Immunonutrition and pharmaconutrition

Agents of immunonutrition (or, pharmaconutrition if you will) investigated in the critical care literature have included specific amino acids (arginine, ornithine, glutamine), varying chain lengths of fatty acids,  omega-3 fatty acids, nucleotides, antioxidants, zinc, copper, selenium, and probably a hundred others. There has been a lot of interest in the use of these "pharmacologically active nutrients" to modify the immune and inflammatory responses in critical illness. The theory is that supplementing these molecules may somehow influence the behaviour of the immune system, making it work in favour of the critically ill patient. The objective is to improve wound healing, dampen the stress response to critical illness, decrease oxidative stress, and diminish the risk of infection. Unfortunately, the promises made regarding these supplements have thus far largely failed to materialise as hard outcomes. The only possible exception to this is selenium which appears to improve mortality in severe sepsis when given in large doses.

This material is rapidly becoming pointlessly esoteric. Question 3  from the second paper of 2003 is the last time the college asked about this issue, riding a wave of interest originating from favourable early papers. However, more recently large trials have dampened this enthusiasm, and there have been no new questions on this topic.

Arguments for and against the use of pharmaconutrients

Rationale for the use of pharmaconutrients in critical illness

  • During critical illness:
    • Oxidative stress depletes naturally available antioxidant molecules
    • Inflammatory processes are unnaturally exaggerated, leading to tissue injury (due to a failure fo nowmal downregulation)
    • Reserves of trace elements are depleted by injured tissues
  • The theoretical benefits of supplementing these pharmaconutrients include
    • Improved wound healing (trace elements supposedly enhance protein synthesis)
    • Improved resistance to infection (trace elements supposedly increase immune cell prodution)
    • Diminished inflammatory and stress responses (immunomodulatory effects, particularly by the omega-3 fatty acids)
    • Decreased organ damage due to oxidative stress  (dyue to scavenging by antioxidants)
  • Immunonutrition has been proposed both for the critical care population as a whole, and for select groups of ICU patients, such as burns patients, high risk surgical patients, patients recovering from gastrointestinal surgery and patients with acute lung injury.
  • The upshot of these proposed physiological benefits are a decreased length of ICU stay and improved recovery from critical illness

Arguments against the use of pharmaconutrients

  • Advantages of immunonutrition are thus far unproven (in other words, they don't work as advertised).
  • Cost (can be significant)
  • Potential for harm (eg. glutamine supplementation appears to increase mortality among patients with multi-organ system failure)
  • Danger of oversupplementation (for instance, toxicity like selenosis)

Evidence regarding specific pharmaconutrient agents


Glutamine supplementation seemed to be associated with an improved outcome, at least for some TPN patients. There was thought to be some sort of systemic antioxidant effect, and theoretically it is known that glutamine is a primary fuel source for gut cells, as well as a major substrate for acute phase reactant synthesis. It actually has numerous roles, among which is an effect on induceable nitric oxide synthease (which might lead to an improvement in the haemodynamic performance of a shocked patient). In critical illness, glutamine is said to be depleted (and the catabolic state prevents the synthesis of more glutamine). This is supported by the finding that many patients admitted to ICU turn out to be glutamine-deficient (Wernerman, 2014) - a finding which has also been associated with increased mortality.

The glutamine supplementation strategy, though originating from studies which may be underpowered, had at least a little support in Australia. However, the Scottish SIGNET trial (Andrews et al, 2011) did not find much difference between the glutamine and non-glutamine groups (though selenium still seem to have some sort of antiinfective effect). The recent meta-analysis by van Zanten et al (2015) did not find much benefit except in terms of slightly decreased hospital stay and improved mortality within the specific population of burns patients. Another similar meta-analysis by Oldani et al (2015) concluded that there was insufficient evidence to recommend the use of glutamine for random generic ICU patients.

These meta-analysis papers were published in the wake of two major nutrition trials, REDOXS (2013) and METAPLUS (2014). Though slightly different in methodology, these large-scale studies essentially compared glutamine with something equally-good-not-glutamine. The outcomes were disappointing: there was no improvement in any of the primary outcome measures, and REDOXS even found an increase in 28-day mortality associated with glutamine use (particularly among the patients with renal failure).

