Abstract
In an effort to reduce morbidity associated with transfusion of blood products, the use of antifibrinolytics to decrease bleeding and transfusions after cardiopulmonary bypass (CPB) is receiving widespread attention. The predominant haemostatic defect induced by CPB and, therefore, the mechanisms by which natural (aprotinin) or synthetic antifibrinolytics (Σ-aminocaproic acid, tranexamic acid) exert their effects have been difficult to define. Nonetheless, all three substances appear to be effective in the treatment or in the prevention of excessive bleeding associated with cardiac surgery. However, the administration of these drugs should not attempt to replace meticulous surgical and anaesthetic care. In particular, the importance of an appropriate transfusion practice cannot be overemphasized. The efficient use of these, sometimes expensive, drugs must take into account not only the initial cost, but also the shortand long-term economic consequences for the health care provider of using, or not using, a given medication. Unfortunately, the comprehensive data on which authoritative conclusions may be reached are not yet available. Pending availability of these data, the present use of antifibrinolytics at the Montreal Heart Institute is the following: (1) patients undergoing elective primary myocardial revascularization or valve surgery do not receive prophylactic antifibrinolytics; (2) patients undergoing repeat myocardial revascularization, repeat valve surgery, or primary or repeat combined procedures, receive prophylactic Σ-aminocaproic acid; (3) Σ-aminocaproic acid may be used to treat excessive chest drainage in the postoperative period; (4) the prophylactic and the therapeutic uses of low doses of aprotinin are currently under investigation.
Résumé
Afin de réduire morbidité associée aux transfusion sanguines, les anesthésistes et les chirurgiens cardiaques utilisent de plus en plus les antifibrinolytiques dans le but de diminuer le saignement et les besoins transfusionnels secondaires à la circulation extracorporelle (CEC). Les modifications de l’hémostase induites par la CEC et, par voie de conséquence, les mécanismes d’action des antifibrinolytiques naturels (l’aprotinine) ou de synthèse (l’acide Σ-aminocaproique et l’acide tranexamique), sont mal connus. Néanmoins, l’efficacité des ces trois médicaments pour prévenir ou trailer le saignement secondaire à la CEC ne semble plus de doute. Toutefois, ces médicaments ne peuvent remplacer les soins attentifs des anesthésistes et des chirurgiens et, tout particuliérement, une pratique transfusionnelle adéquate. Afin de parvenir à une utilisation efficient de ces médicaments parfois coûteux, le dispensateur de soins devra tenir compte non seulement de leur coût d’achat, mais également des conséquences à court et à long terme de leur utilisation ou de leur non-utilisation. Malheureusement, toutes les données nécessaires à cette analyse coût/bénéfice ne sont pas encore disponibles. En attendant les résultats de ces études, le protocole en vigueur à l’Institut de Cardiologie de Motréalpeut se résumer ainsi: 1) les patients subissant une chirurgie élective et de première intention pour revascularisation du myocarde ou remplacement valvulaire ne recoivent pas d’antifibrinolytiques de façon prophylactique; 2) les patients réoperés pour revascularisation du myocarde ou remplacement valvulaire, ou subissant toute chirurgie combinée (primaire ou de réintervention) recoivent de l’acide Σ-aminocaproique en prophylaxie; 3) l’acide Σ-animocaproique peut être utilisé dans le traitement d’un saignement médiastinal excessif dans la période post-opératoire; 4) concurremment, nous sommes à étudier l’efficacité de faibles doses d’aprotinine en chirurgie cardiaque de l’adulte.
Article PDF
Similar content being viewed by others
References
Cooper BA, Leclerc JR. Overview of hemostasis and blood coagulation. In: Leclerc JR (Ed.). Venous Thromboembolic Disorders, Philadelphia: Lea & Febiger, 1991; 1–16.
Adelman B, Michelson AD, Loscalzo J, Greenberg J, Handin RI. Plasmin effect on platelet glycoprotein Ib-von Willebrand factor interaction. Blood 1985; 65: 32–40.
