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Protamine in Cardiac Surgery and Haemostasis (PROTT)

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ClinicalTrials.gov Identifier: NCT01608971
Recruitment Status : Completed
First Posted : May 31, 2012
Results First Posted : November 20, 2015
Last Update Posted : March 27, 2017
Sponsor:
Information provided by (Responsible Party):
Andreas Koster, Heart and Diabetes Center North-Rhine Westfalia

Tracking Information
First Submitted Date May 29, 2012
First Posted Date May 31, 2012
Results First Submitted Date March 17, 2015
Results First Posted Date November 20, 2015
Last Update Posted Date March 27, 2017
Study Start Date January 2011
Actual Primary Completion Date March 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: November 18, 2015)
  • INTEM HEPTEM and FIBTEM Test of the ROTEM Coagulation Analyzer [ Time Frame: Tests will be measured 15 minutes after Protamine infusion ]
    The Intem test of the ROTEM analyzer evaluates the response of the heamostatic system to activation of the intrinsic coagulation system. The following parameters of the INTEM test will be analyzed. CT [seconds](coagulation time), CFT [seconds] (clot formation time) and the CT [seconds] of the HEPTEM test which is non sensitive for residual heparine.
  • Rotem MCF Fibtem and MCF Intem [ Time Frame: 15 Minutes after protamine infusion ]
    The following parameters of the INTEM test will be analyzed: MCF [mm] (maximum clot firmness) which correlates with the platelet count. Furthermore, the MCF [mm] of the FIBTEM test will be analyzed, which correlates with the fibrinogen concentration.
Original Primary Outcome Measures
 (submitted: May 30, 2012)
Intem test of the ROTEM coagulation analyzer [ Time Frame: Intem test will be measured 15 minutes after Protamine infusion ]
The Intem test of the ROTEM analyzer evaluates the response of the heamostatic system to activation of the intrinsic coagulation system. The following parameters of the INTEM test will be analyzed. CT (coagulation time), CFT (clot formation time) and MCF (maximum clot firmness).
Change History Complete list of historical versions of study NCT01608971 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures
 (submitted: November 18, 2015)
  • Transfusion of Blood Products and Coagulation Factors [ Time Frame: From protamine administration until 12 h after surgery ]
    The transfusion of blood products and coagulation factors will be assesed from protamine administration until 12 hours postoperatively .
  • 12 h Postoperative Blood Loss [ Time Frame: 15 min after protamine administration until 12 hours postoperatively ]
    The intra and postoperative blood loss from the time point of protamine administration until 12 hours postoperatively will be analyzed.
Original Secondary Outcome Measures
 (submitted: May 30, 2012)
  • Transfusion of Blood Products and Coagulation Factors [ Time Frame: From protamine administration until 12 h after surgery ]
    The transfusion of blood products and coagulation factors will be assesed from protamine administration until 12 hours postoperatively .
  • Perioperative blood loss [ Time Frame: 15 min after protamine administration until 12 hours postoperatively ]
    The intra and postoperative blood loss from the time point of protamine administration until 12 hours postoperatively will be analyzed.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Protamine in Cardiac Surgery and Haemostasis
Official Title The Effects of Heparin Level Based Versus Weight Based Protamine Dosing on Protamine Demand, Markers of Haemostasis, Blood Product Utilization and Perioperative Blood Loss in Patients Undergoing Extended Cardiac Surgery Cardiac Surgery
Brief 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.

Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
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
Condition
  • Bleeding
  • Hemorrhage
Intervention Not Provided
Study Groups/Cohorts
  • Weight based protamine group
    In this group the dose of protamine is calculated by the weight of the patients (400 IU/kg)
  • Heparin level based protamine group
    In this group the protamine dose will be calculated 1:1 according to the heparin level measured after termination of cardiopulmonary bypass.
Publications * Koster A, Börgermann J, Gummert J, Rudloff M, Zittermann A, Schirmer U. Protamine overdose and its impact on coagulation, bleeding, and transfusions after cardiopulmonary bypass: results of a randomized double-blind controlled pilot study. Clin Appl Thromb Hemost. 2014 Apr;20(3):290-5. doi: 10.1177/1076029613484085. Epub 2013 Apr 4.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Completed
Actual Enrollment
 (submitted: May 30, 2012)
30
Original Actual Enrollment Same as current
Actual Study Completion Date March 2012
Actual Primary Completion Date March 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Primary surgery
  • Preoperative hemoglobin value < 12 g/l
  • Preoperative platelet count < 200 c/µl
  • Patients with a body weight < 50 kg
  • No known defect of the coagulation system
  • Normal pre-operative ROTEM values of the INTEM and FIBTEM
  • Patients with unimpaired renal function (creatinine clearance < 30 ml/kg/min)

Exclusion Criteria:

  • <18 years
  • No informed consent
  • Re-do surgery
  • Known defect of the coagulation system
  • Renal impairment
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries Germany
Removed Location Countries  
 
Administrative Information
NCT Number NCT01608971
Other Study ID Numbers 007
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement
Plan to Share IPD: No
Responsible Party Andreas Koster, Heart and Diabetes Center North-Rhine Westfalia
Study Sponsor Heart and Diabetes Center North-Rhine Westfalia
Collaborators Not Provided
Investigators
Principal Investigator: Andreas Koster, MD Heart & Diabetes Center NRW, Ruhr University Bochum, 32545 Bad Oeynhausen, Germany
PRS Account Heart and Diabetes Center North-Rhine Westfalia
Verification Date February 2017