What is The Effect of Early Enteral Nutrition on Mortality in Critically Ill Patients Receiving Vasopressor Support? : A Systematic Review
Keywords:
Early enteral nutrition, vasopressors, septic shock, mortality, norepinephrine, critical illnessAbstract
Background: The effect of early enteral nutrition (EEN) on mortality in critically ill patients requiring vasopressor support remains debated due to conflicting trial results.
Methods: This systematic review synthesized data from 80 studies (2003-2025), including landmark RCTs (NUTRIREA-2, NUTRIREA-3) and large observational cohorts, focusing on mortality, vasopressor dose-response, enteral tolerance, and safety.
Results: EEN did not reduce 28-day or 90-day mortality in patients with severe shock (norepinephrine ≥0.3 µg/kg/min) in major RCTs [1,2]. However, a clear dose-response relationship was identified: EEN significantly reduced mortality at low (<0.1 µg/kg/min) and medium (0.1-0.3 µg/kg/min) norepinephrine doses but not at high doses (≥0.3 µg/kg/min) [3]. Benefits were seen in transient shock (resolving <24h) but not persistent shock [4]. High-calorie EEN increased gastrointestinal complications, including vomiting (HR 1.89) and bowel ischemia (HR 3.84) [1], while low-calorie feeding (6 kcal/kg/day) reduced these risks [2].
Discussion: The effect of EEN on mortality is highly context-dependent. The lack of benefit in trials like NUTRIREA-2/3 is explained by enrollment of patients on high-dose vasopressors and use of immediate full-dose feeding—a strategy now considered harmful. Observational benefits likely reflect hemodynamic stability at feeding initiation. A safe approach includes starting trophic EEN (6-15 kcal/kg/day) after initial resuscitation when vasopressor doses are stable and ≤0.3 µg/kg/min, with gradual advancement.
Conclusion: EEN does not reduce mortality in patients on high-dose vasopressors (≥0.3 µg/kg/min norepinephrine) but may improve survival in those on low-to-moderate doses with transient shock. Clinical practice should shift from rigid timing to hemodynamic-guided, gradual feeding.
References
J. Reignier, J. Boisramé‐Helms, L. Brisard, et al (2018) Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2). The Lancet. https://doi.org/10.1016/S0140-6736(17)32146-3
J. Reignier, G. Plantefeve, J. Mira, et al (2023) Low versus standard calorie and protein feeding in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3). The Lancet Respiratory Medicine. https://doi.org/10.1016/s2213-2600(23)00092-9
H. Ohbe, T. Jo, H. Matsui, et al (2020) Differences in effect of early enteral nutrition on mortality among ventilated adults with shock requiring low-, medium-, and high-dose noradrenaline: A propensity-matched analysis. Clinical Nutrition. https://doi.org/10.1016/j.clnu.2019.02.020
Wenfang Jiang, Weibang Pan, Tianbin Cai, et al (2025) Association between early enteral nutrition and clinical outcomes among critically ill patients with circulatory shock: A secondary analysis of a large-scale randomized controlled trial. Clinical Nutrition. https://doi.org/10.1016/j.clnu.2025.01.029
Z. Lee, Charles Chin Han Lew, M. Berger, et al (2023) Nutrition during the acute phase of critical illness: discussions on NUTRIREA-3. The Lancet Respiratory Medicine. https://doi.org/10.1016/s2213-2600(23)00214-x
Kiran Asranna, Srinivas Samavedam (2024) Comparison of Early Moderate Enteral Nutrition with Conventional Nutritional Strategies in Ventilated Patients with Shock. Indian Journal of Critical Care Medicine. https://doi.org/10.5005/jaypee-journals-10071-24667.6
