Early enteral nutrition with L-glutamine improves anastomotic healing in rats administered hyperthermic intraperitoneal chemotherapy with cisplatin and 5-FU

Abstract

Background/Aim: One of the most significant aspects of intestinal surgery is anastomotic wound healing. After intestinal surgery, the most serious complication is gastrointestinal leakage, which is associated with a high rate of morbidity and mortality. The rate of morbidity and mortality can be reduced by increasing the mechanical resistance of the anastomosis. Glutamine improves impaired wound healing through effects on the healing process. This study investigated the effects of early enteral glutamine supplementation on colonic anastomosis healing in rats treated with hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin and fluorouracil (5-FU). Methods: Twenty-four rats were divided into three groups. Group 1 underwent colonic anastomosis and intraabdominal hyperthermic saline administration, Group 2 underwent colonic anastomosis and HIPEC, and Group 3 underwent colonic anastomosis and HIPEC and postoperative administration of glutamine solution via an orogastric tube for 7 days. On day 7, all rats were sacrificed and anastomotic bursting pressure (ABP) was evaluated. Tissue specimens were taken to examine tissue hydroxyproline levels and histopathological changes in the anastomotic line. Results: The ABP was significantly greater in Group 2 than in Groups 1 and 3 (P=0.001 and P=0.046, respectively). The tissue hydroxyproline level was higher in Group 1 and Group 3 than in Group 2 (P=0.001 and P=0.043, respectively). The histopathological findings in Group 3 were better than those in Group 2. The histopathological findings were observed to improve in the early enteral nutrition with Glutamine group. Conclusions: The findings of this study indicate that early enteral glutamine supplementation facilitates colonic anastomosis healing following HIPEC with cisplatin and 5-FU, by increasing the ABP and tissue concentrations of hydroxyproline and decreasing the inflammatory response.

Keywords

• Glutamine
• Colonic anastomosis
• Bursting pressure
• Wound Healing,
• Hyperthermic Intraperitoneal Chemotherapy

Kaynakça

1. 1. Carmignani CP, Sugarbaker TA, Bromley CM, Sugarbaker PH. Intraperitoneal cancer dissemination: mechanisms of the patterns of spread. Cancer Metastasis Rev. 2003;22(4):465-72. doi: 10.1023/a:1023791229361. PubMed PMID: 12884919.
2. 2. Chua TC, Yan TD, Saxena A, Morris DL. Should the treatment of peritoneal carcinomatosis by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy still be regarded as a highly morbid procedure?: a systematic review of morbidity and mortality. Ann Surg. 2009;249(6):900-7. doi: 10.1097/SLA.0b013e3181a45d86. PubMed PMID: 19474692.
3. 3. Sugarbaker PH, Jablonski KA. Prognostic features of 51 colorectal and 130 appendiceal cancer patients with peritoneal carcinomatosis treated by cytoreductive surgery and intraperitoneal chemotherapy. Ann Surg. 1995;221(2):124-32. doi: 10.1097/00000658-199502000-00002. PubMed PMID: 7857141; PubMed Central PMCID: PMCPMC1234945.
4. 4. Elias D, Gilly F, Boutitie F, Quenet F, Bereder JM, Mansvelt B, et al. Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study. J Clin Oncol. 2010;28(1):63-8. doi: 10.1200/JCO.2009.23.9285. PubMed PMID: 19917863.
5. 5. Glehen O, Gilly FN, Boutitie F, Bereder JM, Quenet F, Sideris L, et al. Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy: a multi-institutional study of 1,290 patients. Cancer. 2010;116(24):5608-18. doi: 10.1002/cncr.25356. PubMed PMID: 20737573.
6. 6. Younan R, Kusamura S, Baratti D, Oliva GD, Costanzo P, Favaro M, et al. Bowel complications in 203 cases of peritoneal surface malignancies treated with peritonectomy and closed-technique intraperitoneal hyperthermic perfusion. Ann Surg Oncol. 2005;12(11):910-8. doi: 10.1245/ASO.2005.11.030. PubMed PMID: 16177862.
7. 7. Aghayeva A, Benlice C, Bilgin IA, Atukeren P, Dogusoy G, Demir F, et al. The effects of hyperthermic intraperitoneal chemoperfusion on colonic anastomosis: an experimental study in a rat model. Tumori. 2017;103(3):307-13. doi: 10.5301/tj.5000610. PubMed PMID: 28291907.
8. 8. Lopez-Lopez V, Lynn PB, Gil J, Garcia-Salom M, Gil E, Gonzalez A, et al. Effect of Paclitaxel-based Hyperthermic Intraperitoneal Chemotherapy (HIPEC) on colonic anastomosis in a rat model. Clin Transl Oncol. 2019;21(4):505-11. doi: 10.1007/s12094-018-1948-7. PubMed PMID: 30229392.

