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Summary Although evidence for the superiority of continuous feeding over intermittent feeding is lacking, in most paediatric intensive care units (PICU) artificial feeding is administered continuously for 24 h per day. Until now, studies in PICU on intermittent feeding have primarily focused on surrogate endpoints such as nutritional intake and gastro-intestinal complaints and none have studied the effects of an extended fasting period. Intermittent fasting has been proven to have many health benefits in both animal and human studies. The observed beneficial effects are based on multiple metabolic and endocrine changes that are presumed crucial in critical illness as well. One key element is the transition to ketone body metabolism, which, among others, contributes to the stimulation of several cellular pathways involved in stress resistance (neuro)plasticity and mitochondrial biogenesis, and might help preserve brain function. Secondly, the fasting state stimulates the activation of autophagy, a process that is crucial for cellular function and integrity. Of the different intermittent fasting strategies investigated, time-restricted feeding with a daily extended fasting period appears most feasible in the PICU. Moreover, planning the fasting period overnight could help maintain the circadian rhythm. Although not investigated, such an overnight intermittent fasting strategy might improve the metabolic profile, feeding tolerance and perhaps even have beneficial effects on tissue repair, reperfusion injury, muscle weakness, and the immune response. Future studies should investigate practical implications in critically ill children and the optimal duration of the fasting periods, which might be affected by the severity of illness and by age.

Objectives: To explore enteral feeding practices and the achievement of energy targets in children on noninvasive respiratory support, in four European PICUs. Design: A four-center retrospective cohort study. Setting: Four PICUs: Bristol, United Kingdom; Lyon, France; Madrid, Spain; and Rotterdam, The Netherlands. Patients: Children in PICU who required acute noninvasive respiratory support in the first 7 days. The primary outcome was achievement of standardized kcal/goal. Interventions: None. Measurements and Main Results: A total of 325 children were included (Bristol 104; Lyon 99; Madrid 72; and Rotterdam 50). The median (interquartile range) age and weight were 3 months (1-16 mo) and 5 kg (4-10 mo), respectively, with 66% admitted with respiratory failure. There were large between-center variations in practices. Overall, 190/325 (58.5%) received noninvasive respiratory support in order to prevent intubation and 41.5% after extubation. The main modes of noninvasive respiratory support used were high-flow nasal cannula 43.6%, bilevel positive airway pressure 33.2%, and continuous positive airway pressure 21.2%. Most children (77.8%) were fed gastrically (48.4% continuously) and the median time to the first feed after noninvasive respiratory support initiation was 4 hours (interquartile range, 1-9 hr). The median percentage of time a child was nil per oral while on noninvasive respiratory support was 4 hours (2-13 hr). Overall, children received a median of 56% (25-82%) of their energy goals compared with a standardized target of 0.85 of the recommended dietary allowance. Patients receiving step-up noninvasive respiratory support (p = < 0.001), those on bilevel positive airway pressure or continuous positive airway pressure (compared with high-flow nasal cannula) (p = < 0.001), and those on continuous feeds (p = < 0.001) achieved significantly more of their kcal goal. Gastrointestinal complications varied from 4.8 - 20%, with the most common reported being vomiting in 54/325 (16.6%), other complications occurred in 40/325 (12.3%) children, but pulmonary aspiration was rare 5/325 (1.5%). Conclusions: Children on noninvasive respiratory support tolerated feeding well, with relatively few complications, but prospective trials are now required to determine the optimal timing and feeding method for these children.

OBJECTIVES: In children, coronavirus disease 2019 is usually mild but can develop severe hypoxemic failure or a severe multisystem inflammatory syndrome, the latter considered to be a postinfectious syndrome, with cardiac involvement alone or together with a toxic shock like-presentation. Given the novelty of severe acute respiratory syndrome coronavirus 2, the causative agent of the recent coronavirus disease 2019 pandemic, little is known about the pathophysiology and phenotypic expressions of this new infectious disease nor the optimal treatment approach.STUDY SELECTION: From inception to July 10, 2020, repeated PubMed and open Web searches have been done by the scientific section collaborative group members of the European Society of Pediatric and Neonatal Intensive Care.DATA EXTRACTION: There is little in the way of clinical research in children affected by coronavirus disease 2019, apart from descriptive data and epidemiology.DATA SYNTHESIS: Even though basic treatment and organ support considerations seem not to differ much from other critical illness, such as pediatric septic shock and multiple organ failure, seen in PICUs, some specific issues must be considered when caring for children with severe coronavirus disease 2019 disease.CONCLUSIONS: In this clinical guidance article, we review the current clinical knowledge of coronavirus disease 2019 disease in critically ill children and discuss some specific treatment concepts based mainly on expert opinion based on limited experience and the lack of any completed controlled trials in children at this time.

Summary Background & aims Clinicians and researchers often use feeding intolerance (FI) as main cause for insufficient enteral nutrition (EN). However, there is no uniform definition for FI. A uniform definition is essential for future studies focusing on predictors and outcomes of FI and enteral nutrition. A systematic review was performed to investigate the definitions, prevalence, predictors and outcomes of FI in critically ill children. Methods The databases Medline, Embase, Cochrane CENTRAL, Web of Science were searched. Inclusion criteria were interventional, observational or case-control studies (>10 patients) in which a definition of FI was reported in critically ill children (0–21 years). Results FI was defined in 31 unique studies performed in 2973 critically ill children. FI was most commonly defined as presence of gastrointestinal (GI) symptoms and/or large gastric residual volume (GRV) (n = 21), followed by discontinuation of EN due to GI symptoms (n = 7) and inadequate delivery of EN (n = 3). Median prevalence of FI was 20.0% [IQR 7.4%–33.0%]. Large GRV, abdominal distention, diarrhoea and vomiting/emesis, were the predominantly reported GI symptoms to define FI. FI was associated with severity of illness, mortality and nosocomial infections. Conclusions Feeding intolerance is inconsistently defined in the current literature, but appears to be a prevalent concern in critically ill children. FI is most frequently defined by the presence of GI symptoms. A standardized definition is needed for both clinical and research purpose to determine the consequences of FI in relation to short-term and long-term outcomes. The new proposed definition for FI entails the inability to achieve enteral nutrition target intakes in combination with the presence of GI symptoms indicating GI dysfunction. Protocol registration PROSPERO registration number: CRD42018092967. Registered on 07 June 2018.

