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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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“The largest trial on this issue [11] provided a clear confirmation of the toxicity of the first strategy.”
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“For example, the role of supplemental parenteral nutrition is an ongoing debate,(27) and at the time of our study, data regarding harmful effects of parenteral nutrition from the EpANIC trial had not yet been published.(28) We have previously reported our use of parenteral nutrition in this cohort,(29) and in keeping…”
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Self-citationLeukocyte telomere length in paediatric critical illness: effect of early parenteral nutrition
Verstraete, S., Vanhorebeek, I., van Puffelen, E., Derese, I., Ingels, C., Verbruggen, S. C. A. T., Wouters, P. J., Joosten, K., Hanot, J., Guerra, G. G., et al. (2018) · Critical Care · doi:10.1186/s13054-018-1972-6 · Cited by 25
“Also, as previous studies performed in rodent models and in disease-free adults have suggested shortened telomeres as the result of excessive food consumption [14, 15], we further hypothesised that initiation of supplemental PN given early during critical illness, as compared with not using PN for one week in the PICU…”
ResultSelf-citationLew, C. C. H., Wong, G. J. Y., Cheung, K. P., Fraser, R. J., Chua, A. P., Chong, M. F., & Miller, M. (2018) · Annals of Intensive Care · doi:10.1186/s13613-018-0443-1 · Cited by 25
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Early versus late enteral nutrition in critically ill patients receiving vasopressor support
Dorken‐Gallastegi, A., Gebran, A., Gaitanidis, A., Naar, L., Hwabejire, J. O., Parks, J. J., Lee, J., Kaafarani, H. M. A., Velmahos, G. C., & Mendoza, A. E. (2021) · Journal of Parenteral and Enteral Nutrition · doi:10.1002/jpen.2266 · Cited by 25
Oghazian, M. B., Javadi, M. R., Radfar, M., Torkamandi, H., Sadeghi, M., Hayatshahi, A., & Gholami, K. (2015) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.1546 · Cited by 26
“The data of the current study suggest that glargine insulin appears to be at least as effective and safe as regular insulin in PN solution for glycemic control in stable critical care patients receiving PN. Based on the results of our study, successful transition from insulin infusion to basal SC insulin occurs when t…”
MethodInfluentialFeng, Y., Tsai, Y.-H., Xiao, W., Ralls, M. W., Stoeck, A., Wilson, C. L., Raines, E. W., Teitelbaum, D. H., & Dempsey, P. J. (2015) · Molecular and Cellular Biology · doi:10.1128/mcb.00143-15 · Cited by 25
“Several studies have indicated that early TPN administration in critically ill patients is associated with worsened clinical outcomes and increased rates of septicemia, often from enterically derived organisms (1, 2).”
BackgroundNutrition Support for Critically Ill Patients With Cancer
Lach, K., & Peterson, S. J. (2017) · Nutrition in Clinical Practice · doi:10.1177/0884533617712488 · Cited by 27
“No differences in mortality were seen between groups, although infectious complications, time spent on mechanical ventilation, organ dysfunction, and ICU and hospital length of stay were significantly lower in the late PN group, suggesting a benefit of delaying PN initiation in the critically ill population.(63) Criti…”
Shi, J., Wei, L., Huang, R., & Liao, L. (2018) · Medicine · doi:10.1097/md.0000000000011874 · Cited by 25
Role of artificial intelligence in critical care nutrition support and research
Kittrell, H. D., Shaikh, A., Adintori, P. A., McCarthy, P. J., Kohli-Seth, R. D., Nadkarni, G. N., & Sakhuja, A. (2024) · Nutrition in Clinical Practice · doi:10.1002/ncp.11194 · Cited by 25
Ridley, E. J., Bailey, M., Chapman, M. J., Chapple, L. S., Deane, A. M., Gojanovic, M., Higgins, A. M., Hodgson, C. L., King, V. L., Marshall, A. P., et al. (2025) · Critical Care · doi:10.1186/s13054-024-05189-3 · Cited by 27
Russell, J. A., & Walley, K. R. (2013) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201303-0567up · Cited by 24
Should We Aim for Full Enteral Feeding in the First Week of Critical Illness?
McClave, S. A., Codner, P. A., Patel, J. J., Hurt, R. T., Allen, K. S., & Martindale, R. G. (2016) · Nutrition in Clinical Practice · doi:10.1177/0884533616653809 · Cited by 24
Optimising growth in very preterm infants: reviewing the evidence
Young, A., Beattie, R. M., & Johnson, M. J. (2022) · Archives of Disease in Childhood Fetal & Neonatal · doi:10.1136/archdischild-2021-322892 · Cited by 24
How soon should we start interventional feeding in the ICU?
