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REducing Deaths due to OXidative Stress (The REDOXS© Study): rationale and study design for a randomized trial of glutamine and antioxidant supplementation in critically-ill patients

Published online by Cambridge University Press:  07 March 2007

Daren K. Heyland ,
Rupinder Dhaliwal ,
Andrew G. Day ,
John Muscedere ,
John Drover ,
Ulrich Suchner  and
Deborah Cook
Daren K. Heyland*
Affiliation:
Clinical Evaluation Research Unit, Kingston General Hospital, Kingston, Ontario K7L 2V7, Canada
Rupinder Dhaliwal
Affiliation:
Clinical Evaluation Research Unit, Kingston General Hospital, Kingston, Ontario K7L 2V7, Canada
Andrew G. Day
Affiliation:
Clinical Evaluation Research Unit, Kingston General Hospital, Kingston, Ontario K7L 2V7, Canada
John Muscedere
Affiliation:
Clinical Evaluation Research Unit, Kingston General Hospital, Kingston, Ontario K7L 2V7, Canada
John Drover
Affiliation:
Clinical Evaluation Research Unit, Kingston General Hospital, Kingston, Ontario K7L 2V7, Canada
Ulrich Suchner
Affiliation:
Ludwig Maximilians University, Munich, Germany
Deborah Cook
Affiliation:
St Joseph's Healthcare, Hamilton, Ontario L8N 4A6, Canada
*
*Corresponding author: Dr D. K. Heyland, fax +1 613 548 1351, email [email protected]
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Abstract

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Critically-ill patients experience an extent of hyperinflammation, cellular immune dysfunction, oxidative stress and mitochondrial dysfunction. Supplementation with key nutrients, such as glutamine and antioxidants, is most likely to have a favourable effect on these physiological derangements, leading to an improvement in clinical outcomes. The results of two meta-analyses suggest that glutamine and antioxidants may be associated with improved survival. The purpose of the present paper is to report the background rationale and study protocol for the evaluation of the effect of high-dose glutamine and antioxidant supplementation on mortality in a large-scale randomized trial in 1200 mechanically-ventilated, critically-ill patients. Patients admitted to an intensive care unit (ICU) with clinical evidence of severe organ dysfunction will be randomized to one of four treatments in a 2×2 factorial design: (1) glutamine; (2) antioxidant therapy; (3) glutamine and antioxidant therapy; (4) placebo. The primary outcome for this study is 28 d mortality. The secondary outcomes are duration of stay in ICU, adjudicated diagnosis of infection, multiple organ dysfunction, duration of mechanical ventilation, length of stay in hospital and health-related quality of life at 3 and 6 months. A novel design feature is the combined use of parenteral and enteral study nutrients dissociated from the nutrition support. The therapeutic strategies tested in the randomized trial may lead to less morbidity and improved survival in critically-ill patients. The trial will be conducted in approximately twenty tertiary-care ICU in Canada and the first results are expected in 2009.