Objective\ud To explore the perceived barriers by pediatric intensive care healthcare professionals (nurses, dieticians and physicians) in delivering enteral nutrition (EN) to critically ill children across the world.\ud Design\ud Cross-sectional international online survey adapted for use in pediatric settings.\ud Setting and subjects\ud Pediatric Intensive Care physicians, nurses and dietitians across the world\ud Interventions\ud The 20-item adult intensive care ‘Barriers to delivery of enteral nutrition’ survey was modified for pediatric settings, tested and translated into ten languages. The survey was distributed online to pediatric intensive care nurses, physicians and dieticians via professional networks in March – June 2019. Professionals were asked to rate each item indicating the degree to which they perceived it hinders the provision of EN in their pediatric intensive care unit (PICUs) with a 7-point Likert scale from 0 ‘‘not at all a barrier’’ to 6 ‘‘an extreme amount’’. \ud Measurement and Main Results\ud 920 pediatric intensive care professionals responded from 57 countries; 477/920 (52%) nurses, 407/920 (44%) physicians and 36/920 (4%) dieticians. Sixty-two percent had more than five years PICU experience and 49% worked in general PICUs, with 35% working in combined cardiac and general PICUs. The top three perceived barriers across all professional groups were: (1) enteral feeds being withheld in advance of procedures or operating department visits, (2) none or not enough dietitian coverage on weekends or evenings, (3) not enough time dedicated to education and training on how to optimally feed patients.\ud Conclusions\ud This is the largest survey that has explored perceived barriers to the delivery of enteral nutrition across the world by physicians, nurses and dietitians. There were some similarities with adult intensive care barriers. In all professional groups, the perception of barriers reduced with years PICU experience. This survey highlights implications for PICU practice around more focussed nutrition education for all PICU professional groups.

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 (p ≤ 0.0004). Total and free cortisol were only elevated upon PICU-admission (p ≤ 0.0003) and thereafter became normal despite low binding-proteins (p

There are reports of children COVID-19 or COVID-19 like symptoms with hyperinflammatory multisystem syndrome, ARDS, gastrointestinal and atypical Kawasaki disease presenting to PICU worldwide temporally associated with COVID-19, for which there are important nutrition support considerations. As a result, the European Society of Pediatric and Neonatal Intensive Care - Metabolism, Endocrine and Nutrition group (ESPNIC-MEN) and paediatric nutritionists working in PICUs are being consulted regarding nutrition management of critically ill children with COVID-19 or COVID-19 like symptoms. Therefore, the aim of this short report is to provide a summary of nutrition support recommendations for critically ill children with COVID-19. They are based on the ESPNIC-MEN section recommendations published in January 2020 and surviving sepsis recommendations from February 2020.

Background: Immobility during hospital stay is associated with muscle weakness, delirium, and delayed neurocognitive recovery. Early mobilization of critically ill adults improves their physical functioning and shortens the duration of mechanical ventilation. However, comparable research in children is lacking. Aims: To determine the effects of the implementation of an early mobilization (EM) program on mobility activities for critically ill children and to explore barriers and facilitators and clinical outcomes before and after implementation. Study design: A prospective single-centre before-and-after study. Methods: This study was conducted in a PICU of a large tertiary hospital. Children aged from 3 months to 18 years, with an expected stay of ≥3 days were eligible to participate. In the “before” phase, participants received usual care; in the “after” phase we implemented a multicomponent, multidisciplinary EM protocol. The primary outcome was a change in the process outcome “mobilization activities”. Secondary outcomes were PICU staff opinions on mobilization (survey), safety, process measures, involvement of parents and physical therapist, and clinical outcomes (sedative use and prevalence of delirium). Results: A total of 113 children were included; 55 before and 58 after, with a median age of 31 months (IQR: 10–103) and 35 months (IQR: 7–152), respectively. The number of mobilization activities (per patient per day) had significantly increased from 5 (IQR: 2–7) to 6 (IQR: 4–8) (U = 272185.0; p 2 = 6.48; p =.011). In both phases, no mobilization-related adverse events were documented. The survey showed that PICU staff found EM of critically ill children useful and feasible. In the after phase, PICU staff rated the perceived benefit of the support of the physical therapist during mobilization activities significantly higher than in the before phase (X2 = 34.80; p

Graphical abstract, Highlights • Exposure of critically ill children to DEHP in the PICU decreased over the years. • Reduced DEHP exposure in the PICU did not result in improved long-term attention. • Whether alternative plasticizers are neurodevelopmentally safe remains unclear., Background Children who have been critically ill face long-term developmental impairments. Iatrogenic exposure to di(2-ethylhexyl)phthalate (DEHP), a plasticizer leaching from plastic indwelling medical devices used in the pediatric intensive care unit (PICU), has been associated with the pronounced attention deficit observed in children 4 years after critical illness. As concerns about DEHP toxicity increased, governmental authorities urged the phase out of DEHP in indwelling medical devices and replacement with alternative plasticizers. We hypothesized that exposure to DEHP decreased over the years, attenuating the pronounced long-term attention deficit of these vulnerable children. Methods We compared plasma concentrations of 3 oxidative DEHP metabolites (5cx-MEPP, 5OH-MEHP, 5oxo-MEHP) on the last PICU day in 216 patients who participated in the Tight Glucose Control study (2004–2007) and 334 patients who participated in the PEPaNIC study (2012–2015) and survived PICU stay. Corresponding minimal exposures to these metabolites (plasma concentration multiplied with number of days in PICU) were also evaluated. In patients with 4-year follow-up data, we compared measures of attention (standardized reaction times and consistency). Comparisons were performed with univariable analyses and multivariable linear regression analyses adjusted for baseline risk factors. Results In the PEPaNIC patients, last PICU day plasma concentrations of 5cx-MEPP, 5OH-MEHP, 5oxo-MEHP and their sum, and corresponding minimal exposures, were reduced to 17–69% of those in the Tight Glucose Control study (p

Background The use of extracorporeal membrane oxygenation (ECMO) in pediatric patients with underlying malignancies remains controversial. However, in an era in which the survival rates for children with malignancies have increased significantly and several recent reports have demonstrated effective ECMO use in children with cancer, we aimed to estimate the outcome and complications of ECMO treatment in these children. Methods We searched MEDLINE, Embase and CINAHL databases for studies on the use ECMO in pediatric patients with an underlying malignancy from inception to September 2020. This review was conducted in adherence to Preferred Reporting Items for Systematic Review and Meta-Analysis statement. Study eligibility was independently assessed by two authors and disagreements resolved by a third author. Included studies were evaluated for quality using the Newcastle–Ottawa Scale (NOS). Random effects meta-analyses (DerSimonian and Laird) were performed. The primary outcomes were mortality during ECMO or hospital mortality. Results Thirteen retrospective, observational cohort studies were included, most of moderate quality (625 patients). The commonest indication for ECMO was severe respiratory failure (92%). Pooled mortality during ECMO was 55% (95% confidence interval [CI], 47–63%) and pooled hospital mortality was 60% (95% CI 54–67%). Although heterogeneity among the included studies was low, confidence intervals were large. In addition, the majority of the data were derived from registries with overlapping patients which were excluded for the meta-analyses to prevent resampling of the same participants across the included studies. Finally, there was a lack of consistent complications reporting among the studies. Conclusion Significantly higher mortalities than in general PICU patients was reported with the use of ECMO in children with malignancies. Although these results need to be interpreted with caution due to the lack of granular data, they suggest that ECMO appears to represents a viable rescue option for selected patients with underlying malignancies. There is an urgent need for additional data to define patients for whom ECMO may provide benefit or harm.

