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J Thorac Cardiovasc Surg 2005;129:1391-1394
© 2005 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Assessment of hemostatic activation during cardiopulmonary bypass for coronary artery bypass grafting with bivalirudin: Results of a pilot study

^a Department of Anesthesia, Deutsches Herzzentrum Berlin, Berlin, Germany
^b Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany
^c Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio
^d Department of Cardiac Surgery, The Sanger Clinic, Gastonia, NC
^e Department of Cardiothoracic Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio
^f Department of Cardiothoracic Anesthesia, Virginia Commonwealth University, Richmond, Va.

Received for publication June 2, 2004; revisions received September 2, 2004; accepted for publication September 7, 2004.

^_* Address for reprints: Andreas Koster, MD, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. (Email: koster{at}dhzb.de).

	Abstract

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OBJECTIVE: Bivalirudin has been successfully used as a replacement for heparin during on-pump coronary artery bypass grafting. This study was conducted to assess the effects of the currently suggested protocol for bivalirudin on hemostatic activation during cardiopulmonary bypass with and without cardiotomy suction.

METHODS: Ten patients scheduled for coronary artery bypass grafting were enrolled. Bivalirudin was given with a bolus of 50 mg in the priming solution and 1.0 mg/kg for the patient, followed by an infusion of 2.5 mg · kg^–1 · h^–1 until 15 minutes before the conclusion of cardiopulmonary bypass. Cardiopulmonary bypass was performed with a closed system in 5 patients with and in 5 patients without the use of cardiotomy suction. Blood samples were obtained before and after cardiopulmonary bypass. D-dimers, fibrinopeptide A, prothrombin 1 and 2 fragments, thrombin-antithrombin, and factor XIIa were determined.

RESULTS: Values for factor XIIa remained almost unchanged in both groups, indicating a minor effect of contact activation. In patients without cardiotomy suction, post-cardiopulmonary bypass values for D-dimers, fibrinopeptide A, prothrombin 1 and 2 fragments, and thrombin-antithrombin were not significantly increased compared with pre-cardiopulmonary bypass values. In patients with cardiotomy suction, values obtained for these parameters had significantly increased compared with pre-cardiopulmonary bypass values and the values obtained in the group without cardiotomy suction after cardiopulmonary bypass.

CONCLUSIONS: With this protocol, hemostatic activation during cardiopulmonary bypass was almost completely attenuated when cardiotomy suction was avoided. Cardiotomy suction results in considerable activation of the coagulation system and should therefore be restricted and replaced by cell saving whenever possible.

However, cardiac surgery involving CPB induces activation of the coagulation/inflammation system caused by contact of the blood with the large nonendothelial surfaces of CPB, release and reinfusion of tissue factor-enriched blood from the operation field aspirated by cardiotomy suction (CS), surgical trauma, and reperfusion of ischemic tissue. These procoagulant effects have been shown to occur with the use of UFH as anticoagulation therapy and even with the use of coated extracorporeal circuits.^6,7 The currently used bivalirudin scheme for anticoagulation during CPB has not yet been evaluated with regard to its effect on hemostatic activation caused by the same factors. This investigation was performed to evaluate whether the currently suggested protocol for anticoagulation with bivalirudin during CPB provides effective attenuation of hemostatic activation and to assess the influence of CS in this regard.

	Methods

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Patients and Anticoagulation Protocol
After approval by the local ethics committee and informed consent were obtained, 10 patients undergoing elective CABG without known disturbances of the hemostatic system or previous therapy with warfarin, aspirin, or clopidogrel for 5 days before surgery were enrolled in this prospective, randomized investigation. This pilot investigation was designed to assess a slightly different dosing protocol than the previous pilot study.⁴ The bolus for the pump was 50 mg of bivalirudin, and the bolus for the patient was bivalirudin 1 mg/kg followed by a constant infusion of 2.5 mg · kg^–1 · h^–1 until 15 minutes before the conclusion of CPB. Patients were to receive an additional bolus of bivalirudin only if the ecarin clotting time decreased to less than 400 seconds. No change was allowed in the rate of continuous infusion. In all patients, normothermic CPB was performed with a closed non-heparin-coated CPB system with a collapsible venous reservoir and roller pumps. Patients were randomized into 2 groups of 5 patients each. In one group, CS was used in combination with a cell-saving device (anticoagulation with citrate), whereas in the other group, CS was clamped out, the heart was passively vented into the venous reservoir, and blood from the operation field was processed exclusively with a cell-saving device.

