PROTT: Protamine in Cardiac Surgery and Haemostasis

• Sponsor: Heart and Diabetes Center North-Rhine Westfalia (Other)
• Overall Status: Completed
• CT.gov ID: NCT01608971
• Collaborator: (none)
• Enrollment: 30
• Location: 1
• Duration (Months): 14
• Patients Per Site Per Month: 2.1

Study Details

Study Description

Brief Summary

Protamine is used after Cardiopulmonary Bypass (CPB) to reverse the anticoagulant effects of heparin and restore coagulation. Convincing evidence from in-vitro and in-vivo studies suggest that an overdose of protamine has anticoagulant effects which might lead to bleeding complications. Heparin levels usually decrease during cardiac surgery with CPB. Therefore, a protamine regimen based on the initial heparin dose before CPB might lead to overdose of protamine. In contrast, a protamine regimen based on the actual heparin concentration may avoid this condition. The investigators compare both regimens of protamine dosing in patients undergoing complex surgery with CPB and assess its effect on the amount of protamine given, markers of the coagulation system, utilization of blood products and perioperative blood loss.

Condition or Disease	Intervention/Treatment	Phase
Bleeding; Hemorrhage

Detailed Description

Before induction of anesthesia, patients are randomized to the two different dosing regimen for protamine. Both, the anesthetist and the surgeon were blinded regarding the grouping of the patients.

Anesthesia and CPB

Anesthesia is performed as a balanced anesthesia with a bolus of fentanyl, etomidate, pancuronium-bromide followed by a continuous infusion of remifentanil and vaporization of sevoflurane. Additionally, in all patients a continuous infusion of 0.25 µg/kg/min milrinone will be started after induction of anesthesia. Further inotropic or vasoactive agents (Dobutamine 3-5 µg/kg/min; epinephrine 0.05-0.2 µg(kg/min, norepinephrine 0.05-0.2 µg/kg/min) will be only given when a target cardiac index of < 2.2 l/m² BSA and mean arterial pressure of >70 mmHg is not achieved with this therapy.

In order to compensate the degree of hemodilution due to differences in weight, in patients with a body surface area (BSA) of <1.8 m², a CPB system with a priming volume of 1100 ml will be used while in patients with a BSA of >1.8m² a system with a priming volume of 1500 ml was employed. CBP will be performed with open non-coated CPB circuits in mild hypothermia with a core temperature of 32-34°C. Cardioplegia will be achieved using warm blood cardioplegia according to Calafiore.

All patients receive tranexamic acid (TA) with a bolus of 1 g to the patient, 0.5 g added to the CPB volume and a continuous infusion of 0.2 g/hour during CPB.

Heparin and Protamine Management

Heparin will be given with a bolus of 400 IU/kg to achieve a target celite ACT (Actalyke ACT, Helena Lab. Beaumont, TX USA) value of >450 seconds. If this target is not reached, additional boluses of 1/3 rd of the first dose will be given until prolongation to the target value is achieved. Additional 10.000 units of heparin will be given into the priming volume of the CPB circuit.

Heparin concentrations were measured five minutes after beginning of CPB using the white (range 3.4-6.8 IU/ml heparin) heparin protamine titration (HPT) cartridge of the Hepcon HMS Plus™ device (Medtronic INC, Minneapolis, Min, USA) and shortly after termination of CPB using the golden HPT cartridge (range 2.0 - 5.4 IU/ml heparin).

The total protamine dose consists of 100 ml. Of this 80 ml will be given as a short infusion over 10 min. directly after termination of CPB. The remaining 20 ml will be given when the residual CPB blood is re-infused into the patient after arterial decannulation, which will be performed 10-15 minutes after weaning from CPB.

In the weight based protamine group (Group 1, the total amount of protamine will be calculated 1:1 according to the initial heparin dose necessary to achieve the target ACT of

450 sec. In the heparin level based group, the total protamine amount will be calculated 1:1 according to the actual heparin level measured after termination of CPB with the use of Hepcon HMS Plus™ device.

Coagulation Tests

Fifteen minutes after infusion of protamine, the INTEM, FIBTEM and HEPTEM test will be performed on the ROTEM thromboelastometry system (TEM International GmbH, Munich Germany). In all tests, the coagulation time (CT) reflects the period until clot formation starts; the clot formation time (CFT) reflects the period until a clot strength of 20 mm is achieved and the maximal clot firmness MCF)reflects the maximal clot strength. In the INTEM test the intrinsic coagulation pathway is activated.

Transfusion triggers

During CPB the critical hemoglobin (Hb) triggering transfusion of packed red blood cells (PRBC) is defined at 8 g/dl. After CPB, in patients with a CI >2.2 l/m² the critical value is at >8-9 g/dl, while in patients needing further medical support with dobutamine/epinephrine or norepinephrine the minimum target was defined at >9-10 g/dl.

