Pathophysiology of Cardiopulmonary Bypass

  • Ron G. H. Speekenbrink
  • Wim van Oeveren
  • Charles R. H. Wildevuur
  • Leon Eijsman
Chapter
Part of the Contemporary Cardiology book series (CONCARD)

Abstract

From the earliest clinical experiences with cardiopulmonary bypass (CPB) for cardiac operations, it was apparent that significant morbidity and mortality were associated with the CPB procedure itself (1). Often, only the contact of blood with the foreign material of the extracorporeal circuit was held responsible. However, CPB implies more than just connecting the circulation of the patient to an extracorporeal circuit, resulting in the material dependent activation of blood. With CPB a number of other nonphysiological events are introduced, including hemodilution, hypothermia, nonpulsatile blood flow, retransfusion of shed blood, and exclusion of the metabolic function of the lung, resulting in material independent activation. Together, these events cause the massive and systemic activation of the patients’ defense systems with repercussions on nearly every organ system. Signs of this “whole body inflammatory reaction” can be observed in every postoperative patient. In a number of patients, especially neonates, the elderly, and those undergoing large procedures or with severe comorbidity, this phenomenon can escalate into the so-called postperfusion syndrome, which is characterized by elevated cardiac output with decreased vascular resistance, capillary leak, and renal dysfunction, and is associated with increased mortality (2).

Keywords

Cardiopulmonary Bypass Extracorporeal Circuit Terminal Complement Complex Heparin Coating Cardiotomy Suction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Kirklin JW. Open-heart surgery at the Mayo Clinic: the 25th anniversary. Mayo Clin Proc 1980; 55: 339–341.PubMedGoogle Scholar
  2. 2.
    Westaby S. Organ dysfunction after cardiopulmonary bypass: a systemic inflammatory reaction initiated by the extracorporeal circuit. Intensive Care Med 1987; 13: 89–95.PubMedCrossRefGoogle Scholar
  3. 3.
    Gu YJ, Massimo AN, van Oeveren W, Grandjean J, Boonstra PW. Reduction in inflammatory response in patients having minimally invasive coronary artery bypass surgery. Ann Thorac Surg (in press).Google Scholar
  4. 4.
    Edmunds LH, Jr. Blood—surface interactions during cardiopulmonary bypass. J Cardiac Surg 1998; 65: 420–424.Google Scholar
  5. 5.
    Wachtfogel YT, Harpel PC, Edmunds LH Jr, Colman RW. Formation of C l s-C 1-inhibitor, kallikreinC 1-inhibitor and plasmin-alpha 2-plasmin-inhibitor complexes during cardiopulmonary bypass. Blood 1989; 73: 468–471.PubMedGoogle Scholar
  6. 6.
    Burman JF, Chung HI, Lane DA, Philippou H, Adami A, Lincoln JC. Role of factor XII in thrombin generation and fibrinolysis during cardiopulmonary bypass. Lancet 1994; 344: 1192–1193.PubMedCrossRefGoogle Scholar
  7. 7.
    Moorman RM, Reynolds DS, Communale ME. Management of cardiopulmonary bypass in a patient with congenital factor XII deficiency. J Cardiothorac Vasc Anesth 1993; 7: 452–454.PubMedCrossRefGoogle Scholar
  8. 8.
    to Velthuis H, Baufreton C, Jansen PG, et al. Heparin coating of extracorporeal circuits inhibits contact activation during cardiac operations. J Thorac Cardiovasc Surg 1997; 114: 117–122.CrossRefGoogle Scholar
  9. 9.
    Boisclair MD, Lane DA, Philippou H, et al. Mechanisms of thrombin generation during cardiopulmonary bypass. Blood 1993; 82: 3350–3357.PubMedGoogle Scholar
  10. 10.
    Philippou H, Adami A, Boisclair MD, Lane DA. An ELISA for factor X activation peptide: application to the investigation of thrombogenesis in cardiopulmonary bypass. Br J Haematol 1995; 90: 432–437.PubMedCrossRefGoogle Scholar
  11. 11.
    Kazatchkine MD, Nydegger UE. The human alternative pathway: biology and immunopathology of activation and regulation. Prog Allergy 1982; 30: 193–234.PubMedGoogle Scholar
  12. 12.
    Müller-Eberhard HJ. Complement: chemistry and pathways. In: Gallin JI, Goldstein IM, Snyderman R, ed. Inflammation: Basic Principles and Clinical Correlates. Raven, New York; 1988;pp. 21–54.Google Scholar
  13. 13.
    Chenoweth DE, Cooper SW, Hugli TE, Stewart RW, Blackstone EH, Kirklin JW. Complement activation during cardiopulmonary bypass. N Engl J Med 1981; 304: 497–503.PubMedCrossRefGoogle Scholar
  14. 14.
    Parker DJ, Cantrell JW, Karp RB, Stroud RM, Digerness SB. Changes in serum complement and immunoglobins following cardiopulmonary bypass. Surgery 1972; 71: 824–827.PubMedGoogle Scholar
  15. 15.
    Videm V, Fosse E, Mollnes TE, Gaffed P, Svennevig JL. Complement activation with bubble and membrane oxygenators in aortocoronary bypass grafting. Ann Thorac Surg 1990; 50: 387–391.PubMedCrossRefGoogle Scholar
  16. 16.
    Videm V, Mollnes TE. Human complement activation by polygeline and dextran 70. Scand J Immunol 1994; 39: 314–320.PubMedCrossRefGoogle Scholar
  17. 17.
    Cooper NR. The classical complement pathway: activation and regulation of the first complement component. Adv Immunol 1985; 37: 151–216.PubMedCrossRefGoogle Scholar
  18. 18.
    Loos M, Wellek B, Thesen R, Opferkuch W. Antibody-independent interaction of the first component of complement with gram-negative bacteria. Infect Immun 1978; 22: 5–9.PubMedGoogle Scholar
  19. 19.
    Fehr J, Rohr H. In vivo complement activation by polyanion-polycation complexes: evidence that C5a is generated intravascularly during heparin-protamine interaction. Clin Immunol 1983; 29: 7–14.Google Scholar
  20. 20.
