Intravenous maintenance fluid therapy in acutely and critically ill children: state of the evidence.

Intravenous maintenance fluid therapy (IV-MFT) is one of the most prescribed, yet one of the least studied, interventions in paediatric acute and critical care settings. IV-MFT is not typically treated in the same way as drugs with specific indications, contraindications, compositions, and associated adverse effects. In the last decade, societies in both paediatric and adult medicine have issued evidence-based practice guidelines for the use of intravenous fluids in clinical practice. The main objective of this Viewpoint is to summarise and compare the rationales on which these international expert guidelines were based and how these recommendations affect IV-MFT practices in paediatric acute and critical care. Although these guidelines recommend the use of isotonic fluids as a standard in IV-MFT, some discrepancies and uncertainties remain regarding the systematic use of balanced fluids, glucose and electrolyte requirements, and appropriate fluid volume. IV-MFT should be considered in the same way as any other prescription drug and none of the components of IV-MFT prescription should be overlooked (ie, choice of drug, dosing rate, duration of treatment, and de-escalation). Furthermore, most evidence that was used to inform the guidelines comes from high-income countries. Although some principles of IV-MFT are universal, the direct relevance to and feasibility of implementing the guidelines in low-income and middle-income countries is uncertain.

An electroencephalography-based sleep index and supervised machine learning as a suitable tool for automated sleep classification in children.

STUDY OBJECTIVES: Although sleep is frequently disrupted in the pediatric intensive care unit, it is currently not possible to perform real-time sleep monitoring at the bedside. In this study, spectral band powers of electroencephalography data are used to derive a simple index for sleep classification. METHODS: Retrospective study at Erasmus MC Sophia Children's Hospital, using hospital-based polysomnography recordings obtained in non-critically ill children between 2017 and 2021. Six age categories were defined: 6-12 months, 1-3 years, 3-5 years, 5-9 years, 9-13 years, and 13-18 years. Candidate index measures were derived by calculating spectral band powers in different frequent frequency bands of smoothed electroencephalography. With the best performing index, sleep classification models were developed for two, three, and four states via decision tree and five-fold nested cross-validation. Model performance was assessed across age categories and electroencephalography channels. RESULTS: In total 90 patients with polysomnography were included, with a mean (standard deviation) recording length of 10.3 (1.1) hours. The best performance was obtained with the gamma to delta spectral power ratio of the F4-A1 and F3-A1 channels with smoothing. Balanced accuracy was 0.88, 0.74, and 0.57 for two-, three-, and four-state classification. Across age categories, balanced accuracy ranged between 0.83 and 0.92 and 0.72 and 0.77 for two- and three-state classification, respectively. CONCLUSIONS: We propose an interpretable and generalizable sleep index derived from single-channel electroencephalography for automated sleep monitoring at the bedside in non-critically ill children ages 6 months to 18 years, with good performance for two- and three-state classification. CITATION: van Twist E, Hiemstra FW, Cramer ABG, et al. An electroencephalography-based sleep index and supervised machine learning as a suitable tool for automated sleep classification in children. J Clin Sleep Med. 2024;20(3):389-397.

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.

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

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

Barriers and perceived benefits of early mobilisation programmes in Dutch paediatric intensive care units.

BACKGROUND: Early mobilisation of critically ill adults has been proven effective and is safe and feasible for critically ill children. However, barriers and perceived benefits of paediatric intensive care unit (PICU) staff involvement in mobilising critically ill children are largely unknown. AIM: To explore the barriers and perceived benefits regarding early mobilisation of critically ill children as perceived by PICU staff. STUDY DESIGN: A cross-sectional survey study among staff from seven PICUs in the Netherlands has been carried out. RESULTS: Two hundred and fifteen of the 641 health care professionals (33.5%) who were invited to complete a questionnaire responded, of whom 159 (75%) were nurses, 40 (19%) physicians, and 14 (6%) physical therapists. Respondents considered early mobilisation potentially beneficial to shorten the duration of mechanical ventilation (86%), improve wake/sleep rhythm (86%) and shorten the length of stay in the PICU (85%). However, staff were reluctant to mobilise patients on extracorporeal membrane oxygenation (ECMO) (63%), and patients with traumatic brain injury (49%). Perceived barriers to early mobilisation were hemodynamic instability (78%), risk of dislocation of lines/tubes (74%), and level of sedation (62%). In total, 40.3% of PICU nurses stated that physical therapists provided enough support in their PICU, but 84.6% of the physical therapists believed support was sufficient. CONCLUSION: Participating PICU staff considered early mobilisation as potentially beneficial in improving patient outcomes, although barriers were noted in certain patient groups. RELEVANCE TO CLINICAL PRACTICE: We identified barriers to early mobilisation which should be addressed in implementation research projects in order to make early mobilisation in critically ill children work.

