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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.
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“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.
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“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]
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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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BackgroundPatkova, A. R., Joskova, V., Havel, E., Kovařík, M., Kuchařová, M., Zadák, Z., & Hronek, M. (2017) · Advances in Nutrition · doi:10.3945/an.117.015172 · Cited by 75
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MethodInflammation and response to nutrition interventions
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Relevance of non-nutritional calories in mechanically ventilated critically ill patients
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“Early initiation of PN is costly and may result in worse outcomes, as shown in the EPaNIC trial [13].”
BackgroundOchi, T., Feng, Y., Kitamoto, S., Nagao‐Kitamoto, H., Kuffa, P., Atarashi, K., Honda, K., Teitelbaum, D. H., & Kamada, N. (2016) · Scientific Reports · doi:10.1038/srep27634 · Cited by 55
Care of the critically ill patient
Jackson, M., & Cairns, T. (2020) · Surgery (Oxford) · doi:10.1016/j.mpsur.2020.11.002 · Cited by 83
Enteral Nutrition in the Critically Ill
Marik, P. E. (2013) · Critical Care Medicine · doi:10.1097/ccm.0000000000000051 · Cited by 56
“In a landmark study, Casaer et al (61) randomized 4,640 ICU patients to either early (within 48 hr) or delayed (day 8) supplemental PN.”
BackgroundBraunschweig, C. L., Freels, S. A., Sheean, P., Peterson, S. J., Gomez‐Perez, S. L., McKeever, L., Lateef, O., Gurka, D. P., & Fantuzzi, G. (2016) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.116.140764 · Cited by 55
“Only 3 of these trials (3, 4, 11) successfully delivered randomized energy intake at the nationally recommended estimated concentration or measured resting energy expenditure (18) early in ICU stay.”
BackgroundInfluentialLewis, S. R., Schofield-Robinson, O. J., Alderson, P., & Smith, A. F. (2018) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd012276.pub2 · Cited by 118
Nutritional screening for risk prediction in patients scheduled for abdominal operations
Kuppinger, D., Hartl, W. H., Bertok, M., Hoffmann, J. M., Cederbaum, J., Küchenhoff, H., Jauch, K.-W., & Rittler, P. (2012) · British Journal of Surgery · doi:10.1002/bjs.8710 · Cited by 73
Cha, J.-K., Kim, H.-S., Kim, E.-J., Lee, E., Lee, J. H., & Song, I. (2022) · Nutrients · doi:10.3390/nu14112318 · Cited by 55
“These findings might be new or different from previous studies [17,24].”
ResultThe evolution of nutrition in critical care: how much, how soon?
Wischmeyer, P. E. (2013) · Critical Care · doi:10.1186/cc11505 · Cited by 53
Lappas, B. M., Patel, D. A., Kumpf, V. J., Adams, D. W., & Seidner, D. L. (2017) · Gastroenterology Clinics of North America · doi:10.1016/j.gtc.2017.10.001 · Cited by 58
Anterior pituitary function in critical illness
Téblick, A., Langouche, L., & Van den Berghe, G. (2019) · Endocrine Connections · doi:10.1530/ec-19-0318 · Cited by 52
Nutrition support for critically ill patients
Al‐Dorzi, H. M., & Arabi, Y. M. (2021) · Journal of Parenteral and Enteral Nutrition · doi:10.1002/jpen.2228 · Cited by 62
Enteral nutrition is associated with improved outcome in patients with severe sepsis
for the German Competence Network Sepsis (SepNet), Elke, G., Kuhnt, E., Ragaller, M., Schädler, D., Frerichs, I., Brunkhorst, F. M., Löffler, M., Reinhart, K., & Weiler, N. (2013) · Medizinische Klinik - Intensivmedizin und Notfallmedizin · doi:10.1007/s00063-013-0224-4 · Cited by 55
Waele, E. D., Spapen, H. D., Honoré, P. M., Mattens, S., Gorp, V. V., Diltoer, M., & Huyghens, L. (2013) · Journal of Critical Care · doi:10.1016/j.jcrc.2013.02.011 · Cited by 52
Determining energy requirements in the ICU
Guttormsen, A. B., & Pichard, C. (2014) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000028 · Cited by 52
Malnutrition in the ICU Patient Population
Powers, J., & Samaan, K. H. (2014) · Critical Care Nursing Clinics of North America · doi:10.1016/j.ccell.2014.01.003 · Cited by 52
Rahman, A., Agarwala, R., Martin, C. M., Nagpal, D., Teitelbaum, M., & Heyland, D. K. (2016) · Journal of Parenteral and Enteral Nutrition · doi:10.1177/0148607116661839 · Cited by 52
“(%) Surgical elective 642 (82) Surgical emergency 145 (18) BMI, mean ± SD, kg/m(2) 27.”
