Does use of the Hepcon® point-of-care coagulation monitor to optimise Heparin and Protamine dosage for cardiopulmonary bypass decrease bleeding and blood and blood product requirements in adult patients undergoing cardiac surgery?

April 12, 2006

August 11, 2006

Khairul Anuar Abdul Aziza, Omar Masooda, J. Andreas Hoschtitzkya, Andrew Ronald, Specialist Registrars in Cardiothoracic Surgery, Consultant in Cardiothoracic Surgery (Department of Cardiothoracic Surgery, Manchester Royal Infirmary, Department of Cardiac Anaesthesia, Aberdeen Royal Infirmary)

Joel Dunning, Department of Cardiothoracic Surgery, Manchester Royal Infirmary, Department of Cardiac Anaesthesia, Aberdeen Royal Infirmary

In [adult patients undergoing cardiac surgery], does [use of the Hepcon® point-of-care coagulation monitor to determine optimal Heparin and Protamine dosage] decrease [bleeding and blood product requirements].

You have been performing CABG surgery. The anaesthetist has used the Hepcon HMS Plus Hemostasis Management System (Medtronic, Minneapolis, MN) to monitor heparin concentration and calculate protamine dose to reverse anticoagulation. He claims that heparin and protamine dose optimisation decreases coagulation system activation, postoperative bleeding and allogeneic blood and blood component transfusion requirement. You wonder what evidence is available to justify this claim.

MEDLINE 1966 to March Week 2 2006 using Ovid interface
Embase 1980-2006 Week 11.

[CABG.mp OR exp Cardiopulmonary Bypass/ OR Cardiopulmonary bypass.mp. OR exp Coronary Artery Bypass/ OR Coronary art$ bypass.mp. OR exp Cardiovascular Surgical Procedures/ OR Cardiac surgical procedures.mp. OR cardiac transplantation.mp. or exp Heart Transplantation/ OR exp Thoracic Surgery/ OR exp Thoracic Surgical Procedures/] AND [exp Monitoring, Intraoperative/ or exp Blood Coagulation Tests/ or exp Whole Blood Coagulation Time/ or Hepcon.mp. OR heparin dose response.mp. OR protamine dose response.mp. OR activated clotting time.mp. OR ACT.mp.] AND [bleeding.mp. OR platelets.mp. or exp Blood Platelets/ OR blood transfusion.mp. OR exp Blood Transfusion/ OR fresh frozen plasma.mp. or exp Plasma/ OR exp Blood Platelets/ or exp Blood Component Transfusion/ or exp Platelet Transfusion/ or exp Blood Transfusion/ or blood component therapy.mp. or exp Erythrocyte Transfusion/] AND [limit to humans]

680 papers were found in Medline and 879 on Embase using the reported search. A further 2 papers were identified by hand-searching of reference lists. Fourteen papers provided the best evidence and are summarised below.

The Hepcon® point-of care coagulation monitor is designed for use during cardiac surgery. It calculates initial Heparin dose required to institute cardiopulmonary bypass by performing a heparin dose response (HDR), measures blood heparin concentrations during bypass and calculates a Protamine dose based on residual heparin levels. Raymond et al have validated its use, comparing it to a lab-based anti-Xa chromogenic heparin concentration assay which demonstrated that heparin concentration rather than ACT was more closely related to anti-Xa levels. Murray et al found similar correlations . A number of studies have reported that Hepcon® use results in higher total Heparin doses compared to conventional empirical management, although Protamine doses are lower [Yamanishi, Shigeta, Despotis 1995 & 1996, Newsome, Sakarada, Beholz]. It has been suggested that this may cause less coagulation system activation with decreased bleeding and blood component therapy requirement.

Several studies have confirmed apparent decreased activation of the coagulation system and inflammatory markers when the Hepcon® is used to monitor and guide Heparin and Protamine therapy. Ohata et al reported significantly lower Interleukin-8 levels post-Protamine and 12 hours post-CPB, and Shigeta et al noted that lower Hepcon®- guided Protamine doses were associated with attenuation of platelet alpha-granule secretion during heparin neutralization and better preservation of platelet aggregation to thrombin.

In vitro studies in volunteers confirmed not only did Protamine interfere with platelet aggregation and Heparin attenuate aggregation to Thrombin, but lower Protamine concentrations compared to Heparin restored Thrombin-mediated aggregation . Koster et al measured a number of markers post-CPB and noted that anti-Xa levels were significantly higher, and Thrombin-antithrombin complexes (TAT's), D-dimers, and Neutrophil esterase levels lower, in their Hepcon® managed group. In a subgroup of their 1995 study, Despotis et al performed a series of lab-based factor and fibrinolysis marker assays and found significantly better preservation of clotting factors V and VIII, anti-thrombin III, and Fibrinogen in their Hepcon® group prior to Protamine administration. Several inflammatory markers were also significantly decreased in the Hepcon® group including pre-protamine Fibrinopeptide A and D-dimer. They also compared data in patients who bled excessively and noted that their respective D-dimer levels and Plasmin-antiplasmin complexes (PAP's) had been higher, and Factor V, X and platelet counts lower pre-Protamine.