In patients with diffuse bleeding after protamine administration, therapy with fresh frozen plasma (FFP), prothrombin complex concentrate (Beriplex, CSL Behring, Marburg, Ger) , fibrinogen concentrate (Haemocomplettan P®, CSL Behring, Marburg, Germany) and single donor aphaeresis platelet concentrates will be based on the results of the ROTEM analysis. However, these blood products will only be given when diffuse microvascular bleeding is observed in the operation field.

In case of a moderate prolongation of the CT (240-360 sec) in the INTEM test (and comparable result in the HEPTEM test) 3-4 units of FFP will be transfused. If bleeding persists, additional 3-4 units of FFP or in case of a prolongation of the CT>360 sec. 2000-4000 IU of prothrombin complex concentrate will be given.In case of an MCF < 45 mm to platelet concentrates will be transfused.

Study Design

• Study Type: Observational
• Actual Enrollment: 30 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: The Effects of Heparin Level Based Versus Weight Based Protamine Dosing on Protamine Demand, Markers of Haemostasis, Blood Product Utilization and Perioperative Blood Loss in Patients Undergoing Extended Cardiac Surgery Cardiac Surgery
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Weight based protamine group In this group the dose of protamine is calculated by the weight of the patients (400 IU/kg)
Heparin level based protamine group In this group the protamine dose will be calculated 1:1 according to the heparin level measured after termination of cardiopulmonary bypass.

Outcome Measures

Primary Outcome Measures

1. INTEM HEPTEM and FIBTEM Test of the ROTEM Coagulation Analyzer [Tests will be measured 15 minutes after Protamine infusion]

   The Intem test of the ROTEM analyzer evaluates the response of the heamostatic system to activation of the intrinsic coagulation system. The following parameters of the INTEM test will be analyzed. CT [seconds](coagulation time), CFT [seconds] (clot formation time) and the CT [seconds] of the HEPTEM test which is non sensitive for residual heparine.

2. Rotem MCF Fibtem and MCF Intem [15 Minutes after protamine infusion]

   The following parameters of the INTEM test will be analyzed: MCF [mm] (maximum clot firmness) which correlates with the platelet count. Furthermore, the MCF [mm] of the FIBTEM test will be analyzed, which correlates with the fibrinogen concentration.

Secondary Outcome Measures

1. Transfusion of Blood Products and Coagulation Factors [From protamine administration until 12 h after surgery]

   The transfusion of blood products and coagulation factors will be assesed from protamine administration until 12 hours postoperatively .

2. 12 h Postoperative Blood Loss [15 min after protamine administration until 12 hours postoperatively]

   The intra and postoperative blood loss from the time point of protamine administration until 12 hours postoperatively will be analyzed.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Primary surgery

• Preoperative hemoglobin value < 12 g/l

• Preoperative platelet count < 200 c/µl

• Patients with a body weight < 50 kg

• No known defect of the coagulation system

• Normal pre-operative ROTEM values of the INTEM and FIBTEM

• Patients with unimpaired renal function (creatinine clearance < 30 ml/kg/min)

Exclusion Criteria:

• <18 years

• No informed consent

• Re-do surgery

• Known defect of the coagulation system

• Renal impairment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Heart & Diabetes Center NRW	Bad Oeynhausen	North Rhine-Westphalia	Germany	32545

Sponsors and Collaborators

• Heart and Diabetes Center North-Rhine Westfalia

Investigators

• Principal Investigator: Andreas Koster, MD, Heart & Diabetes Center NRW, Ruhr University Bochum, 32545 Bad Oeynhausen, Germany

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Andreas Koster, Senior anaestetist, Heart and Diabetes Center North-Rhine Westfalia
• ClinicalTrials.gov Identifier: NCT01608971
• Other Study ID Numbers: 007
• First Posted: May 31, 2012
• Last Update Posted: Mar 27, 2017
• Last Verified: Feb 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Andreas Koster, Senior anaestetist, Heart and Diabetes Center North-Rhine Westfalia: Protamine; heparin level; haemostasis; thromboelastometry; cardiac surgery; Patients undergoing cardiac surgery
• Additional relevant MeSH terms: Hemorrhage

