Impact of critical illness and withholding of early parenteral nutrition in the pediatric intensive care unit on long-term physical performance of children: a 4-year follow-up of the PEPaNIC randomized controlled trial.

BACKGROUND: Many critically ill children face long-term developmental impairments. The PEPaNIC trial attributed part of the problems at the level of neurocognitive and emotional/behavioral development to early use of parenteral nutrition (early-PN) in the PICU, as compared with withholding it for 1 week (late-PN). Insight in long-term daily life physical functional capacity after critical illness is limited. Also, whether timing of initiating PN affects long-term physical function of these children remained unknown. METHODS: This preplanned follow-up study of the multicenter PEPaNIC randomized controlled trial subjected 521 former critically ill children (253 early-PN, 268 late-PN) to quantitative physical function tests 4 years after PICU admission in Leuven or Rotterdam, in comparison with 346 age- and sex-matched healthy children. Tests included handgrip strength measurement, timed up-and-go test, 6-min walk test, and evaluation of everyday overall physical activity with an accelerometer. We compared these functional measures for the former critically ill and healthy children and for former critically ill children randomized to late-PN versus early-PN, with multivariable linear or logistic regression analyses adjusting for risk factors. RESULTS: As compared with healthy children, former critically ill children showed less handgrip strength (p < 0.0001), completed the timed up-and-go test more slowly (p < 0.0001), walked a shorter distance in 6 min (p < 0.0001) during which they experienced a larger drop in peripheral oxygen saturation (p ≤ 0.026), showed a lower energy expenditure (p ≤ 0.024), performed more light and less moderate physical activity (p ≤ 0.047), and walked fewer steps per day (p = 0.0074). Late-PN as compared with early-PN did not significantly affect these outcomes. CONCLUSIONS: Four years after PICU admission, former critically ill children showed worse physical performance as compared with healthy children, without impact of timing of supplemental PN in the PICU. This study provides further support for de-implementing the early use of PN in the PICU. Trial registration ClinicalTrials.gov, NCT01536275 ; registered on February 22, 2012.

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.

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.

Postoperative Cerebral Oxygen Saturation in Children After Congenital Cardiac Surgery and Long-Term Total Intelligence Quotient: A Prospective Observational Study.

OBJECTIVES: During the early postoperative period, children with congenital heart disease can suffer from inadequate cerebral perfusion, with possible long-term neurocognitive consequences. Cerebral tissue oxygen saturation can be monitored noninvasively with near-infrared spectroscopy. In this prospective study, we hypothesized that reduced cerebral tissue oxygen saturation and increased intensity and duration of desaturation (defined as cerebral tissue oxygen saturation < 65%) during the early postoperative period, independently increase the probability of reduced total intelligence quotient, 2 years after admission to a PICU. DESIGN: Single-center, prospective study, performed between 2012 and 2015. SETTING: The PICU of the University Hospitals Leuven, Belgium. PATIENTS: The study included pediatric patients after surgery for congenital heart disease admitted to the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Postoperative cerebral perfusion was characterized with the mean cerebral tissue oxygen saturation and dose of desaturation of the first 12 and 24 hours of cerebral tissue oxygen saturation monitoring. The independent association of postoperative mean cerebral tissue oxygen saturation and dose of desaturation with total intelligence quotient at 2-year follow-up was evaluated with a Bayesian linear regression model adjusted for known confounders. According to a noninformative prior, reduced mean cerebral tissue oxygen saturation during the first 12 hours of monitoring results in a loss of intelligence quotient points at 2 years, with a 90% probability (posterior ß estimates [80% credible interval], 0.23 [0.04-0.41]). Similarly, increased dose of cerebral tissue oxygen saturation desaturation would result in a loss of intelligence quotient points at 2 years with a 90% probability (posterior ß estimates [80% credible interval], -0.009 [-0.016 to -0.001]). CONCLUSIONS: Increased dose of cerebral tissue oxygen saturation desaturation and reduced mean cerebral tissue oxygen saturation during the early postoperative period independently increase the probability of having a lower total intelligence quotient, 2 years after PICU admission.

Long-term developmental effect of withholding parenteral nutrition in paediatric intensive care units: a 4-year follow-up of the PEPaNIC randomised controlled trial.

