Cardiac Surgery: In Vivo Titration of Protamine

Bleeding Clinical Trial

— Protamine  

Official title:

Cardiac Surgery : In Vivo Titration of Protamine

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00684450
• Other study ID #: ICM 07-997
• Status: Completed
• Phase: N/A
• First received: May 21, 2008
• Last updated: August 24, 2011
• Start date: June 2008
• Est. completion date: June 2011

Study information

• Verified date: August 2011
• Source: Montreal Heart Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health Canada
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 138
• Est. completion date: June 2011
• Est. primary completion date: June 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Bleeding

Intervention

Procedure:
• Titration protamine
10. Study group: celite ACT will be performed every 3 minutes during protamine infusion until ACT values suggest reach of a plateau (defined as 2 similar ACT values, within 10% variability, and ACT = to 160 seconds.), time at which infusion will be stopped. 2cc of blood is required per ACT test, for a maximum total of 10cc.

Drug:
• Standard administration of protamine
1.3 mg of Protamine for 100u héparine

Locations

Country	Name	City	State
Canada	Montreal Heart Institute	Montreal	Quebec

Sponsors (2)

Lead Sponsor	Collaborator
Montreal Heart Institute	Organon

Country where clinical trial is conducted

Canada, 

References & Publications (30)

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. — View Citation

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

Carr ME Jr, Carr SL. At high heparin concentrations, protamine concentrations which reverse heparin anticoagulant effects are insufficient to reverse heparin anti-platelet effects. Thromb Res. 1994 Sep 15;75(6):617-30. — View Citation

de Swart CA, Nijmeyer B, Roelofs JM, Sixma JJ. Kinetics of intravenously administered heparin in normal humans. Blood. 1982 Dec;60(6):1251-8. — View Citation

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. — View Citation

Despotis GJ, Joist JH, Hogue CW Jr, 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 operation. J Thorac Cardiovasc Surg. 1995 Jul;110(1):46-54. — View Citation

Despotis GJ, Levine V, Joiner-Maier D, Joist JH. A comparison between continuous infusion versus standard bolus administration of heparin based on monitoring in cardiac surgery. Blood Coagul Fibrinolysis. 1997 Oct;8(7):419-30. — View Citation

Estes JW, Poulin PF. Pharmocokinetics of heparin. Distribution and elimination. Thromb Diath Haemorrh. 1975 Feb 28;33(1):26-37. — View Citation

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

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. — View Citation

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. — View Citation

Hardy JF, Bélisle 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. — View Citation

Harker LA. Bleeding after cardiopulmonary bypass. N Engl J Med. 1986 May 29;314(22):1446-8. — View Citation

Hattersley PG. ACT in the whole blood. JAMA 1966;196:150-154.

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. — View Citation

Jobes DR, Schwartz AJ, Ellison N, Andrews R, Ruffini RA, Ruffini JJ. Monitoring heparin anticoagulation and its neutralization. Ann Thorac Surg. 1981 Feb;31(2):161-6. — View Citation

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. — View Citation

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. — View Citation

Lowary LR, Smith FA, Coyne E, Dunham NW. Comparative neutralization of lung- and mucosal-derived heparin by protamine sulfate using in vitro and in vivo methods. J Pharm Sci. 1971 Apr;60(4):638-40. — View Citation

Mabry CD, Read RC, Thompson BW, Williams GD, White HJ. Identification of heparin resistance during cardiac and vascular surgery. Arch Surg. 1979 Feb;114(2):129-34. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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(2):123-8. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 30 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Effective heparin neutralization (anti-Xa < 0.3 U/ml)		Pre protamine, 15 min post protamine, 3h post protamine	Yes
Secondary	Frequency of heparin rebound		15 min post protamine and 3 hours post Protamine	Yes
Secondary	Blood losses after surgery and transfusion requirements		discharge	Yes
Secondary	Preservation of the platelet count		Pre operate, Pré Protamine, 15 min post Protamine, 3 hours post Protamine	Yes