More Effective Suppression of Hemostatic System Activation in Patients Undergoing Cardiac Surgery by Heparin Dosing Based on Heparin Blood Concentrations rather than ACT

George J Despotis; J Heinrich Joist; Charles W Hogue Jr; Alexander Alsoufiev; D Joiner-Maier; Samuel A Santoro; Edward Spitznagel; Jeffrey I Weitz; Lawrence T Goodnough

doi:10.1055/s-0038-1650684

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1996; 76(06): 0902-0908
DOI: 10.1055/s-0038-1650684

Original Article

Schattauer GmbH Stuttgart

More Effective Suppression of Hemostatic System Activation in Patients Undergoing Cardiac Surgery by Heparin Dosing Based on Heparin Blood Concentrations rather than ACT

George J Despotis

The Departments of Anesthesiology, Internal Medicine, Pathology, Washington University School of Medicine, St. Louis

,

J Heinrich Joist

²Departments of Internal Medicine and Pathology, St. Louis University School of Medicine, St. Louis

,

Charles W Hogue Jr

The Departments of Anesthesiology, Internal Medicine, Pathology, Washington University School of Medicine, St. Louis

,

Alexander Alsoufiev

The Departments of Anesthesiology, Internal Medicine, Pathology, Washington University School of Medicine, St. Louis

,

D Joiner-Maier

²Departments of Internal Medicine and Pathology, St. Louis University School of Medicine, St. Louis

,

Samuel A Santoro

The Departments of Anesthesiology, Internal Medicine, Pathology, Washington University School of Medicine, St. Louis

,

Edward Spitznagel

³Department of Mathematics, Washington University, St. Louis, MO, USA

,

Jeffrey I Weitz

⁴Department of Medicine, McMaster University & Hamilton Civic Hospitals Research Center, Hamilton, Ontario, Canada

,

Lawrence T Goodnough

The Departments of Anesthesiology, Internal Medicine, Pathology, Washington University School of Medicine, St. Louis

› Institutsangaben

Abstract

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Summary

This study was designed to determine whether the maintenance of higher than usual patient-specific heparin concentrations during cardiopulmonary bypass (CPB) was associated with more effective suppression of hemostasis system activation.

Thirty-one patients scheduled for repeat cardiac sugery or combined procedures (i.e., coronary revascularization + valve repair/replacement) were consented and enrolled in this study. All patients received porcine heparin and protamine and were randomly assigned to monitoring of anticoagulation by either celite ACT alone (Control, n = 16) or by kaolin ACT combined with on-site measurements of whole blood heparin concentration (Intervention, n = 15). Blood specimens collected before administration of heparin, before weaning from CPB and after administration of protamine were analyzed with a battery of coagulation assays.

Patients in the intervention cohort received appreciably greater heparin doses than control patients, resulting in higher anti-Xa heparin levels at the end of CPB. Fibrinopeptide A and D-dimer levels were higher in the control group before discontinuation of CPB. Percent decrease during CPB were greater in the control group for factors V and VIII, fibrinogen and antithrombin III. Percent decrease in complement 3 was greater in the control group after protamine and bleeding times measured in the Intensive Care Unit were significantly more prolonged in this group.

Maintenance of higher patient-specific heparin concentrations during CPB more effectively suppresses excessive hemostatic system activation than do standard heparin doses chosen based on measurement of ACT. These findings may explain, at least in part, the significant reduction in perioperative blood loss and blood product use when higher heparin concentrations are maintained.