ESPNIC clinical practice guidelines: intravenous maintenance fluid therapy in acute and critically ill children- a systematic review and meta-analysis.

PURPOSE: Intravenous maintenance fluid therapy (IV-MFT) prescribing in acute and critically ill children is very variable among pediatric health care professionals. In order to provide up to date IV-MFT guidelines, the European Society of Pediatric and Neonatal Intensive Care (ESPNIC) undertook a systematic review to answer the following five main questions about IV-MFT: (i) the indications for use (ii) the role of isotonic fluid (iii) the role of balanced solutions (iv) IV fluid composition (calcium, magnesium, potassium, glucose and micronutrients) and v) and the optimal amount of fluid. METHODS: A multidisciplinary expert group within ESPNIC conducted this systematic review using the Scottish Intercollegiate Guidelines Network (SIGN) grading method. Five databases were searched for studies that answered these questions, in acute and critically children (from 37 weeks gestational age to 18 years), published until November 2020. The quality of evidence and risk of bias were assessed, and meta-analyses were undertaken when appropriate. A series of recommendations was derived and voted on by the expert group to achieve consensus through two voting rounds. RESULTS: 56 papers met the inclusion criteria, and 16 recommendations were produced. Outcome reporting was inconsistent among studies. Recommendations generated were based on a heterogeneous level of evidence, but consensus within the expert group was high. "Strong consensus" was reached for 11/16 (69%) and "consensus" for 5/16 (31%) of the recommendations. CONCLUSIONS: Key recommendations are to use isotonic balanced solutions providing glucose to restrict IV-MFT infusion volumes in most hospitalized children and to regularly monitor plasma electrolyte levels, serum glucose and fluid balance.

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.

Intermittent fasting in paediatric critical illness: The properties and potential beneficial effects of an overnight fast in the PICU.

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.

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.

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 for children during critical illness: European Society of Pediatric and Neonatal Intensive Care (ESPNIC) metabolism, endocrine and nutrition section position statement and clinical recommendations.

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.

International survey of De-implementation of initiating parenteral nutrition early in Paediatric intensive care units.

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

Phthalate and alternative plasticizers in indwelling medical devices in pediatric intensive care units.

The present study aimed to identify plasticizers present in indwelling plastic medical devices commonly used in the pediatric intensive care unit (PICU). We have analyzed a wide range of medical devices (n = 97) daily used in the PICUs of two academic hospitals in Belgium and the Netherlands. Identified compounds varied between the samples. Most of the indwelling medical devices and essential accessories were found to actively leach phthalates and alternative plasticizers. Results indicated that DEHP was predominantly present as plasticizer (60 of 97 samples), followed by bis(2-ethylhexyl) adipate (DEHA, 32 of 97), bis(2-ethylhexyl) terephthalate (DEHT, 24 of 97), tris(2-ethylhexyl) trimellitate (TOTM, 20 of 97), and tributyl-O-acetyl citrate (ATBC, 10 of 97). Other plasticizers, such as di-isononyl-cyclohexane-1,2-dicarboxylate (DINCH, 2 of 97), di-isononyl phthalate (DiNP, 4 of 97), di(2-propylheptyl) phthalate (DPHP, 4 of 97) and di-isodecyl phthalate (DiDP, 2 of 97) were detected in < 5% of the investigated samples. Several devices contained multiple plasticizers, e.g. devices containing TOTM contained also DEHP and DEHT. Our data indicate that PICU patients are exposed to a wide range of plasticizers, including the controversial DEHP. Future studies should investigate the exposure to APs in children staying in the PICU and the possible health effects thereof.

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.