Background The PEPaNIC multicenter randomized controlled trial (RCT) has shown that early administration of supplemental parenteral nutrition (early-PN) as compared with withholding PN for 1 week (late-PN) induced long-term internalizing, externalizing and total emotional/behavioral problems in critically ill children, as observed 4 years later. Early-PN was further shown to alter the methylation status of 37 CpG-sites in leukocyte DNA between admission and discharge from the pediatric intensive care unit (PICU). In a preplanned subanalysis of the PEPaNIC trial, we now investigated whether the altered methylation of these CpG-sites could statistically explain the negative impact of early-PN on emotion/behavior documented 4 years after PICU admission. Results The combination of DNA methylation data and data on behavior 4 years after PICU admission was available for 403 of the 1440 patients (aged 0–17 years at PICU admission) who were included in the PEPaNIC RCT (192 early-PN and 211 late-PN patients). Mediation analyses with use of bootstrapped multivariable non-linear regression analyses adjusted for baseline risk factors revealed that the adverse alterations by early-PN in methylation of the 37 CpG-sites together statistically explained its harmful impact on internalizing, externalizing and total emotional/behavioral problems. When adding the methylation status of the 37 CpG-sites to the models, the explanatory power improved with a 1.710 to 1.851-fold increase, and the impact of the altered methylation status of the CpG-sites explained the impact of the randomization to early-PN versus late-PN. Conclusions Abnormal DNA methylation induced by the early use of PN in the PICU provides a biological basis for its long-term harmful effect on emotion/behavior of critically ill children 4 years after PICU admission. Trial Registration ClinicalTrials.gov NCT01536275, registered February 17, 2012, https://clinicaltrials.gov/ct2/show/NCT01536275.

An impaired immune response could play a role in the acquisition of secondary infections in critically ill children. Human leukocyte antigen-DR expression on monocytes (mHLA-DR) has been proposed as marker to detect immunosuppression, but its potential to predict secondary infections in critically ill children is unclear. We aimed to assess the association between mHLA-DR expression at several timepoints and the change of mHLA-DR expression over time with the acquisition of secondary infections in critically ill children. In this prospective observational study, children 18 years with fever and/or suspected infection (community-acquired or hospital-acquired) were included at a paediatric intensive care unit in the Netherlands. mHLA-DR expression was determined by flow cytometry on day 1, day 2-3 and day 4-7. The association between delta-mHLA-DR expression (difference between last and first measurement) and secondary infection was assessed by multivariable regression analysis, adjusted for age and Paediatric Logistic Organ Dysfunction-2 score. We included 104 patients at the PICU (median age 1.2 years [IQR 0.3-4.2]), of whom 28 patients (27%) developed a secondary infection. Compared to 93 healthy controls, mHLA-DR expression of critically ill children was significantly lower at all timepoints. mHLA-DR expression did not differ at any of the time points between patients with and without secondary infection. In addition, delta-mHLA-DR expression was not associated with secondary infection (aOR 1.00 [95% CI 0.96-1.04]).Conclusions: Our results confirm that infectious critically ill children have significantly lower mHLA-DR expression than controls. mHLA-DR expression was not associated with the acquisition of secondary infections. What is Known: • An impaired immune response, estimated by mHLA-DR expression, could play an essential role in the acquisition of secondary infections in critically ill children. • In critically ill children, large studies on the association of mHLA-DR expression with secondary infections are scarce. What is New: • Our study confirms that critically ill children have lower mHLA-DR expression than healthy controls. • mHLA-DR expression and change in mHLA-DR was not associated with the acquisition of secondary infection.

INTRODUCTION: Non-thyroidal illness (NTI), which occurs with fasting and in response to illness, is characterized by thyroid hormone inactivation with low triiodothyronine (T3) and high reverse T3 (rT3), followed by suppressed thyrotropin (TSH). Withholding supplemental parenteral nutrition early in pediatric critical illness (late-PN), thus accepting low/no macronutrient intake up to day 8 in the pediatric intensive care unit (PICU), accelerated recovery compared to initiating supplemental parenteral nutrition early (early-PN). Whether NTI is harmful or beneficial in pediatric critical illness and how it is affected by a macronutrient deficit remains unclear. This study investigated the prognostic value of NTI, the impact of late-PN on NTI, and whether such impact explains or counteracts the outcome benefit of late-PN in critically ill children. METHODS: This preplanned secondary analysis of the Early versus Late Parenteral Nutrition in the Pediatric Intensive Care Unit randomized controlled trial quantified serum TSH, total thyroxine (T4), T3, and rT3 concentrations in 982 patients upon PICU admission versus 64 matched healthy children and in 772 propensity score-matched early-PN and late-PN patients upon admission and at day 3 or last PICU day for shorter PICU stay. Associations between thyroid hormone concentrations upon admission and outcome, as well as impact of late-PN on NTI in relation with outcome, were assessed with univariable analyses and multivariable logistic regression, linear regression, or Cox proportional hazard analysis, adjusted for baseline risk factors. RESULTS: Upon PICU admission, critically ill children revealed lower TSH, T4, T3, and T3/rT3 and higher rT3 than healthy children (p

