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Systematic Evaluation of Protamine Doze in Cardiac Surgery (HART)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03787641
Recruitment Status : Recruiting
First Posted : December 25, 2018
Last Update Posted : December 31, 2018
Information provided by (Responsible Party):
Ravi Taneja, Lawson Health Research Institute

Brief Summary:
The precise amount of protamine required to neutralize unfractionated heparin (UFH) remains unknown. This study will systematically identify the doze needed to neutralize UFH following cardiopulmonary bypass (CPB).

Condition or disease Intervention/treatment Phase
Cardiac Surgery With Cardiopulmonary Bypass Drug: Protamine Sulfate Not Applicable

Detailed Description:

The precise dose of protamine needed to neutralize unfractionated heparin (UFH) is unknown. Research suggests that low dose protamine is associated with decreased need for transfusions in cardiac surgery. The ATS guidelines recommend that half of the total UFH dose given for cardiopulmonary bypass (CPB) should be neutralized with protamine. However, it is unknown if this is routinely followed by anesthesiologists. Furthermore, the reference standard for UFH has changed recently and it is unknown how this has affected the dose of protamine in the perioperative period. Protamine does have a very short life and heparin rebound occurs very commonly.

It is common practice to divert the suctioned mediastinal blood following CPB while the patient is still anticoagulated. The traditional practice is that once half dose protamine has been given, suction to the cardiotomy reservoir is turned off. All surgical field blood loss is then diverted to wall suction. The inherent risk of letting too much protamine into the CPB reservoir is that UFH therein may get neutralized and predispose to clot formation in the venous reservoir. This precludes an emergency 'crash' on to CPB, should that be required for some reason. Experience of the Investigators indicates that most surgeons will turn off suction leading to the cardiotomy reservoir once half the total protamine dose has been administered. The concern with this is that "half dose" protamine may be quite different for different anesthesiologists.

The research investigators hypothesize low dose protamine is sufficient to neutralize the effects of UFH as monitored through activated clotting time (ACT). Anesthesiologists administer varying doses of protamine to neutralize UFH in cardiac surgery and the rationale behind such decisions is unclear.

Thus, the primary objective of this study is to evaluate the dose of protamine required to neutralize UFH following CPB. Secondary objectives are 1) to assess the amount of protamine needed to neutralize UFH in intravenously administered cardiotomy reservoir blood. 2) To examine the amount of residual heparin postoperatively in the cardiac surgery ICU; 3) to examine, through semi-structured interviews, the decision-making processes involved in managing (anti)coagulation in cardiac surgery.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Sysytematic Evaluation of Heparin and Protamine in Cardiac Surgery
Actual Study Start Date : September 20, 2018
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : February 28, 2020

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Protamine doze
Protamine Sulfate will be administered through an infusion pump in aliquots at a predefined rate (25 mg/min). Blood samples will be withdrawn after each aliquot and quantified for anti-Xa, IIa and ACT.
Drug: Protamine Sulfate
Protamine Sulfate will be administered via an infusion pump to administer a 50 mg test doze, then 100 mg after 5 min waiting period. Following blood samples, additional alliquots of 50 mg will be measured to a maximum of 300 mg.

Primary Outcome Measures :
  1. Change in heparin activity [ Time Frame: Duriing surgery (at baseline, before and after protamine adminitration following cardiopulmonary bypass). Samples will also be quantified at Intensive Care Unit (ICU) admission and 4 hours following ICU admission. ]

    The functional activity is ideally measured via its ability to accelerate the inhibition of activated coagulation enzymes IIa (thrombin) and Xa respectively.

    These tests are available commercially as ELISA kits. Briefly, an excess of coagulation factor IIa or Xa respectively is added to the sample and residual anti-IIa/Xa activity is quantified with a synthetic chromogenic substrate.

  2. Change in Activated Clotting time (ACT) [ Time Frame: Duriing surgery (at baseline, before and after protamine adminitration following cardiopulmonary bypass). ]
    ACT is the standard point of care test used in cardiac surgery. Blood is added to a tube containing predefined amount of coagulation accelerator (available commercially) and heparin activity is measured by prolongation or neutralization of ACT

Secondary Outcome Measures :
  1. Rationale for choosing a certain doze of protamine [ Time Frame: During surgery. (Average cardiac surgery lasts for 4-6 hours) ]
    Anesthesiologists will undergo semi-structured face to face interviews and asked their rationale for choosing a certain doze of protamine

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Elective cardiac surgery patients > 18 years age who can provide written consent for the study.

Exclusion Criteria:

  • History of any known coagulopathies, liver dysfunction, previous cardiac surgery, preoperative abnormal coagulation profiles, recent exposure to heparin (unfractionated or low molecular weight), warfarin, clopidogrel or other direct thrombin inhibitors in the preceding 7 days.
  • History of heparin resistance
  • History of adverse reactions to protamine
  • Patients identified as having heparin resistance
  • Anticipated CPB time > 2-2.5 hrs

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03787641

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Contact: Ravi Taneja, FRCPC 5196858500

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Canada, Ontario
London Health Sciences Centre Recruiting
London, Ontario, Canada, N6A 5A5
Contact: Ravi Taneja, FRCPC    5196858500   
Sponsors and Collaborators
Lawson Health Research Institute

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Responsible Party: Ravi Taneja, Associate Scientist, Lawson Health Research Institute Identifier: NCT03787641     History of Changes
Other Study ID Numbers: 107681
First Posted: December 25, 2018    Key Record Dates
Last Update Posted: December 31, 2018
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ravi Taneja, Lawson Health Research Institute:
cardiopulmonary bypass
anti-IIa assay
anti-Xa assay
activated clotting time

Additional relevant MeSH terms:
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Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Heparin Antagonists