Enteral Glutamine in Critical Illness

NCT ID: NCT00318331

Randomized Clinical Trial Comparing Enteral Glutamine Supplementation to Standard of Care Enteral Feeding in Critical Illness
Glutamine is an amino acid which is rapidly depleted in critical illness. It is used as energy by cells that line the gut, vital for immune system function, and works as an anti-oxidant. Glutamine supplementation has been shown to improve outcomes in ICU patients. We hypothesize that critically ill patients given extra glutamine will have less of an inflammatory response and therefore better outcomes than patients not given extra glutamine. Our study randomizes patients to tube feeding with OR without extra glutamine to see if it affects patient outcomes as well as markers of inflammation.
Glutamine, a nonessential amino acid, is preferred fuel for rapidly proliferating cells in human body. Those cells include the enterocytes in small intestine, lymphocytes, macrophages, and fibroblasts. Glutamine also transports nitrogen between tissues and serves as a precursor to glutathione which is a potent antioxidant. A healthy human body contains abundant glutamine, either from diet or from skeletal muscle tissue that synthesizes it. During critical illness the demand for glutamine is increased. Rapid depletion of glutamine stores in critically ill patients has been described and correlated to increased mortality. Glutamine depletion may be deleterious in critical illness because of adverse effects on the essential functions mentioned above. For example glutamine depletion may cause gut mucosal barrier function to deteriorate, leading to bacterial translocation and enhanced systemic inflammatory response with increased risk for multisystem organ failure. Clinical trials performed in a wide range of patients with serious illness, including cancer, trauma, burn, major surgery and critical illness, have demonstrated possible benefits of glutamine supplementation. Interpretation of the results of multiple studies is made difficult based on differences in glutamine dosing, route of administration, population studied, and endpoints used. Blood volume analysis has been shown to be a good measure of capillary leak. The DAXOR blood volume analyzer kit was recently approved by the FDA for blood volume analyses and also has the capacity of measuring capillary permeability by looking at the slope of albumin transudation. It is a simpler way to measure capillary permeability than other methods described. Reviewing the previous study results, glutamine supplementation in parental form and with higher dose in various patient populations has shown evidence of being beneficial. Studies of enteral glutamine therapy have also showed benefits, but results are less consistent possibly because of the heterogeneous study methodology described above. Moreover, most of the studies are carried out in burn patients and surgical patients; there were few studies in critical ill medical patients. Finally no study has specifically looked at the mechanism via which glutamine has conferred protection. Comparison: Critically ill patients given enteral tube feeds compared to critically ill patients given enteral tube feeds with supplemental glutamine.
Critical Illness, Sepsis, Respiratory Insufficiency
Glutamine, Critical Illness, Enteral Feeding, Blood Volume Analysis
Christiana Care Health Services
Christiana Care Health Services
Last Updated
09 Mar 2008
Official Link
Alrawi SJ, Miranda LS, Cunningham JN Jr, Acinapura AJ, Raju R. Correlation of blood volume values and pulmonary artery catheter measurements. Saudi Med J. 2002 Nov;23(11):1367-72.

Souba WW, Smith RJ, Wilmore DW. Glutamine metabolism by the intestinal tract. JPEN J Parenter Enteral Nutr. 1985 Sep-Oct;9(5):608-17. Review.

Wernerman J. Glutamine and acute illness. Curr Opin Crit Care. 2003 Aug;9(4):279-85. Review.

Gamrin L, Essén P, Forsberg AM, Hultman E, Wernerman J. A descriptive study of skeletal muscle metabolism in critically ill patients: free amino acids, energy-rich phosphates, protein, nucleic acids, fat, water, and electrolytes. Crit Care Med. 1996 Apr;24(4):575-83.

Conejero R, Bonet A, Grau T, Esteban A, Mesejo A, Montejo JC, López J, Acosta JA. Effect of a glutamine-enriched enteral diet on intestinal permeability and infectious morbidity at 28 days in critically ill patients with systemic inflammatory response syndrome: a randomized, single-blind, prospective, multicenter study. Nutrition. 2002 Sep;18(9):716-21.

Oudemans-van Straaten HM, Bosman RJ, Treskes M, van der Spoel HJ, Zandstra DF. Plasma glutamine depletion and patient outcome in acute ICU admissions. Intensive Care Med. 2001 Jan;27(1):84-90.

Planas M, Schwartz S, Arbós MA, Farriol M. Plasma glutamine levels in septic patients. JPEN J Parenter Enteral Nutr. 1993 May-Jun;17(3):299-300.

Ziegler TR, Young LS, Benfell K, Scheltinga M, Hortos K, Bye R, Morrow FD, Jacobs DO, Smith RJ, Antin JH, et al. Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation. A randomized, double-blind, controlled study. Ann Intern Med. 1992 May 15;116(10):821-8.

Griffiths RD, Jones C, Palmer TE. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition. 1997 Apr;13(4):295-302.

