patients receiving the glutamine-enriched nutrition, there was sig-nificantly less bacteremia, probably explaining the lower TNF-soluble levels. In addition, no gram-negative bacteremias werefound in the glutamine group versus 54% in the patients fed thecontrol diet, possibly because glutamine maintained intestinal in-tegrity, thus preventing bacterial translocation and reducing theinflammatory response. As attractive as this suggestion may be, thestudy was not designed to monitor intestinal integrity or bacterialtranslocation, and further research in this area is needed.

An additional benefit of glutamine-enriched nutrition is thestimulation of renal production of arginine, another importantimmunomodulator. Arginine stimulates lymphocyte responsive-ness and is involved in wound healing.27 Glutamine increases theintestinal production of citrulline, which is converted to arginine inthe kidneys.28 In rats, a glutamine-enriched enteral diet stimulatesrenal arginine production resulting in higher arginine plasma levelswhich was also seen in the multiple trauma patients.29 This mayseem advantageous in terms of immunomodulation but again com-plicates drawing any conclusion on the particular effects of glu-tamine alone.

In our experience and that of others, the rate of feeding in ourstudy was higher than what normally is achieved. This result isexplained by setting goals for high delivery rates and the attentionof a nutritional research fellow.30 In normal clinical practice,physicians tend to feed their patients later and at a lower rate.Nevertheless, despite the high rate of enteral nutrition, a period ofmore than 3 d was necessary to significantly increase plasma levelsof glutamine compared with the control nutrition. In light of thepromising effects of glutamine-enriched nutrition on the rate ofinfections in trauma patients, it would be desirable to start theadministration of glutamine as soon as possible. For future studies,this may be achieved by the immediate administration of glu-tamine by the parenteral route followed by the more preferrableenteral administration as soon as possible.

Despite the promising effects of glutamine and other immu-nonutrients on reducing infection rates, immunonutrition in thecritically ill still is not accepted as standard care. The lack of largerandomized trials investigating a single immunonutritional supple-ment given to well-defined homogeneous patient populations prob-ably underlies this problem. Such studies are needed to help definewhat nutritonal supplement is best suited for selective patientpopulations and will provide the facts needed to end the discus-sion between believers and non-believers in the field ofimmunonutrition.

Alexander P. J. Houdijk, MDPaul A. M. van Leeuwen, MD, PhD

Department of SurgerySlotervaart Ziekenhuis

Ziekenhuis Vrije UniversiteitAmsterdam, The Netherlands

REFERENCES

1. Border JR, Hassett J, LaDuca J, et al. The gut origin states in blunt multipletrauma (ISS5 40) in the ICU. Ann Surg 1987;206:427

2. O’Mahoney JB, Palder SB, Wood JJ, et al. Depression of cellular immunity aftermultiple trauma in the absence of sepsis. J Trauma 1984;10:869

3. Levy EM, Alharbi SA, Grindlinger G, Black PH. Changes in mitogen respon-siveness of lymphocyte subsets after traumatic injury: relation to development ofsepsis. Clin Immunol Immunopathol 1984;32:224

4. Pape HC, Dwenger A, Regel G, et al. Increased gut permeability after multipletrauma. Br J Surg 1994;81:850

5. Frayn KN. Hormonal control of metabolism in trauma and sepsis. Clin Endocri-nol 1986;24:577

6. Souba WW, Klimberg VS, Plumley DA, et al. The role of glutamine in main-taining a healthy gut and supporting the metabolic response to injury andinfection. J Surg Res 1990;48:383

7. McAnena OJ, Moore FA, Moore EE, Jones TN, Parsons P. Selective uptake ofglutamine in the gastrointestinal tract: confirmation in a human study. Br J Surg1991:78:480

8. Hammarqvist F, Wernerman J, von der Decken A, Vinnars E. Alanyl-glutaminecounteracts the depletion of free glutamine and the postoperative decline inprotein synthesis in skeletal muscle. Ann Surg 1990;212:637

