Immunonutrition

Ciaran Walsh, Arrowe Park Hospital

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Immunonutrition refers to the provision of immune enhancing nutrients in amounts greater than the patient would normally encounter with a view to a beneficial modulation of the immune response to surgical and other critical illness stresses. Many nutrients are potentially immune enhancing, or immunonutrients, but the ones that appear to be the most important are L-Arginine, L-Glutamine, nucleotides and Omega-3 fatty acids.

Arginine

A conditionally essential amino acid, arginine is usually synthesised from L-citrulline.

It enhances T lymphocyte numbers and function, it is a precursor of nitric oxide, stimulates growth hormone production and plays a role in wound healing via hydroxyproline metabolism. Arginine stimulates both gluconeogenesis and acute phase protein synthesis. During metabolic stress, illness or growth endogenous synthesis cannot meet body demands. Under these circumstances exogenous sources of arginine appear to be needed for optimal function of both specific and non-specific immunity.

Glutamine

A conditionally essential amino acid which is relatively unstable in solution unless bound to protein. As a result enteral formulas supplemented with glutamine were previously available in powder form. Glutamine is an important precursor of the antioxidant glutathione. It is also an important oxidative fuel for rapidly replicating cells of the gastrointestinal and immune systems including enterocytes, colonocytes, lymphocytes and macrophages. Glutamine aids in the synthesis of visceral protein. During stress and without an exogenous supply of glutamine the body will break down muscle as a means of glutamine production. Providing exogenous glutamine in this context helps minimises muscle catabolism and maintain gut integrity.

Nucleotides

These are the precursors of RNA and DNA. They are involved in almost all-cellular activity. De novo endogenous synthesis is complex and requires a lot of energy. The body will preferentially down regulate endogenous synthesis in favour of preformed dietary sources. This exogenous supply is particularly important during stress when inadequate nucleotide supply will reduce the rate of replication of rapidly growing cells in gastrointestinal mucosa, lymphocytes and macrophages.

Omega-3 Fatty Acids

Unlike arginine, glutamine and nucleotides, omega-3 fatty acids do not stimulate the immune system. Fatty acids are a major component of cell membranes and omega-3 fatty acids compete with the omega-6 fatty acid, arachodonic acid, for cyclooxygenase metabolism. The omega-6 fatty acid, arachodonic acid, suppresses immune function and promotes inflammation. Omega 3 fatty acids act in an anti-inflammatory capacity by downregulating prostaglandin E2 production as well as suppressing eicosanoid and proinflammatory cytokine production

There have been a large number of experimental and clinical studies over the years looking at the effects of dietary manipulation with immunonutrients in different disease states. Many have been in the critical care arena whilst others have concentrated on elective surgical patients with varying degrees of undernutrition. Arguably since the study by Daly et al in 1992, immunonutrition by common usage refers to the enteral administration of immunonutrient mixtures that contain one or more of arginine, nucleotides and omega-3 fatty acids. Immunonutrients can of course be given intravenously, most notably glutamine. There is a large literature on intravenous glutamine as an immunonutrient most notably in the critical care literature.

For the purposes of this presentation I am going to concentrate on the data for enteral immunonutrient formulae and will look mainly at surgical outcomes rather than outcomes in non-surgical critical care patients. Indeed to get an overview of the published data on immunonutrition it is important to differentiate between data from surgical studies on relatively homogenous groups of perioperative patients and the data from ITU studies on heterogeneous groups of critical care patients. In this context it is important to realise that the published meta-analyses include both surgical and non-surgical critical care patients.

There have been three meta-analyses of trials investigating the role of immunonutrition in disease outcome. In 1999 Beale et al looked at 15 randomised controlled trials comparing patients receiving standard enteral nutrition and those receiving a commercial enteral immunonutrient supplement. They concluded that while there was no effect of immunonutrition on mortality there was a significant reduction in the incidence of infection and duration of hospital stay associated with it’s use. Also in 1999 Heys et al looked at 11 prospective randomised trials and found a reduced incidence of infection in patients with critical illnesses if treated with immunonutrition rather than standard enteral nutrition. In 2001 Heyland et al looked at 2419 patients from 22 prospective randomised trials and compared the use of immunonutrition with standard enteral nutrition. There were heterogeneous groups of patients including non-surgical ITU patients, burns patients, trauma patients and elective surgical patients. Overall immunonutrition was associated with a reduced incidence of infectious complications but had no mortality advantage. Subgroup analysis showed that studies on surgical patients found a significant reduction in infectious complication rates and hospital length of stay.

The role of immunonutrition in non-surgical critical care patients is not clear cut. There are even data to suggest that immunonutrition may have deleterious effects with increased mortality in some non-surgical ITU patient groups.

The beneficial effects of perioperative immunonutrition in surgical patients are now well established. Numerous studies from different surgical disciplines have shown benefits in terms of infectious complications and hospital length of stay. The majority of the data are from patients with upper gastrointestinal malignancy and there is convincing Level I evidence that enteral immunonutrition reduces infection rates and hospital lengths of stay in these patients. Initially benefits were recognised in undernourished patients but there is now some good evidence that the beneficial effects may also be seen in normally nourished patients. Earlier studies looked at pre and postoperative supplementation but it now appears that preoperative supplementation is key and postoperative treatment confers no added benefit. This latter finding is relevant to cost benefit analyses as enteral immunonutrition is expensive. Recent data appear to confirm the cost effectiveness of pre operative immunonutrition in well nourished patients undergoing surgery for gastrointestinal cancer.

In summary there appears to be a definite role for immunonutrition as part of the perioperative management package for surgical patients and gastrointestinal oncology patients in particular. The role of immunonutrition in non-surgical critical care patients is uncertain as yet. As regards surgical perioperative care, the future may be to work out the exact place for immunonutrients in the new enlightened age of surgical rapid recovery programmes. In the future it will not be appropriate to look at immunonutrition data in isolation without alluding to other variables in perioperative care. It will be fascinating to see if immunonutrients are able to hold their own in multivariate analyses of prospective randomised trials when all study patients have appropriate preoperative micro and macronutrient support, preoperative carbohydrate loading, no bowel preparation, forced mobilisation, reduced intravenous crystalloid volumes as well as effective short duration thoracic epidurals for major abdominal surgery.

REFERENCES

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