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Immunonutrition

Immunonutrition: The link between malnutrition and impaired immune function has been well documented. ‘Immuno suppression’ caused by malnutrition is so predictable that reduced lymphocyte count and impaired response to antigens have traditionally been used as components of nutrition screening. Hence, the conventional role of nutrition support in immune function has been limited to preventing or reversing Immuno suppression related to malnutrition. However, today, there is an ongoing research into specific nutritional components which favorably affect immune function. This has stimulated the development of commercial enteral and parenteral products designed to improve the outcomes of hospitalized patients.


The capacity for nutrients to modulate the actions of the immune system and to affect clinical outcome has become an important issue in clinical practice and public health. The application of nutrients for this purpose is referred to as ‘Immunonutrition’. A working definition of ‘Immunonutrition’ might be ‘modulation of the activities of the immune system by selective nutrients.’ These nutrients are called as ‘immunonutrients’ and include the amino acids (arginine and glutamine), omega-3 fatty acids, nucleotides and ‘antioxidants’ – vitamins and minerals.


Out of these immunonutrients, glutamine and omega-3 fatty acids have been extensively studied and we shall discuss them in some details. The studies on other immunonutrients have been carried out with combinations of two or more immunonutrients and hence, there is no conclusive evidence regarding their benefits and hence, there is no conclusive evidence regarding their benefits and safety. There is a need for well designed, large scale, double blind, and randomized controlled trials to clarify the safety and efficacy of these immunonutrients. However, several recent studies have suggested the addition of Arginine to enteral feeds may improve outcome in critically ill patients. Arginine is considered to be a ‘conditionally essential’ aminoacids in that the endogenous synthesis may be limited during serious illness. Thus, it is a major component of most commercially available immunonutrients. Enteral nutrition enriched with arginine in post operative cases seems to help in wound healing. However, if the dose of arginine is too large, it can induce lysine deficiency and cloud be harmful. Further, in heterogeneous critically ill population, arginine alone without the addition of omega-3 fatty acids may even be harmful. In this group of patients, studies suggest that both arginine and omega-3 fatty acids need to be given together to see benefits.


Recently, much thought has been given to glutamine as an immune-enhancer. Glutamine is an aminoacids which can be synthesized by virtually all tissues and it accounts for more than 60% of the body’s free amino acid pool. During starvation and particularly during stress, the glutamine pool of the body is reduced markedly. Further, experimental factor associated with glucose intolerance and may have a future potential as nutrient adjuvant during clinical situations associated with insulin resistance, such as diabetes mellitus, sepsis, and trauma etc.


Glutamine is believed to prevent and treat sepsis in two main ways:

1) By protecting the integrity of gut, thereby preventing microbes and endotoxins from passing into the blood stream and contributing to sepsis. Following stress and malnutrition, uptake of glutamine depletion. Glutamine is an essential dietary component for the maintenance of gut metabolism, structure and function, particularly during critical illness when the gut mucosal barrier may become compromised. With translocation syndrome, local and systemic insults can damage the gut epithelium, allowing luminal bacteria and toxins to cross the gut mucosal barrier and enter the general circulation. If systemic response, such as hypermetabolism and persistent catabolism, is self-perpetuating, multiple-system organ failure (MSOF) can result.


2) By promoting lymphocyte activation, thereby enhancing the ability of the immune system to fight infections. Immune cells depend on glutamine availability. Catabolic stress and malnutrition induced glutamine deprivation will severally impair immune function. Glutamine is thus indicated in patients with inflammatory bowel disease, short bowel syndrome, AIDS and malignancy and in most critically ill patients like those with extensive burns, multiple trauma and septic shock.


Daily oral glutamine supplement is best given in divided doses to increase direct contact with the intestinal tract. Many commercially available enteral feeds which contain glutamine and immune nutrients are available for critically ill patients. However, there is much controversy presently concerning the benefit of enteral glutamine in critically ill patients despite considerable supply of glutamine (15-35 g/d). The reasons for the unfavorable results with enteral glutamine supplementation are multifactorial. Theoretically, the presence of bacterial overgrowth in stressed patients might in part explain the observed low circulating glutamine concentrations, because it is well known that bacteria readily consume glutamine as a preferred substrate. It is also possible that increased utilization of glutamine in the gut may contribute to the inability of glutamine-enriched enteral feeds to increase the plasma glutamine levels.


The obvious limitations of using oral free glutamine in routine clinical settings triggered an intensive search for alternative substrates. This has led to the synthesis of intravenous glutamine dipeptides which are stable and highly soluble synthetic dipeptides. Recent studies have shown that in critically ill patients, intravenous glutamine dipeptides supplementation is associated with reduction in infectious complications and decreased hospital stay. Some studies have also shown that it has led to reduction in mortality when given in higher doses and commercial preparations are now available for their clinical use.


Polyunsaturated fatty acids (PUFAs) – Omega 6 fatty acids and Omega 3 fatty acids cannot be synthesized in the body and hence are obtained from the food we eat. PUFAs which are predominant in our normal diet today are obtained from vegetable oils and from depot fat of mammals and these is mainly linoleic acid (omega 6 fatty acids). In contrast, those societies whose food mainly contains a major intake of deep sea fish incorporate larger quantities of alpha-linolenic acid (omega 3 fatty acids). Once consumed, these fatty acids are converted to larger chains of more unsaturated derivatives. Linoleic acid is converted to arachidonic acid (ARA) and alpha-linolenic acid is converted to eicosapentanoic acid (EPA) and docosahexanoic acid (DHA). Both EPA and DHA are produced in algae and plankton, hence, fish oils extracted from deep sea fish (e.g. herring, salmon, mackerel, tuna, sardines) which live on plankton provide the main source of omega 3 fatty acids for humans. Both omega 3 and omega 6 fatty acids are important ‘essential fatty acids’ (EFAs) and their deficiency can lead to a wide array of clinical disorders.


In critically ill patients (especially those with severe sepsis), ARA (omega 65 fatty acids) products are thought to be pro inflammatory mediators where as EPA (omega 3 fatty acids) product act as anti inflammatory or rather less pro inflammatory, which makes their interaction critical considering they are both competitive substrates. It is there for essential to have optimal ratio of omega 6 and omega 3 fatty acids in critical care settings. If SIRS is left unchecked without a proper balance of this ratio, the consequences may be worsening of sepsis and organ failure.


The lipids commonly used in parenteral feeds have been traditionally based on soya bean oil which is rich in omega 6 fatty acids. Hence, adding omega 3 fatty acids as a separate lipid emulsion now commercially available may help in attaining the balanced ratio of omega 6 and omega 3 fatty acids in critically ill patients. Omega 3 fatty acids can be given as a supplement in a relatively small proportion of 10-20% of the total lipids given. This can effectively adjust the fatty acid profile of a parenteral nutrition regimen. Prospective studies in critically ill patients reveal encouraging results so far, however due to limited experience; one should refrain from using the product in grossly unstable patients or patients with severe renal or liver failure and in pregnant women.


In conclusion, one can say that despite the extensive studies and Meta analyses, there is still no definitive evidence to suggest that Immunonutrition improves survival in critically ill patients. However, there is an overall impression that it significantly lowers the rate of infections. It is unlikely that mere substituting one form of nutrition for another will change the course of prognosis in cases of overwhelming sepsis. Hence, the current thinking is to avoid Immunonutrition in life threatening septic patients with APACHE scores more than 20, where such radical changes in nutrients may perhaps adversely affect the outcome. Instead, use it in less serious patients of sepsis or in early sepsis where it is more likely to be of benefit.