Protamine in Cardiac Surgery and Haemostasis
Condition: Bleeding; Hemorrhage
MeSH terms: Hemorrhage
Study type: Observational

Summary: 
      Protamine is used after Cardiopulmonary Bypass (CPB) to reverse the anticoagulant effects of
      heparin and restore coagulation. Convincing evidence from in-vitro and in-vivo studies
      suggest that an overdose of protamine has anticoagulant effects which might lead to bleeding
      complications. Heparin levels usually decrease during cardiac surgery with CPB. Therefore, a
      protamine regimen based on the initial heparin dose before CPB might lead to overdose of
      protamine. In contrast, a protamine regimen based on the actual heparin concentration may
      avoid this condition. The investigators compare both regimens of protamine dosing in patients
      undergoing complex surgery with CPB and assess its effect on the amount of protamine given,
      markers of the coagulation system, utilization of blood products and perioperative blood
      loss.
    

Detailed description: 
      Before induction of anesthesia, patients are randomized to the two different dosing regimen
      for protamine. Both, the anesthetist and the surgeon were blinded regarding the grouping of
      the patients.

      Anesthesia and CPB

      Anesthesia is performed as a balanced anesthesia with a bolus of fentanyl, etomidate,
      pancuronium-bromide followed by a continuous infusion of remifentanil and vaporization of
      sevoflurane. Additionally, in all patients a continuous infusion of 0.25 µg/kg/min milrinone
      will be started after induction of anesthesia. Further inotropic or vasoactive agents
      (Dobutamine 3-5 µg/kg/min; epinephrine 0.05-0.2 µg(kg/min, norepinephrine 0.05-0.2 µg/kg/min)
      will be only given when a target cardiac index of < 2.2 l/m² BSA and mean arterial pressure
      of >70 mmHg is not achieved with this therapy.

      In order to compensate the degree of hemodilution due to differences in weight, in patients
      with a body surface area (BSA) of <1.8 m², a CPB system with a priming volume of 1100 ml will
      be used while in patients with a BSA of >1.8m² a system with a priming volume of 1500 ml was
      employed. CBP will be performed with open non-coated CPB circuits in mild hypothermia with a
      core temperature of 32-34°C. Cardioplegia will be achieved using warm blood cardioplegia
      according to Calafiore.

      All patients receive tranexamic acid (TA) with a bolus of 1 g to the patient, 0.5 g added to
      the CPB volume and a continuous infusion of 0.2 g/hour during CPB.

      Heparin and Protamine Management

      Heparin will be given with a bolus of 400 IU/kg to achieve a target celite ACT (Actalyke ACT,
      Helena Lab. Beaumont, TX USA) value of >450 seconds. If this target is not reached,
      additional boluses of 1/3 rd of the first dose will be given until prolongation to the target
      value is achieved. Additional 10.000 units of heparin will be given into the priming volume
      of the CPB circuit.

      Heparin concentrations were measured five minutes after beginning of CPB using the white
      (range 3.4-6.8 IU/ml heparin) heparin protamine titration (HPT) cartridge of the Hepcon HMS
      Plus™ device (Medtronic INC, Minneapolis, Min, USA) and shortly after termination of CPB
      using the golden HPT cartridge (range 2.0 - 5.4 IU/ml heparin).

      The total protamine dose consists of 100 ml. Of this 80 ml will be given as a short infusion
      over 10 min. directly after termination of CPB. The remaining 20 ml will be given when the
      residual CPB blood is re-infused into the patient after arterial decannulation, which will be
      performed 10-15 minutes after weaning from CPB.

      In the weight based protamine group (Group 1, the total amount of protamine will be
      calculated 1:1 according to the initial heparin dose necessary to achieve the target ACT of
      >450 sec. In the heparin level based group, the total protamine amount will be calculated 1:1
      according to the actual heparin level measured after termination of CPB with the use of
      Hepcon HMS Plus™ device.

      Coagulation Tests

      Fifteen minutes after infusion of protamine, the INTEM, FIBTEM and HEPTEM test will be
      performed on the ROTEM thromboelastometry system (TEM International GmbH, Munich Germany). In
      all tests, the coagulation time (CT) reflects the period until clot formation starts; the
      clot formation time (CFT) reflects the period until a clot strength of 20 mm is achieved and
      the maximal clot firmness MCF)reflects the maximal clot strength. In the INTEM test the
      intrinsic coagulation pathway is activated.

      Transfusion triggers

      During CPB the critical hemoglobin (Hb) triggering transfusion of packed red blood cells
      (PRBC) is defined at 8 g/dl. After CPB, in patients with a CI >2.2 l/m² the critical value is
      at >8-9 g/dl, while in patients needing further medical support with dobutamine/epinephrine
      or norepinephrine the minimum target was defined at >9-10 g/dl.

      In patients with diffuse bleeding after protamine administration, therapy with fresh frozen
      plasma (FFP), prothrombin complex concentrate (Beriplex, CSL Behring, Marburg, Ger) ,
      fibrinogen concentrate (Haemocomplettan P®, CSL Behring, Marburg, Germany) and single donor
      aphaeresis platelet concentrates will be based on the results of the ROTEM analysis. However,
      these blood products will only be given when diffuse microvascular bleeding is observed in
      the operation field.

      In case of a moderate prolongation of the CT (240-360 sec) in the INTEM test (and comparable
      result in the HEPTEM test) 3-4 units of FFP will be transfused. If bleeding persists,
      additional 3-4 units of FFP or in case of a prolongation of the CT>360 sec. 2000-4000 IU of
      prothrombin complex concentrate will be given.In case of an MCF < 45 mm to platelet
      concentrates will be transfused.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Patients undergoing complex cardiac surgery using cardiopulmonary bypass with mitral valve
        repair/replacement and 2-4 coronary artery bypass grafting including the left thoracic
        artery
      
Keywords: Protamine; heparin level; haemostasis; thromboelastometry; cardiac surgery; Patients undergoing cardiac surgery