Immunonutrition

The potential to modulate the activity of the immune system by interventions with specific nutrients is termed immunonutrition. This concept may be applied to any situation in which an altered supply of nutrients is used to modify inflammatory or immune responses. However, immunonutrition has become associated most closely with attempts to improve the clinical course of critically ill and surgical patients, who will often require an exogenous supply of nutrients through the parenteral or enteral routes.

Major surgery is followed by a period of immunosuppression that increases the risk of morbidity and mortality due to infection. Improving immune function during this period may reduce complications due to infection. Critically ill patients are at greater risk of adverse outcomes than surgical patients. In these patients complex variable immune and inflammatory changes occur that are only now being well defined. A biphasic response with an early hyperinflammatory response followed by an excessive compensatory response associated with immunosuppression is seen in many such patients. Here, early treatment is aimed at decreasing the inflammatory response rather than enhancing it, to abrogate the hyperinflammation and prevent the compensatory immunosuppression.

Three potential targets exist for immunonutrition–mucosal barrier function, cellular defence, and local or systemic inflammation. The nutrients most often studied for immunonutrition are arginine, glutamine, branched chain amino acids, n-3 fatty acids, and nucleotides (an overview of their key functions and effects appears on bmj.com).^1–5 Combinations of some or all of these nutrients are present in commercially available enteral feeds. Parenteral formulas containing glutamine or n-3 fatty acids are also available commercially.

Individual components of immunonutrition have been reported to preserve or augment various aspects of cellular immune function and to modify the production of inflammatory mediators.^1–5

Many clinical trials of immunonutrition in critically ill and surgical patients have been performed that used various nutrient combinations. Three meta-analyses give a fairly consistent view of the clinical efficacy of enteral immunonutrition.^6–8 All three considered only randomised controlled trials in either surgical or critically ill patients; the control was a “standard” enteral feed in all. Most trials used a combination of arginine, n-3 fatty acids, and nucleotides, whereas some used a combination of these nutrients and glutamine and branched chain amino acids or of arginine and n-3 fatty acids. The experimental feeds were often much higher in total nitrogen content and contained greater amounts of antioxidant vitamins and minerals such as vitamins A and E and selenium.

All three meta-analyses found that immunonutrition results in notable reductions in infections and in length of stay in hospital. In general the reduced infection rate and length of hospital stay are more pronounced in surgical than critically ill patients.⁸,⁹ Despite these apparent benefits of immunonutrition, none of the meta-analyses identified a significant effect of immunonutrition on mortality either across all trials considered or within surgical or critically ill patients. It is this outcome that has caused the greatest controversy and discussion.⁸,⁹ This is partly because one trial showed significantly increased mortality in critically ill patients receiving immunonutrition, an effect that was more pronounced in patients with sepsis. However, another study showed a reduction in mortality in critically ill patients with sepsis receiving immunonutrition.¹⁰ This effect was much more pronounced in those patients who were less ill, and no advantage in survival was seen in patients with a higher score.¹⁰ The reasons for the contradictory findings with immunonutrition in critically ill patients need to be understood more fully, and whether these relate to the heterogeneous nature of this patient group or to the presence or absence of specific nutrients within the immunonutrient mix needs to be addressed.

Trials have also shown some benefit from the “single” immunonutrient approach. For example, enteral provision of glutamine decreased the incidence of sepsis in premature neonates and the incidence of pneumonia, bacteraemia, and severe sepsis in critically ill patients.² However, in the latter study the decreased rate of infection was not associated with decreased mortality.² Parenteral glutamine decreased the incidence of infections in recipients of bone marrow transplantation and changed the pattern of mortality in patients in intensive care.² These clinical benefits of glutamine seem to be associated with improvements in intestinal integrity and in cellular immune function.²

An enteral feed that differed in lipid composition from the control (among other differences, it contained n-3 fatty acids, which the control feed did not³) was shown to decrease the requirement for supplemental oxygen, time on ventilation support, and length of stay in the intensive care unit in patients with moderate and severe acute respiratory distress syndrome.¹¹ Total length of stay in hospital and mortality also tended to be decreased in the treatment group, and fewer patients developed new organ failure.¹¹ Although several studies report potential immune benefits and anti-inflammatory effects of parenteral n-3 fatty acids,³,⁶ few trials of the effect of this approach on clinical outcomes exist. Recent trials using parenteral n-3 fatty acids in surgical patients show immune benefits and anti-inflammatory effects¹² but no reduction in infection rate or mortality, although postoperative stay in intensive care and in hospital tended to be shorter in the fish oil group.¹²

Trials of immunonutrients indicate several beneficial clinical effects, particularly in surgical patients. However, doubts remain about the efficacy of this approach in critically ill patients, with contradictory findings among trials. Methodological differences among trials hamper comparisons.⁸,⁹ Use of immunonutrition should be approached cautiously in the most critically ill patients.⁸,⁹ Future efforts should try and define the most effective nutrients and optimal mixes for use in different patient groups.