Antioxidant-enriched enteral nutrition and immuno-inflammatory response after major gastrointestinal tract surgery.

Major surgery induces an immuno-inflammatory response accompanied by oxidative stress that may impair cellular function and delay recovery. The objective of the study was to investigate the effect of an enteral supplement, containing glutamine and antioxidants, on circulating levels of immuno-inflammatory markers after major gastrointestinal tract surgery. Patients (n 21) undergoing major gastrointestinal tract surgery were randomised in a single-centre, open-label study. The effects on circulating levels of immuno-inflammatory markers were determined on the day before surgery and on days 1, 3, 5 and 7 after surgery. Major gastrointestinal surgery increased IL-6, TNF receptor 55/60 (TNF-R55) and C-reactive protein (CRP). Surgery reduced human leucocyte antigen-DR (HLA-DR) expression on monocytes. CRP decrease was more pronounced in the first 7 d in the treatment group compared with the control group. In the treatment group, from the moment Module AOX was administered on day 1 after surgery, TNF receptor 75/80 (TNF-R75) level decreased until the third post-operative day and then stabilised, whereas in the control group the TNF-R75 level continued to increase. The results of the present pilot study suggest that enteral nutrition enriched with glutamine and antioxidants possibly moderates the immuno-inflammatory response (CRP, TNF-R75) after surgery.

Antioxidant enriched enteral nutrition and oxidative stress after major gastrointestinal tract surgery.

AIM: To investigate the effects of an enteral supplement containing antioxidants on circulating levels of antioxidants and indicators of oxidative stress after major gastrointestinal surgery. METHODS: Twenty-one patients undergoing major upper gastrointestinal tract surgery were randomised in a single centre, open label study on the effect of postoperative enteral nutrition supplemented with antioxidants. The effect on circulating levels of antioxidants and indicators of oxidative stress, such as F2-isoprostane, was studied. RESULTS: The antioxidant enteral supplement showed no adverse effects and was well tolerated. After surgery a decrease in the circulating levels of antioxidant parameters was observed. Only selenium and glutamine levels were restored to pre-operative values one week after surgery. F2-isoprostane increased in the first three postoperative days only in the antioxidant supplemented group. Lipopolysaccharide binding protein (LBP) levels decreased faster in the antioxidant group after surgery. CONCLUSION: Despite lower antioxidant levels there was no increase in the circulating markers of oxidative stress on the first day after major abdominal surgery. The rise in F2-isoprostane in patients receiving the antioxidant supplement may be related to the conversion of antioxidants to oxidants which raises questions on antioxidant supplementation. Module AOX restored the postoperative decrease in selenium levels. The rapid decrease in LBP levels in the antioxidant group suggests a possible protective effect on gut wall integrity. Further studies are needed on the role of oxidative stress on outcome and the use of antioxidants in patients undergoing major abdominal surgery.

Specific amino acids in the critically ill patient--exogenous glutamine/arginine: a common denominator?

OBJECTIVE: Glutamine and arginine are both used as nutritional supplements in critically ill patients. Although glutamine has been shown to be beneficial for the metabolically stressed patient, considerations about arginine supplementation are not unanimously determined. Our aim is to review the current knowledge on the possible interplay between glutamine and arginine generation in the stressed patient and to elaborate on whether these amino acids may function as a common denominator. Because glutamine can be given by the parenteral and enteral routes, possible different actions on the metabolic fate (e.g., generation of citrulline) with both routes are analyzed. DATA SOURCE: A summary of data on the clinical effect of glutamine and arginine metabolism is given, incorporating data on glutamine and arginine supplementation. Differences between the route of administration, parenteral or enteral, and the molecular form of supplied glutamine, free or as dipeptide, on citrulline generation by the gut and production of arginine are discussed. RESULTS: Glutamine and arginine influence similar organ systems; however, they differ in their targets. For example, glutamine serves as fuel for the immune cells, increases human leukocyte antigen-DR expression on monocytes, enhances neutrophil phagocytosis, and increases heat shock protein expression. Arginine affects the immune system by stimulating direct or indirect proliferation of immune cells. This indirect effect is possibly mediated by nitric oxide, which also enhances macrophage cytotoxicity. Furthermore, glutamine serves as a precursor for the de novo production of arginine through the citrulline-arginine pathway. Glutamine has shown to be beneficial in the surgical and critically ill patient, whereas arginine supplementation is still under debate. The route of glutamine administration (parenteral or enteral) determines the effect on citrulline and on the de novo arginine generation. There is a marked difference between the administration of free glutamine and dipeptide enterally or parenterally. Splanchnic extraction of the hydrolyzed glutamine in mice when administering the dipeptide enterally is higher compared with administering free glutamine from the enteral site. In patients, splanchnic extraction of the dipeptide given enterally is 100% when comparing supplementation of the dipeptide intravenously. CONCLUSIONS: The beneficial effects of free glutamine or dipeptide may depend on the route of administration but also on the metabolic fate of amino acids generated (e.g., citrulline, arginine). Glutamine serves as a substrate for de novo citrulline and arginine synthesis. More research needs to be done to establish the direct clinical relevance of the different metabolic pathways. Future perspectives might include combining enteral and parenteral routes of administrating free glutamine or dipeptide.

