RESUMO
PURPOSE: In critically ill adults, withholding parenteral nutrition until 1 week after intensive care admission (Late-PN) facilitated recovery as compared with early supplementation of insufficient enteral nutrition with parenteral nutrition (Early-PN). However, the impact on long-term mortality and functional outcome, in relation to the estimated nutritional risk, remains unclear. METHODS: In this prospective follow-up study of the multicenter EPaNIC randomized controlled trial, we investigated the impact of Late-PN on 2-year mortality (N = 4640) and physical functioning, assessed by the 36-Item Short Form Health Survey (SF-36; in 3292 survivors, responding 819 [738-1058] days post-randomization). To account for missing data, we repeated the analyses in two imputed models. To identify potential heterogeneity of treatment effects, we investigated the impact of Late-PN in different nutritional risk subgroups as defined by Nutritional Risk Screening-2002-score, modified NUTrition Risk in the Critically Ill-score, and age (above/below 70 years), and we evaluated whether there was statistically significant interaction between classification to a nutritional risk subgroup and the effect of the randomized intervention. Secondary outcomes were SF-36-derived physical and mental component scores (PCS & MCS). RESULTS: Two-year mortality (20.5% in Late-PN, 19.8% in Early-PN; P = 0.54) and physical functioning (70 [40-90] in both study-arms; P = 0.99) were similar in both groups, also after imputation of missing physical functioning data. Likewise, Late-PN had no impact on 2-year mortality and physical functioning in any nutritional risk subgroup. PCS and MCS were similar in both groups. CONCLUSION: Late-PN did not alter 2-year survival and physical functioning in adult critically ill patients, independent of anticipated nutritional risk.
RESUMO
BACKGROUND: Critically ill children suffer from impaired physical/neurocognitive development 2 years later. Glucocorticoid treatment alters DNA methylation within the hypothalamus-pituitary-adrenal (HPA) axis which may impair normal brain development, cognition and behaviour. We tested the hypothesis that paediatric-intensive-care-unit (PICU) patients, sex- and age-dependently, show long-term abnormal DNA methylation within the HPA-axis layers, possibly aggravated by glucocorticoid treatment in the PICU, which may contribute to the long-term developmental impairments. RESULTS: In a pre-planned secondary analysis of the multicentre PEPaNIC-RCT and its 2-year follow-up, we identified differentially methylated positions and differentially methylated regions within HPA-axis genes in buccal mucosa DNA from 818 former PICU patients 2 years after PICU admission (n = 608 no glucocorticoid treatment; n = 210 glucocorticoid treatment) versus 392 healthy children and assessed interaction with sex and age, role of glucocorticoid treatment in the PICU and associations with long-term developmental impairments. Adjusting for technical variation and baseline risk factors and correcting for multiple testing (false discovery rate < 0.05), former PICU patients showed abnormal DNA methylation of 26 CpG sites (within CRHR1, POMC, MC2R, NR3C1, FKBP5, HSD11B1, SRD5A1, AKR1D1, DUSP1, TSC22D3 and TNF) and three DNA regions (within AVP, TSC22D3 and TNF) that were mostly hypomethylated. These abnormalities were sex-independent and only partially age-dependent. Abnormal methylation of three CpG sites within FKBP5 and one CpG site within SRD5A1 and AKR1D1 was partly attributable to glucocorticoid treatment during PICU stay. Finally, abnormal methylation within FKBP5 and AKR1D1 was most robustly associated with long-term impaired development. CONCLUSIONS: Two years after critical illness in children, abnormal methylation within HPA-axis genes was present, predominantly within FKBP5 and AKR1D1, partly attributable to glucocorticoid treatment in the PICU, and explaining part of the long-term developmental impairments. These data call for caution regarding liberal glucocorticoid use in the PICU.