Glutamine may have benefits during immaturity or critical illness in early life but its effects on outcome end hardpoints are controversial. Our aim was to review randomized studies on glutamine supplementation in pups, infants, and children examining whether glutamine affects outcome. Experimental work has proposed various mechanisms of glutamine action but none of the randomized studies in early life showed any effect on mortality and only a few showed some effect on inflammatory response, organ function, and a trend for infection control. Although apparently safe in animal models (pups), premature infants, and critically ill children, glutamine supplementation does not reduce mortality or late onset sepsis, and its routine use cannot be recommended in these sensitive populations. Large prospectively stratified trials are needed to better define the crucial interrelations of “glutamine-heat shock proteins-stress response” in critical illness and to identify the specific subgroups of premature neonates and critically ill infants or children who may have a greater need for glutamine and who may eventually benefit from its supplementation. The methodological problems noted in the reviewed randomized experimental and clinical trials should be seriously considered in any future well-designed large blinded randomized controlled trial involving glutamine supplementation in critical illness. 1. Introduction Amino acids have a crucial role in protein synthesis, trigger signaling cascades that regulate various aspects of fuel and energy metabolism, and serve as precursors for important substrates. Glutamine, the most abundant amino acid in the muscle and plasma of humans traditionally considered a nonessential amino acid, now appears to be a conditionally essential nutrient during stress, injury [1], or illness [2]. During the acute stress of critical illness, large amounts of glutamine are produced by glutamine synthetase from muscle tissue [3] in response to stress and the regulation of glutamine synthetase protein turnover in response to glutamine concentrations [4]. Despite this significant release of glutamine, plasma levels decrease significantly following major burns in adults and remain decreased for over 21 days [5]. This severe glutamine deficiency occurs rapidly in adults and is associated with increased critical illness morbidity and mortality [6]. Similarly, the sudden cessation of glutamine supply from the mother to premature infants, who are already stressed and undergoing rapid growth, may be detrimental [7]. Thus, whereas plasma glutamine
References
[1]
U. B. Fl?ring, O. E. Rooyackers, J. Wernerman, and F. Hammarqvist, “Glutamine attenuates post-traumatic glutathione depletion in human muscle,” Clinical Science, vol. 104, no. 3, pp. 275–282, 2003.
[2]
P. E. Wischmeyer, “Can glutamine turn off the motor that drives systemic inflammation?” Critical Care Medicine, vol. 33, no. 5, pp. 1175–1178, 2005.
[3]
L. Gamrin, P. Essén, A. M. Forsberg, E. Hultman, and J. Wernerman, “A descriptive study of skeletal muscle metabolism in critically ill patients: free amino acids, energy-rich phosphates, protein, nucleic acids, fat, water, and electrolytes,” Critical Care Medicine, vol. 24, no. 4, pp. 575–583, 1996.
[4]
B. I. Labow, W. W. Souba, and S. F. Abcouwer, “Mechanisms governing the expression of the enzymes of glutamine metabolism-glutaminase and glutamine synthetase,” Journal of Nutrition, vol. 131, no. 9, pp. 2467S–2474S, 2001.
[5]
M. Parry-Billings, J. Evans, P. C. Calder, and E. A. Newsholme, “Does glutamine contribute to immunosuppression after major burns?” The Lancet, vol. 336, no. 8714, pp. 523–525, 1990.
[6]
P. E. Wischmeyer, “Glutamine: role in critical illness and ongoing clinical trials,” Current Opinion in Gastroenterology, vol. 24, no. 2, pp. 190–197, 2008.
[7]
Y. Huang, X. M. Shao, and J. Neu, “Immunonutrients and neonates,” European Journal of Pediatrics, vol. 162, no. 3, pp. 122–128, 2003.
[8]
F. Pohlandt, “Plasma amino acid concentrations in newborn infants breast-fed ad libitum,” Journal of Pediatrics, vol. 92, no. 4, pp. 614–616, 1978.
[9]
R. M. Becker, G. Wu, J. A. Galanko et al., “Reduced serum amino acid concentrations in infants with necrotizing enterocolitis,” Journal of Pediatrics, vol. 137, no. 6, pp. 785–793, 2000.
[10]
K. M. Bernt and W. A. Walker, “Human milk as a carrier of biochemical messages,” Acta Paediatrica, International Journal of Paediatrics, Supplement, vol. 88, no. 430, pp. 27–41, 1999.
