fat mass (FM) gain in early life and later cardiometabolic health of infants born preterm. Objectives: To study the association between postnatal weight gain trajectories and body composition in infancy in infants born very preterm. Methods: In infants born <30 weeks gestation, we evaluated associations between weight Z-score trajectories for three consecutive timeframes (NICU stay, level-II hospital stay and at home) and body composition, measured at 2 and 6 months corrected age by air-displacement plethysmography. Results: Of 120 infants included, median gestational age at birth was 27+5 (interquartile range 26+1;28+5) and birth weight 1015 g (801;1250). The majority of infants did not make up for their initial loss of weight Z-score, but growth and later body composition were within term reference values. Weight gain during NICU stay was not associated with fat mass (absolute, %FM or FM index) in infancy. Weight gain during NICU and level II hospital stay was weakly associated with higher absolute lean mass (LM), but not after adjustment for length (LM index). Weight gain in the level-II hospital was positively associated with fat mass parameters at 2 months but not at 6 months. Strongest associations were found between weight gain at home and body composition (at both time points), especially fat mass. Concl

Purpose of review There is ongoing interest in nutritional screening tools in pediatrics to facilitate the identification of children at risk for malnutrition who need further assessment and possible nutritional intervention. The choice for a specific tool depends on various factors. This review aims to provide an overview of recent progress in pediatric nutritional screening methods. Recent findings We present recent studies about newly developed or adjusted tools, the applicability of nutritional screening tools in specific populations, and how to implement screening in the overall process of improving nutritional care in the pediatric hospital setting. Summary Three new screening tools have been developed for use on admission to hospital: two for the mixed pediatric hospitalized population and one for infants. A simple weekly rescreening tool to identify hospital-acquired nutritional deterioration was developed for use in children with prolonged hospital stay. Different from most previous studies that only assessed the relationship between the nutritio

Background: A genome-wide study identifed de novo DNA methylation alterations in leukocytes of children at paediatric intensive care unit (PICU) discharge, ofering a biological basis for their impaired long-term development. Early parenteral nutrition (early-PN) in PICU, compared with omitting PN in the frst week (late-PN), explained diferential methylation of 23% of the afected CpG-sites. We documented the time course of altered DNA methylation in PICU and the impact hereon of early nutritional management. Results: We selected 36 early-PN and 36 late-PN matched patients, and 42 matched healthy children. We quantifed DNA methylation on days 3, 5 and 7 for the 147 CpG-sites of which methylation was normal upon PICU admission in this subset and altered by critical illness at PICU discharge. Methylation in patients difered from healthy children for 64.6% of the 147 CpG-sites on day 3, for 72.8% on day 5 and for 90.5% on day 7 as revealed by ANOVA at each time point. Within-patients methylation time course analyses for each CpG-site identifed diferent patterns based on paired t test p value and direction of change. Rapid demethylation from admission to day 3 occurred for 76.2% of the CpG-sites, of which 67.9% remained equally demethylated or partially remethylated and 32.1% further demethylated beyond day 3. From admission to day 3, 19.7% of the CpG-sites became hypermethylated, of which, beyond day 3, 34.5% remained equally hypermethylated or partially demethylated again and 65.5% further hypermethylated. For 4.1% of the CpG-sites, changes only appeared beyond day 3. Finally, for the CpG-sites afected by early-PN on the last PICU day, earlier changes in DNA methylation were compared for early-PN and late-PN patients, revealing that 38.9% were already diferentially methylated by day 3, another 25.0% by day 5 and another 13.9% by day 7. Conclusions: Critical illness- and early-PN-induced changes in DNA methylation occurred mainly within 3 days. Most abnormalities were at

Background & aims: Early use of parenteral nutrition (early-PN), as compared with withholding it for one week (late-PN), in the PICU, has shown to slow down recovery from critical illness and impair long-term development of 6 neurocognitive/behavioural/emotional functions assessed 2 years later. Given that key steps in brain maturation occur at different times during childhood, we hypothesised that age at time of exposure determines long-term developmental impact of early-PN. Methods: The 786 children who were neurocognitively tested 2 years after participation in the PEPaNIC-RCT were included in this study. First, for each studied long-term outcome, interaction between randomisation to early-PN versus late-PN and age was assessed with multivariable linear regression analysis. Subsequently, for outcomes with an interaction p ≤ 0.15, the impact of early-PN versus late-PN was analysed, after adjustment for risk factors, for 4 subgroups defined based on developmentally-relevant age at time of exposure [≤28 days (n = 121), 29 days to 11 months (n = 239), 11 months to <5 years (n = 223) and ≥5 years (n = 203)]. Results: Interaction between randomisation and age was present for weight, and parent-reported inhibitory control, cognitive flexibility, working memory, planning/organisation, metacognition, total executive functioning, and internalising and total behavioural/emotional problems. Subgroup analyses revealed that none of the age-groups revealed benefit, whereas children aged 29 days to <11 months were most vulnerable to harm by early-PN for development of inhibitory control (p = 0.008), working memory (p = 0.009), planning/organisation (p = 0.004), metacognition (p = 0.008), and total executive functioning (p = 0.004), and for internalising (p = 0.005) and total behavioural/emotional problems (p = 0.01). Children aged 11 months to <5 years revealed harm by early-PN for development of inhibitory control (p = 0.003). In contrast, children aged ≥5 years and neonates ag

BACKGROUND: Breastfeeding is considered the most optimal mode of feeding for neonates and mothers. Human milk changes over the course of lactation in order to perfectly suit the infant's nutritional and immunological needs. Its composition also varies throughout the day. Circadian fluctuations in some bioactive components are suggested to transfer chronobiological information from mother to child to assist the development of the biological clock. This review aims to give a complete overview of studies examining human milk components found to exhibit circadian variation in their concentration. METHODS: We included studies assessing the concentration of a specific human milk component more than once in 24 h. Study characteristics, including gestational age, lactational stage, sampling strategy, analytical method, and outcome were extracted. Methodological quality was graded using a modified Newcastle-Ottawa Scale (NOS). RESULTS: A total of 83 reports assessing the circadian variation in the concentration of 71 human milk components were included. Heterogeneity among studies was high. The methodological quality varied widely. Significant circadian variation is found in tryptophan, fats, triacylglycerol, cholesterol, iron, melatonin, cortisol, and cortisone. This may play a role in the child's growth and development in terms of the biological clock.