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Referenzen

References
1 Ottesen S, Stormorken H, Hatteland K. The value of activated coagulation time in monitoring heparin therapy during extracorporeal circulation. Scand J Thorac Cardiovasc Surg 1984; 18: 123-128
2 Metz S, Keats AS. Low activated coagulation time during cardiopulmonary bypass does not increase postoperative bleeding. Ann Thorac Surg 1990; 49: 440-444
3 Kesteven PJ, Pasaoglu I, Williams BT, Savidge GF. Significance of the whole blood activated clotting time in cardiopulmonary bypass. J Cardiovasc Surg 1986; 27: 85-89
4 Culliford AT, Gitel SN, Starr N, Thomas ST, Baumann FG, Wessler S, Spencer FC. Lack of correlation between activated clotting time and plasma heparin during cardiopulmonary bypass. Annals of Surgery 1981; 193: 105-111
5 Cohen EJ, Cameriengo LJ, Dearing JP. Activated clotting times and cardiopulmonary bypass. I. The effect of hemodilution and hypothermia upon activated clotting time. JECT 1980; 12: 139-141
6 Despotis GJ, Summerfield AL, Joist JH, Foodnough LT, Santoro SA, Spitznagel E, Cox JL, Lappas DG. Comparison of activated coagulation time and whole blood heparin measurements with laboratory plasma anti-Xa heparin concentration in patients having cardiac operations. J Thorac Cardiovasc Surg 1994; 108: 1076-1082
7 Slaughter TF, Le Bleu TH, Douglas Jr JM, Leslie JB, Parker JK, Greenberg CS. Characterization of prothrombin activation during cardiac surgery by hemostatic molecular markers. Anesthesiology 1994; 80: 520-526
8 Jobes DR, Schwartz AJ, Ellison N, Andrews R, Ruffini RA, Ruffini JJ. Monitoring heparin anticoagulation and its neutralization. Ann Thorac Surg 1981; 31: 161-166
9 Gravlee GP, Rogers AT, Dudas LM, Taylor R, Roy RC, Case LD, Triscott M, Brown CW, Mark LJ, Cordell AR. Heparin management protocol for cardiopulmonary bypass influences postoperative heparin rebound but not bleeding. Anesthesiology 1992; 76: 393-401
10 Gravlee GP, Haddon WS, Rothberger HK, Mills SA, Rogers AT, Bean VE, Buss DH, Prough DS, Cordell AR. Heparin dosing and monitoring for cardiopulmonary bypass. A comparison of techniques with measurement of subclinical plasma coagulation. J Thorac Cardiovasc Surg 1990; 99: 518-527
11 Fox DJ, Gaines J, Reed G. Vehicles of heparin management: A comparison. J Exp Corp Tech 1979; 11: 137-141 (Abstract).
12 Harloff M, Taraskiewicz T, Fotouhi C. Comparison study of the hepcon system four and the hemostasis management system. perfusion 1991; 6: 297-301
13 Hashimoto K, Yamagishi M, Sasaki T, Nakano M, Kurosawa H. Heparin and antithrombin III levels during cardiopulmonary bypass: correlation with subclinical plasma coagulation. Ann Thorac Surg 1995; 58: 799-805
14 Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin Ill-independent inhibitors. J Clin Invest 1990; 86: 385-391
15 Tollefsen FA, Fernandez F, Gauthier D, Buchanan MR. Heparin cofactor II and other endogenous factor in the mediation of the antithrombotic and anticoagulant effects of heparin and dermatan sulfate. Semin Thromb Hemost 1985; 86: 385-391
16 Despotis GJ, Joist JH, Hogue CW, Alsoufiev A, Kater K, Goodnough LT, Santoro SA, Spitznagel E, Rosenblum M, Lappas DG. The impact of heparin concentration and activated clotting time monitoring on blood conservation: a prospective, randomized evaluation in patients undergoing cardiac operations. J Thorac Cardiovasc Surg 1995; 110: 46-54
17 Despotis GJ, Santoro SA, Spitznagel E, Kater KM, Cox JL, Barnes P, Lappas DG. Prospective evaluation and clinical utility of on-site monitoring of coagulation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1994; 107: 271-279
