J. Luttikhold

Review article: the role of gastrointestinal hormones in the treatment of delayed gastric emptying in critically ill patients.

Delayed gastric emptying limits the administration of enteral nutrition, leading to malnutrition, which is associated with higher mortality and morbidity. Currently available prokinetics have limitations in terms of sustained efficacy and side effects.

Intravenous glutamine supplementation enhances renal de novo arginine synthesis in humans: a stable isotope study

BACKGROUND Arginine plays a role in many different pathways in multiple cell types. Consequently, a shortage of arginine, caused by pathologic conditions such as cancer or injury, has the potential to disturb many cellular and organ functions. Glutamine is the ultimate source for de novo synthesis of arginine in humans via the intestinal-renal axis. Therefore, we hypothesized that parenteral glutamine supplementation may stimulate the interorgan pathway of arginine production. OBJECTIVES The objectives were to quantify arginine production from its precursor glutamine and to establish the contribution of the kidneys to de novo synthesis of arginine in patients receiving intravenous supplementation of glutamine dipeptide during major abdominal surgery. DESIGN Whole-body and renal metabolism of glutamine, citrulline, and arginine was assessed by stable isotope techniques in 7 patients receiving a perioperative supplement of intravenous alanyl-glutamine (0.5 g · kg(-1) · d(-1)). RESULTS Plasma glutamine, citrulline, and arginine concentrations increased significantly in patients receiving intravenous glutamine dipeptide. At whole-body level, 91% of total citrulline turnover was derived from glutamine, whereas 49% of whole-body citrulline turnover was used for de novo synthesis of arginine. The kidneys were responsible for 75% of whole-body arginine production from citrulline. CONCLUSIONS Glutamine and citrulline are important sources for de novo arginine synthesis. The kidneys are the main production site for endogenous arginine. After comparison of these results with previous similar studies, our data suggest that an intravenous glutamine supplement doubles renal arginine production from citrulline. This trial was registered at www.trialregister.nl as NTR2914.

The Role of a Disturbed Arginine/NO Metabolism in the Onset of Cancer Cachexia: A Working Hypothesis

Cancer cachexia is a complex catabolic state in patients with a malignancy, associated with increased morbidity and mortality. This syndrome is characterized by a redistribution of the bodys protein content and a subsequent muscle wasting. The aetiology of this syndrome seems multifactorial, but remains unclear. It is suggested that this catabolic state occurs in response to the alterations in immune interactions between tumor and host. The amino acid arginine and its derivate nitric oxide (NO) play various roles in anti-tumor immune response and the bodys homeostasis. Glutamine is the precursor for arginine de novo synthesis and the most abundant amino acid in the body, mainly stored in skeletal muscle. Tumors develop a protection mechanism against the specific anti-tumor attack of the immune system by recruiting myeloid derived suppressor cells (MDSC). The MDSC deplete arginine levels and disturb NO production. We here hypothesize that the perturbation of the arginine/NO metabolism plays a significant role in the aetiology of cancer cachexia. Arginine/ NO metabolism is disturbed in patients with cancer. The body will try to correct this perturbation by mobilizing arginine and glutamine from muscles. The decreased arginine levels and the disturbed NO production activate several cascades, which in turn inhibit protein synthesis and promote proteolysis, leading to cachexia. Cachexia remains one of the most frequent and damaging opportunistic syndromes in cancer patients. In this review we will elaborate on a new hypothesised concept and the underlying mechanisms of this syndrome. New studies are essential to ground this hypothesis and to develop interventions to break through the pathological mechanisms underlying cachexia.

Preservation of the gut by preoperative carbohydrate loading improves postoperative food intake

BACKGROUND & AIMS A carbohydrate (CHO) drink given preoperatively changes the fasted state into a fed state. The ESPEN guidelines for perioperative care include preoperative CHO loading and re-establishment of oral feeding as early as possible after surgery. An intestinal ischaemia reperfusion (IR) animal model was used to investigate whether preoperative CHO loading increases spontaneous postoperative food intake, intestinal barrier function and the catabolic response. METHODS Male Wistar rats (n = 65) were subjected to 16 h fasting with ad libitum water and: A) sham laparotomy (Sham fasted, n = 24); B) intestinal ischaemia (IR fasted, n = 27); and C) intestinal ischaemia with preoperatively access to a CHO drink (IR CHO, n = 14). Spontaneous food intake, intestinal barrier function, insulin sensitivity, intestinal motility and plasma amino acids were measured after surgery. RESULTS The IR CHO animals started eating significantly earlier and also ate significantly more than the IR fasted animals. Furthermore, preoperative CHO loading improved the intestinal barrier function, functional enterocyte metabolic mass measured by citrulline and reduced muscle protein catabolism, as indicated by normalization of the biomarker 3-methylhistidine. CONCLUSIONS Preoperative CHO loading improves food intake, preserves the GI function and reduces the catabolic response in an IR animal model. These findings suggest that preoperative CHO loading preserves the intestinal function in order to accelerate recovery and food intake. If this effect is caused by overcoming the fasted state or CHO loading remains unclear.