9. Stehle P, Zander J, Mertes N, et al. Effect of parenteral glutamine peptidesupplements on muscle glutamine loss and nitrogen balance after major surgery.Lancet 1989;1:231

10. Newsholme EA, Crabtree B, Ardawi MSM. The role of high rates of glycolysisand glutamine utilization in rapidly dividing cells. Biosci Rep 1985;5:393

11. Windmueller HG, Spaeth AE. Respiratory fuels and nitrogen metabolism in vivoin small intestine of fed rats. J Biol Chem 1978;253:69

12. O’Dwyer ST, Smith RJ, Hwang TL, Wilmore DW. Maintenance of small bowelmucosa with glutamine-enriched parenteral nutrition. JPEN 1989;13:579

13. Souba WW, Klimberg VS, Hautamaki RD, et al. Oral glutamine reduces bacterialtranslocation following abdominal radiation. J Surg Res 1990;48:1

14. Bai MX, Jiang ZM, Liu YW, et al. Effects of alanyl-glutamine on gut barrierfunction. Nutrition 1996;12:793

15. Furukawa S, Saito H, Inaba T, et al. Glutamine-enriched enteral diet enhancesbacterial clearance in protracted bacterial peritonitis, regardless of glutamineform. JPEN 1997;21:208

16. Van der Hulst RWJ, van Kreel BK, von Meyenfeldt MF, et al. Glutamine and thepreservation of gut integrity. Lancet 1993;341:1363

17. Tremel H, Kienle B, Weilemann LS, Stehle P, Furst P. Glutamine dipeptide-supplemented parenteral nutrition maintains intestinal function in the critically ill.Gastroenterology 1994;107:1595

18. O’Riordain MG, Fearon KC, Ross JA, et al. Glutamine-supplemented totalparenteral nutrition enhances T-lymphocyte response in surgical patients under-going colorectal resection. Ann Surg 1994;220:212

19. Morilion BJ, Stehle P, Wachtler P, et al. Total parenteral nutrition with glutaminedipeptide after major abdominal surgery: a randomized, double blind controlledstudy. Ann Surg 1998;227:302

20. Ziegler TR, Young LS, Benfell K, et al. Clinical and metabolic efficacy ofglutamine supplemented parenteral nutrition after bone marrow transplantation.A randomized double blind controlled study. Ann Intern Med 1992;116:821

21. Neu J, Roig JC, Meetze WH, et al. Enteral glutamine supplementation for verylow birth weight infants decreases morbidity. J Pediatr 1997;131:691

22. Griffiths RD, Jones C, Palmer A. Six-month outcome of critically ill patientsgiven glutamine-supplemented parenteral nutrition. Nutrition 1997;13:295

23. Long CL, Borghesi L, Stahl R, et al. Impact of enteral feeding of a glutamine-supplemented formula on the hypoaminoacidemic response in trauma patients.J Trauma 1996;40:97

24. Kudsk KA, Minard G, Croce MA, et al. A randomized trial of isonitrogenousenteral diets after severe trauma. An immune-enhancing diet reduces septiccomplications. Ann Surg 1996;224:531

25. Kudsk KA, Croce MA, Fabian TC, et al. Enteral versus parenteral feeding.Effects on septic morbidity after blunt and penetrating abdominal trauma. AnnSurg 1992;215:503

26. Houdijk APJ, Rijnsburger ER, Jansen J, et al. Randomised trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multipletrauma. Lancet 1998;352:772

27. Barbul A, Lazarou SA, Efron DT, et al. Arginine enhances wound healing andlymphocyte immune responses in humans. Surgery 1990;108:331

28. Windmueller HG, Spaeth AE. Source and fate of circulating citrulline. Am JPhysiol 1981;241:E473

29. Houdijk APJ, van Leeuwen PAM, Teerlink T, et al. Glutamine enriched enteraldiet increases renal arginine synthesis. JPEN 1994;18:422