Background: In critically ill children, omitting early use of parenteral nutrition (late-PN versus early-PN) reduced infections, accelerated weaning from mechanical ventilation, and shortened PICU stay. We hypothesized that fasting-induced ketogenesis mediates these benefits. Methods: In a secondary analysis of the PEPaNIC RCT (N = 1440), the impact of late-PN versus early-PN on plasma 3-hydroxybutyrate (3HB), and on blood glucose, plasma insulin, and glucagon as key ketogenesis regulators, was determined for 96 matched patients staying ≥ 5 days in PICU, and the day of maximal 3HB-effect, if any, was identified. Subsequently, in the total study population, plasma 3HB and late-PN-affected ketogenesis regulators were measured on that average day of maximal 3HB effect. Multivariable Cox proportional hazard and logistic regression analyses were performed adjusting for randomization and baseline risk factors. Whether any potential mediator role for 3HB was direct or indirect was assessed by further adjusting for ketogenesis regulators. Results: In the matched cohort (n = 96), late-PN versus early-PN increased plasma 3HB throughout PICU days 1–5 (P < 0.0001), maximally on PICU day 2. Also, blood glucose (P < 0.001) and plasma insulin (P < 0.0001), but not glucagon, were affected. In the total cohort (n = 1142 with available plasma), late-PN increased plasma 3HB on PICU day 2 (day 1 for shorter stayers) from (median [IQR]) 0.04 [0.04–0.04] mmol/L to 0.75 [0.04–2.03] mmol/L (P < 0.0001). The 3HB effect of late-PN stat

Background: Pediatric intensive care unit (PICU) survivors are at risk for prolonged morbidities interfering with daily life. The current study examined parent-reported health-related quality of life (HRQoL) in former critically ill children and parents themselves and aimed to determine whether withholding parenteral nutrition (PN) in the first week of critical illness affected children’s and parents’ HRQoL 2 years later. Methods: Children who participated in the pediatric early versus late parenteral nutrition in critical illness (PEPaNIC) trial and who were testable 2 years later (n = 1158) were included. Their HRQoL outcomes were compared with 405 matched healthy controls. At PICU admission, children

Purpose: Prolonged endotracheal intubation may lead to laryngeal damage, with stridor being the most relevant clinical symptom. Our objective was to determine the incidence of post-extubation stridor and their clinical consequences in children within a tertiary referral center and to identify contributing factors. Methods: 150 children, aged 0–16 years, intubated for more than 24 h were prospectively enrolled until discharge of the hospital. Potential relevant factors, thought to mediate the risk of laryngeal damage, were recorded and analyzed. Results: The median duration of intubation was 4 days, ranging from 1 to 31 days. Stridor following extubation occurred in 28 patients (18.7%); 3 of them required reintubation due to

Background: Nutritional support is considered essential for the outcome of paediatric critical illness. There is a lack of methodologically sound trials to provide evidence-based guidelines leading to diverse practices in PICUs worldwide. Acknowledging these limitations, we aimed to summarize the available literature and provide practical guidance for the paediatric critical care clinicians around important clinical questions many of which are not covered by previous guidelines. Objective: To provide an ESPNIC position statement and make clinical recommendations for the assessment and nutritional support in critically ill infants and children. Design: The metabolism, endocrine and nutrition (MEN) section of the European Society of Pediatric and Neonatal Intensive Care (ESPNIC) generated 15 clinical questions regarding different aspects of nutrition in critically ill children. After a systematic literature search, the Scottish Intercollegiate Guidelines Network (SIGN) grading system was applied to assess the quality of the evidence, conducting meta-analyses where possible, to generate statements and clinical recommendations, which were then voted on electronically. Strong consensus (> 95% agreement) and consensus (> 75% agreement) on these statements and recommendations was measured through modified Delphi voting rounds. Results: The final 15 clinical questions generated a total of 7261 abstracts, of which 142 publications were identified relevant to develop 32 recommendations. A strong consensus was reached in 21 (66%) and consensus was reached in 11 (34%) of the recommendations. Only 11 meta-analyses could be performed on 5 questions. Conclusions: We present a position statement and clinical practice recommendations. The general level of evidence of the available literature was low. We have summarised this and provided a practical guidance for the paediatric critical care clinicians around important clinical questions.

Background: Children with syndromic craniosynostosis (sCS) often suffer from obstructive sleep apnea (OSA) and intracranial hypertension (ICH). Both OSA and ICH might disrupt sleep architecture. However, it is unclear how surgically treating OSA or ICH affects sleep architecture. The aim of this study was twofold: to explore the usefulness of sleep architecture analysis in detecting disturbed sleep and to determine whether surgical treatment can improve it. Methods: Eighty-three children with sCS and 35 control subjects, who had undergone a polysomnography (PSG), were included. Linear-mixed models showed the effects of OSA and ICH on sleep architecture parameters. In a subset of 19 patients, linear regression models illustrated the effects of OSA-indicated and ICHindicated surgery on pre-to-postoperative changes. Results: An increase in obstructive-apnea/hypopnea index (oAHI) was significantly associated with an increase in N2-sleep, arousal index, and respiratoryarousal index and a decrease in REM-sleep, N3-sleep, sleep efficiency, and sleep quality. ICH and having sCS were not related to any change in sleep architecture. OSA-indicated surgery significantly increased the total sleep time and sleep efficiency and decreased the arousal index and respiratory-arousal index. ICHindicated surgery significantly decreased REM-sleep, N1-sleep, sleep efficiency, and sleep quality. Conclusions: For routine detection of disturbed sleep in individual subjects, PSGassessed sleep architecture is currently not useful. OSA does disrupt sleep architecture, but ICH does not. OSA-indicated surgery improves sleep architecture, which stresses the importance of treating OSA to assure adequate sleep. ICH-indicated surgery affects sleep architecture, although it is not clear whether this is a positive or negative effect.

