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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.
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“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.
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“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.
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“Adding parenteral nutrition to enteral nutrition to increase intakes was associated with longer ICU stays and higher infection rates.13,14”
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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 previous randomised trials, nutritional interventions affected time to readiness for ICU discharge but not mortality.13,14”
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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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“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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Amino Acid Concentrations in Critically Ill Children Following Cardiac Surgery*
Gielen, M., Vanhorebeek, I., Wouters, P. J., Mesotten, D., Wernerman, J., den Berghe, G. V., & Rooyackers, O. (2014) · Pediatric Critical Care Medicine · doi:10.1097/pcc.0000000000000075 · Cited by 13
Self-citationWhen is parenteral nutrition indicated in the hospitalized, acutely ill patient?
Fragkos, K. C., Sebepos‐Rogers, G., & Rahman, F. Z. (2019) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000000615 · Cited by 13
“All rights rese concomitant prokinetic medicines is the preferred primary feeding route due to its trophic effects and reduction of bacterial translocation [90].”
BackgroundStrategies to optimize enteral feeding and nutrition in the critically ill child: a narrative review
Irving, S. Y., Albert, B. D., Mehta, N. M., & Srinivasan, V. (2021) · Pediatric Medicine · doi:10.21037/pm-21-6 · Cited by 13
“Protein delivery remains low in the acute phase of critical illness (22-24).”
BackgroundHuang, C.-Y., Güiza, F., Vlieger, G. D., Wouters, P. J., Gunst, J., Casaer, M. P., Vanhorebeek, I., Derese, I., den Berghe, G. V., & Meyfroidt, G. (2022) · Journal of Clinical Monitoring and Computing · doi:10.1007/s10877-022-00865-7 · Cited by 13
“The EPaNIC study compared early and late initiation of parenteral nutrition in 4640 adults admitted to seven ICUs between August 2007 and November 2010 [39].”
MethodResultSelf-citationNutrition Therapy for the Critically Ill Surgical Patient With Aortic Aneurysmal Rupture
Rahman, A., Martin, C. M., & Heyland, D. K. (2013) · Journal of Parenteral and Enteral Nutrition · doi:10.1177/0148607113501695 · Cited by 13
Mazeraud, A., Polito, A., & Annane, D. (2014) · Critical Care · doi:10.1186/cc13998 · Cited by 13
“Actually, caloric intake lowering (gastroparesis, intravenous glucose, or enteral nutrition lowering) without insulin adjustment may be one of the most frequent risk factors for hypoglycemia [54,55,60,61], and no study evaluated the effect of gluco-insulinotherapy on hypoglycemia rate.”
Patel, J. J., Rice, T. W., Compher, C. W., & Heyland, D. K. (2019) · Nutrition in Clinical Practice · doi:10.1002/ncp.10320 · Cited by 14
Temporal Trends in the Use of Parenteral Nutrition in Critically Ill Patients
Gershengorn, H. B., Kahn, J. M., & Wunsch, H. (2013) · CHEST Journal · doi:10.1378/chest.13-1597 · Cited by 13
Nutrition support for acute kidney injury 2020-consensus of the Taiwan AKI task force
Hung, K.-Y., Chen, S.-T., Chu, Y.-Y., Ho, G., & Liu, W.-L. (2021) · Journal of the Chinese Medical Association · doi:10.1097/jcma.0000000000000662 · Cited by 15
García‐Grimaldo, A., Rodríguez‐Moguel, N. C., Godínez‐Victoria, M., Rodríguez-Llamazares, S., Ríos‐Ayala, M. A., Cadeza‐Aguilar, J. D., & Osuna‐Padilla, I. A. (2025) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2025.01.044 · Cited by 12
Lauwers, C., Langouche, L., Wouters, P. J., Wilmer, A. P., den Berghe, G. V., Casaer, M. P., & Gunst, J. (2025) · Critical Care · doi:10.1186/s13054-025-05273-2 · Cited by 14
“From the 4640 patients included in the EPaNIC RCT [10], 3520 patients had available plasma phosphate measurements on ICU day 1 and 2, and were included in this secondary analysis (Supplementary Fig.”