30. Houdijk APJ, Haarman HJTM, van Leeuwen PAM. Glutamine-enriched enteralnutrition in patients with multiple trauma. Lancet 1998;352:1553

PII S0899-9007(99)00221-X

More Good News About GlutamineGlutamine is synthesized in skeletal muscle and released into thecirculation. Important consumers of glutamine from the blood-

Correspondence to: Philip C. Calder, PhD, Institute of Human Nutrition,University of Southampton, Bassett Crescent East, Southampton S0167PX, UK. E-mail: pcc@soton.ac.uk

EDITORIAL OPINIONS 71

stream include the gastrointestinal tract, the kidney, the liver, andthe immune system. During stress situations, the demand by theseand perhaps other tissues may exceed the ability of skeletal muscleto supply glutamine. As a result, blood and skeletal muscle glu-tamine concentrations fall. It is proposed that in such situationsglutamine becomes conditionally essential1 and that in an attemptto meet the demand skeletal muscle breakdown occurs, leading tomuscle wasting. Muscle wasting is commonly observed in patientswith human immunodeficiency virus (HIV) infection,2 and it hasbeen proposed that this is driven by the demand for glutamine insuch patients.3 Because it appears that death from wasting in AIDSis related to the magnitude of tissue depletion and is independentof the cause of wasting,2 maintenance of body mass should pro-long survival. It has previously been shown that administration ofan enteral feed (glutamine free) to weight-losing AIDS patientsincreases body cell mass.4 The study by Shabert et al.5 reported inthe 15(11/12) issue ofNutrition is based on the hypothesis that oralglutamine provision to weight-losing HIV patients will decreasethe demand for endogenous glutamine and thus will decreasemuscle wasting. These authors elected to include antioxidants (amix of vitamins C and E,b-carotene, selenium, andN-acetylcysteine) in the regimen on the basis that HIV patients are com-monly deficient in these6 and that this deficiency may be exacer-bated by an increased oxidative stress. The article does not reportplasma glutamine concentrations before or during the treatmentperiod, which seems an important omission. Glutamine was pro-vided as 10 g four times daily (i.e., 40 g/d) in a double-blindmanner using glycine (40 g/d) as placebo. By the start of the study,patients in the glutamine group had lost an average of 10.7% ofweight since the onset of the disease, although all had body massindexes in the “desirable” range (i.e., 20 to 25 kg/m2). Treatmentwith glutamine (plus antioxidants) for 12 wk resulted in weightgain (2.2 kg) and an increase in body cell mass (1.8 kg), total bodywater (1.5 L), and intracellular water (1.7 L); the latter were basedon bioelectric impedance measurements. About 75% of the effectof glutamine (plus antioxidants) occurred over the first 4 wk oftreatment. Curiously, the measures in the placebo group increasedalmost as much as those in the glutamine group over the first 4 wk,but the measures then returned to starting values. The results areencouraging and suggest that exogenous glutamine (plus antioxi-dants) can at least in part reverse the decrease in lean tissue masswhich accompanies HIV infection. A longer term, larger trial isneeded to verify these results and to look at other relevant outcomemeasures. It seems important that the effects of glutamine andantioxidants be studied separately and together (as in the study byShabert et al.) to identify the active component of the mixture andto optimize the treatment regimen.