[11]
S. Verbruggen, J. Sy, A. Arrivillaga, K. Joosten, J. Van Goudoever, and L. Castillo, “Parenteral amino acid intakes in critically Ill children: a matter of convenience,” Journal of Parenteral and Enteral Nutrition, vol. 34, no. 3, pp. 329–340, 2010.
[12]
E. A. Newsholme, B. Crabtree, and M. S. M. Ardawi, “Glutamine metabolism in lymphocytes: its biochemical, physiological and clinical importance,” Quarterly Journal of Experimental Physiology, vol. 70, no. 4, pp. 473–489, 1985.
[13]
H. G. Windmueller and A. E. Spaeth, “Respiratory fuels and nitrogen metabolism in vivo in small intestine of fed rats. Quantitative importance of glutamine, glutamate, and aspartate,” Journal of Biological Chemistry, vol. 255, no. 1, pp. 107–112, 1980.
[14]
S. Rapoport, J. Rost, and M. Schultze, “Glutamine and glutamate as respiratory substrates of rabbit reticulocytes,” European Journal of Biochemistry, vol. 23, no. 1, pp. 166–170, 1971.
[15]
D. Darmaun, D. E. Matthews, J. F. Desjeux, and D. M. Bier, “Glutamine and glutamate nitrogen exchangeable pools in cultured fibroblasts: a stable isotope study,” Journal of Cellular Physiology, vol. 134, no. 1, pp. 143–148, 1988.
[16]
G. C. Ligthart-Melis, M. C. G. Van De Poll, P. G. Boelens, C. H. C. Dejong, N. E. P. Deutz, and P. A. M. Van Leeuwen, “Glutamine is an important precursor for de novo synthesis of arginine in humans,” American Journal of Clinical Nutrition, vol. 87, no. 5, pp. 1282–1289, 2008.
[17]
J. Neu, “Glutamine in the fetus and critically III low birth weight neonate: metabolism and mechanism of action,” Journal of Nutrition, vol. 131, no. 9, pp. 2585S–2589S, 2001.
[18]
D. W. Wilmore, “The effect of glutamine supplementation in patients following elective surgery and accidental injury,” Journal of Nutrition, vol. 131, no. 9, pp. 2543S–2549S, 2001.
[19]
N. Nurjhan, A. Bucci, G. Perriello et al., “Glutamine: a major gluconeogenic precursor and vehicle for interorgan carbon transport in man,” Journal of Clinical Investigation, vol. 95, no. 1, pp. 272–277, 1995.
[20]
G. Mithieux, “New data and concepts on glutamine and glucose metabolism in the gut,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 4, no. 4, pp. 267–271, 2001.
[21]
J. M. Lacey and D. W. Wilmore, “Is glutamine a conditionally essential amino acid?” Nutrition Reviews, vol. 48, no. 8, pp. 297–309, 1990.
[22]
T. C. Welbourne, D. Childress, and G. Givens, “Renal regulation of interorgan glutamine flow in metabolic acidosis,” American Journal of Physiology, vol. 251, no. 5, pp. R859–R866, 1986.
[23]
J. Neu, V. DeMarco, and N. Li, “Glutamine: clinical applications and mechanisms of action,” Current Opinion in Clinical Nutrition & Metabolic Care, vol. 5, no. 1, pp. 69–75, 2002.
[24]
D. L. Waitzberg, H. Saito, L. D. Plank et al., “Postsurgical infections are reduced with specialized nutrition support,” World Journal of Surgery, vol. 30, no. 8, pp. 1592–1604, 2006.
[25]
D. C. Angus, W. T. Linde-Zwirble, J. Lidicker, G. Clermont, J. Carcillo, and M. R. Pinsky, “Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care,” Critical Care Medicine, vol. 29, no. 7, pp. 1303–1310, 2001.
[26]
J. A. Carcillo, J. M. Dean, R. Holubkov, et al., “The randomized comparative pediatric critical illness stress-induced immune suppression (CRISIS) prevention trial,” Pediatric Critical Care Medicine, vol. 13, no. 2, pp. 165–173, 2012.
[27]
S. Dholakia, D. Inwald, H. Betts, and S. Nadel, “Endotoxemia in pediatric critical illness—a pilot study,” Critical Care, vol. 15, no. 3, article R141, 2011.
[28]
G. Y. Larsen, N. Mecham, and R. Greenberg, “An emergency department septic shock protocol and care guideline for children initiated at triage,” Pediatrics, vol. 127, no. 6, pp. e1585–e1592, 2011.