Keywords

Enteral nutritionCritical illnessGlutamineAntioxidants
Type
BAPEN Symposium 4 on ‘Glutamine and antioxidants in critical care’
Information
Proceedings of the Nutrition Society , Volume 65 , Issue 3 , August 2006 , pp. 250 - 263
Copyright
Copyright © The Nutrition Society 2006

References

Abuja, PM (1998) When might an antioxidant become a prooxidant. Acta anaesthesiologica Scandinavica 42 Suppl. 112 229–230Google Scholar
Alonso de Vega, JM, Diaz, J, Serrano, E & Carbonell, LF (2002) Oxidative stress in critically ill patients with systemic inflammatory response syndrome. Critical Care Medicine 30 1782–1786.CrossRefGoogle ScholarPubMed
Angstwurm, MW, Schottdorf, J, Schopohl, J & Gaertner, R (1999) Selenium replacement in patients with severe systemic inflammatory response syndrome improves clinical outcome. Critical Care Medicine 27 1807–1813.CrossRefGoogle ScholarPubMed
Anonymous (1989) CDC definitions for nosocomial infections, 1988. American Review of Respiratory Disease 139 1058–1059.CrossRefGoogle Scholar
Ardawi, MS (1991) Effect of glutamine-enriched total parenteral nutrition on septic rats. Clinical Science 81 215–222.Google Scholar
Ardawi, MS (1992) Effect of glutamine-supplemented total parenteral nutrition on the small bowel of septic rats. Clinical Nutrition 11 207–205.CrossRefGoogle ScholarPubMed
Astiz, ME & Rackow, EC (1998) Septic shock. Lancet 351 1501–1505.CrossRefGoogle ScholarPubMed
Barber, AE, Jones, WG 2nd, Minei, JP, Fahey, TJ 3rd, Moldawer, LL, Rayburn, JL, Fischer, E, Keogh, CV, Shires, GT & Lowry, SF (1990) Vars award. Glutamine or fiber supplementation of a defined formula diet: impact on bacterial translocation, tissue composition, and response to endotoxin. Journal of Parenteral and Enteral Nutrition 14 335–343.CrossRefGoogle ScholarPubMed
Bark, T, Svenberg, T, Theodorsson, E, Uribe, A & Wennberg, AK (1994) Glutamine supplementation does not prevent small bowel mucosal atrophy after total parenteral nutrition in the rat. Clinical Nutrition 13 79–84.CrossRefGoogle Scholar
Bernard, GR, Artigas, A, Brigham, KL, Carlet, J, Falke, K, Hudson, L, Lamy, M, Legall, JR, Morris, A & Spragg, R (1994) The American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. American Journal of Respiratory and Critical Care Medicine 149 818–824.CrossRefGoogle ScholarPubMed
Bernard, GR, Vincent, JL, Laterre, PF, LaRosa, SP, Dhainaut, JF, Lopez-Rodriguez, A, Steingrub, JS, Garber, GE, Helterbrand, JD, Ely, EW & Fisher, CJ Jr (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. New England Journal of Medicine 344 699–709.CrossRefGoogle ScholarPubMed
Blomqvist, BI, Hammarqvist, F, von der Decken, A & Wernerman, J (1995) Glutamine and alpha-ketoglutarate prevent the decrease in muscle free glutamine concentration and influence protein synthesis after total hip replacement. Metabolism 44 1215–1222.Google Scholar
Bone, RC (1996) Sir Issac Newton, Sepsis, SIRS and CARS. Critical Care Medicine 24 1125–1128.CrossRefGoogle Scholar
Brealey, D, Brand, M, Hargreaves, I, Heales, S, Land, J, Smolenski, R, Davies, NA, Cooper, CE & Singer, M (2002) Association between mitochondrial dysfunction and severity of outcome of septic shock. Lancet 360 219–223.CrossRefGoogle ScholarPubMed
Burk, RE & Hill, KE (1999) Orphan selenoproteins. BioEssays 21 231–237.3.0.CO;2-D>CrossRefGoogle ScholarPubMed
Child, CG & Turcotte, JG (1964) Surgery and portal hypertension. In The Liver and Portal Hypertension, pp. 50–64 [Child, CG, editor]. Philadelphia, PA: Saunders.Google ScholarPubMed
Coffier, M, Le Pessot, F, Leplingard, A, Marion, R, Lerebours, E, Ducrotte, P & Dechelotte, P (2002) Acute enteral glutamine infusion enhances heme oxygenase-1 expression in human duodenal mucosa. Journal of Nutrition 132 2570–2573.CrossRefGoogle Scholar
