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

Overview

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.

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: March 12, 2021

Interventions

  • Other: Blood samples PK/ PD protamine
    • PK/ PD protamine

Arms, Groups and Cohorts

  • cardiac surgery with extracorporeal circulation
    • 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

Clinical Trial Outcome Measures

Primary Measures

  • PK/PD Protamine
    • Time Frame: 1 day
    • 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.

Secondary Measures

  • PK/PD Protamine
    • Time Frame: 1 day
    • 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 .
  • postoperative blood loss:
    • Time Frame: 1 day
    • quantities of blood loss in pleural and mediastinal drains during the first 24 hours postoperatively.
  • ratios between the amount of UFH present at the protamine injection and the dose of protamine administered.
    • Time Frame: 1 day

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Centre Hospitalier Universitaire de Saint Etienne
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Julien LANOISELÉE, MD, Principal Investigator, CHU SAINT-ETIENNE

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