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Supplement

The Effect of Glutamine Supplementation in Patients Following Elective Surgery and Accidental Injury¹

Laboratories for Surgical Metabolism and Nutrition, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

	ABSTRACT

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The metabolic response to injury, whether a controlled elective surgical procedure or an accidental injury, is characterized by the breakdown of skeletal muscle protein and the translocation of the amino acids to visceral organs and the wound. At these sites, the substrate serves to enhance host defenses, and support vital organ function and wound repair. Glutamine (GLN) plays a major role in these processes, accounting for approximately one third of the translocated nitrogen. From available data, GLN-supplemented intravenous nutrition in patients undergoing elective surgery improves nitrogen balance, helps correct the decreased GLN concentration found in the free intracellular skeletal muscle amino acid pool and enhances net protein synthesis (particularly in skeletal muscle). Six randomized blind trials (two multicentered investigations) reported a decreased length in hospital stay in postoperative patients receiving GLN supplementation. After blunt trauma, GLN supplementation increased plasma concentrations, attenuated the immunosuppression commonly observed and decreased the rate of infection. Patients with burn injury have low GLN plasma and intramuscular concentrations; turnover and synthesis rate are accelerated, yet apparently inadequate to support normal concentrations. These data suggest that GLN supplementation has important effects in catabolic surgical patients, but the exact mechanisms to explain these events remain unknown, and more research is required to explain the apparent benefits of dietary GLN.

KEY WORDS: • glutamine • elective operation • accidental injury

	INTRODUCTION

TOP ABSTRACT INTRODUCTION General characteristics of the... Glutamine administration in the... Studies of intravenous... Studies of oral GLN... Glutamine metabolism and... DISCUSSION LITERATURE CITED

 
Injury to the body results in a generalized catabolic response associated with weight loss, anorexia, weakness and reduced activity. These clinical signs are associated with rather stereotypic metabolic responses, which have been carefully studied and quantitated (Wilmore 2000 ).

Injury responses vary depending on the extent of tissue damaged. Minor operations (such as a hernia repair) may evoke little or no systemic responses, whereas major accidental injuries (such as a 60% total body surface flame burn) evoke maximal responses. The responses to similar injuries and elective surgeries lie somewhere in between these two extremes.

Because whole-body catabolism is associated with tissue repair and eventual recovery, physicians have hesitated to block these events, but they have attempted to attenuate the deleterious aspects of the responses while supporting those alterations that aid healing and anabolism. Thus, feeding the injured patient, particularly the seriously traumatized individual, has evolved as a standard method of care for critically ill patients. For the previously well-nourished individual who cannot eat after 5–7 d, enteral tube feeding or intravenous nutrient infusions are typically initiated.

Over the past 15 years, clinicians and nutritional scientists have focused not only on the quantity of nutrients in the feedings, but also the composition of the nutrient mix provided. This paper addresses one seemingly minor addition of an amino acid to the nutrient mix, that is, the supplementation of feedings with glutamine (GLN).² Because of its central role in body metabolism, the addition of this amino acid, previously omitted from most enteral feedings and all parenteral infusions because it was thought to be "nonessential" and lacked storage stability in an aqueous environment, has resulted in the claim that addition of this single nutrient has significantly lowered the morbidity and mortality of hospitalized patients.

This paper reviews the clinical studies in patients undergoing elective surgery and after accidental injury in which glutamine was administered and the outcome compared with an unsupplemented group. Several studies with heterogeneous groups of patients (intensive care unit patients with diverse medical and surgical diseases) were reviewed but not included in this report.

	General characteristics of the protein catabolic responses after elective surgery and accidental injury

TOP ABSTRACT INTRODUCTION General characteristics of the... Glutamine administration in the... Studies of intravenous... Studies of oral GLN... Glutamine metabolism and... DISCUSSION LITERATURE CITED

 
The metabolic response to injury, whether a result of accidental injury or a planned elective surgical procedure, is characterized by the loss of nitrogen from the body (Wilmore 2000 ). This negative nitrogen balance is primarily the result of increased excretion of urea and other nitrogenous products in the urine, although individuals with large open wounds (such as flame burns) will also exude serum and lose proteins through the injured tissues.