Purpose: Increased systemic cortisol availability during adult critical illness is determined by reduced binding-proteins and suppressed breakdown rather than elevated ACTH. Dynamics, drivers and prognostic value of hypercortisolism during pediatric critical illness remain scarcely investigated. Methods: This preplanned secondary analysis of the PEPaNIC-RCT (N = 1440), after excluding 420 children treated with corticosteroids before PICU-admission, documented (a) plasma ACTH, (free)cortisol and cortisol-metabolism at PICU-admission, day-3 and last PICU-day, their prognostic value, and impact of withholding early parenteral nutrition (PN), (b) the association between corticosteroid-treatment and these hormones, and (c) the association between corticosteroid-treatment and outcome. Results: ACTH was normal upon PICU-admission and low thereafter

Background: Initiating parenteral nutrition (PN) within 24 h in critically ill children is inferior to withholding PN during the first week, as was found in the PEPaNIC study. The aims of this study were to investigate de-implementation of early initiation of PN at PICUs worldwide, and to identify factors influencing de-implementation. Methods: A cross-sectional online survey was conducted (May - October 2017), consisting of 41 questions addressing current PN practices, the degree of de-implementation, and factors affecting de-implementation. Results: We analysed 81 responses from 39 countries. Of these 81 respondents, 53 (65%) were aware of the findings of the PEPaNIC study, and 43 (53%) have read the article. In these 43 PICUs, PN was completely withheld during the first week in 10 PICUs, of which 5 already withheld PN (12%), and 5 de-implemented early initiation of PN (12%). Partial de-implementation was reported by 17 (40%) and no de-implementation by 16 (37%). Higher de-implementation rates were observed when the interpreted level of evidence and grade of recommendation of PEPaNIC was high. Predominant reasons for retaining early initiation of PN were concerns on withholding amino acids, the safety in undernourished children and neonates, and the long-term consequences. Furthermore, the respondents were waiting for updated guidelines. Conclusions: One year after the publication of the PEPaNIC trial, only two-thirds of the respondents was aware of the study results. Within this group, early initiation of PN was de-implemented completely in 12% of the PICUs, while 40% asserted partial de-implementation. Increasing the awareness, addressing the intervent

_IMPORTANCE_ Undernourishment has been associated with poor outcomes of critical illness in children. The effects of withholding parenteral nutrition (PN) for 1 week in undernourished critically ill children are unknown. _OBJECTIVE_ To assess the outcome effects of withholding PN for 1 week in undernourished critically ill children. _DESIGN, SETTING, AND PARTICIPANTS_ This is a subanalysis of the randomized clinical trial Pediatric Early vs Late Parenteral Nutrition in Intensive Care Unit (PEPaNIC; N = 1440), which focused on the subgroup of pediatric intensive care unit (PICU) patients identified as undernourished on admission. Children included in the PEPaNIC trial were enrolled between June 18, 2012, and July 27, 2015. Undernourishment was defined as weight-for-age z score less than −2 in children younger than 1 year, and body mass index–for-age z score less than −2 in children 1 year or older. Data analysis was conducted from August 3, 2017, to July 6, 2018. _INTERVENTIONS_ Patients were randomized to initiation of supplemental PN within 24 hours (early PN) or after 1 week (late PN) when enteral nutrition was insufficient. _MAIN OUTCOMES AND MEASURES_ Primary end points were risk of new infections acquired in the PICU and time to live PICU discharge, assessed via multivariable logistic regression and Cox proportional hazard analyses, adjusted for risk factors. _RESULTS_ A total of 289 of 1440 children (20.1%), term newborn to age 17 years, were identified as undernourished, of whom 150 of 717 patients (20.9%) were in the late PN group and 139 of 723 patients (19.2%) were in the early PN group. On admission, characteristics were similar among the treatment groups. Mean (SD)weight z scoreswere −3.33 (1.18) in the late PN group and −3.21 (1.09) in the early PN group. Compared with well-nourished PICU patients, undernourishment on admission was associated with lower likelihood of an earlier live PICU discharge. Among undernourished PICU patients, late PN reduced the

Background: In the spectrum of children with symptomatic sleep disordered breathing (SDB), some individuals – such as those with upper airway resistance syndrome (UARS) – do not have abnormalities on polysomnography (PSG). In this study we have assessed whether assessment of respiratory arrhythmia (RA) and heart rate variability (HRV) analysis helps in management of children with syndromic craniosynostosis and none-to-mild obstructive sleep apnea (OSA). Methods: Prospective cohort study in children aged 1–18 years old with syndromic craniosynostosis. Children were selected for HRV analysis from the ECG if their obstructive apnea–hypopnea index (oAHI) was between zero and five per hour (ie, oAHI ≤5/hour). Subjects were divided into groups based on the presence or absence of respiratory arrhythmia (with or without RA respectively) using the electrocardiogram (ECG). The main analysis included studying the relationship between RA and HRV, symptoms, interventions, and sleep architecture. Results: We identified 42 patients with, at worst, mild OSA. We found higher parasympathetic control and higher total power in children with RA during the non-rapid eye movement (non-REM) sleep. Children with RA also have a relatively higher percentage of paradoxical breathing during non-REM sleep (P = 0.042). Intracranial hypertension was distributed equally between groups. Last, RA patients showed increased parasympathetic activity that further increased in non-REM sleep. Conclusion: In syndromic craniosynostosis cases with SDB and PSG showing oAHI ≤5/hour, the presence of RA may indicate subsequent need for treatment interventions, and a trend toward higher occurrence of clinical symptoms. ECG analyses of HRV variables in subjects with RA demonstrate increased parasympathetic activity and total power. Such findings may add to the diagnosis of apparently asymptomatic children.