Wischmeyer PE, Lynch J, Liedel J, Wolfson R, Riehm J, Gottlieb L, Kahana M. Glutamine administration reduces Gram-negative bacteremia in severely burned patients: a prospective, randomized, double-blind trial versus isonitrogenous control. Crit Care Med. 2001 Nov;29(11):2075-80.

Wischmeyer PE. Clinical applications of L-glutamine: past, present, and future. Nutr Clin Pract. 2003 Oct;18(5):377-85.

Garrel D, Patenaude J, Nedelec B, Samson L, Dorais J, Champoux J, D'Elia M, Bernier J. Decreased mortality and infectious morbidity in adult burn patients given enteral glutamine supplements: a prospective, controlled, randomized clinical trial. Crit Care Med. 2003 Oct;31(10):2444-9.

Oberhoffer M, Karzai W, Meier-Hellmann A, Bögel D, Fassbinder J, Reinhart K. Sensitivity and specificity of various markers of inflammation for the prediction of tumor necrosis factor-alpha and interleukin-6 in patients with sepsis. Crit Care Med. 1999 Sep;27(9):1814-8.

Lobo SM, Lobo FR, Bota DP, Lopes-Ferreira F, Soliman HM, Mélot C, Vincent JL. C-reactive protein levels correlate with mortality and organ failure in critically ill patients. Chest. 2003 Jun;123(6):2043-9.

Singleton KD, Serkova N, Beckey VE, Wischmeyer PE. Glutamine attenuates lung injury and improves survival after sepsis: role of enhanced heat shock protein expression. Crit Care Med. 2005 Jun;33(6):1206-13.

Wischmeyer PE. Can glutamine turn off the motor that drives systemic inflammation? Crit Care Med. 2005 May;33(5):1175-8.

De-Souza DA, Greene LJ. Intestinal permeability and systemic infections in critically ill patients: effect of glutamine. Crit Care Med. 2005 May;33(5):1125-35. Review.

Preiser JC, Coëffier M. Heme oxygenase: a new piece in the glutamine puzzle. Crit Care Med. 2005 Feb;33(2):457-8.

Choudhry MA, Haque F, Khan M, Fazal N, Al-Ghoul W, Ravindranath T, Gamelli RL, Sayeed MM. Enteral nutritional supplementation prevents mesenteric lymph node T-cell suppression in burn injury. Crit Care Med. 2003 Jun;31(6):1764-70.

Goeters C, Wenn A, Mertes N, Wempe C, Van Aken H, Stehle P, Bone HG. Parenteral L-alanyl-L-glutamine improves 6-month outcome in critically ill patients. Crit Care Med. 2002 Sep;30(9):2032-7.

Novak F, Heyland DK, Avenell A, Drover JW, Su X. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med. 2002 Sep;30(9):2022-9. Review.

Bérard MP, Zazzo JF, Condat P, Vasson MP, Cynober L. Total parenteral nutrition enriched with arginine and glutamate generates glutamine and limits protein catabolism in surgical patients hospitalized in intensive care units. Crit Care Med. 2000 Nov;28(11):3637-44.

Beale RJ, Bryg DJ, Bihari DJ. Immunonutrition in the critically ill: a systematic review of clinical outcome. Crit Care Med. 1999 Dec;27(12):2799-805.

Coëffier M, Déchelotte P. The role of glutamine in intensive care unit patients: mechanisms of action and clinical outcome. Nutr Rev. 2005 Feb;63(2):65-9. Review.

Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P; Canadian Critical Care Clinical Practice Guidelines Committee.. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. JPEN J Parenter Enteral Nutr. 2003 Sep-Oct;27(5):355-73.

Wischmeyer PE, Riehm J, Singleton KD, Ren H, Musch MW, Kahana M, Chang EB. Glutamine attenuates tumor necrosis factor-alpha release and enhances heat shock protein 72 in human peripheral blood mononuclear cells. Nutrition. 2003 Jan;19(1):1-6.

Chwals WJ. Regulation of the cellular and physiological effects of glutamine. Mini Rev Med Chem. 2004 Oct;4(8):833-8. Review.

Bistrian BR. Practical recommendations for immune-enhancing diets. J Nutr. 2004 Oct;134(10 Suppl):2868S-2872S; discussion 2895S. Review.

Baudouin SV, Evans TW. Nutritional support in critical care. Clin Chest Med. 2003 Dec;24(4):633-44. Review.

Hall JC, Dobb G, Hall J, de Sousa R, Brennan L, McCauley R. A prospective randomized trial of enteral glutamine in critical illness. Intensive Care Med. 2003 Oct;29(10):1710-6.

García-de-Lorenzo A, Zarazaga A, García-Luna PP, Gonzalez-Huix F, López-Martínez J, Miján A, Quecedo L, Casimiro C, Usán L, del Llano J. Clinical evidence for enteral nutritional support with glutamine: a systematic review. Nutrition. 2003 Sep;19(9):805-11. Review.

Sacks GS, Genton L, Kudsk KA. Controversy of immunonutrition for surgical critical-illness patients. Curr Opin Crit Care. 2003 Aug;9(4):300-5. Review.

Oehler R, Roth E. Regulative capacity of glutamine. Curr Opin Clin Nutr Metab Care. 2003 May;6(3):277-82. Review.

