• Immunonutrition involves feeding (enteral or TPN) enriched with various pharmaconutrients (arginine, glutamine, omega-3-fatty acids, nucleotides and anti-oxidants: copper, selenium, zinc, vitamins B, C and E) to improve immune responses and modulate inflammatory responses
  • ‘immune modulating diets’ (IMD) are the complete supplemented nutritional formulations used


  • oxidative stress and SIRS
    -> free radical formation
    -> activation of nuclear factor kappa B (NFKB)
    -> increase TNF alpha, IL-2, IL-2 receptors and shift from Th1 to Th2 cytokine response
    -> amplification of inflammatory cascade
  • anti-oxidants can modulate this response
  • in SIRS vitamins and trace elements are taken from the circulating compartment into tissues and organs
    -> used to increase protein synthesis and immune cell production
  • relative deficit in circulating trace elements and water soluble vitamins –
    > deficit in circulating anti-oxidants


  • some data to suggest benefit (largely speculative – no clear answer in literature)
  • most studies confounded by grouping different immune enhancing formulas and different types of patients together, introducing heterogeneity and perhaps masking treatment effects
  • overall role in ICU not established
  • fits with the physiology of critical illness (SIRS -> increased uptake of pharmaconutrients into tissues, losses from other sources, dilution with resuscitation, insufficient intake)
  • IV replacement better than EN
  • all important rather than just one nutrient or vitamin (give together)
  • risk of toxicities


  • many roles:

(1) oxidative fuel
(2) nucleotide precursor
(3) serves a role in signalling states of injury and illness
(4) tissue protection
(5) anti-inflammatory/immune regulation
(6) preservation of tissue metabolic function in stress states
(7) antioxidant
(8) attenuation of iNOS expression

  • used by enterocytes, lymphocytes, neutrophils and macrophages
  • ‘conditionally’ essential in catabolic illness and vulnerable to depletion
  • in early trials has been shown to improve outcomes in the critically ill
  • in burns patients (Garrel, 2003, CCM) RCT -> decreases bacteraemia, mortality and length of stay
  • subsequent data in larger trials in unselected patients -> no such benefit
  • difficult to put glutamine in TPN -> now more stable as dipeptides: data conflicting but there is a trend towards a mortality reduction.


  • ~25 known selenoproteins
  • crucial to regulation of glutathione peroxidase = major scavenging system for oxygen free radicals
  • small trial: potential benefit if given in high dose
  • recent large trial of IV selenium vs placebo (Angstwurm, 2007, CCM): statistically non-significant reduction in mortality


  • precursor of NO, polyamides (important in lymphocyte aggregation) and nucleosides
  • meta-analysis (Heyland, 2001, JAMA): reduction in hospital stay and infections, no change in mortality, maybe increased mortality in sepsis


  • have focused on 5 micronutrients: copper, selenium, zinc, vitamins B, C and E
  • recent meta-analysis:

-> positive influence on survival (RR 0.65)
-> parenteral antioxidants associated with significant reduction (RR 0.56)
-> no significant difference in enteral supplementation
-> selenium seem to be the most important

  • cardiac and trauma RCT of antioxidants (selenium, zinc, vitamin B1) vs placebo

-> shorter hospital stay
-> resolution of organ failure faster

  • other RCTs (small) of trace element supplementation (copper, selenium, zinc) vs placebo

-> reduction in nosocomial pneumonia


  • all trace elements and vitamins have dose response curves
  • zinc: >50mg/day -> immunosuppression, progressive cholestasis
  • copper: liver damage, haemolytic anemia
  • selenium: >5mcg/kg/day
  • vitamin E: chronic ingestion -> increased mortality

References and Links

Journal articles

  • Garrel D, Patenaude J, Nedelec B, Samson L, Dorais J, Champoux J, D’Elia M, Bernier J. Decreased mortality and infectious morbidity in adult burn patients given enteral glutamine supplements: a prospective, controlled, randomized clinical trial. Crit Care Med. 2003 Oct;31(10):2444-9. PMID: 14530749
  • Heyland D, Muscedere J, Wischmeyer PE, Cook D, Jones G, Albert M, Elke G, Berger MM, Day AG; Canadian Critical Care Trials Group. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013 Apr 18;368(16):1489-97. PMID: 23594003.
  • Kim H. Glutamine as an immunonutrient. Yonsei Med J. 2011 Nov;52(6):892-7. doi: 10.3349/ymj.2011.52.6.892. Review. PubMed PMID: 22028151; PubMed Central PMCID: PMC3220259.
  • Manzanares W, Dhaliwal R, Jiang X, Murch L, Heyland DK. Antioxidant micronutrients in the critically ill: a systematic review and meta-analysis. Crit Care. 2012 Dec 12;16(2):R66. PMID: 22534505.
  • Marik PE, Flemmer M. Immunonutrition in the surgical patient. Minerva Anestesiol. 2012 Mar;78(3):336-42. PMID: 22240611.
  • Marik PE, Zaloga GP. Immunonutrition in critically ill patients: a systematic review and analysis of the literature. Intensive Care Med. 2008 Nov;34(11):1980-90. PMID: 18626628.

FOAM and web resources

CCC 700 6

Critical Care


Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also a Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of three amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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