Heparin Reversal With Two Different Protamine Ratios After Cardiopulmonary By-pass.

Protamine is routinely used as a heparin reversal agent in cardiac surgery. However, its use may be associated with adverse events, while protamine excess may have additional anti-coagulant affect. Although guidelines advise towards a diminished reversal ratio, clinical practice remain heterogenic. The purpose of this study is to compare two different reversal ratios (0.6:1 και 0.8:1) of total heparin regarding the Activated Clotting Time (ACT), viscoelastic assays (Clot-Pro) and clinical hemorrhage.

A baseline ACT value and Clot Pro tests will be obtained prior to the operation start. After the initial reversal, ACT, Clot Pro tests will be conducted again. Coagulation factors are administrated according to Clot Pro results, and in case of ongoing clinical hemorrhage and any indication of heparin excess in the measured values, another 25mg of protamine is administrated, while tests are repeated.

Study Overview

• Status: Completed
• Conditions: Coagulation Disorder; Cardiac Surgery; CAD; Valve Heart Disease
• Intervention / Treatment: Drug: Protamin

Detailed Description

Protamine is routinely administered as a heparin-reversal factor in cardiac surgery. However, protamine is associated with specific adverse events, while it has additional anticoagulant effect while in excess. The literature supports that a reversal ratio lower than 1mg:100 IU (1:1) of heparin is safe and effective. According to recent studies, a ratio equal to 0.84:1 of initial or 0,6 of total heparin is safe and effective in cardiac surgery. Even lower ratios (<0,5:1) have been studied with positive outcomes.

The aim of this study is to evaluate the effectiveness of heparin reversal with two different protamin ratios (0,6:1 και 0,8:1) regarding the Activated Clotting Time (ACT), viscoelastic tests (Clot-Pro) and clinical hemorrhage.

Methods Perioperative management will follow standard department practice. The patients will be randomized to receive an initial dosage of protamine in a ratio 0.8 or 0.6 to 1 of the total heparin post cardiopulmonary by-pass disengagement. ACT and Clot Pro tests (IN, HI, EX and FIB-test) will run. In case of ongoing clinical hemorrhage, coagulation factors will administrated according to Clot Pro results, and in case of persistent clinical hemorrhage and any indication of heparin excess in the measured values, another 25mg of protamine will be administrated, while tests will be repeated. All patients will sign an informed consent prior to their inclusion in the study.

Data collection During pre-operative evaluation, age, weight, height, sex, BSA, ASA classification, Euroscore II, medication and co-morbidities will be documented.

Intraoperatively, anesthesia, cardiopulmonary bypass and aortic cross clamping time will be documented, as well as drugs administered and related adverse events.

Methods Induction in anesthesia will follow standard practice using fentanyl, prorofol and rocuronium. Maintenance will be achieved with sevoflurane. After induction in anesthesia and before heparin administration ACT and viscoelastic (Clot Pro) test results will be run using blood withdrawn form the patient's arterial line.

After disengagement from cardiopulmonary by-pass, protamine will be administered in a dosage according to randomization in a total volume of 60ml (diluted with normal saline). Five minutes later, another blood sample will be withdrawn form the patient's arterial line and ACT and Clot Pro tests (i.e. EX-, FIB-, IN- and HI- TEST) will be run again. In case of ongoing clinical bleeding, clotting factors will be administered according to the Clot PRo tests results. If bleeding persists, and there is and indication of either the ACT value or the IN to HI test ratio that there is heparin excess, another 25mg of protamine will be administered and ACT and Clot Pro tests will be repeated. The step can be repeated as many times as there is an indication of protamine excess and ongoing clinical bleeding. Transfusion and clotting products requirements will be recorded. Finally, the patients will be monitored for mechanical ventilation duration, transfusion requirements during ICU stay, postoperative bleeding and adverse events related to surgery and anesthesia for 48 hours postoperatively. A secondary analysis will depict the changes in thromboelastography before and after cardiopulmonary bypass as depicted in the ClotPro tests.

Purpose of the study The present study aims to evaluate two different ratios of heparin reversal (0.6 and 0.8 of total heparin)with protamine after the end of cardiopulmonary by pass in cardiac surgery patients. It is a prospective, randomized, comparative study of clinical hemorrhage, Activated Clotting Time (ACT) and viscoelastic tests using the ClotPro.Secondary endpoints are transfusion requirements, clotting factors administration, postoperative bleeding, mechanical ventilation duration and ICU length of stay.

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Greece
  • Epirus
    • Ioannina, Epirus, Greece, 45500
      • University Hospital of Ioannina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age > 18 years
• Agreement to participate
• Scheduled for elective cardiac surgery on cardiopulmonary by-pass (CPB)

Exclusion Criteria:

• Age <18 years.
• No consent
• Known allergy to heparin or protamine
• History of Heparin Induced Thrombocytopenia (HIT)
• Off pump surgery

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 0.8:1; This arm will receive an initial administration of 0.8mg of protamine per 100IU of totally given heparin.	Drug: Protamin; ACT and Clot- Pro test will be ran after initial and possible next protamine administrations; Other Names: ACT; viscoelastic testing (Clot-Pro)
Active Comparator: 0.6:1; This arm will receive an initial administration of 0.6mg of protamine per 100IU of totally given heparin.	Drug: Protamin; ACT and Clot- Pro test will be ran after initial and possible next protamine administrations; Other Names: ACT; viscoelastic testing (Clot-Pro)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Activated Clotting Time (in seconds)	ACT values after heparin reversal	Intraoperatively
Viscoelastic testing	CT-HI/CT-IN TEST values ratio after heparin reversal	Intraoperatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transfusion	Number of blood products (RBC, FFP, PLT) administered to the patients	Intraoperatively and up to 24 hours postoperatively
Clotting factors	Number of Clotting factors (PCCs, fibrinogen etc) administered to the patient	Intraoperatively and up to 24 hours postoperatively
Postoperative hemorrhage	Total volume of blood drains and need for re-operation due to postoperative hemorrhage	24 hours postoperatively
ICU LOS	Total ICU Length of Stay	Up to 30 days
Changes in ClotPro values in EX, FIB, IN and HI tests	differences in obtained values before and after cardiopulmonary bypass	intraoperatively

Collaborators and Investigators

• Sponsor: University of Ioannina
• Investigators: Principal Investigator: Evangelia Samara, Md, PhD, University of Ioannina

Study record dates

Study Major Dates

• Study Start (Actual): March 18, 2023
• Primary Completion (Actual): April 30, 2024
• Study Completion (Actual): April 30, 2024

Study Registration Dates

• First Submitted: November 2, 2023
• First Submitted That Met QC Criteria: November 29, 2023
• First Posted (Actual): December 1, 2023

Study Record Updates

• Last Update Posted (Actual): May 31, 2024
• Last Update Submitted That Met QC Criteria: May 29, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: cardiac surgery; coagulopathy; heparin; protamin; coagulopathy, viscoelastic tests
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hematologic Diseases; Hemorrhagic Disorders; Heart Diseases; Hemostatic Disorders; Blood Coagulation Disorders; Heart Valve Diseases; Molecular Mechanisms of Pharmacological Action; Coagulants; Heparin Antagonists; Protamines
• Other Study ID Numbers: 179/23-2-2023

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