18 Khuri SF, Wolfe JA, Josa M, Axford TC, Szymanski I, Assousa S, Ragno G, Patel M, Silverman A, Park M. Hematologic changes during and after cardiopulmonary bypass and their relationship to the bleeding time and nonsurgical blood loss. J Thorac Cardiovasc Surg 1992; 104: 94-107
19 Babson SR, Babson AL. Development and evaluation of a disposable device for performing simultaneous duplicate bleeding time determinations. Am J Clin Pathol 1978; 70: 406-408
20 Hirsh J. Heparin. [Review]. N Engl J Med 1991; 324: 1565-1574
21 Esposito RA, Culliford AT, Colvin SB, Thomas SJ, Lackner H, Spencer FC. Heparin resistance during cardiopulmonary bypass. The role of heparin pretreatment. J Thorac Cardiovasc Surg 1983; 85: 346-353
22 Hill JD, Dontigny L, De Leval M, Mielke Jr CH. A simple method of heparin management during prolonged extracorporeal circulation. Ann Thorac Surg 1974; 17: 129-134
23 Verska JJ. Control of heparinization by activated clotting time during bypass with improved postoperative hemostasis. Ann Thorac Surg 1977; 24: 170-173
24 Babka R, Colby C, El-Etr A, Pifarre R. Monitoring of intraoperative heparinization and blood loss following cardiopulmonary bypass surgery. J Thorac Cardiovasc Surg 1977; 73: 780-782
25 Bull BS, Korpman RA, Huse WM, Briggs BD. Heparin therapy during extracorporeal circulation. I. Problems inherent in existing heparin protocols. J Thorac Cardiovasc Surg 1975; 69: 674-684
26 Akl BF, Vargas GM, Neal J, Robillard J, Kelly P. Clinical experience with the activated clotting time for the control of heparin and protamine therapy during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1980; 79: 97-102
27 Umlas J, Gauvin G, Taff R. Heparin monitoring and neutralization during cardiopulmonary bypass using a rapid plasma separator and a fluorometric assay. Ann Thorac Surg 1984; 37: 301-303
28 Stenbjerg S, Berg E, Albrechtsen OK. Heparin levels and activated clotting time (ACT) during open heart surgery. Scand J Haematol 1981; 26: 281-284
29 Gravlee GP. Anticoagulation for cardiopulmonary bypass. In: Cardiopulmonary Bypass: Principles and Practice Gravlee GP, Utley RF. eds. Baltimore: Williams & Wilkens: 1993: 340-380
30 Moorehead MT, Westengard JC, Bull BS. Platelet involvement in the activated coagulation time of heparinized blood. Anesth Analg 1984; 63: 394-398
31 Jobes DR, Schaffer GW, Aitken GL. Increased accuracy and precision of heparin and protamine dosing reduces blood loss and transfusion in patients undergoing primary cardiac operations. J Thorac Cardiovasc Surg 1995; 110: 36-45
32 Saleem A, Shenaq SS, Yawn DH, Harshberger K, Diemunsch P, Mohindra P. Heparin monitoring during cardiopulmonary bypass. Ann Clin Lab Sci 1984; 14: 474-479
33 Boldt J, Schindler E, Osmer C, Wittstock M, Stertmann WA, Hempelmann G. Influence of different anticoagulation regimens on platelet function during cardiac surgery. Br J Anaesth 1994; 73: 639-644
34 Despotis GJ, Filos KS, Zoys TN, Hogue CWJ, Spitznagel E, Lappas DG. Factors associated with excessive postoperative blood loss and hemostatic transfusion requirements: A multivariate analysis in cardiac surgical patients. Anesth Analg 1996; 82: 13-21
35 Thomas DP, Barrowcliffe TW, Johnson EA. The influence of tissue source, salt and molecular weight and heparin activity. [Review]. Scand J Haematol Suppl 1980; 36: 40-49
36 Rinder CS, Bohnert J, Rinder HM, Mitchell J, Ault K, Hillman R. Platelet activation and aggregation during cardiopulmonary bypass. Anesthesiology 1991; 75: 388-393
37 Addonizio Jr VP, Colman RW, Edmunds Jr LH. The effect of blood flow rate and circuit surface area on platelet loss during extracorporeal circulation. Trans Am Soc Artif Intern Organs 1978; 24: 650-655
38 Despotis FJ, Grishaber JE, Goodnough LT. The effect of an intraoperative treatment algorithm on physicians’ transfusion practice in cardiac surgery. Transfusion 1994; 34: 290-296