The pattern of protein catabolism is related to the extent of the injury in a dose-responsive manner. That is, the greater the injury, the larger the nitrogen loss. Nitrogen loss is also dependent on nutritional state of the patient and the size of the lean body mass. Thus, a muscular, well-nourished person will lose more nitrogen than a depleted individual after similar stress, such as a comparable operation. The response pattern follows a time course, with nitrogen excretion increasing in the first few days after injury, peaking for several days or weeks, and then gradually returning to equilibrium as the inflammation resolves and/or the wound heals. This course, and the degree of the negative nitrogen balance, can be attenuated, but not abolished by food intake and exercise.

The major loss of body protein arises from skeletal muscle (Aulick and Wilmore 1979 , Wilmore et al. 1980 ), although there is some evidence that the gastrointestinal tract may initially respond by releasing amino acids in the first 48 h (Bessey and Lowe 1993 , Molina and Abumrad 1994 ). Although visceral organs may hypertrophy in the early part of the catabolic phase of injury, eventually they lose protein toward the end of a prolonged period of illness (Plank et al. 1998 ). However, after a moderate-to-severe injury, net catabolism of skeletal muscle occurs; arterial-venous measurements of amino acids across the uninjured extremities of injured patients showed a marked release of amino acids from the periphery, reflecting skeletal muscle net proteolysis (Aulick and Wilmore 1979 ). Moreover, these observations support the concept that protein catabolism is a generalized response to trauma and does not reflect the simple loss of protein from injured tissue. Catheterization studies of the visceral organs of injured subjects showed an accelerated uptake of amino acid substrate in the splanchnic bed and kidneys (Wilmore et al. 1980 )

That muscle is the main source of the nitrogen lost from the body is also supported by observation that there is an increased excretion of potassium and phosphorous in the urine, and these elements along with nitrogen are lost in proportion to their concentrations found in skeletal muscle (Moore 1959 ). In addition, there is increased excretion of creatinine and 3-methyl-histidine, both substances found predominantly in muscle tissue (Neuhauser et al. 1980 ). Finally, weakness and muscle atrophy are commonly observed in patients after a major operation or injury.

A characteristic pattern is observed in the amino acid released from skeletal muscle, with alanine (ALA) and GLN comprising 50–70% of the amino acid nitrogen exported to visceral tissues (Brooks et al. 1986 , Mulbacher et al. 1984 ). This increased release rate of ALA and GLN represents acceleration of de novo synthesis for these two amino acids; hydrolysis of skeletal muscle reveals that ALA and GLN contribute <10% to the overall nitrogen residues. Moreover, the large intracellular store of free glutamine in the free amino acid pool within skeletal muscle is rapidly depleted after surgical stress, and investigators have related the degree of intracellular depletion to outcome (Roth et al. 1982 ). Depending on the extent of the injury, there is a fall in the plasma concentration of GLN, despite increased GLN production and turnover (Mittendorfer et al. 1999 ). Both GLN and ALA support the enhanced gluconeogenesis that occurs in injured patients, and GLN is also utilized as a primary fuel source for the enterocytes of the small bowel, leukocytes and macrophages of the immunological system and other cells involved in wound repair. GLN is also taken up by the kidneys, where it contributes ammonia, which combines with hydrogen ions to form ammonium, which is excreted in the urine. This pathway is a major component of acid-base homeostasis and important for off loading the large acid load that is generated after injury.

