BleedingProtamineNCT00684450
Cardiac Surgery: In Vivo Titration of Protamine
A study testing Titration protamine and Standard administration of protamine in people with Bleeding, run by Montreal Heart Institute at 1 site in Canada.
Trial summary
Safe use of cardiopulmonary bypass (CPB) requires massive doses of intravenous unfractionated heparin. At end-CPB, residual heparin is neutralized with intravenous injection of protamine sulfate. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Bleeding
- What is being tested?
- Titration protamine and Standard administration of protamine
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 138 participants
- Where
- 1 siteCanada
- Study dates
- Jun 2008to Jun 2011
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- First intention, elective, cardiac surgery: either Coronary Artery Bypass Graft (CABG)or valve repair/replacement.
- Patients on preoperative aspirin, clopidogrel or heparin will be included.
Who cannot join
- Combination of CABG and valve surgery
- Second intention cardiac surgery
- ASA 5 patients
- Pre-existing hemostatic disorder (as evidenced by history)
- Pregnancy
- PLavix < 5 days before de surgery
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Cardiac Surgery : In Vivo Titration of Protamine
Safe use of cardiopulmonary bypass (CPB) requires massive doses of intravenous unfractionated heparin. At end-CPB, residual heparin is neutralized with intravenous injection of protamine sulfate. This prospective, randomized, controlled study will be conducted in 82 voluntary subjects admitted for elective, first intention, cardiac surgery requiring cardiopulmonary bypass. Each will be randomly assigned to one of two groups. The control group will be submitted to a standard protamine infusion of 1.3mg :100U of the total heparin dose given during bypass. The test group will receive an infusion of protamine (over 15 minutes) until activated clotting time (ACT) values (determined every 3 minutes) depict a plateau, sign that the optimal protamine to heparin ratio has been attained. The investigators hypothesize this new in vivo titration method to be as efficient as the standard protocol (adequacy of heparin neutralization, % heparin rebound, bleeding, and transfusion), and potentially safer by its ability to prevent protamine overdose and its deleterious impact on platelet function.15
Principal Objective
Read more
Evaluate a new in vivo method of titration of protamine sulfate.
Secondary Objective
Evaluate the impact of this method on the adequacy of heparin neutralization by measuring:
- platelet count
- postoperative bleeding
- transfusion exposure a
- incidence of heparin rebound
Read the detailed description
Protamine sulfate is administered to reverse the anticoagulant effects of heparin upon completion of cardiopulmonary bypass (CPB). In most cases, protamine is given in amounts sufficient to neutralize the total dose of heparin.9 This dose is usually calculated with a ratio of 1.3mg protamine for every 100U heparin given.10 In the literature, reported doses of intraoperatively administered protamine range from 0 to 8mg per 100U of heparin. Given in excess, protamine can, in addition to complement activation and hemodynamic instability,11 induce platelet dysfunctions.12-16 The latter significantly increases both the cost and morbidity of cardiac interventions as it is one of the main causes of postoperative bleeding. The optimal protamine/heparin ratio is difficult to individualize for each patient because of the great interpatient variability in heparin's metabolism4-7 and of the absence of correlation between ACT and heparin's plasma concentration.8 Consumption of heparin may vary from 0.01 to 3.86U/Kg per minute during CPB.30 The exact concentration of remaining circulating heparin at the end of bypass is not easily obtained.
- Conditions
- Bleeding
- Being tested
- Titration protamine, Standard administration of protamine
- Keywords
- titration of protamine, exact dose, protamine, neutralize heparin
- Medical subject headings
- Hemorrhage
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Titration protamineProcedure or surgery
Also called Protamine in vivo titration in cardiac surgery
- Study group: celite ACT will be performed every 3 minutes during protamine infusion until ACT values suggest reach of a plateau (defined as 2 similar ACT values, within 10% variability, and ACT ≤ to 160 seconds.), time at which infusion will be stopped. 2cc of blood is required per ACT test, for a maximum total of 10cc.