OBJECTIVES: The use of mortality prediction scores in clinical trials in the PICU is essential for comparing patient groups. Because of the decline in PICU mortality over the last decades, leading to a shift toward later deaths, recent trials use 90-day mortality as primary outcome for estimating mortality and survival more accurately. This study assessed and compared the performance of two frequently used PICU mortality prediction scores for prediction of PICU and 90-day mortality. DESIGN: This secondary analysis of the randomized controlled Early versus Late Parenteral Nutrition in the Pediatric Intensive Care Unit trial compared the discrimination (area under the receiver operating characteristic curve) and calibration of the Pediatric Index of Mortality 3 and the Pediatric Risk of Mortality III scores for prediction of PICU and 90-day mortality. SETTING: Three participating PICUs within academic hospitals in Belgium, the Netherlands, and Canada. PATIENTS: One-thousand four-hundred twenty-eight critically ill patients 0-17 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Although Pediatric Index of Mortality 3 only includes information available at the time of PICU admission, thus before any intervention in the PICU, it showed good discrimination (area under the receiver operating characteristic curve, 0.894; 95% CI, 0.892-0.896) and good calibration (no deviation from the diagonal, p = 0.58) for PICU mortality. Pediatric Risk of Mortality III, which involves the worst values for the evaluated variables during the first 24 hours of PICU stay, was statistically more discriminant (area under the receiver operating characteristic curve, 0.920; 95% CI, 0.918-0.921; p = 0.04) but poor in calibration (significant deviation from the diagonal; p = 0.04). Pediatric Index of Mortality 3 and Pediatric Risk of Mortality III discriminated equally well between 90-day mortality and survival (area under the receiver operating characteristic curve, 0.867; 95% CI, 0.866-0.869 and area under the receiver operating characteristic curve, 0.882; 95% CI, 0.880-0.884, respectively, p = 0.77), but Pediatric Risk of Mortality III was not well calibrated (p = 0.04), unlike Pediatric Index of Mortality 3 (p = 0.34). CONCLUSIONS: Pediatric Index of Mortality 3 performed better in calibration for predicting PICU and 90-day mortality than Pediatric Risk of Mortality III and is not influenced by intervention or PICU quality of care. Therefore, Pediatric Index of Mortality 3 seems a better choice for use in clinical trials with 90-day mortality as primary outcome. ispartof: Pediatr Crit Care Med vol:20 issue:2 pages:113-119 ispartof: location:United States status: published

BACKGROUND: The paediatric early versus late parenteral nutrition in critical illness (PEPaNIC) multicentre, randomised, controlled trial showed that, compared with early parenteral nutrition, withholding supplemental parenteral nutrition for 1 week in the paediatric intensive care unit (PICU; late parenteral nutrition) reduced infections and accelerated recovery from critical illness in children. We aimed to investigate the long-term impact on physical and neurocognitive development of early versus late parenteral nutrition. METHODS: In this preplanned 2-year follow-up study, all patients included in the PEPaNIC trial (which was done in University Hospitals Leuven, Belgium; Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, Netherlands; and Stollery Children's Hospital, Edmonton, AB, Canada) were approached for possible assessment of physical and neurocognitive development compared with healthy children who were matched for age and sex, and who had never been admitted to a neonatal ICU or a PICU. Assessed outcomes comprised anthropometric data; health status; parent-reported or caregiver-reported executive functions and emotional and behavioural problems; and tests for intelligence, visual-motor integration, alertness, motor coordination, inhibitory control, cognitive flexibility, and memory. To address partial responses among the children tested, we did multiple data imputation by chained equations before univariable and multivariable linear and logistic regression analyses adjusted for risk factors. This trial is registered with ClinicalTrials.gov, number NCT01536275. FINDINGS: At the 2-year follow-up, 60 (8%) of 717 children who received late parenteral nutrition and 63 (9%) of 723 children who received early parenteral nutrition had died (p=0·81). 68 (9%) of 717 children who received late and 91 (13%) of 723 children who received early parenteral nutrition were too disabled for neurocognitive assessment (p=0·059), and 786 patients (395 assigned to late and 391 assigned to early parenteral nutrition) consented for testing. 786 patients and 405 healthy control children underwent long-term outcome testing between Aug 4, 2014, and Jan 19, 2018, and were included in the imputation model for subsequent multivariable analyses. Late parenteral nutrition did not adversely affect anthropometric data, health status, or neurological functioning, and improved parent-reported or caregiver-reported executive functioning (late vs early parenteral nutrition β estimate -2·258, 95% CI -4·012 to -0·504; p=0·011), more specifically inhibition (-3·422, -5·171 to -1·673; p=0·0001), working memory (-2·016, -3·761 to -0·270; p=0·023), and meta-cognition (-1·957, -3·694 to -0·220; p=0·027). Externalising behavioural problems (β estimate -1·715, 95% CI -3·325 to -0·106; p=0·036) and visual-motor integration (0·468, 0·087 to 0·850; p=0·016) were also improved in the late parenteral nutrition group compared with the early parenteral nutrition group. After Bonferroni correction for multiple comparisons, the effect on inhibitory control remained significant (p=0·0001). INTERPRETATION: Withholding early parenteral nutrition for 1 week in the PICU did not negatively affect survival, anthropometrics, health status, and neurocognitive development, and improved inhibitory control 2 years after PICU admission. FUNDING: European Research Council Advanced Grant, Methusalem programme provided by the Flemish Government, Flemish Agency for Innovation by Science and Technology (IWT), Research Foundation Flanders (FWO), Sophia Children's Hospital Foundation (SSWO), Stichting Agis Zorginnovatie, Erasmus Trustfonds, and European Society for Parenteral and Enteral Nutrition (ESPEN) research grant. ispartof: Lancet Respiratory Medicine vol:7 issue:2 pages:141-153 ispartof: location:England status: published

Background: Widespread variation exists in pediatric critical care nutrition practices, largely because of the scarcity of evidence to guide best practice recommendations. Objective: The objective of this paper was to develop a list of topics to be prioritized for nutrition research in pediatric critical care in the next 10 years. Methods: A modified 3-round Delphi process was undertaken by a newly established multidisciplinary group comprising 11 international researchers in the field of pediatric critical care nutrition. Items were ranked on a 5-point Likert scale. Results: Forty-five research topics (with a mean priority score >3(0-5) were identified within the following 10 domains: the pathophysiology and impact of malnutrition in critical illness; nutrition assessment: nutrition risk assessment and biomarkers; accurate assessment of energy requirements in all phases of critical illness; the role of protein intake; the role of pharmaco-nutrition; effective and safe delivery of enteral nutrition; enteral feeding intolerance: assessment and management; the role of parenteral nutrition; the impact of nutrition status and nutrition therapies on long-termpatient outcomes; and nutrition therapies for specific populations. Ten top research topics (that received a mean score >4(0-5) were identified as the highest priority for research. Conclusions: This paper has identified important consensus-derived priorities for clinical research in pediatric critical care nutrition. Future studies should determine topics that are a priority for patients and parents. Research funding should target these priority areas and promote an international collaborative approach to research in this field, with a focus on improving relevant patient outcomes.