T. Rice, S. Mogan, M. Hays, et al (2011) Randomized trial of initial trophic versus full-energy enteral nutrition in mechanically ventilated patients with acute respiratory failure. Critical Care Medicine. https://doi.org/10.1097/CCM.0b013e31820a905a
I. Khalid, P. Doshi, B. Digiovine (2010) Early enteral nutrition and outcomes of critically ill patients treated with vasopressors and mechanical ventilation. American Journal of Critical Care. https://doi.org/10.4037/ajcc2010197
C. Merchan, Diana Altshuler, Caitlin Aberle, et al (2017) Tolerability of Enteral Nutrition in Mechanically Ventilated Patients With Septic Shock Who Require Vasopressors. Journal of Intensive Care Medicine. https://doi.org/10.1177/0885066616656799
L. Ortiz-Reyes, J. Patel, Xuran Jiang, et al (2022) Early versus delayed enteral nutrition in mechanically ventilated patients with circulatory shock: a nested cohort analysis of an international multicenter, pragmatic clinical trial. Critical Care. https://doi.org/10.1186/s13054-022-04047-4
L. Brisard, A. Le Gouge, J. Lascarrou, et al (2014) Impact of early enteral versus parenteral nutrition on mortality in patients requiring mechanical ventilation and catecholamines: study protocol for a randomized controlled trial (NUTRIREA-2). Trials. https://doi.org/10.1186/1745-6215-15-507
W. Hartl, G. Elke (2023) Nutrition during the acute phase of critical illness: discussions on NUTRIREA-3. The Lancet Respiratory Medicine. https://doi.org/10.1016/s2213-2600(23)00212-6
J. Reignier, A. Le Gouge, J. Lascarrou, et al (2021) Impact of early low-calorie low-protein versus standard-calorie standard-protein feeding on outcomes of ventilated adults with shock: design and conduct of a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3). BMJ Open. https://doi.org/10.1136/bmjopen-2020-045041
Fan Qi, Guangqing Huang, Hunian Li, et al (2023) Correlation analysis of norepinephrine dose on enteral nutrition tolerance and prognosis in patients with septic shock. BMC Infectious Diseases. https://doi.org/10.1186/s12879-023-08366-x
E. Elmezoughi, K. de Vasconcellos (2020) An evaluation of feeding practices and determination of barriers to providing nutritional support in a multidisciplinary South African intensive care unit. Southern African Journal of Critical Care. https://doi.org/10.7196/SAJCC.2020.v36i1.412
C. Grillo‐Ardila, Diego Tibavizco-Palacios, Luis C. Triana, et al (2024) Early Enteral Nutrition (within 48 h) for Patients with Sepsis or Septic Shock: A Systematic Review and Meta-Analysis. Nutrients. https://doi.org/10.3390/nu16111560
J. Patel, M. Kozeniecki, William J. Peppard, et al (2020) Phase 3 Pilot Randomized Controlled Trial Comparing Early Trophic Enteral Nutrition With "No Enteral Nutrition" in Mechanically Ventilated Patients With Septic Shock. JPEN - Journal of Parenteral and Enteral Nutrition. https://doi.org/10.1002/jpen.1706
A. Tebani, Zoé Demailly, S. Bekri, et al (2025) Clinical and metabolic phenotyping of continuous versus intermittent ENteral NUTrition in ventilated adults with shock: ENNUT trial protocol. BMJ Open. https://doi.org/10.1136/bmjopen-2025-099761
Luís Henrique Simo Es Covello, Marcella Giovana Gava-Brandolis, M. Castro, et al (2020) Vasopressors and Nutrition Therapy: Safe Dose for the Outset of Enteral Nutrition? Critical Care Research and Practice. https://doi.org/10.1155/2020/1095693
J. Reignier, J. Lascarrou, A. Le Gouge (2023) Nutrition during the acute phase of critical illness: discussions on NUTRIREA-3 - Authors' reply. The Lancet Respiratory Medicine. https://doi.org/10.1016/s2213-2600(23)00215-1
E. Ridley, T. Rice (2023) NUTRIREA-3: where to next? The Lancet Respiratory Medicine. https://doi.org/10.1016/s2213-2600(23)00128-5