Fremont, R. D., & Rice, T. W. (2014) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000000047 · Cited by 24
Antioxidant Strategies in Neurocritical Care
Hanafy, K. A., & Selim, M. H. (2011) · Neurotherapeutics · doi:10.1007/s13311-011-0085-6 · Cited by 24
Haddad, S. H., Yousef, Z., Al-Azzam, S., Al‐Dawood, A., Al‐Zahrani, A. A., Alzamel, H., Tamim, H., Deeb, A., & Arabi, Y. M. (2014) · Injury · doi:10.1016/j.injury.2014.07.025 · Cited by 24
Evidence for the use of parenteral nutrition in the pediatric intensive care unit
Fivez, T., Kerklaan, D., Mesotten, D., Verbruggen, S. C. A. T., Joosten, K., & den Berghe, G. V. (2015) · Clinical Nutrition · doi:10.1016/j.clnu.2015.11.004 · Cited by 25
Self-citationSummers, M. J., Chapple, L. S., McClave, S. A., & Deane, A. M. (2016) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.115.122200 · Cited by 24
“The point estimate favored a benefit for the intervention in 5 of these studies (12–14, 17, 18) and harm for 5 studies (15, 16, 19, 21, 22).”
BackgroundThe clinical potential of GDF15 as a “ready-to-feed indicator” for critically ill adults
Dyck, L. V., Gunst, J., Casaer, M. P., Peeters, B., Derese, I., Wouters, P. J., de Zegher, F., Vanhorebeek, I., & den Berghe, G. V. (2020) · Critical Care · doi:10.1186/s13054-020-03254-1 · Cited by 24
Self-citationBoscarino, G., Chiara, M. D., Cellitti, R., Nardo, M. C. D., Conti, M. G., Parisi, P., Spalice, A., Mario, C. D., Ronchi, B., Russo, A., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-98088-4 · Cited by 24
Supplemental parenteral nutrition in critically ill patients
Casaer, M. P., Wilmer, A. P., & den Berghe, G. V. (2013) · The Lancet · doi:10.1016/s0140-6736(13)61068-5 · Cited by 24
Self-citationA patient-level meta-analysis of intensive glucose control in critically ill adults
Adigbli, D., Li, Y., Hammond, N., Chatoor, R., Devaux, A. G., Li, Q., Billot, L., Annane, D., Arabi, Y., Bilotta, F., et al. (2024) · NEJM Evidence · doi:10.1056/evidoa2400082 · Cited by 25
“49 Most recently a large randomized trial from the same group reported that intensive glucose control conferred no mortality benefit in critically ill patients not receiving early parenteral nutrition.”
Nutrition support in the critically ill
Huynh, D. K., Chapman, M. J., & Nguyen, N. Q. (2013) · Current Opinion in Gastroenterology · doi:10.1097/mog.0b013e32835c9c83 · Cited by 23
Body cell mass evaluation in critically ill patients: killing two birds with one stone
Fiaccadori, E., Morabito, S., Cabassi, A., & Regolisti, G. (2014) · Critical Care · doi:10.1186/cc13852 · Cited by 23
“Indeed, recent data suggest that individual tailoring of calorie supplementation in terms of both timing [8] and intake [9,10] could impact significantly on the effects of nutritional support on patients’ prognosis.”
BackgroundIngels, C., Møller, H. J., Hansen, T. K., Wouters, P. J., Vanhorebeek, I., & den Berghe, G. V. (2012) · Journal of Clinical Immunology · doi:10.1007/s10875-012-9830-9 · Cited by 23
Self-citationBerger, M. M., Soguel, L., Charrière, M., Theriault, B. M., Pralong, F. P., & Schaller, M. D. (2015) · Clinical Nutrition · doi:10.1016/j.clnu.2015.12.002 · Cited by 25
Controversies in Critical Care Nutrition Support
Patel, J. J., & Codner, P. A. (2016) · Critical Care Clinics · doi:10.1016/j.ccc.2015.11.002 · Cited by 28
Kuiken, N. S. S., Rings, E. H. H. M., van den Heuvel‐Eibrink, M. M., van de Wetering, M. D., & Tissing, W. J. E. (2017) · Supportive Care in Cancer · doi:10.1007/s00520-017-3715-7 · Cited by 25
“Furthermore, adult patients with early initiated TPN had more infections, 26 versus 22% and a higher incidence of cholestasis [19].”