Critical Care Nutrition (2006) Ongoing nutrition support studies. www.criticalcarenutrition.com/tableofcontents/htm (last accessed May 2006).Google Scholar
Deitch, E (2001) Role of the gut lymphatic system in multiple organ failure. Current Opinion in Critical Care 7 92–98.CrossRefGoogle ScholarPubMed
Dhar, A, Kujath, S & Van Way, CW (2003) Glutamine administration during parenteral nutrition protects liver adenosine nucleotides during and after subsequent hemorrhagic shock. Journal of Parenteral and Enteral Nutrition 27 246–251.CrossRefGoogle ScholarPubMed
Ely, EW, Bennett, PA, Bowton, DL, Murphy, SM, Florance, AM & Haponik, E (1999) Large scale implementation of a respiratory therapist-driven protocol for ventilator weaning. American Journal of Respiratory and Critical Care Medicine 159 439–446.CrossRefGoogle ScholarPubMed
Essink-Bot, ML, Krabbe, PFM, Bonsel, GJ & Aaronson, NK (1997) An empirical comparison of four generic health status measures. Medical Care 35 522–537.CrossRefGoogle ScholarPubMed
Flaring, UB, Rooyackers, OE, Wernerman, J & Hammarqvist, F (2003) Glutamine attenuates post-traumatic glutathione depletion in human muscle. Clinical Science (London) 104 275–282.Google Scholar
Forceville, X, Vitoux, D, Gauzit, R, Combes, A, Lahilaire, P & Chappuis, P (1998) Selenium, systemic immune response syndrome, sepsis and outcome in critically ill patients. Critical Care Medicine 26 1536–1544.CrossRefGoogle ScholarPubMed
Gadek, JE, DeMichele, SJ, Karlstad, MD, Pacht, ER, Donahoe, M, Albertson, TE, Van Hoozen, C, Wennberg, AK, Nelson, JL & Noursalehi, M (1999) Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Critical Care Medicine 27 1409–1420.Google Scholar
Garrel, D, Patenaude, J, Nedelec, B, Samson, L, Dorais, J, Champoux, J, D'Elia, M & Bernier, J (2003) Decreased mortality and infectious morbidity in adult burn patients given enteral glutamine supplements: a prospective, controlled, randomized clinical trial. Critical Care Medicine 31 2444–2449.Google Scholar
Gianotti, L, Alexander, JW, Gennari, R, Pyles, T & Babcock, GF (1995) Oral glutamine decreases bacterial translocation and improves survival in experimental gut-origin sepsis. Journal of Parenteral and Enteral Nutrition 19 69–74.Google Scholar
Goode, HF, Cowley, HC, Walker, BE, Howdle, PD & Webster, NR (1995) Decreased antioxidant status and increased lipid peroxidation in patients with septic shock and secondary organ dysfunction. Critical Care Medicine 23 646–651.CrossRefGoogle ScholarPubMed
Griffiths, RD, Jones, C & Palmer, TE (1997) Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition 13 295–302.Google ScholarPubMed
Grimble, RF (1994) Nutritional antioxidants and the modulation of inflammation: Theory and practice. New Horizons 2 175–185.Google Scholar
Hall, JC, Dobb, G, Hall, J, De Sousa, R, Brennan, L & McCauley, R (2003) A prospective randomized trial of enteral glutamine in critical illness. Intensive Care Medicine 29 1710–1706.CrossRefGoogle ScholarPubMed
Heyland, DK (2002) Immunonutrition in the critically ill patient: putting the cart before the horse. Nutrition in Clinical Practice 17 267–272.CrossRefGoogle Scholar
Heyland, DK, Dhaliwal, R, Drover, JW, Gramlich, L & Dodek, P, for the Guidelines Committee (2003a) Clinical practice guidelines for nutrition support in the adult critically ill patient. Journal of Parenteral and Enteral Nutrition 27 355–373.Google Scholar
Heyland, DK, Dhaliwal, R, Suchner, U & Berger, M (2005) Antioxidant nutrients: A systematic review of vitamins and trace elements in the critically ill patient. Intensive Care Medicine 31 327–337.CrossRefGoogle ScholarPubMed