    Kirklin JK, Chenoweth DE, Naftel DC, et al. Effects of protamine administration after cardiopulmonary bypass on complement, blood elements, and the hemodynamic state. Ann Thorac Surg 1986; 41: 193–199.PubMedCrossRefGoogle Scholar
  21. 21.
    Salama A, Hugo F, Heinrich D, et al. Deposition of terminal C5b-9 complement complexes on erythrocytes and leukocytes during cardiopulmonary bypass. New Engl J Med 1988; 318: 408–414.PubMedCrossRefGoogle Scholar
  22. 22.
    Schreurs HH, Wijers MJ, Gu YJ, et al. Heparin coated bypass circuits: effects on inflammatory response in paediatric cardiac surgery. Ann Thorac Surg (in press).Google Scholar
  23. 23.
    Hugli TE, Müller-Eberhard HJ. Anaphylatoxins C3a and C5a. Adv Immunol 1978; 26: 1–53.PubMedCrossRefGoogle Scholar
  24. 24.
    Charo IF, Yuen C, Perez HD, Goldstein IM. Chemotactic peptides modulate adherence of human polymorphonuclear leukocytes to monolayers of cultured endothelial cells. J Immunol 1986; 136: 3412–3419.PubMedGoogle Scholar
  25. 25.
    Tonnesen MG, Smedly LA, Henson PM. Neutrophil-endothelial cell interactions. J Clin Invest 1984; 74: 1581–1592.PubMedCrossRefGoogle Scholar
  26. 26.
    Bender JG, van Epps DE. Stimulus interactions in release of superoxide anion (02) from human neutrophils. Inflammation 1985; 9: 67–86.PubMedCrossRefGoogle Scholar
  27. 27.
    Bender JG, Mc Phail LC, van Epps DE. Exposure of human neutrophils to chemotactic factors potentiates activation of the respiratory burst enzyme. J Immunol 1983; 130: 2316–2323.PubMedGoogle Scholar
  28. 28.
    Henson PM, Zanolari B, Schwartzman NA, Hong SR. Intracellular control of human neutrophil secretion. I. C5a-induced stimulus-specific desensitisation and the effects of cytochalasin Br. J Immunol 1978; 121: 851–855.Google Scholar
  29. 29.
    Clancy RM, Dahinden CA, Hugh TE. Arachidonate metabolism by human polymorphonuclear leukocytes stimulated by N-formyl-Met-Leu-Phe or complement component C5a is independent of phospholipase activation. Proc Natl Acad Sci USA 1983; 80: 7200–7204.PubMedCrossRefGoogle Scholar
  30. 30.
    Palmer RMJ, Salmon JA. Release of leukotriene B4 from human neutrophils and its relationship to degranulation induced by n-formyl-methionyl-leucyl-phenylalanine, serum-treated zymosan and the ionophore A23187. Immunology 1983; 50: 65–73.PubMedGoogle Scholar
  31. 31.
    Cochrane CG, Spragg RG, Revak SD. Studies on the pathogenesis of the adult respiratory distress syndrome: evidence of oxidants in the broncheoalveolar lavage fluid. J Clin Invest 1983; 71: 754–761.PubMedCrossRefGoogle Scholar
  32. 32.
    Royston D, Minty BD, Higenbottam TW, Wallwork J, Jones GJ. The effect of surgery with cardiopulmonary bypass on alveolar-capillary barrier function in human beings. Ann Thorac Surg 1985; 40: 139–143.PubMedCrossRefGoogle Scholar
  33. 33.
    Rinaldo JE, Rogers RM. Adult respiratory distress syndrome: changing concepts of lung injury and repair. N Engl J Med 1982; 306: 900–909.PubMedCrossRefGoogle Scholar
  34. 34.
    Dinarello CA. Interleukin-1. Rev Infect Dis 1984; 6: 51–95.PubMedCrossRefGoogle Scholar
  35. 35.
    Smith RJ, Speziale SC, Bowman BJ. Properties of interleukin-1 as a complete secretagogue for human neutrophils. Biochem Biophys Res Commun 1982; 130: 1233–1240.CrossRefGoogle Scholar
  36. 36.
    Mizel SB. Interleukin 1 and T cell activation. Immunol Rev 1982; 63: 51–72.PubMedCrossRefGoogle Scholar
  37. 37.
    Falkoff RJM, Muraguchi A, Hong JX, Buttler JL, Dinarello CA, Fanci AS. The effects of interleukin 1 on human B cell activation and proliferation. J Immunol 1983; 131: 801–805.PubMedGoogle Scholar
  38. 38.
    Old LJ. Tumor necrosis factor (TNF). Science 1985; 230: 630–632.PubMedCrossRefGoogle Scholar
  39. 39.
    Dinarello CA, Cannon JG, Wolff SM, et al. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med 1986; 163: 1433–1450.PubMedCrossRefGoogle Scholar
  40. 40.
    Nawroth PP, Stern D. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 1986; 164: 740–745.CrossRefGoogle Scholar
  41. 41.
    Nawroth PP, Bank I, Handley D, Cassimeris J, Chess L, Stern D. Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1. J Exp Med 1986; 163: 1363–1375.PubMedCrossRefGoogle Scholar
  42. 42.
    Jansen NJ, van Oeveren W, van de Broek L, et al. Inhibition by dexamethasone of the reperfusion phenomena in cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991; 102: 515–525.PubMedGoogle Scholar
  43. 43.
    Jansen NJ, van Oeveren W, Gu YJ, van Vliet MH, Eijsman L, Wildevuur CR. Endotoxin release and tumor necrosis factor formation during cardiopulmonary bypass. Ann Thorac Surg 1992; 54: 744–748.PubMedCrossRefGoogle Scholar
  44. 44.
    Wan S, Marchant A, DeSmet JM, et al. Human cytokine responses to cardiac transplantation and coronary artery bypass grafting. J Thorac Cardiovasc Surg 1996; 111: 469–477.PubMedCrossRefGoogle Scholar
  45. 45.
    Butler J, Chong GL, Baigrie RJ, Pillai R, Westaby S, Rocker GM. Cytokine responses to cardiopulmonary bypass with membrane and bubble oxygenation. Ann Thorac Surg 1992; 53: 833–838.PubMedCrossRefGoogle Scholar
  46. 46.
