Immunonutrition

OVERVIEW

• 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

CRITICAL ILLNESS RESPONSE

• 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

GENERAL PRINCIPLES

• 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

GLUTAMINE

• 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.

SELENIUM

• ~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

ARGININE

• 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

ANTI-OXIDANT SUPPLEMENT TRIALS

• 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

TOXICITIES

• 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

• 72. Harris on Oxidative Stress – The Intensive Care Network