Purpose of review The metabolic stress response of a critically ill child evolves over time and thus it seems reasonable that nutritional requirements change during their course of illness as well. This review proposes strategies and considerations for nutritional support during the recovery phase to gain optimal (catch-up) growth with preservation of lean body mass. Recent findings Critical illness impairs nutritional status, muscle mass and function, and neurocognition, but early and high intakes of artificial nutrition during the acute phase cannot resolve this. Although (parenteral) nutrient restriction during the acute phase appears to be beneficial, persistent nutrient restriction, when the metabolic stress response resolves, has short-term and long-term detrimental consequences. Requirements increase markedly during the recovery phase to enable recovery and catch-up growth. Such large amounts of intake demand for alternate approach, especially when intestinal problems constitute a barrier for full enteral feeding. As part of the nutritional recovery, mobilization and exercise are essential to achieve catch-up growth with an optimal body composition. Summary During the recovery phase of paediatric critical illness (catch-up) growth and muscle recovery require nutritional intakes at least two times the resting energy expenditure

Background: Enteral feeding is challenging in critically ill infants. Target intakes are often not achieved as a result of fluid restriction, procedural interruptions and perceived enteral feeding intolerance. In those infants perceived to have poor feeding tolerance, the use of a peptide nutrient-energy dense enteral feed (PEF) may improve nutritional intake and minimise feeding interruptions as a result of gastrointestinal symptoms. The aim of this observational study was to characterise the use of a PEF amongst critically ill infants in two paediatric intensive care units (PICUs). Methods: Records from critically ill infants aged

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ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Venous access

ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition : Iron and trace minerals

BACKGROUND & AIMS: In the absence of methodologically sound randomized controlled trials (RCTs), current recommendations for timing and amount of enteral nutrition (EN) in critically ill children are based on observational studies. These studies have associated achievement of a higher EN intake in critically ill children with improved outcome. Inherent to the observational design of these underlying studies, thorough insight in possible confounding factors to correct for is essential. We evaluated the associations between EN intake and 1) patient and daily clinical characteristics and 2) clinical outcomes adjusted for these patient and clinical characteristics during the first week of critical illness with a multivariable mixed model. METHODS: This secondary analysis of the multicentre PEPaNIC RCT investigated a subgroup of critically ill children with daily prospectively recorded gastrointestinal symptoms and EN intake during the first week with multivariable analyses using two-part mixed effect models, including multiple testing corrections using Holm's method. These models combined a mixed-effects logistic regression for the dichotomous outcome EN versus no EN, and a linear mixed-effects model for the patients who received any EN intake. EN intake per patient was expressed as mean daily EN as % of predicted resting energy expenditure (% of EN/REE). Model 1 included 40 fixed effect baseline patient characteristics, and daily parameters of illness severity, feeding, medication and gastrointestinal symptoms. Model 2 included these patient and daily variables as well as clinical outcomes. RESULTS: Complete data were available for 690 children. EN was provided in 503 (73%) patients with a start after a median of 2 (IQR 2-3) days and a median % of EN/REE of 38.8 (IQR 14.1-79.5) over the first week. Multivariable mixed model analyses including all patients showed that admission after gastrointestinal surgery (-49%EN/REE; p = 0.002), gastric feeding (-31% EN/REE; p

Background: The European Society of Pediatric and Neonatal Intensive Care (ESPNIC) published 32 clinical recommendations\ud around supporting nutrition in critically ill children following an extensive review of the literature\ud online in January 2020. The challenge now is to engage with paediatric intensive care unit teams to implement\ud these into their practice.\ud Objective: This practical implementation guide uses a recognised implementation model to guide pediatric intensive\ud care professionals to implement these evidence-based clinical recommendations into clinical practice.\ud Results and conclusions: We use the Pronovost implementation of evidence into practice model to provide a practical\ud framework with associated documents to facilitate PICU healthcare professional's implementation of these\ud clinical recommendations into PICU practice. The paper is structured around the four steps in this model: summarising\ud the evidence, identifying local barriers to implementation, measuring performance and ensuring all patients\ud receive the intervention and useful checklists for implementation and compliance monitoring are provided,\ud in addition to tables outlining key professional roles and responsibilities around nutrition in the paediatric intensive\ud care unit.

BACKGROUND AND AIMS: Following the results of the paediatric early versus late parenteral nutrition in critical illness (PEPaNIC) multicentre, randomised, controlled trial, the new ESPGHAN/ESPEN/ESPR/CSPEN and ESPNIC guidelines recommend to consider withholding parenteral macronutrients for 1 week, while providing micronutrients, in critically ill children if enteral nutrition is insufficient. Critically ill children are suspected to be vulnerable to micronutrient deficiencies due to inadequate enteral nutrition, increased body's demands and excessive losses. Hitherto, micronutrient requirements in PICU are estimated based on recommended daily intakes for healthy children and expert opinion. We aimed to provide an overview of the current practice of micronutrient administration and practical considerations in the three participating centres of the PEPaNIC study, and compare these therapies with the recommendations in the new ESPGHAN/ESPEN/ESPR/CSPEN guidelines. METHODS: We describe the current composition and preparation of the prescribed parenteral micronutrients (consisting of vitamins, trace elements and electrolytes) in the three centres (Leuven, Rotterdam and Edmonton) that participated in the PEPaNIC RCT, and compare this per micronutrient with the ESPGHAN/ESPEN/ESPR/CSPEN guidelines recommendations. RESULTS: The three centres use a different micronutrient supplementation protocol during the first week of critical illness in children, with substantial differences regarding the amounts administered. Leuven administers commercial vitamins, trace elements and electrolytes in separate infusions both in 4 h. Rotterdam provides commercial vitamins and trace elements simultaneously via 8-h infusion and electrolytes continuously over 24 h. Lastly, Edmonton administers commercial vitamins and institutionally prepared trace elements solutions in 1 h and electrolytes on demand. Comparison with the ESPGHAN/ESPEN/ESPR/CSPEN guidelines yields in differences between the recommendations and the administered amounts, which are most substantial for vitamins. CONCLUSION: The practice of intravenous micronutrient administration differs substantially between the three PEPaNIC centres and in comparison with the current guideline recommendations. This deviation is at least partially explained by the inability to provide all recommended amounts with the currently available commercial products and by the lack of strong evidence supporting these recommendations. ispartof: Clinical nutrition ESPEN vol:42 pages:244-251 ispartof: location:England status: published

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

An impaired immune response could play a role in the acquisition of secondary infections in critically ill children. Human leukocyte antigen-DR expression on monocytes (mHLA-DR) has been proposed as marker to detect immunosuppression, but its potential to predict secondary infections in critically ill children is unclear. We aimed to assess the association between mHLA-DR expression at several timepoints and the change of mHLA-DR expression over time with the acquisition of secondary infections in critically ill children. In this prospective observational study, children Conclusions: Our results confirm that infectious critically ill children have significantly lower mHLA-DR expression than controls. mHLA-DR expression was not associated with the acquisition of secondary infections. What is Known:• An impaired immune response, estimated by mHLA-DR expression, could play an essential role in the acquisition of secondary infections in critically ill children.• In critically ill children, large studies on the association of mHLA-DR expression with secondary infections are scarce. What is New:• Our study confirms that critically ill children have lower mHLA-DR expression than healthy controls.• mHLA-DR expression and change in mHLA-DR was not associated with the acquisition of secondary infection.

