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Supplement

Glutamine Alimentation in Catabolic State¹

Department of Surgery, University Hospital Vrije Universiteit, Amsterdam, The Netherlands

³To whom correspondence should be addressed. E-mail: pam.vleeuwen{at}azvu.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION Catabolic state Mechanism of muscle wasting Glutamine-enriched nutrition in... Parenteral glutamine Enteral glutamine DISCUSSION LITERATURE CITED

 
Glutamine should be reclassified as a conditionally essential amino acid in the catabolic state because the body’s glutamine expenditures exceed synthesis and low glutamine levels in plasma are associated with poor clinical outcome. After severe stress, several amino acids are mobilized from muscle tissue to supply energy and substrate to the host. Glutamine is one of the most important amino acids that provide this function. Glutamine acts as the preferred respiratory fuel for lymphocytes, hepatocytes and intestinal mucosal cells and is metabolized in the gut to citrulline, ammonium and other amino acids. Low concentrations of glutamine in plasma reflect reduced stores in muscle and this reduced availability of glutamine in the catabolic state seems to correlate with increased morbidity and mortality. Adding glutamine to the nutrition of clinical patients, enterally or parenterally, may reduce morbidity. Several excellent clinical trials have been performed to prove efficacy and feasibility of the use of glutamine supplementation in parenteral and enteral nutrition. The increased intake of glutamine has resulted in lower septic morbidity in certain critically ill patient populations. This review will focus on the efficacy and the importance of glutamine supplementation in diverse catabolic states.

KEY WORDS: • glutamine • catabolic state • trauma • surgery • critically ill

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Catabolic state Mechanism of muscle wasting Glutamine-enriched nutrition in... Parenteral glutamine Enteral glutamine DISCUSSION LITERATURE CITED

 
Glutamine, a nonessential amino acid, has recently received increasing attention. Several investigators have claimed that this amino acid is conditionally essential because of the body’s inability to synthesize sufficient amounts of glutamine during stress (Lacey and Wilmore 1990 ).

Catabolic states, such as major trauma, sepsis, major surgery and bone marrow transplantation as well as intense chemotherapy and radiotherapy, are associated with low plasma levels of glutamine (Roth et al.1982 , Rennie 1985 , Ardawi 1988 , Parry-Billings et al. 1989 , Hammarqvist et al. 1989 , Stehle et al. 1989 , Newsholme et al. 1987 , Scheltinga et al. 1991 , Ziegler et al. 1992 , Schloerb and Amare 1993 , Van der Hulst et al. 1993 , Tremel et al. 1994 , McBurney et al. 1994 , O’Riordain et al. 1994 , Jensen et al. 1996 , Weingartmann et al. 1996 , Lacey et al. 1996 , Neu et al. 1997 , Bozzetti et al. 1997 , Griffiths et al. 1997 , de Beaux et al. 1998 , Morlion et al. 1998 , Brown et al. 1998 , Houdijk et al. 1998 , Powell-Tuck et al. 1999 , Decker-Baumann et al. 1999 , Jiang et al. 1999 , Jacobi et al. 1999 , Jones et al. 1999 , Shabert et al. 1999 , Schloerb and Skikne 1999 , Coghlin-Dickson et al. 2000 , Van Acker et al. 2000 ). Reduced availability of glutamine in these conditions may lead to an impaired immune function because of a reduced capacity of immune cells to proliferate (Newsholme et al. 1987 ). Glutamine is the respiratory fuel for the lymphocytes, hepatocytes and the mucosal cells of the gut (Elia et al. 1989 , Yoshida et al. 1992 ). In addition, glutamine is one of the most important substrates for ammoniagenesis, not only in the gut, but also in the kidney, because of its important role in the regulation of acid-base homeostasis (Halperin et al. 1990 , 1992 ). Moreover, glutamine can serve as a metabolic substrate for renal tubular cells and functions as a precursor for nucleotides, such as purine, pyrimidine and the important antioxidant glutathion (Cao et al. 1998 ).