__Background:__ Children who have suffered from critical illnesses that required treatment in a paediatric intensive care unit (PICU) have long-term physical and neurodevelopmental impairments. The mechanisms underlying this legacy remain largely unknown. In patients suffering from chronic diseases hallmarked by inflammation and oxidative stress, poor long-term outcome has been associated with shorter telomeres. Shortened telomeres have also been reported to result from excessive food consumption and/or unhealthy nutrition. We investigated whether critically ill children admitted to the PICU have shorter-than-normal telomeres, and whether early parenteral nutrition (PN) independently affects telomere length when adjusting for known determinants of telomere length. __Methods:__ Telomere length was quantified in leukocyte DNA from 342 healthy children and from 1148 patients who had been enrolled in the multicenter, randomised controlled trial (RCT), PEPaNIC. These patients were randomly allocated to initiation of PN within 24 h (early PN) or to withholding PN for one week in PICU (late PN). The impact of early PN versus late PN on the change in telomere length from the first to last PICU-day was investigated with multivariable linear regression analyses. __Results:__ Leukocyte telomeres were 6% shorter than normal upon PICU admission (median 1.625 (IQR 1.446-1.825) telomere/single-copy-gene ratio (T/S) units vs. 1.727 (1.547-1.915) T/S-units in healthy children (P < 0.0001)). Adjusted for potential baseline determinants and leukocyte composition, early PN was associated with telomere shortening during PICU stay as compared with late PN (estimate early versus late PN -0.021 T/S-units, 95% CI -0.038; 0.004, P = 0.01). Other independent determinants of telomere length identified in this model were age, gender, baseline telomere length and fraction of neutrophils in the sample from which the DNA was extracted. Telomere shortening with early PN was independent of post-rand

__Background:__ The multicentre randomised controlled PEPaNIC trial showed that withholding parenteral nutrition (PN) during the first week of critical illness in children was clinically superior to providing early PN. This study descr

_Background & aims:_ At the 37th annual ESPEN congress in Lisbon, a new Special Interest Group (SIG) in Paediatric Clinical Nutrition was formed. As a first activity of this group, a survey was sent out to all ESPEN members to collect opinions about the objectives of this SIG, explore the interest of ESPEN members in paediatric related nutrition research and clinical practice and to offer to the opportunity for a wider future participation. _Methods:_ A web-based questionnaire survey was distributed to all members of ESPEN via the regular society's newsletter. _Results:_ In total, 123/2828 (4.3%) ESPEN members from 50 countries completed the survey. Fifty-nine of the responders were working in paediatric clinical practice and/or research, 42 in adult medicine, and 20 in both. Fifty-seven (51%) respondents agreed that there is inadequate representation of paediatric nutrition in the current ESPEN activities and 90% of all would like to see more paediatric topics at the ESPEN annual congresses. The development of paediatric clinical practice guidelines should be the scope of this SIG, as indicated by 85 (69%) respondents. Seventy-six (69%) believed that the creation of a Paediatric Clinical Nutrition SIG is likely to impact positively on the society's membership. _Conclusions:_ There is an unmet need for more paediatric related topics and representation with the activities of the ESPEN group. The SIG in Paediatrics aspires to foster multicentre research, development of guidelines and provide a hub for interaction and knowledge exchange.

Background: The predisposition for obesity is suggested to originate in the prenatal period. Prenatal markers are needed to identify foetuses at risk for neonatal adiposity, as early marker of childhood obesity. Objective: The aim of this study is to assess the association between foetal fractional thigh volume (TVol) and neonatal percentage fat mass from mid-gestation onward. Methods: In this perinatal cohort study, singleton pregnancies

Aim: In sick children who are unable to be weighed estimation of weight is often required, but the routinely used equations lack accuracy and precision. This study aimed to develop a novel equation (Children's European Estimator of Weight-CEEW) using measurements of mid-upper arm circumference (MUAC) and other predictors in multinational groups of sick children in Europe. Methods: Weight estimation equations were developed in 2086 children from the UK, Greece and the Netherlands, using a combination of demographics, MUAC and height measurements. The final CEEW equations were compared against the performance of the European Resuscitation Council (ERC), Advanced Paediatric Life Support (APLS) and the Cattermole equations. Results: Two final CEEW equations were developed, incorporating measurements of age, gender and MUAC, with (CEEW1) or without (CEEW2) the inclusion of height. Both equations presented very high coefficients of determination (R2 >96.5%), minimal mean prediction error and narrower limits of agreement than the comparator equations. 88% (CEEW1) and 77% (CEEW2) of weight estimates fell within 15% of measured body weight. These figures compared with less than 57%, 57% and 37% for the ERC, APLS and Cattermole equations respectively. Conclusion: The CEEW equations performed substantially better than other routinely used equations for weight estimation. An electronic application for mobile use is presented.

Craniofacial microsomia (CFM) is characterized by underdevelopment of the structures derived from the first and second pharyngeal arches resulting in aesthetic, psychological, and functional problems including feeding and swallowing difficulties. The aim of this study is to gain more insight into swallowing difficulties in patients with CFM. A retrospective study was conducted in the population of patients diagnosed with CFM at three major craniofacial units. Patients with feeding difficulties and those who underwent video fluoroscopic swallow (VFS) studies were included for further analyses. The outcome of the VFS-studies was reviewed with regard to the four phases of swallowing. In our cohort, 13.5% of the 755 patients were diagnosed with swallowing difficulties. The outcome of the VFS-studies of 42 patients showed difficulties in the oral and pharyngeal phases with both thin and thick liquids. Patients with more severe mandibular hypoplasia showed more difficulties to form an appropriate bolus compared to patients who were less severely affected. This is the first study to document swallowing problems in patients with CFM. Difficulties were seen in both the oral and pharyngeal phases. We recommend routine screening for swallowing issues by a speech and language therapist in all patients with CFM and to obtain a VFS-study in patients with a type III mandible.