Early versus late parenteral nutrition in critically ill, term neonates: a preplanned secondary subgroup analysis of the PEPaNIC multicentre, randomised controlled trial.

BACKGROUND: Previous randomised studies showed that withholding parenteral nutrition for 1 week of critical illness was superior to early initiation (<24-48 h) of parenteral nutrition in children and adults. However, neonates are considered more susceptible to macronutrient deficits. We investigated the effect of withholding parenteral nutrition for 1 week in critically ill, term neonates. METHODS: We previously did a randomised, controlled study (PEPaNIC) of children aged up to 17 years admitted to paediatric intensive-care units (ICUs) in three hospitals in Belgium, Canada, and the Netherlands randomly assigned (1:1) to either standard care of parenteral nutrition initiated early within 24 h of admission to an ICU or late parenteral nutrition (where supplemental parenteral nutrition was withheld for 1 week after admission to the ICU). In this preplanned, secondary subanalysis of PEPaNIC, we looked at data from critically ill, term neonate participants (gestational age ≥37 weeks) aged up to 28 days (studied in overlapping age groups of ≤4 weeks, ≤1 week, and <1 day-ie, age at admission). In both the early parenteral nutrition and late parenteral nutrition groups, enteral nutrition was initiated as soon as possible and increased according to local protocols. Outcome assessors and investigators not directly involved in the paediatric ICU were not informed of treatment allocation. The primary endpoints were incidence of new infections and duration of paediatric ICU dependency (quantified as the number of days in the paediatric ICU and likelihood of earlier live discharge from the ICU), analysed based on intention to treat. Multivariable analyses were adjusted for the following risk factors: centre, Paediatric Logistic Organ Dysfunction score, Paediatric Index of Mortality 2 score, diagnosis group, and weight-for-age Z scores on admission. Secondary safety outcomes were mortality (at 90 days, during the intervention, in the paediatric ICU, and in the hospital) and hypoglycaemic incidents during the intervention. All patients in the respective groups were included in the safety analysis. FINDINGS: Between June 18, 2012, and July 27, 2015, we included 209 participants in this substudy, 145 of whom were aged up to and including 1 week and 45 aged younger than 1 day. In neonates aged up to and including 4 weeks, late parenteral nutrition increased the likelihood of earlier live discharge from the paediatric ICU compared with early parenteral nutrition (adjusted hazard ratio [HR] 1·61, 95% CI 1·19-2·20; p=0·0021) but did not affect the risk of infection. The risk of infection in neonates aged up to and including 1 week and younger than 1 day was lower with late parenteral nutrition than with early parenteral nutrition (adjusted odds ratios [OR] 0·36, 95% CI 0·15-0·83, p=0·017; and 0·10, 0·01-0·64, p=0·015, respectively). For neonates aged up to and including 1 week, the likelihood of an earlier live discharge from the ICU was higher with late parenteral nutrition (adjusted HR 1·69, 95% CI 1·16-2·46; p=0·0063). For neonates younger than 1 day, adjusted HR was 1·95 (95% CI 0·93-4·12; p=0·078). Mortality at all studied timepoints was similar between the groups for all ages; however, in neonates aged up to and including 4 weeks and aged up to and including 1 week, the risk of hypoglycaemia was higher with late parenteral nutrition (23% vs 14%; adjusted OR 3·05, 95% CI 1·27-7·35, p=0·013; and 24% vs 14%; 3·57, 1·23-10·45, p=0·019, respectively. INTERPRETATION: In critically ill, term neonates, withholding parenteral nutrition for 1 week was clinically superior to standard care of initiating parenteral nutrition within 24 h for short-term outcomes. However, withholding parenteral nutrition for 1 week significantly increased the risk of developing hypoglycaemia, which necessitates long-term follow-up of these children before late parenteral nutrition can be confidently recommended for this vulnerable patient group. FUNDING: Flemish Agency for Innovation through Science and Technology, Methusalem-Programme Flemish Government, European Research Council, Fonds NutsOhra, Stichting Agis-Zorginnovatie, and the Sophia Research-Foundation.

Outcomes of Delaying Parenteral Nutrition for 1 Week vs Initiation Within 24 Hours Among Undernourished Children in Pediatric Intensive Care: A Subanalysis of the PEPaNIC Randomized Clinical Trial.

