Physical, Emotional/Behavioral, and Neurocognitive Developmental Outcomes From 2 to 4 Years After PICU Admission: A Secondary Analysis of the Early Versus Late Parenteral Nutrition Randomized Controlled Trial Cohort*

Abstract

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.

Editor’s Choice Articles for March

“…Over 400 children contributed to the primary outcome and these new data add insight into the complexity of outcomes and the potential scope of psychological interventions to support parents of children who experience perioperative morbidities. Add this reading to the authors’ recent report on postoperative morbidities and neurodevelopment (7), and we are now building a more complete picture of how best to study late outcomes after critical illness (8, 9).…”

Measuring growth in critically ill neonates and children

“…The post‐PICU discharge period is a particularly vulnerable period of development 72,73 . Verlinden et al evaluated neurodevelopmental outcomes of the post‐PICU discharge patient population and concluded that, relative to their healthy controls, the post‐PICU discharge patients had worse neurocognitive, emotional, and behavioral outcomes 74 . The authors concluded that, after adjusting for patient, center, and socioeconomic factors, former PICU patients demonstrated reduced growth in height and a worse trajectory of recovery in the domains of executive function and intelligence.…”

Editor’s Choice Articles for August

“…Verlinden I, Guiza F, Dulfer K, et al: Physical, Emotional/Behavioral, and Neurocognitive Developmental Outcomes From 2 to 4 Years After PICU Admission: A Secondary Analysis of the Early Versus Late Parenteral Nutrition Randomized Controlled Trial Cohort (1).…”

“…My first Editor’s Choice article is a unique pre-specified secondary analysis of the PEPaNIC (early versus late parenteral nutrition in the pediatric ICU) trial cohort data (1). Over 600 post-PICU patients were assessed at 2 and 4 years after illness.…”