[29]
H. R. Wong, N. Z. Cvijanovich, G. L. Allen, et al., “Validation of a gene expression-based subclassification strategy for pediatric septic shock,” Critical Care Medicine, vol. 39, no. 11, pp. 2511–2517, 2011.
[30]
M. K. Dahmer, A. Randolph, S. Vitali, and M. W. Quasney, “Genetic polymorphisms in sepsis,” Pediatric Critical Care Medicine, vol. 6, supplement 3, pp. S61–S73, 2005.
[31]
D. K. Heyland, F. Novak, J. W. Drover, M. Jain, X. Su, and U. Suchner, “Should immunonutrition become routine in critically III patients? A systematic review of the evidence,” Journal of the American Medical Association, vol. 286, no. 8, pp. 944–953, 2001.
[32]
P. E. Wischmeyer, “Glutamine: mode of action in critical illness,” Critical Care Medicine, vol. 35, no. 9, pp. S541–S544, 2007.
[33]
R. Curi, C. J. Lagranha, S. Q. Doi et al., “Molecular mechanisms of glutamine action,” Journal of Cellular Physiology, vol. 204, no. 2, pp. 392–401, 2005.
[34]
R. Babu, S. Eaton, D. P. Drake, L. Spitz, and A. Pierro, “Glutamine and glutathione counteract the inhibitory effects of mediators of sepsis in neonatal hepatocytes,” Journal of Pediatric Surgery, vol. 36, no. 2, pp. 282–286, 2001.
[35]
T. Bongers, R. D. Griffiths, and A. McArdle, “Exogenous glutamine: the clinical evidence,” Critical Care Medicine, vol. 35, no. 9, pp. S545–S552, 2007.
[36]
N. Li, P. Lewis, D. Samuelson, K. Liboni, and J. Neu, “Glutamine regulates Caco-2 cell tight junction proteins,” American Journal of Physiology, vol. 287, no. 3, pp. G726–G733, 2004.
[37]
S. Eaton, “Impaired energy metabolism during neonatal sepsis: the effects of glutamine,” Proceedings of the Nutrition Society, vol. 62, no. 3, pp. 745–751, 2003.
[38]
B. Zingarelli, M. Sheehan, and H. R. Wong, “Nuclear factor-κB as a therapeutic target in critical care medicine,” Critical Care Medicine, vol. 31, no. 1, pp. S105–S111, 2003.
[39]
K. D. Singleton, V. E. Beckey, and P. E. Wischmeyer, “Glutamine prevents activation of NF-κB and stress kinase pathways, attenuates inflammatory cytokine release, and prevents acute respiratory distress syndrome (ARDS) following sepsis,” Shock, vol. 24, no. 6, pp. 583–589, 2005.
[40]
T. J. Borges, L. Wieten, M. J. van Herwijnen et al., “The anti-inflammatory mechanisms of Hsp70,” Frontiers in Immunology, vol. 3, article 95, 2012.
[41]
Y. Lai, C. Stange, S. R. Wisniewski et al., “Mitochondrial heat shock protein 60 is increased in cerebrospinal fluid following pediatric traumatic brain injury,” Developmental Neuroscience, vol. 28, no. 4-5, pp. 336–341, 2006.
[42]
M. Song, M. R. Pinsky, and J. A. Kellum, “Heat shock factor 1 inhibits nuclear factor-κB nuclear binding activity during endotoxin tolerance and heat shock,” Journal of Critical Care, vol. 23, no. 3, pp. 406–415, 2008.
[43]
Y. G. Weiss, Z. Bromberg, N. Raj et al., “Enhanced heat shock protein 70 expression alters proteasomal degradation of IκB kinase in experimental acute respiratory distress syndrome,” Critical Care Medicine, vol. 35, no. 9, pp. 2128–2138, 2007.
[44]
P. E. Wischmeyer, J. Riehm, K. D. Singleton et al., “Glutamine attenuates tumor necrosis factor-α release and enhances heat shock protein 72 in human peripheral blood mononuclear cells,” Nutrition, vol. 19, no. 1, pp. 1–6, 2003.
[45]
M. Co?ffier, S. Claeyssens, B. Hecketsweiler, A. Lavoinne, P. Ducrotté, and P. Déchelotte, “Enteral glutamine stimulates protein synthesis and decreases ubiquitin mRNA level in human gut mucosa,” American Journal of Physiology, vol. 285, no. 2, pp. G266–G273, 2003.
