Does use of the Hepcon point-of-care coagulation monitor to optimise heparin and protamine dosage for cardiopulmonary bypass decrease bleedi
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《血管的通路杂志》
a Department of Cardiothoracic Surgery, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL, UK
b Department of Anaesthesia, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, AB25 2ZN, UK
Abstract
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether use of the Hepcon point-of-care coagulation monitor (Medtronic, Minneapolis, MN) to optimise and monitor heparin and protamine dosage for cardiopulmonary bypass could decrease bleeding and blood and blood product requirements in adult patients undergoing cardiac surgery. Altogether 680 papers were identified on Medline, and 879 on Embase using the reported search strategy. Two further relevant papers were found by hand-searching of reference lists. Fourteen papers represented the best evidence on the topic. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses were tabulated. We conclude that in patients undergoing cardiac surgery, use of the Hepcon coagulation monitor will increase the dose of heparin but decrease the dose of protamine administered compared to more empirical ACT-based dosing regimes. There is some evidence that this leads to less activation of the coagulation system and may be associated with decreased postoperative bleeding and blood product requirements but more work is required to quantify the magnitude of this effect.
Key Words: Cardiac surgery; Cardiopulmonary bypass; Coagulation management; Heparin; Protamine; Blood products
1. Introduction
A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
2. Clinical scenario
During CABG surgery your anaesthetist uses the Hepcon HMS Plus Hemostasis Management System (Medtronic, Minneapolis, MN) to monitor heparin concentration and calculate protamine dose, claiming 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.
3. Three-part question
In [adult patients undergoing cardiac surgery], does [use of the Hepcon] decrease [bleeding and blood product requirements].
4. Search strategy
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].
5. Search outcome
Six hundred and eighty papers were found in Medline and 879 on Embase using the reported search. Two further papers were identified by hand-searching reference lists. Fourteen papers provided the best evidence and are summarised in Table 1.
6. Results
The Hepcon point-of-care coagulation monitor calculates Heparin doses required to institute cardiopulmonary bypass by performing a heparin dose response (HDR), measures heparin concentrations during bypass and calculates protamine doses based on residual heparin levels. Raymond et al. validated it, comparing it to a lab-based anti-Xa assay which demonstrated that heparin concentration rather than ACT was related to anti-Xa levels [2]. Murray et al. found similar correlations [3]. A number of studies report that Hepcon use results in higher total heparin and lower protamine doses than conventional management [4–10]. It has been suggested that this may cause less coagulation system activation, decreased bleeding and blood component therapy requirement.
Several studies have confirmed decreased coagulation system and inflammatory marker activation using Hepcon- guided therapy. Ohata et al. demonstrated significantly lower Interleukin-8 levels post-protamine and post-CPB [11], and Shigeta et al. noted that lower Hepcon-guided protamine doses attenuated platelet alpha-granule secretion during heparin neutralisation with better preservation of platelet aggregation to thrombin [5]. Volunteer studies confirmed protamine interfered with platelet aggregation and heparin attenuated aggregation to thrombin, but lower protamine concentrations compared to heparin restored thrombin-mediated aggregation [5]. Koster et al. measured various markers post-CPB noting that anti-Xa levels were significantly higher, and thrombin-antithrombin complexes (TATs), D-dimers, and neutrophil esterase levels lower, in their Hepcon-managed group [12]. In a subgroup of their 1995 study, Despotis et al. found significantly better preservation of clotting factors V and VIII, anti-thrombin III, and fibrinogen in their Hepcon group prior to protamine administration [7]. Several inflammatory markers were also significantly decreased in their Hepcon group. They also compared data in patients who bled excessively noting that respective D-dimer levels and plasmin-antiplasmin complexes (PAPs) had been higher, and Factor V, X and platelet counts lower pre-protamine [7].
But does this affect bleeding and blood component therapy requirement Neither Yamanishi et al. nor Sakaruda et al. found excessive bleeding in their Hepcon groups despite higher heparin and lower protamine doses [4,9]. Shigeta et al. similarly observed no difference in bleeding although Hepcon-management improved platelet preservation [5]. In a larger study investigating hemostatic-inflammatory activation, Koster et al. reported no differences in postoperative blood loss, or Red cells or FFP requirement in a Hepcon-guided group [12].
