Dose for Reversal of Heparin After Cardiopulmonary Bypass

Lower Protamine Dose for Reversal of Heparin After Cardiopulmonary Bypass: Is it Safe? Comparative Prospective Randomized Trial.

Protamine sulfate is routinely used to reverse heparin anticoagulation after cardiopulmonary bypass (CPB). The conventional dosing strategy of 1 mg protamine per 100 IU of heparin may result in excess protamine exposure, which has been associated with anticoagulant effects, platelet dysfunction, and hemodynamic instability. Recent evidence suggests that lower protamine doses may provide adequate heparin reversal while reducing potential adverse effects. 

This multicenter, prospective, randomized, double-blind, controlled trial aims to compare three protamine-to-heparin dosing ratios (1:1, 0.8:1, and 0.75:1) in adult patients undergoing elective cardiac surgery requiring cardiopulmonary bypass. The primary outcome is activated clotting time (ACT) measured 5 minutes after protamine administration. Secondary outcomes include the need for additional protamine administration, protamine-related adverse events, postoperative bleeding, blood product transfusion requirements, and length of intensive care unit stay. 

The results of this study may help determine whether reduced protamine dosing can safely achieve effective heparin reversal while minimizing drug exposure and potential complications after cardiopulmonary bypass. 

Study Overview

• Status: Recruiting
• Conditions: Open Heart Surgery
• Intervention / Treatment: Drug: Protamine sulfate

Detailed Description

Heparin is routinely administered during cardiopulmonary bypass (CPB) to prevent clot formation in the extracorporeal circuit. At the end of CPB, protamine sulfate is used to neutralize the anticoagulant effect of heparin. The conventional protamine dosing strategy is 1 mg of protamine for every 100 IU of the initial heparin dose administered. However, emerging evidence suggests that this standard dosing regimen may result in excessive protamine exposure, which has been associated with adverse effects such as hypotension, pulmonary hypertension, platelet dysfunction, and paradoxical anticoagulation.

Recent studies have suggested that reduced protamine dosing strategies may achieve adequate reversal of heparin anticoagulation while minimizing potential complications associated with protamine administration. However, the optimal protamine-to-heparin ratio remains uncertain.

This randomized clinical study aims to compare different protamine dosing strategies for heparin reversal after cardiopulmonary bypass in adult patients undergoing cardiac surgery. Participants will be randomized to receive one of three protamine dosing regimens based on the initial heparin dose administered during CPB: the conventional 1:1 ratio (1 mg protamine per 100 IU heparin), a reduced dose ratio of 0.8:1, or a further reduced ratio of 0.75:1.

The study will evaluate the effectiveness of these dosing strategies in achieving adequate heparin reversal as measured by activated clotting time (ACT), as well as clinical outcomes including the need for additional protamine administration, postoperative bleeding, transfusion requirements, protamine-related adverse events, re-exploration for bleeding, and duration of intensive care unit stay.

• Study Type: Interventional
• Enrollment (Estimated): 195
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Asmaa S Farghaly, MD; Phone Number: +20 10 20283823; Email: asmaasaad@med.sohag.edu.eg

Study Locations

• Egypt
  • Sohag, Egypt
    • Recruiting
    • Sohag University Hospital
    • Contact: Asmaa S Farghaly, MD; Phone Number: +20 10 20283823; Email: asmaasaad@med.sohag.edu.eg

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age ≥18 years
• Patients scheduled for elective cardiac surgery requiring cardiopulmonary bypass (CABG, valve surgery, or combined procedures)
• Patients receiving systemic heparinization according to the institutional cardiopulmonary bypass protocol
• Ability to provide written informed consent before surgery

Exclusion Criteria:

• Known allergy or hypersensitivity to protamine
• Pre-existing coagulopathy or bleeding disorders
• Patients receiving chronic anticoagulation that cannot be safely discontinued before surgery
• Severe renal dysfunction
• Severe hepatic dysfunction
• Emergency cardiac surgery
• Pregnancy
• Off-pump cardiac surgery

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard Protamine Dose (1:1); Participants will receive protamine sulfate at a ratio of 1 mg per 100 IU of the initial heparin dose administered during cardiopulmonary bypass. Protamine will be administered intravenously over 5-10 minutes at the termination of cardiopulmonary bypass for heparin reversal.	Drug: Protamine sulfate; Protamine sulfate will be administered intravenously for reversal of heparin anticoagulation after cardiopulmonary bypass. The dose will be calculated according to the randomized study group based on the initial heparin dose administered during cardiopulmonary bypass.; Other Names: Protamine
Experimental: Reduced Protamine Dose (0.8:1); Participants will receive protamine sulfate at a ratio of 0.8 mg per 100 IU of the initial heparin dose administered during cardiopulmonary bypass. Protamine will be administered intravenously over 5-10 minutes at the termination of cardiopulmonary bypass for heparin reversal.	Drug: Protamine sulfate; Protamine sulfate will be administered intravenously for reversal of heparin anticoagulation after cardiopulmonary bypass. The dose will be calculated according to the randomized study group based on the initial heparin dose administered during cardiopulmonary bypass.; Other Names: Protamine
Experimental: Reduced Protamine Dose (0.75:1); Participants will receive protamine sulfate at a ratio of 0.75 mg per 100 IU of the initial heparin dose administered during cardiopulmonary bypass. Protamine will be administered intravenously over 5-10 minutes at the termination of cardiopulmonary bypass for heparin reversal.	Drug: Protamine sulfate; Protamine sulfate will be administered intravenously for reversal of heparin anticoagulation after cardiopulmonary bypass. The dose will be calculated according to the randomized study group based on the initial heparin dose administered during cardiopulmonary bypass.; Other Names: Protamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-protamine Activated Clotting Time (ACT)	Activated clotting time measured 5 minutes after completion of protamine administration to assess adequacy of heparin reversal after cardiopulmonary bypass.	5 minutes after protamine administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Need for additional protamine administration	Requirement for additional protamine if activated clotting time exceeds 130 seconds after initial protamine administration.	5 minutes after initial protamine administration
Postoperative chest tube drainage	Total volume of chest tube drainage measured during the first 24 hours after cardiac surgery.	Within 24 hours after surgery
Blood transfusion requirements	Total number of blood product units (red blood cells, fresh frozen plasma, platelets, or cryoprecipitate) transfused within the first 24 hours after surgery.	Within 24 hours after surgery
Protamine-related adverse events	Incidence of protamine-related adverse events including hypotension requiring vasopressors, allergic reactions, or anaphylaxis.	From protamine administration until 24 hours after surgery
Re-exploration for bleeding	Need for surgical re-exploration due to postoperative bleeding.	Within 24 hours after surgery

Collaborators and Investigators

• Sponsor: Sohag University
• Investigators: Principal Investigator: Asmaa S Farghaly, MD, Faculty of Medicine, Sohag University

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2026
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: March 9, 2026
• First Submitted That Met QC Criteria: March 13, 2026
• First Posted (Actual): March 17, 2026

Study Record Updates

• Last Update Posted (Actual): May 5, 2026
• Last Update Submitted That Met QC Criteria: May 4, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Protamine; Cardiac surgery; Heparin; Activated clotting time; Postoperative bleeding
• Additional Relevant MeSH Terms: Postoperative Complications; Pathologic Processes; Hemorrhage; Pathological Conditions, Signs and Symptoms; Postoperative Hemorrhage; Amino Acids, Peptides, and Proteins; Proteins; Nuclear Proteins; Nucleoproteins; Protamines
• Other Study ID Numbers: Soh-Med-26-1-5PD

Drug and device information, study documents

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