Manxmen EF, Koets MH, Washington BC, et al. Hemostasis changes during cardiopulmonary bypass surgery. Semin Thromb Hemost 1985; 11: 281–92.
Harker LA, Malpass TW, Branson HE, Hessel EA II,Slichter SJ. Mechanism of abnormal bleeding in patients undergoing cardiopulmonary bypass: acquired transient platelet dysfunction associated with selective alpha-granule release. Blood 1980; 56: 824–34.
Harker LA. Bleeding after cardiopulmonary bypass. N Engl J Med 1986; 314: 1446–8.
Umlas J. Transfusion therapy of patients undergoing cardiopulmonary bypass. In: Churchill WH, Kuntz SR (Eds.). Transfusion Medicine, Chicago: Blackwell Scientific Publication, 1988; 249–64.
Campbell FW, Addonizio VP Jr. Platelet function alterations during cardiac surgery. In: Ellison N, Jobes DR (Eds.) Effective Hemostasis in Cardiac Surgery. Philadelphia: W. B. Saunders Company, 1988; 85–109.
Woodman RC, Harker LA. Bleeding complications associated with cardiopulmonary bypass. Blood 1990; 76: 1680–97.
Czer LSC. Mediastinal bleeding after cardiac surgery: etiologies, diagnostic considerations, and blood conservation methods. Journal of Cardiothoracic Anesthesia 1989; 3: 760–75.
Gluszko P, Rucinski B, Musial J, et al. Fibrinogen receptors in platelet adhesion to surfaces of extracorporeal circuit. Am J Physiol 1987; 252: H615–21.
van Oeveren W, Harder HP, Roozendaal KJ, Eijsman L, Wildevuur CRH. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990; 99: 788–97.
Rinder CS, Bohnert J, Rinder HM, Mitchell J, Ault K, Hillman R. Platelet activation and aggregation during cardiopulmonary bypass. Anesthesiology 1991; 75: 388–93.
Verstraete M. Clinical application of inhibitors of fibrinolysis. Drugs 1985; 29: 236–61.
Ogston D. Current status of antifibrinolytic drugs. Blood Rev 1989; 3: 1–4.
Andersson L, Nilsson IM, Colleen S, Grandstrand B, Melander B. Role of urokinase and tissue activator in sustaining bleeding and the management thereof with EACA and AMCA. Ann N Y Acad Sci 1969; 146: 642–58.
Horrow JC, Hlavacek J, Strong D, et al. Prophylactic tranexamic acid decreases bleeding after cardiac operations. J Thorac Cardiovasc Surg 1990; 99: 70–4.
Vander Salm TJ, Ansell JE, Okike ON, et al. The role of epsilon-aminocaproic acid in reducing bleeding after cardiac operation: a double-blind randomized study. J Thorac Cardiovasc Surg 1988; 95: 538–40.
DelRossi AJ, Cernaianu AC, Botros S, Lemole GM, Moore R. Prophylactic treatment of postperfusion bleeding using EACA. Chest 1989; 96: 27–30.
Horrow JC. Desmopressin and antifibrinolytics. Int Anesthesiol Clin 1990; 28: 230–6.
Gralnick HR, Greipp P. Thrombosis with epsilon aminocaproic acid therapy. Am J Clin Path 1971; 56: 151–4.
Latour JG, Liger-Gauthier C, Daoust-Fiorilli J. Vasoactive agents and production of thrombosis during intravascular coagulation 1 —comparative effects of norepinephrine in thrombin and adenosine diphosphate (ADP) treated rabbits. Pathology 1984; 16: 411–7.
Fischbach DP, Fogdall RP. Coagulation: the Essentials. 1st ed. Baltimore: Williams & Wilkins, 1981.
Marin HM. Hemostatic mechanism in extracorporeal circulation. Arch Surg 1964; 88: 988–98.
Brodsky I, Gill DN, Lusch CJ. Fibrinolysis in congenital heart disease —preoperative treatment with Σ-aminocaproic acid. Am J Clin Path 1969; 51: 51–7.
