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

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

Enteral Feeding of Children on Noninvasive Respiratory Support: A Four-Center European Study.

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.

Barriers to Delivery of Enteral Nutrition in Pediatric Intensive Care: A World Survey.

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.

Nutritional support in the recovery phase of critically ill children.

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.

Continuous Versus Intermittent Nutrition in Pediatric Intensive Care Patients: Protocol for a Randomized Controlled Trial.

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.

Supplementation of vitamins, trace elements and electrolytes in the PEPaNIC Randomised Controlled Trial: Composition and preparation of the prescription.

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.

Long-term developmental effect of withholding parenteral nutrition in paediatric intensive care units: a 4-year follow-up of the PEPaNIC randomised controlled trial.

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 (ß-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 ß-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 (ß-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. FUNDING: European Research Council, Methusalem, Flanders Institute for Science and Technology, Research Foundation Flanders, Sophia Foundation, Stichting Agis Zorginnovatie, Erasmus Trustfonds, and the European Society for Clinical Nutrition and Metabolism.

Long-term developmental effects of withholding parenteral nutrition for 1 week in the paediatric intensive care unit: a 2-year follow-up of the PEPaNIC international, randomised, controlled trial.

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 ß 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 (ß 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.