9. 9. Kovacevic Z, McGivan JD. Mitochondrial metabolism of glutamine and glutamate and its physiological significance. Physiol Rev. 1983;63(2):547-605. doi: 10.1152/physrev.1983.63.2.547. PubMed PMID: 6132422.
10. 10. Goswami S, Kandhare A, Zanwar AA, Hegde MV, Bodhankar SL, Shinde S, et al. Oral L-glutamine administration attenuated cutaneous wound healing in Wistar rats. Int Wound J. 2016;13(1):116-24. doi: 10.1111/iwj.12246. PubMed PMID: 24690128.
11. 11. Sapidis N, Tziouvaras C, Ioannidis O, Kalaitsidou I, Botsios D. The effect of glutamine and synbiotics on the healing of colonic anastomosis. Rev Esp Enferm Dig. 2014;106(4):255-62. PubMed PMID: 25075656.
12. 12. Cohen J. A power primer. Psychol Bull. 1992;112(1):155-9. doi: 10.1037//0033-2909.112.1.155. PubMed PMID: 19565683.
13. 13. Erdem E, Dinc S, Erdem D, Ustun H, Caydere M, Alagol H. Effects of intraperitoneal chemotherapy and GM-CSF on anastomotic healing: an experimental study in rats. J Surg Res. 2002;108(1):1-6. doi: 10.1006/jsre.2002.6425. PubMed PMID: 12443708.
14. 14. Phillips JD, Kim CS, Fonkalsrud EW, Zeng H, Dindar H. Effects of chronic corticosteroids and vitamin A on the healing of intestinal anastomoses. Am J Surg. 1992;163(1):71-7. doi: 10.1016/0002-9610(92)90255-p. PubMed PMID: 1733376.
15. 15. Jahne J. Cytoreduction including total gastrectomy for pseudomyxoma peritonei (Br J Surg 2002; 89: 208-12). Br J Surg. 2002;89(7):938-9; discusssion 9. doi: 10.1046/j.1365-2168.2002.02161_4.x. PubMed PMID: 12081750.
16. 16. Glehen O, Osinsky D, Cotte E, Kwiatkowski F, Freyer G, Isaac S, et al. Intraperitoneal chemohyperthermia using a closed abdominal procedure and cytoreductive surgery for the treatment of peritoneal carcinomatosis: morbidity and mortality analysis of 216 consecutive procedures. Ann Surg Oncol. 2003;10(8):863-9. doi: 10.1245/aso.2003.01.018. PubMed PMID: 14527903.
17. 17. Jafari MD, Halabi WJ, Stamos MJ, Nguyen VQ, Carmichael JC, Mills SD, et al. Surgical outcomes of hyperthermic intraperitoneal chemotherapy: analysis of the american college of surgeons national surgical quality improvement program. JAMA Surg. 2014;149(2):170-5. doi: 10.1001/jamasurg.2013.3640. PubMed PMID: 24352601.
18. 18. Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003;21(20):3737-43. doi: 10.1200/JCO.2003.04.187. PubMed PMID: 14551293.
19. 19. Blaj S, Nedelcut S, Mayr M, Leebmann H, Leucuta D, Glockzin G, et al. Re-operations for early postoperative complications after CRS and HIPEC: indication, timing, procedure, and outcome. Langenbecks Arch Surg. 2019;404(5):541-6. doi: 10.1007/s00423-019-01808-8. PubMed PMID: 31352505.
20. 20. Jaehne J. Cytoreductive procedures-strategies to reduce postoperative morbidity and management of surgical complications with special emphasis on anastomotic leaks. J Surg Oncol. 2009;100(4):302-5. doi: 10.1002/jso.21328. PubMed PMID: 19697435.