[46]
Y. F. Huang, Y. Wang, and M. Watford, “Glutamine directly downregulates glutamine synthetase protein levels in mouse C2C12 skeletal muscle myotubes,” Journal of Nutrition, vol. 137, no. 6, pp. 1357–1362, 2007.
[47]
K. D. Singleton and P. E. Wischmeyer, “Effects of HSP70.1/3 gene knockout on acute respiratory distress syndrome and the inflammatory response following sepsis,” American Journal of Physiology, vol. 290, no. 5, pp. L956–L961, 2006.
[48]
R. Oehler and E. Roth, “Regulative capacity of glutamine,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 6, no. 3, pp. 277–282, 2003.
[49]
J. Gong and L. Jing, “Glutamine induces heat shock protein 70 expression via O-GlcNAc modification and subsequent increased expression and transcriptional activity of heat shock factor-1,” Minerva Anestesiologica, vol. 77, no. 5, pp. 488–495, 2011.
[50]
K. D. Singleton and P. E. Wischmeyer, “Glutamine induces heat shock protein expression via O-glycosylation and phosphorylation of HSF-1 and Sp1,” Journal of Parenteral and Enteral Nutrition, vol. 32, no. 4, pp. 371–376, 2008.
[51]
A. L. Morrison, M. Dinges, K. D. Singleton, K. Odoms, H. R. Wong, and P. E. Wischmeyer, “Glutamine's protection against cellular injury is dependent on heat shock factor-1,” American Journal of Physiology, vol. 290, no. 6, pp. C1625–C1632, 2006.
[52]
P. E. Wischmeyer, M. Kahana, R. Wolfson, H. Ren, M. M. Musch, and E. B. Chang, “Glutamine induces heat shock protein and protects against endotoxin shock in the rat,” Journal of Applied Physiology, vol. 90, no. 6, pp. 2403–2410, 2001.
[53]
P. E. Wischmeyer, M. W. Musch, M. B. Madonna, R. Thisted, and E. B. Chang, “Glutamine protects intestinal epithelial cells: role of inducible HSP70,” American Journal of Physiology, vol. 272, no. 4, pp. G879–G884, 1997.
[54]
M. W. Musch, D. Hayden, K. Sugi, D. Straus, and E. B. Chang, “Cell-specific induction of hsp72-mediated protection by glutamine against oxidant injury in IEC18 cells,” Proceedings of the Association of American Physicians, vol. 110, no. 2, pp. 136–139, 1998.
[55]
A. Chow and R. Zhang, “Glutamine reduces heat shock-induced cell death in rat intestinal epithelial cells,” Journal of Nutrition, vol. 128, no. 8, pp. 1296–1301, 1998.
[56]
T. C. Pithon-Curi, R. I. Schumacher, J. J. S. Freitas et al., “Glutamine delays spontaneous apoptosis in neutrophils,” American Journal of Physiology, vol. 284, no. 6, pp. C1355–C1361, 2003.
[57]
W. K. Chang, K. D. Yang, H. Chuang, J. T. Jan, and M. F. Shaio, “Glutamine protects activated human T cells from apoptosis by up-regulating glutathione and Bcl-2 levels,” Clinical Immunology, vol. 104, no. 2, pp. 151–160, 2002.
[58]
L. Jing, Q. Wu, and F. Wang, “Glutamine induces heat-shock protein and protects against Escherichia coli lipopolysaccharide-induced vascular hyporeactivity in rats,” Critical Care, vol. 11, article R34, 2007.
[59]
Y. M. Hu, M. H. Pai, C. L. Yeh, Y. C. Hou, and S. L. Yeh, “Glutamine administration ameliorates sepsis-induced kidney injury by down regulating the high-mobility group box protein-1-mediated pathway in mice,” American Journal of Physiology, vol. 302, no. 1, pp. 150–158, 2012.
[60]
W. Y. Kwon, G. J. Suh, K. S. Kim et al., “Glutamine attenuates acute lung injury by inhibition of high mobility group box protein-1 expression during sepsis,” British Journal of Nutrition, vol. 103, no. 6, pp. 890–898, 2010.
[61]
K. D. Singleton, N. Serkova, V. E. Beckey, and P. E. Wischmeyer, “Glutamine attenuates lung injury and improves survival after sepsis: role of enhanced heat shock protein expression,” Critical Care Medicine, vol. 33, no. 6, pp. 1206–1213, 2005.
