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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
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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.
In the citing paper
“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]
The cited source says what the claim attributes to it.
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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Design of nutrition trials in critically ill patients: food for thought
Arabi, Y. M., Al‐Dorzi, H. M., McIntyre, L., & Mehta, S. (2016) · Annals of Translational Medicine · doi:10.21037/atm.2016.05.02 · Cited by 4
“Table 1 summarizes and contrasts eight recent multicenter trials which compared different doses of enteral nutrition (1,3-5), or enteral versus parenteral nutrition (6-9).”
BackgroundResultUtilization of Intensive Care Unit Nutrition Consultation Is Associated With Reduced Mortality
Tignanelli, C. J., Sheetz, K. H., Petersen, A. J., Park, P. K., Napolitano, L. M., Cooke, C. R., & Cherry‐Bukowiec, J. R. (2019) · Journal of Parenteral and Enteral Nutrition · doi:10.1002/jpen.1534 · Cited by 4
Hecker, M., Felbinger, T. W., & Mayer, K. (2013) · Medizinische Klinik - Intensivmedizin und Notfallmedizin · doi:10.1007/s00063-012-0199-6 · Cited by 4
Enteral Nutrition in Shock: Less May Be More
Patel, J. J., Heyland, D. K., & Rice, T. W. (2019) · Critical Care Medicine · doi:10.1097/ccm.0000000000003797 · Cited by 4
The History of Critical Care Nutrition
Martindale, R. G., Hurt, R. T., Mundi, M. S., & McClave, S. A. (2024) · Critical Care Clinics · doi:10.1016/j.ccc.2024.09.001 · Cited by 2
Nutritional Considerations in Neonates Requiring Gastrointestinal Surgery.
Tzeng, T. H., Nayak, S. P., & Huff, K. A. (2025) · NeoReviews · doi:10.1542/neo.26-3-021 · Cited by 3
Nutritional support in trauma and critically ill patients
González-Castillo, A. M., Picazo, L., Manzo, E., Marcucci, F., & Latifi, R. (2025) · European surgery. Supplement/European surgery · doi:10.1007/s10353-025-00872-3 · Cited by 6
“When EN is not feasible due to conditions such as bowel ischemia, ileus, or perforation, total parenteral nutrition (TPN) becomes necessary [4, 5].”
Sinatra, N., Maniaci, A., Cuttone, G., Testa, T. S., Tutino, S., Paternò, D. S., Girombelli, A., Ippati, G., Caputo, G., Sorbello, M., et al. (2025) · Journal of Personalized Medicine · doi:10.3390/jpm15110545 · Cited by 5
“Conversely, the EPaNIC trial, one of the largest randomized controlled trials in this field, found that delaying PN until day 8 reduced ICU infections, shortened mechanical ventilation, and decreased overall healthcare costs, without increasing mortality [33].”
Zhuang, Z., Liu, X., Lu, H., Wu, Q., Chen, Y., & Ni, Q. Y. (2025) · European journal of medical research · doi:10.1186/s40001-025-03560-w · Cited by 3
“In addition, hypoalbuminemia, resulting from the escape of albumin into the intercellular matrix and indicative of nutritional decline [44], impairs immune function, promotes fluid retention, and increases susceptibility to infection [45], thereby exacerbating atherosclerosis, thrombosis, and other…”
Shin, D.-W. (2025) · Journal of Gastric Cancer · doi:10.5230/jgc.2026.26.e1 · Cited by 2
“…randomized trial published in the New England Journal of Medicine in 2011 comparing early and late parenteral nutrition has reported that early SPN was inferior in terms of postoperative recovery and incidence of complications, additional efforts to collect more evidence have continued [22].”