Gralnick HR. Σ-aminocaproic acid in preoperative correction of haemostatic defect in cyahotic congenital heartdisease. Lancet 1970; 1: 1204–5.
Gomes MMR, McGoon DC. Bleeding patterns after openheart surgery. J Thorac Cardiovasc Surg 1970; 60: 87–97.
Midell AI, Hallman GL, Bloodwell RD, Beall JrAC, Yashar JJ, Cooley DA. Epsilon-aminocaproic acid for bleeding after cardiopulmonary bypass. Ann Thorac Surg 1971; 11: 577–82.
Kevy SV, Glickman RM, Bernhard WF, Diamond LK, Gross RE. The pathogenesis and control of the hemorrhagic defect in open heart surgery. Surg Gynec Obstet 1966; 123: 313–8.
Stems LP, Lillehei CW. Effect of epsilon aminocaproic acid upon blood loss following open-heart surgery: an analysis of 340 patients. Can J Surg 1967; 10: 304–7.
McClure PD, Izsak J. The use of epsilon-aminocaproic acid to reduce bleeding during cardiac bypass in children with congenital heart disease. Anesthesiology 1974; 40: 604–8.
Gralnick HR, Fischer RD. The hemostatic response to open-heart operations. J Thorac Cardiovasc Surg 1971; 61: 909–15.
Rhodes GR, Silver D. Periepicardial fibrinolytic activity: relation to cardiac bleeding. Surg 1975; 78: 230–7.
Bick RL. Hemostasis defects associated with cardiac surgery, prosthetic devices, and other extracorporeal circuits. Semin Thromb Hemost 1985; 11: 249–80.
Kucuk O, Kwaan HC, Frederickson J, Wade L, Green D. Increased fibrinolytic activity in patients undergoing cardiopulmonary bypass operation. Am J Hematol 1986; 23: 223–9.
Tanaka K, Takao M, Yada I, Yuasa H, Kusagawa M, Deguchi K. Alterations in coagulation and fibrinolysis associated with cardiopulmonary bypass during open heart surgery. Journal of Cardiothoracic Anesthesia 1989; 3: 181–8.
Lambert CJ, Marengo-Rowe AJ, Leveson JE, et al. The treatment of postperfusion bleeding using Σ-aminocaproic acid, cryoprecipitate, fresh-frozen plasma, and protamine sulfate. Ann Thorac Surg 1979; 28: 440–4.
Karski J, Teasdale S, Young P, Carroll J, Ivanov J, Glynn M. Antifibrinolysin therapy for the prevention of postCPB bleeding. Can J Anaesth 1991; 38: A97.
Horrow JC, Van Riper DF, Parmet J, Strong MD, Brodsky I, Osborne D. Tranexamic acid, not desmopressin or both, decreases bleeding after open heart surgery. Anesthesiology 1990; 73: A63.
Fritz H, Wunderer G. Biochemistry and applications of aprotinin, the kallikrein inhibitor from bovine organs. Arzneimittelforsch 1983; 33: 479–94.
Hoffmann H, Siebeck M, Thetter O, Jochum M, Fritz H. Aprotinin concentrations effective for the inhibition of tissue kallikrein and plasma kallikrein in vitro and in vivo. Adv Exp Med Biol 1989; 247B: 35–42.
Kaller H, Patzschke K, Wegner LA, Horster FA. Pharmacokinetic observations following intravenous administration of radioactive labelled aprotinin in volunteers. Eur J Drug Metab Pharmacokinet 1978; 2: 79–85.
D’Ambra MN, Risk SC. Aprotinin, erythropoietin and blood substitutes. Int Anesthesiol Clin 1990; 28: 237–40.
Emerson TE Jr. Pharmacology of aprotinin and efficacy during cardiopulmonary bypass. Cardiovasc Drug Rev 1989; 7: 127–40.
van Oeveren W, Jansen NJG, Bidstrup BP, et al. Effects of aprotinin on hemostatic mechanisms during cardiopulmonary bypass. Ann Thorac Surg 1987; 44: 640–5.