    Kukielka GL, Smith CW, Manning AM, Youker KA, Michael LH, Entman ML. Induction of interleukin-6 synthesis in the myocardium: potential role in postreperfusion inflammatory injury. Circulation 1995; 92: 1866–1875.PubMedCrossRefGoogle Scholar
  47. 47.
    Jorens PG, Jongh R de, Backer W de, et al. Interleukin-8 production in patients undergoing cardiopulmonary bypass. The influence of pre-treatment with methylprednisolone. Am Rev Respir Dis 1993; 148: 890–895.PubMedCrossRefGoogle Scholar
  48. 48.
    Ivey CL, Williams FW, Collins PD, Jose PJ, Williams TJ. Neutrophil chemoattractants generated in two phases during reperfusion of ischemic myocardium in the rabbit. Evidence for a role for C5a and interleukin-8. J Clin Invest 1995; 95: 2720–2728.PubMedCrossRefGoogle Scholar
  49. 49.
    Gearing AJH, Newman W. Circulating adhesion molecules in disease. Immunol Today 1993; 14: 506–512.PubMedCrossRefGoogle Scholar
  50. 50.
    Gu YJ, van Oeveren W, Boonstra PW, de Haan J, Wildevuur CR. Leukocyte activation with increased membrane expression of CR3 receptors induced by cardiopulmonary bypass. Ann Thorac Surg 1992; 53: 839–844.PubMedCrossRefGoogle Scholar
  51. 51.
    Gillinov AM, Bator JM, Zehr KJ, et al. Neutrophil adhesion molecule expression during cardiopulmonary bypass with bubble and membrane oxygenators. Ann Thorac Surg 1993; 56: 847–853.PubMedCrossRefGoogle Scholar
  52. 52.
    Arnaout MA, Hakim RM, Todd RF III, Dana N, Colten HR. Increased expression of an adhesion-promoting surface glycoprotein in the granulocytopenia of hemodialysis. N Engl J Med 1985; 312: 457462.Google Scholar
  53. 53.
    Etzioni A. Adhesion molecules-their role in health and disease. Pediatr Res 1996; 39: 191–198.PubMedCrossRefGoogle Scholar
  54. 54.
    Dreyer WJ, Michael LH, Millman EE, Berens KL. Neutrophil activation and adhesion molecule expression in a canine model of open heart surgery with cardiopulmonary bypass. Cardiovasc Res 1995; 29: 775–781.PubMedGoogle Scholar
  55. 55.
    van Oeveren W, Eijsman L, Roozendaal KJ, Wildevuur CR. Platelet preservation by aprotinin during cardiopulmonary bypass. Lancet 1988; 19: 644.CrossRefGoogle Scholar
  56. 56.
    Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329: 2002–2012.PubMedCrossRefGoogle Scholar
  57. 57.
    Speziale G, Ruvolo G, Marino B. A role for nitric oxide in the vasoplegic syndrome. J Cardiovasc Surg (Torino) 1996; 37: 301–303.Google Scholar
  58. 58.
    Finkel MS, Oddis CV, Jacob TD, et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992; 257: 387–389.PubMedCrossRefGoogle Scholar
  59. 59.
    Alican I, Kubes P. A critical role for nitric oxide in intestinal barrier function and dysfunction. Am J Physiol 1996; 270: G225 - G237.PubMedGoogle Scholar
  60. 60.
    Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411–415.PubMedCrossRefGoogle Scholar
  61. 61.
    Yoshizawa T, Osamu S, Giaid A, et al. Endothelin, a novel peptide in the posterior pituitary system. Science 1989; 247: 462–464.CrossRefGoogle Scholar
  62. 62.
    to Velthuis H, Jansen PG, Oudemans-van Straaten HM, et al. Circulating endothelin in cardiac operations: influence of blood pressure and endotoxin. Ann Thorac Surg 1996; 61: 904–908.CrossRefGoogle Scholar
  63. 63.
    Kirshbom PM, Tsui SS, Di Bernardo LR, et al. Blockade of endothelia-converting enzyme reduces pulmonary hypertension after cardiopulmonary bypass and circulatory arrest. Surgery 1995; 118: 440PubMedCrossRefGoogle Scholar
  64. 64.
    Matheis G, Haak T, Beyersdorf F, Baretti R, Polywka C, Winkelmann BR. Circulating endothelin in patients undergoing coronary artery bypass grafting. Eur J Cardiothorac Surg 1995; 9: 269–274.PubMedCrossRefGoogle Scholar
  65. 65.
    Nakamura H, Kim DK, Philbin DM, et al. Heparin-enhanced plasma phospholipase A2 activity and prostacyclin synthesis in patients undergoing cardiac surgery. J Clin Invest 1995; 95: 1062–1070.PubMedCrossRefGoogle Scholar
  66. 66.
    Tabuchi N, Gallandat Huet RC, Sturk A, Eijsman L, Wildevuur CR. Aprotinin effects on aspirin treated platelets and hemostasis during cardiopulmonary bypass. Ann Thorac Surg 1994; 58: 1036–1039.PubMedCrossRefGoogle Scholar
  67. 67.
    Videm V, Svennevig JL, Fosse E, Semb G, Osterud A, Mollnes TE. Reduced complement activation with heparin-coated oxygenator and tubings in coronary bypass operations. J Thorac Cardiovasc Surg 1992; 103: 806–813.PubMedGoogle Scholar
  68. 68.
    Ovrum E, Mollnes TE, Fosse E, et al. Complement and granulocyte activation in two different types of heparinized extracorporeal circuits. J Thorac Cardiovasc Surg 1995; 110: 1623–1632.PubMedCrossRefGoogle Scholar
  69. 69.
    Lundblad R, Moen O, Fosse E. Endothelin-1 and neutrophil activation during heparin-coated cardiopulmonary bypass. Ann Thorac Surg 1997; 63: 1361–1367.PubMedCrossRefGoogle Scholar
  70. 70.
    Moen O, Fosse E, Brockmeier V, et al. Disparity in blood activation by two different heparin-coated cardiopulmonary bypass systems. Ann Thorac Surg 1995; 60: 1317–23.PubMedCrossRefGoogle Scholar
  71. 71.
    Steinberg BM, Grossi EA, Schwartz DS, et al. Heparin bonding of bypass circuits reduces cytokine release during cardiopulmonary bypass. Ann Thorac Surg 1995; 60: 525–529.PubMedCrossRefGoogle Scholar
  72. 72.
