Elevated High-Sensitivity Troponin and NT-proBNP Values in Febrile Children.

OBJECTIVES: The COVID-19 pandemic and subsequent rise of multisystem inflammatory syndrome in children have raised interest in high-sensitivity troponin (hs-TnT) and N-terminal probrain natriuretic peptide (NT-proBNP) because these have been found to be elevated in many cases of multisystem inflammatory syndrome in children. Our aim was to study hs-TnT and NT-proBNP concentrations in febrile children not affected by COVID-19. METHODS: We retrospectively measured cardiac markers, hs-TnT, and NT-proBNP in leftover blood samples of febrile children (0-18 years) diagnosed and treated in a single-center emergency department (ED) (N = 67) and pediatric intensive care unit (PICU) (N = 19) that participated in a multicenter, prospective study of infection biomarkers (PERFORM). RESULTS: Concentrations of hs-TnT, median 1.8 ng/L (interquartile range [IQR], 0.0-15.1), and NT-proBNP, 194 pg/mL (IQR, 54.9-706), were higher in febrile children than in controls (N = 25, hs-TnT 0.0 [IQR, 0-0]; NT-proBNP 56.3 [IQR, 29.7-109], both P < 0.001), whereas PICU patients had higher concentrations (hs-TnT 15.1 [IQR, 10.3-102] and NT-proBNP 828 [IQR, 657-4712], both P < 0.001) than ED patients (hs-TnT 0 [IQR, 0-7.4] and NT-proBNP 104 [IQR, 39.5-363]). No differences were found between viral and bacterial infections. Highest concentrations were found in children with either comorbidity predisposing to elevated concentrations (eg, chronic cardiac or renal disease) or children with critical illness or multiorgan failure such as those with septic shock. CONCLUSIONS: Concentrations of hs-TnT and NT-proBNP are often elevated in febrile children with different causes of fever. Concentrations were higher in children admitted to the PICU than in children attending the ED, and seem to reflect disease severity rather than the underlying cause of fever.

Insulin resistance in critical illness: consequences for nutrition therapy and glucose management.

PURPOSE OF REVIEW: Critically ill patients usually develop insulin resistance and hyperglycemia, which is aggravated by early parenteral nutrition. In observational studies, the lowest mortality risk associates with glucose concentrations close to the antecedent average glucose level. This review summarizes the most recent evidence regarding glucose control in critical illness. RECENT FINDINGS: Although pioneer randomized controlled trials showed morbidity and mortality benefit by normalizing blood glucose in intensive care, the largest multicenter randomized controlled trial found increased mortality. Differences in glucose targets, the accuracy of the glucose control protocol, and differences in feeding strategy may explain these differences.Recent randomized controlled trials investigating the impact of individualized glucose control did not show benefits of targeting individualized or looser glucose values in critically ill patients with poorly controlled diabetes. SUMMARY: It remains unclear whether tight glucose control in critical illness is beneficial or not in the absence of early parenteral nutrition, which is currently being studied in the multicenter TGC-fast randomized controlled trial. Without new evidence, it seems prudent to avoid severe hyperglycemia and hypoglycemia in all patients.

The association of hypoglycemia with outcome of critically ill children in relation to nutritional and blood glucose control strategies.

