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Early versus Late Parenteral Nutrition in Critically Ill Adults
Open accessAbstract
BACKGROUND: Controversy exists about the timing of the initiation of parenteral nutrition in critically ill adults in whom caloric targets cannot be met by enteral nutrition alone. METHODS: In this randomized, multicenter trial, we compared early initiation of parenteral nutrition (European guidelines) with late initiation (American and Canadian guidelines) in adults in the intensive care unit (ICU) to supplement insufficient enteral nutrition. In 2312 patients, parenteral nutrition was initiated within 48 hours after ICU admission (early-initiation group), whereas in 2328 patients, parenteral nutrition was not initiated before day 8 (late-initiation group). A protocol for the early initiation of enteral nutrition was applied to both groups, and insulin was infused to achieve normoglycemia. RESULTS: Patients in the late-initiation group had a relative increase of 6.3% in the likelihood of being discharged alive earlier from the ICU (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.13; P=0.04) and from the hospital (hazard ratio, 1.06; 95% CI, 1.00 to 1.13; P=0.04), without evidence of decreased functional status at hospital discharge. Rates of death in the ICU and in the hospital and rates of survival at 90 days were similar in the two groups. Patients in the late-initiation group, as compared with the early-initiation group, had fewer ICU infections (22.8% vs. 26.2%, P=0.008) and a lower incidence of cholestasis (P<0.001). The late-initiation group had a relative reduction of 9.7% in the proportion of patients requiring more than 2 days of mechanical ventilation (P=0.006), a median reduction of 3 days in the duration of renal-replacement therapy (P=0.008), and a mean reduction in health care costs of €1,110 (about $1,600) (P=0.04). CONCLUSIONS: Late initiation of parenteral nutrition was associated with faster recovery and fewer complications, as compared with early initiation. (Funded by the Methusalem program of the Flemish government and others; EPaNIC ClinicalTrials.gov number, NCT00512122.).
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“In this circumstance, it is becoming likely that nutrition support may even delay healing due to potential interference with clearance of damage.150, 151, 152”
From Hypoalbuminemia: Pathogenesis and Clinical Significance (2019) · cites this paper as [150]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Late, as compared with early initiation of PN, was associated with lower mortality, less need for ventilation and renal support, shorter ICU and hospital stay, and fewer infectious complications [36].”
From Nutrition in Sepsis: A Bench-to-Bedside Review. (2020) · cites this paper as [36]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Casaer et al. (16) observed that early (supplemental or exclusive) PN is associated with increased morbidity including prolonged ICU dependency and mechanical ventilation, and increased infection rate and need for renal replacement therapy.”
From ESPEN guideline on clinical nutrition in the intensive care unit. (2019) · cites this paper as [16]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In a sub-group analysis of the EPaNIC study, early and late PN was compared in complicated pulmonary/esophageal and abdomino-pelvic surgery patients.Reduced infection rates in late vs early PN were observed (29.9% vs. 40.2%,p=0.01) with no difference in any mortality outcomes, whereas all these patients received virtually no EN during the seven study days (16).”
From ESPEN guideline on clinical nutrition in the intensive care unit. (2019) · cites this paper as [16]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Casaer et al. [14] observed that early (supplemental or exclusive) PN is associated with increased morbidity including prolonged ICU dependency and mechanical ventilation, and increased infection rate and need for renal replacement therapy.”
From ESPEN practical and partially revised guideline: Clinical nutrition in the intensive care unit (2023) · cites this paper as [14]
Experimental — accuracy not yet measured
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In the citing paper
“Reduced infection rates in late vs early PN were observed (29.9% vs. 40.2%,p ¼ 0.01) with no difference in any mortality outcomes, whereas all these patients received virtually no EN during the seven study days [14].”
From ESPEN practical and partially revised guideline: Clinical nutrition in the intensive care unit (2023) · cites this paper as [14]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Adding parenteral nutrition to enteral nutrition to increase intakes was associated with longer ICU stays and higher infection rates.13,14”
The cited source says what the claim attributes to it.
