Role of age of critically ill children at time of exposure to early or late parenteral nutrition in determining the impact hereof on long-term neurocognitive development: A secondary analysis of the PEPaNIC-RCT

Abstract

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.

Keywords: Children; Critical illness; Long-term outcome; Neurocognitive development; Parenteral nutrition; Pediatric intensive care unit.

Conflict of interest statement

Conflict of Interest We declare no competing interests.

Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1

CONSORT diagram of study participants. d: days, m: months, PICU: paediatric intensive care unit, PEPaNIC: Paediatric Early versus Late Parenteral Nutrition in Intensive Care Unit, RCT: randomised controlled trial, PN: parenteral nutrition.

Fig. 2

Impact of early-PN, as compared with late-PN, during stay in the PICU on developmental outcome (physical, neurocognitive and behavioural/emotional functions) of children assessed two years later, according to age at time of exposure. Data are presented as β-estimate (dot) and 95% CI (line) for the effect of early-PN, versus late-PN, on those outcomes that revealed interaction between randomization and age at time of exposure. Results represent the combined β-estimates and p-values from 31 datasets generated by multiple data imputation by chained equations under a missing-at-random assumption for 786 PEPaNIC patients divided into 4 a priori defined developmentally-relevant age categories, with data from the total study population, previously published [9], added for comparison. β-estimates were adjusted for centre, sex, race, geographical origin, language, the education and occupational status of the parents (appendix), risk of malnutrition (screening tool for risk on nutritional status and growth [STRONGkids] score), severity of illness upon PICU admission (paediatric index of mortality 3 [PIM3] score and paediatric logistic organ dysfunction [PeLOD] score), diagnosis group (surgical-cardiac, surgical-other, neurosurgery/neurology, trauma/burn, transplantation/hematology/oncology, medical-other), history of malignancy, diabetes, a predefined syndrome (appendix), and parental smoking behaviour. For the developmental outcomes red indicates worse scores and green indicates better scores. For weight, red indicates ‘heavier’ and green indicates ‘lighter’ weight-for-age z-score than the average for that age. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)