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

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 Overview

• Status: Completed
• Conditions: Cardiac Surgery Requiring Extracorporeal Circulation
• Intervention / Treatment: Other: Blood samples PK/ PD protamine

• Study Type: Observational
• Enrollment (Actual): 70

Contacts and Locations

Study Locations

• France
  • Saint-Étienne, France, 42055
    • CHU Saint-etienne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

patients with cardiac surgery under CEC

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

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

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Saint Etienne

Study record dates

Study Major Dates

• Study Start (Actual): November 13, 2019
• Primary Completion (Actual): March 12, 2021
• Study Completion (Actual): March 12, 2021

Study Registration Dates

• First Submitted: September 9, 2019
• First Submitted That Met QC Criteria: September 16, 2019
• First Posted (Actual): September 17, 2019

Study Record Updates

• Last Update Posted (Actual): March 26, 2021
• Last Update Submitted That Met QC Criteria: March 25, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Coagulants; Heparin Antagonists; Protamines
• Other Study ID Numbers: 19CH046; 2019-000859-14 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No