Clinical Trial Comparing Heparin and Protamine Fixed and Titrated Doses in Cardiac Surgery With Cardiopulmonary Bypass

Study Overview
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Brief Summary
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There are currently several schemes described for anticoagulation with heparin and its reversal with protamine during cardiac surgery with CPB. The oldest, and most used in our routine environment, is the scheme of fixed doses, in which a bolus dose of heparin at the start of CPB is established in IU/kg of body weight and the dose of protamine at the end of CPB is calculated based on the initial dose of heparin administered. These schemes do not take into account the variability inter-patients and can result in overdose or sub-doses of one or both drugs. The titration schedule of doses of heparin and protamine through the principle of dose-response curve of Bull promotes individualization of dosage according to the response of each patient. This scheme has been associated with an effective reversal of the effect of heparin after CPB and with reduction of post-operatory bleeding and transfusion. The restoration of a state of anticoagulation by heparin after its reversal by protamine is called rebound effect. It is a phenomenon explained by the recirculation of heparin stored in the reticulum-endothelial system and connective tissue, or by free residual concentration of heparin after clearance of protamine. This effect may be present for more than 6 hours of post-operatory and may contribute to increase post-operatory bleeding.

Detailed Description
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The objectives were, primarily, to compare intraoperative fixed versus titrated doses of heparin and protamine in cardiac surgeries with CPB regarding blood loss and transfusion requirements during the first 24 post-operative (PO) hours. Secondarily, the investigators compared continuous infusion of small doses of protamine (25mg/hour) and placebo during the first 6 PO hours to neutralize heparin rebound effect. The investigators measured KTTP and fibrinogen levels during the first 24 PO hours and also the difference in blood loss and transfusion requirements between the groups. The study included patients from 18 to 75 years-old submitted to Cardiac surgeries with Cardiopulmonary Bypass.

Official Title
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Phase 4 Study of Fixed-dose and Titration Schemes of Heparin and Protamine in Cardiopulmonary Bypass Cardiac Surgeries : Evaluation of Post-operatory Blood Loss and Transfusion Requirements

Conditions
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Cardiac Surgery, Cardiopulmonary Bypass, Anticoagulation

Intervention / Treatment
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* Drug: Heparin fixed doses
* Drug: PO continuous infusion of Protamine
* Drug: Heparin and protamine titration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients submitted to an Elective Cardiac Surgery with Cardiopulmonary Bypass Age 18 to 75 years-old Exclusion Criteria: Hematocrit < 30 INR > 1,3 Platelets < 100,000 Altered KTTP Receiving Non-fractioned Heparin or Low-Molecular Weight Heparin Renal Insufficiency or Creatinine > 2,0 Liver Failure or altered ALT/AST Von Willebrands'disease, Haemophilia, sepsis Use in the past 7 days of antiplatelet-therapy(Ticlopidine or Clopidogrel)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Fixed doses plus PO protamine<br>Intraoperative fixed dose schemes (as in fixed doses plus placebo group) plus continuous infusion of 25mg/hour of protamine during first 6 PO hours | Drug: Heparin fixed doses<br>* Fixed doses of 400 units/ kg of patient's body weight before CPB to achieve an ACT > 480 sec. Supplemental doses of 50mg of heparin if ACT <480 sec during CPB. Reversal doses of protamine in a 1:1 ratio (1mg of protamine for every mg of heparin administered), plus 0.8mg/kg of protamine at the end of the surgery.<br>Drug: PO continuous infusion of Protamine<br>* 25mg/hour in IV continuous infusion during first 6 PO hours<br>|
| Active Comparator: Titrated doses plus PO protamine<br>Same as titrated doses arm, plus continuous infusion of 25mg/ hour of protamine during first 6 PO hours | Drug: PO continuous infusion of Protamine<br>* 25mg/hour in IV continuous infusion during first 6 PO hours<br>Drug: Heparin and protamine titration<br>* Titrated doses of heparin during CPB were manually calculated using Bull´s dose-response curve, which was based in periodic assessment of Activated-Coagulation Times (ACT)- baseline ACT, after 2mg/kg of heparin at cannulation and every 15 to 30 minutes during CPB. Reversal doses of protamine were calculated as a 1:1 ratio of the actual estimated heparin concentration (in mg/kg) at the end of CPB, using the Bull´s dose response curve.<br>|
| No Intervention: Fixed doses plus placebo<br>Before CPB, fixed heparin dose of 400 Units per kg of body weight to achieve an Activated Coagulation Time (ACT) > 480 seconds. Reversal of heparin after CPB using 1 : 1 ratio (1 mg of protamine for each 100 units (1mg) of heparin), plus 0.8 mg/kg of protamine at the end of the surgery. Continuous infusion of placebo (saline 0.9%) during the first 6 PO hours. | Drug: Heparin fixed doses<br>* Fixed doses of 400 units/ kg of patient's body weight before CPB to achieve an ACT > 480 sec. Supplemental doses of 50mg of heparin if ACT <480 sec during CPB. Reversal doses of protamine in a 1:1 ratio (1mg of protamine for every mg of heparin administered), plus 0.8mg/kg of protamine at the end of the surgery.<br>|
| Active Comparator: Titrated doses plus placebo<br>Titrated doses of heparin before and during CPB and reversal with protamine after CPB calculated by the construction of individualized Bull's dose-response curve. Continuous infusion of placebo (saline 0.9%) during first 6 PO hours. | Drug: Heparin and protamine titration<br>* Titrated doses of heparin during CPB were manually calculated using Bull´s dose-response curve, which was based in periodic assessment of Activated-Coagulation Times (ACT)- baseline ACT, after 2mg/kg of heparin at cannulation and every 15 to 30 minutes during CPB. Reversal doses of protamine were calculated as a 1:1 ratio of the actual estimated heparin concentration (in mg/kg) at the end of CPB, using the Bull´s dose response curve.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mediastinal blood drainage (ml) | The mediastinal blood drainage was measured hourly during the first 6 post-operatory (PO) hours, and every 6 hours from the 7th to 24th PO hours. | First 24 PO hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transfusion of blood components | We measured the incidence(%) of transfusion of Packed Red Blood Cells, Plasma or Platelet during first 24 PO hours | First 24 PO hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heparin, Protamine, Cardiopulmonary Bypass, Titration