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

NCT01267487 | Completed Phase 4 DMC

• 1 other identifier: UP 4316/09
• Study Type: interventional
• Target: 240
• Locations: 1 country
• Sites: 1

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.

Conditions

Cardiac Surgery; Cardiopulmonary Bypass; Anticoagulation

Keywords

Heparin; Protamine; Cardiopulmonary Bypass; Titration

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Transfusion of blood components

  First 24 PO hours

Study Arms (4)

Fixed doses plus PO protamine

ACTIVE COMPARATOR

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; Drug: PO continuous infusion of Protamine

Titrated doses plus PO protamine

ACTIVE COMPARATOR

Same as "titrated doses" arm, plus continuous infusion of 25mg/ hour of protamine during first 6 PO hours

Drug: PO continuous infusion of Protamine; Drug: Heparin and protamine titration

Fixed doses plus placebo

NO INTERVENTION

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

Titrated doses plus placebo

ACTIVE COMPARATOR

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

Interventions

Heparin fixed doses DRUG

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.

Fixed doses plus PO protamine; Fixed doses plus placebo

PO continuous infusion of Protamine DRUG

25mg/hour in IV continuous infusion during first 6 PO hours

Fixed doses plus PO protamine; Titrated doses plus PO protamine

Heparin and protamine titration DRUG

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.

Titrated doses plus PO protamine; Titrated doses plus placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients submitted to an Elective Cardiac Surgery with Cardiopulmonary Bypass
• Age 18 to 75 years-old

You may not qualify if:

• 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)

Sponsors & Collaborators

• SANE-Society of Anesthesiology: lead
• Instituto de Cardiologia do Rio Grande do Sul: collaborator
• Fundação Universitária de Cardiologia (University Foundation of Cardiology): collaborator

Study Sites (1)

Instituto de Cardiologia do Rio Grande do Sul

Porto Alegre, Rio Grande do Sul, 90620-001, Brazil

Location

Related Publications (10)

• 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.

  PMID: 9466020 BACKGROUND

• 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.

  PMID: 15282457 BACKGROUND

• 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.

  PMID: 17201083 BACKGROUND

• 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.

  PMID: 11429331 BACKGROUND

• 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.

  PMID: 1127967 BACKGROUND

• 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.

  PMID: 17462454 BACKGROUND

• 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.

  PMID: 7609566 BACKGROUND

• 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.

  PMID: 19224768 BACKGROUND

• 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.

  PMID: 7609568 BACKGROUND

• 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.

  PMID: 20303507 BACKGROUND

MeSH Terms

Interventions

Heparin

Intervention Hierarchy (Ancestors)

Glycosaminoglycans; Polysaccharides; Carbohydrates

Study Officials

• Maria B Chuquer, M. D.

  SANE-Society of Anesthesiology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: December 27, 2010
• First Posted: December 28, 2010
• Study Start: July 1, 2009
• Primary Completion: March 1, 2010
• Study Completion: November 1, 2010
• Last Updated: December 28, 2010

Record last verified: 2010-12

Locations

BR (1)