In the citing paper
“In the EpaNIC randomised trial of early versus late parenteral nutrition to supplement insufficient enteral intakes, mortality was similar in the two groups, but benefits in the late group included fewer ICU-acquired infections and shorter durations of mechanical ventilation, renal replacement therapy, and ICU stay.13”
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“the toleration of a nutritional deficit during the first week of critical illness resulted in fewer complications and accelerated recovery [91].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [91]
The cited source says what the claim attributes to it.
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“In our trial, ICU-acquired infections were less common than in EpaNIC despite greater critical illness severity and higher mortality of patients, perhaps because all infections were adjudicated by an independent committee.”
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In the citing paper
“In previous randomised trials, nutritional interventions affected time to readiness for ICU discharge but not mortality.13,14”
The cited source says what the claim attributes to it.
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“A similar strategy regarding this endpoint has been used previously in studies on nutrition in the ICU.13,14”
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“However, results of this study revealed the potential harm of nutritional intervention aiming at full, possibly overestimated calorie targets during the acute phase of critical illness.”
From ESPEN guideline on clinical nutrition in the intensive care unit. (2019) · cites this paper as [16]
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“This was also the conclusions of the EPaniC study including more than 1000 septic patients (16).”
From ESPEN guideline on clinical nutrition in the intensive care unit. (2019) · cites this paper as [16]
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“Additionally, one study showed possible benefit of a further delay of PN if EN is not possible/tolerated in non-malnourished ICU patients (16).”
From ESPEN guideline on clinical nutrition in the intensive care unit. (2019) · cites this paper as [16]
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“Additionally, one study showed possible benefit of a further delay of PN if EN is not possible/ tolerated [14].”
From ESPEN practical and partially revised guideline: Clinical nutrition in the intensive care unit (2023) · cites this paper as [14]
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In the citing paper
“However, results of this study revealed the potential harm of nutritional intervention aiming at full, possibly overestimated calorie targets during the acute phase of critical illness.”
From ESPEN practical and partially revised guideline: Clinical nutrition in the intensive care unit (2023) · cites this paper as [14]
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Self-citationPharmacological therapies for acute respiratory distress syndrome
Spieth, P. M., & Zhang, H. (2013) · Current Opinion in Critical Care · doi:10.1097/mcc.0000000000000056 · Cited by 33
Cao, C., Gao, T., Cheng, M., Xi, F., Zhao, C., & Yu, W. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.06.135 · Cited by 34
van Puffelen, E., Polinder, S., Vanhorebeek, I., Wouters, P. J., Bossche, N., Peers, G., Verstraete, S., Joosten, K., den Berghe, G. V., Verbruggen, S. C. A. T., et al. (2018) · Critical Care · doi:10.1186/s13054-017-1936-2 · Cited by 34
“Our results confirmed previously published results of studies in critically ill adults that have compared early with late initiation of PN [20, 21].”
ResultSelf-citationJung, Y. T., Park, J. Y., Jeon, J., Kim, M. J., Lee, S. H., & Lee, J. G. (2018) · Nutrients · doi:10.3390/nu10111589 · Cited by 36
Adiamah, A., Ranat, R. A., & Gomez, D. (2019) · HPB · doi:10.1016/j.hpb.2019.01.005 · Cited by 34
Less is more in critical care is supported by evidence-based medicine
Auriemma, C. L., den Berghe, G. V., & Halpern, S. D. (2019) · Intensive Care Medicine · doi:10.1007/s00134-019-05771-2 · Cited by 33
Nutritional support in sepsis: when less may be more
van Niekerk, G., Meaker, C., & Engelbrecht, A. (2020) · Critical Care · doi:10.1186/s13054-020-2771-4 · Cited by 36
“This observation raises a question: why, given the “paucity of studies”, are there no high-quality clinical trials on the efficacy of permissive underfeeding in sepsis? Indeed, initiating early parenteral nutrition has even been found to solicit detrimental effects in at least some large clinical trials [4, 5], and it…”
BackgroundMoonen, H. P. F. X., & van Zanten, A. R. H. (2020) · Current Opinion in Critical Care · doi:10.1097/mcc.0000000000000741 · Cited by 35
Baumgartner, A., Hasenboehler, F., Cantone, J., Hersberger, L., Bargetzi, A., Bargetzi, L., Kaegi-Braun, N., Tribolet, P., Gomes, F., Hoess, C., et al. (2021) · Clinical Nutrition · doi:10.1016/j.clnu.2020.10.009 · Cited by 34
“infectious complications and prolonged length of hospital and intensive care stay in critically-ill patients treated with parenteral nutrition in addition to partial enteral nutrition [38].”
