Clinical Trial Comparing Heparin and Protamine Fixed and Titrated Doses in Cardiac Surgery With Cardiopulmonary Bypass
Condition: Cardiac Surgery; Cardiopulmonary Bypass; Anticoagulation
Study type: Interventional
Phase: Phase 4

Summary: 
      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: 
      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.
    

Intervention name(s): Heparin fixed doses; PO continuous infusion of Protamine; Heparin and protamine titration
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 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.; 25mg/hour in IV continuous infusion during first 6 PO hours; 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.
Intervention MeSH terms: Heparin; Calcium heparin; Protamines
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Heparin; Protamine; Cardiopulmonary Bypass; Titration