In catabolism, plasma levels of glutamine are insufficient to meet increased demands. The stressed catabolic patient has a compromised immune system (Newsholme et al. 1987 ), requiring increased mobilization of muscle nitrogen to maintain homeostasis (Roth et al. 1982 , Rennie 1985 , Ardawi 1988 , Parry-Billings et al. 1989 , Hammarqvist et al. 1989 , Stehle et al. 1989 ). Many investigations have shown that during severe stress the consumption of glutamine exceeds glutamine synthesis, resulting in depletion of glutamine stores (Lacey and Wilmore 1990 , Roth et al. 1982 , Rennie 1985 , Ardawi 1988 , Parry-Billings et al. 1989 , Hammarqvist et al. 1989 , Stehle et al. 1989 ). Although advances have been made in nutritional support for catabolic patients including changes in amino acid content, a promising solution seems to be the enrichment of the nutrition with glutamine (Hammarqvist et al. 1989 , Jensen et al. 1996 , Van Acker et al. 2000 ). It has become clear that glutamine may be an essential amino acid in catabolic patients and clinical studies suggest a direct relationship between low extracellular glutamine and clinical outcome.

This manuscript highlights the catabolic conditions resulting in the depletion of glutamine stores and reviews glutamine function and mechanisms of protein degradation. Additionally, recent publications on clinical prospective, double-blind, controlled trials implementing either enteral or parenteral glutamine supplementation are evaluated.

	Catabolic state

TOP ABSTRACT INTRODUCTION Catabolic state Mechanism of muscle wasting Glutamine-enriched nutrition in... Parenteral glutamine Enteral glutamine DISCUSSION LITERATURE CITED

 
Metabolic response to trauma is correlated with the extent and duration of injury. The specific immunologic and metabolic consequences appearing after trauma resemble the pathogenic mechanisms of infection and sepsis (Connolly and Vernon 2000 ). The catabolic state is characterized by destructive metabolism, resulting in a rapid loss of lean body mass and a change in body composition. Damaging events can initiate the stress response, consisting of a complex cascade of neurohormonal events, mediated by the sympatic nervous system, glucagon, cortisol, insulin, growth hormone, cytokines and lipid mediators. The most distinctive clinical features of this response are tachycardia, tachypnea, loss of body weight, fat and skeletal muscle, as well as expansion of extracellular body fluid. The mobilized body fat and skeletal muscle proteins are used as fuel for the high energy expenditures during catabolism (Wilmore 2000 ).

In the early phase after trauma, the metabolism slows, oxygen consumption decreases and energy is primarily provided to the vital organs. Energy is supplied by increasing plasma glucose recruited from glycogen stores in the liver and muscle through glycogenolysis, and for a lesser part, from the breakdown of proteins providing amino acids for gluconeogenesis. Increased metabolism, oxygen consumption, body temperature and catabolism characterize the later phase. Within 60 h after injury, glycogen stores are depleted and gluconeogenesis increases to fulfill the energy needs. Additionally, a large efflux of amino acids from the muscles occurs. This results in depletion of muscle proteins and increased ureagenesis, leading to muscle loss, negative nitrogen balance, loss of function of vital organs and a delay in wound healing (Wilmore 1983 ). In the first 14 days after trauma, the hypermetabolism can result in a depletion of essential protein stores with the consequence that patients are at risk of developing serious complications, such as sepsis and multiple organ failure (Wapnir and Lifshitz 1977 ).

Glutamine, the most abundant free amino acid in the human body (Roth et al. 1990 ), is mainly formed in the skeletal muscle and is released in increasing amounts during catabolism into the circulation to be chiefly taken up as preferred energy substrate by the splanchnic area, liver and immunocompetent cells (Souba et al. 1985 ) During the catabolic states, glutamine is important for the gut, because the cells of the intestinal mucosae and the gut-associated lymphoid tissue use glutamine as a fuel to maintain the integrity of the intestinal mucosa. If the glutamine availability declines, there is a risk of weakening the gut barrier between the bacterial content of the lumen of the intestine and the circulation and impaired immune competence of the gut-associated lymphoid tissue (Deitch and Bridges 1987 , Deitch et al. 1987 , Souba et al. 1990a and 1990b , Said et al. 1989 , Pietsch et al. 1989 , Salloum et al. 1991 , Sarantos et al. 1994 ).