Effects of preoperative flavonoid supplementation on different organ functions in rats.

BACKGROUND: Previously it has been reported that preoperative feeding preserves heart function in rats after intestinal ischemia-reperfusion. To further improve postoperative organ function, bioactive nutrition compounds were selected in vitro against the xanthine oxidase radical cascade, an enzyme suggested to play a key role in the induction of single- or multiple-organ dysfunction. METHODS: Flavonoids were selected in vitro for their capacity to (1) inhibit xanthine oxidase, (2) scavenge superoxide, and (3) scavenge peroxylradicals. The most bioactive flavonoids were added to the preoperative nutrition to study their effect on postintestinal ischemia-reperfusion organ function. RESULTS: A combination of flavonoids selected on basis of effective flavonoid xanthine oxidase inhibition and superoxide scavenging resulted in increased superoxide scavenging. In vivo, the selected flavonoid mixture significantly lowered postischemic intestinal apoptosis and intestinal oxidative stress indicated by malondialdehyde concentration when compared with ischemia-reperfusion fasted and sham-fasted animals. Moreover, this flavonoid mixture significantly lowered plasma creatinine and urea concentration, both indicating a better postoperative kidney function. Furthermore, oxidative stress measured as this flavonoid mixture when compared with control significantly lowered plasma malondialdehyde concentration in fed rats. CONCLUSIONS: Coadministration of bioactive flavonoid mixture to preoperative nutrition, in contrast to fasting, attenuates ischemia-reperfusion injury by preserving kidney function in the rat and decreasing apoptosis in the intestine.

Route of administration (enteral or parenteral) affects the contribution of L-glutamine to de novo L-arginine synthesis in mice: a stable-isotope study.

A pathway from enteral L-glutamine as substrate for L-arginine synthesis is suggested by previous studies. L-Glutamine and L-glutamine dipeptides exhibit numerous beneficial effects in experimental and clinical studies. In trauma patients, enteral L-glutamine supply increased plasma L-arginine. The present study was designed to quantify the contribution of L-glutamine to the de novo L-citrulline and L-arginine synthesis in mice when L-glutamine is administered in a high dose of labeled L-glutamine or L-alanyl-L-glutamine by the enteral or parenteral route. For this purpose, male Swiss mice (n = 43) underwent a laparotomy, and catheters were inserted for sampling and infusion. A primed, constant, and continuous infusion of L-alanyl-L-[2-(15)N]glutamine (dipeptide groups) or L-[2-(15)N]glutamine (free L-glutamine groups), simultaneously with L-[ureido-(13)C,(2)H(2)]citrulline and L-[guanidino-(15)N(2),(2)H(2)]arginine, was given (steady-state model). Mice received the L-glutamine tracers intravenously (jugular vein) or enterally (duodenum). Enrichments of metabolites were measured by LC-MS. Arterial L-glutamine concentrations were the highest in the intravenous dipeptide group. L-Glutamine was converted to L-citrulline and L-arginine when L-[2-(15)N]glutamine and L-alanyl-L-[2-(15)N]glutamine were given by enteral or parenteral route. The contribution of L-glutamine to the de novo synthesis of L-citrulline and L-arginine was higher in the enteral groups when compared with the intravenous groups (P < 0.005). Therefore, the route of administration (enteral or parenteral) affects the contribution of L-glutamine, provided as free molecule or dipeptide, to the de novo synthesis of L-arginine in mice.

