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 &amp; 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 Continuous versus 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-β-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 &lt; 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.</p

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 PEPaNIC RCT. 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 three and day five. ENA was defined as kcal EN provided as % of predicted resting energy expenditure (pREE). 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 two-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 (Q1); third quartile (Q3): 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 five days of pediatric critical illness.</p

Energy expenditure in critically ill children

In critically ill children, optimal nutritional intake can improve recovery. During stay in the pediatric intensive care unit (PICU), both underfeeding and overfeeding have to be avoided. The assessment of energy requirements is difficult during critical illness because of lack of devices to measure it. In addition, energy requirements vary during the different phases of critical illness; i.e. the acute, stable and recovery phase. Energy expenditure is affected by the illness itself, but also by the conditions of the PICU such as mechanical ventilation, sedation, fever and the lack of physical activity. During the acute phase, energy intake has to be increased gradually while not exceeding resting energy expenditure (REE). The latter may be estimated using the Schofield equation or ideally be measured using a validated indirect calorimeter. After the acute phase, energy intake has to be increased to enable recovery and growth. The aim of this review is to give an overview of the current knowledge concerning REE in critically ill children and factors that may affect REE. The principles of measurement or calculation of REE will be described. The available evidence will be synthesized and practical recommendations will be provided for guiding energy intake during the different phases of illness

Intermittent fasting in paediatric critical illness

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. Se

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