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

Rationale: Feeding intolerance (FI) is common and associated with feeding-related complications and poor clinical outcomes, but is difficult to predict in individual critically ill children. Cholecystokinin (CCK), leptin, intestinal fatty acid-binding protein (I-FABP2), and glucagon are involved in various gastrointestinal functions and might therefore be predictive for FI. This study aimed to examine the course of these gastrointestinal biomarkers and their association with FI during paediatric intensive care unit (PICU) stay.

Background & aims: Hypophosphatemia during critical illness has been associated with adverse outcome. The reintroduction of enteral or parenteral nutrition, leading to refeeding hypophosphatemia (RFH), has been presented as potential risk factor. We investigated the occurrence of early RFH, its association with clinical outcome, and the impact of early parenteral nutrition (PN) on the development of early RFH in pediatric critical illness. Methods: This is a secondary analysis of the PEPaNIC randomized controlled trial (N = 1440), which showed that withholding supplemental parenteral nutrition (PN) for 1 week (late-PN) in the pediatric intensive care unit (PICU) accelerated recovery and reduced new infections compared to early-PN (<24 h). Patients with renal replacement therapy or unavailable phosphate concentrations were excluded from this analysis. Early RFH was defined as serum/plasma phosphate <0.65 mmol/L and a drop of >0.16 mmol/L within 3 days of admission to the PICU. The association between baseline characteristics and early RFH, and the association of early RFH with clinical outcome were investigated using logistic and linear regression models, both uncorrected and corrected for possible confounders. To examine the impact of nutritional intake on phosphate concentrations, structural nested mean models with propensity score and censoring models were used. Results: A total of 1247 patients were eligible (618 early-PN, 629 late-PN). Early RFH occurred in 40 patients (3%) in total, significantly more in the early-PN group (n = 31, within-group occurrence 5%) than in the late-PN-group (n = 9, within-group occurrence 1%, p < 0.001). Patients who were older (OR 1.14 (95% CI 1.08; 1.21) per year added, p < 0.001) and who had a higher Pediatric Risk of Mortality (PIM3) score had a higher risk of developing early RFH (OR 1.36 (95% CI 1.15; 1.59) per unit added, p < 0.001), whereas patients in the late-PN group had a lower risk of early RFH (OR 0.24 (95% CI 0.10; 0.49), p < 0.001). Early RFH was significantly associated with a 56% longer PICU stay (p = 0.003) and 42% longer hospital stay (p = 0.007), but not with new infections (OR 2.01 (95% CI 0.90; 4.30), p = 0.08) or length of mechanical ventilatory support (OR 1.05 (95% CI -3.92; 6.03), p = 0.68), when adjusted for possible confounders. Increase of parenteral nutrition intake (in % kcal of predicted resting energy expenditure) decreased phosphate concentrations (c = -0.002 (95% CI -0.002; -0.001). Conclusions: Early RFH occurred in 3% of critically ill children. Patients randomized to late-PN had a lower chance of developing early RFH, which may be explained by the more gradual build-up of nutrition. As early RFH might impact recovery, it is important to closely monitor phosphate concentrations in patients, especially of those at risk for early RFH. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background & aims: Critically ill COVID-19 patients seem hypermetabolic and difficult to feed enterally, due to gastro-intestinal (GI) symptoms such as high gastric residual volumes (GRV) and diarrhea. Our aim was to describe the association of nutritional intake and GI symptoms during first 14 days of ICU admission.Methods: Observational study including critically ill adult COVID-19 patients. Data on nutritional intake [enteral nutrition (EN) or parenteral nutrition] and GI symptoms were collected during 14 days after ICU admission. Target energy and protein feeding goals were calculated conform ESPEN guidelines. GI symptoms included GRV (ml/d), vomiting, abdominal distension, and faeces (ml/d). High GRV's were classified as >= 2 times >= 150 ml/d and diarrhea as Bristol stool chart >= 6. GI symptoms were defined as mild if at least one symptom occurred and as moderate when >= 2 symptoms occurred. Acute gastroin-testinal injury (AGI) grades of III were classified as GI dysfunction and grades of IV were considered as GI failure with severe impact on distant organs. Linear mixed model analysis was performed to explore the development of nutritional intake and GI symptoms over time at day (D) 0, 4, 10, and 14.Results: One hundred and fifty patients were included [75% male; median age 64 years (IQR 54-70)]. BMI upon admission was 28 kg/m2 (IQR 25-33), of which 43% obese (BMI > 30 kg/m2). Most patients received EN during admission (98% D4; 96% D10-14). Mean energy goals increased from 87% at D4 to 93% D10-14 and protein goals (g/kg) were increasingly achieved during admission (84% D4; 93% D10-14). Presence of moderate GI symptoms decreased (10% D0; 6% D4-10; 5% D14), reversely mild GI symp-toms increased. Occurrence of GI dysfunction fluctuated (1% D0; 18% D4; 12% D10; 8% D14) and none of patients developed grade IV GI failure. Development of high GRV fluctuated (5% D0; 23% D4; 14% D10; 8% D14) and occurrence of diarrhea slightly increased during admission (5% D0; 22% D4; 25% D10; 27% D14). Linear mixed models showed only an association between AGI grades III and lower protein intake at day 10 (p = 0.020).Conclusion: Occurrence of GI symptoms was limited and seems no major barrier for EN in our group of critically COVID-19 patients. Nutritional intake was just below requirements during the first 14 days of ICU admission. The effect on nutritional status remains to be studied.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