The feeding route (enteral or parenteral) affects the plasma response of the dipetide Ala-Gln and the amino acids glutamine, citrulline and arginine, with the administration of Ala-Gln in preoperative patients.

Enhancement of depressed plasma concentrations of glutamine and arginine is associated with better clinical outcome. Supplementation of glutamine might be a way to provide the patient with glutamine, and also arginine, because glutamine provides the kidney with citrulline, from which the kidney produces arginine when plasma levels of arginine are low. The aim of the present study was to investigate the parenteral and enteral response of the administered dipeptide Ala-Gln, glutamine, citrulline and arginine. Therefore, seven patients received 20 g Ala-Gln, administered over 4 h, parenterally or enterally, on two separate occasions. Arterial blood samples were taken before and during the administration of Ala-Gln. ANOVA and a paired t test were used to test differences (P<0.05). Ala-Gln was undetectable with enteral administration, whereas Ala-Gln remained stable at a plasma concentration of 268 micromol/l throughout parenteral infusion and rapidly decreased towards zero after infusion was stopped. The highest level of glutamine was observed with parenteral infusion of the dipeptide, although enteral infusion also significantly increased plasma levels of glutamine. The highest plasma response of citrulline was observed with the enteral administration of the dipeptide, although parenteral administration also increased plasma levels of citrulline. Plasma arginine increased significantly with parenteral infusion, but not with enteral administration of Ala-Gln. In conclusion, administrations of Ala-Gln, parenteral or enteral, resulted in an increased plasma glutamine response, as compared with baseline. Interestingly, in spite of the high availability of citrulline with enteral administration of the dipeptide, only parenteral infusion of Ala-Gln increased plasma arginine concentration.

Glutamine-enriched enteral nutrition increases in vitro interferon-gamma production but does not influence the in vivo specific antibody response to KLH after severe trauma. A prospective, double blind, randomized clinical study.

BACKGROUND & AIMS: Severe trauma leads to an immune suppression, characterized by a Type 2 T-lymphocyte response, contributing to the susceptibility of infectious complications. Plasma concentrations of glutamine (GLN), the preferred fuel for immunocompetent cells, severely decrease after trauma. Since administering glutamine-enriched enteral nutrition (EN) reduces infectious complications in trauma patients, we compared the effect of glutamine-enriched EN with an isocaloric, isonitrogenous enteral control (Con) feeding, on the Type 1 and 2 T-lymphocyte responses. METHODS: Thirty-eight trauma patients (Injury Severity Score >20) were sensitized with Keyhole Limpet Hemocyanin (KLH) within 12 h after trauma (17 GLN group). Healthy volunteers served as controls (HV, n=17). In vitro interferon-gamma (IFN-gamma), IL-4 and IL-10 productions of phytohemagglutinin (PHA)-stimulated PBMCs were determined by ELISA technique. KLH-specific IgG, IgM, IgA, IgG1, IgG2, IgG3, IgG4 and IgE were measured in serum. RESULTS: Both patient groups had a low in vitro (IFN-) production of stimulated PBMCs on d1. On d14, the IFN-gamma production increased significantly in the glutamine group as compared to the controls. IL-4 production was not different between the groups on day 1 (d1). On d14, IL-4 decreased in the control group as compared to the glutamine group. KLH-specific antibodies reached comparable levels in both patients groups and healthy volunteers at d14. CONCLUSIONS: In conclusion, trauma caused a suppressed in vitro cellular immune response presented by a low IFN-gamma production and depressed the IgG and IgM response to KLH directly after trauma. Glutamine increased IFN-gamma production (d14), maintained a normal IL-4 production, but was not acquired for the development of KLH-specific humoral response on d14, in sync suggesting that dietary glutamine supports the restoration of the Type-1 T-lymphocyte responsiveness.

Glutamine: recent developments in research on the clinical significance of glutamine.

PURPOSE OF REVIEW: The aim of this review is to describe the clinical relevance of supplementation of glutamine from the recent literature. First, new basic research is examined and subsequently recent clinical trials and a metaanalysis are illustrated. RECENT FINDINGS: Glutamine has a major impact on the functionality of the immune system. It has recently been established that glutamine not only has a protective effect on cells of the immune system, but also on other cells of the body, for instance cardiomyocytes. Evidence is accumulating for an effect of glutamine via glutathione, heat shock proteins as well as taurine. Another area of interest is the way glutamine enhances gut barrier function. More and more research is concentrating on the positive effect of glutamine on the gut-associated lymphoid tissue. SUMMARY: Based on a recent meta-analysis and up-to-date clinical trials, we may conclude that glutamine has a beneficial effect on infectious complications and reduces hospital stay. In critically ill patients glutamine supplementation may reduce morbidity and mortality. The greatest effect was observed in patients receiving high dose parenteral glutamine. A recent study with high dose enteral glutamine demonstrated a reduced mortality in the glutamine supplemented group. In the future more trials with larger numbers of participants are needed, especially with high dose enteral glutamine in the perioperatively and the intensive care unit setting.