Standard administration of protamineDrug
1.3 mg of Protamine for 100u héparine
| Study group | Role | What they receive |
|---|---|---|
| 1 | Active comparator | in vivo protamine titration in cardiac surgery. The titration is done during administration of protamine each 3 minutes to reach 2 consecutive ACT defined as 2 similar ACT values, within 10% variability, and ACT ≤ to 160 seconds. .The protamine is stopped when this values are obtain. Follow-up is done 15 minutes and 3 hours post-protamine Receives: Procedure: Titration protamine |
| 2 | Active comparator | standard protamine administration ACT is done during administration of protamine each 3 minutes the values are recorded but the totality of protamine is given. Follow-up is done 15 minutes and 3 hours post-protamine Receives: Drug: Standard administration of protamine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Effective heparin neutralization (anti-Xa < 0.3 U/ml)
Measured: Pre protamine, 15 min post protamine, 3h post protamine
Secondary outcomes (3)
Frequency of heparin rebound
Measured: 15 min post protamine and 3 hours post Protamine
Blood losses after surgery and transfusion requirements
Measured: discharge
Preservation of the platelet count
Measured: Pre operate, Pré Protamine, 15 min post Protamine, 3 hours post Protamine
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 May 2008 (estimated)
- Study startJun 2008
- Primary completionJun 2011
- Study completionJun 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (30)Papers the sponsor has linked to this study.
- Other trials for BleedingStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 138 participants (actual)
Sponsor and investigators
- Lead sponsor
- Montreal Heart Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Organon
- Responsible party
- Principal investigator, Antoine Rochon, Montreal Heart Institute
- Investigators
- Antoine G Rochon, Principal investigator, Montreal Heart Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00684450
- Sponsor's protocol ID
- ICM 07-997
- Acronym
- Protamine
- Status last verified
- Aug 2011
- First submitted
- 21 May 2008
- Last updated
- 25 Aug 2011
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Hattersley PG. Activated coagulation time of whole blood. JAMA. 1966 May 2;196(5):436-40. No abstract available.
PubMed 5952227Young JA, Kisker CT, Doty DB. Adequate anticoagulation during cardiopulmonary bypass determined by activated clotting time and the appearance of fibrin monomer. Ann Thorac Surg. 1978 Sep;26(3):231-40. doi: 10.1016/s0003-4975(10)63676-4.
PubMed 110273Babka R, Colby C, El-Etr A, Pifarre R. Monitoring of intraoperative heparinization and blood loss following cardiopulmonary bypass surgery. J Thorac Cardiovasc Surg. 1977 May;73(5):780-2.
PubMed 850438McAvoy TJ. Pharmacokinetic modeling of heparin and its clinical implications. J Pharmacokinet Biopharm. 1979 Aug;7(4):331-54. doi: 10.1007/BF01062533.
PubMed 512841de Swart CA, Nijmeyer B, Roelofs JM, Sixma JJ. Kinetics of intravenously administered heparin in normal humans. Blood. 1982 Dec;60(6):1251-8.
PubMed 7139119Estes JW, Poulin PF. Pharmocokinetics of heparin. Distribution and elimination. Thromb Diath Haemorrh. 1975 Feb 28;33(1):26-37. No abstract available.
PubMed 47194Despotis GJ, Levine V, Joiner-Maier D, Joist JH. A comparison between continuous infusion versus standard bolus administration of heparin based on monitoring in cardiac surgery. Blood Coagul Fibrinolysis. 1997 Oct;8(7):419-30. doi: 10.1097/00001721-199710000-00007.
PubMed 9391723Gravlee GP, Case LD, Angert KC, Rogers AT, Miller GS. Variability of the activated coagulation time. Anesth Analg. 1988 May;67(5):469-72. No abstract available.
PubMed 3364767Despotis GJ, Gravlee G, Filos K, Levy J. Anticoagulation monitoring during cardiac surgery: a review of current and emerging techniques. Anesthesiology. 1999 Oct;91(4):1122-51. doi: 10.1097/00000542-199910000-00031.
PubMed 10519514Lowary LR, Smith FA, Coyne E, Dunham NW. Comparative neutralization of lung- and mucosal-derived heparin by protamine sulfate using in vitro and in vivo methods. J Pharm Sci. 1971 Apr;60(4):638-40. doi: 10.1002/jps.2600600436. No abstract available.
PubMed 5128383Kirklin JK, Chenoweth DE, Naftel DC, Blackstone EH, Kirklin JW, Bitran DD, Curd JG, Reves JG, Samuelson PN. Effects of protamine administration after cardiopulmonary bypass on complement, blood elements, and the hemodynamic state. Ann Thorac Surg. 1986 Feb;41(2):193-9. doi: 10.1016/s0003-4975(10)62668-9.
PubMed 3947172Carr ME Jr, Carr SL. At high heparin concentrations, protamine concentrations which reverse heparin anticoagulant effects are insufficient to reverse heparin anti-platelet effects. Thromb Res. 1994 Sep 15;75(6):617-30. doi: 10.1016/0049-3848(94)90174-0.
PubMed 7831681Harker LA. Bleeding after cardiopulmonary bypass. N Engl J Med. 1986 May 29;314(22):1446-8. doi: 10.1056/NEJM198605293142209. No abstract available.