Objective: The objective of this cross-sectional study is to assess the prevalence, course, and management of obstructive sleep apnea (OSA) in children with Robin sequence (RS) aged 1–18 years. Materials and methods: A cross-sectional study was conducted in 63 children aged 1 to18 years with RS. Patient data were collected on baseline characteristics and management. OSA was evaluated by polysomnography. Results: Sixty-three children with RS were included (median age 8.0 years) and divided into two groups based on the initial treatment: prone positioning or respiratory support. Respiratory support was more often indicated in children with a non-isolated RS (p < 0.05). At cross section, in the prone positioning group (n = 32), one child was diagnosed with OSA. In the respiratory support group (n = 31), 13 children (42 %) had respiratory problems of whom 10 needed respiratory support. Conclusions: Between the age of 1 and 18 years, almost one out of four children with RS still has respiratory problems. Children with RS, who can be treated with prone positioning only as an infant, are not likely to develop obstructive airway problems at a later age. In contrast, children who need respiratory support early after birth are at risk of continuing or re-developing OSA after the age of 1 year. Clinical relevance: This study shows that those who need respiratory support at an early age need careful monitoring until adulthood.

Background: Children with Apert and Crouzon-Pfeiffer syndromes are at risk of intracranial hypertension. Until 2005, when the authors switched to occipital expansion, their institution's preferred treatment was fronto-orbital advancement. However, it was still unclear whether (1) occipitofrontal head circumference (i.e., intracranial volume) was greater after occipital expansion than after fronto-orbital advancement; (2) the incidences of tonsillar herniation and papilledema were lower; and (3) visual acuity was better during follow-up. In these patients, the authors therefore compared fronto-orbital advancement with occipital expansion as the first surgical procedure. Methods: Measurements included repeated occipitofrontal head circumference as a measure for intracranial volume; neuroimaging to evaluate tonsillar herniation; funduscopy to identify papilledema; and visual acuity testing. Results: The authors included 37 patients (Apert syndrome, n = 18; Crouzon-Pfeiffer syndrome, n = 19). Eighteen underwent fronto-orbital advancement and 19 underwent occipital expansion (age at surgery, 1.0 versus 1.5 years; p = 0.13). Follow-up time in both groups was 5.7 years. The increase in occipitofrontal head circumference (+1.09 SD) was greater after occipital expansion than after fronto-orbital advancement (+0.32 SD) (p = 0.03). After occipital expansion, fewer patients with Crouzon-Pfeiffer syndrome had tonsillar herniation (occipital, three of 11; fronto-orbital advancement, seven of eight; p = 0.02); for both syndromes together, fewer patients had papilledema (occipital, four of 19; fronto-orbital advancement, 11 of 18; p = 0.02). Visual acuity was similar after fronto-orbital advancement and occipital expansion (0.09 versus 0.13 logarithm of the minimum angle of resolution) (p = 0.28). Conclusions: The authors' preference for occipital expansion as the initial craniofacial procedure in Apert and Crouzon-Pfeiffer syndromes is supported by the greater increase it produces

In adults with heart failure, central sleep apnea (CSA), often manifested as Cheyne–Stokes respiration, is common, and has been associated with adverse outcome. Heart failure in children is commonly caused by dilated cardiomyopathy (DCM). It is unknown whether children with heart failure secondary to DCM have CSA, and whether CSA is related to the severity of heart failure. In this prospective observational study, 37 patients (<18 year) with heart failure secondary to DCM were included. They underwent polysomnography, clinical and laboratory evaluation and echocardiographic assessment. After a median follow-up time of 2 years, eight patients underwent heart transplantation. CSA (apnea–hypopnea index [AHI] ≥1) was found in 19 % of the patients. AHI ranged from 1.2 to 4.5/h. The occurrence of CSA was not related to the severity of heart failure. Three older patients showed a breathing pattern mimicking Cheyne–Stokes respiration, two of whom required heart transplantation. CSA was found in 19 % of the children with heart failure secondary to DCM. No relation was found with the severity of heart failure. In a small subset of children with severe DCM, a pattern mimicking Cheyne–Stokes respiration was registered.

Purpose: In hospitalized children with a chronic disease, malnutrition was associated with a lower subjective health status. In outpatient children with a chronic disease attending special schools, this association has never been studied. The aim of this study was to assess the association between nutritional status and subjective health status in chronically ill children attending special schools. Methods: Overall, 642 children, median age 9.8 years (IQR 7.7–11.5), 60 % male, 72 % Caucasian, were included in this prospective study in nine special schools for chronically ill children in the Netherlands. Overall malnutrition was assessed as: acute malnutrition (<−2 SDS for weight for height (WFH)) and chronic malnutrition (<−2 SDS for height for age). The malnutrition risk was assessed with the nutritional risk-screening tool STRONGkids. Subjective health status was assessed with EQ-5D. Results: Overall, 16 % of the children had overall malnutrition: 3 % acute and 13 % chronic malnutrition. Nurses reported ‘some/severe problems’ on the health status dimensions mobility (15 %), self-care (17 %), usual activities (19 %), pain/discomfort (22 %), and anxiety/depression (22 %) in chronically ill children. Their mean visual analogue scale score (VAS) was 73.0 (SD 11.1). Malnutrition, medication usage, and younger age explained 38 % of the variance of the VAS score. Conclusions: The presence of overall malnutrition in chronically ill children attending special schools was associated with lower subjective health status, especially in younger children and in those with chronic medication usage. Therefore, it is important to develop and use profile-screening tools to identify these children.

