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Impact of withholding early parenteral nutrition completing enteral nutrition in pediatric critically ill patients (PEPaNIC trial): study protocol for a randomized controlled trial.

ABSTRACT: The state-of-the-art nutrition used for critically ill children is based essentially on expert opinion and extrapolations from adult studies or on studies in non-critically ill children. In critically ill adults, withholding parenteral nutrition (PN) during the first week in ICU improved outcome, as compared with early supplementation of insufficient enteral nutrition (EN) with PN. We hypothesized that withholding PN in children early during critical illness reduces the incidence of new infections and accelerates recovery.The Pediatric Early versus Late Parenteral Nutrition in Intensive Care Unit (PEPaNIC) study is an investigator-initiated, international, multicenter, randomized controlled trial (RCT) in three tertiary referral pediatric intensive care units (PICUs) in three countries on two continents. This study compares early versus late initiation of PN when EN fails to reach preset caloric targets in critically ill children. In the early-PN (control, standard of care) group, PN comprising glucose, lipids and amino acids is administered within the first days to reach the caloric target. In the late-PN (intervention) group, PN completing EN is only initiated beyond PICU-day 7, when EN fails. For both study groups, an early EN protocol is applied and micronutrients are administered intravenously. The primary assessor-blinded outcome measures are the incidence of new infections during PICU-stay and the duration of intensive care dependency. The sample size (n?=?1,440, 720 per arm) was determined in order to detect a 5% absolute reduction in PICU infections, with at least 80% 1-tailed power (70% 2-tailed) and an alpha error rate of 5%. Based on the actual incidence of new PICU infections in the control group, the required sample size was confirmed at the time of an a priori- planned interim-analysis focusing on the incidence of new infections in the control group only.Clinical evidence in favor of early administration of PN in critically ill children is currently lacking, despite potential benefit but also known side effects. This large international RCT will help physicians to gain more insight in the clinical effects of omitting PN during the first week of critical illness in children.ClinicalTrials.gov: NCT01536275 on 16 February 2012.

SUBMITTER: Fivez T

PROVIDER: S-EPMC4422419 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Impact of withholding early parenteral nutrition completing enteral nutrition in pediatric critically ill patients (PEPaNIC trial): study protocol for a randomized controlled trial.

Fivez Tom T Kerklaan Dorian D Verbruggen Sascha S Vanhorebeek Ilse I Verstraete Sören S Tibboel Dick D Guerra Gonzalo Garcia GG Wouters Pieter J PJ Joffe Ari A Joosten Koen K Mesotten Dieter D Van den Berghe Greet G

Trials 20150501

<h4>Background</h4>The state-of-the-art nutrition used for critically ill children is based essentially on expert opinion and extrapolations from adult studies or on studies in non-critically ill children. In critically ill adults, withholding parenteral nutrition (PN) during the first week in ICU improved outcome, as compared with early supplementation of insufficient enteral nutrition (EN) with PN. We hypothesized that withholding PN in children early during critical illness reduces the incide ...[more]

PMID: 25927936

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Project description:Abstract Aim: Between 2012-2015, the PEPaNIC randomized controlled trial, which included 1440 critically ill infants and children, showed that withholding parenteral nutrition during the first week in the pediatric intensive care unit (PICU) (late-PN), as compared with initiating supplemental PN early (early-PN), improved PICU outcomes (1) and improved neurocognitive development assessed 2 years later (2). The latter was explained by avoiding early-PN induced adversely altered DNA-methylation of 37 CpG sites (3). As a large number of patients were younger than 1 year of age at randomization and given that assessment of most neurocognitive domains is only possible from 4 years of age onwards, we performed a 4-year follow-up to determine the impact of late-PN versus early-PN on physical, neurocognitive, and emotional/behavioral development. This pre-planned, 4-year follow-up study of the 1440 PEPaNIC patients and of 369 matched healthy children was blinded for treatment allocation (ClinicalTrials.gov-NCT01536275). Methods: Studied clinical outcomes included anthropometrics, health status, parent/caregiver-reported executive functions, and emotional/behavioral problems, and clinical tests for intelligence, visual-motor integration, alertness, motor coordination and memory. Univariable and multivariable linear and logistic regression analyses adjusted for risk factors assessed the impact of late-PN versus early-PN on the outcomes and investigated a potential mediation role of the adversely altered DNA-methylation of 37 CpG sites previously shown to be evoked by late-PN as compared with early-PN (3). Results: Overall, at 4 years follow-up, patients (356 late-PN patients, 328 early-PN patients) could be tested neurocognitively. They revealed worse anthropometric, health status, neurocognitive and emotional/behavioral developmental outcomes than the healthy control children. Outcomes of late-PN patients were never worse than those of early-PN patients. In contrast, late-PN patients had fewer internalizing (P=0.042) and externalizing problems (P=0.046), and fewer total emotional/behavioral problems (P=0.007) than early-PN patients, which were normalized by late-PN. Avoiding the early-PN induced adversely altered DNA-methylation status of the 37 CpG sites statistically explained its impact on the behavioral outcomes. Conclusion: Four years after randomization to late-PN or early-PN in the PICU, late-PN did not show harm, and was found to protect against emotional/behavioral problems, with altered DNA-methylation as a potential biological mediator hereof. These data further support de-implementation of PN-use early during critical illness in infants and children. (1) Fivez et al. N Eng J Med 2016 (2) Verstraete et al. Lancet Respir Med 2019 (3) Guiza et al. Lancet Respir Med 2020 (in press)

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Impact of withholding early parenteral nutrition completing enteral nutrition in pediatric critically ill patients (PEPaNIC trial): study protocol for a randomized controlled trial.

Publications

Impact of withholding early parenteral nutrition completing enteral nutrition in pediatric critically ill patients (PEPaNIC trial): study protocol for a randomized controlled trial.

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