Jun Xu, H. Cai, Xia Zheng (2023) Timing of vasopressin initiation and mortality in patients with septic shock: analysis of the MIMIC-III and MIMIC-IV databases. BMC Infectious Diseases. https://doi.org/10.1186/s12879-023-08147-6
D. Opgenorth, Nadia Baig, Kirsten M. Fiest, et al (2022) LIBERATE: a study protocol for midodrine for the early liberation from vasopressor support in the intensive care unit (LIBERATE): protocol for a randomized controlled trial. Trials. https://doi.org/10.1186/s13063-022-06115-0
A. Pontes-Arruda, A. Aragão, J. Albuquerque (2006) Effects of enteral feeding with eicosapentaenoic acid, γ-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock*. Critical Care Medicine. https://doi.org/10.1097/01.CCM.0000234033.65657.B6
M. Kott, W. Hartl, G. Elke (2019) Enteral vs. parenteral nutrition in septic shock: are they equivalent? Current Opinion in Critical Care. https://doi.org/10.1097/MCC.0000000000000618
G. Piton, A. Le Gouge, J. Boisramé‐Helms, et al (2022) Factors associated with acute mesenteric ischemia among critically ill ventilated patients with shock: a post hoc analysis of the NUTRIREA2 trial. Intensive Care Medicine. https://doi.org/10.1007/s00134-022-06637-w
Xiaoyong Dai, Wei Hua, Qinghua Pu, et al (2018) Correlation analysis on the timing of enteral nutrition support and the prognosis in patients with septic shock. Clinical Medicine of China. https://doi.org/10.3760/CMA.J.ISSN.1008-6315.2018.03.017
Y. Liu, Wei Zhao, Wenxiu Chen, et al (2018) Effects of Early Enteral Nutrition on Immune Function and Prognosis of Patients With Sepsis on Mechanical Ventilation. Journal of Intensive Care Medicine. https://doi.org/10.1177/0885066618809893
Jing Xu, Junli Zhang, Libin Yang, et al (2025) Influence of early enteral nutrition on mortality of adult patients with sepsis: a meta-analysis of randomized controlled trials. European Journal of Medical Research. https://doi.org/10.1186/s40001-025-03340-6
Yan-ge Guo, Jing Cheng, Yongjian Li (2018) [Influence of enteral nutrition initiation timing on curative effect and prognosis of acute respiratory distress syndrome patients with mechanical ventilation]. Zhonghua wei zhong bing ji jiu yi xue. https://doi.org/10.3760/cma.j.issn.2095-4352.2018.06.014
Samantha Lu, Phillip Stokes, B. Solis, et al (2012) 514: SECOND VASOPRESSOR CHOICE FOR PATIENTS WITH REFRACTORY SEPTIC SHOCK ON NOREPINEPHRINE IN THE INTENSIVE CARE UNIT. https://doi.org/10.1097/01.ccm.0000424732.43397.7f
Gurasees S Chawla, M. Fazzari, Sarah W. Baron, et al (2021) S1430 Early Enteral Nutrition Reduces In-Hospital Mortality of Critically Ill COVID-19 Patients. American Journal of Gastroenterology. https://doi.org/10.14309/01.ajg.0000779252.47675.af
Luping Wang, Xi Zhong, Hao Yang, et al (2024) When can we start early enteral nutrition safely in patients with shock on vasopressors? Clinical Nutrition ESPEN. https://doi.org/10.1016/j.clnesp.2024.03.007
Yongpo Jiang, Bangchuan Hu, S. Zhang, et al (2020) Effects of early enteral nutrition on the prognosis of patients with sepsis: secondary analysis of acute gastrointestinal injury study. Annals of Palliative Medicine. https://doi.org/10.21037/apm-20-1650
N. Nguyen, R. Fraser, L. Bryant, et al (2008) The impact of delaying enteral feeding on gastric emptying, plasma cholecystokinin, and peptide YY concentrations in critically ill patients*. Critical Care Medicine. https://doi.org/10.1097/CCM.0b013e31816fc457
H. Al-Dorzi, Y. Arabi (2020) Enteral Nutrition Safety With Advanced Treatments (Extracorporeal Membrane Oxygenation, Prone Positioning, and Infusion of Neuromuscular Blockers). Nutrition in clinical practice. https://doi.org/10.1002/ncp.10621
