Clinical trial NCT01267487: Clinical Trial Comparing Heparin and Protamine Fixed and Titrated Doses in Cardiac Surgery With Cardiopulmonary Bypass
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Cardiac Surgery
Cardiopulmonary Bypass
Anticoagulation
Keywords: Heparin
Protamine
Cardiopulmonary Bypass
Titration
Lead sponsor: SANE-Society of Anesthesiology
Sponsor class: OTHER
Collaborators: name: Instituto de Cardiologia do Rio Grande do Sul
name: Fundação Universitária de Cardiologia (University Foundation of Cardiology)
First posted: 2010-12-28
Enrollment: 240
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: PREVENTION

Brief 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.

Eligibility 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)

Primary outcomes:
measure: Mediastinal blood drainage (ml)
timeFrame: First 24 PO hours
Secondary outcomes:
measure: Transfusion of blood components
timeFrame: First 24 PO hours
Other outcomes:
Locations:
city: Porto Alegre
country: Brazil
facility: Instituto de Cardiologia do Rio Grande do Sul
state: Rio Grande do Sul
Study officials:
affiliation: SANE-Society of Anesthesiology
name: Maria B Chuquer, M. D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.