BackgroundLooijaard, W. G. P. M., Denneman, N., Broens, B., Girbes, A. R. J., Weijs, P. J. M., & Straaten, H. M. O. (2018) · Clinical Nutrition · doi:10.1016/j.clnu.2018.11.012 · Cited by 22
“Furthermore, high protein delivery may be accompanied by high energy delivery which seems detrimental [3,4,25,26], possibly due to refeeding or disease-related endogenous energy production [2,27].”
BackgroundAre periods of feeding and fasting protective during critical illness?
Puthucheary, Z., & Gunst, J. (2020) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000718 · Cited by 24
Early Enteral Nutrition in Mechanically Ventilated Patients With COVID‐19 Infection
Farina, N., Nordbeck, S., Montgomery, M., Cordwin, L., Blair, F., Cherry‐Bukowiec, J. R., Kraft, M. D., Pleva, M. R., & Raymond, E. (2021) · Nutrition in Clinical Practice · doi:10.1002/ncp.10629 · Cited by 27
“00 Severe hypophosphatemia, n (%) 12 (24) 6 (12) .”
Characteristics and Current Practice of Parenteral Nutrition in Hospitalized Patients
Wischmeyer, P. E., Weitzel, L. B., Mercaldi, K., Zaloga, G. P., Hise, M. E., Pontes‐Arruda, A., & Turpin, R. S. (2012) · Journal of Parenteral and Enteral Nutrition · doi:10.1177/0148607112444448 · Cited by 23
Nutrition in the Elderly. Frequently Asked Questions
John, B. K., Bullock, M., Brenner, L., McGaw, C., & Scolapio, J. S. (2013) · The American Journal of Gastroenterology · doi:10.1038/ajg.2013.125 · Cited by 22
Ingels, C., Vanhorebeek, I., Steffensen, R., Derese, I., Jensen, L., Wouters, P. J., Hermans, G., Thiel, S., & den Berghe, G. V. (2013) · Pediatric Research · doi:10.1038/pr.2013.180 · Cited by 23
Self-citationParenteral nutrition: never say never
Oshima, T., & Pichard, C. (2015) · Critical Care · doi:10.1186/cc14723 · Cited by 24
“Recently, a few voices have suggested that parenteral nutrition (PN) was potentially dangerous for the critically ill patient [5].”
BackgroundMethodvan der Kolk, M. B. M., van den Boogaard, M., Becking-Verhaar, F. L., Custers, H., van der Hoeven, H., Pickkers, P., & van Laarhoven, C. J. H. M. (2017) · Journal of Gastrointestinal Surgery · doi:10.1007/s11605-017-3459-1 · Cited by 23
“37 TPN should be started on day 3 if patients had a MUSTscore of 1 and enteral feeding had not been started on day 3.”
BackgroundHill, A., Heyland, D. K., Elke, G., Schaller, S. J., Stocker, R. A., Haberthür, C., von Loeffelholz, C., Suchner, U., Puthucheary, Z., Bear, D. E., et al. (2020) · Nutrition Research Reviews · doi:10.1017/s0954422420000165 · Cited by 24
How to feed a patient with acute kidney injury
Ostermann, M., Macedo, E. M., & Straaten, H. M. O. (2019) · Intensive Care Medicine · doi:10.1007/s00134-019-05615-z · Cited by 23
Autophagy flux in critical illness, a translational approach
Tardif, N., Polia, F., Tjäder, I., Gustafsson, T., & Rooyackers, O. (2019) · Scientific Reports · doi:10.1038/s41598-019-45500-9 · Cited by 24
Ekpe, K., Novara, A., Mainardi, J., Fagon, J.-Y., & Faisy, C. (2014) · Intensive Care Medicine · doi:10.1007/s00134-014-3502-6 · Cited by 22
Evaluation of the Safety of Early Compared to Late Enteral Nutrition in Canine Septic Peritonitis
Hoffberg, J. E., & Koenigshof, A. M. (2017) · Journal of the American Animal Hospital Association · doi:10.5326/jaaha-ms-6513 · Cited by 22
Nutritional Support for Critically Ill Patients (Review)
Пасечник, И. Н. (2020) · General Reanimatology · doi:10.15360/1813-9779-2020-4-40-59 · Cited by 23
“In one of the first large-scale studies aimed at finding the optimal timing of starting the PN in critically ill patients, hypercaloric feeding initiated from the first day of ICU stay was demonstrated to associate with increased rate of complications [34].”
BackgroundBruyn, A. D., Langouche, L., Perre, S. V., Gunst, J., & den Berghe, G. V. (2021) · Critical Care · doi:10.1186/s13054-021-03519-3 · Cited by 22
When is parenteral nutrition indicated?
Berger, M. M., & Pichard, C. (2022) · Journal of Intensive Medicine · doi:10.1016/j.jointm.2021.11.006 · Cited by 22
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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