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Cytokine activation (tumor necrosis factor - a) and clinical response induced by cardiopulmonary bypass

Luiz Antônio Brasil; Walter José Gomes; Reinaldo Salomão; Ênio Buffolo

DOI: 10.1590/S0102-76381996000300009

ABSTRACT

Systemic inflammatory response syndrome induced by cardiopulmonary bypass (CPB) is responsible for organ dysfunctions observed in some patients. The tumor necrosis factor-alpha (TNF-a) has been implicated in many clinical manifestations following cardiac operations with CPB, mainly in the vasoplegic syndrome. The purpose of this study was to verify the TNF-a release and its possible effects in patients with coronary atherosclerosis undergoing coronary artery surgery with and without CPB. Twenty patients were studied, 10 with CPB(Group I) and 10 without CPB(Group II). Serial blood samples were obtained during and until 48 hours after surgery in order to measure circulating TNF-a presence (using enzyme-linked immunosorbent assay-ELISA), leukocyte count and erythrocytes sedimentation rate. Hemodynamic parameters as blood pressure and cardiac rate, body temperature, orotracheal tubing time, postoperative bleeding and inotropic drugs requirements were also compared. Statistical significance was assumed when the p value was less than 0.05. Serum levels of TNF-a (limit detection of the assay = 10 pg/mL) were detected in 6 patients from Group I (60%). This cytokine was detected in Group II. The TNF-a peaked soon after the CPB starting and remained detectable 48 hours postoperatively. The patients of Group I had hypotension in relation to Group II (7.4 ± 1.0 vs 8.5 ± 0.67). They also required more inotropic drugs (8 vs 1), had a higher cardiac rate (114.2 ± 8.0 vs 98 ± 10 bpm), hyperthermia (37.17 ± 0.54 vs 36.67 ± 0.35ºC), more postoperative bleeding (820 ± 120 mL vs 360 ± 84 mL), a longer orotracheal tubing time (13.6 ± 2.2 vs 9.3 ± 1.4 horas) and a more pronounced leucocytosis. We concluded that CPB induces the TNF a release and leads hemodynamic and organic alterations that can be deleterious to patients. It may play a role on the pathophysiology of the alterations observed in this study and the inhibition of the TNFa could contribute to minimize these effects.

RESUMO

A síndrome de resposta inflamatória sistêmica induzida pela circulação extracorpórea (CEC) é responsável pela disfunção de órgãos observada em alguns pacientes. O fator de necrose tumoral alfa (TNFa) tem sido implicado em várias manifestações clínicas no pós-operatório de cirurgia cardíacas com utilização de CEC, principalmente na síndrome vasoplégica. O objetivo deste estudo foi verificar a liberação e os possíveis efeitos do TNFa em pacientes com aterosclerose coronária, submetidos a revascularização do miocárdio, com ou sem CEC. Foram estudados 20 pacientes, sendo 10 com uso de CEC (Grupo I) e 10 sem CEC (Grupo II). Amostras sangüíneas seriadas foram colhidas durante a intervenção e até 48 horas após, sendo analisados a presença de TNFa circulante (método imunoenzimático ELISA), contagem de leocócitos e velocidade de hemosedimentação (VHS). Também foram comparados na evolução pós-operatória dos pacientes os parâmetros hemodinâmicos (pressão arterial e freqüência cardíaca), temperatura, tempo de intubação orotraqueal, sangramento pós-operatório e necessidade de drogas vasoativas. Na análise estatística foram considerados significativos valores de p<0,05. No Grupo I, níveis plasmáticos de TNFa (> 10 pg/ml) foram detectados em 6 (60%) pacientes. No Grupo II não ocorreu detecção da citocina. Os picos de TNFa ocorreram logo após o inicio da CEC e foram detectados até 48 horas após. Houve maior predominância no Grupo I em relação ao Grupo II de hipotensão arterial (7,4 ± 1,0 vs 8,5 ± 0,67), maior necessidade de drogas vasoativas (8 vs 1), freqüência cardíaca mais elevada (114,2 ± 8,0 vs 98 ± 10 bpm), maior hipertemia (37,17 ± 0,54 vs 36,67 ± 0,35ºC), maior sangramento pós-operatório (820 ± 120 ml vs 360 ± 84 mL), tempo de intubação orotraqueal mais prolongado (13,6 ± 2,2 vs 9,3 ± 1,4 horas) e maior leucocitose. Concluímos que a CEC induz a liberação de TNFa e predispõe a alterações hemodinâmicas e orgânicas que podem ser deletérias para os pacientes. É possível que o TNF a esteja envolvido na fisiopatogenia das alterações observadas no presente estudo e a inibição de sua ativação poderia, então, contribuir para minimizar estes efeitos.
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REFERENCES

1. Westaby S - Organ dysfunction after cardiopulmonary bypass: a systemic inflammatory reaction by the extracorporeal circuit. Intensive Care Med 1987; 13: 89-5.