BACKGROUND: Withholding parenteral nutrition (PN) until one week after PICU admission facilitated recovery from critical illness and protected against emotional and behavioral problems 4 years later. However, the intervention increased the risk of hypoglycemia, which may have counteracted part of the benefit. Previously, hypoglycemia occurring under tight glucose control in critically ill children receiving early PN did not associate with long-term harm. We investigated whether hypoglycemia in PICU differentially associates with outcome in the context of withholding early PN, and whether any potential association with outcome may depend on the applied glucose control protocol. METHODS: In this secondary analysis of the multicenter PEPaNIC RCT, we studied whether hypoglycemia in PICU associated with mortality (N = 1440) and 4-years neurodevelopmental outcome (N = 674) through univariable comparison and multivariable regression analyses adjusting for potential confounders. In patients with available blood samples (N = 556), multivariable models were additionally adjusted for baseline serum NSE and S100B concentrations as biomarkers of neuronal, respectively, astrocytic damage. To study whether an association of hypoglycemia with outcome may be affected by the nutritional strategy or center-specific glucose control protocol, we further adjusted the models for the interaction between hypoglycemia and the randomized nutritional strategy, respectively, treatment center. In sensitivity analyses, we studied whether any association with outcome was different in patients with iatrogenic or spontaneous/recurrent hypoglycemia. RESULTS: Hypoglycemia univariably associated with higher mortality in PICU, at 90 days and 4 years after randomization, but not when adjusted for risk factors. After 4 years, critically ill children with hypoglycemia scored significantly worse for certain parent/caregiver-reported executive functions (working memory, planning and organization, metacognition) than patients without hypoglycemia, also when adjusted for risk factors including baseline NSE and S100B. Further adjustment for the interaction of hypoglycemia with the randomized intervention or treatment center revealed a potential interaction, whereby tight glucose control and withholding early PN may be protective. Impaired executive functions were most pronounced in patients with spontaneous or recurrent hypoglycemia. CONCLUSION: Critically ill children exposed to hypoglycemia in PICU were at higher risk of impaired executive functions after 4 years, especially in cases of spontaneous/recurrent hypoglycemia.

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.

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.

Neurocognitive functioning and health-related quality of life of children after pediatric intensive care admission: a systematic review.

OBJECTIVE: This study systematically reviewed recent findings on neurocognitive functioning and health-related quality of life (HRQoL) of children after pediatric intensive care unit admission (PICU). DATA SOURCES: Electronic databases searched included Embase, Medline Ovid, Web of Science, Cochrane CENTRAL, and Google Scholar. The search was limited to studies published in the last five years (2015-2019). STUDY SELECTION: Original studies assessing neurocognitive functioning or HRQoL in children who were previously admitted to the PICU were included in this systematic review. DATA EXTRACTION: Of the 3649 identified studies, 299 met the inclusion criteria based on title abstract screening. After full-text screening, 75 articles were included in the qualitative data reviewing: 38 on neurocognitive functioning, 33 on HRQoL, and 4 on both outcomes. DATA SYNTHESIS: Studies examining neurocognitive functioning found overall worse scores for general intellectual functioning, attention, processing speed, memory, and executive functioning. Studies investigating HRQoL found overall worse scores for both physical and psychosocial HRQoL. On the short term (≤ 12 months), most studies reported HRQoL impairments, whereas in some long-term studies HRQoL normalized. The effectiveness of the few intervention studies during and after PICU admission on long-term outcomes varied. CONCLUSIONS: PICU survivors have lower scores for neurocognitive functioning and HRQoL than children from the general population. A structured follow-up program after a PICU admission is needed to identify those children and parents who are at risk. However, more research is needed into testing interventions in randomized controlled trials aiming on preventing or improving impairments in critically ill children during and after PICU admission.

Physical, Emotional/Behavioral, and Neurocognitive Developmental Outcomes From 2 to 4 Years After PICU Admission: A Secondary Analysis of the Early Versus Late Parenteral Nutrition Randomized Controlled Trial Cohort.