How much underfeeding can the critically ill adult patient tolerate?
Tatucu-Babet, O. A., & Ridley, E. J. (2022) · Journal of Intensive Medicine · doi:10.1016/j.jointm.2022.01.002 · Cited by 39
“[58] Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, et al.”
BackgroundInfluentialKuslapuu, M., Jõgela, K., Starkopf, J., & Blaser, A. R. (2015) · Intensive & Critical Care Nursing · doi:10.1016/j.iccn.2015.03.001 · Cited by 34
The 2013 Arvid Wretlind lecture: Evolving concepts in parenteral nutrition
Berger, M. M. (2014) · Clinical Nutrition · doi:10.1016/j.clnu.2014.03.005 · Cited by 34
Determining energy needs in critically ill patients
Cooney, R. N., & Frankenfield, D. C. (2012) · Current Opinion in Critical Care · doi:10.1097/mcc.0b013e3283514bbc · Cited by 34
Supplemental Parenteral Nutrition: Review of the Literature and Current Nutrition Guidelines
Russell, M. K., & Wischmeyer, P. E. (2018) · Nutrition in Clinical Practice · doi:10.1002/ncp.10096 · Cited by 34
Our Scientific Journey through the Ups and Downs of Blood Glucose Control in the ICU
den Berghe, G. V., Vanhorebeek, I., Langouche, L., & Gunst, J. (2023) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202309-1696so · Cited by 34
Lou, J., Kong, H., Xiang, Z., Zhu, X., Cui, S., Li, J., Jin, G., Huang, N., Le, X., Fan, Y., et al. (2025) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2025.1603104 · Cited by 33
Protein for the critically ill patient—what and when?
Plank, L. D. (2013) · European Journal of Clinical Nutrition · doi:10.1038/ejcn.2013.34 · Cited by 33
Early versus late parenteral nutrition for critically ill term and late preterm infants
Moon, K., Athalye‐Jape, G., Rao, U., & Rao, S. C. (2020) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd013141.pub2 · Cited by 33
Zonies, D. H., Codner, P. A., Park, P. K., Martin, N. D., Lissauer, M. E., Evans, S. L., Cocanour, C. S., & Brasel, K. J. (2019) · Trauma Surgery & Acute Care Open · doi:10.1136/tsaco-2019-000304 · Cited by 34
Intermittent or continuous feeding: any difference during the first week?
Dyck, L. V., & Casaer, M. P. (2019) · Current Opinion in Critical Care · doi:10.1097/mcc.0000000000000617 · Cited by 33
“This RCT demonstrated that late parenteral nutrition enhanced recovery and avoided complications, such as new infections and muscle weakness [7,8].”