    Weerwind PW, Maessen JG, van Tits LJ, et al. Influence of Duraflo II heparin-treated extracorporeal circuits on the systemic inflammatory response in patients having coronary bypass. J Thorac Cardiovasc Surg 1995; 110: 1633–1641.PubMedCrossRefGoogle Scholar
  73. 73.
    Bozdayi M, Borowiec J, Nilsson L, Venge P, Thelin S, Hansson HE. Effects of heparin-coating of cardiopulmonary bypass circuits on in vitro oxygen free radical production during coronary bypass surgery. Artif Organs1996; 20: 1008–1016.Google Scholar
  74. 74.
    Moen O, Hogasen K, Fosse E, et al. Attenuation of changes in leukocyte surface markers and complement activation with heparin-coated cardiopulmonary bypass. Ann Thorac Surg 1997; 63: 105–111.PubMedCrossRefGoogle Scholar
  75. 75.
    Fukutomi M, Kobayashi S, Niwaya K, Hamada Y, Kitamura S. Changes in platelet, granulocyte and complement activation during cardiopulmonary bypass using heparin-coated equipment. Artif Organs 1996; 20: 767–776.PubMedCrossRefGoogle Scholar
  76. 76.
    Gu YJ, van Oeveren W, Akkerman C, Boonstra PW, Huyzen RJ, Wildevuur CR. Heparin-coated circuits reduce the inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 1993; 55: 917–922.PubMedCrossRefGoogle Scholar
  77. 77.
    to Velthuis H, Jansen PGM, Hack CE, Eijsman L, Wildevuur CR. Specific complement inhibition by heparin-coated extracorporeal circuits. Ann Thorac Surg 1996; 61: 1153–1157.CrossRefGoogle Scholar
  78. 78.
    van der Kamp KW, van Oeveren W. Contact, coagulation and platelet interaction with heparin treated equipment during heart surgery. Int J Artif Organs 1993; 16: 836–842.Google Scholar
  79. 79.
    Gorman RC, Ziats N, Rao AK, et al. Surface-bound heparin fails to reduce thrombin formation during clinical cardiopulmonary bypass. J Thorac Cardiovasc Surg 1996; 111: 1–12.PubMedCrossRefGoogle Scholar
  80. 80.
    Ovrum E, Brosstad F, Am Holen E, Tangen G, Abdelnoor M. Effects on coagulation and fibrinolysis with reduced versus full heparinization and heparin coated cardiopulmonary bypass. Circulation 1995; 92: 2579–2584.PubMedCrossRefGoogle Scholar
  81. 81.
    von Segesser LK, Weiss BM, Garcia E, von Felten A, Turina MI. Reduction and elimination of systemic heparinization during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1992; 103: 790–799.Google Scholar
  82. 82.
    Ovrum E, Holen EA, Tangen G, et al. Completely heparinized cardiopulmonary bypass and reduced systemic heparin: clinical and hemostatic effects. Ann Thorac Surg 1995; 60: 365–371.PubMedCrossRefGoogle Scholar
  83. 83.
    Edmunds LH Jr. Surface-bound heparin: panacea or peril? Ann Thorac Surg 94; 85: 2855–2860.Google Scholar
  84. 84.
    Ranucci M, Cirri S, Conti D, et al. Beneficial effects of Duraflo II heparin-coated circuits on post-perfusion lung dysfunction. Ann Thorac Surg 1996; 61: 76–81.PubMedCrossRefGoogle Scholar
  85. 85.
    Jansen PG, to Velthuis H, Huybrechts RA, et al. Reduced complement activation and improved postoperative performance after cardiopulmonary bypass with heparin-coated circuits. J Thorac Cardiovasc Surg 1995; 110: 829–834.PubMedCrossRefGoogle Scholar
  86. 86.
    Jansen PG, Baufreton C, Le Besnerais P, Loisance DY, Wildevuur ChRH. Heparin-coated circuits and aprotinin prime for coronary artery bypass grafting. Ann Thorac Surg 1996; 61: 1363–1366.PubMedCrossRefGoogle Scholar
  87. 87.
    Baufreton C, Le Besnerais P, Jansen P, et al. Clinical outcome after coronary surgery with heparin-coated extracorporeal circuits for cardiopulmonary bypass. Perfusion 1996; 11: 437–443.PubMedCrossRefGoogle Scholar
  88. 88.
    Wildevuur CR, Jansen PG, Bezemer PD, et al. Clinical evaluation of Duraflo II treated extracorporeal Circuits (2nd version): The European Working Group on heparin coated extracorporeal circulation circuits. Eur J Cardiothorac Surg 1997; 11: 616–623.PubMedCrossRefGoogle Scholar
  89. 89.
    Verstraete M. Clinical application of inhibitors of fibrinolysis. Drugs 1985; 29: 236–261.PubMedCrossRefGoogle Scholar
  90. 90.
    van Oeveren W, Jansen NJ, Bidstrup BP, et al. Effects of aprotinin on hemostatic mechanisms during cardiopulmonary bypass. Ann Thor Surg 1987; 44: 640–645.CrossRefGoogle Scholar
  91. 91.
    Wildevuur CR, Eijsman L, Roozendaal KJ, Harder MP, Chang MP, van Oeveren W. Platelet preservation during cardiopulmonary bypass with aprotinin. Eur J Cardiothorac Surg 1989; 3: 533–538.PubMedCrossRefGoogle Scholar
  92. 92.
    van Oeveren W, Harder MP, Roozendaal KJ, Eijsman L, Wildevuur CR. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990; 99: 788–797.PubMedGoogle Scholar
  93. 93.
    Speekenbrink RG, Wildevuur CR, Sturk A, Eijsman L. Low-dose and high-dose aprotinin improve hemostasis in coronary surgery. J Thorac Cardiovasc Surg 1996; 112: 523–530.PubMedCrossRefGoogle Scholar
  94. 94.
    Tatar H, Cicek S, Demirkilic U, et al. Topical use of aprotinin in open heart operations. Ann Thor Surg 1993; 55: 659–661.CrossRefGoogle Scholar
  95. 95.
