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

SANE-Society of Anesthesiology

Status and phase: Completed; Phase 4

Conditions: Cardiac Surgery; Anticoagulation; Cardiopulmonary Bypass

Treatments: Drug: Heparin fixed doses; Drug: Heparin and protamine titration; Drug: PO continuous infusion of Protamine

Study type: Interventional

Funder types: Other

Identifiers

NCT01267487

UP 4316/09

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 240 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

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)

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Triple Blind

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240 participants in 4 patient groups

Fixed doses plus PO protamine

Active Comparator group

Description:

Intraoperative fixed dose schemes (as in "fixed doses plus placebo" group) plus continuous infusion of 25mg/hour of protamine during first 6 PO hours

Treatment:

Drug: Heparin fixed doses

Drug: PO continuous infusion of Protamine

Titrated doses plus PO protamine

Active Comparator group

Description:

Same as "titrated doses" arm, plus continuous infusion of 25mg/ hour of protamine during first 6 PO hours

Treatment:

Drug: Heparin and protamine titration

Drug: PO continuous infusion of Protamine

Fixed doses plus placebo

No Intervention group

Description:

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.

Treatment:

Drug: Heparin fixed doses

Titrated doses plus placebo

Active Comparator group

Description:

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.

Treatment:

Drug: Heparin and protamine titration