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

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

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.

Study Overview

• Status: Completed
• Conditions: Cardiac Surgery; Cardiopulmonary Bypass; Anticoagulation
• Intervention / Treatment: Drug: Heparin fixed doses; Drug: PO continuous infusion of Protamine; Drug: Heparin and protamine titration

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.

• Study Type: Interventional
• Enrollment (Actual): 240
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • Rio Grande do Sul
    • Porto Alegre, Rio Grande do Sul, Brazil, 90620-001
      • Instituto de Cardiologia do Rio Grande do Sul

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mediastinal blood drainage (ml)	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.	First 24 PO hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transfusion of blood components	We measured the incidence(%) of transfusion of Packed Red Blood Cells, Plasma or Platelet during first 24 PO hours	First 24 PO hours

Collaborators and Investigators

• Sponsor: SANE-Society of Anesthesiology
• Collaborators: 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

Publications and helpful links

General Publications

• Society of Thoracic Surgeons Blood Conservation Guideline Task Force, Ferraris VA, Ferraris SP, Saha SP, Hessel EA 2nd, Haan CK, Royston BD, Bridges CR, Higgins RS, Despotis G, Brown JR; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion, Spiess BD, Shore-Lesserson L, Stafford-Smith M, Mazer CD, Bennett-Guerrero E, Hill SE, Body S. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg. 2007 May;83(5 Suppl):S27-86. doi: 10.1016/j.athoracsur.2007.02.099.
• Jobes DR, Aitken GL, Shaffer GW. Increased accuracy and precision of heparin and protamine dosing reduces blood loss and transfusion in patients undergoing primary cardiac operations. J Thorac Cardiovasc Surg. 1995 Jul;110(1):36-45. doi: 10.1016/S0022-5223(05)80007-8.
• Shore-Lesserson L, Reich DL, DePerio M. Heparin and protamine titration do not improve haemostasis in cardiac surgical patients. Can J Anaesth. 1998 Jan;45(1):10-8. doi: 10.1007/BF03011985.
• Despotis GJ, Joist JH, Hogue CW Jr, Alsoufiev A, Kater K, Goodnough LT, Santoro SA, Spitznagel E, Rosenblum M, Lappas DG. The impact of heparin concentration and activated clotting time monitoring on blood conservation. A prospective, randomized evaluation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg. 1995 Jul;110(1):46-54. doi: 10.1016/S0022-5223(05)80008-X.
• Teoh KH, Young E, Blackall MH, Roberts RS, Hirsh J. Can extra protamine eliminate heparin rebound following cardiopulmonary bypass surgery? J Thorac Cardiovasc Surg. 2004 Aug;128(2):211-9. doi: 10.1016/j.jtcvs.2003.12.023.
• Pappalardo F, Franco A, Crescenzi G, De Simone F, Torracca L, Zangrillo A. Anticoagulation management in patients undergoing open heart surgery by activated clotting time and whole blood heparin concentration. Perfusion. 2006 Dec;21(5):285-90. doi: 10.1177/0267659106074770.
• Griffin MJ, Rinder HM, Smith BR, Tracey JB, Kriz NS, Li CK, Rinder CS. The effects of heparin, protamine, and heparin/protamine reversal on platelet function under conditions of arterial shear stress. Anesth Analg. 2001 Jul;93(1):20-7. doi: 10.1097/00000539-200107000-00005.
• Bull BS, Huse WM, Brauer FS, Korpman RA. Heparin therapy during extracorporeal circulation. II. The use of a dose-response curve to individualize heparin and protamine dosage. J Thorac Cardiovasc Surg. 1975 May;69(5):685-9.
• Levy JH, Tanaka KA. Anticoagulation and reversal paradigms: is too much of a good thing bad? Anesth Analg. 2009 Mar;108(3):692-4. doi: 10.1213/ane.0b013e31819614dd. No abstract available.
• Lobato RL, Despotis GJ, Levy JH, Shore-Lesserson LJ, Carlson MO, Bennett-Guerrero E. Anticoagulation management during cardiopulmonary bypass: a survey of 54 North American institutions. J Thorac Cardiovasc Surg. 2010 Jun;139(6):1665-6. doi: 10.1016/j.jtcvs.2010.02.038. Epub 2010 Mar 19. No abstract available.

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): March 1, 2010
• Study Completion (Actual): November 1, 2010

Study Registration Dates

• First Submitted: December 27, 2010
• First Submitted That Met QC Criteria: December 27, 2010
• First Posted (Estimate): December 28, 2010

Study Record Updates

• Last Update Posted (Estimate): December 28, 2010
• Last Update Submitted That Met QC Criteria: December 27, 2010
• Last Verified: December 1, 2010

More Information

Terms related to this study

• Keywords: Protamine; Cardiopulmonary Bypass; Heparin; Titration
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Coagulants; Heparin Antagonists; Heparin; Calcium heparin; Protamines
• Other Study ID Numbers: UP 4316/09