Abnormal carnitine concentrations in critical illness associated with compromised outcome
Lauwers, C., Langouche, L., Güiza, F., Pardo, E., Mebis, L., Perre, S. V., Wouters, P. J., Vermeersch, P., den Berghe, G. V., Gunst, J., et al. (2026) · Critical Care · doi:10.1186/s13054-025-05746-4 · Cited by 3
Self-citationCombret, Y., Machefert, M., Hilfiker, R., Schnell, G., Bachasson, D., Lamia, B., Prieur, G., & Médrinal, C. (2026) · Critical Care Medicine · doi:10.1097/ccm.0000000000007059 · Cited by 4
“…on the prevention of ICU-AW. preventive and therapeutic strategies for ICU-AW include adaptations to the individual’s metabolism (avoiding hyperglycemia or early parenteral nutrition), individualization of drug use (i.e., sedation), and direct muscle stimulation to reduce muscle wasting (38, 39).”
Feeding the injured brain: nutrients, dose, timing, and monitoring
Arabi, Y. M., Stoppe, C., Casaer, M. P., Ridley, E. J., Reignier, J., Al‐Dorzi, H. M., Annoni, F., & Preiser, J. (2026) · Intensive Care Medicine · doi:10.1007/s00134-026-08324-6 · Cited by 3
Self-citationNutrition support in the ICU: current evidence and evolving standards
Peake, S., Ridley, E. J., & Reignier, J. (2026) · Intensive Care Medicine · doi:10.1007/s00134-026-08474-7 · Cited by 3
“These guidelines also recommend delaying supplemental parenteral nutrition for 3–7 days in patients intolerant to enteral feeding, based on the EPaNIC RCT [3].”
Arbeloa, C. S., de la Gándara, A. M., Cinto, C. L., Lasierra, J. L. F., & Vácaro, J. A. M. (2020) · Medicina Intensiva (English Edition) · doi:10.1016/j.medine.2019.12.008 · Cited by 4
May, C. C., Harris, E. A., Hannawi, Y., & Smetana, K. S. (2021) · Journal of Parenteral and Enteral Nutrition · doi:10.1002/jpen.2282 · Cited by 3
Wang, X., Miao, S., Yang, Y., Yang, Q., Meng, D., & Hong, L. (2024) · Nutrition Journal · doi:10.1186/s12937-023-00894-1 · Cited by 3
“The target energy was determined by considering corrected ideal body weight, age, and gender (the target energy is based on the calculation of the fiber index) [19, 20].”
BackgroundRabheru, R., Langan, A., Merriweather, J. L., Connolly, B. A., Whelan, K., & Bear, D. E. (2024) · American Journal of Clinical Nutrition · doi:10.1016/j.ajcnut.2024.12.028 · Cited by 5
“%) studies measured and reported nutritional risk at baseline, whereby 5 studies used the Nutritional Risk Score (NRS)- 2002 [12,14,21,25,36] and 2 studies used the Nutritional Risk in Critically ill (NUTRIC) score [21,39], and 1 study classi fi ed nutritional risk using BMI categories [23].”
Timing of the initiation of parenteral nutrition in critically ill adults
Metodologica, G. D. A., Ceriani, E., & Rusconi, A. M. (2011) · Internal and Emergency Medicine · doi:10.1007/s11739-011-0731-3 · Cited by 3
Issues of energy and protein feeding in critically ill: the permissive underfeeding trial.
Weijs, P. J. M. (2015) · PubMed Central · doi:10.3978/j.issn.2072-1439.2015.08.23 · Cited by 3
“Since both feeding strategies were aimed at underfeeding, the level of unknown overfeeding is probably low in this study contrary to other large RCTs (6,8).”
BackgroundResultErnährungsmanagement kritisch kranker Kinder
Weber, K., Kohl‐Sobania, M., & Härtel, C. (2018) · Intensivmedizin up2date · doi:10.1055/s-0043-121061 · Cited by 3
“[14] Casaer MP, Mesotten D, Hermans G et al.”
BackgroundMiyajima, I., Yatabe, T., Kuroiwa, H., Tamura, T., & Yokoyama, M. (2019) · Clinical Nutrition · doi:10.1016/j.clnu.2019.01.010 · Cited by 3
Protein in der klinischen Ernährung kritisch kranker Patienten
Kreymann, K. G., & de Heer, G. (2019) · Aktuelle Ernährungsmedizin · doi:10.1055/a-0843-6733 · Cited by 3
“Eine ähnliche Diskussion hat sich nach der Veröffentlichung der PEPaNIC-Studie ergeben [33].”