A detailed discussion of the mechanisms that control the translocation of protein from skeletal muscle to visceral tissue is found in several recent reviews (Garlick and Wernerman 1997 , Wilmore 2000 ). Factors related to treatment of the patient are important to the protein catabolic response, and involve prolonged bed rest, decreased mobilization and diminished food intake. However, the hormonal and inflammatory environment is a major regulator of this catabolic response. Initially, insulin levels are low and then they gradually rise, although insulin resistance is present. Resistance to growth hormone has also been observed and insulin-like growth factor-1 usually remains at subnormal concentrations throughout a catabolic course (Ross and Chew 1995 ). The elaboration of the counterregulatory hormones cortisol, glucagon and catecholamines is increased, and these factors play a central role in the response. In fact, the response pattern can be mimicked by infusing these substances into animals or humans (Bessey et al. 1984 ). More specifically, cortisol has a pronounced effect in upregulating GLN synthesis in skeletal muscle (Max et al. 1988 ), and glucagon appears essential in enhancing hepatic uptake of this amino acid and facilitating ureagenesis (Krishna et al. 2000 ).

In addition to the hormonal response, inflammatory factors (such as the proinflammatory cytokines, leukotrienes and other factors) contribute to the catabolic response, either directly or indirectly (Watters et al. 1986 ) (stimulating elaboration of catabolic hormones, causing anorexia through central nervous system mechanisms and increasing body temperature).

In summary, muscle breaks down at accelerated rates to provide GLN to other parts of the body to perform essential functions. In doing so, skeletal muscle intracellular levels fall, production rate and turnover of GLN increase and plasma levels may decrease. These findings have formed the basis of the hypothesis that protein catabolism can be attenuated and/or the necessary functions served by GLN can be augmented by providing exogenous GLN.

	Glutamine administration in the elective surgical patient

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After elective surgery, patients have a mild catabolic response, which has been well studied. By standardizing the operation and anesthesia provided and by excluding patients with associated disease (such as diabetes mellitus or those requiring steroids) from the studies, investigations have been performed to determine the effect of various manipulation on the postoperative catabolic response. Such investigations have been performed to evaluate GLN administration.

	Studies of intravenous administration

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Effect on nitrogen balance, plasma and skeletal muscle concentrations.

Almost a dozen studies have been carried out to determine the effect of GLN-supplemented parenteral nutrition on the protein catabolic response after elective surgery. These investigations were based on initial studies in animals, which demonstrated that infusion of L-GLN had positive effects on nitrogen balance and skeletal muscle amino acid flux, promoting net nitrogen retention (Kapadia et al. 1985 ).

Eight studies provide sufficient data for analysis (Fürst 1999 , Hammarqvist et al. 1989 and 1990 , Jiang et al. 1999 , Morlion et al. 1998 , O’Riordain et al. 1994 , Schulzki et al. 1999 , Stehle et al. 1989 ) (Table 1). In general, comparable quantities of energy and amino acids were administered to the postoperative patients in all studies. However, the type of surgery performed varied, which caused variation in the surgical stress. Two studies (Hammarqvist et al. 1989 and 1990 ) were performed in patients after open cholecystectomy (a rather minor procedure), whereas the other investigations were performed in patients undergoing more extensive procedures, including pancreatectomy and colectomy, often for cancer. In addition, anesthesia was not standardized and the GLN substrate infused varied in dose and composition.

The average dose of GLN administrated was 0.27 g/(kg · d) (range 0.18–0.4). The difference in nitrogen loss between control and GLN-infused groups ranged from 0.2 to 3.1 g nitrogen/d (average 1.7 g/d). There was no relationship between the dose of GLN administered and the nitrogen balance observed (Fig. 1 ).

View larger version (14K): [in this window] [in a new window]   Figure 1. Dose response data after elective surgical procedures. Data were derived from the reported nitrogen balance determined during the first 4–5 postoperative days. Controlled data expressed as mean ± SEM. No significant relationship could be established.

More consistent were the changes in intracellular concentrations of GLN in the free amino acid pool of skeletal muscle (Table 1) . In the three studies in which this was reported (Hammarqvist et al. 1989 and 1990 , Stehle et al. 1989 ), the intracellular GLN concentration fell an average of 39.0% in controls and only 16.8% in the GLN-supplemented patients (this difference was significant in all 3 studies). Protection of the intracellular GLN pool seemed unrelated to plasma GLN concentrations, which did not change significantly in the three studies reporting skeletal muscle biopsy data.