The goal of nutritional support during critical illness is to provide the appropriate amount of nutrition accounting for the acute, stable and recovery phase in order to accelerate recovery and to improve short-term and long-term outcomes. Although the preferred route to provide nutritional support during paediatric critical illness is via enteral route, reaching target intakes is often difficult due to (perceived) feeding intolerance, fluid restriction, and interruptions around procedures. Because undernourishment in these children has been associated with impaired outcome, parenteral nutrition (PN) has therefore been viewed as an optimal alternative for reaching early and high nutritional targets. However, PN recommendations regarding timing, dose and composition varied widely and were based on studies using intermediate or surrogate endpoints and observational studies. It was not until the paediatric early versus late PN in critically ill children (PEPaNIC) randomized controlled trial (RCT) that the advice to reach high and early macronutrient goals via PN was challenged. The PEPaNIC study showed that omitting supplemental PN during the first week of paediatric intensive care unit (PICU) admission as compared with early initiation of PN (

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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 P P 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 P = 0.0002) and on time to live PICU discharge (P = 0.004). Further adjustment for regulators of ketogenesis did not alter these findings. Conclusion Withholding early-PN in critically ill children significantly increased plasma 3HB, a direct effect that statistically mediated an important part of its outcome benefit.

Aim: Between 2012-2015, the PEPaNIC randomized controlled trial, which included 1440 critically ill infants and children, showed that withholding parenteral nutrition during the first week in the pediatric intensive care unit (PICU) (late-PN), as compared with initiating supplemental PN early (early-PN), improved PICU outcomes (1) and improved neurocognitive development assessed 2 years later (2). The latter was explained by avoiding early-PN induced adversely altered DNA-methylation of 37 CpG sites (3). As a large number of patients were younger than 1 year of age at randomization and given that assessment of most neurocognitive domains is only possible from 4 years of age onwards, we performed a 4-year follow-up to determine the impact of late-PN versus early-PN on physical, neurocognitive, and emotional/behavioral development. This pre-planned, 4-year follow-up study of the 1440 PEPaNIC patients and of 369 matched healthy children was blinded for treatment allocation (ClinicalTrials.gov-NCT01536275). Methods: Studied clinical outcomes included anthropometrics, health status, parent/caregiver-reported executive functions, and emotional/behavioral problems, and clinical tests for intelligence, visual-motor integration, alertness, motor coordination and memory. Univariable and multivariable linear and logistic regression analyses adjusted for risk factors assessed the impact of late-PN versus early-PN on the outcomes and investigated a potential mediation role of the adversely altered DNA-methylation of 37 CpG sites previously shown to be evoked by late-PN as compared with early-PN (3). Results: Overall, at 4 years follow-up, patients (356 late-PN patients, 328 early-PN patients) could be tested neurocognitively. They revealed worse anthropometric, health status, neurocognitive and emotional/behavioral developmental outcomes than the healthy control children. Outcomes of late-PN patients were never worse than those of early-PN patients. In contrast, late-PN patients had fewer internalizing (P=0.042) and externalizing problems (P=0.046), and fewer total emotional/behavioral problems (P=0.007) than early-PN patients, which were normalized by late-PN. Avoiding the early-PN induced adversely altered DNA-methylation status of the 37 CpG sites statistically explained its impact on the behavioral outcomes. Conclusion: Four years after randomization to late-PN or early-PN in the PICU, late-PN did not show harm, and was found to protect against emotional/behavioral problems, with altered DNA-methylation as a potential biological mediator hereof. These data further support de-implementation of PN-use early during critical illness in infants and children. (1) Fivez et al. N Eng J Med 2016 (2) Verstraete et al. Lancet Respir Med 2019 (3) Guiza et al. Lancet Respir Med 2020 (in press)

Background The PEPaNIC RCT, which investigated critically ill children admitted to the pediatric intensive care unit, showed that early administration of parenteral nutrition (early PN) as compared with withholding PN for 1 week (late PN) negatively affected 6 neurocognitive functions assessed 2 years later (1). However, it is theoretically possible that age at time of exposure determines whether early PN has negative or positive impact on long-term physical and cognitive development, possibly resulting in a neutral outcome for the total study population. In this secondary analysis of the PEPaNIC RCT, we investigated whether age at exposure to early PN determined its 2 years developmental impact. Methods The 786 children who were evaluated 2 years after inclusion in the PEPaNIC RCT for health status, anthropometrics, executive functioning, emotional and behavioral problems, intelligence and visual motor integration were categorized for age at randomization (0–17 years). We defined 4 ±similarly sized age groups based on previously reported timing of cerebral maturation spurts: neonates ≤28 days old (n=121), infants 29 days to Results Interaction between randomization and age group was identified for weight, development of inhibitory control, flexibility, working memory, planning and organization, metacognition, total executive functioning and internalizing and total behavioral problems. In particular among infants 29 days to Conclusion Critically ill children who were exposed to early PN at an age between 29 days and 11 months were found to be most vulnerable for neurocognitive developmental harm evoked by early administration of PN, as assessed 2 years later. 1 Verstraete et al. Lancet Respir Med 2018

