Glutamine, fish oil and antioxidants in critical illness: MetaPlus trial post hoc safety analysis
Open accessAbstract
BACKGROUND: The role of plasma glutamine, fish oil and antioxidants concentrations in the treatment effect of immune-modulating high-protein versus high-protein enteral nutrition on 6-month mortality in critically ill patients is explored, as unexpected negative outcomes of recent large randomized controlled trials on immune-modulating nutrients have raised questions about safety of these interventions. METHODS: Post hoc analysis of the MetaPlus randomized controlled trial which was performed in a total of 301 medical, surgical and trauma critically ill patients in fourteen European intensive care units. Patients received either immune-modulating (glutamine, fish oil and antioxidant enriched) high-protein (IMHP) or isocaloric high-protein (HP) enteral nutrition. Six-month mortality and baseline, day 4 and day 8 plasma concentrations of glutamine, (eicosapentaenoicacid + decosahexaenoicacid)/long-chain fatty acid plasma level ratio ((epa + dha)/lcf ratio), selenium, vitamin c, vitamin e and zinc were measured. RESULTS: The harmful treatment effect of the IMHP versus HP enteral nutrition on 6-month mortality was only demonstrated in the medical subgroup (HR 2.52, 95% CI 1.36-4.78, P = 0.004). Among medical patients, when corrected for age groups and APACHE-II scores, there were no statistically significant associations between baseline plasma levels and 6-month mortality, except for zinc (HR 1.06, 95% CI 1.00-1.12, P = 0.026). IMHP feeding resulted in statistically significant increase in plasma levels of glutamine, vitamin e, vitamin c and (epa + dha)/lcf ratio from baseline to day 4, while only the change from baseline to day 4 of (epa + dha)/lcf ratio was statistically significant associated with 6-month mortality (HR 1.18, 95% CI 1.02-1.35, P = 0.021) and identified as mediator for the harmful treatment effect of IMHP enteral nutrition among medical ICU patients. CONCLUSION: We hypothesize that the harmful effect of IMHP compared to HP enteral nutrition in a heterogeneous group of critically ill patients is limited to the medical critically ill patients and mediated by an early increase in (epa + dha)/lcf ratio. Trial Registration Dutch Trial Register 26 January 2010 (NTR2181 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2181 ).
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Enteral formulae enriched in borage oil and/or omega-3 fatty acids have been administered in patients suffering from ARDS, acute lung injury and sepsis with positive effects regarding length of stay, length of ventilation and even mortality.
“Enteral formulae enriched in borage oil and/or omega-3 FA have been administered in patients suffering from ARDS, acute lung injury (ALI) and sepsis with positive effects regarding length of stay, length of ventilation and even mortality (239,240,245,248).”
From ESPEN guideline on clinical nutrition in the intensive care unit. (2019) · cites this paper as [248]
Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn the post-hoc analysis of the MetaPlus study, only the change from baseline to day 4 of EPA + DHA/long chain triglyceride (LCT) ratio was statistically significantly associated with six month mortality (hazard ratio 1.18, 95%CI 1.02e1.35,p = 0.021) suggesting a harmful effect of these nutrients in medical ICU patients.
“In the post-hoc analysis of the MetaPlus study [90], administrating GLN, EPA/DHA and antioxidants to critically ill patients, only the change from baseline to day 4 of EPA þ DHA/long chain triglyceride (LCT) ratio was statistically significantly associated with six month mortality (hazard ratio 1.18, 95%CI 1.02e1.35,p ¼ 0.021) suggesting a harmful effect of these nutrients in medical ICU patients.”
From ESPEN practical and partially revised guideline: Clinical nutrition in the intensive care unit (2023) · cites this paper as [90]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredA post hoc analysis of MetaPlus found that the harmful effect of enteral feeding enriched with glutamine, ω-3 fatty acids, and antioxidants on mortality in the medical subgroup was probably mediated by an early increase in (EPA + DHA)/long-chain fatty acid plasma ratio.
“A post hoc analysis of the MetaPlus trial found that the harmful effect of enteral feeding enriched with glutamine, ω-3 fatty acids, and antioxidants on mortality in the medical subgroup was probably mediated by an early increase in (EPA + DHA)/long-chain fatty acid plasma ratio [63].”
