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

Abstract

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. 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. 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 (β-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 β-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 (β-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. 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. 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.