These depressing papers prompted people to write counter-articles (eg. Wernerman, 2015) to address the percieved shortcomings of the two big trials and the subsequent meta-analysis papers. Wernerman argued that the meta-analysis papers cannot be believed because the patient nutritional status was not properly characterised, the supplements were not standardised, the mechanism of benefit is incompletely understood, and that it is unclear whether the route of administration has any influence at all. Lastly, it is argued that there may be a population of patients who have some sort of occult "hypoglutaminaemia", and that this under-investigated cohort is the one which stands to benefit most from glutamine supplements. However, in spite of such objections, the various venerable Societies have changed their guidelines, and do not recommend  enteral or parenteral glutamine anymore.


Arginine is an α-amino acid which is the immeidate precursor of nitric oxide, among other things. An excellent article by Stechmiller et al (2004) goes into more detail about it. Why is it special? In brief, it is an important substrate for the urea cycle. It is 32% nitrogen by mass, whereas most other amino acids are only 16% nitrogen, and that makes it an excellent substrate for the detoxification of ammonia and the excretion of nitrogen.  The enthusiasm for the use of arginine arose from several animal and human studies which suggested that it may enhance immunocompetence, increase the weight of the thymus and enhance the prolieration of monocytes and lymphocytes. But what of the clinical trial evidence? A meta-analysis by Kang et al (2014) enrolled 321 patients from 11 eligible trials specifically involving L-arginine supplements. There was evidence of immunomodulatory function: the arginine-supplemented patients had a decreased incidence of infectious complications. However, this has only resulting in a clinically significant improvement in the outcomes of elective surgical patients (Drover et al, 2011). For the critically ill population, this thorough review by the Canadian Clinical Practice Guidelines (2015) could not recommend the use of arginine.

Ornithine ketoglutarate

Supplemental enteral arginine is metabolized to ornithine.  Ornithine is in turn a precursor to arginine. It is unclear as to how one might benefit by substituting one for the other. Again, the clinical trials (in burns patients) have failed to demonstrate any mortality benefit. Nutrition indices and wound healing apparently improved, and this would have been a good finding if only it was not rendered meaningless by inconsistensies in measuring either parameter. In short, ornithine supplementation cannto be recommended.

Omega-3 fatty acids and fish oil

This is one of the failed experimental therapies for ARDS. Enteral omega-3 fatty acids (the OMEGA trial) were tested by the ARDSNet people - neither harm nor benefit were found, and the investigators blamed this on insufficient duration of therapy (only 12 hours).

Small scale studies (eg. Tihista et al, 2017) tend to occasionall find benefit in selected patient groups; in the case of the abovementioned paper it was severe burns patients (~38% BSA) who seemed to have fewer episodes of sepsis if they had 50% of their fat intake delivered as fish oil. Unfortunately, the comparator group had a low fat diet, which we already know has disastrous immunologic consequences. Moral of the story: don't intentionally sabotage your control group.


This micronutrient is incorporated into several essential protens ("selenoproteins") as a specific amino acid variant (selenocysteine). These proteins play various vital roles in the metabolism of glutathione, iodine, and in antioxidant systems. The proposed benefit is again some sort of ill-defined immune tonic effect. Two recent meta-analysis articles are available. Huang et al (2013) took a look at its role in critical illness broadly, and Alhazzani et al (2013) reviewed its efficacy in sepsis specifically. Significant heterogeneity of trials prevented good quality analysis, but the authors concluded that selenium does actually improve mortality from sepsis at doses higher than daily requirement (the odds ratio was 0.83)

In summary:


Montejo, Juan C., et al. "Immunonutrition in the intensive care unit. A systematic review and consensus statement." Clinical Nutrition 22.3 (2003): 221-233.

Bertolini, Guido, et al. "Early enteral immunonutrition in patients with severe sepsis." Intensive care medicine 29.5 (2003): 834-840.

Heyland, Daren K., et al. "Should immunonutrition become routine in critically ill patients?: A systematic review of the evidence." Jama 286.8 (2001): 944-953.

Marik, Paul E., and Gary P. Zaloga. "Immunonutrition in High-Risk surgical patients a systematic review and analysis of the literature." Journal of Parenteral and Enteral Nutrition 34.4 (2010): 378-386.

Hübner, Ma, et al. "Preoperative immunonutrition in patients at nutritional risk: results of a double-blinded randomized clinical trial." European journal of clinical nutrition 66.7 (2012): 850-855.

Cerantola, Y., et al. "Immunonutrition in gastrointestinal surgery." British Journal of Surgery 98.1 (2011): 37-48.

Marik, Paul E., and Gary P. Zaloga. "Immunonutrition in critically ill patients: a systematic review a

Mizock, Barry A. "Immunonutrition and critical illness: an update." Nutrition 26.7 (2010): 701-707.