Title: The place of n-3 PUFA enteral nutrition in clinical management
Key words: enteral, parenteral, n-3 PUFA, n-6 PUFA, polyunsaturated fatty acids, cell membranes, eicosanoids, inflammatory markers, leukocyte, macrophages, surgery, trauma, sepsis, enteral nutrition, parenteral nutrition, Th1, Th2, glutamine, arginine, immunonutrition, nucleotides, gastrointestinal surgery, immunomodulating, malnourished, nutritional support,
Date: Oct 2006
Author: Morgan, G
The place of n-3 PUFA enteral nutrition in clinical management
Both enteral and parenteral nutrition have a place in the management of the seriously ill. This review will look at the place of enteral nutrition and assess whether the introduction of the n-3 PUFA-based emulsions has improved clinical outcome. Earlier work using the n-6 PUFAs in parenteral nutrition indicated these types of emulsions to be immunosuppressive (Battistella 1997). By contrast, n-3 PUFAs have been shown to lead to changes in the n-3 to n-6 fatty acid composition of cell membranes with the production of a less pro-inflammatory eicosanoid profile. Inflammatory markers such a PGE2, TNF-alpha and the leukotriene B4 to B5 ratio are favourably modulated by the n-3 PUFAs (Chapkin 1991, Wachtler 1997, Wallace 2000). As well as moderating the inflammatory reaction, the n-3 PUFAs also favourably effect leukocyte and macrophage activity (Mayer 1998, Grimm 2002). Surgery and trauma, the main indication for enteral nutrition, can lead to the initiation of a state of hyper-inflammation with an acute phase reaction and suppression of the immune system leading to sepsis in some patients (O’Flaherty 1999). Impaired polymorph function is a prerequisite for sepsis and is impaired following surgery (Stephan 2002), along with poor Th1-mediated cell-mediated immunity (Ferguson 1999). It is now thought that the inflammatory and anti-inflammatory arms of the healing response to trauma or surgery are not biphasic, as originally thought, but are synchronous (Tschaichowsky 2002). Both are necessary in the fight against sepsis. Modulation of Th1-mediated cytokines, such as TNF- alpha, through the use of agents such as the n-3 PUFAs, helps to rebalance the inflammatory and anti-inflammatory arms of this system, thus inhibiting a hyper-inflammatory response. They also activate polymorph and lymphocyte activity. Glutamine, which activates white cells and increases the production of the Th1-mediated cytokines, has also been shown to reduce the early hyper-inflammatory response, reducing levels of sepsis in the critically ill (Calder 1999, Andrews 2002). It is effective parenterally but has also produced results when added to n-3 PUFA-containing enteral feeds (Houdijk 1998).
In clinical practice few studies have been conducted looking at the effect of the n-3 PUFAs alone in modulating inflammation via enteral feeding. Of the four studies (Kenler 1996,Swails 1997, Wachtler 1997, Weiss 2002), three reported a reduction in pro-inflammatory and an increase in anti-inflammatory markers, with a reduced incidence of sepsis and shorter hospital stay. Many more studies have been carried out looking at the use of n-3 PUFAs combined with glutamine, arginine and nucleotides, all possessing promotory effects on lymphocyte and immune function. Some 15 studies have now been published analysing the efficacy of the n-3 PUFA-containing immunonutrition agent Impact, for example. A meta- analysis of the results has been carried out (Marik 2001). From this it is clear that, in the groups of upper gastrointestinal surgery analysed, the use of Impact led to a more favourable immunological profile and significant reductions in sepsis, complications, and hospital stay. Overall mortality, however, appeared to be unchanged. Certain conclusions can be drawn from this work.
Firstly, immunotherapy appears to be most effective when given in the preoperative or early post- operative period (Braga 2002). Second, that the effect is dose dependent (Senkal 1995, Braga 1999) and, thirdly, that the reduction in the inflammatory markers and the sepsis rate only become apparent after the 5th day (Senkal 2000). The effectiveness also appears to be more pronounced in the malnourished (Suchner 2000, Braga 2002) and less effective in severe sepsis (Suchner 2000, Galban 2000). Its efficacy has been most well documented in upper abdominal cancer surgery (Marik 2001). Its use in medical ICU cases is less well defined (Griffiths 2003).
Sepsis remains the leading determinant of a favourable outcome following surgery and severe trauma. The early use of enteral nutrition with n-3 PUFA-containing formulae reduces the incidence of this complication in such groups. Early use of the bowel is feasible and helps to prevent mucosal atrophy, impaired gut immune function, increased gut permeability, and bacterial translocation, all related to postoperative sepsis (Jolliet 1999).
In summary, the enteral use n-3 PUFA-containing formulae provides an energy-dense, cost effective, source of nutrition with beneficial immunomodulating properties. These formulae help to support gut function and have been shown to reduce the incidence of sepsis and other complications in selected perioperative abdominal surgery and trauma patients, particularly in the malnourished. Though still requiring judicious use, in these patients requiring nutritional support during the acute phase of their illness, they help to improve clinical outcome.
