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Summary Background & aims Early use of parenteral nutrition (early-PN), as compared with withholding it for one week (late-PN), in the PICU, has shown to slow down recovery from critical illness and impair long-term development of 6 neurocognitive/behavioural/emotional functions assessed 2 years later. Given that key steps in brain maturation occur at different times during childhood, we hypothesised that age at time of exposure determines long-term developmental impact of early-PN. Methods The 786 children who were neurocognitively tested 2 years after participation in the PEPaNIC-RCT were included in this study. First, for each studied long-term outcome, interaction between randomisation to early-PN versus late-PN and age was assessed with multivariable linear regression analysis. Subsequently, for outcomes with an interaction p ≤ 0.15, the impact of early-PN versus late-PN was analysed, after adjustment for risk factors, for 4 subgroups defined based on developmentally-relevant age at time of exposure [≤28 days (n = 121), 29 days to 11 months (n = 239), 11 months to <5 years (n = 223) and ≥5 years (n = 203)]. Results Interaction between randomisation and age was present for weight, and parent-reported inhibitory control, cognitive flexibility, working memory, planning/organisation, metacognition, total executive functioning, and internalising and total behavioural/emotional problems. Subgroup analyses revealed that none of the age-groups revealed benefit, whereas children aged 29 days to <11 months were most vulnerable to harm by early-PN for development of inhibitory control (p = 0.008), working memory (p = 0.009), planning/organisation (p = 0.004), metacognition (p = 0.008), and total executive functioning (p = 0.004), and for internalising (p = 0.005) and total behavioural/emotional problems (p = 0.01). Children aged 11 months to <5 years revealed harm by early-PN for development of inhibitory control (p = 0.003). In contrast, children aged ≥5 years and neonates aged ≤28 days appeared less vulnerable. Conclusions Critically ill children aged 29 days to 11 months at time of exposure were identified as most vulnerable to developmental harm evoked by early-PN. Clinical trials.gov NCT01536275.

Background A genome-wide study identified de novo DNA methylation alterations in leukocytes of children at paediatric intensive care unit (PICU) discharge, offering a biological basis for their impaired long-term development. Early parenteral nutrition (early-PN) in PICU, compared with omitting PN in the first week (late-PN), explained differential methylation of 23% of the affected CpG-sites. We documented the time course of altered DNA methylation in PICU and the impact hereon of early nutritional management. Results We selected 36 early-PN and 36 late-PN matched patients, and 42 matched healthy children. We quantified DNA methylation on days 3, 5 and 7 for the 147 CpG-sites of which methylation was normal upon PICU admission in this subset and altered by critical illness at PICU discharge. Methylation in patients differed from healthy children for 64.6% of the 147 CpG-sites on day 3, for 72.8% on day 5 and for 90.5% on day 7 as revealed by ANOVA at each time point. Within-patients methylation time course analyses for each CpG-site identified different patterns based on paired t test p value and direction of change. Rapid demethylation from admission to day 3 occurred for 76.2% of the CpG-sites, of which 67.9% remained equally demethylated or partially remethylated and 32.1% further demethylated beyond day 3. From admission to day 3, 19.7% of the CpG-sites became hypermethylated, of which, beyond day 3, 34.5% remained equally hypermethylated or partially demethylated again and 65.5% further hypermethylated. For 4.1% of the CpG-sites, changes only appeared beyond day 3. Finally, for the CpG-sites affected by early-PN on the last PICU day, earlier changes in DNA methylation were compared for early-PN and late-PN patients, revealing that 38.9% were already differentially methylated by day 3, another 25.0% by day 5 and another 13.9% by day 7. Conclusions Critical illness- and early-PN-induced changes in DNA methylation occurred mainly within 3 days. Most abnormalities were at least partially maintained or got worse with longer time in PICU. Interventions targeting aberrant DNA methylation changes should be initiated early.

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.