Laboratory Analysis
Blood samples for determination of bivalirudin concentrations and ecarin clotting time were obtained at 15-minute intervals. Blood samples for the determination of hemostatic activation were collected 10 minutes after administration of the bivalirudin bolus (immediately before the start of CPB) and immediately after termination of CPB. Concentrations of bivalirudin were measured as described previously.² D-dimers, fibrinopeptide A, prothrombin fragments 1 and 2 (PTF1+), thrombin-antithrombin (TAT), and factor XIIa (FXIIa) were determined by standard commercially available enzyme-linked immunosorbent assay techniques.

Statistical Analysis
Statistical analysis was performed with analysis of variance by using the Duncan multiple-range test for post hoc analysis.

	Results

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There were 4 men and 1 woman with a mean age of 55.8 ± 6.1 years in the CS group and 5 male patients with a mean age of 66.4 ± 6.3 years (P = .03) in the group without CS. The mean duration of CPB was 114 ± 12.6 minutes in the CS group and 94.6 ± 27.8 minutes in the group without CS (P = .18). Eighty-five data points were obtained for measurement of bivalirudin concentrations during CPB. Of these, 82 were above the target concentration of 10 µg/mL during CPB. The mean bivalirudin concentrations during CPB were 13.0 ± 2.5 µg/mL (range, 9.5–18.5 µg/mL) in the CS group and 13.3 ± 2.3 µg/mL (range, 8.0–17.4 µg/mL) in the group without CS (P = .67). No patient required an additional bolus of bivalirudin.

The postoperative blood loss was 520 ± 279 mL in the CS group and 500 ± 281 mL in the group without CS (P = .93). During the entire course in the hospital, in the CS group, 4 units of packed red blood cells (median, 0) and 4 units of fresh frozen plasma (median, 0) were transfused. In the group without CS, 12 units of packed red blood cells (median, 2), 5 units of fresh frozen plasma (median, 0), and 1 unit of platelets were transfused. However, most transfusions in the group without CS were given to 1 patient, who underwent reoperation because of postoperative blood loss exceeding 1500 mL; bleeding from a sternal artery was found to be the source of hemorrhage. All patients had an otherwise uneventful postoperative course and were discharged from the hospital on schedule.

Hemostatic activation data are presented in Table 1. Regarding the marker of the contact activation system, FXIIa, no significant changes were observed between pre- and post-CPB values in the 2 groups. The values for D-dimers, PTF1+, fibrinopeptide A, and TAT as markers for thrombin and fibrin generation obtained after CPB revealed only a moderate increase in the patients in the group without CS as compared with pre-CPB values, whereas the values in the CS patients were significantly increased as compared with pre-CPB values and with the values obtained from the group without CS after CPB.

	Discussion

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Despite the marked thrombin generation in the group with CS, no thrombosis of the CPB circuit or thromboembolic complication of the patients was observed. The fact that bivalirudin concentrations were maintained at an equivalent level as compared with the group in which CS was strictly avoided suggests that the larger amounts of thrombin generated did not significantly decrease bivalirudin concentrations. Therefore, the observed hemostatic activation may not be associated with CPB thrombosis or thromboembolism, although larger studies are needed to test this assumption.

This investigation was limited by the small number of patients involved and the fact that only patients scheduled for CABG with a closed system were enrolled. However, even on the basis of this small set of data, our results provide convincing evidence that, with the current protocol for bivalirudin, hemostatic activation during CPB is effectively attenuated if CS is strictly avoided. The significant increases of selected parameters of hemostatic activation observed in the group with CS strongly suggest that aspiration of blood from the operation field should be avoided whenever possible and replaced by cell saving if bivalirudin is used for anticoagulation during CPB. This may limit indications for this agent if massive reinfusion of blood via the CS line and storage of large volumes in the cardiotomy reservoir are anticipated. However, it remains to be demonstrated how far this problem may be overcome by innovations in perfusion technique.

Further safety studies to assess the use of bivalirudin for anticoagulation during CPB are warranted. These studies have to particularly address the effect of CS on patient outcome. Accordingly, until these safety data have been compiled, particularly in view of the fact that the use of this agent for this indication is "off label," bivalirudin should be used cautiously for anticoagulation during CPB if extended use of CS during the procedure is necessary.

	Acknowledgments

 
We are grateful to Anne Gale, ELS, of the Deutsches Herzzentrum Berlin for editorial assistance.

	Footnotes

 
Supported by The Medicines Company (Parsippany, NJ).

Drs Koster, Dyke, and Spiess have a consultancy agreement with The Medicines Company.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Ruhi Yeter Semih Buz Roland Hetzer Cornelius M. Dyke Nicholas G. Smedira Bruce Spiess Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Koster, A. Articles by Spiess, B. Search for Related Content PubMed PubMed Citation Articles by Koster, A. Articles by Spiess, B. Related Collections Extracorporeal circulation