BackgroundSelf-citationWang, C.-Y., Fu, P., Chao, W., Wang, W.-N., Chen, C., & Huang, Y. (2020) · Nutrients · doi:10.3390/nu12113518 · Cited by 35
Early Enteral Feeding Improves Tolerance of Parenteral Nutrition in Preterm Newborns
Boscarino, G., Conti, M. G., Chiara, M. D., Bianchi, M., Onestà, E., Faccioli, F., Deli, G., Repole, P., Oliva, S., Cresi, F., et al. (2021) · Nutrients · doi:10.3390/nu13113886 · Cited by 33
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Nutritional support in the recovery phase of critically ill children
Joosten, K., Eveleens, R. D., & Verbruggen, S. C. A. T. (2018) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000549 · Cited by 35
van den Berg, M., Shi, Z., Claassen, W. J., Hooijman, P. E., Lewis, C. T. A., Andersen, J. L., van der Pijl, R. J., Bogaards, S. J. P., Conijn, S., Peters, E. L., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adg3894 · Cited by 32
“…illness is often accompanied by a hypermetabolic state related to the activation of catabolic hormones, resulting in elevated energy expenditure and malnutrition ( 42 ), an SRX state–induced reduction of energy consumption may benefit the nutritional status and energy balance of the patients.”
BackgroundMuscle weakness after critical illness: unravelling biological mechanisms and clinical hurdles
Pierre, A., Favory, R., Bourel, C., Howsam, M., Romien, R., Lancel, S., & Préau, S. (2025) · Critical Care · doi:10.1186/s13054-025-05462-z · Cited by 39
“This may be attributed to anabolism resistance, worsening of hyperglycaemia, insulin needs, and autophagy dysfunction [35, 36].”
The role of dietitians in critical care
Terblanche, E. (2018) · Journal of the Intensive Care Society · doi:10.1177/1751143718774715 · Cited by 34
Clinical Nutrition of Critically Ill Patients in the Context of the Latest ESPEN Guidelines
Gostyńska, A., Stawny, M., Dettlaff, K., & Jelińska, A. (2019) · Medicina · doi:10.3390/medicina55120770 · Cited by 34
“Despite the mentioned studies comparing early EN and PN in ICU patients, withholding early parenteral nutrition for 1 week, as suggested in the EPaNIC study [11], and conducting a trophic EN may be the best clinical option.”
BackgroundResultShould We Increase Protein Delivery During Critical Illness?
van Zanten, A. R. H. (2016) · Journal of Parenteral and Enteral Nutrition · doi:10.1177/0148607115626905 · Cited by 32
The science and art of pediatric critical care nutrition
Martinez, E. E., & Mehta, N. M. (2016) · Current Opinion in Critical Care · doi:10.1097/mcc.0000000000000316 · Cited by 33
Nutrition: A Primary Therapy in Pediatric Acute Respiratory Distress Syndrome
Wilson, B., & Typpo, K. (2016) · Frontiers in Pediatrics · doi:10.3389/fped.2016.00108 · Cited by 31
“Research in the adult patient population have demonstrated mixed results with regard to days of mechanical ventilation and morbidity, such as infection and renal insufficiency (78, 86, 88).”
BackgroundResultCurrent Pharmacological Approach to ARDS: The Place of Bosentan
Araz, Ö. (2020) · Eurasian Journal of Medicine · doi:10.5152/eurasianjmed.2020.19218 · Cited by 32
“reported with aggressive early caloric supplementation with parenteral nutrition [27].”