Study Results

Participant Flow

Arm/Group Title	Heparin Level Based Protamine Group	Weight Based Protamine Group
Arm/Group Description	In this group the protamine dose will be calculated 1:1 according to the heparin level measured after termination of cardiopulmonary bypass.	In this group the dose of protamine is calculated by the weight of the patients (400 IU/kg)
Period Title: Overall Study
STARTED	15	15
COMPLETED	15	15
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Weight Based Protamine Group	Heparin Level Based Protamine Group	Total
Arm/Group Description	In this group the dose of protamine is calculated by the weight of the patients (400 IU/kg)	In this group the protamine dose will be calculated 1:1 according to the heparin level measured after termination of cardiopulmonary bypass.	Total of all reporting groups
Overall Participants	15	15	30
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	4 26.7%	3 20%	7 23.3%
>=65 years	11 73.3%	12 80%	23 76.7%
Sex: Female, Male (Count of Participants)
Female	5 33.3%	9 60%	14 46.7%
Male	10 66.7%	6 40%	16 53.3%
Region of Enrollment (participants) [Number]
Germany	15 100%	15 100%	30 100%

Outcome Measures

1. Primary Outcome

Title	INTEM HEPTEM and FIBTEM Test of the ROTEM Coagulation Analyzer
Description	The Intem test of the ROTEM analyzer evaluates the response of the heamostatic system to activation of the intrinsic coagulation system. The following parameters of the INTEM test will be analyzed. CT [seconds](coagulation time), CFT [seconds] (clot formation time) and the CT [seconds] of the HEPTEM test which is non sensitive for residual heparine.
Time Frame	Tests will be measured 15 minutes after Protamine infusion

Outcome Measure Data

Analysis Population Description

Rotem INTEM CT, CFT, MCF and FIBTEM MCF and Heptem CT

Arm/Group Title	Heparin Level Based Protamine Group	Weight Based Protamine Group
Arm/Group Description	In this group the protamine dose will be calculated 1:1 according to the heparin level measured after termination of cardiopulmonary bypass.	In this group the dose of protamine is calculated by the weight of the patients (400 IU/kg)
Measure Participants	15	15
CFT Intem	98	117
CT Intem	178	253
CT Heptem	185	267

2. Secondary Outcome

Title	Transfusion of Blood Products and Coagulation Factors
Description	The transfusion of blood products and coagulation factors will be assesed from protamine administration until 12 hours postoperatively .
Time Frame	From protamine administration until 12 h after surgery

Outcome Measure Data

Analysis Population Description

Transfusion of RBC

Arm/Group Title	Weight Based Protamine Group	Heparin Level Based Protamine Group
Arm/Group Description	In this group the dose of protamine is calculated by the weight of the patients (400 IU/kg)	In this group the protamine dose will be calculated 1:1 according to the heparin level measured after termination of cardiopulmonary bypass.
Measure Participants	15	15
RBC transfusion	76.7	80
PCC transfusion	20	60
FFP transfusiom	20	60
RDPC transfusion	7	15
Fibrinogen transfusion	33.3	20

3. Secondary Outcome

Title	12 h Postoperative Blood Loss
Description	The intra and postoperative blood loss from the time point of protamine administration until 12 hours postoperatively will be analyzed.
Time Frame	15 min after protamine administration until 12 hours postoperatively

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Weight Based Protamine Group	Heparin Level Based Protamine Group
Arm/Group Description	In this group the dose of protamine is calculated by the weight of the patients (400 IU/kg)	In this group the protamine dose will be calculated 1:1 according to the heparin level measured after termination of cardiopulmonary bypass.
Measure Participants	15	15
Median (Inter-Quartile Range) [ml/12 hour]	620	723

4. Primary Outcome

Title	Rotem MCF Fibtem and MCF Intem
Description	The following parameters of the INTEM test will be analyzed: MCF [mm] (maximum clot firmness) which correlates with the platelet count. Furthermore, the MCF [mm] of the FIBTEM test will be analyzed, which correlates with the fibrinogen concentration.
Time Frame	15 Minutes after protamine infusion

Outcome Measure Data

Analysis Population Description

Patients of both groups

Arm/Group Title	Heparin Level Based Protamine Group	Weight Based Protamine Group
Arm/Group Description	In this group the protamine dose will be calculated 1:1 according to the heparin level measured after termination of cardiopulmonary bypass.	In this group the dose of protamine is calculated by the weight of the patients (400 IU/kg)
Measure Participants	15	15
MCF Intem	55	57
MCF Fibtem	9	13

Adverse Events

Time Frame	3 months
Arm/Group Title	Heparin Level Based Protamine Group		Weight Based Protamine Group
Arm/Group Description	In this group the protamine dose will be calculated 1:1 according to the heparin level measured after termination of cardiopulmonary bypass.		In this group the dose of protamine is calculated by the weight of the patients (400 IU/kg)
All Cause Mortality
	Heparin Level Based Protamine Group		Weight Based Protamine Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Heparin Level Based Protamine Group		Weight Based Protamine Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Blood and lymphatic system disorders
Excessive bleeding	0/15 (0%)	0	0/15 (0%)	0
Other (Not Including Serious) Adverse Events
	Heparin Level Based Protamine Group		Weight Based Protamine Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)

Limitations/Caveats

small study cohort

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.