This study follows a number of others in recent years that haveidentified a role for glutamine as an inexpensive yet effectivecomponent in the therapy of a variety of conditions involvingcatabolic stress. For example, glutamine (or its precursors) hasbeen shown to have some beneficial effects (e.g., decreasing thenegative nitrogen balance and maintenance of muscle mass and gutintegrity) after major surgery,7–9 after bone marrow transplanta-tion,10 in patients in intensive care,11–13 and in very low birth-weight babies.14

One common component of catabolic states is the increasedsusceptibility to infection, which occurs through the combinationof increased gut permeability to infectious agents and diminishedimmune defense. Because the immune system appears to have arequirement for glutamine to retain optimal function,15,16 mainte-nance of plasma glutamine concentrations in catabolic patientsmight have an added benefit of improving immune function andthus help to combat infection. There is now evidence for thisemerging from both animal and clinical studies. Enrichment of thediet with glutamine increases ex vivo proliferation of T lympho-cytes from rats,17 pigs,18 and mice.19 The latter study has reportedthat a glutamine-enriched diet also increases the proportion ofCD41 lymphocytes in the murine spleen, increases the proportion

of stimulated lymphocytes bearing the interleukin-2 receptor, andincreases interleukin-2 production. In another recent murine study,the production of tumor necrosis factor-a and of interleukins-1band 6 was greater by stimulated macrophages from mice fed aglutamine-enriched diet.20 That such immunoenhancing effects ofglutamine are important has been demonstrated by a series ofstudies in which glutamine-supplemented parenteral nutritionmarkedly improved survival of rats after cecal ligation and punc-ture21 and after intraperitoneal administration of liveEscherichiacoli.22,23 Likewise, dietary glutamine markedly increased the sur-vival of mice inocculated intravenously with liveStaphylococcusaureus.24 Taken together, these animal studies indicate that provi-sion of glutamine either parenterally or enterally increases thefunction of various immune cells and that this might lead toenhanced resistance to infection.

The provision of glutamine intravenously to patients after bonemarrow transplantation resulted in a lower level of infection (12%of patients with clinical infections versus 42% in the controlgroup) and a shorter stay in the hospital (296 1 d versus 366 2 d)than seen for patients receiving glutamine-free parenteral nutri-tion.10 A subsequent report by this group showed that glutaminetreatment resulted in greater numbers of total lymphocytes, Tlymphocytes, and CD41 lymphocytes (but not B lymphocytes ornatural killer cells) in the bloodstream after the patients weredischarged.25 Very-low-birthweight babies who received aglutamine-enriched premature feeding formula had a much lowerrate of sepsis (11% versus 31%) than did babies who received astandard formula.14 In a study of patients in intensive care, glu-tamine provision decreased mortality compared with standard par-enteral nutrition (43% versus 67%) and changed the pattern ofmortality.12 In a recent study, patients who received enteral glu-tamine from within 48 h of the trauma showed a significantreduction in the 15-d incidence of pneumonia (17% versus 45% inthe control group), bacteremia (7% versus 42%), and severe sepsis(4% versus 26%).13 Such effects may be related to improvedimmune function because enteral glutamine increased the bloodlymphocyte CD4:CD8 ratio in patients in intensive care,11 andparenteral glutamine increased mitogen-stimulated proliferation ofblood lymphocytes from patients after colorectal surgery.8

Thus, there is increasing evidence that glutamine has beneficialeffects on nitrogen balance, lean tissue mass, gut integrity, andimmune function. This evidence supports the use of glutamine indifferent patient groups, and it is now regarded by some as thequintessential pharmaconutrient. The article by Shabert et al.5

suggests a novel application of glutamine, which will need con-firmation. Furthermore, more needs to be known about the mech-anism of action of glutamine, particularly within gut and immunecells, if we are to maximize the benefit that can be obtained fromits provision.