Heyland, DK, Groll, D & Caeser, M (2003b) Long-term follow of survivors of ARDS: A significant correlation between lung function, respiratory symptoms, and health related quality of life. Critical Care Medicine 31 A8.Google Scholar
Heyland, DK, Hopman, W, Coo, H, Tranmer, J & McColl, MA (2001) Long-term health related in survivors of sepis. Short Form 36: a valid and reliable measure of health-related quality of life. Critical Care Medicine 28 3599–3605.CrossRefGoogle Scholar
Heyland, DK & Samis, A (2002) Does immunonutrition in septic patients do more harm than good. Intensive Care Medicine 29 669–671.CrossRefGoogle Scholar
Inoue, Y, Grant, JP & Snyder, PJ (1993) Effect of glutamine-supplemented parenteral nutrition on survival after Escherichia coli-induced peritonitis. Journal of Parenteral and Enteral Nutrition 17 41–46.CrossRefGoogle ScholarPubMed
Kelly, F (1994) Vitamin E supplementation in the critically ill patient. Too narrow of view. NCP Bulletin (Nutrition Center of the Philippines) 9 19–25.Google Scholar
Khan, J, Iiboshi, Y, Cui, L, Wasa, M, Sando, K, Takagi, Y & Okada, A (1999) Alanyl-glutamine-supplemented parenteral nutrition increases luminal mucus gel and decreases permeability in the rat small intestine. Journal of Parenteral and Enteral Nutrition 23 24–31.CrossRefGoogle ScholarPubMed
Knaus, WA, Draper, EA, Wagner, DP & Zimmerman, JE (1985) APACHE II:, a severity of disease classification system. Critical Care Medicine 13 818–829.Google Scholar
Kolaczkowska, E, Shahzidi, S, Seljelid, R, Van Rooijen, N & Plytycz, B (2002) Early vascular permeability in murine experimental peritonitis is co-mediated by resident peritoneal macrophages and mast cells: crucial involvement of macrophage-derived cysteinyl-leukotrienes. Inflammation 26 61–71.Google Scholar
Kudsk, KA, Wu, Y, Fukatsu, K, Zarzaur, BL, Johnson, CD, Wang, R & Hanna, MK (2000) Glutamine-enriched TPN maintains intestinal interleukin-4 and mucosal immunoglobulin A levels. Journal of Parenteral and Enteral Nutrition 24 270–275.CrossRefGoogle ScholarPubMed
Lan, KKG & DeMets, DL (1983) Discrete sequential boundaries for clinical trials. Biometrika 70 659–663.CrossRefGoogle Scholar
Lovat, R & Preiser, JC (2003) Antioxidant therapy in intensive care. Current Opinion in Critical Care 9 266–270.CrossRefGoogle ScholarPubMed
McAlister, FA, Straus, SE, Sackett, DL & Altman, DG (2003) Analyzing and reporting of factorial trials. Journal of the American Medical Association 289 2545–2553.CrossRefGoogle Scholar
Manhart, N, Vierlinger, K, Spittler, A, Bergmeister, H, Sautner, T & Roth, E (2001) Oral feeding with glutamine prevents lymphocyte and glutathione depletion of Peyer's patches in endotoxemic mice. Annals of Surgery 234 92–97.CrossRefGoogle ScholarPubMed
Marion, R, Coeffier, M, Leplingard, A, Favennec, L, Ducrotte, P & Dechelotte, P (2003) Cytokine-stimulated nitric oxide production and inducible NO-synthase mRNA level in human intestinal cells: lack of modulation by glutamine. Clinical Nutrition 22 523–528.Google Scholar
Metnitz, PGH, Bartens, C, Fischer, M, Fridrich, P, Steltzer, H & Druml, W (1999) Antioxidant status in patients with acute respiratory distress syndrome. Intensive Care Medicine 25 180–185.CrossRefGoogle ScholarPubMed
Moreno, R, Vincent, JL, Matos, R, Mendonca, A, Cantraine, F, Thijs, L, Takala, J, Sprung, C, Antonelli, M, Bruining, H & Willatts, S (1999) The use of maximum SOFA score to quantify organ dysfunction/failure in intensive care. Results of a prospective multicenter study. Intensive Care Medicine 25 686–696.CrossRefGoogle Scholar
Motoyama, T, Okamoto, K, Kukita, I, Hamaguchi, M, Kinoshita, Y & Ogawa, H (2003) Possible role of increased oxidant stress in multiple organ failure after systemic inflammatory response syndrome. Critical Care Medicine 31 1048–1052.CrossRefGoogle ScholarPubMed