BackgroundServiá, L., Delgado, J. C. L., Carmona, T. G., Trujillano, J., Bordejé, M.-L., Marco, E. M., Portugal-Rodríguez, E., Lorencio, C., Montejo, J. C., Vera, P., et al. (2021) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2021.11.018 · Cited by 35
Metabolic acidosis during parenteral nutrition: Pathophysiological mechanisms
Dounousi, E. C., Zikou, X. T., Koulouras, V., & Katopodis, K. P. (2015) · Indian Journal of Critical Care Medicine · doi:10.4103/0972-5229.156473 · Cited by 31
Nutrition Support in Critical Illness — Bridging the Evidence Gap
Ziegler, T. R. (2011) · New England Journal of Medicine · doi:10.1056/nejme1106612 · Cited by 31
Thibault, R., Bear, D. E., Fischer, A., Montejo, J. C., Hiesmayr, M., Tamási, P., Uyar, M., Waele, E. D., Weber‐Carstens, S., & Singer, P. (2023) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2023.06.033 · Cited by 35
Acute Hepatic Failure and Nutrition
Kappus, M. R. (2019) · Nutrition in Clinical Practice · doi:10.1002/ncp.10462 · Cited by 34
S3-Leitlinie Sepsis – Prävention, Diagnose, Therapie und Nachsorge
Deutsche Sepsis Gesellschaft e., V., Brunkhorst, F. M., Weigand, M. A., Pletz, M. W., Gastmeier, P., Lemmen, S., Meier‐Hellmann, A., Ragaller, M., Weyland, A., Marx, G., et al. (2020) · Medizinische Klinik - Intensivmedizin und Notfallmedizin · doi:10.1007/s00063-020-00671-6 · Cited by 31
Waele, E. D., Jakubowski, J. R., Stocker, R. A., & Wischmeyer, P. E. (2020) · Clinical Nutrition · doi:10.1016/j.clnu.2020.12.032 · Cited by 34
Nutrition in the Neurocritical Care Unit: a New Frontier
Tavarez, T., Roehl, K., & Koffman, L. (2021) · Current Treatment Options in Neurology · doi:10.1007/s11940-021-00670-8 · Cited by 32
Sickness-Associated Anorexia: Mother Nature’s Idea of Immunonutrition?
van Niekerk, G., Isaacs, A. W., Nell, T. A., & Engelbrecht, A. (2016) · Mediators of Inflammation · doi:10.1155/2016/8071539 · Cited by 32
“Indeed, it was found in one study that patients receiving early parenteral nutrition (on day 3 in the intensive care unit) had a small but significantly higher incidence of infection [23] while another study showed a decrease in mortality associated with permissive underfeeding (60–70% of caloric goal) [24].”
BackgroundResultRalls, M. W., Demehri, F. R., Feng, Y., Raskind, S., Ruan, C., Schintlmeister, A., Loy, A., Hanson, B. T., Berry, D., Burant, C., et al. (2016) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00088.2016 · Cited by 30
Metadata
- Authors
- Casaer, M. P., Mesotten, D., Hermans, G., Wouters, P. J., Schetz, M., Meyfroidt, G., Van Cromphaut, S., Ingels, C., Meersseman, P., Muller, J., Vlasselaers, D., Debaveye, Y., Desmet, L., Dubois, J., Van Assche, A., Vanderheyden, S., Wilmer, A., & Van den Berghe, G.
- Affiliations
- KU Leuven (BE)
- Jessa Hospital (BE)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2011-08-11
- Volume
- 365
- Issue
- 6
- Pages
- 506-517
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2162310928
- Semantic Scholar
- 43f68b96b74375a705c7271a7c056f6279b2a02c
- Cited by
- 1,696
- References
- 63
- Citations by year
- 2026: 85 · 2025: 102 · 2024: 99 · 2023: 77 · 2022: 82 · 2021: 111 · 2020: 119 · 2019: 107 · 2018: 101 · 2017: 123 · 2016: 115 · 2015: 154 · 2014: 162 · 2013: 135 · 2012: 93
- FWCI
- 122.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek
- Vlaamse regering
- 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
- parenteral nutrition, timing of parenteral nutrition initiation, critically ill adults, intensive care unit, enteral nutrition, insulin infusion, normoglycemia, intensive care unit discharge, hospital discharge, cholestasis, mechanical ventilation duration, renal replacement therapy, health care costs, functional status
- MeSH terms
- Adult, Aged, Energy Intake, Enteral Nutrition, Female, Humans, Infections, Inflammation, Intensive Care Units, Length of Stay, Male, Middle Aged, Parenteral Nutrition, Prospective Studies, Time Factors, Critical Illness, Practice Guidelines as Topic, Kaplan-Meier Estimate
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