Cardiac Surgery: In Vivo Titration of Protamine - Full Text View

Purpose

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:

platelet count
postoperative bleeding
transfusion exposure a
incidence of heparin rebound

Condition	Intervention
Bleeding	Procedure: Titration protamine Drug: Standard administration of protamine

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	Cardiac Surgery : In Vivo Titration of Protamine

Resource links provided by NLM:

MedlinePlus related topics: Blood Thinners Heart Surgery

Drug Information available for: Protamine

U.S. FDA Resources

Further study details as provided by Montreal Heart Institute:

Primary Outcome Measures:

Effective heparin neutralization (anti-Xa < 0.3 U/ml) [ Time Frame: Pre protamine, 15 min post protamine, 3h post protamine ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Frequency of heparin rebound [ Time Frame: 15 min post protamine and 3 hours post Protamine ] [ Designated as safety issue: Yes ]
Blood losses after surgery and transfusion requirements [ Time Frame: discharge ] [ Designated as safety issue: Yes ]
Preservation of the platelet count [ Time Frame: Pre operate, Pré Protamine, 15 min post Protamine, 3 hours post Protamine ] [ Designated as safety issue: Yes ]

Enrollment:	138
Study Start Date:	June 2008
Study Completion Date:	June 2011
Primary Completion Date:	June 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: 1 in vivo protamine titration in cardiac surgery. The titration is done during administration of protamine each 3 minutes to reach 2 consecutive ACT defined as 2 similar ACT values, within 10% variability, and ACT ≤ to 160 seconds. .The protamine is stopped when this values are obtain. Follow-up is done 15 minutes and 3 hours post-protamine	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. Other Name: Protamine in vivo titration in cardiac surgery
Active Comparator: 2 standard protamine administration ACT is done during administration of protamine each 3 minutes the values are recorded but the totality of protamine is given. Follow-up is done 15 minutes and 3 hours post-protamine	Drug: Standard administration of protamine 1.3 mg of Protamine for 100u héparine

Arms

Assigned Interventions

Active Comparator: 1

in vivo protamine titration in cardiac surgery. The titration is done during administration of protamine each 3 minutes to reach 2 consecutive ACT defined as 2 similar ACT values, within 10% variability, and ACT ≤ to 160 seconds. .The protamine is stopped when this values are obtain. Follow-up is done 15 minutes and 3 hours post-protamine

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.

Other Name: Protamine in vivo titration in cardiac surgery

Active Comparator: 2

standard protamine administration ACT is done during administration of protamine each 3 minutes the values are recorded but the totality of protamine is given. Follow-up is done 15 minutes and 3 hours post-protamine

Drug: Standard administration of protamine

1.3 mg of Protamine for 100u héparine

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

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00684450

Locations

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

Sponsors and Collaborators

Montreal Heart Institute

Organon

Investigators

Principal Investigator:

Antoine G Rochon

Montreal Heart Institute

More Information

Publications:

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

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.

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

Estes JW, Poulin PF. Pharmacokinetics of Heparin: Distribution and Elimination. Thrombos Diathes Haemorrh (Stuttg) 1975; 33: 26-37.

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.

Gravlee GP, Case LD, Angert KC, Rogers AT, Miller GS. Variability of the activated coagulation time. Anesth Analg. 1988 May;67(5):469-72. No abstract available.

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.

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. No abstract available.

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.

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.

Harker LA. Bleeding after cardiopulmonary bypass. N Engl J Med. 1986 May 29;314(22):1446-8. No abstract available.

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. No abstract available.

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.

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.

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.

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.

24. Shore-Lesserson L., Reich DL., DePerio M. Department of Anesthesiology, Mount Sinai Medical Center, New York, NY 10029, USA. Heparin and protamine titration do not improve haemostasis in cardiac surgical patients [see comments]. Comment in: Can J Anaesth 1998 Jan; 45(1): 1-5 Can J Anaesth 1998; 45(1): 10-18.

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.

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.

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.

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.

Responsible Party:	Antoine Rochon, M.D. FRCPC, Montreal Heart Institute
ClinicalTrials.gov Identifier:	NCT00684450 History of Changes
Other Study ID Numbers:	ICM 07-997
Study First Received:	May 21, 2008
Last Updated:	August 24, 2011
Health Authority:	Canada: Health Canada

Keywords provided by Montreal Heart Institute:

titration of protamine
exact dose
protamine
neutralize heparin

Additional relevant MeSH terms:

Hemorrhage
Pathologic Processes
Protamines
Heparin Antagonists
Molecular Mechanisms of Pharmacological Action

Pharmacologic Actions
Coagulants
Hematologic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on May 16, 2013