Antioxidative properties of flavonoids

Evidence accumulates that a family of plant compounds, known as flavonoids, can prevent or slow down the progression of cardiovascular diseases, cancer, inflammatory and neurodegenerative diseases. Flavonoids are considered beneficial, this is often attributed to their powerful antioxidant properties. In this role, certain types of flavonoids are considered to be far more powerful than the two most common antioxidants, vitamin C and vitamin E, at preventing cellular damage brought on by free radicals. Interestingly, flavonoids exert those activities not only through direct radical scavenging, but also through regulating nitric oxide, and chelating metals. In addition, flavonoids are thought to facilitate/promote other important biological processes, resulting in modulation of enzymes, a decrease in leukocyte immobilization, inhibition of cell proliferation and angiogenesis, and effects on signaling pathways. The results of in vitro studies have demonstrated that the antioxidative property of flavonoids is unambiguous; however it is still not supported by strong consistent evidence in vivo. Therefore, the antioxidant theory as a mechanism of action of flavonoids is controversial. As a result, flavonoids are hypothesized to exert their activities partly through cell signaling pathways. This review intends to acquaint the reader with different pathways in which flavonoids function or might function. Furthermore, we will provide insight into the beneficial health effects of these substances

Novel nutritional substrates in surgery.

Pharmaco-nutrients have beneficial effects on protective and immunological mechanisms in patients undergoing surgery, which are important for recovery after injury and in combating infectious agents. The aim of this review article was to outline the potential of the administration of nutritional substrates to surgical patients and the underlying mechanisms that make them particularly important in peri-operative care. Surgery causes a stress response, which has catabolic effects on the bodys substrate stores. The amino acid glutamine is a stimulating agent for immune cells. It activates protective mechanisms through its role as a precursor for antioxidants and it improves the barrier function of the gut. Arginine also enhances the function of the immune system, since it is the substrate for T-lymphocytes. Furthermore, n-3 PUFA stabilise surgery-induced hyper-inflammation. Taurine is another substrate that may counteract the negative effects of surgical injury on acid-base balance and osmotic balance. These pharmaco-nutrients rapidly become deficient under the influence of surgical stress. Supplementation of these nutrients in surgical patients may restore their protective and immune-enhancing actions and improve clinical outcome. Moreover, pre-operative fasting is still common practice in the Western world, although fasting has a negative effect on the patients condition and the recovery after surgery. This may be counteracted by a simple intervention such as administering a carbohydrate-rich supplement just before surgery. In conclusion, there are various nutritional substrates that may be of great value in improving the condition of the surgical patient, which may be beneficial for post-operative recovery.

Jejunal feeding is followed by a greater rise in plasma cholecystokinin, peptide YY, glucagon-like peptide 1, and glucagon-like peptide 2 concentrations compared with gastric feeding in vivo in humans: a randomized trial.

BACKGROUND Jejunal feeding is preferred instead of gastric feeding in patients who are intolerant to gastric feeding or at risk of aspiration. However, the impact of gastric feeding compared with that of jejunal feeding on postprandial circulating plasma glucose and amino acid concentrations and the associated endocrine response in vivo in humans remains largely unexplored. OBJECTIVE We compared the impact of administering enteral nutrition as either gastric feeding or jejunal feeding on endocrine responses in vivo in humans. DESIGN In a randomized, crossover study design, 12 healthy young men (mean ± SD age: 21 ± 2 y) received continuous enteral nutrition that contained noncoagulating proteins for 12 h via a nasogastric tube or a nasojejunal tube placed 30-40 cm distal to the ligament of Treitz. Blood samples were collected during the 12-h postprandial period to assess the rise in plasma glucose, amino acid, and gastrointestinal hormone concentrations. RESULTS No differences were observed in the postprandial rise in circulating plasma amino acid and glucose concentrations between regimens. Jejunal feeding resulted in higher peak plasma insulin concentrations than did gastric feeding (392 ± 53 compared with 326 ± 54 pmol/L, respectively; P < 0.05). The postprandial rise in plasma cholecystokinin, peptide YY (PYY), glucagon-like peptide 1 (GLP-1), and glucagon-like peptide 2 (GLP-2) concentrations was greater after jejunal feeding than after gastric feeding, with higher peak concentrations and a greater postprandial incremental AUC for GLP-1 and cholecystokinin (all P < 0.05). Plasma ghrelin concentrations did not differ between regimens. CONCLUSIONS Enteral nutrition with gastric or jejunal feeding in healthy young men results in similar postprandial plasma amino acid and glucose concentrations. However, the endocrine response differs substantially, with higher peak plasma cholecystokinin, PYY, GLP-1, and GLP-2 concentrations being attained after jejunal feeding. This effect may result in an improved anabolic response, greater insulin sensitivity, and an improved intestinotropic effect. Nevertheless, it may also lead to delayed gastric emptying. This trial was registered at trialregister.nl as NTR2801.