[62]
M. Ugurlucan, D. Erer, O. Karatepe et al., “Glutamine enhances the heat shock protein 70 expression as a cardioprotective mechanism in left heart tissues in the presence of diabetes mellitus,” Expert Opinion on Therapeutic Targets, vol. 14, no. 11, pp. 1143–1156, 2010.
[63]
P. E. Wischmeyer, J. Lynch, J. Liedel et al., “Glutamine administration reduces Gram-negative bacteremia in severely burned patients: a prospective, randomized, double-blind trial versus isonitrogenous control,” Critical Care Medicine, vol. 29, no. 11, pp. 2075–2080, 2001.
[64]
K. D. Singleton and P. E. Wischmeyer, “Oral glutamine enhances heat shock protein expression and improves survival following hyperthermia,” Shock, vol. 25, no. 3, pp. 295–299, 2006.
[65]
Y. Iwashita, T. Sakiyama, M. W. Musch, M. J. Ropeleski, H. Tsubouchi, and E. B. Chang, “Polyamines mediate glutamine-dependent induction of the intestinal epithelial heat shock response,” American Journal of Physiology, vol. 301, no. 1, pp. G181–G187, 2011.
[66]
L. A. Sonna, L. Hawkins, M. E. Lissauer et al., “Core temperature correlates with expression of selected stress and immunomodulatory genes in febrile patients with sepsis and noninfectious SIRS,” Cell Stress & Chaperones, vol. 15, no. 1, pp. 55–66, 2010.
[67]
D. P. Gelain, M. A. De Bittencourt Pasquali, C. M. Comim et al., “Serum heat shock protein 70 levels, oxidant status, and mortality in sepsis,” Shock, vol. 35, no. 5, pp. 466–470, 2011.
[68]
K. W. McConnell, A. C. Fox, A. T. Clark et al., “The role of heat shock protein 70 in mediating age-dependent mortality in sepsis,” Journal of Immunology, vol. 186, no. 6, pp. 3718–3725, 2011.
[69]
C. Kee, K. Y. Cheong, K. Pham, G. W. Waterer, and S. E. L. Temple, “Genetic variation in heat shock protein 70 is associated with septic shock: narrowing the association to a specific haplotype,” International Journal of Immunogenetics, vol. 35, no. 6, pp. 465–473, 2008.
[70]
G. W. Waterer, L. ElBahlawan, M. W. Quasney, Q. Zhang, L. A. Kessler, and R. G. Wunderink, “Heat shock protein 70-2 + 1267 AA homozygotes have an increased risk of septic shock in adults with community-acquired pneumonia,” Critical Care Medicine, vol. 31, no. 5, pp. 1367–1372, 2003.
[71]
R. G. Garrett-Cox, A. Pierro, L. Spitz, and S. Eaton, “Body temperature and heat production in suckling rat endotoxaemia: beneficial effects of glutamine,” Journal of Pediatric Surgery, vol. 38, no. 1, pp. 37–44, 2003.
[72]
F. V. L. Ladd, A. A. B. L. Ladd, A. A. C. M. Ribeiro et al., “Zinc and glutamine improve brain development in suckling mice subjected to early postnatal malnutrition,” Nutrition, vol. 26, no. 6, pp. 662–670, 2010.
[73]
D. S. C. de Lima, L. M. S. de Seixas Maia, E. de Andrade Barboza, R. de Almeida Duarte, L. S. de Souza, and R. C. A. Guedes, “l-Glutamine supplementation during the lactation period facilitates cortical spreading depression in well-nourished and early-malnourished rats,” Life Sciences, vol. 85, no. 5-6, pp. 241–247, 2009.
[74]
R. G. Garrett-Cox, G. Stefanutti, C. Booth, N. J. Klein, A. Pierro, and S. Eaton, “Glutamine decreases inflammation in infant rat endotoxemia,” Journal of Pediatric Surgery, vol. 44, no. 3, pp. 523–529, 2009.
[75]
B. Potsic, N. Holliday, P. Lewis, D. Samuelson, V. DeMarco, and J. Neu, “Glutamine supplementation and deprivation: effect on artificially reared rat small intestinal morphology,” Pediatric Research, vol. 52, no. 3, pp. 430–436, 2002.
[76]
B. B. Poindexter, R. A. Ehrenkranz, B. J. Stoll et al., “Parenteral glutamine supplementation does not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants,” Pediatrics, vol. 113, no. 5, pp. 1209–1215, 2004.