Changes in skeletal muscle protein synthesis.

Muscle protein synthesis is related to changes in intracellular ribosome concentration, and this measure has been used to index changes in skeletal muscle protein synthesis after surgery. Using this methodology in two studies, Hammarqvist et al. (1989 and 1990) found that skeletal muscle protein synthesis decreased markedly in the control patients (21%), but was preserved in those receiving GLN (0%). Petersson et al. (1994) performed serial biopsies in postoperative patients. Ribosome levels decreased at d 3 in control individuals and remained low for 30 d. The ribosomal levels were maintained in patients receiving GLN, but these levels fell when the infusion was discontinued.

Finally, Rennie and associates infused the stable isotope of L-leucine and performed muscle biopsies before and after GLN supplementation in patients on d 2 after esophagectomy (Barua et al. 1992 ). They found that supplementation of a conventional amino acid solution with L-GLN resulted in a 60–80% increase in the rate of muscle protein synthesis (the variation was due to the use of different precursors in the calculations.)

In conclusion, the data are consistent in showing that GLN supplementation of parenteral nutrition attenuates the fall of intracellular GLN and enhances skeletal muscle protein synthesis compared with controls. This occurred despite the lack of major changes in GLN plasma concentrations.

Changes in the intestinal tract.

Original observations in animals reported that the atrophy of the intestinal mucus that occurred with parental feedings was greatly attenuated with GLN supplementation (O’Dwyer et al. 1989 ). This finding was subsequently confirmed in patients (Van der Hulst et al. 1993 ). Bowel permeability was determined using nonmetabolizable markers; control patients who were fed intravenously had increased permeability to these molecules, whereas those receiving GLN supplementation were able to maintain an intact and functional intestinal barrier.

Only one such study has been performed in postoperative patients; it was based on preliminary animal data. Oral lactulose (L) and manitol (M) were administered preoperatively and 7 d after an abdominal operation to patients receiving GLN-supplemented nutrition and unsupplemented individuals (Jiang et al. 1999 ). Urine was collected over a 6-h period, the sugar content analyzed and the L/M ratio compared between the two groups. In the 30 patients receiving standard parenteral nutrition, the ratio rose 179%, demonstrating that increased bowel permeability occurred in the postoperative period. The increased permeability was greatly attenuated by GLN supplementation (L/M rose only 67%, and this difference was significant, P < 0.02). The clinical significance of this finding is not known.

The effect of GLN on immunological changes.

Immunosuppression is known to occur after elective surgery, and GLN has been reported to improve immunological function in other patient groups. O’Riordain et al. (1994) were the first to report immunological changes after GLN administration in postoperative patients. They measured T-cell DNA synthesis and cytokine production from postoperative patients receiving standard or GLN-supplemented nutrition. After 5 d of GLN nutrition, T-cell DNA synthesis was increased compared with preoperative values. No change was observed in the controls. Moreover, GLN infusion did not influence the production of proinflammatory cytokines.

In another randomized controlled trial, Morlion et al. (1998) monitored the number of circulating lymphocytes after surgery; polymorphonuclear neutrophil granulocytes were harvested and the generation of cysteinyl-leukotrienes assessed. There was improved recovery of lymphocytes in the GLN group by 6 d postsurgery (2.41 vs. 1.52 cells/nL, GLN vs. controls) and the generation of cysteinyl-leukotrienes was significantly enhanced (25.7 vs. 5.03 ng/mL). Because these leukotrienes contain the potent antioxidant glutathione, it is thought that these data support the thesis that GLN supplementation enhances the immunological (? antioxidant) responses after surgery. This is consistent with observations in studies in cells, animals and patients (Hong et al. 1992 , Wernerman et al. 1999 ).

Finally, Karwowska et al. (2000) administered GLN to patients after elective aortic aneurysm repair. The patients receiving the GLN-enriched parenteral nutrition had a greater number of lymphocytes on d 11 postsurgery compared with controls, similar to findings in other patient groups (Ziegler et al. 1998 ). In addition, immunoglobulin A levels were 65% greater than controls with GLN supplementation.