Naka, S, Saito, H, Hashiguchi, Y, Lin, MT, Furukawa, S, Inaba, T, Fukushima, R, Wada, N & Muto, T (1996) Alanyl-glutamine-supplemented total parenteral nutrition improves survival and protein metabolism in rat protracted bacterial peritonitis model. Journal of Parenteral and Enteral Nutrition 20 417–423.Google Scholar
Novak, F, Heyland, DK, Avenell, A, Drover, J & Su, X (2002) Glutamine supplementation in serious illness: A systematic review of the evidence. Critical Care Medicine 30 2022–2029.Google Scholar
Oehler, R, Pusch, E, Dungel, P, Zellner, M, Eliasen, MM, Brabec, M & Roth, E (2002) Glutamine depletion impairs cellular stress response in human leucocytes. British Journal of Nutrition 87 S17–S21.Google Scholar
Oppong, KNW, Al-Mardini, H, Thick, M & Record, CO (1997) Oral glutamine challenge in cirrhotics pre- and post-liver transplantation: a psychometric and analyzed EEG study. Hepatology 26 870–876.CrossRefGoogle ScholarPubMed
Oudemans-Van Straaten, HM, Bosman, RJ, Treskes, M, van der Spoel, JHI & Zandstra, DF (2001) Plasma glutamine depletion and patient outcome in acute ICU admissions. Intensive Care Medicine 27 84–90.CrossRefGoogle ScholarPubMed
Parry-Billings, M, Baigrie, RJ, Lamont, PM, Morris, PJ & Newsholme, EA (1992) Effects of major and minor surgery on plasma glutamine and cytokine levels. Archives of Surgery 127 1237–1240.CrossRefGoogle ScholarPubMed
Parry-Billings, M, Evans, J, Calder, PC & Newsholme, EA (1990) Does glutamine contribute to immunosuppression after major burns. Lancet 336 523–525.CrossRefGoogle ScholarPubMed
Planas, M, Schwartz, S, Arbos, MA & Farriol, M (1993) Plasma glutamine levels in septic patients. Journal of Parenteral and Enteral Nutrition 17 299–300.CrossRefGoogle ScholarPubMed
Platell, C, McCauley, R, McCulloch, R & Hall, J (1993) The influence of parenteral glutamine and branched-chain amino acids on total parenteral nutrition-induced atrophy of the gut. Journal of Parenteral and Enteral Nutrition 17 348–354.CrossRefGoogle ScholarPubMed
Potsic, B, Holliday, N, Lewis, P, Samuelson, D, De Marco, V & Neu, J (2002) Glutamine supplementation and deprivation: Effect on artificially reared rat small intestinal morphology. Pediatric Research 52 430–436.CrossRefGoogle ScholarPubMed
Quasim, T, Mcmillan, DC, Talwar, D, Sattar, N, O'Reilly, D & Kinsella, J (2003) Lower concentrations of carotenoids in the critically ill patient are related to a systemic inflammatory response and increased lipid peroxidation. Clinical Nutrition 22 459–462.CrossRefGoogle ScholarPubMed
Rayman, MP (2000) The importance of selenium to human health. Lancet 356 233–241.Google Scholar
Revelly, JP, Tappy, L, Berger, M, Gersbach, P, Cayeux, C & Chiolero, R (2001) Early metabolic and splanchnic responses to enteral nutrition in postoperative cardiac surgery patients with circulatory compromise. Intensive Care Medicine 27 540–547.CrossRefGoogle ScholarPubMed
Roth, E, Funovics, J, Muhlbacher, F, Schemper, M, Mauritz, W & Sporn, P (1982) Metabolic disorders in severe abdominal sepsis: glutamine deficiency in skeletal muscle. Clinical Nutrition 1 25–41.CrossRefGoogle ScholarPubMed
Sacks, GS (1999) Glutamine supplementation in catabolic patients. Annals of Pharmacotherapy 33 348–354.CrossRefGoogle ScholarPubMed
Schroeer, J, Alteheld, B, Stehle, P, Cayeux, MC, Chiolero, RL & Berger, MM (2005) Safety and intestinal tolerance of high-dose enteral antioxidants and glutamine peptides after upper gastrointestinal surgery. European Journal of Clinical Nutrition 59 307–310.CrossRefGoogle Scholar
