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

This study has been completed.
Sponsor:
Collaborators:
Instituto de Cardiologia do Rio Grande do Sul
Fundação Universitária de Cardiologia (University Foundation of Cardiology)
Information provided by:
SANE-Society of Anesthesiology
ClinicalTrials.gov Identifier:
NCT01267487
First received: December 27, 2010
Last updated: NA
Last verified: December 2010
History: No changes posted
  Purpose

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.


Condition Intervention Phase
Cardiac Surgery
Cardiopulmonary Bypass
Anticoagulation
Drug: Heparin fixed doses
Drug: PO continuous infusion of Protamine
Drug: Heparin and protamine titration
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: 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

Resource links provided by NLM:


Further study details as provided by SANE-Society of Anesthesiology:

Primary Outcome Measures:
  • Mediastinal blood drainage (ml) [ Time Frame: First 24 PO hours ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Transfusion of blood components [ Time Frame: First 24 PO hours ] [ Designated as safety issue: No ]
    We measured the incidence(%) of transfusion of Packed Red Blood Cells, Plasma or Platelet during first 24 PO hours


Enrollment: 240
Study Start Date: July 2009
Study Completion Date: November 2010
Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Fixed doses plus PO protamine
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

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.

Drug: PO continuous infusion of Protamine
25mg/hour in IV continuous infusion during first 6 PO hours
Active Comparator: Titrated doses plus PO protamine
Same as "titrated doses" arm, plus continuous infusion of 25mg/ hour of protamine during first 6 PO hours
Drug: PO continuous infusion of Protamine
25mg/hour in IV continuous infusion during first 6 PO hours
Drug: Heparin and protamine titration

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.

No Intervention: Fixed doses plus placebo

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

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.

Active Comparator: Titrated doses plus placebo

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

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.


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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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)
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01267487

Locations
Brazil
Instituto de Cardiologia do Rio Grande do Sul
Porto Alegre, Rio Grande do Sul, Brazil, 90620-001
Sponsors and Collaborators
SANE-Society of Anesthesiology
Instituto de Cardiologia do Rio Grande do Sul
Fundação Universitária de Cardiologia (University Foundation of Cardiology)
Investigators
Principal Investigator: Maria B Chuquer, M. D. SANE-Society of Anesthesiology
  More Information

Publications:

Responsible Party: Maria Beatriz Couto Chuquer, CET/ SBA - SANE
ClinicalTrials.gov Identifier: NCT01267487     History of Changes
Other Study ID Numbers: UP 4316/09
Study First Received: December 27, 2010
Last Updated: December 27, 2010
Health Authority: Brazil: Ethics Committee of The Cardiology Institute of Rio Grande do Sul, Porto Alegre

Keywords provided by SANE-Society of Anesthesiology:
Heparin
Protamine
Cardiopulmonary Bypass
Titration

Additional relevant MeSH terms:
Calcium heparin
Heparin
Protamines
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Cardiovascular Agents
Heparin Antagonists
Coagulants

ClinicalTrials.gov processed this record on April 15, 2014