From Nutrition in Sepsis: A Bench-to-Bedside Review. (2020) · cites this paper as [63]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Baron, R. M., & Kenny, D. A. (1986) · Journal of Personality and Social Psychology · doi:10.1037//0022-3514.51.6.1173 · Cited by 91,542 · see citing works
Baron, R. M., & Kenny, D. A. (1986) · Journal of Personality and Social Psychology · doi:10.1037/0022-3514.51.6.1173 · Cited by 91,532 · see citing works
McClave, S. A., Taylor, B. E., Martindale, R. G., Warren, M. M., Johnson, D. R., Braunschweig, C., McCarthy, M. S., Davanos, E., Rice, T. W., Cresci, G. A., et al. (2016) · Journal of Parenteral and Enteral Nutrition · doi:10.1177/0148607115621863 · Cited by 3,982 · see citing works
Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy
Hotchkiss, R. S., Monneret, G., & Payen, D. (2013) · Nature Reviews Immunology · doi:10.1038/nri3552 · Cited by 2,772 · see citing works
McClave, S. A., Martindale, R. G., Vanek, V. W., McCarthy, M., Roberts, P., Taylor, B., Ochoa, J. B., Napolitano, L., Cresci, G., the A.S.P.E.N. Board of Directors, et al. (2009) · Journal of Parenteral and Enteral Nutrition · doi:10.1177/0148607109335234 · Cited by 1,873 · see citing works
Taylor, B. E., McClave, S. A., Martindale, R. G., Warren, M. M., Johnson, D. R., Braunschweig, C., McCarthy, M. S., Davanos, E., Rice, T. W., Cresci, G. A., et al. (2016) · Critical Care Medicine · doi:10.1097/ccm.0000000000001525 · Cited by 1,476 · see citing works
A Randomized Trial of Glutamine and Antioxidants in Critically Ill Patients
Heyland, D., Muscedere, J., Wischmeyer, P. E., Cook, D., Jones, G., Albert, M., Elke, G., Berger, M. M., & Day, A. G. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1212722 · Cited by 904 · see citing works
Enteral Omega-3 Fatty Acid, γ-Linolenic Acid, and Antioxidant Supplementation in Acute Lung Injury
Rice, T. W. (2011) · JAMA · doi:10.1001/jama.2011.1435 · Cited by 552 · see citing works
Andrews, P. J. D., Avenell, A., Noble, D. W., Campbell, M. K., Croal, B. L., Simpson, W. G., Vale, L. D., Battison, C. G., Jenkinson, D. J., Cook, J. A., et al. (2011) · BMJ · doi:10.1136/bmj.d1542 · Cited by 379 · see citing works
Plasma glutamine depletion and patient outcome in acute ICU admissions
Straaten, H. M. O., Bosman, R. J., Treskes, M., van der Spoel, H. J. I., & Zandstra, D. F. (2000) · Intensive Care Medicine · doi:10.1007/s001340000703 · Cited by 322 · see citing works
van Zanten, A. R. H., Sztark, F., Kaisers, U. X., Zielmann, S., Felbinger, T. W., Sablotzki, A. R., De Waele, J. J., Timsit, J.-F., Honing, M. L. H., Keh, D., et al. (2014) · JAMA · doi:10.1001/jama.2014.7698 · Cited by 279 · see citing works
Self-citationMarimuthu, K., Varadhan, K. K., Ljungqvist, O. H., & Lobo, D. N. (2012) · Annals of Surgery · doi:10.1097/sla.0b013e318252edf8 · Cited by 239 · see citing works
Saadatian-Elahi, M., Slimani, N., Chajès, V., Jenab, M., Goudable, J., Biessy, C., Ferrari, P., Byrnes, G., Autier, P., Peeters, P. H., et al. (2009) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.2008.26834 · Cited by 213 · see citing works
Glutamine and glutathione at ICU admission in relation to outcome
Rodas, P. C., Rooyackers, O., Hebert, C., Norberg, Å., & Wernerman, J. (2012) · Clinical Science · doi:10.1042/cs20110520 · Cited by 184 · see citing works
n−3 Fatty acids, inflammation, and immunity— Relevance to postsurgical and critically III patients
Calder, P. C. (2004) · Lipids · doi:10.1007/s11745-004-1342-z · Cited by 159 · see citing works
Osland, E., Hossain, M. B., Khan, S., & Memon, M. A. (2013) · Journal of Parenteral and Enteral Nutrition · doi:10.1177/0148607112474825 · Cited by 143 · see citing works
Vermeulen, M. A. R., van de Poll, M. C. G., Ligthart‐Melis, G. C., Dejong, C. H. C., van den Tol, M. P., Boelens, P. G., & van Leeuwen, P. A. M. (2007) · Critical Care Medicine · doi:10.1097/01.ccm.0000278600.14265.95 · Cited by 86 · see citing works
Zhu, D., Zhang, Y., Li, S., Gan, L., Feng, H., & Nie, W. (2014) · Intensive Care Medicine · doi:10.1007/s00134-014-3244-5 · Cited by 68 · see citing works
Role of glutamine supplementation in critical illness given the results of the REDOXS study.