InfluentialSelf-citationLoi, M. V., Wang, J. L., Ong, C., & Lee, J. H. (2017) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2017.02.005 · Cited by 13
Impact of early protein provision on the mortality of acute critically ill stroke patients
Wang, D., Lin, Z., Xie, L., Huang, K., Ji, Z., Gu, C., & Wang, S. (2021) · Nutrition in Clinical Practice · doi:10.1002/ncp.10768 · Cited by 12
Heming, N., Carlier, R., Prigent, H., Mekki, A., Jousset, C., Lofaso, F., Ambrosi, X., Bounab, R., Maxime, V., Mansart, A., et al. (2022) · Critical Care · doi:10.1186/s13054-022-04232-5 · Cited by 16
Acute liver injury in COVID-19 patients hospitalized in the intensive care unit: Narrative review
Polyzogopoulou, E., Amoiridou, P., Abraham, T. P., & Ventoulis, I. (2022) · World Journal of Gastroenterology · doi:10.3748/wjg.v28.i47.6662 · Cited by 12
Hill, N. E., Murphy, K. G., Saeed, S. M. B., Phadke, R., Chambers, D., Wilson, D. R., Brett, S. J., & Singer, M. (2017) · PLoS ONE · doi:10.1371/journal.pone.0182659 · Cited by 12
Vlieger, G. D., Vanhorebeek, I., Wouters, P. J., Derese, I., Casaer, M. P., Debaveye, Y. A., Hermans, G., Meersseman, P., Møller, H. J., den Berghe, G. V., et al. (2019) · Critical Care · doi:10.1186/s13054-019-2549-8 · Cited by 12
Self-citationMcKeever, L., Peterson, S. J., Lateef, O., Freels, S. A., Fonseca, T. L., Bocco, B. M. L. C., Fernandes, G. W., Roehl, K., Nowak, K., Mozer, M., et al. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgz077 · Cited by 12
Grinevich, V. B., Kravchuk, Y. A., Ei, T., Першко, А. М., Ped, V. I., Sas, I. E., Владимировна, Г. И., Lazebnik, L. B., & Stefanyuk, O. V. (2020) · Экспериментальная и клиническая гастроэнтерология · doi:10.31146/1682-8658-ecg-176-4-3-18 · Cited by 12
Hartwell, J. L., Cotton, A. B., Wenos, C. D., Timsina, L., Zarzaur, B. L., & Rozycki, G. S. (2019) · Annals of Surgery · doi:10.1097/sla.0000000000003708 · Cited by 13
“It is important to note, however, that the Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) study included many patients in medical ICUs and nearly 20% had a diagnosis of cancer, which makes comparisons between the EPaNIC patients and our trauma population problematic.(…”
ResultSaseedharan, S., Chada, R. R., Kadam, V., Chiluka, A., & Balakrishna, N. (2022) · Journal of Parenteral and Enteral Nutrition · doi:10.1002/jpen.2393 · Cited by 11
Vlieger, G. D., Ingels, C., Wouters, P. J., Debaveye, Y. A., Vanhorebeek, I., Wauters, J., Wilmer, A. P., Casaer, M. P., & den Berghe, G. V. (2018) · Clinical Microbiology and Infection · doi:10.1016/j.cmi.2018.05.017 · Cited by 12
Self-citationThe patient needing prolonged mechanical ventilation: a narrative review
Ambrosino, N. (2019) · Multidisciplinary Respiratory Medicine · doi:10.4081/mrm.2018.104 · Cited by 12
Preiser, J., & Wernerman, J. (2013) · Journal of Parenteral and Enteral Nutrition · doi:10.1177/0148607113495893 · Cited by 12
Ensuring Optimal Survival and Post-ICU Quality of Life in High-Risk ICU Patients
Wischmeyer, P. E. (2015) · Critical Care Medicine · doi:10.1097/ccm.0000000000001098 · Cited by 12
“Early versus late Parenteral Nutrition in Critically Ill adults (6) EDEN Trial (Pilot) (4) EDEN Trial (Full Randomized Controlled Trial) (3) arabi Trial (2) Early PN (7) The Tight Calorie Control Trial (9) SPN (8) Wei et al (5)”
BackgroundZhao, V. M., & Ziegler, T. R. (2012) · Wiley eBooks · doi:10.1002/9781119946045.ch57 · Cited by 12
Rethinking energy and protein provision for critically ill patients
Stoppe, C., Ridley, E. J., & Lee, Z. (2024) · Intensive Care Medicine · doi:10.1007/s00134-024-07726-8 · Cited by 15
Patel, J. J., Hurt, R. T., McClave, S. A., & Martindale, R. G. (2017) · Critical Care Clinics · doi:10.1016/j.ccc.2016.12.006 · Cited by 36
Reignier, J., Le Gouge, A., Lascarrou, J.-B., Annane, D., Argaud, L., Hourmant, Y., Asfar, P., Badie, J., Nay, M.-A., Botoc, N.-V., et al. (2021) · BMJ Open · doi:10.1136/bmjopen-2020-045041 · Cited by 17
“17 18 Higher protein intakes during the acute phase may be associated with greater muscle wasting and ICU-acquired weakness.”