    Speekenbrink RG, Vonk AB, Wildevuur CR, Eijsman L. Hemostatic efficacy of dipyridamole, tranexamic acid and aprotinin in coronary bypass grafting. Ann Thorac Surg 1995; 59: 438–42.PubMedCrossRefGoogle Scholar
  96. 96.
    Horrow JC, Hlavacek J, Strong MD, et al. Prophylactic tranexamic acid decreases bleeding after cardiac operations. J Thorac Cardiovasc Surg 1990; 99: 70–74.PubMedGoogle Scholar
  97. 97.
    John LC, Rees GM, Kovacs IB. Reduction of heparin binding to and inhibition of platelets by aprotinin. Ann Thorac Surg 1993; 55: 1175–1179.PubMedCrossRefGoogle Scholar
  98. 98.
    Wachtfogel YT, Kucich U, Hack CE, et al. Aprotinin inhibits the contact, neutrophil, and platelet activation systems during simulated extracorporeal perfusion. J Thorac Cardiovasc Surg 1993; 106: 1–10.PubMedGoogle Scholar
  99. 99.
    Hill GE, Alonso A, Spurzem JR, Stammers AH, Robbins RA. Aprotinin and methylprednisolone equally blunt cardiopulmonary bypass-induced inflammation in humans. J Thorac Cardiovasc Surg 1995; 110: 1658–1662.PubMedCrossRefGoogle Scholar
  100. 100.
    Hill GE, Pohorecki R, Alonso A, Rennard SI, Robbins RA. Aprotinin reduces interleukin-8 production and neutrophil accumulation after cardiopulmonary bypass. Anesth Analg 1996; 83: 696–700.PubMedGoogle Scholar
  101. 101.
    Hill GE, Taylor JA, Robbins RA. Differing effects of aprotinin and e-aminocaproic acid on cytokine-induced inducible nitric oxide synthase expression. Ann Thorac Surg 1997; 63: 74–77.PubMedCrossRefGoogle Scholar
  102. 102.
    Hill GE, Springal DR, Robbins RA. Aprotinin is associated with a decrease in nitric oxide production during cardiopulmonary bypass. Surgery 1997; 121: 449–455.PubMedCrossRefGoogle Scholar
  103. 103.
    van Oeveren W, van Oeveren B, Wildevuur CR. Anticoagulation policy during use of aprotinin in cardiopulmonary bypass. J Thorac Cardiovasc Surg 1992; 104: 210–211.PubMedGoogle Scholar
  104. 104.
    Feindt P, Seyfert U, Volkmar I, Huwer H, Kalweit G, Gams E. Is there a phase of hypercoagulability when aprotinin is used in cardiac surgery? Eur J Cardiothor Surg 1994; 8: 308–314.CrossRefGoogle Scholar
  105. 105.
    Bidstrup BP, Underwood SR, Sapsford RN. Effect of aprotinin (Trasylol) on aorta-coronary bypass graft patency. J Thorac Cardiovasc Surg 1993; 105: 147–153.PubMedGoogle Scholar
  106. 106.
    Westaby S. Aprotinin in perspective. Ann Thorac Surg 1993; 55: 1033–1041.PubMedCrossRefGoogle Scholar
  107. 107.
    Speekenbrink RG, Bertina RM, Espana F, Wildevuur CR, Eijsman L. Activation of the protein C system during cardiopulmonary bypass with and without adrotinin. Ann Thor Surg (in press).Google Scholar
  108. 108.
    Weiler JM, Packard B. Methylprednisolone inhibits the alternative and amplification pathways of complement. Infect Immun 1982; 38: 122–126.PubMedGoogle Scholar
  109. 109.
    Boscoe MJ, Yewdall VM, Thompson MA, Cameron JS. Complement activation during cardiopulmonary bypass: quantitative study of effects of methylprednisolone and pulsatile flow. Br Med J (Clin Res Ed) 1983; 287: 1747–1750.CrossRefGoogle Scholar
  110. 110.
    Jansen NJ, van Oeveren W, van Vliet M, Stoutenbeek CP, Eijsman L, Wildevuur CR. The role of different types of corticosteroids on the inflammatory mediators in cardiopulmonary bypass. Eur J Cardiothorac Surg 1991; 5: 211–217.PubMedCrossRefGoogle Scholar
  111. 111.
    Hill GE, Snider S, Galbraith TA, Forst S, Robbins RA. Glucocorticoid reduction of bronchial epithelial inflammation during cardiopulmonary bypass. Am J Respir Crit Care Med 1995; 152: 1791–1795.PubMedGoogle Scholar
  112. 112.
    Kawamura T, Inada K, Okada H, Okada K, Wakusawa R. Methylprednisolone inhibits increase of interleukin 8 and 6 during open heart surgery. Can J Anaesth 1995; 42: 399–403.PubMedCrossRefGoogle Scholar
  113. 113.
    Teoh KH, Bradley CA, Gauldie J, Burrows H. Steroid inhibition of cytokine-mediated vasodilation after warm heart surgery. Circulation 1995; 92: 347–353.CrossRefGoogle Scholar
  114. 114.
    Tabardel Y, Duchateau J, Schmartz D, et al. Corticosteroids increase blood interleukin-10 levels during cardiopulmonary bypass in men. Surgery 1996; 119: 76–80.PubMedCrossRefGoogle Scholar
  115. 115.
    Hill GE, Alonso A, Thiele GM, Robbins RA. Glucocorticoids blunt neutrophil CD1 lb surface glycoprotein upregulation during cardiopulmonary bypass in humans. Anesth Analg 1994; 79: 23–27.PubMedCrossRefGoogle Scholar
  116. 116.
    Cronstein BN, Kimmel SC, Levin RI, Martiniuk F, Weissman G. A mechanism for the anti-inflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1. Proc Natl Acad Sci USA 1992; 89: 9991–9995.PubMedCrossRefGoogle Scholar
  117. 117.
    Busuttil RW. George WJ. Hewitt RL. Protective effect of methylprednisolone on the heart during ischemic arrest. J Thorac Cardiovasc Surg 1975; 70: 955–965.PubMedGoogle Scholar
  118. 118.
    Hill DG, Aguilar MJ, Kosek JC, Hill JD. Corticosteroids and prevention of pulmonary damage following cardiopulmonary bypass in puppies. Ann Thorac Surg 1976; 22: 36–40.PubMedCrossRefGoogle Scholar
  119. 119.