BACKGROUND:Intermittent fasting is a time-restricted feeding strategy with proven health benefits, which is based on multiple metabolic and endocrine changes, in several patient populations and healthy participants. In the pediatric intensive care unit (PICU), artificial feeding is usually administered 24 hours a day, although solid evidence supporting this practice is lacking. This discards the potential benefits of fasting in this population. We hypothesize that intermittent nutrition with a focus on an overnight feeding interruption (intermittent fasting), as compared with 24-hour continuous nutrition, is a feasible and safe strategy, with potential benefits, for critically ill children.OBJECTIVE:The aim of the Continuous versus Intermittent Nutrition in Pediatric Intensive Care randomized controlled trial (RCT) is to investigate a strategy of intermittent nutrition with a focus on an overnight feeding interruption period versus 24-hour nutrition during the first 14 days in the PICU.METHODS:The Continuous versus Intermittent Nutrition in Pediatric Intensive Care study is an investigator-initiated RCT in a tertiary referral PICU. Critically ill children (term newborn to 18 years), expected to stay in the PICU for ≥48 hours, and dependent on artificial nutrition, are eligible for inclusion. This study will randomize critically ill children (n=140) to a continuous versus intermittent nutrition strategy. In both groups, similar daily caloric targets will be prescribed. In the continuous group (control), nutrition will be administered 24 hours a day, with a maximum interruption period of 2 hours. In the intermittent group (intervention), nutrition will be interrupted during an age-dependent overnight fasting period. The study intervention will last until admission day 14, initiation of oral intake, or discharge from the PICU, whichever comes first. The primary outcome is the difference in ketosis between the groups under the condition of noninferiority regarding caloric intake. Secondary outcomes are feeding intolerance; the proportion of severe and resistant hypoglycemic events and severe gastrointestinal complications; and additional observed effects on nutritional intake, circadian rhythm, and clinically relevant outcome measures of the intermittent feeding strategy compared with continuous nutrition.RESULTS:The study was approved by the Dutch national ethical review board in February 2020. The first patient was enrolled on May 19, 2020. By May 2022, a total of 132 patients had been included in the study. Recruitment of the last patient is expected in Q3 2022.CONCLUSIONS:Although intermittent fasting has been proven to have many health benefits in both animal and human studies, the feasibility and safety of this strategy in a PICU setting must be investigated. This RCT will help physicians gain more insight into the feasibility, safety, and potential clinical effects of intermittent feeding with overnight fasting in critically ill children.TRIAL REGISTRATION:Netherlands Trial Register NL7877; https://trialsearch.who.int/Trial2.aspx?TrialID=NL7877.INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):DERR1-10.2196/36229.

