Increased ureagenesis revealing metabolic intolerance to enhanced nutrition in the PICU: a secondary analysis of the PEPaNIC RCT
In brief
Higher urea tracked 75% higher infection odds in critically ill children
In a secondary analysis of 1,328 children not receiving kidney replacement therapy, early parenteral nutrition raised urea levels, and higher first-week urea-to-creatinine ratios tracked more infections, slower discharge and higher 90-day mortality. The marker statistically explained part of early nutrition's harm, but the analysis cannot show that urea itself caused worse outcomes; whether monitoring it can guide feeding remains unknown.
- Journal
- Critical care (London, England) (Q1)
- Published
- 25 September 2026
- Study design
- Randomized controlled trial
- Evidence level
- Level 1, High (CEBM 1b)
- Authors
- Ilse Vanhorebeek, Nazlı Umman Serin, Sascha C A T Verbruggen, Koen F M Joosten, Greet Van den Berghe, Jan Gunst
- PMID
- 42791581
- DOI
- 10.1186/s13054-026-06345-7
Why clinicians should know about it
- Picked for Neonatology (top studies of the week, 27 September 2026): Metabolic intolerance to early PN in PICU children
- Picked for Nephrology (top studies of the week, 27 September 2026): Higher ureagenesis linked to infection risk in early PN
- Picked for Critical Care and Intensive Care Medicine (top studies of the week, 27 September 2026): Early PN increases infection risk via metabolic intolerance
Abstract
BACKGROUND: As compared with withholding parenteral nutrition (PN) for one week (late-PN), early supplementation of insufficient enteral nutrition with PN (early-PN) increased infection risk and delayed recovery of critically ill children in the PEPaNIC-RCT, with harm attributed to higher amino acid doses. We hypothesized that this harm could be explained by increased ureagenesis, revealing metabolic intolerance to enhanced feeding. METHODS: This is a secondary analysis of the PEPaNIC-RCT (ClinicalTrials.gov-NCT01536275), in which patients (newborn-17 years) admitted to pediatric intensive care units (PICUs, Leuven-Rotterdam-Edmonton) were randomly allocated to early-PN or late-PN. For patients not receiving renal replacement therapy (RRT), we documented plasma/serum urea and urea/creatinine ratio (UCR) profiles throughout two PICU weeks and investigated whether an increased maximum value in the randomized intervention window (first week) statistically explained harm by early-PN, via multivariable logistic regression and Cox proportional hazards analyses. We studied risk of new infections and duration of PICU dependency as primary outcomes, 90-day mortality as safety outcome, and duration of hospital dependency as secondary outcome. RESULTS: Of 1440 PEPaNIC-patients recruited, 665 early-PN and 663 late-PN non-RRT patients had UCR data. Urea concentrations and UCRs were higher in early-PN than in late-PN patients throughout the first 11 days. Higher first week maximum UCR independently associated with (OR/HR expressed per 30 age-normalized units) an increased risk of new infection [adjusted OR (95%CI) 1.746 (1.353-2.265), p < 0.0001], lower likelihood of earlier live PICU [adjusted HR 0.745 (0.671-0.824), p < 0.0001] and hospital discharge [adjusted-HR 0.778 (0.703-0.860), p < 0.0001], and increased 90-day mortality [adjusted OR 1.432 (1.029-1.993), p = 0.033], and statistically explained (part of) any effect of the randomized intervention. Similar results were obtained for urea concentrations. CONCLUSIONS: Increased plasma/serum urea or UCR with early-PN partially explained the harm by early-PN, suggesting these may identify critically ill children metabolically intolerant to enhanced nutrition. This opens perspectives for incorporating urea or UCR into a dynamic monitoring tool to guide the appropriate timing and dosing of nutritional support. TRIAL REGISTRATION: ClinicalTrials.gov NCT01536275, registered February 2012.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.