    Tabuchi N, de Haan J, Boonstra PW, van Oeveren W. Activation of fibrinolysis in the pericardial cavity during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993; 106: 828–833.PubMedGoogle Scholar
  120. 120.
    Nieuwland R, Berckmans RJ, Rotteveel-Eijkman RC, et al. Cell-derived microparticles generated in patients during cardiopulmonary bypass are highly procoagulant. Circulation 1997; 96: 3534–3541.PubMedCrossRefGoogle Scholar
  121. 121.
    Chung JH, Gikakis N, Rao AK, Drake TA, Colman RW, Edmunds LH Jr. Pericardial blood activates the extrinsic coagulation pathway during clinical cardiopulmonary bypass. Circulation 1996; 93: 2014–2018.PubMedCrossRefGoogle Scholar
  122. 122.
    van Hinsbergh VW, Kooistra T, Scheffer MA, van Bockel JH, van Muijen GN. Characterization and fibrinolytic properties of human omental tissue mesothelial cells: comparison with endothelial cells. Blood 1990; 75: 1490–1497.PubMedGoogle Scholar
  123. 123.
    Adelman B, Michelson AD, Loscalzo J, Greenberg J, Handin RI. Plasmin effect on platelet glycoprotein Ib-von Willebrand’s factor interaction. Blood 1985; 65: 32–40.PubMedGoogle Scholar
  124. 124.
    Coller BS. Platelet and thrombolytic therapy. N Engl J Med 1990; 99: 518–527.Google Scholar
  125. 125.
    de Haan J, Boonstra PW, Monnink SH, Ebels T, van Oeveren W. Retransfusion of suctioned blood during cardiopulmonary bypass impairs hemostasis. Ann Thorac Surg 1995; 59: 901–907.PubMedCrossRefGoogle Scholar
  126. 126.
    Schönberger JP, van Oeveren W, Bredee JJ, Everts PA, de Haan J, Wildevuur CR. Systemic blood activation during and after autotransfusion. Ann Thorac Surg 1994; 57: 1256–1262.PubMedCrossRefGoogle Scholar
  127. 127.
    Schönberger JP, Bredee JJ, Speekenbrink RG, Everts PA, Wildevuur CR. Autotransfusion of shed blood contributes additionally to blood saving in patients receiving aprotinin (2 million KIU). Eur J Cardiothorac Surg 1993; 7: 474–477.PubMedCrossRefGoogle Scholar
  128. 128.
    Boonstra PW, van Imhoff GW, Eijsman L, et al. Reduced platelet activation and improved hemostasis after controlled cardiotomy suction during clinical membrane oxygenator perfusions. J Thorac Cardiovasc Surg 1985; 89: 900–906.PubMedGoogle Scholar
  129. 129.
    Menasché P, Piwnica A. Free radicals and myocardial protection: a surgical viewpoint. Ann Thorac Surg 1989; 47: 939–945.PubMedCrossRefGoogle Scholar
  130. 130.
    Royston D, Fleming JS, Desar JB, Westaby S, Taylor KM. Increased production of peroxidation products associated with cardiac operations. J Thorac Cardiovasc Surg 1986; 91: 759–766.PubMedGoogle Scholar
  131. 131.
    Lefer AM. Role of selectins in myocardial ischemia-reperfusion injury. Ann Thorac Surg 1995; 60: 773–777.PubMedCrossRefGoogle Scholar
  132. 132.
    Seccombe JF, Schaff HV. Coronary artery endothelial function after myocardial ischemia and reperfusion. Ann Thorac Surg 1995; 60: 778–788.PubMedCrossRefGoogle Scholar
  133. 133.
    Menasché P, Grousset C, Gauduel Y, Piwnica A. A comparative study of free radical scavengers in cardioplegic solutions: improved protection with peroxidase. J Thorac Cardiovasc Surg 1986; 92: 264–271.PubMedGoogle Scholar
  134. 134.
    Bochenek A, Religa Z, Spyt TJ, et al. Protective influence of pretreatment with allopurinol on myocardial function in patients undergoing coronary artery surgery. Eur J Cardiothorac Surg 1990; 4: 538–542.PubMedCrossRefGoogle Scholar
  135. 135.
    Lichtenstein SV, Kassam AA, El Dalati H, Cusimano RJ, Panos A, Slutsky AS. Warm heart surgery. J Thorac Cardiovasc Surg 1991; 101: 269–274.PubMedGoogle Scholar
  136. 136.
    Taggart DP, El-Fiky MM, Carter R, Bowman A, Wheatley DJ. Respiratory dysfunction after uncomplicated cardiopulmonary bypass. Ann Thorac Surg 1993; 56: 1123–1128.PubMedCrossRefGoogle Scholar
  137. 137.
    Ratcliff NB, Young WG Jr, Hackel DB, et al. Pulmonary injury secondary to extracorporeal circulation: An ultrastructural study. J Thorac Cardiovasc Surg 1973; 65: 425–432.Google Scholar
  138. 138.
    Hillman ND, Cheifetz IM, Craig DM, Smith PK, Ungerleider RM, Meliones JN. Inhaled nitric oxide, right ventricular efficiency, and pulmonary vascular mechanics: selective vasodilation of small pulmonary vessels during hypoxic pulmonary vasoconstriction. J Thorac Cardiovasc Surg 1997; 113: 1006–1013.PubMedCrossRefGoogle Scholar
  139. 139.
    King RC, Binns OA, Kanithanon RC, et al. Low-dose sodium nitroprusside reduces pulmonary reperfusion injury. Ann Thorac Surg 1997; 63: 1398–1404.PubMedCrossRefGoogle Scholar
  140. 140.
    MacNee W, Selby C. Neutrophil kinetics in the lungs. Clin Science 1990; 79: 97–107.Google Scholar
  141. 141.
    Tönz M, Mihaljevic T, von Segesser LK, Fehr J, Schmid ER, Turina MI. Acute lung injury during cardiopulmonary bypass: are the neutrophils responsible? Chest 1995; 108: 1551–1556.PubMedCrossRefGoogle Scholar
  142. 142.
    Bando K, Pillai R, Cameron DE, et al. Leukocyte depletion ameliorates free radical-mediated lung injury after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990; 99: 873–877.PubMedGoogle Scholar
  143. 143.