2. Butler J, Chong G L, Baigrie R J, Pillai R, Westaby S, Rocher G M - Cytokine response to cardiopulmonary bypass with membrane and bubble oxygenation. Ann Thorac Surg 1992; 53: 833-8. [MedLine]

3. Chenoweth D E, Cooper S W, Hugli T E, Stewart R W, Blackstone E H, Kirklin J W - Complement activation during cardiopulmonary bypass: evidence for generation of C3a and C5a anaphylatoxis. N Engl J Med 1981; 304: 497-503. [MedLine]

4. Kirklin J K, Westaby S, Blackstone E H, Kirklin J W, Chenoweth D E, Pacifico A D - Complement and the damaging effcts of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983; 86: 845-57. [MedLine]

5. Casey L C - Role of cytokines in the pathogenesis of cardiopulmonary-induced multisystem organ failure. Ann Thorac Surg 1993; 56: 92-6. [MedLine]

6. Steinberg B, Grossi E A, Scwartz D S et al. - Heparin bonding of bypass circuits reduces cytokine release during cardiopumonary bypass. Ann Thorac Surg 1995; 60: 525-9. [MedLine]

7. Jansen N J, Van Oeveren W, Gu Y J, Van Vliet M H, Eijsman L, Wildevuur C R - Endotoxin release and tumor necrosis factor formation during cardiopulmonary bypass. Ann Thorac Surg 1992; 54: 744-8.

8. Andersen L W, Baek L, Degn H, Lehd J, Krasnik M, Rasmussen S P - Presence of circulating endotoxins during cardiac operations. J Thorac Cardiovasc Surg 1987; 93: 115-9. [MedLine]

9. Rocke D A, Gaffin S L, Wells M T, Koen Y, Brock-Utine J G - Endotoxemia associated with cardiopulmonary bypass. J Thorac Cardiovasc Surg 1987; 93: 832-7. [MedLine]

10. Butler J, Rocher G M, Westaby S - Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 1993; 55: 552-9. [MedLine]

11. Andersen L W, Landow L, Jansen E, Barker S - Association between gastric intramucosal pH and splanchnic endotoxin, antibody to endotoxin, and tumor necrosis factor-alpha concentrations in patients undergoing cardiopulmonary bypass. Crit Care Med 1993; 21:210-7. [MedLine]

12. Gomes W J, Carvalho A C, Palma J H, Gonçalves Jr. I, Buffolo E - Vasoplegia syndorme: a new dilemma. J Thorac Cardiovasc Surg 1994; 107: 942-3. [MedLine]

13. Haeffner-Cavaillon N, Rousselier N, Ponzio O - Induction of interleukin-1 production in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1989; 98: 1100-6. [MedLine]

14. Jansen N J, Van Oeveren W, Van Der Broek L et al. - Inhibition by dexamethasone of the reperfusion phenomena in cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991; 102:515-25. [MedLine]

15. Moat N E,Shore D F, Evans T W - Organ dysfcunction and cardiopulmonary bypass: the role of complement and complement regulatory proteins. Eur J Cardiothorac Surg 1993; 7: 563-73. [MedLine]

16. Beutler B & Cerami A - Cachetin: more than a tumor necrosis factor. N Engl J Med 1987; 316: 379-85. [MedLine]

17. Beutler B & Cerami A - The common mediator of shock cachexia and tumor necrosis. Adv Immunol 1988; 42: 213-31. [MedLine]

18. Tracey K J, Fong Y, Hesse D G et al. - Anti-cachetin / TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987; 330: 682-4.

19. Michie H R, Manogue K R, Spriggs D R et al. - Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 1988; 318: 1481-6. [MedLine]

20. Nathan C & Sporn M - Cytokines in context. J Cell Biol 1991; 113: 981-6. [MedLine]

21. Beutler B & Cerami A - Tumor necrosis, cachexia, shock and inflammation: a common mediator. Ann Rev Biochem 1988; 57: 505-18.