Background Many critically ill children face long-term developmental impairments. The PEPaNIC trial attributed part of the problems at the level of neurocognitive and emotional/behavioral development to early use of parenteral nutrition (early-PN) in the PICU, as compared with withholding it for 1 week (late-PN). Insight in long-term daily life physical functional capacity after critical illness is limited. Also, whether timing of initiating PN affects long-term physical function of these children remained unknown. Methods This preplanned follow-up study of the multicenter PEPaNIC randomized controlled trial subjected 521 former critically ill children (253 early-PN, 268 late-PN) to quantitative physical function tests 4 years after PICU admission in Leuven or Rotterdam, in comparison with 346 age- and sex-matched healthy children. Tests included handgrip strength measurement, timed up-and-go test, 6-min walk test, and evaluation of everyday overall physical activity with an accelerometer. We compared these functional measures for the former critically ill and healthy children and for former critically ill children randomized to late-PN versus early-PN, with multivariable linear or logistic regression analyses adjusting for risk factors. Results As compared with healthy children, former critically ill children showed less handgrip strength ( p < 0.0001), completed the timed up-and-go test more slowly ( p < 0.0001), walked a shorter distance in 6 min ( p < 0.0001) during which they experienced a larger drop in peripheral oxygen saturation ( p ≤ 0.026), showed a lower energy expenditure ( p ≤ 0.024), performed more light and less moderate physical activity ( p ≤ 0.047), and walked fewer steps per day ( p = 0.0074). Late-PN as compared with early-PN did not significantly affect these outcomes. Conclusions Four years after PICU admission, former critically ill children showed worse physical performance as compared with healthy children, without impact of timing of supplemental PN in the PICU. This study provides further support for de-implementing the early use of PN in the PICU. Trial registration ClinicalTrials.gov, NCT01536275 ; registered on February 22, 2012.

Background & aims: Different metabolic phases can be distinguished in critical illness, which influences nutritional treatment. Achieving optimal nutritional treatment during these phases in critically ill patients is challenging. COVID-19 patients seem particularly difficult to feed due to gastrointestinal problems. Our aim was to describe measured resting energy expenditure (mREE) and feeding practices and tolerance during the acute and late phases of critical illness in COVID-19 patients. Methods: Observational study including critically ill mechanically ventilated adult COVID-19 patients. Indirect calorimetry (Q-NRGthorn, Cosmed) was used to determine mREE during the acute (day 0-7) and late phase (>day 7) of critical illness. Data on nutritional intake, feeding tolerance and urinary nitrogen loss were collected simultaneously. A paired sample t-test was performed for mREE in both phases. Results: We enrolled 21 patients with a median age of 59 years [44-66], 67% male and median BMI of 31.5 kg/m(2) [25.7-37.8]. Patients were predominantly fed with EN in both phases. No significant difference in mREE was observed between phases (p = 0.529). Sixty-five percent of the patients were hypermetabolic in both phases. Median delivery of energy as percentage of mREE was higher in the late phase (94%) compared to the acute phase (70%) (p = 0.001). Urinary nitrogen losses were significant higher in the late phase (p = 0.003). Conclusion: In both the acute and late phase, the majority of the patients were hypermetabolic and fed enterally. In the acute phase patients were fed hypocaloric whereas in the late phase this was almost normocaloric, conform ESPEN guidelines. No significant difference in mREE was observed between phases. Hypermetabolism in both phases in conjunction with an increasing loss of urinary nitrogen may indicate that COVID-19 patients remain in a prolonged acute, catabolic phase. (C) 2021 The Author(s). Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism.

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 micro nutrients (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 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. (C) 2021 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.

Aims & Objectives: To develop a pediatric quality improvement instrument for enteral nutrition (EN) delivery in critically ill children and to explore the perceived barriers by pediatric intensive care healthcare professionals (HCP) (nurses, dieticians and physicians) across the world. Methods: Cross-sectional online survey to PICU HCP across the world containing 25 items Results: 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. There were also significant differences in 14 perceived barriers when comparing continents. Across all continents, the biggest perceived barrier was enteral feeds being withheld for procedures and operating department visits, and this was the highest perceived barrier in Southern America. Other top perceived barriers were: none or not enough dietitian coverage on weekends or evenings, and not enough time dedicated to education and training on how to optimally feed patients. Conclusions: This is the largest survey that has explored perceived barriers to the delivery of enteral nutrition across the world by HCP. Many perceived barriers to enteral feeding remain in PICUs internationally. These barriers relate to organisational and staff factors as well as clinical patient factors. Whether the barrier is real or not, if clinicians believe these, then this still inhibits the delivery of enteral nutrition. Further education to improve awareness of the existing evidence and facilitate the implementation of best evidence into local unit guidelines is required.