Gastrointestinal obstruction by solidification of enteral nutrition: a result of impaired digestion in critically ill patients

Introduction:Solidification of enteral nutrition may cause gastrointestinal obstruction, with severe complications. The effect of the composition of enteral nutrition on the tendency of casein to coagulate is increasingly acknowledged and new formulas may prevent solidification. To recognize patients in need of specific enteral nutrition, we have to identify the clinical risk factors for the development of gastrointestinal obstruction by the solidification of enteral nutrition. Materials and methods:The 58 cases summarized in this review were identified through a PubMed search. Results:Critically ill patients have several risk factors, including impaired digestion, and they are treated with medication that interferes with gastrointestinal function. Surgery of the upper gastrointestinal tract is thought to be the most important risk factor, leading to changes in both the anatomical structure and neurohormonal functioning of the gastrointestinal tract, and to altered secretion of digestive enzymes. Conclusions:Awareness of risk factors in critically ill patients may help intensivists and surgeons take appropriate measures to prevent this complication. Critically ill patients with impaired digestion (e.g. after Whipple surgery) should be considered for alternative enteral nutrition formulas with noncoagulating proteins or hydrolyzed proteins.

Preoperative oral nutritional interventions in surgery, including arginine- and glutamine-enhanced supplements

The patients’ condition prior to surgery is of major importance for clinical outcome. It is believed nowadays that artificial nutrition in the form of a preoperative drink may improve postoperative outcome. Until now, a clear overview concerning the effects of preoperative supplementation on patients’ well-being has been lacking. The aim of this review is to summarize the results of randomized clinical trials investigating the effects of different preoperative supplements such as carbohydrate (CHO)-rich beverages, oral nutritional supplements (ONSs), immunonutrition and lemonades on clinical, metabolic and immunological parameters. We reviewed the relevant articles published between 1995 and 2012. Preoperative CHO-rich drinks appear to be safe, do not affect gastric emptying time and switch the fasted state to a fed state. Moreover, a significant reduction of postoperative insulin resistance, an improved well-being of the patient and prevention of surgery-induced immunodepression was found. For ONSs, beneficial effects were found according to muscle metabolism and strength, glucose storage and cost-effectiveness. Preoperative supplementation of immunonutrition resulted in improved immune function, restricted inflammatory response after surgery, prevention of organ damage, improved nutritional status with subsequently decreased postoperative complication rates and reduced length of hospital stay. Preoperative oral supplements have beneficial effects on many aspects of patient’s well-being and recovery. Different supplements, preferably in combination with each other, can help to reduce postoperative complications after surgery and length of hospital stay. Nutritional support must not be overlooked when considering optimal surgical care.

Reply to GC Ligthart-Melis et al.

generated can be incorporated into the ureido group of citrulline and subsequently the guanidino group of arginine, thus labeling the third nitrogen group of these compounds. Furthermore, [2-N]glutamine can contribute the other nitrogen in the guanidino group of arginine via aspartate through transamination. These pathways are shown in Figure 1. In addition, the infusion of [2-N]glutamine also generates [5-N] glutamine (8). By using LC–tandem MS (LC-MS/MS) and looking at different fragments we have shown this scrambling of the amino nitrogen of glutamine and the labeling of the 3 nitrogen groups of citrulline in mouse models (8). We recently confirmed using the same analytic approach these findings in postprandial surgical patients who received alanyl-[2-N]glutamine as a stable isotope to investigate the precursor relation between glutamine, citrulline, and arginine (GC Ligthart-Melis GC, unpublished results, 2014). Had Buijs et al. used a similar LCMS/MS analytic approach that allows for the measurement of the positional isomers of glutamine and citrulline (10), they would have observed this same phenomenon. For this reason and because every single assumption on the use of [2-N]glutamine to determine precursor-product relations is violated, the conversion data generated by Buijs et al. cannot be interpreted. We agree with Buijs et al. that “the development of optimal nutrition strategies relies on distinct insights into the effect of a supplemental component on metabolic pathways.” For these reasons, we believe that the correct approach to the interpretation of glutamine supplementation in surgical patients has to be done on the basis of fluxes and that the precursor-product relation between glutamine and citrulline can only be determined utilizing tracers that follow the carbon skeleton of these compounds.