Aim: Pediatric intensive care relies on plastic indwelling medical devices softened by phthalates. Phthalates leach into the circulation and concerns about toxicity were raised. Exceeding a certain threshold of di(2-ethylhexyl)phthalate (DEHP) exposure in the pediatric intensive care unit (PICU) has been associated with an attention deficit 4 years later (1). Moreover, DEHP and its metabolites have endocrine disrupting properties. Critically ill children reveal the non-thyroidal illness syndrome (2) and unexplained relatively low cortisol (3). Whether DEHP exposure in PICU has endocrine disruptive effects is unknown. We investigated whether DEHP exposure in the PICU, exceeding the previously identified “toxic” threshold for attention, is independently associated with thyroid- and HPA-axis alterations upon PICU discharge. Methods: In this preplanned secondary analysis of the PEPaNIC RCT (N=1440) (4), plasma DEHP metabolite concentrations (MEHP, 5OH-MEHP, 5cx-MEPP, 5oxo-MEHP) were quantified for all patients with a last PICU day sample (N=920). Minimal DEHP exposure was defined as the product of the total DEHP metabolite concentrations on the last PICU day and duration of PICU stay, with 0.551 µmol/L.days identified as “toxic” threshold (1). Serum TSH, total T4, total T3 and rT3 concentrations were quantified for patients with an available last day sample (N=913). For patients with a last day plasma sample and who did not receive corticosteroids (N=391), plasma ACTH, total cortisol, albumin and CBG concentrations were quantified and free cortisol calculated. Multivariable linear regression analyses, adjusted for baseline risk factors and for duration of PICU stay, assessed whether exceeding the previously determined threshold of toxic DEHP exposure was independently associated with the hormone levels on the last PICU day. Main results: Median total DEHP metabolite concentration was 0.101 (IQR 0.049 - 0.279) µmol/L on the last PICU day. Minimal DEHP exposure was 0.337 (IQR 0.161 - 0.880) µmol/l.days, and 328 patients (35.7%) exceeded the toxic threshold. Exceeding this threshold was independently associated with lower total T4 (P=0.002), total T3 (P=0.02) and total cortisol (P=0.001), and higher rT3 (P=0.01) concentrations on the last PICU day, but not with TSH, ACTH or free cortisol. Conclusion: Critically ill children had DHEP metabolites in plasma upon PICU discharge and more than a third were exposed to toxic levels. Toxic DEHP exposure was an independent contributor to the severity of the non-thyroidal illness phenotype and to lower cortisol upon PICU discharge. Future research should assess whether such endocrine-disruptive impact of DHEP exposure in the PICU plays a role in the long-term developmental legacy of critical illness in children. 1 Verstraete et al Intensive Care Med 2016 2 Jacobs et al Thyroid 2019 3 Jacobs et al Intensive Care Med 2019 4 Fivez et al N Engl J Med 2016

Introduction: In adults and children, withholding parenteral nutrition (PN) for 1 week in ICU (late PN), hereby accepting macronutrient deficit early during critical illness, as compared with supplementing insufficient enteral nutrition with PN (early PN), accelerates weaning from mechanical ventilation, reduces infections, and shortens ICU stay1,2. We hypothesized that these benefits are in part mediated by fasting-induced ketogenesis. Methods: This is a secondary analysis of the Early versus Late Parenteral Nutrition in the Pediatric ICU (PEPaNIC) RCT (N=1440)2. First, for a matched subset of 96 patients with a PICU stay of ≥5 days, daily plasma 3-hydroxybutyrate (3HB) concentrations were determined to identify the time point of maximal effect of late PN versus early PN, if any, on 3HB. Thereafter, for all patients with a plasma sample available on that “maximal effect day” (or last day for shorter stayers), plasma 3HB and insulin concentrations were quantified (N=1142). The independent association between plasma 3HB on that day and outcome was assessed by multivariable Cox proportional hazard analysis for time to live weaning from mechanical ventilation and for time to live PICU discharge and by multivariable logistic regression for incidence of new infection and PICU mortality, adjusted for randomization to late PN versus early PN and baseline risk factors (demographics, diagnosis, illness severity). In a sensitivity analysis, models were further adjusted for key regulators of ketogenesis (plasma insulin, blood glucose, corticosteroids and catecholamines) to assess whether any effect was direct or indirect. Results: In the matched cohort, late PN increased plasma 3HB as compared with early PN (P Conclusion: Withholding early PN increased plasma 3HB concentrations in critically ill children, a direct effect that mediated an important part of its beneficial impact on recovery. 1Casaer M. et al, N Engl J Med 20112Fivez T. et al, N Engl J Med 2016

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. Electronic supplementary material The online version of this article (10.1007/s00134-019-05922-5) contains supplementary material, which is available to authorized users.

BACKGROUND: Early use of parenteral nutrition in the paediatric intensive care unit (PICU) negatively affects development of executive functions, externalising behaviour, and visual-motor integration 2 years later, compared with omitting parenteral nutrition until PICU day 8 (late parenteral nutrition). The molecular basis of this finding is uncertain. We aimed to test the hypothesis that DNA methylation changes occur during critical illness and that early parenteral nutrition (or a specific macronutrient component hereof) contributes to these changes, which could explain its negative effects on neurocognitive development. METHODS: This pre-planned secondary analysis of the multicentre PEPaNIC trial (2012-18) included all patients with a last PICU day blood sample (n=825, aged 0-17 years at PICU admission) who were randomly allocated (1:1) to early parenteral nutrition or late parenteral nutrition, as compared with 352 demographically matched healthy children. Investigators were masked to treatment allocation. We used the Infinium Human MethylationEPIC BeadChip to determine the genome-wide peripheral blood leukocyte DNA methylation of 865 859 CpG sites, yielding high-quality results for 403 patients allocated to early parenteral nutrition and for 411 patients allocated to late parenteral nutrition. Applying a false discovery rate of less than 0·05, DNA methylation of patients on the last PICU day was compared with that of healthy children, after excluding all CpG sites differentially methylated upon PICU admission, because these reflected pre-admission conditions and altered leukocyte composition. We used bootstrapped multivariable linear and non-linear regression analyses to assess the effect of early parenteral nutrition versus late parenteral nutrition on illness-induced alterations in DNA methylation and to what extent differentially methylated CpG sites explained impaired neurocognitive development 2 years later. FINDINGS: During PICU stay, 159 CpG sites were methylated differently in patients admitted to the PICU than in healthy children, with mean effect sizes of 2·6% (SD 2·5) up to 21·6% (p

Purpose This study aimed to examine health-related quality of life (HRQoL) of children and their parents, 6 months after the child’s admission to the Pediatric Intensive Care Unit (PICU). Associations between parents’ reports regarding HRQoL of their child and of themselves were investigated, as well as associations between children’s baseline variables and their parent-reported HRQoL outcomes. Methods This is a secondary analysis of cross-sectional data collected in a group of children who participated in the PEPaNIC trial. Six months after discharge from the PICU, parents of critically ill children completed the Infant–Toddler Quality of Life Questionnaire (ITQOL, for age 0–3 years) or the Child Health Questionnaire-Parent Form 50 (CHQ-PF50, for age 4–18 years), which are parallel questionnaires. Parents completed the Short Form Health Survey (SF-12) regarding their own HRQoL. Results were compared with normative data. Results At 6 months’ follow-up, 86 children of the 1343 (6%) had died which resulted in 1257 eligible children. Parents of 576 surviving children (46%) completed the questionnaires. Children of responding parents had less often an acute reason for admission and differed in diagnosis compared with children of non-responders. PICU children scored lower on most ITQOL (n = 390) scales and CHQ-PF50 (n = 186) scales compared with normative data. Parents reported (n = 570) higher scores on the physical (p p p Conclusions Six months after PICU discharge, critically ill children have lower HRQoL compared with normative data. The mental component of HRQoL is impaired in parents and is associated with lower overall parent-reported HRQoL of their child.