BackgroundDesai, S. V., McClave, S. A., & Rice, T. W. (2014) · CHEST Journal · doi:10.1378/chest.13-1158 · Cited by 54
Intensive care management of acute-on-chronic liver failure
Bernal, W. E., Karvellas, C. J., Saliba, F., Saner, F. H., & Meersseman, P. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2020.10.024 · Cited by 55
Self-citationWhen should we add parenteral to enteral nutrition?
Vincent, J., & Preiser, J. (2012) · The Lancet · doi:10.1016/s0140-6736(12)61893-5 · Cited by 51
Dyck, L. V., Vanhorebeek, I., Wilmer, A. P., Schrijvers, A., Derese, I., Mebis, L., Wouters, P. J., den Berghe, G. V., Gunst, J., & Casaer, M. P. (2020) · Critical Care · doi:10.1186/s13054-020-02987-3 · Cited by 53
“3055 for insulin requirements) were based on changes observed in the EPaNIC RCT [4], during which nutrition was abruptly increased from day 7 to day 8 in a subset of patients.”
BackgroundMethodInfluentialSelf-citationTiming of (supplemental) parenteral nutrition in critically ill patients: a systematic review
Bost, R. B. C., Tjan, D. H. T., & van Zanten, A. R. H. (2014) · Annals of Intensive Care · doi:10.1186/s13613-014-0031-y · Cited by 50
“Casaer [13] found a significant shorter duration of renal replacement therapy (RRT) among patients on LPN compared with EPN (median 7 versus 10 days, p = 0.”
BackgroundMethodResultInfluentialBruyn, A. D., Gunst, J., Goossens, C., Perre, S. V., Guerra, G. G., Verbruggen, S. C. A. T., Joosten, K., Langouche, L., & den Berghe, G. V. (2020) · Critical Care · doi:10.1186/s13054-020-03256-z · Cited by 51
Recovery from AKI in the critically ill: potential confounders in the evaluation
Schetz, M., Gunst, J., Vlieger, G. D., & den Berghe, G. V. (2015) · Intensive Care Medicine · doi:10.1007/s00134-015-3946-3 · Cited by 50
Self-citationMedical Nutrition Therapy in Hospitalized Patients with Diabetes
Gosmanov, A. R., & Umpierrez, G. E. (2011) · Current Diabetes Reports · doi:10.1007/s11892-011-0236-5 · Cited by 48
Impact of Hypoglycemia in Hospitalized Patients
Carey, M., Boucai, L., & Zonszein, J. (2012) · Current Diabetes Reports · doi:10.1007/s11892-012-0336-x · Cited by 49
Attenuating Muscle Mass Loss in Critical Illness: the Role of Nutrition and Exercise
Chapple, L. S., Parry, S. M., & Schaller, S. J. (2022) · Current Osteoporosis Reports · doi:10.1007/s11914-022-00746-7 · Cited by 50
Reignier, J., Roux, B. G., Dequin, P. F., Maluf, V. A. B., Bohé, J., Casaer, M. P., Delbove, A., Dupuis, C., Fontaine, E. M., Gamon, P., et al. (2025) · Annals of Intensive Care · doi:10.1186/s13613-025-01509-0 · Cited by 55
“Moreover, compared to gastric feeding, postpyloric feeding is less physiological, and the need for specific expertise and equipment may delay EN initiation.”
Self-citationBlood glucose control in the ICU: don’t throw out the baby with the bathwater!