But does this have any affect on bleeding and requirement for blood component therapy? Neither Yamanishi et al or Sakaruda et al reported an excess of bleeding in their Hepcon® groups despite higher Heparin and lower Protamine doses (these studies are unfortunately in Japanese and only available in the UK in abstract form). Shigeta et al similarly found no difference in bleeding although platelet preservation was improved in their Hepcon® group. In a larger study which investigated haemostatic-inflammatory activation, Koster et al reported no differences in postoperative blood loss, or requirement for Red cells or FFP in their Hepcon® group

Other studies have shown decreases in postoperative bleeding and / or blood component therapy requirements. In another Japanese paper, Ohata et al found patients required less blood transfusion when Protamine was given according to Hepcon® Heparin concentration. Despotis et al compared Hepcon®-guided management to empirical management in 254 patients undergoing cardiac surgery and found that Hepcon® use was associated with significantly less bleeding in the first 4 hours, more rapid chest closure, and decreased requirement for "haemostatic intervention. Whilst red cell use just failed to reach significance, requirement for FFP, Platelets and Cryoprecipitate were all significantly less in the Hepcon® group. More recently Avidan et al used Hepcon®, Thromboelastography and PFA-100 platelet function monitoring in combination and compared bleeding and blood component requirements with patients monitored using "rapidly available lab tests". Both techniques were associated with similar bleeding to that seen in a retrospective case-control cohort, but requirement for blood and blood components were significantly less. There were however no differences in outcomes between "point of care" and "lab test" groups.

In contrast, Beholz et al reported excessive bleeding using the Hepcon® leading to increased autologous retransfusion requirement but no additional blood products, and a retrospective study by Newsome et al comparing Hepcon® and Rapidpoint® (Bayer Healthcare LLC, Tarrytown, NY) coagulation monitors, reported increased bleeding and requirement for both FFP and red cells in the Hepcon® group, which the authors attributed to the higher Heparin dose.

Other protamine-titration monitors are available. The Hemocron RxDx® device (ITC, Edison, NJ) is a dose-response assay system that quantifies Heparin and Protamine doses on a patient-specific basis. Its use also leads to higher Heparin and lower Protamine doses [Bennett,Shore-Lesserson] but Shore-Lesserson et al were unable to demonstrate associated effects on bleeding or red cell, FFP or platelet transfusion
requirement.

In patients undergoing cardiac surgery, the use of the Hepcon® point-of care coagulation monitor (Medtronic, Minneapolis, MN) to titrate heparin and protamine doses during CPB is associated with higher Heparin and lower Protamine doses and may decrease activation of the coagulation and inflammatory cascades. Some studies have shown this may be associated with decreased postoperative bleeding and need for blood component therapy but further large trials are required to investigate this further.

1. Raymond PD, Ray MJ, Callen SN, Marsh NA.. Heparin monitoring during cardiac surgery. Part 1: validation of whole blood heparin concentration and activated clotting time.
2. Murray DJ, Brosnahan WJ, Pennell B, Kapalanski D, Weiler JM, Olson J.. Heparin detection by the activated coagulation time: a comparison of the sensitivity of coagulation tests and heparin assays.
3. Yamanishi H, Watanabe S, Hayashi K, Tomioka H, Minami M, Nozaki Y, Aoki T, Kawai Y, Kishino K, Ohta S.. A clinical evaluation of the Hepcon/HMS: a new device of monitoring hemostasis management during cardiopulmonary bypass.
4. Shigeta O, Kojima H, Hiramatsu Y, Jikuya T, Terada Y, Atsumi N, Sakakibara Y, Nagasawa T, Mitsui T.. Low-dose protamine based on heparin-protamine titration method reduces platelet dysfunction after cardiopulmonary bypass.
5. 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.
6. Despotis GJ. Joist JH. Hogue CW Jr. Alsoufiev A. Joiner-Maier D. Santoro SA. Spitznagel E. Weitz JI. Goodnough LT.. More effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT.
7. Newsome J. Stipanovich K. Flaherty S.. Comparison of heparin administration using the Rapidpoint Coag and Hepcon HMS.
8. Sakurada T, Kikuchi Y, Koushima R, Nakashima S, Hachiro Y, Kagaya H.. Clinical evaluation of heparin concentration and activated clotting time monitoring (HEPCON HMS) system
9. Beholz S, Grubitzsch H, Bergmann B, Wollert H-G, Eckel L.. Haemostasis management by use of the Hepcon/HMS®: Increased bleeding without increased need for blood transfusion.
10. Ohata T, Sawa Y, Ohtake S, Nishimura M, Chan CJ, Suzuki K, Matsuda H.. Clinical role of blood heparin level monitoring during open heart surgery.
11. Koster A, Fischer T, Praus M, Haberzettl H, Kuebler WM, Hetzer R, Kuppe H.. Hemostatic activation and inflammatory response during cardiopulmonary bypass: impact of heparin management.
12. Avidan MS, Alcock EL, Da Fonseca J, Ponte J, Desai JB, Despotis GJ, Hunt BJ.. Comparison of structured use of routine laboratory tests or near-patient assessment with clinical judgement in the management of bleeding after cardiac surgery.
13. Shore-Lesserson L. Reich DL. DePerio M.. Heparin and protamine titration do not improve haemostasis in cardiac surgical patients.
14. Bennett KM. Briggins D. Zucker M. LaDuca F.. A four-year experience with patient individualized heparin and protamine dosing using the Hemochron RxDx system.