BackgroundMalnutrition and perioperative nutritional rehabilitation in major operations
Lasithiotakis, K. G., Andreou, A., Migdadi, H., & Kritsotakis, E. I. (2025) · European surgery. Supplement/European surgery · doi:10.1007/s10353-025-00863-4 · Cited by 16
Balancing the promise and risks of geroscience interventions
Cohen, A. A., Beard, J., Ferrucci, L., Fülöp, T., Gladyshev, V. N., Moqri, M., Rikkert, M. G. M. O., & Picard, M. A. (2025) · Nature Aging · doi:10.1038/s43587-024-00788-9 · Cited by 20
Hadi, V., Khosroshahi, R. A., Imani, H., Jahangirfard, B., Majari, K., Kiany, F., & Hadi, S. (2025) · European journal of medical research · doi:10.1186/s40001-025-02579-3 · Cited by 13
“For example, Casaer et al. and Arabi et al. found no significant difference in mortality between early and delayed feeding [19, 20].”
InfluentialThe nutritional energy to clinical outcome relation revisited
Casaer, M. P. (2014) · Critical Care · doi:10.1186/cc13861 · Cited by 11
“If future RCTs confirm the impossibility to improve survival or functional outcome through enhanced feeding early in critical illness [3-7], the mechanisms behind this failure need to be unraveled to improve therapy.”
BackgroundInfluentialSelf-citationAmbrose, T., Silva, A. D., Naghibi, M., Saunders, J. A., Smith, T. R., Coleman, R. L., & Stroud, M. A. (2021) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2020.11.028 · Cited by 11
Nakamura, K., Hatakeyama, J., Liu, K., Kanda, N., Yamakawa, K., Nishida, T., Ohshimo, S., Inoue, S., Hashimoto, S., Maruyama, S., et al. (2022) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqac014 · Cited by 12
“Because this result was consistent with previous findings (31, 32), marked changes in nutrition delivery may be needed at the transition of the early and late periods in the acute phase, particularly for protein delivery.”
ResultHogenbirk, R. N. M., Hentzen, J. E. K. R., van der Plas, W. Y., Campmans-Kuijpers, M. J. E., Kruijff, S., & Klaase, J. M. (2023) · Cancers · doi:10.3390/cancers15030969 · Cited by 12
“It is suggested that early initiation of parenteral nutrition could induce suppression of this necessary autophagy and endogenous catabolism [58,59].”
Backgroundvan Gassel, R. J. J., Bels, J. L. M., Tartaglia, K., van Bussel, B. C. T., van Kuijk, S. M. J., Deane, A. M., Puthucheary, Z., Weijs, P. J. M., Vloet, L. C. M., Beishuizen, B., et al. (2023) · Trials · doi:10.1186/s13063-023-07380-3 · Cited by 11
“during the trial {11d} During the first 7 days of ICU stay parenteral nutrition will be prohibited [15, 20].”
BackgroundSelf-citationEarly feeding during critical illness
Bear, D. E., Puthucheary, Z., & Hart, N. (2013) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(13)70262-5 · Cited by 12
Tight Junction Ultrastructure Alterations in a Mouse Model of Enteral Nutrient Deprivation
Demehri, F. R., Krug, S. M., Feng, Y., Lee, I.-F. M., Schulzke, J. D., & Teitelbaum, D. H. (2015) · Digestive Diseases and Sciences · doi:10.1007/s10620-015-3991-3 · Cited by 11
Early Enteral Nutrition in Trauma: Is There Still Any Doubt?
Miller, K. R., Smith, J. W., Harbrecht, B. G., & Benns, M. V. (2016) · Current Trauma Reports · doi:10.1007/s40719-016-0045-z · Cited by 11
Shock Management for Cardio-surgical Intensive Care Unit Patient: The Silver Days
Hauffe, T., Krüger, B. D., Béttex, D., & Rudiger, A. (2016) · Cardiac failure review · doi:10.15420/cfr.2015:27:2 · Cited by 10
Trophic or full nutritional support?
Arabi, Y. M., & Al‐Dorzi, H. M. (2018) · Current Opinion in Critical Care · doi:10.1097/mcc.0000000000000508 · Cited by 11
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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