Background: The state-of-the-art nutrition used for critically ill children is based essentially on expert opinion and extrapolations from adult studies or on studies in non-critically ill children. In critically ill adults, withholding parenteral nutrition (PN) during the first week in ICU improved outcome, as compared with early supplementation of insufficient enteral nutrition (EN) with PN. We hypothesized that withholding PN in children early during critical illness reduces the incidence of new infections and accelerates recovery. Methods/Design: The Pediatric Early versus Late Parenteral Nutrition in Intensive Care Unit (PEPaNIC) study is an investigator-initiated, international, multicenter, randomized controlled trial (RCT) in three tertiary referral pediatric intensive care units (PICUs) in three countries on two continents. This study compares early versus late initiation of PN when EN fails to reach preset caloric targets in critically ill children. In the early-PN (control, standard of care) group, PN comprising glucose, lipids and amino acids is administered within the first days to reach the caloric target. In the late-PN (intervention) group, PN completing EN is only initiated beyond PICU-day 7, when EN fails. For both study groups, an early EN protocol is applied and micronutrients are administered intravenously. The primary assessor-blinded outcome measures are the incidence of new infections during PICU-stay and the duration of intensive care dependency. The sample size (n = 1,440, 720 per arm) was determined in order to detect a 5% absolute reduction in PICU infections, with at least 80% 1-tailed power (70% 2-tailed) and an alpha error rate of 5%. Based on the actual incidence of new PICU infections in the control group, the required sample size was confirmed at the time of an a priori- planned interim-analysis focusing on the incidence of new infections in the control group only. Discussion: Clinical evidence in favor of early administration of PN

Background & aims: Accurate assessment of resting energy expenditure (REE) and metabolic state is essential to optimize nutrient intake in critically ill patients. We aimed to examine the accuracy of a simplified equation for predicting REE using carbon dioxide elimination (VCO2) values. Methods: We conducted a two-center study of metabolic data from mechanically ventilated children less than 18 years of age. Mean respiratory quotient (RQ) from the derivation set (n=72 subjects) was used to modify the Weir equation to obtain a simplified equation based on VCO2 measurements alone. This equation was then applied to subjects at the second institution (validation dataset, n=94) to predict resting energy expenditure. Bland-Altman analysis was used to assess the agreement betw

Background: Arginine is considered an essential amino acid during critical illness in children, and supplementation of arginine has been proposed to improve arginine availability to facilitate nitric oxide (NO) synthesis. Protein-energy-enriched enteral formulas (PE-formulas) can improve nutrient intake and promote anabolism in critically ill infants. However, the effect of increased protein and energy intake on arginine metabolism is not known Objective: We investigated the effect of a PE-formula compared with that of a standard infant formula (S-formula) on arginine kinetics in critically ill infants Design: A 2-h stable-isotope tracer protocol was conducted in 2 groups of critically ill infants with respiratory failure because of viral bronchiolitis, who received either a PE-formula (n = 8) or S-formula (n = 10) in a randomized, blinded, controlled setting. Data were reported as means 6 SDs Results: The intake of a PE-formula in critically ill infants (aged 0.23 6 0.14 y) resulted in an increased arginine appearance (PEformula: 248 6 114 mmol $ kg21 $ h21; S-formula: 130 6 53 mmol $ kg21 $ h21; P = 0.012) and NO synthesis (PE-formula: 1.92 6 0.99 mmol $ kg21 $ h21; S-formula: 0.84 6 0.36 mmol $ kg21 $ h21; P = 0.003), whereas citrulline production and plasma arginine concentrations were unaffected Conclusion: In critically ill infants with respiratory failure because of viral bronchiolitis, the intake of a PE-formula increases arginine availability by increasing arginine appearance, which leads to increased NO synthesis, independent of plasma arginine concentrations.

Background: A large single-center randomized trial showed that treating hyperglycemia in critically ill children improved outcome, despite an increased incidence of hypoglycemia, especially in infants. Objectives: We evaluated the efficacy and incidence of hypoglycemia using a tight glucose protocol in critically ill term neonates. Methods: Term hyperglycemic (>8 mmol·l -1; >144 mg·dl -1) neonates treated with a tight glucose protocol during a 3.5-year period i

This study aimed to evaluate the time course of perioperative blood glucose levels of children undergoing cardiac surgery for congenital heart disease in relation to endogenous stress hormones, inflammatory mediators, and exogenous factors such as caloric intake and glucocorticoid use. The study prospectively included 49 children undergoing cardiac surgery. Blood glucose levels, hormonal alterations, and inflammatory responses were investigated before and at the end of surgery, then 12 and 24 h afterward. In general, blood glucose levels were highest at the end of surgery. Hyperglycemia, defined as a glucose level higher than 8.3 mmol/l (>150 mg/dl) was present in 52% of the children at the end of surgery. Spontaneous normalization of blood glucose occurred in 94% of the children within 24 h. During surgery, glucocorticoids were administered to 65% of the children, and this was the main factor associated with hyperglycemia at the end of surgery (determined by univariate analysis of variance). Hyperglycemia disappeared spontaneously without insulin therapy after 12-24 h for the majority of the children. Postoperative morbidity was low in the study group, so the presumed positive effects of glucocorticoids seemed to outweigh the adverse effects of iatrogenic hyperglycemia.

Introduction: The purpose of this study was to evaluate associations between long-term physical and psychological outcome variables in patients who survived meningococcal septic shock (MSS) in childhood.Methods: The study population was made up of all MSS patients requiring intensive care treatment between 1988 and 2001.Results: A total of 120 patients visited the follow-up clinic (age at paediatric intensive care unit (PICU) admission 3.1 years; follow-up interval 9.8 years; age at follow-up 14.5 years (all medians)). Four major outcomes were considered: 1) major physical sequelae (defined as major scars and/or orthopaedic sequelae) (29/120), 2) mild neurological impairments (39/120), 3) problem behaviour (defined as a total score above the 90thpercentile of the reference groups on questionnaires to screen for psychopathology) (16/114) and 4) total intelligence quotient < 85 (18/115). No differences were found between patients with major physical sequelae and patients without major physical sequelae as to the presence of problem behaviour or total IQ < 85. Also, no differences were found between patients with mild neurological impairments and patients without as to the presence of problem behaviour or total IQ < 85. Finally, no differences were found between patients with major physical sequelae and patients without as to the presence of mild neurological sequelae. Less favourable scores on behavioural and emotional problems were significantly associated with poorer health-related quality of life (HR-QoL). HR-QoL scores were to a lesser amount predicted by severity of illness at time of PICU admission or by adverse physical outcome.Conclusions: Long-term adverse physical and psychological outcomes in survivors of MSS did not seem to be associated. Poorer HR-QoL was mainly predicted by problem behaviour.