[77]
S. C. Kalhan, P. S. Parimi, L. L. Gruca, and R. W. Hanson, “Glutamine supplement with parenteral nutrition decreases whole body proteolysis in low birth weight infants,” Journal of Pediatrics, vol. 146, no. 5, pp. 642–647, 2005.
[78]
S. W. Thompson, B. G. McClure, and T. R. J. Tubman, “A randomized, controlled trial of parenteral glutamine in ill, very low birth-weight neonates,” Journal of Pediatric Gastroenterology and Nutrition, vol. 37, no. 5, pp. 550–553, 2003.
[79]
M. J. I. J. Albers, E. W. Steyerberg, F. W. J. Hazebroek et al., “Glutamine supplementation of parenteral nutrition does not improve intestinal permeability, nitrogen balance, or outcome in newborns and infants undergoing digestive-tract surgery: results from a double-blind, randomized, controlled trial,” Annals of Surgery, vol. 241, no. 4, pp. 599–606, 2005.
[80]
C. Des Robert, O. L. Bacquer, H. Piloquet, J. C. Rozé, and D. Darmaun, “Acute effects of intravenous glutamine supplementation on protein metabolism in very low birth weight infants: a stable isotope study,” Pediatric Research, vol. 51, no. 1, pp. 87–93, 2002.
[81]
Z. H. Li, D. H. Wang, and M. Dong, “Effect of parenteral glutamine supplementation in premature infants,” Chinese Medical Journal, vol. 120, no. 2, pp. 140–144, 2007.
[82]
J. M. Lacey, J. B. Crouch, K. Benfell et al., “The effects of glutamine-supplemented parenteral nutrition in premature infants,” Journal of Parenteral and Enteral Nutrition, vol. 20, no. 1, pp. 74–80, 1996.
[83]
B. B. Poindexter, R. A. Ehrenkranz, B. J. Stoll, National Institute of Child Health and Human Development Neonatal Research Network, et al., “Effect of parenteral glutamine supplementation on plasma amino acid concentrations in extremely low-birth-weight infants,” The American Journal of Clinical Nutrition, vol. 77, no. 3, pp. 737–743, 2003.
[84]
Y. Wang, Y. X. Tao, W. Cai, Q. Y. Tang, Y. Feng, and J. Wu, “Protective effect of parenteral glutamine supplementation on hepatic function in very low birth weight infants,” Clinical Nutrition, vol. 29, no. 3, pp. 307–311, 2010.
[85]
E. G. Ong, S. Eaton, A. M. Wade et al., “Randomized clinical trial of glutamine-supplemented versus standard parenteral nutrition in infants with surgical gastrointestinal disease,” British Journal of Surgery, vol. 99, no. 7, pp. 929–938, 2012.
[86]
J. Neu, J. C. Roig, W. H. Meetze et al., “Enteral glutamine supplementation for very low birth weight infants decreases morbidity,” Journal of Pediatrics, vol. 131, no. 5, pp. 691–699, 1997.
[87]
P. Vaughn, P. Thomas, R. Clark, and J. Neu, “Enteral glutamine supplementation and morbidity in low birth weight infants,” Journal of Pediatrics, vol. 142, no. 6, pp. 662–668, 2003.
[88]
A. Van Den Berg, R. M. Van Elburg, E. A. M. Westerbeek, J. W. R. Twisk, and W. P. F. Fetter, “Glutamine-enriched enteral nutrition in very-low-birth-weight infants and effects on feeding tolerance and infectious morbidity: a randomized controlled trial,” American Journal of Clinical Nutrition, vol. 81, no. 6, pp. 1397–1404, 2005.
[89]
A. van den Berg, R. M. van Elburg, E. A. M. Westerbeek et al., “The effect of glutamine-enriched enteral nutrition on intestinal microflora in very low birth weight infants: a randomized controlled trial,” Clinical Nutrition, vol. 26, no. 4, pp. 430–439, 2007.
[90]
A. Van Den Berg, W. P. F. Fetter, E. A. M. Westerbeek, I. M. Van Der Vegt, H. R. A. Van Der Molen, and R. M. Van Elburg, “The effect of glutamine-enriched enteral nutrition on intestinal permeability in very-low-birth-weight infants: a randomized controlled trial,” Journal of Parenteral and Enteral Nutrition, vol. 30, no. 5, pp. 408–414, 2006.
