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Cardiac Surgery: In Vivo Titration of Protamine

Information source: Montreal Heart Institute
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Bleeding

Intervention: Titration protamine (Procedure); Standard administration of protamine (Drug)

Phase: N/A

Status: Completed

Sponsored by: Montreal Heart Institute

Official(s) and/or principal investigator(s):
Antoine G Rochon, Principal Investigator, Affiliation: Montreal Heart Institute

Summary

Safe use of cardiopulmonary bypass (CPB) requires massive doses of intravenous unfractionated heparin. At end-CPB, residual heparin is neutralized with intravenous injection of protamine sulfate. This prospective, randomized, controlled study will be conducted in 82 voluntary subjects admitted for elective, first intention, cardiac surgery requiring cardiopulmonary bypass. Each will be randomly assigned to one of two groups. The control group will be submitted to a standard protamine infusion of 1. 3mg :100U of the total heparin dose given during bypass. The test group will receive an infusion of protamine (over 15 minutes) until activated clotting time (ACT) values (determined every 3 minutes) depict a plateau, sign that the optimal protamine to heparin ratio has been attained. The investigators hypothesize this new in vivo titration method to be as efficient as the standard protocol (adequacy of heparin neutralization, % heparin rebound, bleeding, and transfusion), and potentially safer by its ability to prevent protamine overdose and its deleterious impact on platelet function. 15 Principal Objective Evaluate a new in vivo method of titration of protamine sulfate. Secondary Objective Evaluate the impact of this method on the adequacy of heparin neutralization by measuring: 1. platelet count 2. postoperative bleeding 3. transfusion exposure a 4. incidence of heparin rebound

Clinical Details

Official title: Cardiac Surgery : In Vivo Titration of Protamine

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome: Effective heparin neutralization (anti-Xa < 0.3 U/ml)

Secondary outcome:

Frequency of heparin rebound

Blood losses after surgery and transfusion requirements

Preservation of the platelet count

Detailed description: Protamine sulfate is administered to reverse the anticoagulant effects of heparin upon completion of cardiopulmonary bypass (CPB). In most cases, protamine is given in amounts sufficient to neutralize the total dose of heparin. 9 This dose is usually calculated with a ratio of 1. 3mg protamine for every 100U heparin given. 10 In the literature, reported doses of intraoperatively administered protamine range from 0 to 8mg per 100U of heparin. Given in excess, protamine can, in addition to complement activation and hemodynamic instability,11 induce platelet dysfunctions. 12-16 The latter significantly increases both the cost and morbidity of cardiac interventions as it is one of the main causes of postoperative bleeding. The optimal protamine/heparin ratio is difficult to individualize for each patient because of the great interpatient variability in heparin's metabolism4-7 and of the absence of correlation between ACT and heparin's plasma concentration. 8 Consumption of heparin may vary from 0. 01 to 3. 86U/Kg per minute during CPB. 30 The exact concentration of remaining circulating heparin at the end of bypass is not easily obtained.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- First intention, elective, cardiac surgery: either Coronary Artery Bypass Graft

(CABG)or valve repair/replacement.

- Patients on preoperative aspirin, clopidogrel or heparin will be included.

Exclusion Criteria:

- Combination of CABG and valve surgery

- Second intention cardiac surgery

- ASA 5 patients

- Pre-existing hemostatic disorder (as evidenced by history)

- Pregnancy

- PLavix < 5 days before de surgery

Locations and Contacts

Montreal Heart Institute, Montreal, Quebec H1T 1C8, Canada
Additional Information

Related publications:

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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 Sep;26(3):231-40.

Babka R, Colby C, El-Etr A, Pifarré R. Monitoring of intraoperative heparinization and blood loss following cardiopulmonary bypass surgery. J Thorac Cardiovasc Surg. 1977 May;73(5):780-2.

McAvoy TJ. Pharmacokinetic modeling of heparin and its clinical implications. J Pharmacokinet Biopharm. 1979 Aug;7(4):331-54.

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Gravlee GP, Case LD, Angert KC, Rogers AT, Miller GS. Variability of the activated coagulation time. Anesth Analg. 1988 May;67(5):469-72.

Despotis GJ, Gravlee G, Filos K, Levy J. Anticoagulation monitoring during cardiac surgery: a review of current and emerging techniques. Anesthesiology. 1999 Oct;91(4):1122-51. Review.

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Kirklin JK, Chenoweth DE, Naftel DC, Blackstone EH, Kirklin JW, Bitran DD, Curd JG, Reves JG, Samuelson PN. Effects of protamine administration after cardiopulmonary bypass on complement, blood elements, and the hemodynamic state. Ann Thorac Surg. 1986 Feb;41(2):193-9.

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Miyashita T, Nakajima T, Hayashi Y, Kuro M. Hemostatic effects of low-dose protamine following cardiopulmonary bypass. Am J Hematol. 2000 Jun;64(2):112-5.

Mochizuki T, Olson PJ, Szlam F, Ramsay JG, Levy JH. Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass. Anesth Analg. 1998 Oct;87(4):781-5.

Shigeta O, Kojima H, Hiramatsu Y, Jikuya T, Terada Y, Atsumi N, Sakakibara Y, Nagasawa T, Mitsui T. Low-dose protamine based on heparin-protamine titration method reduces platelet dysfunction after cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1999 Aug;118(2):354-60.

Berger RL, Ramaswamy K, Ryan TJ. Reduced protamine dosage for heparin neutralization in open-heart operations. Circulation. 1968 Apr;37(4 Suppl):II154-7.

Guffin AV, Dunbar RW, Kaplan JA, Bland JW Jr. Successful use of a reduced dose of protamine after cardiopulmonary bypass. Anesth Analg. 1976 Jan-Feb;55(1):110-3.

Moriau M, Masure R, Hurlet A, Debeys C, Chalant C, Ponlot R, Jaumain P, Servaye-Kestens Y, Ravaux A, Louis A, Goenen M. Haemostasis disorders in open heart surgery with extracorporeal circulation. Importance of the platelet function and the heparin neutralization. Vox Sang. 1977;32(1):41-51.

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Keeler JF, Shah MV, Hansbro SD. Protamine--the need to determine the dose. Comparison of a simple protamine titration method with an empirical dose regimen for reversal of heparinisation following cardiopulmonary bypass. Anaesthesia. 1991 Nov;46(11):925-8.

Jobes DR, Aitken GL, Shaffer GW. 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 Jul;110(1):36-45.

Shore-Lesserson L, Reich DL, DePerio M. Heparin and protamine titration do not improve haemostasis in cardiac surgical patients. Can J Anaesth. 1998 Jan;45(1):10-8.

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Hardy JF, BĂ©lisle S, Robitaille D, Perrault J, Roy M, Gagnon L. Measurement of heparin concentration in whole blood with the Hepcon/HMS device does not agree with laboratory determination of plasma heparin concentration using a chromogenic substrate for activated factor X. J Thorac Cardiovasc Surg. 1996 Jul;112(1):154-61.

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 Mar;76(3):393-401.

Martin P, Horkay F, Gupta NK, Gebitekin C, Walker DR. Heparin rebound phenomenon--much ado about nothing? Blood Coagul Fibrinolysis. 1992 Apr;3(2):187-91.

Shanberge JN, Murato M, Quattrociocchi-Longe T, van Neste L. Heparin-protamine complexes in the production of heparin rebound and other complications of extracorporeal bypass procedures. Am J Clin Pathol. 1987 Feb;87(2):210-7.

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Starting date: June 2008
Last updated: August 24, 2011

Page last updated: August 23, 2015

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