Background: The mortality for children with prolonged stay in pediatric intensive care units (PICU) is much higher than overall mortality. The incidence of withdrawal or limitation of therapy in this group is unknown. Purpose: To assess mortality and characteristics of children admitted for ≥28 days to our ICU, and to describe the extent to which limitations of care were involved in the terminal phase preceding death. Methods: For the period 2003 to 2005 clinical data were collected retrospectively for children with prolonged stay (defined as ≥28 days) in a medical/surgical PICU of a university children's hospital. Results: In the PICU, 4.4% of the children (116/2,607, equal gender, mean age 29 days) had a prolonged stay. Median (range) stay was 56 (28-546) days. These children accounted for 3% of total admissions and occupied 63% of total admission days. Mortality during admission for this group was five

SIDS and ALTE are different entities that somehow show some similarities. Both constitute heterogeneous conditions. The Netherlands is a low-incidence country for SIDS. To study whether the same would hold for ALTE, we studied the incidence, etiology, and current treatment of ALTE in The Netherlands. Using the Dutch Pediatric Surveillance Unit, pediatricians working in second- and third-level hospitals in the Netherlands were asked to report any case of ALTE presented in their hospital from January 2002 to January 2003. A questionnaire was subsequently sent to collect personal data, data on pregnancy and birth, condition preceding the incident, the incident itself, condition after the incident, investigations performed, monitoring or treatment initiated during admission, any diagnosis made at discharge, and treatment or parental support offered after discharge. A total of 115 cases of ALTE were reported, of which 110 questionnaires were filled in and returned (response rate 97%). Based on the national birth rate of 200,000, the incidence of ALTE amounted 0.58/1,000 live born infants. No deaths occurred. Clinical diagnoses could be assessed in 58.2%. Most frequent diagnoses were (percentages of the total of 110 cases) gastro-esophageal reflux and respiratory tract infection (37.3% and 8.2%, respectively); main symptoms were change of color and muscle tone, choking, and gagging. The differences in diagnoses are heterogeneous. In 34%, parents shook their infants, which is alarmingly high. Pre- and postmature infants were overrepresented in this survey (29.5% and 8.2%, respectively). Ten percent had recurrent ALTE. In total, 15.5% of the infants were discharged with a home monitor. In conclusion, ALTE has a low incidence in second- and third-level hospitals in the Netherlands. Parents should be systematically informed about the possible devastating effects of shaking an infant. Careful history taking and targeted additional investigations are of utmost importance.

Context: The annual death rate of Prader-Willi syndrome (PWS) patients is very high (3%). Many of these deaths are sudden and unexplained. Objective: Because most deaths occur during moderate infections and PWS patients suffer from various hypothalamic insufficiencies, we investigated whether PWS patients suffer from central adrenal insufficiency (CAI) during stressful conditions. Design: Overnight single-dose metyrapone tests were performed. Metyrapone (30 mg/kg) was administered at 2330 h. At 0400, 0600, and 0730 h, ACTH, 11-deoxycortisol, cortisol, and glucose levels were measured. Diurnal salivary cortisol profiles were assessedona different day at wake-up, 30 min after wake-up, at 1400 h, and at 2000 h. Setting: The study was conducted in a pediatric intensive care unit. Patients: Patients included 25 randomly selected PWS patients. Main Outcome Measure: Patients were considered as having CAI when ACTH levels remained below 33 pmol/liter at 0730 h. Results: Median (interquartile range) age was 9.7 (6.8-13.6) yr. Fifteen patients (60%) had an insufficient ACTH response (CAI, P < 0.001). There was no significant difference in age, gender, genotype, and body mass index SD score between patients with CAI and those without. Morning salivary cortisol levels and diurnal profiles were normal in all children, suggesting that CAI becomes apparent only during stressful conditions. Conclusions: Strikingly, 60% of our PWS patients had CAI

Objective: To investigate the effect of one single bolus of etomidate used for intubation on adrenal function in children with meningococcal sepsis. Design: Retrospective study conducted between 1997 and 2004. Setting: University-affiliated paediatric intensive care unit (PICU). Patients and participants: Sixty children admitted to the PICU with meningococcal sepsis, not treated with steroids. Interventions: Adrenal hormone concentrations were determined as soon as possible after PICU admission, and after 12 h and 24 h. To assess disease severity, PRISM score and selected laboratory parameters were determined. Measurements and main results: On admission, before blood was drawn, 23 children had been intubated with etomidate, 8 without etomidate and 29 were not intubated. Children who were intubated had significantly higher disease severity parameters than those not intubated, whereas none of these parameters significantly differed between children intubated with or without etomidate. Children who received etomidate had significantly lower cortisol, higher ACTH and higher 11-deoxycortisol levels than those who did not receive etomidate. Arterial glucose levels were significantly lower in children who were intubated with etomidate than in non-intubated children. When children were intubated with etomidate, cortisol levels were 3.2 times lower for comparable 11-deoxycortisol levels. Eight children died, seven of whom had received etomidate. Within 24 h cortisol/ACTH and cortisol/11-deoxycortisol ratios increased significantly in children who received etomidate, but not in children who did not, resulting in comparable cortisol/ACTH ratios with stil