PubMed 3702953Miyashita T, Nakajima T, Hayashi Y, Kuro M. Hemostatic effects of low-dose protamine following cardiopulmonary bypass. Am J Hematol. 2000 Jun;64(2):112-5. doi: 10.1002/(sici)1096-8652(200006)64:23.0.co;2-n.
PubMed 10814990Mochizuki T, Olson PJ, Szlam F, Ramsay JG, Levy JH. Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass. Anesth Analg. 1998 Oct;87(4):781-5. doi: 10.1097/00000539-199810000-00008.
PubMed 9768770
Study at a glance
From the registry record, last updated by the sponsor on 25 Aug 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cardiac Surgery : In Vivo Titration of Protamine
- ClinicalTrials.gov ID
- NCT00684450
- Acronym / sponsor ID
- Protamine / ICM 07-997
- Conditions
- Bleeding
- Keywords
- titration of protamine, exact dose, protamine, neutralize heparin
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 138 participants (actual)
- Lead sponsor
- Montreal Heart InstituteUniversity, hospital or other
- Collaborators
- Organon
- Study start
- Jun 2008
- Primary completion
- Jun 2011 (actual)
- Study completion
- Jun 2011 (actual)
- First posted
- 26 May 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Safe use of cardiopulmonary bypass (CPB) requires massive doses of intravenous unfractionated heparin. At end-CPB, residual heparin is neutralized with intravenous injection of protamine sulfate. This prospective, randomized, controlled study will be conducted in 82 voluntary subjects admitted for elective, first intention, cardiac surgery requiring cardiopulmonary bypass. Each will be randomly assigned to one of two groups. The control group will be submitted to a standard protamine infusion of 1.3mg :100U of the total heparin dose given during bypass. The test group will receive an infusion of protamine (over 15 minutes) until activated clotting time (ACT) values (determined every 3 minutes) depict a plateau, sign that the optimal protamine to heparin ratio has been attained. The investigators hypothesize this new in vivo titration method to be as efficient as the standard protocol (adequacy of heparin neutralization, % heparin rebound, bleeding, and transfusion), and potentially safer by its ability to prevent protamine overdose and its deleterious impact on platelet function.15
Principal Objective
Evaluate a new in vivo method of titration of protamine sulfate.
Secondary Objective
Evaluate the impact of this method on the adequacy of heparin neutralization by measuring:
- platelet count
- postoperative bleeding
- transfusion exposure a
- incidence of heparin rebound
Detailed description
Protamine sulfate is administered to reverse the anticoagulant effects of heparin upon completion of cardiopulmonary bypass (CPB). In most cases, protamine is given in amounts sufficient to neutralize the total dose of heparin.9 This dose is usually calculated with a ratio of 1.3mg protamine for every 100U heparin given.10 In the literature, reported doses of intraoperatively administered protamine range from 0 to 8mg per 100U of heparin. Given in excess, protamine can, in addition to complement activation and hemodynamic instability,11 induce platelet dysfunctions.12-16 The latter significantly increases both the cost and morbidity of cardiac interventions as it is one of the main causes of postoperative bleeding. The optimal protamine/heparin ratio is difficult to individualize for each patient because of the great interpatient variability in heparin's metabolism4-7 and of the absence of correlation between ACT and heparin's plasma concentration.8 Consumption of heparin may vary from 0.01 to 3.86U/Kg per minute during CPB.30 The exact concentration of remaining circulating heparin at the end of bypass is not easily obtained.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1 | Active comparator | Procedure: Titration protaminein vivo protamine titration in cardiac surgery. The titration is done during administration of protamine each 3 minutes to reach 2 consecutive ACT defined as 2 similar ACT values, within 10% variability, and ACT ≤ to 160 seconds. .The protamine is stopped when this values are obtain. Follow-up is done 15 minutes and 3 hours post-protamine |
| 2 | Active comparator | Drug: Standard administration of protaminestandard protamine administration ACT is done during administration of protamine each 3 minutes the values are recorded but the totality of protamine is given. Follow-up is done 15 minutes and 3 hours post-protamine |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- First intention, elective, cardiac surgery: either Coronary Artery Bypass Graft (CABG)or valve repair/replacement.
- Patients on preoperative aspirin, clopidogrel or heparin will be included.
