Cited by 307Clinical Nutrition and GastroenterologyHyperglycemia and glycemic control in critically ill and hospitalized patientsEnhanced Recovery After Surgery

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Role of Disease and Macronutrient Dose in the Randomized Controlled EPaNIC Trial

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Casaer, Michael P., Wilmer, Alexander, Hermans, Greet, Wouters, Pieter J., Mesotten, Dieter, Van den Berghe, Greet·2013·American Journal of Respiratory and Critical Care Medicine

DOI 10.1164/rccm.201206-0999oc

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Abstract

Rationale: Early parenteral nutrition to supplement insufficient enteral feeding during intensive care (early PN) delays recovery as compared with withholding parenteral nutrition for 1 week (late PN). Objectives: To assess whether deleterious effects of early PN relate to severity of illness or to the dose or type of macronutrients. Methods: Secondary analyses of a randomized controlled trial (EPaNIC; n = 4,640) performed in seven intensive care units from three departments in two Belgian hospitals. In part 1, all patients were included to assess the effect of the randomized allocation to early PN or late PN in subgroups of patients with increasing-on-admission severity of illness. In part 2, observationally, the association of the amount and type of macronutrients with recovery was documented in those patient cohorts still present in intensive care on Days 3, 5, 7, 10, and 14. Measurements and Main Results: The primary end point was time to live discharge from the intensive care unit. For part 1, a secondary end point, acquisition of new infections, was also analyzed. All statistical analyses were performed by univariable and adjusted multivariable methods. In none of the subgroups defined by type or severity of illness was a beneficial effect of early PN observed. The lowest dose of macronutrients was associated with the fastest recovery and any higher dose, administered parenterally or enterally, was associated with progressively more delayed recovery. The amount of proteins/amino acids rather than of glucose appeared to explain delayed recovery with early feeding. Conclusions: Early combined parenteral/enteral nutrition delayed recovery irrespective of severity of critical illness. No dose or type of macronutrient was found to be associated with improved outcome. Clinical trial registered with www.clinicaltrials.gov (NCT00512122).

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Additional file 2 of Replacing protein via enteral nutrition in a stepwise approach in critically ill patients: the REPLENISH randomized clinical trial protocol
Arabi, Y. M., Al-Dorzi, H. M., Sadat, M., Muharib, D., Algethamy, H. M., Al-Hameed, F., Mady, A. M., Alghamdi, A., Almekhlafi, G. A., Al-Fares, A. A., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26607517
Additional file 2 of Towards a fasting-mimicking diet for critically ill patients: the pilot randomized crossover ICU-FM-1 study
Dyck, L. V., Vanhorebeek, I., Wilmer, A., Schrijvers, A., Derese, I., Mebis, L., Wouters, P. J., Van den Berghe, G., Gunst, J., & Casaer, M. P. (2020) · Figshare · doi:10.6084/m9.figshare.12364937
Self-citation
Additional file 1 of High-protein intake and early exercise in adult intensive care patients: a prospective, randomized controlled trial to evaluate the impact on functional outcomes
de Azevedo, J. R. A., Lima, H. C. M., Frota, P. H. D. B., Nogueira, I. R. O. M., Souza, S. C. D. C., Fernandes, E. A. A., & Cruz, A. M. D. S. (2021) · Figshare · doi:10.6084/m9.figshare.17007161
Additional file 2 of High-protein intake and early exercise in adult intensive care patients: a prospective, randomized controlled trial to evaluate the impact on functional outcomes
de Azevedo, J. R. A., Lima, H. C. M., Frota, P. H. D. B., Nogueira, I. R. O. M., Souza, S. C. D. C., Fernandes, E. A. A., & Cruz, A. M. D. S. (2021) · Figshare · doi:10.6084/m9.figshare.17007164
Additional file 1 of Statistical analysis plan for the replacing protein via enteral nutrition in a stepwise approach in critically ill patients (REPLENISH) randomized clinical trial
Arabi, Y. M., Al-Dorzi, H. M., Aldibasi, O. S., Sadat, M., Jose, J., Muharib, D., Algethamy, H. M., Al-Fares, A. A., Al-Hameed, F., Mady, A. M., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25744410
Additional file 1 of Impact of early high protein intake in critically ill patients: a randomized controlled trial
Wang, Y., Ye, Y., Xuan, L., Xu, L., Wang, P., Ma, J., Wang, Y., Chen, Y., Miao, J., Wang, W., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26129650
Additional file 1 of Towards a fasting-mimicking diet for critically ill patients: the pilot randomized crossover ICU-FM-1 study
Dyck, L. V., Vanhorebeek, I., Wilmer, A., Schrijvers, A., Derese, I., Mebis, L., Wouters, P. J., Van den Berghe, G., Gunst, J., & Casaer, M. P. (2020) · Figshare · doi:10.6084/m9.figshare.12364928
Self-citation
Additional file 3 of Towards a fasting-mimicking diet for critically ill patients: the pilot randomized crossover ICU-FM-1 study
Dyck, L. V., Vanhorebeek, I., Wilmer, A., Schrijvers, A., Derese, I., Mebis, L., Wouters, P. J., Van den Berghe, G., Gunst, J., & Casaer, M. P. (2020) · Figshare · doi:10.6084/m9.figshare.12364943
Self-citation
Additional file 3 of Replacing protein via enteral nutrition in a stepwise approach in critically ill patients: the REPLENISH randomized clinical trial protocol
Arabi, Y. M., Al-Dorzi, H. M., Sadat, M., Muharib, D., Algethamy, H. M., Al-Hameed, F., Mady, A. M., Alghamdi, A., Almekhlafi, G. A., Al-Fares, A. A., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26607520
Additional file 1 of Replacing protein via enteral nutrition in a stepwise approach in critically ill patients: the REPLENISH randomized clinical trial protocol
Arabi, Y. M., Al-Dorzi, H. M., Sadat, M., Muharib, D., Algethamy, H. M., Al-Hameed, F., Mady, A. M., Alghamdi, A., Almekhlafi, G. A., Al-Fares, A. A., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26607514
Additional file 2 of Statistical analysis plan for the replacing protein via enteral nutrition in a stepwise approach in critically ill patients (REPLENISH) randomized clinical trial
Arabi, Y. M., Al-Dorzi, H. M., Aldibasi, O. S., Sadat, M., Jose, J., Muharib, D., Algethamy, H. M., Al-Fares, A. A., Al-Hameed, F., Mady, A. M., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25744446
The impact of lipid-rich nutrition on ketogenesis and muscle weakness in sepsis
Lauwers, C., Gunst, J., Dawy, S. E., Derde, S., Pauwels, L., Derese, I., Perre, S. V., den Berghe, G. V., Casaer, M. P., & Langouche, L. (2026) · Intensive Care Medicine Experimental · doi:10.1186/s40635-026-00867-8
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Macronutrient excess in critical illness: too much of a good thing?
Alcaide, M. J., Puthucheary, Z., & Prowle, J. R. (2026) · Current Opinion in Critical Care · doi:10.1097/mcc.0000000000001369
High-protein, low-carbohydrate enteral nutrition in intensive care unit: Achieving nutritional targets with minimal gastrointestinal side effects - an Italian multi-centre observational study - ITARGET
Guido, S., Genovese, T., Sguazzotti, I., Ballestra, M., Ferrante, M., & Lattuada, M. (2026) · Clinical Nutrition Open Science · doi:10.1016/j.nutos.2026.100676
Long term outcomes after ICU
Aerde, N. V., & Hermans, G. (2026) · Best practice & research. Clinical anaesthesiology · doi:10.1016/j.bpa.2026.05.003
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Nutrition support in acute cardiac care
Casaer, M. P., & den Berghe, G. V. (2021) · Oxford University Press eBooks · doi:10.1093/med/9780198849346.003.0030_update_001
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Is normoglycemia a reachable state in safe, effective glycemic control in critical care? A review and steady-state analysis showing the need for dual insulin and nutrition control
Chase, J. G., Seret, M., Uyttendaele, V., Knopp, D. J., Shannon, H., & Desaive, T. (2026) · Annual Reviews in Control · doi:10.1016/j.arcontrol.2026.101072
Increased ureagenesis revealing metabolic intolerance to enhanced nutrition in the PICU: a secondary analysis of the PEPaNIC RCT
Vanhorebeek, I., Serin, N. U., Verbruggen, S. C. A. T., Joosten, K., den Berghe, G. V., & Gunst, J. (2026) · Critical Care · doi:10.1186/s13054-026-06345-7