[91]
A. Van Den Berg, R. M. Van Elburg, L. Vermeij et al., “Cytokine responses in very low birth weight infants receiving glutamine-enriched enteral nutrition,” Journal of Pediatric Gastroenterology and Nutrition, vol. 48, no. 1, pp. 94–101, 2009.
[92]
G. Briassoulis, O. Filippou, E. Hatzi, I. Papassotiriou, and T. Hatzis, “Early enteral administration of immunonutrition in critically ill children: results of a blinded randomized controlled clinical trial,” Nutrition, vol. 21, no. 7-8, pp. 799–807, 2005.
[93]
G. Briassoulis, O. Filippou, M. Kanariou, and T. Hatzis, “Comparative effects of early randomized immune or non-immune-enhancing enteral nutrition on cytokine production in children with septic shock,” Intensive Care Medicine, vol. 31, no. 6, pp. 851–858, 2005.
[94]
G. Briassoulis, O. Filippou, M. Kanariou, I. Papassotiriou, and T. Hatzis, “Temporal nutritional and inflammatory changes in children with severe head injury fed a regular or an immune-enhancing diet: a randomized, controlled trial,” Pediatric Critical Care Medicine, vol. 7, no. 1, pp. 56–62, 2006.
[95]
T. Namba, K. Tanaka, T. Hoshino, A. Azuma, and T. Mizushima, “Suppression of expression of heat shock protein 70 by gefitinib and its contribution to pulmonary fibrosis,” PLoS ONE, vol. 6, no. 11, Article ID e27296, 2011.
[96]
D. K. Heyland and A. Samis, “Does immunonutrition in patients with sepsis do more harm than good?” Intensive Care Medicine, vol. 29, no. 5, pp. 669–671, 2003.
[97]
J. Xu, Z. Yunshi, and R. Li, “Immunonutrition in surgical patients,” Current Drug Targets, vol. 10, no. 8, pp. 771–777, 2009.
[98]
A. P. J. Houdijk, E. R. Rijnsburger, J. Jansen et al., “Randomised trial of glut ami ne-enriched enterai nutrition on infectious morbidity in patients with multiple trauma,” The Lancet, vol. 352, no. 9130, pp. 772–776, 1998.
[99]
G. Bertolini, G. Iapichino, D. Radrizzani et al., “Early enteral immunonutrition in patients with severe sepsis: results of an interim analysis of a randomized multicentre clinical trial,” Intensive Care Medicine, vol. 29, no. 5, pp. 834–840, 2003.
[100]
T. Grau, A. Bonet, E. Mi?ambres et al., “The effect of l-alanyl-l-glutamine dipeptide supplemented total parenteral nutrition on infectious morbidity and insulin sensitivity in critically ill patients,” Critical Care Medicine, vol. 39, no. 6, pp. 1263–1268, 2011.
[101]
P. J. Andrews, A. Avenell, D. W. Noble et al., “Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients,” British Medical Journal, vol. 342, p. d1542, 2011.
[102]
T. R. Tubman, S. W. Thompson, and W. McGuire, “Glutamine supplementation to prevent morbidity and mortality in preterm infants,” Cochrane Database of Systematic Reviews, no. 1, Article ID CD001457, 2008.
[103]
E. Barbosa, E. A. Moreira, J. E. Goes, and J. Faintuch, “Pilot study with a glutamine-supplemented enteral formula in critically ill infants,” Revista do Hospital das Clínicas, vol. 54, no. 1, pp. 21–24, 1999.
[104]
P. S. Parimi, S. Devapatla, L. L. Gruca, S. B. Amini, R. W. Hanson, and S. C. Kalhan, “Effect of enteral glutamine or glycine on whole-body nitrogen kinetics in very-low-birth-weight infants,” American Journal of Clinical Nutrition, vol. 79, no. 3, pp. 402–409, 2004.
[105]
S. R. D. Van Der Schoor, H. Schierbeek, P. M. Bet et al., “Majority of dietary glutamine is utilized in first pass in preterm infants,” Pediatric Research, vol. 67, no. 2, pp. 194–199, 2010.
[106]
J. C. Roig, W. H. Meetze, N. Auestad et al., “Enteral glutamine supplementation for the very low birthweight infant: plasma amino acid concentrations,” Journal of Nutrition, vol. 126, no. 4, pp. 1115S–1120S, 1996.