: 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 (<24 hours) reduced new acquired infections and accelerated recovery. The provision of amino acids in particular was negatively associated with short-term outcomes, probably explained by the suppression of the activation of autophagy. Autophagy is an evolutionary conserved intracellular degradation process and it is crucial for maintaining cellular integrity and function, which becomes even more important during acute stress. Results of the long-term PEPaNIC follow-up study showed that withholding early PN did not negatively affect anthropometrics and health status but improved neurocognitive and psychosocial development 2 and 4 years later. Current guidelines therefore advise to consider withholding parenteral macronutrients for the first week of PICU admission, while providing micronutrients. Although parenteral restriction during the first week of critical illness has been found beneficial, further research beyond the acute phase is warranted to determine the best role of PN in terms of optimal timing, dose and composition in order to improve short-term recovery and long-term developmental outcomes.

Rationale: The optimal feeding strategy in critically ill COVID-19 patients is challenging. They seem particularly difficult to feed enterally, presenting with high gastric residual volumes (GRV) and diarrhoea. Our aim was to describe feeding practises and measured resting energy expenditure (mREE) during the acute and late phases of critical illness. Methods: Observational study including critically ill mechanically ventilated adult COVID-19 patients. Indirect calorimetry (IC; Q-NRG+) was used to determine mREE during the acute (day 1-7) and late phase (> day 7) of critical illness. Data on enteral nutrition (EN) and parenteral nutrition (PN) were collected on the same day. Comparison of mREE and predicted REE (pREE) (mREE/pREE *100%) was performed to explore hypometabolism (<90%) and hypermetabolism (>110%). In both phases parameters for intolerance to EN were collected on consequent days such as GRV (mL/d), vomiting, abdominal distention and diarrhoea. Results: We enrolled 35 patients in whom 42 IC measurements were performed (20 acute phase; 22 late phase). Median age 63 year [IQR 47-69], 80% male. BMI upon admission was 27.8 kg/m2 [IQR 24.2-34.0], 43% obese (BMI>30 kg/m2). During the acute phase mREE was 1956 kcal [IQR 1846-2441] and respiratory quotient (RQ) 0,72 [IQR 0,67-0,81]; 10% was hypometabolic, 60% hypermetabolic. The median delivery of energy was 64% of mREE . All patients received EN; 70% via nasogastric tube (NGT) and 30% via nasoduodenal tube (NDT). Median GRV was 195 mL/d [IQR 41-450], 5% vomited, 5% abdominal distention and 20% diarrhoea. In the late phase mREE was 2374 kcal [IQR 1828-2711] and RQ 0,81 [IQR 0,74-0,86]; 9% was hypometabolic and 68% hypermetabolic. The median delivery of energy was 92% of mREE. All patients except one received EN; 50% NGT and 50% NDT, with a median GRV of 48 mL/d [IQR 15-180]. A total of 5% vomited, 9% abdominal distention and 15% diarrhoea. Conclusion: In both the acute and late phase the majority of the patients were hypermetabolic. Almost all patients were fed enterally, with a slightly higher presence of EN intolerance parameters during the acute phase. In the acute phase patients were fed hypocaloric whereas in the late phase this was almost normocaloric (64% vs 92% of mREE) conform our ESPEN based nutrition protocol. Elaborate data analysis are planned and will be presented at the conference. Disclosure of Interest: None declared

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.

Abstract 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 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 lateparenteral 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 (beta-estimate -2.11 [95% CI -3.15 to -1.06]; p<0.0001) and head circumference (-0.42 [-0.67 to -0.18]; p=0.00077); and worse health status (eg, hospital admission odds ratio 4.27 [95% CI 3.12 to 5.84]; p<0.0001), neurocognitive (eg, parent-reported or caregiver-reported total executive functioning beta-estimate 3.57 [95% CI 1.95 to 5.18], p<0.0001; total intelligence quotient -7.35 [-9.31 to -5.39], p<0.0001), and parent-reported or caregiver-reported emotional and behavioural developmental outcomes (internalising 2.73 [1.19 to 4.28], p=0.00055; externalising 1.63 [0.19 to 3.08], p=0.027; and total behavioural problems 2.95 [1.44 to 4.46], p=0.00013), adjusted for risk factors. Outcomes were never worse in the late-parenteral nutrition group compared with the early-parenteral nutrition group, but patients in the late-parenteral nutrition group had fewer parent-reported or caregiver-reported internalising (beta-estimate -1.88 [95% CI -3.69 to -0.07]; p=0.042), externalising (-1.73 [-3.43 to -0.03]; p=0.046), and total emotional and behavioural problems (-2.44 [-4.22 to -0.67]; p=0.0070) than patients who had received early-parenteral nutrition, after adjusting for risk factors, and were no longer different from healthy controls for these outcomes. Interpretation Omitting early parenteral nutrition use for critically ill children did not adversely affect long-term outcomes 4 years after randomisation and protected against emotional and behavioural problems, further supporting the deimplementation of early parenteral nutrition. Copyright (c) 2020 Elsevier Ltd. All rights reserved.