Meng-Chun Lu, Mei‐Due Yang, Ping-chun Li, et al (2018) Effects of Nutritional Intervention on the Survival of Patients with Cardiopulmonary Failure Undergoing Extracorporeal Membrane Oxygenation Therapy. In Vivo. https://doi.org/10.21873/invivo.11315
Fuchao Xu, Jianxin Xu, Jinjin Ma, et al (2024) Early versus delayed enteral nutrition in ICU patients with sepsis: a propensity score-matched analysis based on the MIMIC-IV database. Frontiers in Nutrition. https://doi.org/10.3389/fnut.2024.1370472
E. Ridley, A. Davies, R. Parke, et al (2018) Supplemental parenteral nutrition versus usual care in critically ill adults: a pilot randomized controlled study. Critical Care. https://doi.org/10.1186/s13054-018-1939-7
F. Shah, G. Kitsios, S. Yende, et al (2021) A Pilot Double-Blind Placebo-Controlled Randomized Clinical Trial to Investigate the Effects of Early Enteral Nutrients in Sepsis. Critical Care Explorations. https://doi.org/10.1097/CCE.0000000000000550
Shuofei Yang, Xingjiang Wu, Wenkui Yu, Jie‐shou Li (2014) Early enteral nutrition in critically ill patients with hemodynamic instability: an evidence-based review and practical advice. Nutrition in clinical practice. https://doi.org/10.1177/0884533613516167
G. Doig, F. Simpson, Elizabeth A. Sweetman, et al (2013) Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a randomized controlled trial. Journal of the American Medical Association (JAMA). https://doi.org/10.1001/jama.2013.5124
M. Ramamurthy (2015) Trial of the route of early nutritional support in critically ill adults. New England Journal of Medicine. https://doi.org/10.1056/NEJMc1414479
O. Ojo, O. Ojo, Qianqian Feng, et al (2022) The Effects of Enteral Nutrition in Critically Ill Patients with COVID-19: A Systematic Review and Meta-Analysis. Nutrients. https://doi.org/10.3390/nu14051120
G. Bertolini, G. Iapichino, D. Radrizzani, et al (2003) Early enteral immunonutrition in patients with severe sepsis. Intensive Care Medicine. https://doi.org/10.1007/s00134-003-1711-5
G. Doig, F. Simpson, S. Finfer, et al (2008) Effect of evidence-based feeding guidelines on mortality of critically ill adults: a cluster randomized controlled trial. Journal of the American Medical Association (JAMA). https://doi.org/10.1001/jama.2008.826
B. Shankar, D. K. Daphnee, N. Ramakrishnan, R. Venkataraman (2015) Feasibility, safety, and outcome of very early enteral nutrition in critically ill patients: Results of an observational study. Journal of critical care. https://doi.org/10.1016/j.jcrc.2015.02.009
D. Heyland, J. Muscedere, P. Wischmeyer, et al (2013) A randomized trial of glutamine and antioxidants in critically ill patients. New England Journal of Medicine. https://doi.org/10.1056/NEJMoa1212722
A. Davies, S. Morrison, M. Bailey, et al (2012) A multicenter, randomized controlled trial comparing early nasojejunal with nasogastric nutrition in critical illness*. Critical Care Medicine. https://doi.org/10.1097/CCM.0b013e318255d87e
Mahsa Malekahmadi, N. Pahlavani, Safieh Firouzi, et al (2021) Effect of enteral immunomodulatory nutrition formula on mortality and critical care parameters in critically ill patients: A systematic review with meta-analysis. Nursing Critical Care. https://doi.org/10.1111/nicc.12687
R. Beale, T. Sherry, K. Lei, et al (2008) Early enteral supplementation with key pharmaconutrients improves Sequential Organ Failure Assessment score in critically ill patients with sepsis: Outcome of a randomized, controlled, double-blind trial*. Critical Care Medicine. https://doi.org/10.1097/01.CCM.0000297954.45251.A9
Anuj Shukla, M. Chapman, J. Patel (2020) Enteral nutrition in circulatory shock: friend or foe? Current opinion in clinical nutrition and metabolic care. https://doi.org/10.1097/MCO.0000000000000731