BackgroundInfluentialSpecialized nutrition support in burns, wasting, deconditioning, and hypermetabolic conditions
Song, J., Wolf, S. E., Wade, C. E., & Ziegler, T. R. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-818460-8.00034-4 · Cited by 3
Variability in Parenteral Nutrition Use in US Children's Hospitals
Pettit, R. J., Pruitt, L. C. C., Iantorno, S. E., & Bucher, B. T. (2020) · Journal of Parenteral and Enteral Nutrition · doi:10.1002/jpen.2014 · Cited by 3
Haraguchi, M., Ichinose, K., Miyaaki, H., Hanada, M., Fukushima, M., Sasaki, R., Miuma, S., Hara, T., Kugiyama, T., Soyama, A., et al. (2021) · Trials · doi:10.1186/s13063-021-05086-y · Cited by 3
“Early administration of nutrition after transplant has been associated with a worse prognosis among seriously ill patients, suggesting that protein loading during the hypercatabolic state may negatively influence prognosis [25].”
BackgroundRosen, A. N., Ross, R. C., Tran, K. K., & Franck, A. J. (2022) · Journal of Pharmacy Practice · doi:10.1177/08971900221074932 · Cited by 3
Ochoa, J. B., Berger, A. L., Hussein, R., & Huhmann, M. B. (2022) · Clinical Nutrition · doi:10.1016/j.clnu.2022.10.020 · Cited by 7
Gunst, J., Bruyn, A. D., Jacobs, A., Langouche, L., Derese, I., Dulfer, K., Güiza, F., Guerra, G. G., Wouters, P. J., Joosten, K. F. M., et al. (2023) · Critical Care · doi:10.1186/s13054-023-04514-6 · Cited by 3
“The current feeding practice of withholding PN in the acute phase of critical illness not only lowers the severity of hyperglycemia, it also increases the risk of hypoglycemia [10, 44].”
BackgroundSelf-citationNutritional support in oncology: the place of parenteral nutrition (literature review)
Пасечник, И. Н., Skobelev, E. I., & Сергеевна, Б. Т. (2023) · Journal of Modern Oncology · doi:10.26442/18151434.2023.3.202261 · Cited by 3
Nutrition Considerations in the Intensive Care Unit
Burnette, A., & Allen, C. (2024) · AACN Advanced Critical Care · doi:10.4037/aacnacc2024643 · Cited by 3
Why One-Size-Fits-All Doesn’t Work in Intensive Care Unit Nutrition?
Bear, D. E., Lambell, K., & Stoppe, C. (2024) · Critical Care Clinics · doi:10.1016/j.ccc.2024.09.008 · Cited by 3
Ernährungstherapie bei Schädel-Hirn-Trauma
Marcus, H. E., Spöhr, F., Böttiger, B. W., Grau, S. J., & Padosch, S. A. (2012) · Der Anaesthesist · doi:10.1007/s00101-012-2061-x · Cited by 3
“Less Is More”: The New Paradigm in Critical Care
Marik, P. E. (2014) · Springer eBooks · doi:10.1007/978-3-319-11020-2_2 · Cited by 3
Development and Pilot Trial Results of Stochastic Targeted (STAR) Glycemic Control in a Medical ICU
Fisk, L., Compte, A. J. L., Shaw, G. M., Penning, S., Desaive, T., & Chase, J. G. (2012) · IFAC Proceedings Volumes · doi:10.3182/20120829-3-hu-2029.00044 · Cited by 3
In critically ill adults, supplemental parenteral nutrition reduced nosocomial infections
Chertow, D. S., & O’Grady, N. P. (2013) · Annals of Internal Medicine · doi:10.7326/0003-4819-158-8-201304160-02003 · Cited by 3
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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