Plasma taurine concentrations increase after enteral glutamine supplementation in trauma patients and stressed rats.

BACKGROUND: Taurine is a unique amino acid with antioxidant and osmolytic properties. Glutamine serves as the preferred fuel for the gut, liver, and immune cells and as a precursor for antioxidants. Trauma patients have low glutamine concentrations. OBJECTIVES: We investigated the effect of glutamine-enriched enteral nutrition on plasma taurine concentrations in patients with severe trauma (injury severity score >20). Additionally, plasma taurine concentrations and organ fluxes were studied in a stressed rat model. DESIGN: Twenty-nine patients with multiple trauma received glutamine-enriched nutrition and 31 patients received isocaloric, isonitrogenous control solution for 5 d. Plasma taurine and glutamine concentrations were measured. Male Wistar rats (250-300 g) received a glutamine-enriched diet (12%, by wt) or a control solution for 2 wk. Plasma taurine concentrations were measured. Taurine fluxes and fractional extraction rates in the liver, kidneys, and gut were assessed with a radioactive microsphere technique. RESULTS: Both patient groups had low taurine concentrations on day 1. From day 3 onward, the glutamine-fed patients had significantly higher taurine concentrations. Rats fed a glutamine-enriched diet had significantly higher plasma taurine concentrations than did the controls. A high taurine uptake was found in the liver, kidneys, and gut of the glutamine-fed rats. Fractional extraction rates were not significantly different between the rat groups. CONCLUSIONS: Glutamine enrichment increases plasma taurine in trauma patients and in stressed rats. Because of increased availability, organ fluxes showed a higher taurine uptake in the liver, kidneys, and gut. The reduction in morbidity with glutamine enrichment could be explained in part by increased taurine availability.

Glutamine-enriched enteral nutrition increases HLA-DR expression on monocytes of trauma patients.

The aim of this study was to investigate the effect of glutamine-(Gln)-enriched enteral nutrition (EN) on human leukocyte antigen (HLA)-DR and FcgammaR1/CD64 expression on monocytes and plasma glutamine concentrations in multi-trauma patients. HLA-DR expression on monocytes is crucial in the presentation of foreign antigen to the immune system and is severely reduced in trauma patients. In vitro monocyte HLA-DR and FcgammaRI/CD64 expression is dependent on glutamine availability. To study the effect of glutamine supplemented enteral nutrition on HLA-DR and FcgammaRI/CD64 expression on CD14(+) monocytes, 55 multi-trauma patients were studied in a randomized, double-blinded, controlled trial. Trauma patients received either a Gln-enriched EN (glutamine group, n = 28) or an isocaloric, isonitrogenous control EN (control group, n = 27) and were compared with a group of age-matched healthy volunteers (healthy volunteers, n = 53). On d 1, 5, 9 and 14 after trauma, expressions of HLA-DR and FcgammaRI/CD64 were determined on CD14(+) monocytes using FACS analysis. Plasma glutamine levels were measured using HPLC. Plasma glutamine was lower in both trauma patient groups compared with healthy volunteers and from d 3 to d 5; glutamine was higher in the glutamine group than in the control group. On d 1, HLA-DR expression was much lower in both trauma patient groups than in healthy volunteers. HLA-DR expression was greater on d 5, 9 and 14 in the glutamine group than in the control group. FcgammaRI/CD64 expression on monocytes of trauma patients was not different than the expression of healthy volunteers. This study showed that glutamine-enriched enteral nutrition was associated with a higher HLA-DR expression on CD14(+) monocytes of trauma patients. No difference in monocyte FcgammaRI/CD64 expression was detected between patients that received the two enteral diets and between trauma patients and the healthy volunteers. Increased HLA-DR expression may improve cellular immune function and may be involved in the beneficial effect of glutamine on the occurrence of infections in trauma patients.