Royston D, Bidstrup BD, Taylor KM, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987; 1: 1289–94.
Bidstrup BP, Royston D, Sapsford RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (trasylol). J Thorac Cardiovasc Surg 1989; 97: 364–72.
Blauhut B, Gross C, Necek S, et al. Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement and renal function after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991; 101: 958–67.
Freeman JG, Turner GA, Venables CW, Latner AL. Serial use of aprotinin and incidence of allergic reactions. Curr Med Res Opin 1983; 8: 559–61.
Bohrer H, Fleischer F, Lang J, Vahl C. Early formation of thrombi on pulmonary artery catheters in cardiac surgical patients receiving high-dose aprotinin. Journal of Cardiothoracic Anesthesia 1990; 4: 222–5.
Youngberg JA. Aprotinin and thrombus formation on pulmonary artery catheters: a piece of the coagulation puzzle. Journal of Cardiothoracic Anesthesia 1990; 4: 155–8.
Tuxen DV, Cade JF. Effects of aprotinin in adult respiratory distress syndrome. Anaesth Intensive Care 1986; 14: 390–9.
Sunamori M, Innami R, Amano J, Suzuki A, Harrison CE. Role of protease inhibition in myocardial preservation in prolonged hypothermic cardioplegia followed by reperfusion. J Thorac Cardiovasc Surg 1988; 96: 314–20.
Tice DA, Worth MH Jr, Clauss RH, Reed GH. The inhibition of Trasylol of fibrinolytic activity associated with cardiovascular operations. Surg Gynecol Obstet 1964; 119: 71–4.
Mammen EF. Natural proteinase inhibitors in extracorporeal circulation. Ann NY Acad Sci 1968; 146: 754–62.
Ambrus JL, Schimert G, Laps TZ, et al. Effect on antifibrinolytic agents and estrogens on blood loss and blood coagulation factors during open heart surgery. J Med 1971; 2: 65–81.
Dietrich W, Spannagl M, Jochum M, et al. Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Anesthesiology 1990; 73: 1119–26.
Alajmo F, Calamai G, Perna AM, et al. High-dose aprotinin: hemostatic effects in open heart operations. Ann Thorac Surg 1989; 48: 536–9.
Dietrich W, Barankay A, Dilthey G, et al. Reduction of homologous blood requirements in cardiac surgery by intraoperative aprotinin application —clinical experience in 152 cardiac surgical patients. Thorac Cardiovasc Surg 1989; 37: 92–8.
Fraedrich G, Weber C, Bernard C, Hettwer A, Schlosser V. Reduction of blood transfusion requirement in open heart surgery by administration of high doses of aprotinin —preliminary results. Thorac Cardiovasc Surg 1989; 37: 89–91.
Wildevuur CRH, Eijsman L, Roozendaal KJ, Harder MP, Chang M, van Oeveren W. Platelet preservation during cardiopulmonary bypass with aprotinin. Eur J Cardiothorac Surg 1989; 3: 533–8.
Harder MP, Eijsman L, Roozendaal KJ, van Oeveren W, Wildevuur CRH. Aprotinin reduces intraoperative and postoperative blood loss in membrane oxygenator cardiopulmonary bypass. Ann Thorac Surg 1991; 51: 936–41.
Havel M, Teufelsbauer H, Knobl P, et al. Effect of intraoperative aprotinin administration on postoperative bleeding in patients undergoing cardiopulmonary bypass operation. J Thorac Cardiovasc Surg 1991; 101: 968–72.
Murkin JM, Shannon NA. High-dose aprotinin decreases blood product usage in cardiac patients undergoing repeat sternotomy. Can J Anaesth 1991; 38: A76.
Ferraris VA, Ferraris SF, Lough FC, Berry WR. Preoperative aspirin ingestion increases operative blood loss after coronary artery bypass grafting. Ann Thorac Surg 1988; 45: 71–4.
Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Aprotinin (Trasylol) reduces bleeding after open heart surgery in patients taking Aspirin and those with renal failure. Anesthesiology 1989; 71: A6.
Wiman B. On the reaction of plasmin or plasminstreptokinase complex with aprotinin or alpha2-antiplasmin. Thromb Res 1980; 17: 143–52.
Angelini GD, Cooper GJ, Lamarra M, Bryan AJ. Unorthodox use of aprotinin to control life-threatening bleeding after cardiopulmonary bypass. Lancet 1990; 335: 799–800.
Stibbe J, Kluft C, Brommer EJP, Gomes M, De Jong DS, Nauta J. Enhanced fibrinolytic activity during cardiopulmonary bypass in open heart surgery in man is caused by extrinsic (tissue-type) plasminogen activator Eur J Clin Invest 1984; 14: 375–82.
Edmunds LH Jr, Niewiarowski S, Colman RW. Invited letter concerning Aprotinin. J Thorac Cardiovasc Surg 1991; 101: 1103–4.
Rodgers RPC, Levin J. A critical reappraisal of the bleeding time. Semin Thromb Hemostas 1990; 16: 1–20.
Marx G, Pokar H, Reuter H, Doering V, Tilsner V. The effects of aprotinin on hemostatic function during cardiac surgery. Journal of Cardiothoracic and Vascular Anesthesia 1991; 5: 467–74.
Philipp E. Calculations and hypothetical considerations on the inhibition of plasmin and plasma kallikrein by Trasylol. In: Davidson JF, Rowan RM, Samama MM, Desnoyers PC (Eds.). Progress in Chemical Fibrinolysis and Thrombolysis, volume 3, New York: Raven Press, 1978; 291–5.
Clasen C, Jochum M, Mueller-Esterl W. Feasability study of very high aprotinin dosage in polytrauma patients. In: Redl H, Schlag G (Eds). First Vienna Shock Forum, New York: Alan R Liss Inc., 1987; 175–83.
Isetta C, Samat C, Kotaiche M, Jourdan J, Grimaud D. Low dose aprotinin or tranexamic acid treatment in cardiac surgery. Anesthesiology 1991; 75: A80.
Benmosbah L, Modi S, Castel S, Kieffer JP, Cousin MT. Does low dose aprotinin reduce blood loss following cardiopulmonary bypass? Anesthesiology 1991; 75: A983.
Royston D, Bidstrup BP, Sapsford RM. Reduced blood loss following open heart surgery with aprotinin (trasylol) is associated with an increase in intraoperative activated clotting time (ACT). Journal of Cardiothoracic Anesthesia 1989; 3(Suppl 1): 80.
e Smet A, Joen M, van Oeveren W, et al. Increased anticoagulation during cardiopulmonary bypass by aprotinin. J Thorac Cardiovasc Surg 1990; 100: 520–7.
Dietrich W, Hähnel C, Richter JA. Routine application of high-dose aprotinin in open heart surgery —a study on 1,784 patients. Anesthesiology 1990; 73: A146.
Hardy JF, Perrault J, Tremblay N, Robitaille D, Blain R, Carrier M. The stratification of cardiac surgical procedures according to use of blood products: a retrospective analysis of 1,480 cases. Can J Anaesth 1991; 38: 511–7.
Boldt J, Zickmann B, Czeke A, Herold C, Dapper F, Hempelmann G. Blood conservation techniques and platelet function in cardiac surgery. Anesthesiology 1991; 75: 426–32.
Goodnough LT, Johnston MFM, Toy PTCY and the Transfusion Medicine Academic Award Group. The variability of transfusion practice in coronary artery bypass surgery. JAMA 1991; 265: 86–90.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hardy, JF., Desroches, J. Natural and synthetic antifibrinolytics in cardiac surgery. Can J Anaesth 39, 353–365 (1992). https://doi.org/10.1007/BF03009046
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF03009046