Heyland, D., & Dhaliwal, R. (2013) · JPEN - Journal of Parenteral and Enteral Nutrition · doi:10.1177/0148607113488421 · Cited by 52 · see citing works
van Zanten, A. V., Hofman, Z., & Heyland, D. (2015) · JPEN - Journal of Parenteral and Enteral Nutrition · doi:10.1177/0148607114567201 · Cited by 51 · see citing works
Self-citationAltered balance of the aminogram in patients with sepsis – The relation to mortality
Hirose, T., Shimizu, K., Ogura, H., Tasaki, O., Hamasaki, T., Yamano, S., Ohnishi, M., Kuwagata, Y., & Shimazu, T. (2013) · Clinical Nutrition · doi:10.1016/j.clnu.2013.11.017 · Cited by 46 · see citing works
Sakr, Y. L., Maia, V. P., Santos, C., Stracke, J., Zeidan, M. A., Bayer, O., & Reinhart, K. (2014) · Critical Care · doi:10.1186/cc13825 · Cited by 40 · see citing works
van Zanten, A. R. H. (2015) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000152 · Cited by 31 · see citing works
Low Glutamine Levels during Critical Illness — Adaptive or Maladaptive?
den Berghe, G. V. (2013) · New England Journal of Medicine · doi:10.1056/nejme1302301 · Cited by 22 · see citing works
Delodder, F., Tappy, L., Liaudet, L., Schneiter, P., Perrudet, C., & Berger, M. M. (2014) · Clinical Nutrition · doi:10.1016/j.clnu.2014.07.005 · Cited by 15 · see citing works
Immunonutrition in Critical Illness
Rice, T. W. (2014) · JAMA · doi:10.1001/jama.2014.7699 · Cited by 14 · see citing works
Glutamine – from conditionally essential to totally dispensable?
Wernerman, J. (2014) · Critical Care · doi:10.1186/cc13964 · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
ESPEN guideline on clinical nutrition in the intensive care unit.
Singer, P., Blaser, A. R., Berger, M. M., Alhazzani, W., Calder, P. C., Casaer, M. P., Hiesmayr, M., Mayer, K., Montejo, J. C., Pichard, C., et al. (2019) · Clinical Nutrition · doi:10.1016/j.clnu.2018.08.037 · Cited by 2,904 · see citing works
ESPEN practical and partially revised guideline: Clinical nutrition in the intensive care unit
Singer, P., Blaser, A. R., Berger, M. M., Calder, P. C., Casaer, M., Hiesmayr, M., Mayer, K., Montejo-Gonzalez, J. C., Pichard, C., Preiser, J.-C., et al. (2023) · Clinical Nutrition · doi:10.1016/j.clnu.2023.07.011 · Cited by 793 · see citing works
Nutrition in Sepsis: A Bench-to-Bedside Review.
De Waele, E., Malbrain, M. L. N. G., & Spapen, H. (2020) · Nutrients · doi:10.3390/nu12020395 · Cited by 140 · see citing works
Hoeger, J., Simon, T.-P., Beeker, T., Marx, G., Haase, H., & Schuerholz, T. (2017) · PLOS ONE · doi:10.1371/journal.pone.0176069 · Cited by 78 · see citing works
Nutrition in the critically ill patient
Koekkoek, K. W. A. C., & van Zanten, A. R. H. (2017) · Current Opinion in Anaesthesiology · doi:10.1097/aco.0000000000000441 · Cited by 45 · see citing works
Nutrition in the ICU: new trends versus old-fashioned standard enteral feeding?