Low plasma levels of glutamine also mean a decreased availability of glutamine for macrophages and lymphocytes and decreased citrulline levels, thereby reducing arginine synthesis. Arginine is produced in the kidney from the conversion of citrulline, which is a product of intestinal glutamine metabolism. Windmueller and Spaeth (1981 ) have shown that the most important source of circulating citrulline is the gut. Considering the multiple important properties of arginine, the presumed deficiency of glutamine in catabolic states might be explained in part by decreased renal arginine synthesis (Houdijk et al. 1994 ).

	Mechanism of muscle wasting

TOP ABSTRACT INTRODUCTION Catabolic state Mechanism of muscle wasting Glutamine-enriched nutrition in... Parenteral glutamine Enteral glutamine DISCUSSION LITERATURE CITED

 
The muscle wasting that occurs in catabolic states results primarily from accelerated breakdown of the long-living myofibrillar proteins, such as actin and myosin, which account for 60–70% of the muscle protein of males. Unlike other proteins, actin and myosin contain a unique amino acid 3-methyl-histidine; therefore, breakdown can be monitored by the release of this amino acid (Tawa and Goldberg 1994 ).

Medical conditions that are associated with muscle wasting are sepsis, trauma, burns, acquired immunodeficiency syndrome (AIDS),⁴ major surgery and intensive treatment with chemotherapy and/or radiotherapy. In these conditions, a specific pathway of muscle wasting is activated. Recently, this pathway of the accelerated breakdown of proteins during catabolic states has been identified as the ubiquitin-proteosome system (Wing and Goldberg 1993 , Mitch et al. 1994 , Price et al. 1996 ). Other known pathways of proteolysis are lysosomal and mitochondrial protein degradation. However, if these two pathways are artificially blocked in catabolic experiments in rats, muscle is still broken down by the ubiquitin-proteosome system. Furthermore, when maximal accelerated protein degradation occurs in catabolic states, an increased content of ubiquitin-conjugated proteins is found, and an increased expression of ubiquitin and proteasome subunits mRNA is described. These events can be reversed after restoring normal metabolism and refeeding (Wing et al. 1995 ).

Cytokines mediate a major part of this ATP-dependent proteolysis. Many of the secondary responses to sepsis result from the rapid release of cytokines by activated macrophages. Proinflammatory cytokines, such as TNF, IL-1 and IL-6, are responsible for important host defense responses, such as fever and the acute phase protein production. Together with glucocorticoids, these cytokines also stimulate the ubiquitin-proteosome pathway in muscle (Zamir et al. 1992a ). This effect is blocked with pentoxifylline, a substance that is known to inhibit TNF (Breuille et al. 1993 ).

TNF stimulates proteolysis together with IL-1. The inhibitors of IL-1, the IL-1 receptor antagonists, also prevent muscle breakdown in response to exogenous endotoxin in isolated muscle studies (Zamir et al. 1992b ). Additionally, IL-6 may stimulate muscle protein breakdown in combination with a novel protein recently isolated in studies in mice and in patients with cachexia (Todorov et al. 1996 ).

Interferon-, an enhancer of TNF production and antigen presentation, is also capable of stimulating catabolism. This cytokine induces a proteasome activator (PA28) and three novel subunits of 20S core proteosomes that are incorporated instead of normal homologous subunits. These modifications cause cleavage of additional proteins (Tanahashi et al. 2000 ).

