Cardiac Surgery: In Vivo Titration of Protamine

This study has been completed.
Sponsor:
Collaborator:
Organon
Information provided by (Responsible Party):
Antoine Rochon, Montreal Heart Institute
ClinicalTrials.gov Identifier:
NCT00684450
First received: May 21, 2008
Last updated: August 24, 2011
Last verified: August 2011
  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:

  1. platelet count
  2. postoperative bleeding
  3. transfusion exposure a
  4. 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:


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

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

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 April 17, 2014