39 Van der Graaf F, Keus FJ, Vlooswijk RA, Bouma BN. The contact activation mechanism in human plasma: activation induced by dextran sulfate. Blood 1982; 59: 1225-1233
40 Heimark RL, Kurachi K, Fujikawa K, Davie EW. Surface activation of blood coagulation, fibrinolysis and kinin formation. Nature 1980; 286: 456-460
41 Boisclair MD, Lane DA, Philippou H, Esnouf MP, Sheikh S, Hunt B, Smith KJ. Mechanisms of thrombin generation during surgery and cardiopulmonary bypass. Blood 1993; 82: 3350-3357
42 Holloway DS, Summaria L, Sandesara J, Vagher JP, Alexander JC, Caprini JA. Decreased platelet number and function and increased fibrinolysis contribute to postoperative bleeding in cardiopulmonary bypass patients. Thromb Haemost 1988; 59: 62-67
43 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
44 Gram J, Janetzko T, Jespersen J, Bruhn HD. Enhanced effective fibrinolysis following the neutralization of heparin in open heart surgery increases the risk of post-surgical bleeding. Thromb Haemost 1990; 63: 241-245
45 Young JA, Kisker CT, Doty DB. Adequate anticoagulation during cardiopulmonary bypass determined by activated clotting time and the appearance of fibrin monomer. Ann Thorac Surg 1978; 26: 231-240
46 Dietrich W, Dilthey G, Spannagl M, Jochum M, Braun SL, Richter JA. Influence of high-dose aprotinin on anticoagulation, heparin requirement, and celite- and kaolin-activated clotting time in heparin-pretreated patients undergoing open-heart surgery. Anesthesiology 1995; 83: 679-689
47 Dietrich W, Spannagl M, Schramm W, Vogt W, Barankay A, Richter JA. The influence of preoperative anticoagulation on heparin response during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991; 102: 505-514
48 Abildgaard U. Heparin/low molecular weight heparin and tissue factor pathway inhibitor. [Review]. Haemostasis 1993; 23 (Suppl. 01) 103-106
49 Lindahl AK, Abildgaard U, Staalesen R. The anticoagulant effect in heparinized blood and plasma resulting from interactions with extrinsic pathway inhibitor. Thromb Res 1991; 64: 155-168
50 Salzman EW, Rosenberg RD, Smith MH, Lindon JN, Favreau L. Effect of heparin and heparin fractions on platelet aggregation. [Review]. J Clin Invest 1980; 65: 64-73
51 Holmer E, Lindahl U, Backstrom G, Thunberg L, Sandberg H, Soderstrom G, Anderson LO. Anticoagulant activities and effects on platelets of a heparin fragment with high affinity for antithrombin. Thromb Res 1980; 18: 861-869
52 Fernandez F, N’guyen P, Van Ryn J, Ofosu FA, Hirsh J, Buchanan MR. Hemorrhagic doses of heparin and other glycosaminoglycans induce a platelet defect. Thromb Res 1986; 43: 491-495
53 John LC, Rees GM, Kovacs IB. Inhibition of platelet function by heparin. An etiologic factor in postbypass hemorrhage. J Thorac Cardiovasc Surg 1993; 105: 816-822
54 Suzuki K, Nishioka J, Hashimoto S. Inhibition of factor VUI-associated platelet aggregation by heparin and dextran sulfate, and its mechanism. Biochim Biophys Acta 1979; 585: 416-426
55 Sobel M, McNeill PM, Carlson PL, Kermode JC, Adelman B, Conroy R, Marques D. Heparin inhibition of von Willebrand factor-dependent platelet function in vitro and in vivo. Journal of Clinical Investigation 1991; 87: 1787-1793
56 Guffin AV, Dunbar RW, Kaplan JA, Bland Jr JW. Successful use of a reduced dose of protamine after cardiopulmonary bypass. Anesth Analg 1976; 55: 110-113
57 Shastri KA, Logue GL, Stern MP, Raza S, O’Connor BM, Bovill JJ, Hoover EL. Neutrophil lactoferrin release during open heart surgery is unrelated to complement activation. ASAIO J 1994; 40: 56-61
58 Moorman RM, Zapol WM, Lowenstein E. Neutralization of Heparin Anticoagulation. In: Cardiopulmonary Bypass: Principles and Practice Gravlee GP, Utley RF. eds. Baltimore: Williams & Wilkens: 1993: 381-382