	Glutamine-enriched nutrition in elective surgical and catabolic patients

TOP ABSTRACT INTRODUCTION Catabolic state Mechanism of muscle wasting Glutamine-enriched nutrition in... Parenteral glutamine Enteral glutamine DISCUSSION LITERATURE CITED

 
In this overview, we will summarize clinical studies using total parenteral nutrition (TPN) supplemented with free glutamine (L-GLN; Table 1 ) or dipeptide (ALA-GLN or GLY-GLN; Table 2 ), and studies investigating glutamine-enriched enteral nutrition (EN; Table 3 ). We will not discuss studies, such as those in bone marrow transplant patients, which are reviewed elsewhere in this volume.

	Parenteral glutamine

TOP ABSTRACT INTRODUCTION Catabolic state Mechanism of muscle wasting Glutamine-enriched nutrition in... Parenteral glutamine Enteral glutamine DISCUSSION LITERATURE CITED

Stehle et al. (1989 ) produced more evidence of the beneficial effects of glutamine enrichment in a study of 12 patients undergoing elective resection of the colon or rectum. Glutamine was administered as a dipeptide (L-ALA-L-GLN). Enrolled patients received TPN with 54 mg dipeptide/g · kg^-1 · d^-1 or TPN with a similar amount of alanyl nitrogen (ALA-N) and glycine nitrogen (GLY-N), in the first five postoperative days. Results of this study showed no differences in blood parameters that were measured, but an improved nitrogen balance in L-ALA-L-GLN group with a significantly better intracellular muscle glutamine pool compared with controls.

Van der Hulst et al. (1993 ) examined the effect of glutamine on the integrity of the small intestine after surgical trauma. Twenty patients were randomized to receive TPN enriched with the dipeptide GLY-L-GLN (0.23 g · kg^-1 · d^-1) for 12 d or standard TPN. The integrity of intestine was maintained by the glutamine supplementation as reflected by an unchanged intestinal permeability and an unaltered villus height.

Tremel et al. (1994 ) conducted a study with 12 intensive care unit (ICU) patients receiving 9 d of enriched glutamine (ALA-GLN 20 g/L) or placebo TPN. Tremel et al. used a quantification method of serum and urine D-xylose concentrations. They demonstrated that the intestinal function, as defined as the mucosal uptake of D-xylose, was better preserved in the glutamine group.

Glutamine enrichment of T lymphocyte response in patients undergoing colorectal surgery was demonstrated by O’Riordain et al. (1994 ). Twenty-two patients were randomized to receive either standard/glutamine-free or glutamine-enriched TPN (0.18 g GLY-L-GLN kg/d) for 6 d postoperatively. No significant difference in either cytokine production or clinical infection was detected between the two groups.

The same group found a difference in IL-8 plasma concentrations in patients with severe pancreatitis randomized to receive glutamine (0.22 g glutamine/kg per day as glycyl-glutamine; n = 6) or standard TPN (n = 7) (de Beaux et al. 1998 ). Glutamine enrichment decreased IL-8, an important mediator of acute respiratory distress syndrome.

The effect of L-glutamine-enriched TPN on glutamine content of the muscle in very severely ill patients was studied by Palmer et al. (1996 ). Thirty-eight patients were prospectively randomized to receive TPN containing either 25 g per 24 h or a control solution, 3 d after ICU admission. A muscle biopsy was taken before the feeding and 5 d later. The first biopsy showed a very low glutamine content and no improvement was seen with the glutamine supplementation.

Weingartmann et al. (1996 ) investigated the safety and efficacy of the dipeptide glycyl-glutamine in a dose-finding study in poly-traumatized patients compared with a control group. Nine poly-traumatized patients received the dipeptide in three different doses: 280 (14 g), 450 (21 g) and 570 (28 g) mg per kilogram of body per day. Seven patients served as controls. The highest dose was necessary to induce a sustained effect on plasma glutamine plasma levels.

The first study to describe a reduced 6-mo survival of the critically ill patients receiving an average of 18 g L-glutamine was conducted by Griffiths et al. (1997 ). Eighty-four ICU patients were given TPN for an average of 5 d. Twenty-two patients in the glutamine group and 25 patients in the control group (almost glutamine-free) were fed TPN for an average of 14 d and 15 d, respectively.