OBJECTIVES: PICU patients face long-term developmental impairments, partially attributable to early parenteral nutrition (PN) versus late-PN. We investigated how this legacy and harm by early-PN evolve over time. DESIGN: Preplanned secondary analysis of the multicenter PEPaNIC-RCT (ClinicalTrials.gov, NCT01536275) that enrolled 1,440 critically ill children from 2012 to 2015 and its 2- (2014-2018) and 4-year (2016-2019) cross-sectional follow-up studies. SETTING: PICUs of Leuven (Belgium), Rotterdam (The Netherlands), and Edmonton (Canada). PATIENTS: Patients and demographically matched healthy control children that underwent longitudinal assessment for physical/emotional/behavioral/neurocognitive functions at both follow-up time points. INTERVENTIONS: In the PEPaNIC-RCT, patients were randomly allocated to early-PN versus late-PN. MEASUREMENTS AND MAIN RESULTS: This within-individual longitudinal study investigated changes in physical/emotional/behavioral/neurocognitive functions from 2 to 4 years after PICU admission for 614 patients (297 early-PN and 317 late-PN, tested at mean ± sd age 5.4 ± 4.2 and 7.3 ± 4.3 yr) and for 357 demographically matched healthy children tested at age 5.6 ± 4.3 and 7.5 ± 4.3 years. We determined within-group time-courses, interaction between time and group, and independent impact of critical illness and early-PN on these time-courses. Most deficits in patients versus healthy children remained prominent over the 2 years ( p ≤ 0.01). Deficits further aggravated for height, body mass index, the executive function metacognition, intelligence, motor coordination (alternating/synchronous tapping), and memory learning-index, whereas verbal memory deficits became smaller (working/immediate/delayed memory) ( p ≤ 0.05). Adjustment for risk factors confirmed most findings and revealed that patients "grew-into-deficit" for additional executive functions (flexibility/emotional control/total executive functioning) and "grew-out-of-deficit" for additional memory functions (recognition/pictures) ( p ≤ 0.05). Time-courses were largely unaffected by early-PN versus late-PN, except for weight loss and limited catch-up for visual-motor integration and alertness in early-PN patients ( p ≤ 0.05). CONCLUSIONS: From 2- to 4-year post-PICU admission, developmental impairments remained prominent. Within that time-window, impaired growth in height, executive functioning and intelligence aggravated, and impaired memory and harm by early-PN only partially recovered. Impact on development into adulthood requires further investigation.

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.

Performance of Pediatric Mortality Prediction Scores for PICU Mortality and 90-Day Mortality.

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

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.

Leukocyte telomere length in paediatric critical illness: effect of early parenteral nutrition.

BACKGROUND: Children who have suffered from critical illnesses that required treatment in a paediatric intensive care unit (PICU) have long-term physical and neurodevelopmental impairments. The mechanisms underlying this legacy remain largely unknown. In patients suffering from chronic diseases hallmarked by inflammation and oxidative stress, poor long-term outcome has been associated with shorter telomeres. Shortened telomeres have also been reported to result from excessive food consumption and/or unhealthy nutrition. We investigated whether critically ill children admitted to the PICU have shorter-than-normal telomeres, and whether early parenteral nutrition (PN) independently affects telomere length when adjusting for known determinants of telomere length. METHODS: Telomere length was quantified in leukocyte DNA from 342 healthy children and from 1148 patients who had been enrolled in the multicenter, randomised controlled trial (RCT), PEPaNIC. These patients were randomly allocated to initiation of PN within 24 h (early PN) or to withholding PN for one week in PICU (late PN). The impact of early PN versus late PN on the change in telomere length from the first to last PICU-day was investigated with multivariable linear regression analyses. RESULTS: Leukocyte telomeres were 6% shorter than normal upon PICU admission (median 1.625 (IQR 1.446-1.825) telomere/single-copy-gene ratio (T/S) units vs. 1.727 (1.547-1.915) T/S-units in healthy children (P < 0.0001)). Adjusted for potential baseline determinants and leukocyte composition, early PN was associated with telomere shortening during PICU stay as compared with late PN (estimate early versus late PN -0.021 T/S-units, 95% CI -0.038; 0.004, P = 0.01). Other independent determinants of telomere length identified in this model were age, gender, baseline telomere length and fraction of neutrophils in the sample from which the DNA was extracted. Telomere shortening with early PN was independent of post-randomisation factors affected by early PN, including longer length of PICU stay, larger amounts of insulin and higher risk of infection. CONCLUSIONS: Shorter than normal leukocyte telomeres are present in critically ill children admitted to the PICU. Early initiation of PN further shortened telomeres, an effect that was independent of other determinants. Whether such telomere-shortening predisposes to long-term consequences of paediatric critical illness should be further investigated in a prospective follow-up study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01536275 . Registered on 16 February 2012.

Nutritional support and the role of the stress response in critically ill children.