BACKGROUND: The PEPaNIC randomised controlled trial, which recruited 1440 critically ill infants and children in 2012-15, showed that withholding parenteral nutrition for 1 week (late-parenteral nutrition), compared with early supplementation within 24 h of admission to the paediatric intensive care unit (early-parenteral nutrition), prevented infections, accelerated recovery, and improved neurocognitive development assessed 2 years later. Because several neurocognitive domains can only be thoroughly assessed from age 4 years onwards, we aimed to determine the effect of late-parenteral nutrition versus early-parenteral nutrition on physical, neurocognitive, and emotional and behavioural development 4 years after randomisation. METHODS: This is a preplanned, blinded, 4-year follow-up study of participants included in the PEPaNIC trial (done at University Hospitals Leuven, Belgium; Erasmus Medical Centre Sophia Children's Hospital, Rotterdam, Netherlands; and Stollery Children's Hospital, Edmonton, AB, Canada) and of matched healthy children. Studied outcomes were anthropometrics; health status; parent-reported or caregiver-reported executive functions, and emotional and behavioural problems; and clinical tests for intelligence, visual-motor integration, alertness, motor coordination, and memory. Through multivariable linear and logistic regression analyses, after imputation for missing values (≤30%) and adjustment for risk factors, we investigated the effect of early-parenteral nutrition versus late-parenteral nutrition. This trial is registered with ClinicalTrials.gov, NCT01536275. FINDINGS: Between March 8, 2016, and Nov 8, 2019, 684 children from the original PEPaNIC trial (356 from the late-parenteral nutrition group and 328 from the early-parenteral nutrition group) were assessed for neurocognitive development at 4-years follow-up. Compared with the control group (369 healthy children), children who had critical illness had lower height (ß-estimate -2·11 [95% CI -3·15 to -1·06]; p<0·0001) and head circumference (-0·42 [-0·67 to -0·18]; p=0.00077); and worse health status (eg, hospital admission odds ratio 4·27 [95% CI 3·12 to 5·84]; p<0·0001), neurocognitive (eg, parent-reported or caregiver-reported total executive functioning ß-estimate 3·57 [95% CI 1·95 to 5·18], p<0·0001; total intelligence quotient -7·35 [-9·31 to -5·39], p<0·0001), and parent-reported or caregiver-reported emotional and behavioural developmental outcomes (internalising 2·73 [1·19 to 4·28], p=0·00055; externalising 1·63 [0·19 to 3·08], p=0·027; and total behavioural problems 2·95 [1·44 to 4·46], p=0·00013), adjusted for risk factors. Outcomes were never worse in the late-parenteral nutrition group compared with the early-parenteral nutrition group, but patients in the late-parenteral nutrition group had fewer parent-reported or caregiver-reported internalising (ß-estimate -1·88 [95% CI -3·69 to -0·07]; p=0·042), externalising (-1·73 [-3·43 to -0·03]; p=0·046), and total emotional and behavioural problems (-2·44 [-4·22 to -0·67]; p=0·0070) than patients who had received early-parenteral nutrition, after adjusting for risk factors, and were no longer different from healthy controls for these outcomes. INTERPRETATION: Omitting early parenteral nutrition use for critically ill children did not adversely affect long-term outcomes 4 years after randomisation and protected against emotional and behavioural problems, further supporting the deimplementation of early parenteral nutrition. FUNDING: European Research Council, Methusalem, Flanders Institute for Science and Technology, Research Foundation Flanders, Sophia Foundation, Stichting Agis Zorginnovatie, Erasmus Trustfonds, and the European Society for Clinical Nutrition and Metabolism.

Long-term developmental effects of withholding parenteral nutrition for 1 week in the paediatric intensive care unit: a 2-year follow-up of the PEPaNIC international, randomised, controlled trial.

BACKGROUND: The paediatric early versus late parenteral nutrition in critical illness (PEPaNIC) multicentre, randomised, controlled trial showed that, compared with early parenteral nutrition, withholding supplemental parenteral nutrition for 1 week in the paediatric intensive care unit (PICU; late parenteral nutrition) reduced infections and accelerated recovery from critical illness in children. We aimed to investigate the long-term impact on physical and neurocognitive development of early versus late parenteral nutrition. METHODS: In this preplanned 2-year follow-up study, all patients included in the PEPaNIC trial (which was done in University Hospitals Leuven, Belgium; Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, Netherlands; and Stollery Children's Hospital, Edmonton, AB, Canada) were approached for possible assessment of physical and neurocognitive development compared with healthy children who were matched for age and sex, and who had never been admitted to a neonatal ICU or a PICU. Assessed outcomes comprised anthropometric data; health status; parent-reported or caregiver-reported executive functions and emotional and behavioural problems; and tests for intelligence, visual-motor integration, alertness, motor coordination, inhibitory control, cognitive flexibility, and memory. To address partial responses among the children tested, we did multiple data imputation by chained equations before univariable and multivariable linear and logistic regression analyses adjusted for risk factors. This trial is registered with ClinicalTrials.gov, number NCT01536275. FINDINGS: At the 2-year follow-up, 60 (8%) of 717 children who received late parenteral nutrition and 63 (9%) of 723 children who received early parenteral nutrition had died (p=0·81). 68 (9%) of 717 children who received late and 91 (13%) of 723 children who received early parenteral nutrition were too disabled for neurocognitive assessment (p=0·059), and 786 patients (395 assigned to late and 391 assigned to early parenteral nutrition) consented for testing. 786 patients and 405 healthy control children underwent long-term outcome testing between Aug 4, 2014, and Jan 19, 2018, and were included in the imputation model for subsequent multivariable analyses. Late parenteral nutrition did not adversely affect anthropometric data, health status, or neurological functioning, and improved parent-reported or caregiver-reported executive functioning (late vs early parenteral nutrition ß estimate -2·258, 95% CI -4·012 to -0·504; p=0·011), more specifically inhibition (-3·422, -5·171 to -1·673; p=0·0001), working memory (-2·016, -3·761 to -0·270; p=0·023), and meta-cognition (-1·957, -3·694 to -0·220; p=0·027). Externalising behavioural problems (ß estimate -1·715, 95% CI -3·325 to -0·106; p=0·036) and visual-motor integration (0·468, 0·087 to 0·850; p=0·016) were also improved in the late parenteral nutrition group compared with the early parenteral nutrition group. After Bonferroni correction for multiple comparisons, the effect on inhibitory control remained significant (p=0·0001). INTERPRETATION: Withholding early parenteral nutrition for 1 week in the PICU did not negatively affect survival, anthropometrics, health status, and neurocognitive development, and improved inhibitory control 2 years after PICU admission. FUNDING: European Research Council Advanced Grant, Methusalem programme provided by the Flemish Government, Flemish Agency for Innovation by Science and Technology (IWT), Research Foundation Flanders (FWO), Sophia Children's Hospital Foundation (SSWO), Stichting Agis Zorginnovatie, Erasmus Trustfonds, and European Society for Parenteral and Enteral Nutrition (ESPEN) research grant.