Another study applying a glutamine dipeptide to patients undergoing elective abdominal surgery was conducted by Morlion et al. (1998 ). This study focused on metabolic, immunological and clinical variables. Twenty-eight patients received either TPN with 0.3 g ALA-GLN/kg per day or the control solution for 5 d. There was an improved nitrogen balance and maintenance of glutamine plasma levels in the glutamine group. Enhanced recovery of lymphocytes on d 6 and improved cysteinyl-leukotrienes from polymorphonuclear neutrophil granulocytes were seen. The groups receiving glutamine had a shorter hospital stay of 6.2 d.

Powell-Tuck et al. (1999 ) designed a study with the intent to reduce mortality in ICU patients. One hundred sixty-eight patients were investigated. Eighty-three patients received glutamine-free, standard TPN and 85 received 20 g L-glutamine-enriched TPN for an average of 8 d. No differences were seen between the groups regarding infectious complications and length of hospital stay. Mortality in the glutamine group (16.9%) was less, but not significantly different from the control group (24%).

To analyze the effect of 0.4 g/kg per day alanyl-glutamine on immune function in patients after gastrointestinal surgery, a study was performed by Jacobi et al. (1999 ). Beneficial differences in the expression of CD-3, CD-4 or CD-8 on lymphocytes and HLA-DR on monocytes were seen in the glutamine group.

A recent study by Van Acker et al. (2000 ) investigated the effect of a primed continuous, 6-h intravenous infusion of L-GLN and L-LEU before and after 8–10 d of TPN enriched with glutamine, on glutamine kinetics in nutritionally depleted patients undergoing elective gastrointestinal surgery. Twenty-three patients were randomized to receive the glutamine dipeptide. The lack of a significant rise in plasma glutamine levels with the glutamine infusion suggested that the tissues used glutamine exceedingly well.

	Enteral glutamine

TOP ABSTRACT INTRODUCTION Catabolic state Mechanism of muscle wasting Glutamine-enriched nutrition in... Parenteral glutamine Enteral glutamine DISCUSSION LITERATURE CITED

 
Jensen et al. (1996 ) investigated the plasma amino acid levels in 28 ICU patients (APACHE II > 10) randomized to receive isonitrogeneous and isoenergetic nasojejunal feedings with 289 g glutamine/kg protein (n = 10) or 50 g glutamine/kg protein (n = 9). Results showed blunting of the hyperaminoacidemia and an elevated aromatic amino acid response.

In a study by Houdijk et al. (1998 , 1999 ), trauma patients, with an injury severity score of 20 or more, were randomized to receive EN enriched with glutamine (n = 35) vs. a control diet (n = 37). The glutamine-enriched group received 30.5 g glutamine/100 g protein. The control diet was isonitrogenous and isocaloric with the glutamine formula enriched by the addition of alanine, aspartate, glycine, proline and serine. The control feeding contained 3.5 g glutamine/100 g of protein. The EN was started within 48 h after the trauma and was given continuously to provide 75% of the calculated energy expenditure. The nutrition was given for at least 5 d by a nasoduodenal tube until the patients were tolerating an oral diet. None of the patients received parenteral feeding. Groups were comparable for clinical parameters and surgical intervention. The total number of days of EN and the amount of calories given were similar between the groups. Infectious morbidity during the first 15 d after trauma was the primary endpoint. Secondary endpoints included the plasma levels of glutamine, arginine and soluble TNF receptors. Levels of both glutamine and arginine decreased significantly after trauma. Interestingly, arginine levels returned to physiological levels during the glutamine supplementation, whereas glutamine levels could not be raised above 540 µmol/L in the first 2 wk (physiological levels are 650 µmol/L). A significantly lower incidence of pneumonia was seen in the glutamine-supplemented group (17%) compared with the control group (45%; P < 0.02). Moreover, a significant reduction in bacteremia and sepsis was found. It is worthwhile mentioning that the single episode of sepsis observed in the glutamine group was caused by a Staphylococcus aureus, whereas mainly Gram-negative bacteria were cultured in the control group. Plasma-soluble TNF receptors were significantly lower in the glutamine group (Houdijk et al. 1998 ).