Senkal, M, Haaker, R, Deska, T, Hummel, T, Steinfort, C, Zumtobel, V, Alteheld, B & Stehle, P (2004) Early enteral gut feeding with conditionally indispensable pharmaconutrients is metabolically safe and is well tolerated in postoperative cancer patients–a pilot study. Clinical Nutrition 23 1193–1198.CrossRefGoogle ScholarPubMed
Singleton, KD, Serkova, N, Beckey, VE & Wischmeyer, PE (2005) Glutamine attenuates lung injury and improves survival after sepsis: role of enhanced heat shock protein expression. Critical Care Medicine 33 1206–1213.Google Scholar
Spallholz, JE (1997) Free radical generation by selenium compounds and their prooxidant toxicity. Biomedical and Environmental Sciences 10 260–270.Google ScholarPubMed
Suzuki, I, Matsumoto, Y, Adjei, AA, Asato, L, Shinjo, S & Yamamoto, S (1993) Effect of a glutamine-supplemented diet in response to methicillin-resistant Staphylococcus aureus infection in mice. Journal of Nutritional Science and Vitaminology 39 405–410.Google Scholar
Taylor, SJ, Fettes, SB, Jewkes, C & Nelson, RJ (1999) Prospective, randomized controlled trial to determine the effect of early enhanced enteral nutrition on clinical outcome in mechanically ventilated patients suffering head injury. Critical Care Medicine 27 2525–2531.Google Scholar
Therond, P, Bonnefont-Rousselot, D, Davit-Spraul, A, Conti, M & Legrand, A (2000) Biomarkers of oxidative stress: an analytical approach. Current Opinion in Clinical Nutrition and Metabolic Care 3 373–384.CrossRefGoogle ScholarPubMed
Thies, F, Nebe-von-Caron, G, Powell, JR, Yaqoob, P, Newsholme, EA & Calder, PC (2001) Dietary supplementation with eicosapentaenoic acid, but not with other long-chain n-3 or n-6 polyunsaturated fatty acids, decreases natural killer cell activity in healthy subjects aged >55 y. American Journal of Clinical Nutrition 73 539–548.Google Scholar
Van Der Hulst, RRWJ, Deutz, NEP, Von Meyenfeldt, MF, Elbers, JMH, Stockbrugger, RW & Soeters, PB (1994) Decrease of mucosal glutamine concentration in the nutritionally deplete patient. Clinical Nutrition 13 228–233.CrossRefGoogle ScholarPubMed
Vendemiale, G, Grattagliano, I & Altomare, E (1999) An update on the role of free radicals and antioxidant defense in human disease. International Journal of Clinical and Laboratory Research 29 49–55.CrossRefGoogle ScholarPubMed
Ware, JE (1996) The SF-36 health survey. In Quality of Life and Pharmacoeconomics in Clinical Trials, pp. 337–346 [Spilker, B, editor]. Philadelphia, PA: Lippincott-Raven Publishers.Google Scholar
Wischmeyer, PE, Jayakar, D, Williams, U, Singleton, KD, Riehm, J, Bacha, EA, Jeevanandam, V, Christians, U & Serkova, N (2003) Single dose of glutamine enhances myocardial tissue metabolism, glutathione content, and improves myocardial function following ischemia-reperfusion injury. Journal of Parenteral and Enteral Nutrition 27 396–403.CrossRefGoogle Scholar
Wischmeyer, PE, Kahana, M, Wolfson, R, Ren, H, Musch, MM & Chang, EB (2001a) Glutamine induces heat shock protein and protects against endotoxin shock in the rat. Journal of Applied Physiology 90 2403–2410.CrossRefGoogle ScholarPubMed
Wischmeyer, PE, Kahana, M, Wolfson, R, Ren, H, Musch, MM & Chang, EB (2001b) Glutamine reduces cytokine release, organ damage, and mortality in a rat model of endotoxemia. Shock 16 398–402.Google Scholar
Zapata-Sirvent, RL, Hansbrough, JF, Ohara, MM, Rice-Asaro, M & Nyhan, WL (1994) Bacterial translocation in burned mice after administration of various diets including fiber- and glutamine-enriched enteral formulas. Critical Care Medicine 22 690–696.Google Scholar
Zhou, QP, Jiang, ZM, Sun, YH, Wang, XR, Ma, EL & Wilmore, D (2003) The effect of supplemental enteral glutamine on plasma levels, gut function, and outcome in severe burns: A randomized, double-blind, controlled clinical trial. Journal of Parenteral and Enteral Nutrition 27 241–245.Google Scholar