Koekkoek, K. W. A. C., & van Zanten, A. R. H. (2018) · Current Opinion in Anaesthesiology · doi:10.1097/aco.0000000000000571 · Cited by 38 · see citing works
Plasma Glutamine Levels in Relation to Intensive Care Unit Patient Outcome
Blaauw, R., Nel, D. G., & Schleicher, G. K. (2020) · Nutrients · doi:10.3390/nu12020402 · Cited by 30 · see citing works
Li, Q., Zhang, Z., Xie, B., Ji, X., Lu, J., Jiang, R., Lei, S., Mao, S., Ying, L., Lu, D., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0182393 · Cited by 23 · see citing works
Diretriz BRASPEN de Terapia Nutricional no Paciente Grave
Castro, M. G., Ribeiro, P. C., de Matos, L. B. N., de Abreu, H. B., de Assis, T., Barreto, P. A., Ceniccola, G. D., da Cunha, H. F. R., Gonçalves, R. C., Gonçalves, T. J. M., et al. (2023) · Braspen Journal · doi:10.37111/braspenj.diretrizdoentegrave · Cited by 18 · see citing works
An update of the effects of vitamins D and C in critical illness
Hill, A., Starchl, C., Dresen, E., Stoppe, C., & Amrein, K. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2022.1083760 · Cited by 17 · see citing works
Chapela, S. P., Burgos, I., Congost, C., Canzonieri, R., Muryan, A., Alonso, M., & Stella, C. A. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/1928945 · Cited by 16 · see citing works
Nutrition: reducing the hypermetabolic response to thermal injury
Price, C. (2018) · British Journal of Nursing · doi:10.12968/bjon.2018.27.12.661 · Cited by 10 · see citing works
Ni, C., Cao, J., Li, D., Wu, W., Cao, L., & Zhu, C. (2020) · Cellular and Molecular Biology · doi:10.14715/cmb/2020.66.3.8 · Cited by 8 · see citing works
Immunmodulation durch Ernährung bei kritisch kranken Patienten
Hirschberger, S., Schmid, A., & Kreth, S. (2023) · Die Anaesthesiologie · doi:10.1007/s00101-023-01258-4 · Cited by 8 · see citing works
Enteral Nutrition and Tube Feeding
Larsen, J. A. (2023) · doi:10.1002/9781119375241.ch20 · Cited by 8 · see citing works
Seven Deadly Sins of Nutrition Therapy in Critically Ill Patients
Loss, S. H., Franzosi, O. S., Nunes, D. S. L., Teixeira, C., & Viana, L. V. (2019) · Nutrition in Clinical Practice · doi:10.1002/ncp.10430 · Cited by 6 · see citing works
Martinuzzi, A. L. N., Crivelli, A., Lopez, A., Sgarzini, D., Aragon, V., Galeano, F., Billinger, M. C., Doeyo, M., Matano, M., Salomone, P., et al. (2024) · Nutrition · doi:10.1016/j.nut.2024.112501 · Cited by 5 · see citing works
Vesterlund, G. K., Thomsen, T., Møller, M. H., & Perner, A. (2019) · Acta Anaesthesiologica Scandinavica · doi:10.1111/aas.13468 · Cited by 4 · see citing works
Nutrition in the critically ill patient
Koekkoek, W. A. C. (2023) · doi:10.33540/1675 · Cited by 3 · see citing works
Nutrición enteral del paciente crítico en el siglo XXI
Santana, S. R. (2018) · Nutrición Hospitalaria · doi:10.20960/nh.1957 · Cited by 2 · see citing works
van Zanten, A. R. H. (2022) · doi:10.18174/572227 · Cited by 2 · see citing works
Spezielle Ernährungslösungen für Intensivpatienten: Tool or Toy?
Dresen, E., Notz, Q., & Roeder, D. (2025) · AINS - Anästhesiologie · Intensivmedizin · Notfallmedizin · Schmerztherapie · doi:10.1055/a-2292-8998 · Cited by 1 · see citing works
Metabolism in the Trauma Patient
Pelekhaty, S. L., & Kozar, R. A. (2020) · Springer eBooks · doi:10.1007/978-3-030-39781-4_6
Goh, V. L., & Barsky, D. (2019) · Encyclopedia of Gastroenterology · doi:10.1016/b978-0-12-801238-3.66031-2
Free Radical–Associated Gene Signature Predicts Survival in Sepsis Patients
Feng, A., Pokharel, M. D., Liang, Y., Ma, W., Aggarwal, S., Black, S. M., & Wang, T. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25084574
Spezielle Ernährungslösungen für Intensivpatient*innen: Tool or Toy?
Dresen, E., Notz, Q., & Roeder, D. (2026) · Aktuelle Ernährungsmedizin · doi:10.1055/a-2774-2561
Glutamine metabolism in health and disease
Zhao, J., Lin, Y., Gao, R., Gao, H., & Li, L. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02981-1
- Authors
- Hofman, Z., Swinkels, S., & van Zanten, A. R. H.
- Affiliations
- Nutricia Research (Netherlands) (NL)
- ORCID
- Hofman, Zandrie
- Venue
- Annals of Intensive Care
- Publisher
- Elsevier BV
- Published
- 2016
- Volume
- 6
- Issue
- 1
- Pages
- 119
- ISSN
- 2110-5820 (ISSN-L)
- PMC
- PMC5153384
- OpenAlex
- W2563482547
- Cited by
- 27
- References
- 26
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 6 · 2022: 1 · 2020: 4 · 2019: 3 · 2018: 5 · 2017: 3
- FWCI
- 3.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Annals of Intensive Care (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Clinical Nutrition and Gastroenterology
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Keywords
- glutamine, fish oil, antioxidants, critical illness, 6-month mortality, eicosapentaenoic acid, docosahexaenoic acid, long-chain fatty acids, selenium, vitamin C, vitamin E, zinc, plasma biomarkers, treatment safety, medical ICU patients
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