PURPOSE OF REVIEW: Nutrition impacts outcome in critically ill children. Based on evolving neuro-endocrine, immunologic and metabolic alterations, three different phases can be proposed during the course of illness. The different phases each demand for tailored macronutrient intakes in critically ill children. RECENT FINDINGS: Early enteral nutrition is associated with decreased morbidity and mortality, but several misconceptions concerning the provision of enteral nutrition prevent adequate intake. Parenteral nutrition in critically ill children is associated with potential disadvantages, as nosocomial infections, but evidence on the effect on clinical outcome is lacking. Nutrient restriction early during critical illness might be beneficial for short and long-term outcomes by decreasing the incidence of side-effects and possibly by amplifying the acute catabolic stress response and stimulating autophagy and muscle integrity. Higher caloric and protein intake via the enteral route are associated with higher 60-day survival, asking for a more aggressive feeding approach in subsequent phases. SUMMARY: Understanding the stress response to critical illness and its phases is essential for nutritional recommendations in critically ill children. Although parenteral nutrient restriction during the acute phase might be beneficial, inclining requirements ask for a more aggressive approach during the stable and recovery phase to enable recovery, growth and catch-up growth.

Use of Indirect Calorimetry to Detect Overfeeding in Critically Ill Children: Finding the Appropriate Definition.

OBJECTIVES: Overfeeding during critical illness is associated with adverse effects such as metabolic disturbances and increased risk of infection. Because of the lack of sound studies with clinical endpoints, overfeeding is arbitrarily defined as the ratio caloric intake/measured resting energy expenditure (mREE) or alternatively as a comparison of measured respiratory quotient (RQ) to the predicted RQ based on the macronutrient intake (RQmacr). We aimed to compare definitions of overfeeding in critically ill mechanically ventilated children based on mREE, RQ, and caloric intake to find an appropriate definition. METHODS: Indirect calorimetry measurements were performed in 78 mechanically ventilated children, median age 6.3 months. Enteral and/or parenteral nutrition was provided according to the local guidelines. Definitions used to indicate overfeeding were the ratio caloric intake/mREE of >110% and >120% and by the measured RQ > RQmacr + 0.05. RESULTS: The proportion of patients identified as overfed varied widely depending on the definition used, ranging from 22% (RQ > RQmacr + 0.05), to 40% and 50% (caloric intake/mREE of >120% and >110%, respectively). Linear regression analysis showed that all patients would be identified as overfed with the definition RQ > RQmacr + 0.05 when the ratio caloric intake/mREE exceeded 165%. Caloric intake was higher in children with a standard deviation-score weight for age <-2. CONCLUSIONS: The proportion of mechanically ventilated patients identified as overfed ranged widely depending on the definition applied. These currently used definitions fail to take into account several relevant factors affecting metabolism during critical illness and are therefore not generally applicable to the pediatric intensive care unit population.

Worldwide Survey of Nutritional Practices in PICUs.

OBJECTIVE: To assess current nutritional practices in critically ill children worldwide. DESIGN: A two-part online, international survey. The first part, "the survey", was composed of 59 questions regarding nutritional strategies and protocols (July-November 2013). The second part surveyed the "point prevalence" of nutritional data of patients present in a subgroup of the responding PICUs (May-September 2014). SETTING: Members of the World Federation of Pediatric Intensive and Critical Care Societies were asked to complete the survey. SUBJECTS: Pediatric critical care providers. INTERVENTIONS: Survey. MEASUREMENTS AND MAIN RESULTS: We analyzed 189 responses from 156 PICUs in 52 countries (survey). We received nutritional data on 295 patients from 41 of these 156 responding PICUs in 27 countries (point prevalence). According to the "survey", nutritional protocols and support teams were available in 52% and 57% of the PICUs, respectively. Various equations were in use to estimate energy requirements; only in 14% of PICUs, indirect calorimetry was used. Nutritional targets for macronutrients, corrected for age/weight, varied widely. Enteral nutrition would be started early (within 24 hr of admission) in 60% of PICUs, preferably by the gastric route (88%). In patients intolerant to enteral nutrition, parenteral nutrition would be started within 48 hours in 55% of PICUs. Overall, in 72% of PICUs supplemental parenteral nutrition would be used if enteral nutrition failed to meet at least 50% of energy delivery goal. Several differences between the intended (survey) and the actual (point prevalence) nutritional practices were found in the responding PICUs, predominantly overestimating the ability to adequately feed patients. CONCLUSION: Nutritional practices vary widely between PICUs worldwide. There are significant differences in macronutrient goals, estimating energy requirements, timing of nutrient delivery, and threshold for supplemental parenteral nutrition. Uniform consensus-based nutrition practices, preferably guided by evidence, are desirable in the PICU.