Effect on outcome.

Six randomized, double-blind studies evaluated outcome in patients receiving intravenous GLN after elective surgical procedures. Although detailed reports of rates of specific complications are unavailable, the patients receiving GLN did better in all studies as reflected by reduced length of hospital stay. Patients receiving GLN were discharged an average of 4.0 d sooner than the control group (length of stay 13.1 d for the GLN group vs. 17.1 for controls, Table 2 ). None of the reports specified criteria for discharge and the individuals discharging the patients varied within and between studies. However, all physicians and patients were unaware of what they had received, and two of the larger studies were multicentered trials (Fürst 1999 , Jiang et al. 1999 ). Such reduction in length of stay is consistent with observations of improved outcome in other patient groups (Ziegler et al. 1992 ). Thus, it appears that GLN somehow exerted an effect to enhance feelings of well-being and/or accelerate recovery in some manner after a major operation. The mechanisms involved in these responses are unknown at this time.

	Studies of oral GLN in postoperative patients

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In another study, Aosasa et al. (1999) gave oral glutamine to patients receiving preoperative parenteral nutrition and compared their findings with nonsupplemented individuals. After surgery, they harvested blood mononuclear cells and stimulated their production of tumor necrosis factor and interleukin-10. In patients receiving standard parenteral nutrition, there was an increase in cytokine production; this was greatly attenuated in the GLN group, supporting the concept that GLN may modulate the proinflammatory cytokine response.

	Glutamine metabolism and administration in trauma patients

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Few studies have been published in trauma patients in which GLN has been administered by the enteral or parenteral routes as the sole nutrient to be evaluated. One outcome study that evaluated GLN in patients after blunt trauma was published, and a variety of metabolic studies have been performed in injured and burn patients.

GLN in patients after blunt trauma.

Long et al. (1995) performed flux studies in 30 patients after multiple trauma; approximately one half of the group received GLN-enriched tube feeding; the others received a nearly identical diet with the GLN removed and other nonessential amino acids substituted isonitrogenously for the GLN. Metabolic studies were performed after 3 d of feeding. There was no change in the plasma concentrations of GLN between the two groups, and nitrogen balance was also similar, despite the average intake of 27.1 g GLN/d for 3 d. In addition, there was no difference in protein turnover, or protein synthesis or breakdown rates. Similarly, glucose turnover, oxidation and recycling were similar between the two groups.

In a large outcome study (n = 60) (Houdijk et al. 1998 ), patients with an Injury Severity Score 20 (indicating patients with moderate-to-severe injury) were randomized to receive the same diets as those administered by Long et al. (1995) . The authors found a significant reduction in infectious complications in the GLN-supplemented patients (Table 3). Five of 29 patients (17%) in the GLN group had pneumonia compared with 14 of 31 (45%) in the control group (P < 0.005). One patient in the control group had sepsis compared with eight (26%) in the control group. The authors concluded that there was a lower frequency of infection in patients with multiple trauma who received GLN-supplemented nutrition. This finding is similar to that observed in other patient groups susceptible to infection, such as those following bone marrow transplantation and premature infants. It appears that GLN supplementation reduces the rates of infection in these susceptible individuals.

Studies of glutamine metabolism in burn patients.

Several studies of GLN metabolism have been performed in patients after thermal injury. Parry-Billings et al. (1990) measured serum GLN levels in burn patients and examined the function of circulating lymphocytes harvested from normal individuals at various concentrations of GLN. After burn injury, GLN concentration fell to a low of 200 mol/L. When leukocytes from normal individuals were studied at these concentrations, thymidine incorporation was greatly impaired. The authors concluded that the low levels of GLN may have contributed to the impaired immunological function occurring after burn injury.

Several investigators have attributed the decreased plasma concentrations of GLN to a deficiency in peripheral GLN production. Gore and Jahoor (2000) studied amino acid release from the extremities of five acutely injured children and three controls. They found that the rate of GLN production was significantly reduced in the injured patients so that the net efflux was similar in burn patients and controls.