Gabriel Cedeño, J. M. Zaldumbide, E. M. Mogrovejo, et al (2026) P-21. Impact of Enteral and Parenteral Nutrition on Mortality and Morbidity in Critically Ill patients with Sepsis: A Systematic Review and Meta Analysis. Open Forum Infectious Diseases. https://doi.org/10.1093/ofid/ofaf695.252
A. V. van Zanten, F. Sztark, U. Kaisers, et al (2014) High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: a randomized clinical trial. Journal of the American Medical Association (JAMA). https://doi.org/10.1001/jama.2014.7698
G. Elke, E. Kuhnt, M. Ragaller, et al (2013) Enteral nutrition is associated with improved outcome in patients with severe sepsis. Medizinische Klinik - Intensivmedizin und Notfallmedizin. https://doi.org/10.1007/s00063-013-0224-4
Yuanting Zhou, Yi Chen, Le Chang (2024) Shock Patients and Enteral Nutrition? International Journal of Biology and Life Sciences. https://doi.org/10.54097/2frt1b93
M. Chapman, S. Peake, R. Bellomo, et al (2018) Energy‐Dense versus Routine Enteral Nutrition in the Critically Ill. New England Journal of Medicine. https://doi.org/10.1056/NEJMoa1811687
M. J. Allingstrup, J. Kondrup, J. Wiis, et al (2017) Early goal-directed nutrition versus standard of care in adult intensive care patients: the single-centre, randomised, outcome assessor-blinded EAT-ICU trial. Intensive Care Medicine. https://doi.org/10.1007/s00134-017-4880-3
Brian M. Dee, J. Bruno, L. Lal, T. Canada (2011) Effects of Immune-Enhancing Enteral Nutrition on Mortality and Oxygenation in Acute Lung Injury and Acute Respiratory Distress Syndrome: A Meta-Analysis. Hospital Pharmacy. https://doi.org/10.1310/hpj4601-33
S. Rugeles, Luis Gabriel Villarraga-Angulo, A. Ariza-Gutiérrez, et al (2016) High-protein hypocaloric vs normocaloric enteral nutrition in critically ill patients: A randomized clinical trial. Journal of critical care. https://doi.org/10.1016/j.jcrc.2016.05.004
K. A. Phan, C. Dux, E. Osland, M. Reade (2017) Effect of Hypocaloric Normoprotein Or Trophic Feeding versus Target Full Feeding on Patient Outcomes in Critically Ill Adults: A Systematic Review. Anaesthesia and Intensive Care. https://doi.org/10.1177/0310057X1704500604
Livia Dainelli, Silvia Delgado, Raffaele Lagravinese, et al (2023) Early versus late enteral nutrition in US COVID-19 patients: a systematic literature review and meta-analysis. Clinical Nutrition Open Science. https://doi.org/10.1016/j.nutos.2023.10.007
A. Schneider, A. Markowski, M. Momma, et al (2011) Tolerability and efficacy of a low-volume enteral supplement containing key nutrients in the critically ill. Clinical Nutrition. https://doi.org/10.1016/j.clnu.2011.04.003
Alvin Richards-Belle, M. Hylands, Fiona Muttalib, et al (2022) Lower Versus Higher Exposure to Vasopressor Therapy in Vasodilatory Hypotension: A Systematic Review With Meta-Analysis*. Critical Care Medicine. https://doi.org/10.1097/CCM.0000000000005736
A. Mukhopadhyay, Z. Tan, Samantha Hui Ling Cheong, et al (2020) Differential Effects of Early Energy and Protein Inadequacies on the Outcome of Critically Ill Patients. Nutrition in clinical practice. https://doi.org/10.1002/ncp.10543
Guiliang Wang, Jianbo Wen, Linfang Xu, et al (2013) Effect of enteral nutrition and ecoimmunonutrition on bacterial translocation and cytokine production in patients with severe acute pancreatitis. Journal of Surgical Research. https://doi.org/10.1016/j.jss.2012.12.010
Jia-Kui Sun, Wen-hao Zhang, Wenxiu Chen, et al (2019) Effects of early enteral nutrition on Th17/Treg cells and IL-23/IL-17 in septic patients. World Journal of Gastroenterology. https://doi.org/10.3748/wjg.v25.i22.2799