BACKGROUND: The PEPaNIC randomised controlled trial, which recruited 1440 critically ill infants and children in 2012-15, showed that withholding parenteral nutrition for 1 week (late-parenteral nutrition), compared with early supplementation within 24 h of admission to the paediatric intensive care unit (early-parenteral nutrition), prevented infections, accelerated recovery, and improved neurocognitive development assessed 2 years later. Because several neurocognitive domains can only be thoroughly assessed from age 4 years onwards, we aimed to determine the effect of late-parenteral nutrition versus early-parenteral nutrition on physical, neurocognitive, and emotional and behavioural development 4 years after randomisation. METHODS: This is a preplanned, blinded, 4-year follow-up study of participants included in the PEPaNIC trial (done at University Hospitals Leuven, Belgium; Erasmus Medical Centre Sophia Children's Hospital, Rotterdam, Netherlands; and Stollery Children's Hospital, Edmonton, AB, Canada) and of matched healthy children. Studied outcomes were anthropometrics; health status; parent-reported or caregiver-reported executive functions, and emotional and behavioural problems; and clinical tests for intelligence, visual-motor integration, alertness, motor coordination, and memory. Through multivariable linear and logistic regression analyses, after imputation for missing values (≤30%) and adjustment for risk factors, we investigated the effect of early-parenteral nutrition versus late-parenteral nutrition. This trial is registered with ClinicalTrials.gov, NCT01536275. FINDINGS: Between March 8, 2016, and Nov 8, 2019, 684 children from the original PEPaNIC trial (356 from the late-parenteral nutrition group and 328 from the early-parenteral nutrition group) were assessed for neurocognitive development at 4-years follow-up. Compared with the control group (369 healthy children), children who had critical illness had lower height (β-estimate -2·11 [95% CI -3·15 to -1·06]; p

Summary Background No evidence based recommendations for micronutrient requirements during paediatric critical illness are available, other than those arising from recommended nutrient intakes (RNI) for healthy children and expert opinion. Objectives The objective of this review is to examine the available evidence from micronutrient status in critically ill children considering studies which describe 1) micronutrient levels, 2) associations between micronutrient levels and clinical outcome, and 3) impact on clinical outcome with micronutrient supplementation during PICU admission. Design Scoping review. Eligibility criteria Any study which used a qualitative and quantitative design considering causes and consequences of micronutrient levels or micronutrient supplementation during paediatric critical illness. Sources of evidence NICE Healthcare Databases Advanced Search website (https://hdas.nice.org.uk/) was used as a tool for multiple searches, with a content analysis and charting of data extracted. Results 711 records were identified, 35 were included in the review. Studies evaluated serum micronutrient status was determined on admission day in majority of patients. A content analysis identified (n = 49) initial codes, (n = 14) sub-categories and (n = 5) overarching themes during critical illness, which were identified as: i) low levels of micronutrients, ii) causes of aberrant micronutrient levels, iii) associations between micronutrients levels and outcome, iv) supplementation of micronutrients. Conclusion During critical illness, micronutrients should be provided in sufficient amounts to meet reference nutrient intakes for age. Although, there is insufficient data to recommend routine supplementations of micronutrients at higher doses during critical illness, the ‘absence of evidence should not imply evidence of absence’, and well designed prospective studies are urgently needed to elucidate paediatric micronutrient requirements during critical illness. The absence of reliable biomarkers make it challenging to determine whether low serum levels are reflective of a true deficiency or as a result redistribution, particularly during the acute phase of critical illness. As more children continue to survive a PICU admission, particularly those with complex diseases micronutrient supplementation research should also be inclusive of the recovery phase following critical illness.

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 had been randomly assigned to early-PN or late-PN. In the early-PN group, PN was initiated within 24 h after PICU admission. In the late-PN group, PN was withheld for up to 1 week in the PICU. Parents completed the Infant Toddler Quality of Life Questionnaire (ITQOL; age 2–3 years) or the Child Health Questionnaire-Parent Form 50 (CHQ-PF50; age 4–18 years). Besides, they completed the Health Utility Index (HUI) and the Short Form Health Survey (SF-12) regarding their child’s and their own HRQoL, respectively. Results For the total age group of 786 post-PICU survivors, parents reported lower scores for almost all HRQoL scales compared to healthy children. Age-specifically, younger critically ill children (2.5 to 3 years old) scored worse for growth and development and older children (4–18 years old) scored worse for role functioning and mental health. Parents’ own mental and physical HRQoL was comparable to that of healthy control parents. No HRQoL differences were found between children in the late-PN and those in the early-PN group. Conclusions Parent-reported HRQoL of children 2 years after critical illness was impaired compared with healthy controls. In relation to their child’s HRQoL, parents reported impairments in emotions, personal time, and family activities; however, their own HRQoL was not impaired. Withholding PN in the first week during critical illness had no impact on longer-term HRQoL of the child. Trial registration Clinical trials, NCT01536275. Registered 22 February 2012

Background A genome-wide study identified de novo DNA methylation alterations in leukocytes of children at paediatric intensive care unit (PICU) discharge, offering a biological basis for their impaired long-term development. Early parenteral nutrition (early-PN) in PICU, compared with omitting PN in the first week (late-PN), explained differential methylation of 23% of the affected 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 quantified 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 differed 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 identified different 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 affected 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 differentially 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 least partially maintained or got worse with longer time in PICU. Interventions targeting aberrant DNA methylation changes should be initiated early.

Objective: The objective of this research is to study effects of a 4-week high-protein (HP) diet on energy intake, resting energy expenditure (REE), protein turnover and body composition in children with obesity. Methods: In this randomized placebo-controlled single-blind crossover study, children with obesity (n = 14; mean age: 10.1 years ± 1.2 standard deviation; body mass index–standard deviation score [BMI-SDS]: 2.8 ± 0.5) received an ad libitum HP (+50 g protein per day) or normal-protein (NP) diet for 4 weeks with a washout period of ≥2 weeks. Energy intake, REE, protein turnover, weight, BMI-SDS and body composition were measured. Results: No differences were found in energy intake or REE between HP and NP. There was an increased urea production and phenylalanine hydroxylation after HP compared with NP (p

ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Lipids