Key exclusion criteria (6 listed)
- Combination of CABG and valve surgery
- Second intention cardiac surgery
- ASA 5 patients
- Pre-existing hemostatic disorder (as evidenced by history)
- Pregnancy
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Titration protamineAlso: Protamine in vivo titration in cardiac surgery10. Study group: celite ACT will be performed every 3 minutes during protamine infusion until ACT values suggest reach of a plateau (defined as 2 similar ACT values, within 10% variability, and ACT ≤ to 160 seconds.), time at which infusion will be stopped. 2cc of blood is required per ACT test, for a maximum total of 10cc. | Procedure or surgery | 1 |
| Standard administration of protamine1.3 mg of Protamine for 100u héparine | Drug | 2 |
Primary outcome
Effective heparin neutralization (anti-Xa < 0.3 U/ml)
Time frame: Pre protamine, 15 min post protamine, 3h post protamine
3 secondary outcomes
Frequency of heparin rebound
Time frame: 15 min post protamine and 3 hours post Protamine
Blood losses after surgery and transfusion requirements
Time frame: discharge
Preservation of the platelet count
Time frame: Pre operate, Pré Protamine, 15 min post Protamine, 3 hours post Protamine
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Aug 2011.
- Background: PubMed 5952227Hattersley PG. Activated coagulation time of whole blood. JAMA. 1966 May 2;196(5):436-40. No abstract available.
- Background: PubMed 110273Young JA, Kisker CT, Doty DB. Adequate anticoagulation during cardiopulmonary bypass determined by activated clotting time and the appearance of fibrin monomer. Ann Thorac Surg. 1978 Sep;26(3):231-40. doi: 10.1016/s0003-4975(10)63676-4.
- Background: PubMed 850438Babka R, Colby C, El-Etr A, Pifarre R. Monitoring of intraoperative heparinization and blood loss following cardiopulmonary bypass surgery. J Thorac Cardiovasc Surg. 1977 May;73(5):780-2.
- Background: PubMed 512841McAvoy TJ. Pharmacokinetic modeling of heparin and its clinical implications. J Pharmacokinet Biopharm. 1979 Aug;7(4):331-54. doi: 10.1007/BF01062533.
- Background: PubMed 7139119de Swart CA, Nijmeyer B, Roelofs JM, Sixma JJ. Kinetics of intravenously administered heparin in normal humans. Blood. 1982 Dec;60(6):1251-8.
- Background: PubMed 47194Estes JW, Poulin PF. Pharmocokinetics of heparin. Distribution and elimination. Thromb Diath Haemorrh. 1975 Feb 28;33(1):26-37. No abstract available.
- Background: PubMed 9391723Despotis GJ, Levine V, Joiner-Maier D, Joist JH. A comparison between continuous infusion versus standard bolus administration of heparin based on monitoring in cardiac surgery. Blood Coagul Fibrinolysis. 1997 Oct;8(7):419-30. doi: 10.1097/00001721-199710000-00007.
- Background: PubMed 3364767Gravlee GP, Case LD, Angert KC, Rogers AT, Miller GS. Variability of the activated coagulation time. Anesth Analg. 1988 May;67(5):469-72. No abstract available.
- Background: PubMed 10519514Despotis GJ, Gravlee G, Filos K, Levy J. Anticoagulation monitoring during cardiac surgery: a review of current and emerging techniques. Anesthesiology. 1999 Oct;91(4):1122-51. doi: 10.1097/00000542-199910000-00031.
- Background: PubMed 5128383Lowary LR, Smith FA, Coyne E, Dunham NW. Comparative neutralization of lung- and mucosal-derived heparin by protamine sulfate using in vitro and in vivo methods. J Pharm Sci. 1971 Apr;60(4):638-40. doi: 10.1002/jps.2600600436. No abstract available.
- Background: PubMed 3947172Kirklin JK, Chenoweth DE, Naftel DC, Blackstone EH, Kirklin JW, Bitran DD, Curd JG, Reves JG, Samuelson PN. Effects of protamine administration after cardiopulmonary bypass on complement, blood elements, and the hemodynamic state. Ann Thorac Surg. 1986 Feb;41(2):193-9. doi: 10.1016/s0003-4975(10)62668-9.
- Background: PubMed 7831681Carr ME Jr, Carr SL. At high heparin concentrations, protamine concentrations which reverse heparin anticoagulant effects are insufficient to reverse heparin anti-platelet effects. Thromb Res. 1994 Sep 15;75(6):617-30. doi: 10.1016/0049-3848(94)90174-0.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Antoine G Rochon principal investigator
Montreal Heart Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Titration protamine and Standard administration of protamine in people with Bleeding, run by Montreal Heart Institute at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Aug 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Effective heparin neutralization (anti-Xa < 0.3 U/ml) (time frame: Pre protamine, 15 min post protamine, 3h post protamine). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00684450, which also lists 30 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Aug 2011.