22. Beutler B - TNF in pathophysiology: biosynthetic regulation. J Invest Dermat 1990; 95 (Suppl.): 81-4.

23. Beutler B - The tumor necrosis factors: cachetin and lymphotoxin. Hosp Pract 1990; 15: 45-58.

24. Kutteh W H, Rainey W E, Beutler B, Carr B R - Tumor necrosis factor-alpha and interleukin-1 beta production by human fetal kupffer cell. Am J Obstet Gynecol 1991; 165: 112-20. [MedLine]

25. Djeu J Y, Blanchard D K, Richards A L, Friedman H - Tumor necrosis factor induction by Candida albicans from human natural killer cells and monocytes. J Immunol 1988; 141: 4047-52. [MedLine]

26. Tracey K J, Vlassara H, Cerami A - Cachetin/tumor necrosis factor. Lancet 1989; 1: 1122-6. [MedLine]

27. Waage A, Halstensen A, Espevik T - Association between tumor necrosis factor and fatal outcome in patients with meningococcal disease. Lancet 1987; 14: 355-7.

28. Rothe J, Lesslauer W, Lotsher H et al. - Mice lacking the tumor necrosis factor receptor 1 are resistent to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature 1993; 364: 798-802. [MedLine]

29. Aggarwal B B, Kohr B J, Hass P E et al. - Human tumor necrosis factor production, purification and characterization. J Biol Chem 1985; 260: 2345-54. [MedLine]

30. Beutler B, Milsark I W, Cerami A - Cachetin/Tumor necrosis factor: production, distribution and metabolic fate in vivo. J Immunol 1985; 135: 3972-7. [MedLine]

31. Staubep G B, Aiyer R A, Aggarwall B B - Human tumor necrosis factor-alpha receptor: purification by immunoaffinity chromatografhy and initial characterization. J Biol Chem 1988; 263: 19098-104. [MedLine]

32. Flick D A & Gifford G E - Comparison of in vitro cell cytotoxic assays for tumor necrosis factor. J Immunol Methods 1984; 68: 167-75. [MedLine]

33. Santos B F C - Produção do fator de necrose de tumor por leucócitos mononucleares humanos [Tese. Mestrado] São Paulo: Escola Paulista de Medicina da Universidade Federal de São Paulo, 1992. 65p.

34. Karhawi A S K - Avaliação dos níveis plasmáticos de fator de necrose tumoral-alpha (TNF-alpha), interleucina-6 (IL-6) e contagem de linfócitos-T CD4+ e CD8+ em pacientes com paracoccidioidomícose [Tese. Mestrado] São Paulo: Escola Paulista de Medicina da Universidade Federal de São Paulo, 1994. 123p.

35. Rus H G, Niculescu F, Vlaicu R - Tumor necrosis factor-alpha in human arterial wall with atherosclerosis. Atherosclerosis 1993; 89: 247-54.

36. Vaddi K, Nicolini F A, Metha P, Metha J L - Increased secretion of tumor necrosis factor-alpha and interferon gama by mononuclear leukocytes in patients with ischemic heart disease. Circulation 1994; 90: 694-9. [MedLine]

37. Casey W F, Hauser G J, Hanrallah R S, Midgley F M, Khan W N - Circulating endotoxin and tumor necrosis factor during pediatric cardiac surgery. Crit Care Med 1992; 20: 1090-6. [MedLine]

38. Holzheimer R G, Molloy R G, Gorlach H, Wilkert S, Herlein F - IL6 and TNF-alpha release in association with neutrophil activation after cardiopulmonary bypass surger. Infection 1994; 22: 37-42. [MedLine]

39. Kharazmi A, Andersen L W, Baek L, Valerius N H, Laub M, Rasmussen J P - Endotoxemia and enhanced generation of oxygen radicals by neuthophils from patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1989; 98: 381-5. [MedLine]

40. Nilsson L, Kulander L, Nystrom S O, Eriksson O - Endotoxins in cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990; 100: 777-80. [MedLine]

41. Andersen L W, Baek L, Thomsen B S - Effect of methylprednisolone on endotoxaemia and complement activation during cardiac surgery. J Cardiothorac Anesth 1989; 3: 544-9. [MedLine]