21. 21. Yamaguchi R, Terashima H, Yoneyama S, Tadano S, Ohkohchi N. Effects of platelet-rich plasma on intestinal anastomotic healing in rats: PRP concentration is a key factor. J Surg Res. 2012;173(2):258-66. doi: 10.1016/j.jss.2010.10.001. PubMed PMID: 21074782.
22. 22. Makrin V, Lev-Chelouche D, Even Sapir E, Paran H, Rabau M, Gutman M. Intraperitoneal heated chemotherapy affects healing of experimental colonic anastomosis: an animal study. J Surg Oncol. 2005;89(1):18-22. doi: 10.1002/jso.20161. PubMed PMID: 15612012.
23. 23. Pelz JO, Doerfer J, Decker M, Dimmler A, Hohenberger W, Meyer T. Hyperthermic intraperitoneal chemoperfusion (HIPEC) decrease wound strength of colonic anastomosis in a rat model. Int J Colorectal Dis. 2007;22(8):941-7. doi: 10.1007/s00384-006-0246-y. PubMed PMID: 17245567.
24. 24. Aarts F, Bleichrodt RP, de Man B, Lomme R, Boerman OC, Hendriks T. The effects of adjuvant experimental radioimmunotherapy and hyperthermic intraperitoneal chemotherapy on intestinal and abdominal healing after cytoreductive surgery for peritoneal carcinomatosis in the rat. Ann Surg Oncol. 2008;15(11):3299-307. doi: 10.1245/s10434-008-0070-4. PubMed PMID: 18712445.
25. 25. Ziegler TR, Bazargan N, Leader LM, Martindale RG. Glutamine and the gastrointestinal tract. Curr Opin Clin Nutr Metab Care. 2000;3(5):355-62. doi: 10.1097/00075197-200009000-00005. PubMed PMID: 11151079.
26. 26. Mertes N, Schulzki C, Goeters C, Winde G, Benzing S, Kuhn KS, et al. Cost containment through L-alanyl-L-glutamine supplemented total parenteral nutrition after major abdominal surgery: a prospective randomized double-blind controlled study. Clin Nutr. 2000;19(6):395-401. doi: 10.1054/clnu.2000.0142. PubMed PMID: 11104589.
27. 27. Kuhn KS, Schuhmann K, Stehle P, Darmaun D, Furst P. Determination of glutamine in muscle protein facilitates accurate assessment of proteolysis and de novo synthesis-derived endogenous glutamine production. Am J Clin Nutr. 1999;70(4):484-9. doi: 10.1093/ajcn/70.4.484. PubMed PMID: 10500016.
28. 28. Miller AL. Therapeutic considerations of L-glutamine: a review of the literature. Altern Med Rev. 1999;4(4):239-48. PubMed PMID: 10468648.
29. 29. Cruzat VF, Bittencourt A, Scomazzon SP, Leite JS, de Bittencourt PI, Jr., Tirapegui J. Oral free and dipeptide forms of glutamine supplementation attenuate oxidative stress and inflammation induced by endotoxemia. Nutrition. 2014;30(5):602-11. doi: 10.1016/j.nut.2013.10.019. PubMed PMID: 24698353.
30. 30. Da Costa MA, Campos AC, Coelho JC, de Barros AM, Matsumoto HM. Oral glutamine and the healing of colonic anastomoses in rats. JPEN J Parenter Enteral Nutr. 2003;27(3):182-5; discussion 5-6. doi: 10.1177/0148607103027003182. PubMed PMID: 12757111.
31. 31. Gökpinar I, Gürleyik E, Pehlivan M, Özcan Ö, Özaydın İ, Aslaner A, et al. Early enteral and glutamine enriched enteral feeding ameliorates healing of colonic anastomosis. Turkish Journal of Trauma and Emergency Surgery. 2006;12(1):17-21. PubMed PMID: 16456746.