Gunst, J., & den Berghe, G. V. (2016) · Intensive Care Medicine · doi:10.1007/s00134-016-4350-3 · Cited by 50
Taverny, G., Lescot, T., Pardo, E., Thonon, F., Maarouf, M., & Alberti, C. (2019) · Critical Care · doi:10.1186/s13054-018-2303-7 · Cited by 48
Nutrition Management in Patients With Traumatic Brain Injury: A Narrative Review
Lee, H. Y., & Oh, B. (2022) · Brain & Neurorehabilitation · doi:10.12786/bn.2022.15.e4 · Cited by 54
“[36], early PN was associated with an increased morbidity and infection rate.”
BackgroundThe Japanese Critical Care Nutrition Guideline 2024
Nakamura, K., Yamamoto, R., Higashibeppu, N., Yoshida, M., Tatsumi, H., Shimizu, Y., Izumino, H., Oshima, T., Hatakeyama, J., Ouchi, A., et al. (2025) · Journal of Intensive Care · doi:10.1186/s40560-025-00785-z · Cited by 53
Risk analysis, diagnosis and management of gastrointestinal mucositis in pediatric cancer patients
Kuiken, N. S. S., Rings, E. H. H. M., & Tissing, W. J. E. (2014) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2014.12.009 · Cited by 47
“In general, the downside is that patients receiving PN are at greater risk of developing infectious complications [86,87].”
BackgroundRehal, M. S., Fiskaare, E., Tjäder, I., Norberg, Å., Rooyackers, O., & Wernerman, J. (2016) · Critical Care · doi:10.1186/s13054-016-1232-6 · Cited by 48
Weimann, A., Breitenstein, S., Breuer, J.-P., Gabor, S., Holland-Cunz, S. G., Kemen, M., Längle, F., Rayes, N., Reith, B., Rittler, P., et al. (2013) · Aktuelle Ernährungsmedizin · doi:10.1055/s-0033-1359887 · Cited by 49
Prevention and Therapy of Acute Kidney Injury in the Developing World
Kher, V., Srisawat, N., Noiri, E., Gharbi, M. B., Shetty, M. S., Yang, L., Bagga, A., Chakravarthi, R. M., & Mehta, R. L. (2017) · Kidney International Reports · doi:10.1016/j.ekir.2017.03.015 · Cited by 50
“A large randomized trial of early parenteral nutrition versus enteral nutrition showed that early parenteral nutrition was associated with prolonged ICU and hospital stay, increased infections, prolonged ventilatory support, and prolonged AKI recovery.(110) In the absence of adequately designed trials, most nutritiona…”
BackgroundCholestatic Alterations in the Critically Ill
Jenniskens, M., Langouche, L., & den Berghe, G. V. (2017) · CHEST Journal · doi:10.1016/j.chest.2017.08.018 · Cited by 47
Nutrition Therapy Issues in Esophageal Cancer
Miller, K. R., & Bozeman, M. C. (2012) · Current Gastroenterology Reports · doi:10.1007/s11894-012-0272-6 · Cited by 46
Nutrition in the critically ill patient
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Nutritional Support in the ICU
Reignier, J., Rice, T. W., Arabi, Y. M., & Casaer, M. P. (2025) · BMJ · doi:10.1136/bmj-2023-077979 · Cited by 57
Self-citationGlycemic Targets and Approaches to Management of the Patient with Critical Illness
Mesotten, D., & den Berghe, G. V. (2011) · Current Diabetes Reports · doi:10.1007/s11892-011-0241-8 · Cited by 45
Self-citationde Koning, M.-S. L. Y., Koekkoek, W. A. C., Kars, J. C. N., & van Zanten, A. R. H. (2019) · Journal of Parenteral and Enteral Nutrition · doi:10.1002/jpen.1663 · Cited by 47
Vankrunkelsven, W., Gunst, J., Amrein, K., Bear, D. E., Berger, M. M., Christopher, K. B., Fuhrmann, V., Hiesmayr, M., Ichaï, C., Jakob, S. M., et al. (2020) · Clinical Nutrition · doi:10.1016/j.clnu.2020.06.005 · Cited by 46
Self-citationHigh protein intake during the early phase of critical illness: Yes or no?
Preiser, J.-C. (2018) · Critical Care · doi:10.1186/s13054-018-2196-5 · Cited by 44
Stoian, M., Andone, A., Bândilă, S. R., Onișor, D. M., Babă, D.-F., Niculescu, R., Stoian, A., & Azamfirei, L. (2025) · Nutrients · doi:10.3390/nu17101659 · Cited by 52
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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