Abstract
BackgroundThe PEPaNIC multicenter randomized controlled trial (RCT) has shown that early administration of supplemental parenteral nutrition (early-PN) as compared with withholding PN for 1 week (late-PN) induced long-term internalizing, externalizing and total emotional/behavioral problems in critically ill children, as observed 4 years later. Early-PN was further shown to alter the methylation status of 37 CpG-sites in leukocyte DNA between admission and discharge from the pediatric intensive care unit (PICU). In a preplanned subanalysis of the PEPaNIC trial, we now investigated whether the altered methylation of these CpG-sites could statistically explain the negative impact of early-PN on emotion/behavior documented 4 years after PICU admission.ResultsThe combination of DNA methylation data and data on behavior 4 years after PICU admission was available for 403 of the 1440 patients (aged 0–17 years at PICU admission) who were included in the PEPaNIC RCT (192 early-PN and 211 late-PN patients). Mediation analyses with use of bootstrapped multivariable non-linear regression analyses adjusted for baseline risk factors revealed that the adverse alterations by early-PN in methylation of the 37 CpG-sites together statistically explained its harmful impact on internalizing, externalizing and total emotional/behavioral problems. When adding the methylation status of the 37 CpG-sites to the models, the explanatory power improved with a 1.710 to 1.851-fold increase, and the impact of the altered methylation status of the CpG-sites explained the impact of the randomization to early-PN versus late-PN.ConclusionsAbnormal DNA methylation induced by the early use of PN in the PICU provides a biological basis for its long-term harmful effect on emotion/behavior of critically ill children 4 years after PICU admission.Trial Registration ClinicalTrials.gov NCT01536275, registered February 17, 2012, https://clinicaltrials.gov/ct2/show/NCT01536275.
Highlights
The PEPaNIC multicenter randomized controlled trial (RCT) has shown that early administration of supplemental parenteral nutrition as compared with withholding PN for 1 week induced long-term internalizing, externalizing and total emotional/behavioral problems in critically ill children, as observed 4 years later
In a non-linear model adjusted for baseline risk factors, randomization to early-PN versus late-PN was found to be a significant predictor of the internalizing, externalizing, and total emotional/behavioral problems at 4-year follow-up of the tested patient cohort (Fig. 2A)
Mediation analysis revealed that the early-PN-induced adversely altered Deoxyribonucleic acid (DNA) methylation of 37 CpG-sites statistically explained its harmful impact on the three behavioral outcomes (Fig. 2B)
Summary
The PEPaNIC multicenter randomized controlled trial (RCT) has shown that early administration of supplemental parenteral nutrition (early-PN) as compared with withholding PN for 1 week (late-PN) induced long-term internalizing, externalizing and total emotional/behavioral problems in critically ill children, as observed 4 years later. The multicenter ‘Pediatric Early versus Late Parenteral Nutrition in Critical Illness’ (PEPaNIC) randomized controlled trial (RCT) demonstrated that initiating supplemental PN within the first 24 h after admission (early-PN) was clinically inferior to postponing the initiation of supplemental PN until day 8 of PICU stay (late-PN), as patients in the early-PN group recovered more slowly and acquired more infections during PICU stay [3] This nutritional strategy appeared to contribute to long-term harm, as 2 years after PICU admission, early-PN patients showed worse parent/caregiver reported executive functioning (inhibitory control, working memory, meta-cognition and total executive functioning), externalizing behavioral problems and visual-motor integration [4]. A secondary analysis of the PEPaNIC RCT provided a possible molecular basis for the adverse effects of critical illness on long-term development and the role of nutritional management [5] This large epigenome-wide study has shown that the administration of early-PN during critical illness altered the DNA methylation status of 37 CpG-sites. The aim of the current study was to investigate whether altered methylation of the 37 CpG-sites with the use of early-PN, as was previously identified, is statistically explanatory for its negative impact on behavior documented 4 years after PICU admission
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