Systematic Evaluation of Protamine Doze in Cardiac Surgery (HART)

Sysytematic Evaluation of Heparin and Protamine in Cardiac Surgery

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).

Study Overview

• Status: Unknown
• Conditions: Cardiac Surgery With Cardiopulmonary Bypass
• Intervention / Treatment: Drug: Protamine Sulfate

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.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ravi Taneja, FRCPC; Phone Number: 5196858500; Email: Ravi.Taneja@lhsc.on.ca

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • Recruiting
      • London Health Sciences Centre
      • Contact: Ravi Taneja, FRCPC; Phone Number: 5196858500; Email: Ravi.Taneja@lhsc.on.ca

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in heparin activity	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.	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.
Change in Activated Clotting time (ACT)	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	Duriing surgery (at baseline, before and after protamine adminitration following cardiopulmonary bypass).

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Lawson Health Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2018
• Primary Completion (Anticipated): December 31, 2019
• Study Completion (Anticipated): February 28, 2020

Study Registration Dates

• First Submitted: May 13, 2016
• First Submitted That Met QC Criteria: December 24, 2018
• First Posted (Actual): December 26, 2018

Study Record Updates

• Last Update Posted (Actual): December 31, 2018
• Last Update Submitted That Met QC Criteria: December 27, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: cardiopulmonary bypass; heparin; protamine; activated clotting time; anti-IIa assay; anti-Xa assay
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Coagulants; Heparin Antagonists; Protamines
• Other Study ID Numbers: 107681

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No