Authors: Casaer, M. P., Wilmer, A., Hermans, G., Wouters, P. J., Mesotten, D., & Van den Berghe, G.
Affiliations: Universitair Ziekenhuis Leuven (BE)
KU Leuven (BE)
Laboratory and Department of Intensive Care Medicine and
Corresponding author: Casaer, Michael P.
ORCID: Casaer, Michael P.
Wilmer, Alexander
Hermans, Greet
Mesotten, Dieter
Venue: American Journal of Respiratory and Critical Care Medicine
Publisher: Oxford University Press (OUP)
Published: 2013-02-01
Volume: 187
Issue: 3
Pages: 247-255
ISSN: 1073-449X (ISSN-L)
1535-4970
DOI: 10.1164/rccm.201206-0999oc
OpenAlex: W1840057839
Semantic Scholar: 37a3fd62d1564a467a4fe20b913801329a33e0e8
Cited by: 307
References: 46
Citations by year: 2026: 15 · 2025: 20 · 2024: 26 · 2023: 22 · 2022: 24 · 2021: 28 · 2020: 18 · 2019: 23 · 2018: 33 · 2017: 27 · 2016: 12 · 2015: 27 · 2014: 23 · 2013: 9
FWCI: 17.54
Type: journal article
Language: en
Open access: green
lirias.kuleuven.be
Licence: other-oa
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations: American Journal of Respiratory and Critical Care Medicine (publishedVersion)
PubMed (publishedVersion)
Lirias (KU Leuven) (submittedVersion, other-oa)
Funders: European Commission
Vlaamse regering
FP7 Ideas: European Research Council (321670)
Topics: Health Sciences › Nursing › Nutrition and Dietetics › Clinical Nutrition and Gastroenterology
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hyperglycemia and glycemic control in critically ill and hospitalized patients
Health Sciences › Medicine › Surgery › Enhanced Recovery After Surgery
Keywords: early parenteral nutrition, critical illness, glucose supplementation, enteral nutrition, intensive care unit discharge, infection acquisition, disease severity
MeSH terms: Aged, Belgium, Energy Intake, Critical Care, Cross Infection, Dietary Carbohydrates, Dietary Proteins, Enteral Nutrition, Female, Humans, Intensive Care Units, Length of Stay, Lipids, Male, Middle Aged, Parenteral Nutrition, Severity of Illness Index, Time Factors, Cohort Studies, Causality, Odds Ratio, Critical Illness, Dietary Supplements, Kaplan-Meier Estimate

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Role of Disease and Macronutrient Dose in the Randomized Controlled EPaNIC Trial

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