Cardiac Surgery: In Vivo Titration of Protamine

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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Cardiac Surgery : In Vivo Titration of Protamine

Conditions
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Bleeding

Intervention / Treatment
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* Procedure: Titration protamine
* Drug: Standard administration of protamine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>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<br>* 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.<br>* Other names: Protamine in vivo titration in cardiac surgery;|
| Active Comparator: 2<br>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<br>* 1.3 mg of Protamine for 100u héparine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effective heparin neutralization (anti-Xa < 0.3 U/ml) |  | Pre protamine, 15 min post protamine, 3h post protamine | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of heparin rebound |  | 15 min post protamine and 3 hours post Protamine | 
| Blood losses after surgery and transfusion requirements |  | discharge | 
| Preservation of the platelet count |  | Pre operate, Pré Protamine, 15 min post Protamine, 3 hours post Protamine | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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titration of protamine, exact dose, protamine, neutralize heparin