Heparin Antagonization by Protamine in Cardiac Surgery: Pharmacokinetic/Pharmacodynamic Study

Study Overview
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Brief Summary
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Protamine is currently used during cardiac surgery to neutralize unfractionated heparin (UFH) at the end of extra-corporeal circulation (ECC). The optimal dose of protamine is currently unknown, and the administration of protamine is done empirically. Protamine and UFH pharmacokinetics are characterized by a large inter-individual variability. A dose of protamine proportional to the amount of UFH administrated during the surgery may be therefore not adapted to most of the patients and exposed them to a risk of under or over dosage. In this study, research investigators hypothesize that an accurate characterization of the pharmacokinetic/pharmacodynamic (PK/PD) relationship of protamine may help to optimize propose an optimal dosing regimen.

Official Title
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Heparin Antagonization by Protamine in Cardiac Surgery: Pharmacokinetic/Pharmacodynamic Study

Conditions
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Cardiac Surgery Requiring Extracorporeal Circulation

Intervention / Treatment
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* Other: Blood samples PK/ PD protamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients benefiting from scheduled or emergency at the Saint-Etienne University Hospital (coronary artery bypass grafting, valve replacements, aortic dissections). Exclusion Criteria: Patients with a contraindication to UFH Patients with a contraindication to protamine Patients requiring early resurgery. Patients receiving an injection of antithrombin III. Pregnant women. Patient for whom aprotinin use is planned during 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| cardiac surgery with extracorporeal circulation<br>during the operation Intervention Blood sample : - Choay Heparin (pharmacokinetic) concentration: t = 5, 15, 30 minutes after the start of the heparin injection + t = 5, 30, 60 minutes after the start of extracorporeal circulation protamine dosage: t = 2, 5, 8, 10 and 15 min after protamine injection anti-X activity t = 0 before administration and at time 2, 5, 8, 10 and 15 min then at time 1, 3, 5, 6 and 7 hours after protamine injection thrombin generation test (TGT) activity (thrombinography) : t = 2, 5, 8, 10 and 15 min after protamine injection | Other: Blood samples PK/ PD protamine<br>* PK/ PD protamine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK/PD Protamine | Pharmacokinetics (PK) : plasma concentration of protamine measured by liquid chromatography coupled with mass spectrometry. Pharmacodynamics (PD) :The effect of protamine corresponds to the kinetics of the disappearance of UFH in the blood. To do this, the investigators measure its concentration using an anti-Xa activity measurement technique. | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK/PD Protamine | PK: evolution of protamine concentrations over time (plasma concentration of protamine measured by liquid chromatography coupled with mass spectrometry). PD: ts neutralizing effect evaluated by thrombinography . | 1 day | 
| postoperative blood loss: | quantities of blood loss in pleural and mediastinal drains during the first 24 hours postoperatively. | 1 day | 
| ratios between the amount of UFH present at the protamine injection and the dose of protamine administered. |  | 1 day |