[107]
A. Van Den Berg, R. M. Van Elburg, T. Teerlink, H. N. Lafeber, J. W. R. Twisk, and W. P. F. Fetter, “A randomized controlled trial of enteral glutamine supplementation in very low birth weight infants: plasma amino acid concentrations,” Journal of Pediatric Gastroenterology and Nutrition, vol. 41, no. 1, pp. 66–71, 2005.
[108]
A. Van Den Berg, A. Van Zwol, H. A. Moll, W. P. F. Fetter, and R. M. Van Elburg, “Glutamine-enriched enteral nutrition in very low-birth-weight infants: effect on the incidence of allergic and infectious diseases in the first year of life,” Archives of Pediatrics and Adolescent Medicine, vol. 161, no. 11, pp. 1095–1101, 2007.
[109]
A. Van Zwol, H. A. Moll, W. P. F. Fetter, and R. M. Van Elburg, “Glutamine-enriched enteral nutrition in very low birthweight infants and allergic and infectious diseases at 6 years of age,” Paediatric and Perinatal Epidemiology, vol. 25, no. 1, pp. 60–66, 2011.
[110]
A. Van Zwol, A. Van Den Berg, J. Huisman et al., “Neurodevelopmental outcomes of very low-birth-weight infants after enteral glutamine supplementation in the neonatal period,” Acta Paediatrica, International Journal of Paediatrics, vol. 97, no. 5, pp. 562–567, 2008.
[111]
A. Van Zwol, A. Van Den Berg, J. Knol, J. W. R. Twisk, W. P. F. Fetter, and R. M. Van Elburg, “Intestinal microbiota in allergic and nonallergic 1-year-old very low birth weight infants after neonatal glutamine supplementation,” Acta Paediatrica, International Journal of Paediatrics, vol. 99, no. 12, pp. 1868–1874, 2010.
[112]
A. Van Zwol, A. Van Den Berg, E. E. S. Nieuwenhuis, J. W. R. Twisk, W. P. F. Fetter, and R. M. Van Elburg, “Cytokine profiles in 1-yr-old very low-birth-weight infants after enteral glutamine supplementation in the neonatal period,” Pediatric Allergy and Immunology, vol. 20, no. 5, pp. 467–470, 2009.
[113]
J. F. de Kieviet, J. Oosterlaan, A. van Zwol, G. Boehm, H. N. Lafeber, and R. M. van Elburg, “Effects of neonatal enteral glutamine supplementation on cognitive, motor and behavioural outcomes in very preterm and/or very low birth weight children at school age,” British Journal of Nutrition, vol. 7, pp. 1–6, 2012.
[114]
C. Chuntrasakul, S. Siltham, S. Sarasombath et al., “Comparison of a immunonutrition formula enriched arginine, glutamine and omega-3 fatty acid, with a currently high-enriched enteral nutrition for trauma patients,” Journal of the Medical Association of Thailand, vol. 86, no. 6, pp. 552–561, 2003.
[115]
D. L. Yang and J. F. Xu, “Effect of dipeptide of glutamine and alanine on severe traumatic brain injury,” Chinese Journal of Traumatology, vol. 10, no. 3, pp. 145–149, 2007.
[116]
A. Eroglu, “The effect of intravenous alanyl-glutamine supplementation on plasma glutathione levels in intensive care unit trauma patients receiving enteral nutrition: the results of a randomized controlled trial,” Anesthesia and Analgesia, vol. 109, no. 2, pp. 502–505, 2009.
[117]
M. Luo, N. Bazargan, D. P. Griffith et al., “Metabolic effects of enteral versus parenteral alanyl-glutamine dipeptide administration in critically ill patients receiving enteral feeding: a pilot study,” Clinical Nutrition, vol. 27, no. 2, pp. 297–306, 2008.
[118]
L. Soguel, R. L. Chioléro, C. Ruffieux, and M. M. Berger, “Monitoring the clinical introduction of a glutamine and antioxidant solution in critically ill trauma and burn patients,” Nutrition, vol. 24, no. 11-12, pp. 1123–1132, 2008.
[119]
E. Mok and R. Hankard, “Glutamine supplementation in sick children: is it beneficial?” Journal of Nutrition and Metabolism, vol. 2011, Article ID 617597, 41 pages, 2011.
[120]
H. E. Skillman and N. M. Mehta, “Nutrition therapy in the critically ill child,” Current Opinion in Critical Care, vol. 18, no. 2, pp. 192–198, 2012.