Philip C. Calder, PhD, DPhilInstitute of Human Nutrition

University of SouthamptonSouthampton, UK

REFERENCES

1. Lacey JM, Wilmore DW. Is glutamine a conditionally essential amino acid? NutrRev 1990;48:297

2. Kotler DO, Tierney AR, Wang J, Pierson RN. Magnitude of body cell massdepletion and the timing of death from wasting in AIDS. Am J Clin Nutr1989;50:444

3. Shabert J, Wilmore DW. Glutamine deficiency as a cause of human immunode-ficiency virus wasting. Med Hypoth 1996;46:252

4. Kotler DP, Tierney A, Ferraro R, et al. Enteral alimentation and repletion of bodycell mass in malnourished patients with acquired immunodeficiency syndrome.Am J Clin Nutr 1991;53:149

5. Shabert JK, Winslow C, Lacey JM, Wilmore DW. Glutamine-antioxidant sup-

EDITORIAL OPINIONS72

plementation increases body cell mass in AIDS patients with weight loss: arandomised, double blind controlled trial. Nutrition 1999;15:860

6. Semba RD, Tang AM. Micronutrients and the pathogenesis of human immuno-deficiency virus infection. Br J Nutr 1999;81:181

7. Stehle P, Zander J, Mertes N, et al. Effect of parenteral glutamine dipeptidesupplements on muscle glutamine loss and nitrogen balance after major surgery.Lancet 1989;i:231

8. O’Riordain M, Fearon KC, Ross JA, et al. Glutamine supplemented parenteralnutrition enhances T-lymphocyte response in surgical patients undergoing colo-rectal resection. Ann Surg 1994;220:212

9. Hammarqvist F, Wernerman J, von der Decken A, Vinnars E. Alanyl-glutaminecounteracts the depletion of free glutamine and post-operative decline in proteinsynthesis in muscle. Ann Surg 1990;212:637

10. Ziegler TR, Young LS, Benfell K, et al. Clinical and metabolic efficacy ofglutamine-supplemented parenteral nutrition following bone marrow transplan-tation: a double-blinded, randomized, controlled trial. Ann Intern Med 1992;116:821

11. Jensen GL, Miller RH, Talabiska DG, Fish J, Gianferante L. A double blind,prospective, randomized study of glutamine-enriched compared with standardpeptide-based feeding in critically ill patients. Am J Clin Nutr 1996;64:615

12. Griffiths RD, Jones C, Palmer TEA. Six-month outcome of critically ill patientsgiven glutamine-supplemented parenteral nutrition. Nutrition 1997;13:295

13. Houdijk APK, Rijnsburger ER, Jansen J, et al. Randomised trial of glutamine-enriched parenteral nutrition on infectious morbidity in patients with multipletrauma. Lancet 1998;352:772

14. Neu J, Roig JC, Meetze WH, et al. Enteral glutamine supplementation for verylow birthweight infants decreases morbidity. J Pediatr 1997;131:691

15. Calder PC. Glutamine and the immune system. Clin Nutr 1994;13:216. Wilmore DW, Shabert JK. Role of glutamine in immunologic responses. Nutri-

tion 1998;14:61817. Shewchuk LD, Baracos VE, Field CJ. L-glutamine supplementation reduces

growth of the Morris Hepatoma 7777 in exercise-trained and sedentary rats. JNutr 1997;127:158

18. Yoo SS, Field CJ, McBurney MI. Glutamine supplementation maintains intra-muscular glutamine concentrations and normalizes lymphocyte function in in-fected early weaned pigs. J Nutr 1997;127:2253

19. Kew S, Wells SM, Yaqoob P, et al. Dietary glutamine enhances murineT-lymphocyte responsiveness. J Nutr 1999;129:1524

20. Wells SM, Kew S, Yaqoob P, Wallace FA, Calder PC. Dietary glutamineenhances cytokine production by murine macrophages. Nutrition 1999;15:881

21. Ardawi MSM. Effect of glutamine-enriched total parenteral nutrition on septicrats. Clin Sci 1991;81:215

22. Inoue Y, Grant JP, Snyder PJ. Effect of glutamine-supplemented intravenousnutrition on survival afterEscherichia coli-induced peritonitis. JPEN 1993;17:41

23. Naka S, Saito H, Hashiguchi Y, et al. Alanyl-glutamine-supplemented totalparenteral nutrition improves survival and protein metabolism in rat protractedbacterial peritonitis model. JPEN 1996;20:417