Background: To gain insight into factors that might affect results of future case-control studies, we performed an analysis of children with sepsis and purpura admitted to the paediatric intensive care unit (PICU) of Erasmus MC-Sophia Children's Hospital (Rotterdam, The Netherlands). Methods: Between 1988 and 2006, all 287 children consecutively admitted with sepsis and purpura were included in various sepsis studies. Data regarding age, gender, ethnicity, serogroup of Neisseria meningitidis, severity, therapy, and survival were collected prospectively. These data were pooled into one database and analyzed retrospectively. Results: The case fatality rate (CFR) from sepsis and purpura was 15.7%. During the study period, survival improved significantly. Younger age was significantly associated with more severe disease and a higher CFR. Children under the median age of 3.0 years had an increased risk of case fatality (odds ratio 4.3, 95% confidence interval 2.1 to 9.2; p < 0.001). Gender was not associated with CFR. However, males did have higher Paediatric Risk of Mortality scores, fewer PICU-free days, and more presence of shock. The course of sepsis and purpura was not related to ethnic origin. A causative organism was isolated in 84.3% of cases. N. meningitidis was the major organism (97.5%). Although N. meningitidis serogroup B was observed more often in younger children, serogroups were not associated with severity or survival. During the study period, the use of inotropic agents and corticosteroids changed substantially (less dopamine and more dobutamine, norepineph

Objective: We determined incidences of underfeeding and overfeeding in children who were admitted to a multidisciplinary tertiary pediatric intensive care and evaluated the usefulness of the respiratory quotient (RQ) obtained from indirect calorimetry to assess feeding adequacy. Methods: Children 18 y and younger who fulfilled the criteria for indirect calorimetry entered our prospective, observational study and were studied until day 14. Actual energy intake was recorded, compared with required energy intake (measured energy expenditure plus 10%), and classified as underfeeding (<90% of required), adequate feeding (90% to 110% of required), or

Septic shock is the most severe clinical manifestation of meningococcal disease and is predominantly seen in children under 5 yr of age. Very limited research has been performed to elucidate the alterations of the GH/IGF-I axis in critically ill children. We evaluated the GH/IGF-I axis and the levels of IGF-binding proteins (IGFBPs)

To get insight in the endocrine and metabolic responses in children with meningococcal sepsis 26 children were studied the first 48 h after admission. On admission there was a significant difference in cortisol/ACTH levels between nonsurvivors (n = 8) and survivors (n = 18). Nonsurvivors showed an inadequate cortisol stress response in combination to very high ACTH levels, whereas survivors showed a normal stress response with significantly higher cortisol levels (0.62 vs. 0.89 micromol/L) in combination with moderately increased ACTH levels (1234 vs. 231 ng/L). Furthermore, there was a significant difference between nonsurvivors and survivors regarding pediatric risk of mortality score (31 vs. 17), TSH (0.97 vs. 0.29 mE/L), T3 (0.53 vs. 0.38 nmol/L), reverse T3 (rT3) (0.75 vs. 1.44 nmol/L), C-reactive protein (34 vs. 78 mg/L), nonesterified fatty acids (0.32 vs. 0.95 mmol/L), and lactate (7.3 vs. 3.2 mmol/L). In those who survived, the most important

Part 1 provides the aims of the studies (chapter 1) and a general overview and discussion of the current literature of metabolic, endocrine and nutritional aspects in critically ill children (chapter 2). In Part 2 the clinical use of an indirect calorimeter is tested and validated for use in critically ill mechanically ventilated children. In chapter 3 a new indirect calorimeter is tested in a laboratory setting using a ventilated lung model and a butane burner system to determine the accuracy of the calorimeter for use in young infants and children. The influence of low tidal volumes and low levels of oxygen consumption and carbon dioxide production with different levels of inspired oxygen concentrations is investigated. [n chapter 4 it is questioned how accurately total daily energy expenditure of mechanically ventilated pediatric patients can be estimated from measurement periods . of less than 24 hours. In addition, the influence of tube leakage on energy expenditure measurements is determined. In Part 3 the clinical use of the indirect calorimeter is tested in mechanically ventilated children. In chapter 5 using indirect calorimetry the following issues were studied: 1 What are the actual energy needs are for critically ill mechanically ventilated chil

Part 1 provides the aims of the studies (chapter 1) and a general overview and discussion of the current literature of metabolic, endocrine and nutritional aspects in critically ill children (chapter 2). In Part 2 the clinical use of an indirect calorimeter is tested and validated for use in critically ill mechanically ventilated children. In chapter 3 a new indirect calorimeter is tested in a laboratory setting using a ventilated lung model and a butane burner system to determine the accuracy of the calorimeter for use in young infants and children. The influence of low tidal volumes and low levels of oxygen consumption and carbon dioxide production with different levels of inspired oxygen concentrations is investigated. [n chapter 4 it is questioned how accurately total daily energy expenditure of mechanically ventilated pediatric patients can be estimated from measurement periods . of less than 24 hours. In addition, the influence of tube leakage on energy expenditure measurements is determined. In Part 3 the clinical use of the indirect calorimeter is tested in mechanically ventilated children. In chapter 5 using indirect calorimetry the following issues were studied: 1 What are the actual energy needs are for critically ill mechanically ventilated chil

To assess the relationship between capillary leakage and inflammatory mediators during sepsis, blood samples were taken on hospital admission, as well as 24 and 72 h later, from 52 children (median age, 3.3 years) with severe meningococcal sepsis, of whom 38 survived and 14 died. Parameters related to cytokines (interleukin 6 [IL-6] IL-8, plasma phospholipase A2, and C-reactive protein [CRP]), to neutrophil degranulation (elastase and lactoferrin), to complement activation (C3a, C3b/c, C4b/c, and C3- and C4-CRP complexes), and to complement regulation (functional and inactivated C1 inhibitor and C4BP) were determined. The degree of capillary leakage was derived from the amount of plasma infused and the severity of disease by assessing the pediatric risk of mortality (PRISM) score. Levels of IL-6, IL-8, C3b/c, C3-CRP complexes, and C4BP on admission, adjusted for the duration of skin lesions, were significantly different in survivors and nonsurvivors (C3b/c levels were on average 2.2 times higher in nonsurvivors, and C3-CRP levels were 1.9 times higher in survivors). Mortality was independently related to the levels of C3b/c and C3-CRP complexes. In agreement with this, levels of complement activation products correlated well with the PRISM score or capillary leakage. Thus, these data show that complement activation in patients with severe meningococcal sepsis is associated with a poor outcome and a more severe disease course. Further studies should reveal whether complement activation may be a target for therapeutical intervent