Clinical Topics

The Effect of Immunonutrition on Veterans Undergoing Major Surgery for Gastrointestinal Cancer

A randomized controlled trial found that providing immunonutrition supplementation before surgery reduced the rate of postoperative complications and the length of hospital stays.

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Immunonutrition involves the use of omega-3 fatty acids, glutamine, arginine, and/or nucleotides individually or in combination at therapeutic levels to specifically modulate the immune system against altering inflammatory and metabolic pathways.1 Current literature supports the routine use of immune-enhancing formulas (containing both arginine and fish oil) in surgical patients.2-4 Although most of the literature favors the use of immunonutrition in surgical patients, some studies reported no benefit over standard oral nutrition supplementation.5


Most studies evaluating the effect of immunonutrition for those undergoing elective surgery have been conducted in surgical oncology patients.6-12 Advanced cancers and older age can lead to cancer cachexia and sarcopenia, respectively. These conditions increase a patient’s surgical morbidity and mortality risk likely because of the negative effects on lean body mass, nutrient intake, and inflammatory and metabolic profile.13 However, early detection of some cancers through routine screening might lead to earlier surgical intervention that minimizes these negative tumor effects on the patient. Immunonutrition provided to well-nourished and malnourished patients has shown benefits, which supports the premise that a combination of immunonutrients included in immune-enhancing diets might have a beneficial pharmacotherapeutic effect beyond that of providing energy, protein, vitamins, and minerals for nutritional support.7,14

There are a lack of data regarding whether there is a window of opportunity for improved outcomes. Is the greatest need for immunonutrients during the peak of the injury, which might be immediately after surgery, or is it before the procedure? Arginine is a conditionally essential amino acid that has been shown to have a beneficial effect on the immune system by enhancing T-lymphocyte response when supplemented in surgical patients. When the arginase 1 (ARG 1) enzyme in myeloid cells is expressed during the inflammatory response to injury, accelerated use of arginine can deplete endogenous arginine, making it conditionally essential.

If adequate arginine cannot be synthesized or an exogenous source is not provided, T-cell dysfunction and decreased nitric oxide production leads to immune and vascular dysfunction, respectively.15,16 Providing arginine and omega-3 fatty acids might have a synergistic effect by shifting to an anti-inflammatory prostaglandin profile that has been shown to decrease ARG 1 expression while providing an exogenous source of arginine.17 Postsurgical inflammation might be caused in part by pro-inflammatory mediators and the anti-inflammatory properties of omega-3 fatty acids might offset this if cell membranes are loaded preoperatively.18 Therefore, preoperative immunonutrition might allow tissues to recover from planned surgical trauma. Bouwens and colleagues demonstrated that intake of eicosapentaenoic acid/docosahexaenoic acid over 26 weeks can alter the gene expression profiles of immune cells to a more anti-inflammatory status.19 However, Senkal and colleagues recommended that 3 to 7 days preoperatively is adequate to positively alter the lipid profile of tissues.20

Oncology patients preparing for surgery often are exposed to the physiologic stress of radiation and chemotherapy as neoadjuvant treatment to surgery. Oncology treatment and the adverse nutritional effects of treatment increase risk for arginine deficiency, such as poor nutrition intake, increased requirements, decreased production. Braga and colleagues demonstrated improved gut microprofusion and gut oxygenation intraoperatively, an effect that continued for up to 5 days after surgery.21 Waitzberg conducted a systematic review of randomized clinical trials evaluating immunonutrition in preoperative, postoperative, and perioperative periods. The results showed that the greatest improvements in postoperative infections and length of stay occurred in patients receiving preoperative 0.5 to 1 L/d of an immune nutrition product containing supplemental omega-3 fatty acids, arginine, and nucleotides for 5 to 7 days.22

It is unclear which population of surgical patients benefit the most from immunonutrition. Some results in the literature favor use in malnourished patients.18,23 However, other studies also have found benefit in well-nourished patients.7,14,21

Veterans who seek medical care at the Department of Veteran Affairs (VA) have higher rates of cancer, obesity, and diabetes mellitus, which complicate surgical outcomes.24 In addition to comorbidities, veterans who seek medical care at the VA are more likely to have been deployed overseas and have more physical and mental health disorders compared with that of nonveteran patients or veterans who do not use the VA. Because of higher comorbidities, unique deployment history, and mental health disorders, all of which may impact quality of life concerns, veterans are clinically more complex, which makes comparisons with the private sector difficult. The VA has the advantage of providing comprehensive care to veterans in all settings, including preparation for surgery and postsurgical follow-up with an interdisciplinary team.

The objective of this study was to compare surgical outcomes in veterans who receive preoperative supplementation using an immune-modulating formula with veterans who received a standard oral supplement. Although practice guidelines have been developed from studies in US nonveteran populations, there are no high- quality randomized studies of veterans.

This study design also would allow the VA to gauge cost-effectiveness of immunonutrition before implementing new protocols. There is convincing data supporting significant economic benefit; however, more cost-benefit studies are needed to fully assess.18,25-27 Immunonutrition products are more expensive than are standard nutrition supplements, but overall cost of care when immunonutrition products are used could be lower because of reduction of complications and hospital resources.


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