24. Suzuki I, Matsumoto Y, Adjei AA, et al. Effect of a glutamine-supplemented dietin response to methicillin-resistantStaphylococcus aureusinfection in mice. JNutr Sci Vitaminol 1993;39:405

25. Ziegler TR, Bye RL, Persinger RL, et al. Effects of glutamine supplementation oncirculating lymphocytes after bone marrow transplantation: a pilot study. Am JMed Sci 1998;315:4

PII S0899-9007(99)00233-6

Arginine and Immunonutrition:A ReevaluationArginine has been classified as a semiessential amino acid becauseof its nutritional requirement for the optimal growth of somespecies, but not humans. Over the past two decades, studies haveshown arginine to be a powerful mediator of multiple biologicalprocesses including the release of several hormones, collagensynthesis during wound healing, antitumor activity, and immune

cell responses. Although all hold significant interest to clinicians,the latter has the furthest reaching implications.

Early animal experiments have delineated some of the effectsthat arginine has on the immune system. Normal rodents given a1% arginine HCl supplementation to their normal diet (1.8%arginine content) have demonstrated increased thymic weight sec-ondary to increased numbers of total thymic T lymphocytes.1 Thisthymotropic effect correlates functionally with increased thymiclymphocyte blastogenesis in response to mitogens. Supplementaldietary arginine also minimizes or abrogates posttraumatic thymicinvolution and T cell suppression.2 In the athymic mouse, supple-mental arginine increases the number of T cells and heightensdelayed-type hypersensitivity responses, suggesting a thymic-independent mechanism for the effect of arginine on T cell activ-ity.3 Although the function of other cells of the immune system hasnot been studied after dietary arginine supplementation, there isincreasing evidence that arginine and its metabolites are integral tothe activity and interactions of macrophages and polymorphonu-clear cells.

The clinical significance of arginine’s immunomodulatory abil-ity has been evaluated primarily in experimental models of bacte-rial peritonitis and burns. Rats subjected to cecal ligation andpuncture have demonstrated a significantly increased survivalwhen given doses of 100 mg of arginine HCl by gavage three timesa day; the survival advantage was further improved when gavagetreatment preceded the onset of sepsis.4 Balb/C mice undergoingcecal ligation and puncture and fed a 2% arginine supplementeddiet had a doubling of survival rates (28% to 56%).5 Guinea pigssubjected to 30% total body surface burns and supplemented with2% arginine had a 30% greater survival rate.6 The same level ofsupplementation decreased bacterial translocation to liver andspleen in mice subjected to 20% body surface burn injury.5

Human studies have shown that arginine increases T cell mi-togenic responses when given at doses of 30 g/d. This effect hasbeen noted in healthy volunteers and in severely ill intensive carepatients.7,8 There is a lack of well-conducted studies examining theeffect of arginine supplementation on clinical outcome benefits inpatients.

Recently, special enteral diets have been formulated to containhigh amounts of arginine together withv-3 fatty acids, glutamine,and nucleic acids. The intent is to enhance or preserve the respon-siveness of the cellular components of the immune system and/orto reduce harmful and exaggerated inflammatory responses. Thistherapeutic approach has been termedimmunonutrition. Previousanimal and human investigation has demonstrated that a supple-mentation of 5 to 12 g of arginine/1000 kcal induces enhanced Tcell activity. The arginine concentrations of the commerciallyavailable dietary formulations vary greater than two-fold, but allcontain higher amounts than those required for normal or postin-jury nutriture (Fig. 1).

The concept of immunonutrition has gained much clinical

Correspondence to: Adrian Barbul, MD, Department of Surgery, SinaiHospital, 2401 West Belvedere Avenue, Baltimore, MD 21215, USA.E-mail: abarbul@welchlink.welch.jhu.edu

FIG. 1. Amounts of arginine in specialized enteral diets (US products).

EDITORIAL OPINIONS 73