Kelly D, Wischmeyer PE. Role of L-glutamine in critical illness: new insights. Curr Opin Clin Nutr Metab Care. 2003 Mar;6(2):217-22. Review.

Koretz RL. Immunonutrition: fact, fantasy, and future. Curr Gastroenterol Rep. 2002 Aug;4(4):332-7. Review.

Andrews F, Griffiths R. Glutamine-enhanced nutrition in the critically ill patient. Hosp Med. 2002 Mar;63(3):144-7. Review.

Oehler R, Pusch E, Dungel P, Zellner M, Eliasen MM, Brabec M, Roth E. Glutamine depletion impairs cellular stress response in human leucocytes. Br J Nutr. 2002 Jan;87 Suppl 1:S17-21.

Andrews FJ, Griffiths RD. Glutamine: essential for immune nutrition in the critically ill. Br J Nutr. 2002 Jan;87 Suppl 1:S3-8. Review.

Velasco N, Hernandez G, Wainstein C, Castillo L, Maiz A, Lopez F, Guzman S, Bugedo G, Acosta AM, Bruhn A. Influence of polymeric enteral nutrition supplemented with different doses of glutamine on gut permeability in critically ill patients. Nutrition. 2001 Nov-Dec;17(11-12):907-11.

Griffiths RD. The evidence for glutamine use in the critically-ill. Proc Nutr Soc. 2001 Aug;60(3):403-10. Review.

Heyland DK, Novak F, Drover JW, Jain M, Su X, Suchner U. Should immunonutrition become routine in critically ill patients? A systematic review of the evidence. JAMA. 2001 Aug 22-29;286(8):944-53. Review.

Labow BI, Souba WW. Glutamine. World J Surg. 2000 Dec;24(12):1503-13. Review.

Barbosa E, Moreira EA, Goes JE, Faintuch J. Pilot study with a glutamine-supplemented enteral formula in critically ill infants. Rev Hosp Clin Fac Med Sao Paulo. 1999 Jan-Feb;54(1):21-4.

Mittendorfer B, Gore DC, Herndon DN, Wolfe RR. Accelerated glutamine synthesis in critically ill patients cannot maintain normal intramuscular free glutamine concentration. JPEN J Parenter Enteral Nutr. 1999 Sep-Oct;23(5):243-50; discussion 250-2.

Saito H, Furukawa S, Matsuda T. Glutamine as an immunoenhancing nutrient. JPEN J Parenter Enteral Nutr. 1999 Sep-Oct;23(5 Suppl):S59-61. Review.

Sacks GS. Glutamine supplementation in catabolic patients. Ann Pharmacother. 1999 Mar;33(3):348-54. Review.

Jones C, Palmer TE, Griffiths RD. Randomized clinical outcome study of critically ill patients given glutamine-supplemented enteral nutrition. Nutrition. 1999 Feb;15(2):108-15.

Jackson NC, Carroll PV, Russell-Jones DL, Sönksen PH, Treacher DF, Umpleby AM. The metabolic consequences of critical illness: acute effects on glutamine and protein metabolism. Am J Physiol. 1999 Jan;276(1 Pt 1):E163-70.

Griffiths RD. Outcome of critically ill patients after supplementation with glutamine. Nutrition. 1997 Jul-Aug;13(7-8):752-4. Review.

van der Hulst RR, von Meyenfeldt MF, Soeters PB. Glutamine: an essential amino acid for the gut. Nutrition. 1996 Nov-Dec;12(11-12 Suppl):S78-81. Review.

Heberer M, Babst R, Juretic A, Gross T, Hörig H, Harder F, Spagnoli GC. Role of glutamine in the immune response in critical illness. Nutrition. 1996 Nov-Dec;12(11-12 Suppl):S71-2.

Jensen GL, Miller RH, Talabiska DG, Fish J, Gianferante L. A double-blind, prospective, randomized study of glutamine-enriched compared with standard peptide-based feeding in critically ill patients. Am J Clin Nutr. 1996 Oct;64(4):615-21.

MacFie J, O'Boyle C, Mitchell CJ, Buckley PM, Johnstone D, Sudworth P. Gut origin of sepsis: a prospective study investigating associations between bacterial translocation, gastric microflora, and septic morbidity. Gut. 1999 Aug;45(2):223-8.

Preiser JC, Wernerman J. Glutamine, a life-saving nutrient, but why? Crit Care Med. 2003 Oct;31(10):2555-6.

Rector WG Jr, Ibarra F. Intravascular volume in cirrhosis. Reassessment using improved methodology. Dig Dis Sci. 1988 Apr;33(4):460-6.

Haraldsson B, Rippe B. Influence of perfusate oncotic pressure on the transcapillary clearance of albumin in maximally vasodilated rat skeletal muscle. Acta Physiol Scand. 1987 Jun;130(2):219-28.

Margarson MP, Soni NC. Effects of albumin supplementation on microvascular permeability in septic patients. J Appl Physiol (1985). 2002 May;92(5):2139-45.

United States