42. Martinez-Pellus A E, Merino P, Bru M, et al. - Can selective digestive decontamination avoid the endotoxemia and cytokine activation promoted by cardiopulmonary bypass? Crit Care Med 1993; 21: 1684-91. [MedLine]

43. Beutler B, Mahoney J, Trang N L, Pekala P, Cerami A - Purification of cachectin a lipoprotein lipase-supressing hormone secreted by endotoxin-induced RAW 264.7 cells. J Exp Med 1985; 161: 984-95. [MedLine]

44. Fong Y, Moldawer L L, Shires G T, Lowry S F - The biologic characteristics of cytokines and their implications in surgical injury. Surg Gynecol Obstet 1990; 170: 363-78. [MedLine]

45. Carswell E A, Old L J, Kassel R L, Green S, Fiore N, Williamson B - An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 1975; 72: 3666-70.

46. Beutler B, Milsark I W, Cerami A - Passive immunization against cachetin / tumor necrosis factor protects mice from lethal effect of endotoxin. Science 1985; 229: 869-71. [MedLine]

47. Okusawa S, Yancey K B, Van Der Meer J W M - C5a stimulates secretion of tumor necrosis factor form human mononuclear in vitro: comparison with secretion of interleukin-1 beta and interleukin-1 alfa. J Exp Med 1988; 168: 443-8. [MedLine]

48. Casey L C, Balk R A, Bone R C - Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med 1993; 119: 771-8. [MedLine]

49. Hennein H A, Ebba H, Rodriguez J L et al. - Relationship of the proinflammatory cytokines to myocardial ischemia and dysfunction after uncomplicated coronary revascularization. J Thorac cardiovasc Surg 1994; 108: 626-35. [MedLine]

50. Lahat N, Zlotnick A Y, Shtiller R, Bar I, Merin G - Serum levels of IL-1, IL-6 and tumor necrosis factors in patients undergoing coronary artery bypass grafts or cholecystectomy. Clin Exp Immunol 1992; 89: 255-60. [MedLine]

51. Millar A B, Foley N M, Singer M, Johnson N M, Meager A, Rook G A W - Tumor necrosis factor in bronchopulmonary secretions of patients with adult respiratory distress syndrome. Lancet 1989; 2: 712-4. [MedLine]

52. Markewitz A, Faist E, Lang S, Endres S, Hultner L, Reichart B - Regulation of acute phase response after cardiopulmonary bypass by immunomodulation. Ann Thorac Surg 1993; 55: 389-94. [MedLine]

53. Hill G E, Alonso E, Thiele G M, Robbins R A - Glucocorticoids blunt neutrophil CD11b surface glycoprotein impregnation during cardiopulmonary bypass in humans. Anesth Analg 1994; 79: 23-7. [MedLine]

54. Inaba H, Kochi A, Yorozu S - Suppression by methylprednisolone of augmented plasma endotoxin-like activity and interleukin-6 during cardiopulmonary bypass. Br J Anaesth 1994; 72: 348-50. [MedLine]

55. Journois D, Pouard P, Greeley W J, Mauriat P, Vouhe P, Safran D - Hemofiltration during cardiopulmonary bypass in pediatric cardiac surgery. Effects on hemostasis, cytokines and complement components. Anesthesiology 1994; 81: 1181-9.

56. Millar A B, Armstrong L, Van Der Linden J et al. - Cytokine production and hemofiltration in children undergoing cardiopulmanary bypass. Ann Thorac Surg 1993; 56: 1499-502. [MedLine]

57. Gu Y J, Van Oeveren W, Akkerman C, Boonstra P W, Huyzen R J, Wildevuur C R - Heparin-coated circuits reduce the inflamatory response to cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993; 105: 234-41. [MedLine]

58. Lilly C M, Sandhu J S, Ishizaka A - Pentoxifylline prevents tumor necrosis factor-induced lung injury. Am Rev Respir Dis 1989; 139: 1361-8. [MedLine]

59. Sullivan G W, Carper H T, Novick W J, Mandell G L - Inhibition of the inflamatory action of interleukin-1 and tumor necrosis factor (alpha) on neutrophil function by pentoxifyline. Infect Immunol 1988; 56: 1722-9.

60. Buffolo E, Gomes W J, Andrade J C S et al. - Revascularização miocárdica sem circulação extracorpórea: resultados cirúrgicos em 1090 pacientes. Arq Bras Cardiol 1994; 62: 149-53. [MedLine]

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