K. Shirai, S. Yoshida, Naoki Matsumaru, et al (2015) Effect of enteral diet enriched with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with sepsis-induced acute respiratory distress syndrome. Journal of Intensive Care. https://doi.org/10.1186/s40560-015-0087-2
Chunmiao Zhong, C. Ji, Zhuquan Dai, et al (2017) [Effect of early enteral nutrition standardized treatment on blood glucose and prognosis in acute respiratory distress syndrome patients with mechanical ventilation]. Zhonghua wei zhong bing ji jiu yi xue. https://doi.org/10.3760/cma.j.issn.2095-4352.2017.12.016
D. Ma, Jun Lu, Fei Wang, et al (2019) [Value of early enteral nutrition in patients with severe heart failure undergoing mechanical ventilation]. Zhonghua wei zhong bing ji jiu yi xue. https://doi.org/10.3760/cma.j.issn.2095-4352.2019.07.021
E. Ibrahim (2018) Enteral nutrition with omega-3 fatty acids in critically ill septic patients: A randomized double-blinded study. Saudi Journal of Anaesthesia. https://doi.org/10.4103/sja.SJA_50_18
Y. Arabi, S. Haddad, A. Aldawood, et al (2012) Permissive underfeeding versus target enteral feeding in adult critically ill patients (PermiT Trial): a study protocol of a multicenter randomized controlled trial. Trials. https://doi.org/10.1186/1745-6215-13-191
Ondřej Hrdý, K. Vrbica, Jaroslav Duba, et al (2025) Intermittent enteral nutrition shortens the time to achieve nutritional goals in critically ill patients. Scientific Reports. https://doi.org/10.1038/s41598-025-86633-4
L. Ke, Jiajia Lin, G. Doig, et al (2022) Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial. Critical Care. https://doi.org/10.1186/s13054-022-03921-5
Mohammad Amin Valizade Hasanloei, Mehran Rahimlou, Hamed Shojaa, et al (2021) The effect of wheat germ-enriched enteral formula on clinical and anthropometric factors in mechanically ventilated patients admitted to the intensive care unit. Clinical Nutrition ESPEN. https://doi.org/10.1016/j.clnesp.2021.09.001
Lei Zou, L. Ke, Wei-qin Li, et al (2014) Enteral nutrition within 72 h after onset of acute pancreatitis vs delayed initiation. European Journal of Clinical Nutrition. https://doi.org/10.1038/ejcn.2014.164
Jia-Kui Sun, Shuai Nie, Yong-Ming Chen, et al (2021) Effects of permissive hypocaloric vs standard enteral feeding on gastrointestinal function and outcomes in sepsis. World Journal of Gastroenterology. https://doi.org/10.3748/wjg.v27.i29.4900
Nianbin Ma, M. Shen, Zheng Wan, et al (2018) [Impact of permissive underfeeding versus standard enteral feeding on outcomes in critical patients requiring mechanical ventilation: a prospective randomized controlled study]. Zhonghua wei zhong bing ji jiu yi xue. https://doi.org/10.3760/cma.j.issn.2095-4352.2018.02.016
P. Williams (2018) Study protocol for the Augmented versus Routine Approach to Giving Energy Trial (TARGET). Critical Care and Resuscitation. https://doi.org/10.1016/s1441-2772(23)00734-2
A. G. E. M. HALA M. EL-GENDY, M.D., G. F. E. M. ASHRAF M. FARIED, M.D. (2018) Nutrition as a Predictor of Outcome in Patients with Severe Traumatic Brain Injury. The Medical journal of Cairo University. https://doi.org/10.21608/mjcu.2018.57863
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Landong Sijabat, Raka Jati Prasetya, Mutia Juliana (Author)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Authors publishing here keep copyright but grant the journal first publication rights, under a Creative Commons Attribution-NonCommercial 4.0 License. They can distribute their work non-exclusively elsewhere with an acknowledgment of its first publication in this journal. Posting the work online before and during submission for earlier and greater citation is encouraged, reflecting Open Access benefits.