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 < 0.001), treatment with inotropic agents (-22%EN/REE; p = 0.026) and large gastric residual volume (-64%EN/REE; p < 0.001) were independently associated with a low mean EN intake. In univariable analysis, low mean EN intake was associated with new acquired infections, hypoglycaemia, duration of PICU and hospital stay and duration of mechanical ventilation. However, after adjustment for confounders, these associations were no longer present, except for low EN and hypoglycaemia (-39%EN/REE; p = 0.018). Conclusions: Several patient and clinical characteristics during the first week of critical illness were associated with EN intake. No independent associations were found between EN intake and clinical outcomes such as mortality, new acquired infection and duration of stay. These data emphasize the necessity of adequate multivariable adjustment in nutritional support research and the need for future RCTs investigating optimal EN intake. (c) 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Objectives: To explore the perceived barriers by pediatric intensive care healthcare professionals (nurses, dieticians, and physicians) in delivering enteral nutrition to critically ill children across the world. Design: Cross-sectional international online survey adapted for use in pediatric settings. Setting: PICUs across the world. Subjects: PICU nurses, physicians, and dietitians. Interventions: The 20-item adult intensive care “Barriers to delivery of enteral nutrition” survey was modified for pediatric settings, tested, and translated into 10 languages. The survey was distributed online to pediatric intensive care nurses, physicians, and dieticians via professional networks in March 2019 to June 2019. Professionals were asked to rate each item indicating the degree to which they perceived it hinders the provision of enteral nutrition in their PICUs with a 7-point Likert scale from 0 “not at all a barrier” to 6 “an extreme amount.” Measurement and Main Results: Nine-hundred twenty pediatric intensive care professionals responded from 57 countries; 477 of 920 nurses (52%), 407 of 920 physicians (44%), and 36 of 920 dieticians (4%). Sixty-two percent had more than 5 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 as follows: 1) enteral feeds being withheld in advance of procedures or operating department visits, 2) none or not enough dietitian coverage on weekends or evenings, and 3) not enough time dedicated to education and training on how to optimally feed patients. Conclusions: 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 focused nutrition education for all PICU professional groups.

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 & 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.

BACKGROUNDEnteral 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).METHODSRecords from critically ill infants aged <12 months admitted to two PICUs were retrospectively reviewed with a PICU length of stay (LOS) ≥ 7 days. Achievement of nutritional targets for the duration of PEF was reviewed. Gastrointestinal symptoms, including gastric residual volume, constipation and vomiting, were evaluated as tolerance parameters.RESULTSIn total, 53 infants were included, with a median age on admission of 2.6 months. Median admission weight was 3.9 kg in PICU-1 and 4.7 kg in PICU-2. Median (interquatile range) energy intake in PICU-1 and PICU-2 was 68 (47-92) and 90 (63-124) kcal kg-1 , respectively, and median (interquatile range) protein intake 1.7 (1.1-2.4) g kg-1 and 2.5 (1.6-3.2) g kg-1 , respectively. Feeding was withheld because of feeding intolerance in one infant (4%) on two occasions in PICU-1 for 2.5 h and in two infants (7%) on two occasions in PICU-2 for 19.5 h. Gastric residual mean (SD) volumes were 3.5 (5.4) mL kg-1 in PICU-1 and 16.9 (15.6) mL kg-1 in PICU-2.CONCLUSIONSPeptide nutrient-energy dense feeding in infants admitted to the PICU is feasible, well tolerated and nutritional targets are met. However, with this study design, it is not possible to draw any conclusions regarding the benefit of PEF over standard PE feed in critically ill children and future work is required to clarify this further.