    Johnson D, Thomson D, Mycyk T, Burbridge B, Mayers I. Depletion of leucocytes transiently improves postoperative cardiorespiratory status. Chest 1995; 107: 1253–1259.PubMedCrossRefGoogle Scholar
  144. 144.
    Gu YJ, de Vries AJ, Boonstra PW, van Oeveren W. Leukocyte depletion results in improved lung function and reduced inflammatory response after cardiac surgery. J Thorac Cardiovasc Surg 1996; 112: 494–500.PubMedCrossRefGoogle Scholar
  145. 145.
    Boldt J, Zickmann B, Dapper F, Hempelmann G. Does the technique of cardiopulmonary bypass affect lung water content? Eur J Cardiothorac Surg 1991; 5: 22–26.PubMedCrossRefGoogle Scholar
  146. 146.
    Matheis G, Haak T, Beyersdorf F, Baretti R, Polywka C, Winkelmann BR. Circulating endothelin in patients undergoing coronary artery bypass grafting. Eur J Cardiothorac Surg 1995; 9: 269–274.PubMedCrossRefGoogle Scholar
  147. 147.
    Dobell AR, Bailey JS. Charles Drew and the origins of deep hypothermic circulatory arrest. Ann Thorac Surg 1997; 63: 1193–1199.PubMedCrossRefGoogle Scholar
  148. 148.
    Bochenek A, Religa Z, Kokot F, et al. Biocompatibility of extracorporeal circulation with autooxygenation. Eur J Cardiothorac Surg 1992; 6: 397–402.PubMedCrossRefGoogle Scholar
  149. 149.
    Beattie HW, Evans G, Garnett ES, Webber CE. Sustained hypovolemia and extracellular fluid volume expansion following cardiopulmonary bypass. Surgery 1972; 71: 891–897.Google Scholar
  150. 150.
    Utley JR, Wachtel C, Cain RB, Spaw AE, Collins JC, Stephens DB. Effects of hypothermia, hemodilution, and pump oxygenation on organ water content, blood flow, and oxygen delivery, and renal function. Ann Thorac Surg 1981; 31: 121–133.PubMedCrossRefGoogle Scholar
  151. 151.
    Jansen PG, to Velthuis H, Bulder ER, et al. Reduction in prime volume attenuates the hyperdynamic response after cardiopulmonary bypass. Ann Thorac Surg 1995; 60: 544–550.PubMedCrossRefGoogle Scholar
  152. 152.
    Jansen PG, to Velthuis H, Wildevuur WR, et al. Cardiopulmonary bypass with modified fluid gelatin and heparin-coated circuits. Br J Anaesth 1996; 6: 13–19.CrossRefGoogle Scholar
  153. 153.
    Schönberger JP, Bredee JJ, Tjian D, Everts PA, Wildevuur CR. Intraoperative predonation contributes to blood saving. Ann Thorac Surg 1993; 56: 893–898.PubMedCrossRefGoogle Scholar
  154. 154.
    Schönberger JP, Woolley S, Tavilla G, et al. Efficacy and safety of a blood conservation program including low-dose aprotinin in routine myocardial revascularization. J Cardiovasc Surg (Torino) 1996; 37: 35–44.Google Scholar
  155. 155.
    Menasché P, Haydar S, Peynet J, et al. A potential mechanism of vasodilation after warm heart surgery. J Thorac Cardiovasc Surg 1994; 107: 293–299.PubMedGoogle Scholar
  156. 156.
    Menasché P, Peynet J, Lariviere J, et al. Does normothermia during cardiopulmonary bypass increase neutrophil-endothelium interactions? Circulation 1994;90:II275–1I279.Google Scholar
  157. 157.
    Haddix TL, Pohlman TH, Noel RF, Sato TT, Boyle EM Jr, Verrier ED. Hypothermia inhibits human E-selectin transcription. J Surg Res 1996; 64: 176–183.PubMedCrossRefGoogle Scholar
  158. 158.
    Menasché P, Peynet J, Haeffner-Cavaillon N, et al. Influence of temperature on neutrophil trafficking during clinical cardiopulmonary bypass. Circulation 1995; 92 (Suppl II): 334–340.CrossRefGoogle Scholar
  159. 159.
    Frering B, Philip I, Dehoux M, Rolland C, Langlois JM, Desmonts JM. Circulating cytokines in patients undergoing normothermic cardiopulmonary bypass. J Thorac Cardiovasc Surg 1994; 108: 636–641.PubMedGoogle Scholar
  160. 160.
    Birdi I, Regragui I, Izzat MB, Bryan AJ, Angelini GD. Influence of normothermic systemic perfusion during coronary artery bypass operations: a randomized prospective study. J Thorac Cardiovasc Surg 1997; 114: 475–481.PubMedCrossRefGoogle Scholar
  161. 161.
    Tonz M, Mihaljevic T, von SegesserLK, Shaw S, Luscher TF, Turina M. Postoperative hemodynamics depend on cardiopulmonary bypass temperature: the potential role of endothelin-1. Eur J Cardiothorac Surg 1997; 11: 157–161.PubMedCrossRefGoogle Scholar
  162. 162.
    Ranucci M, Soro G, Frigiola A, et al. Normothermic perfusion and lung function after cardiopulmonary bypass: effects in pulmonary risk patients. Perfusion 1997; 12: 309–315.PubMedGoogle Scholar
  163. 163.
    Ohata T, Sawa Y, Kadoba K, Masai T, Ichikawa H, Matsuda H. Effect of cardiopulmonary bypass under tepid temperature on inflammatory reactions. Ann Thorac Surg 1997; 64: 124–128.PubMedCrossRefGoogle Scholar
  164. 164.
    Vingerhoets G, Van Nooten G, Vermassen F, De Soete G, Jannes C. Short-term and long-term neuropsychological consequences of cardiac surgery with extracorporeal circulation. Eur J Cardiothorac Surg 1997; 11: 424–431.PubMedCrossRefGoogle Scholar
  165. 165.
    Sotaniemi KA. Long-term neurologic outcome after cardiac operation. Ann Thorac Surg 1995; 59: 1336–1339.PubMedCrossRefGoogle Scholar
  166. 166.