Mittendorfer et al. (1999) utilized stable isotopic techniques to study amino acid metabolism and combined these flux studies with evaluation of metabolism in skeletal muscle biopsy specimens. They found low intracellular levels of glutamine, but the rate of GLN transport into the blood stream was similar to that observed in normal controls (Table 4). They concluded that the accelerated production of GLN by skeletal muscle could not maintain intracellular concentrations of GLN because of the accelerated outward transport of this amino acid and increases in local consumption.

	DISCUSSION

TOP ABSTRACT INTRODUCTION General characteristics of the... Glutamine administration in the... Studies of intravenous... Studies of oral GLN... Glutamine metabolism and... DISCUSSION LITERATURE CITED

 
These studies demonstrate that there are reproducible and beneficial effects observed when GLN is administered to elective surgical and trauma patients. In all of these studies, no side effects or complications related to the administration of L-GLN or its dipeptides were reported. In patients undergoing elective surgery, GLN supplementation attenuated the negative postoperative nitrogen balance, diminished the fall in intracellular concentrations of GLN in the skeletal muscle free amino acids pool and supported muscle protein synthesis. In addition, GLN enhanced immunological alterations thought to be of benefit to the patient and reduced bowel permeability. Most surprising, GLN supplementation reduced length of hospital stay an average of 4 d.

In the trauma patients, a single study demonstrated that a GLN-supplemented enteral diet significantly reduced the incidence of infection in severely traumatized patients.

Despite these multiple studies, additional investigations are warranted. For specific patient groups, dose response and time course data are needed. Studies are also needed to evaluate the time at which GLN-administration should be initiated (e.g., should it be started before an operation in an elective surgical patient?) and when it should be discontinued. Responses to the two different routes of administration (enteral vs. intravenous) should also be carefully evaluated. Finally, studies should be performed administering GLN as a single nutrient or in isotonic solutions with dextrose (Nattakom et al. 1994 ). The potential for GLN-supplemented intravenous solutions to be used as the standard parenteral infusion in the operating room should be examined with both outcome and cost assessed as end points.

A review of the published data indicates that there are several important research questions that need to be pursued. The mechanism for the maintenance of intracellular concentrations of GLN in skeletal muscle when changes in plasma concentration are unaltered should be explored. Could the explanation be related to the effect of GLN on intracellular redox potential?

Another important issue is the decreased length of stay in the GLN-supplemented patients observed in all studies reported to date. Is this effect due to enhanced protein synthesis, a central nervous system effect of perceived wellness, or an increase in patient activity and enhanced immune function? This clearly is an area of great research potential for a multiple disciplinary group of biological scientists.

Finally, the general concept of how exogenous GLN functions in the various clinical settings should be considered. Initially, it was proposed that GLN served as a conditionally essential amino acid, with the conditions for increased tissue requirements generally being injury and inflammation (Lacey and Wilmore 1990 ). It may well be that many of the clinical effects observed occur because of the unique pharmacologic characteristics of this amino acid. If this is so, then the dose of GLN administered per unit weight becomes important, along with route of delivery, distribution space and disappearance characteristics. More considerations and research of this issue should be addressed in the future.

In conclusion, positive effects appear to be observed in patients receiving GLN, but more studies are required to understand the potential of this most versatile of amino acids.

	FOOTNOTES

 
¹ Presented at the International Symposium on Glutamine, October 2–3, 2000, Sonesta Beach, Bermuda. The symposium was sponsored by Ajinomoto USA, Incorporated. 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 Abbreviations used: ALA, alanine; GLN, glutamine; L, lactulose; M, mannitol. correctness of the other 3 units as rewritten.

	LITERATURE CITED

TOP ABSTRACT INTRODUCTION General characteristics of the... Glutamine administration in the... Studies of intravenous... Studies of oral GLN... Glutamine metabolism and... DISCUSSION LITERATURE CITED

 

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