1. Battistella FD, Widergren JT, Anderson JT, Siepler JK, Weber JC, MacColl K (1997) A prospective, randomized trial of intravenous fat emulsion administration in trauma victims requiring total parenteral nutrition. J Traum Inj Infect Crit Care 43: 52-8
2. Chapkin RS, Akoh CC, Miller CC (1991) Influence of dietary n-3 fatty acids on macrophage glycerophospholipid molecular species and peptidoleukotriene synthesis. J Lipid Res 32: 1205-13
3. Wachtler P, Konig W, Senkal M, Kemen M, Koller M (1997) Influence of total parenteral nutrition enriched with omega-3 fatty acids on leukotriene synthesis of peripheral leucocytes and systemic cytokine levels in patients with major surgery. J Traum Inj Infect Crit Care 42: 191-8
4. Wallace FA, Neely SJ, Miles EA, Calder PC (2000) Dietary fats affect macrophage-mediated cytotoxicity toward tumour cells. Immunol Cell Biol 78: 40-48
5. Mayer K, Seeger W, Grimminger F (1998) Clinical use of lipids to control inflammatory disease. Curr Opin Clin Nutr Metab Care 1: 179-184
6. Grimm H, Mayer K, Mayser P, Eigenbrodt E (2002) Regulatory potential of n-3 fatty acids in immunological and inflammatory processes. Br J Nutr 87 Suppl 1: S59-S67
7. O’Flaherty L, Bouchier-Hayes DJ (1999) Immunonutrition and surgical practice. Proc Nutr Soc 58: 831-7
8. Stephan F, et al. (2002) Impairment of polymorphonuclear neutrophil function preceded nosocomial infections in critically ill patients. Crit Care Med 30: 315-22
9. Ferguson NR, Galley HF, Webster NR (1999) T-helper cell subset ratios in patients with severe sepsis. Intens Care Med 25: 106-9
10. Tschaikowski K, Hedwig-Geissing M, Schiele A, Bremer F, Schywalsky M, Schuttler J (2002) Coincidence of pro- and anti- inflammatory responses in the early phase of severe sepsis: Long- itudinal study of mononuclear histocompatibility leucocyte antigen-DR expression, procalcitonon, C-reactive protein, and changes in T-cell subsets in septic and postoperative patients. Crit Care Med 30: 1015-23
11. Calder PC, Yaqoob P (1999) Glutamine and the immune system. Amino Acids 17: 227-241
12. Andrews FJ, Griffiths RD (2002) Glutamine: essential for immune nutrition in the critically ill. Br J Nutr 87 Suppl 1: S3-S8
13. Houdijk APJ, et al. (1998) Randomised trial of glutamine-enriched enteral nutrition in infectious morbidity in patients with multiple trauma. Lancet 352: 772-776
14. Kenler AS, et al. (1996) Early enteral feeding in postsurgical cancer patients. Ann Surg 3: 316-333
15. Swails WS, Kenler AS, Driscoll DF (1997) Effects of fish oil structured lipid-based diet on prostaglandin release from mono- nuclear cells in cancer patients after surgery. J Parent Enteral Nutr 21: 266
16. Weiss G, Meyer F, Matthies B, Pross M, Koenig W, Lippert H (2002) Immunomodulation by perioperative administration of n-3 fatty acids. Br J Nutr 87 Suppl 1: S89-S94
17. Marik PE, Zaloga GP (2001) Early enteral nutrition in acutely ill patients: a systematic review. Crit Care Med 29: 2264-2270
18. Braga M, Gianotti L, Vignali A, Carlo VD (2002) Preoperative oral arginine and n-3 fatty acid supplementation improves the immuno- metabolic host response and outcome after colorectal resection for cancer. Surgery 132: 805-14
19. Senkal M, Kemen M, Homann HH, Eickhoff U, Baier J, Zumtobel V (1995) Modulation of postoperative immune response by enteral nutrition with a diet enriched with arginine, RNA, and omega-3 fatty acids in patients with upper gastrointestinal cancer. Eur J Surg 161: 115-22
20. Braga M, et al. (1999) Perioperative immunonutrition in patients undergoing cancer surgery. Results of a randomised double-blind phase-3 trial. Arch Surg 134: 428-33
21. Senkal M, et al. (2002) Early postoperative enteral immunonutrition: clinical outcome and cost-comparison analysis in surgical patients. Crit Care Med 25: 1489-96
22. Suchner U, Kuhn KS, Furst P (2000) The scientific basis of immuno- nutrition. Proc Nutr Soc 59: 553-63
23. Galban C, et al. (2000) An immune-enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic intensive care unit patients. Crit Care Med 28: 643-8
24. Griffiths RD (2003) Nutrition support in critically ill septic patients. Curr Opin Cli Nutr Metab Care 6: 203-210
25. Jolliet P, et al. (1999) Enteral nutrition in intensive care patients: a practical approach. Clin Nutr 18: 47-56