Abnormal DNA methylation within HPA-axis genes years after paediatric critical illness.

BACKGROUND: Critically ill children suffer from impaired physical/neurocognitive development 2 years later. Glucocorticoid treatment alters DNA methylation within the hypothalamus-pituitary-adrenal (HPA) axis which may impair normal brain development, cognition and behaviour. We tested the hypothesis that paediatric-intensive-care-unit (PICU) patients, sex- and age-dependently, show long-term abnormal DNA methylation within the HPA-axis layers, possibly aggravated by glucocorticoid treatment in the PICU, which may contribute to the long-term developmental impairments. RESULTS: In a pre-planned secondary analysis of the multicentre PEPaNIC-RCT and its 2-year follow-up, we identified differentially methylated positions and differentially methylated regions within HPA-axis genes in buccal mucosa DNA from 818 former PICU patients 2 years after PICU admission (n = 608 no glucocorticoid treatment; n = 210 glucocorticoid treatment) versus 392 healthy children and assessed interaction with sex and age, role of glucocorticoid treatment in the PICU and associations with long-term developmental impairments. Adjusting for technical variation and baseline risk factors and correcting for multiple testing (false discovery rate < 0.05), former PICU patients showed abnormal DNA methylation of 26 CpG sites (within CRHR1, POMC, MC2R, NR3C1, FKBP5, HSD11B1, SRD5A1, AKR1D1, DUSP1, TSC22D3 and TNF) and three DNA regions (within AVP, TSC22D3 and TNF) that were mostly hypomethylated. These abnormalities were sex-independent and only partially age-dependent. Abnormal methylation of three CpG sites within FKBP5 and one CpG site within SRD5A1 and AKR1D1 was partly attributable to glucocorticoid treatment during PICU stay. Finally, abnormal methylation within FKBP5 and AKR1D1 was most robustly associated with long-term impaired development. CONCLUSIONS: Two years after critical illness in children, abnormal methylation within HPA-axis genes was present, predominantly within FKBP5 and AKR1D1, partly attributable to glucocorticoid treatment in the PICU, and explaining part of the long-term developmental impairments. These data call for caution regarding liberal glucocorticoid use in the PICU.

Predicting adverse long-term neurocognitive outcomes after pediatric intensive care unit admission.

BACKGROUND AND OBJECTIVE: Critically ill children may suffer from impaired neurocognitive functions years after ICU (intensive care unit) discharge. To assess neurocognitive functions, these children are subjected to a fixed sequence of tests. Undergoing all tests is, however, arduous for former pediatric ICU patients, resulting in interrupted evaluations where several neurocognitive deficiencies remain undetected. As a solution, we propose using machine learning to predict the optimal order of tests for each child, reducing the number of tests required to identify the most severe neurocognitive deficiencies. METHODS: We have compared the current clinical approach against several machine learning methods, mainly multi-target regression and label ranking methods. We have also proposed a new method that builds several multi-target predictive models and combines the outputs into a ranking that prioritizes the worse neurocognitive outcomes. We used data available at discharge, from children who participated in the PEPaNIC-RCT trial (ClinicalTrials.gov-NCT01536275), as well as data from a 2-year follow-up study. The institutional review boards at each participating site have also approved this follow-up study (ML8052; NL49708.078; Pro00038098). RESULTS: Our proposed method managed to outperform other machine learning methods and also the current clinical practice. Precisely, our method reaches approximately 80% precision when considering top-4 outcomes, in comparison to 65% and 78% obtained by the current clinical practice and the state-of-the-art method in label ranking, respectively. CONCLUSIONS: Our experiments demonstrated that machine learning can be competitive or even superior to the current testing order employed in clinical practice, suggesting that our model can be used to severely reduce the number of tests necessary for each child. Moreover, the results indicate that possible long-term adverse outcomes are already predictable as early as at ICU discharge. Thus, our work can be seen as the first step to allow more personalized follow-up after ICU discharge leading to preventive care rather than curative.

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.