    Blauth CI. Macroemboli and microemboli during cardiopulmonary bypass. Ann Thorac Surg 1995; 59: 1300–1303.PubMedCrossRefGoogle Scholar
  167. 167.
    Liu JF, Su ZK, Ding WX. Quantitation of particulate microemboli during cardiopulmonary bypass: experimental and clinical studies. Ann Thorac Surg 1992; 54: 1196–1202.PubMedCrossRefGoogle Scholar
  168. 168.
    Moody DM, Brown WR, Challa VR, Stump DA, Reboussin DM, Legault C. Brain microemboli associated with cardiopulmonary bypass: a histologic and magnetic resonance imaging study. Ann Thorac Surg 1995; 59: 1304–1307.PubMedCrossRefGoogle Scholar
  169. 169.
    Plourde G, Leduc AS, Morin JE, et al. Temperature during cardiopulmonary bypass for coronary artery operations does not influence postoperative cognitive function: a prospective, randomized trial. J Thorac Cardiovasc Surg 1997; 114: 123–128.PubMedCrossRefGoogle Scholar
  170. 170.
    Engelman RM, Pleet AB, Rousou JA, et al. What is the best perfusion temperature for coronary revascularization? J Thorac Cardiovasc Surg 1996; 112: 1622–1632.PubMedCrossRefGoogle Scholar
  171. 171.
    Regragui I, Birdi I, Izzat MB, et al. The effects of cardiopulmonary bypass temperature on neuropsychologic outcome after coronary artery operations: a prospective randomized trial. J Thorac Cardiovasc Surg 1996; 112: 1036–1045.PubMedCrossRefGoogle Scholar
  172. 172.
    Mora CT, Henson MB, Weintraub WS, et al. The effect of temperature management during cardiopulmonary bypass on neurologic and neuropsychologic outcomes in patients undergoing coronary revascularization. J Thorac Cardiovasc Surg 1996; 112: 514–522.PubMedCrossRefGoogle Scholar
  173. 173.
    McLean RF, Wong BI, Naylor CD, et al. Cardiopulmonary bypass, temperature, and central nervous system dysfunction. Circulation 1994;90:I1250–II255.Google Scholar
  174. 174.
    Martin TD, Craver JM, Gott JP, et al. Prospective, randomized trial of retrograde warm blood cardioplegia: myocardial benefit and neurological threat. Ann Thorac Surg 1994; 57: 298–304.PubMedCrossRefGoogle Scholar
  175. 175.
    Johnsson P, Lundqvist C, Lindgren A, Ferencz I, Alling C, Stahl E. Cerebral complications after cardiac surgery assessed by S-100 and NSE levels in blood. J Cardiothorac Vasc Anesth 1995; 9: 694–699.PubMedCrossRefGoogle Scholar
  176. 176.
    Westaby S, Johnsson P, Parry A, et al. Serum S 100 protein: a potential marker for cerebral events during cardiopulmonary bypass. Ann Thorac Surg 1996; 61: 88–92.PubMedCrossRefGoogle Scholar
  177. 177.
    Taggart DP, Mazel JW, Bhattacharya K, et al. Comparison of serum S-100f3 levels during CABG and intracardiac operations. Ann Thorac Surg 1997; 63: 492–496.PubMedCrossRefGoogle Scholar
  178. 178.
    Taggart DP, Bhattacharya K, Meston N, et al. Serum S-100 protein concentration after cardiac surgery: a randomized trial of arterial line filtration. Eur J Cardiothorac Surg 1997; 11: 645–649.PubMedCrossRefGoogle Scholar
  179. 179.
    Khuri SF, Valeri CR, Loscalzo J. Heparin causes platelet dysfunction and induces fibrinolysis before cardiopulmonary bypass. Ann Thorac Surg 1995; 60: 1008–1014.PubMedCrossRefGoogle Scholar
  180. 180.
    Upchurch GR, Valeri CR, Khuri SF, et al. Effect of heparin on fibrinolytic activity and platelet function in vivo. Am J Physiol 1996; 271: 528–534.Google Scholar
  181. 181.
    John LCH, Rees GM, Kovacs IB. Inhibition of platelet function by heparin. J Thorac Cardiovasc Surg 1993; 105: 816–822.PubMedGoogle Scholar
  182. 182.
    Wahba A, Black G, Koksch M, et al. Cardiopulmonary bypass leads to a preferential loss of activated platelets: a flow cytometric assay of platelet surface antigens. Eur J Cardiothorac Surg 1996; 10: 768773.Google Scholar
  183. 183.
    Videm V. Heparin in clinical doses “primes” granulocytes to subsequent activation as measured by myeloperoxidase release. Scand J Immunol 1996; 43: 385–390.PubMedCrossRefGoogle Scholar
  184. 184.
    Shastri KA, Logue GL, Stern MP, Rehman S, Raza S. Complement activation by heparin-protamine complexes during cardiopulmonary bypass: effect of C4a null allele. J Thorac Cardiovasc Surg 1997; 114: 482–488.PubMedCrossRefGoogle Scholar
  185. 185.
    Levy JH, Cormack JG, Morales A. Heparin neutralization by recombinant platelet factor 4 and protamine. Anesth Analg 1995; 81: 35–37.PubMedGoogle Scholar
  186. 186.
    Dehmer GJ, Fisher M, Tate DA, Teo S, Bonnem EM. Reversal of heparin anticoagulation by recombinant platelet factor 4 in humans. Circulation 1995; 91: 2188–2194.PubMedCrossRefGoogle Scholar
  187. 187.
    Riess FC, Potsch B, Behr I, et al. Recombinant hirudin as an anticoagulant during cardiac operations: experiments in a pig model. Eur J Cardiothorac Surg 1997; 11: 739–745.PubMedCrossRefGoogle Scholar
  188. 188.
    Bernabei A, Rao AK, Niewiarowski S, Colman RW, Sun L, Edmunds LH Jr. Recombinant desulphatohirudin as a substitute for heparin during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1994; 108: 381, 382.Google Scholar
  189. 189.
    Edmunds LH Jr. HIT, HITT and desulphatohirudin: look before you leap. J Thorac Cardiovasc Surg 1995; 110: 1–3.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Ron G. H. Speekenbrink
  • Wim van Oeveren
  • Charles R. H. Wildevuur
  • Leon Eijsman

There are no affiliations available

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