Jones et al. (1999 ) presented results from a randomized study concerning 78 ICU patients (Injury severity score > 11). These patients were allocated to receive either EN with 5 g glutamine or glycine per 500 mL of formula. TPN was given to patients intolerant to enteral feeding. Four groups were evaluated with or (almost) without glutamine and with or without TPN feeding in addition to the enteral feed. Reductions in the median postintervention ICU and hospital patient costs were observed.

The first investigation of the effect of glutamine in AIDS patients (n = 26) with > 5% weight loss was conducted by Shabert et al. (1999 ). These patients were randomized to receive 40 g oral glutamine or glycine. Results showed increased intracellular water, a significant increase in body weight and a significantly increased body cell mass in the glutamine group.

	DISCUSSION

TOP ABSTRACT INTRODUCTION Catabolic state Mechanism of muscle wasting Glutamine-enriched nutrition in... Parenteral glutamine Enteral glutamine DISCUSSION LITERATURE CITED

 
A variety of investigations have provided evidence that glutamine has become an important and, possibly essential, amino acid during stress. This switch to becoming an essential amino acid appears when the demand of the body for glutamine increases markedly. The plasma glutamine use exceeds the glutamine synthesis of the skeletal muscle and the liver in catabolic conditions. Circulating glutamine is an important substrate for the enterocyte, hepatocyte and immune cells as an oxidative fuel as well as a substrate for nucleotide synthesis.

The clinical trials discussed in this report provide important confirmation that dietary glutamine supplementation is indeed associated with amelioration of metabolic response to stress and injury. Moreover, in selected critically ill patients, glutamine seems to improve outcome. The mechanisms of these effects remain elusive and are the subject of ongoing investigations. Despite the need to identify the mechanisms, several observations are pertinent. Exogenous glutamine improves nitrogen balance and preserves the concentration of glutamine in skeletal muscle. In selected patients, glutamine preserves normal distribution of body water by preventing expansion of extracellular water and reducing fluid retention. Supplementation of dietary glutamine maintains and may even increase body weight in malnourished patients with AIDS or in those patients with cancer who are receiving chemotherapy. In the critically ill patient with breakdown of the intestinal barrier, exogenous glutamine may protect the host from gut-derived endotoxemic complications. A possible mechanism for the salutary effects of glutamine on the stressed gut is the increased production of arginine, which serves as a precursor for nitric oxide, a potent vasodilator.

In summary, additional investigations are needed to determine the efficacy of glutamine supplementation to catabolic patients. These investigations are expensive and will only be possible with the creation of multicenter study groups. In the absence of such investigations, the clinician must rely upon his or her experience and perceived outcome benefits.

	FOOTNOTES

 
¹ Presented at the International Symposium on Glutamine, October 2–3, 2000, Sonesta Beach, Bermuda. The symposium was sponsored by Ajinomoto USA, Inc. The proceedings are published as a supplement to The Journal of Nutrition. Editors for the symposium publication were Douglas W. Wilmore, the Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School and John L. Rombeau, the Department of Surgery, the University of Pennsylvania School of Medicine.

² Robert J. Nijveldt and Alexander P. J. Houdijk are recipients of a fellowship from the Council for Medical Research of the Netherlands Organization for Scientific Research.

⁴ Abbreviations used: AIDS, acquired immunodeficiency syndrome; ALA-N, alanyl nitrogen; EN, enteral nutrition; GLN-N, glycine nitrogen; L-GLN, free glutamine; ICU, intensive care unit; TPN, total parenteral nutrition.

	LITERATURE CITED

TOP ABSTRACT INTRODUCTION Catabolic state Mechanism of muscle wasting Glutamine-enriched nutrition in... Parenteral glutamine Enteral glutamine DISCUSSION LITERATURE CITED

 

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