Importance: Undernourishment has been associated with poor outcomes of critical illness in children. The effects of withholding parenteral nutrition (PN) for 1 week in undernourished critically ill children are unknown. Objective: To assess the outcome effects of withholding PN for 1 week in undernourished critically ill children. Design, Setting, and Participants: This is a subanalysis of the randomized clinical trial Pediatric Early vs Late Parenteral Nutrition in Intensive Care Unit (PEPaNIC; N = 1440), which focused on the subgroup of pediatric intensive care unit (PICU) patients identified as undernourished on admission. Children included in the PEPaNIC trial were enrolled between June 18, 2012, and July 27, 2015. Undernourishment was defined as weight-for-age z score less than -2 in children younger than 1 year, and body mass index-for-age z score less than -2 in children 1 year or older. Data analysis was conducted from August 3, 2017, to July 6, 2018. Interventions: Patients were randomized to initiation of supplemental PN within 24 hours (early PN) or after 1 week (late PN) when enteral nutrition was insufficient. Main Outcomes and Measures: Primary end points were risk of new infections acquired in the PICU and time to live PICU discharge, assessed via multivariable logistic regression and Cox proportional hazard analyses, adjusted for risk factors. Results: A total of 289 of 1440 children (20.1%), term newborn to age 17 years, were identified as undernourished, of whom 150 of 717 patients (20.9%) were in the late PN group and 139 of 723 patients (19.2%) were in the early PN group. On admission, characteristics were similar among the treatment groups. Mean (SD) weight z scores were -3.33 (1.18) in the late PN group and -3.21 (1.09) in the early PN group. Compared with well-nourished PICU patients, undernourishment on admission was associated with lower likelihood of an earlier live PICU discharge (adjusted hazard ratio, 0.86; 95% CI, 0.75-0.99; P = .03). Among undernourished PICU patients, late PN reduced the risk of new infections by 11.0% (adjusted odds ratio, 0.39; 95% CI, 0.19-0.78; P = .01), and shortened the duration of PICU stay by a median of 2 days (earlier live PICU discharge: adjusted hazard ratio, 1.37; 95% CI, 1.06-1.75; P = .01). The safety outcomes mortality, incidence of hypoglycemia during the first week, and incidence of weight deterioration during PICU stay were similar between the treatment groups. Conclusions and Relevance: In undernourished critically ill children, withholding PN for 1 week was clinically superior to early PN. Trial Registration: ClinicalTrials.gov Identifier: NCT01536275.

Validation of ventilator-derived VCO2 measurements to determine energy expenditure in ventilated critically ill children.

BACKGROUND & AIMS: Indirect calorimetry (IC) is considered the gold standard to determine resting energy expenditure (REE) but its availability in PICUs worldwide is limited. Ventilator-derived VCO2 could potentially improve the possibility of performing REE measurements. We investigated whether ventilator-derived VCO2 values are comparable to IC-derived VCO2 values and can clinically be used in clinical practice to determine REE. METHODS: VCO2-values were simultaneously collected in mechanically ventilated children from IC (Deltatrac®) and Servo-I® ventilator on a minute base over at least 10 min period of steady state. REE was calculated using the modified Weir formula (for IC) or REE = 5.5*VCO2 (L/min)*1440 (for the Servo-I values) and compared with frequently used predictive equations by Schofield and the WHO to calculate REE. RESULTS: Measurements were performed in 41 children; median age 2 years. The mean relative difference between VCO2 measured by IC and Servo-I® was 15.6% (p = 0.002), and limits of agreement in the Bland-Altman analysis were wide. Comparable measurements, defined as a difference ≤10% between IC and Servo-I® VCO2 values, were seen in 18 (44%) children, but this proportion was 70% in children ≥15 kg. In this group, REE could be accurately predicted using Servo-I® derived VCO2 values and this method was superior to the use of predictive equations. The Servo-I® derived VCO2 values were not sufficiently accurate for the large proportion of children weighing <15 kg. CONCLUSIONS: In children ≥15 kg, VCO2 measurements of the Servo-I® seem sufficiently accurate for use in clinical practice and may be used to determine energy expenditure in the future.