Other studies have shown decreases in postoperative bleeding and/or blood component therapy requirements. Ohata et al. found patients required less blood transfusion when protamine was given according to Hepcon heparin concentration [11]. Despotis et al. found that Hepcon use was associated with significantly less bleeding in the first 4 h, more rapid chest closure, and decreased requirement for ‘hemostatic intervention’ [6]. Whilst red cell use just failed to reach significance, FFP, platelets and cryoprecipitate requirements were all significantly less in the Hepcon group [6]. More recently Avidan et al. used Hepcon, thromboelastography and PFA-100 platelet function monitoring in combination comparing bleeding and blood component requirements with patients monitored using ‘rapidly available lab tests’. Both techniques were associated with similar bleeding to a retrospective case-control cohort, but blood and blood components requirements were less [13]. There were, however, no differences in outcomes between groups.
In contrast, Beholz et al. reported excessive bleeding using the Hepcon leading to increased autologous retransfusion requirement but no additional blood products [10], 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 [8].
Other protamine-titration monitors are available. The Hemocron RxDx device (ITC, Edison, NJ) quantifies heparin and protamine doses on a patient-specific basis. Its use also leads to higher heparin and lower protamine doses [14,15] but Shore-Lesserson et al. were unable to demonstrate effects on bleeding or blood, FFP or platelet transfusion requirement [15].
7. Clinical bottom line
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 blood component therapy requirement. Larger trials are required to investigate this further.
References
Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact Cardiovasc Thorac Surg 2003; 2:405–409.
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. Perfusion 2003; 18:269–276.
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. J Cardiothorac Vasc Anesth 1997; 11:24–28.
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. Kyobu Geka – Jpn J Thorac Surg 1997; 50:459–62. (in Japanese).
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. J Thorac Cardiovasc Surg 1999; 118:354–360.
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. J Thorac Cardiovasc Surg 1995; 110:46–54.
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. Thrombosis & Haemostasis 1996; 76:902–908.
Newsome J, Stipanovich K, Flaherty S. Comparison of heparin administration using the Rapidpoint Coag and Hepcon HMS. J Extra-Corporeal Technol 2004; 36:139–144.
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. Nippon Kyobu Geka Gakkai Zasshi-J Jpn Assoc Thorac Surg 1997; 45:836–840. (in Japanese).
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. Thorac Cardiovasc Surgeon 1999; 47:322–327.
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. Nihon Kyobu Geka Gakkai zasshi-Jpn J Thorac Cardiovasc Surg 1999; 47:600–606.
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. Anesthesiology 2002; 97:837–841.
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. Br J Anaesth 2004; 92:178–186.
Bennett KM, Briggins D, Zucker M, LaDuca F. A four-year experience with patient individualized heparin and protamine dosing using the Hemochron RxDx system. J Extra-Corporeal Technol 2001; 33:19–22.
Shore-Lesserson L, Reich DL, DePerio M. Heparin and protamine titration do not improve haemostasis in cardiac surgical patients. Can J Anaesth 1998; 45:10–18.(Khairul Anuar Abdul Aziz,)
b Department of Anaesthesia, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, AB25 2ZN, UK
Abstract
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether use of the Hepcon point-of-care coagulation monitor (Medtronic, Minneapolis, MN) to optimise and monitor heparin and protamine dosage for cardiopulmonary bypass could decrease bleeding and blood and blood product requirements in adult patients undergoing cardiac surgery. Altogether 680 papers were identified on Medline, and 879 on Embase using the reported search strategy. Two further relevant papers were found by hand-searching of reference lists. Fourteen papers represented the best evidence on the topic. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses were tabulated. We conclude that in patients undergoing cardiac surgery, use of the Hepcon coagulation monitor will increase the dose of heparin but decrease the dose of protamine administered compared to more empirical ACT-based dosing regimes. There is some evidence that this leads to less activation of the coagulation system and may be associated with decreased postoperative bleeding and blood product requirements but more work is required to quantify the magnitude of this effect.
Key Words: Cardiac surgery; Cardiopulmonary bypass; Coagulation management; Heparin; Protamine; Blood products
1. Introduction
A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
2. Clinical scenario
During CABG surgery your anaesthetist uses the Hepcon HMS Plus Hemostasis Management System (Medtronic, Minneapolis, MN) to monitor heparin concentration and calculate protamine dose, claiming 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.
3. Three-part question
In [adult patients undergoing cardiac surgery], does [use of the Hepcon] decrease [bleeding and blood product requirements].
4. Search strategy
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].
5. Search outcome
Six hundred and eighty papers were found in Medline and 879 on Embase using the reported search. Two further papers were identified by hand-searching reference lists. Fourteen papers provided the best evidence and are summarised in Table 1.
6. Results
The Hepcon point-of-care coagulation monitor calculates Heparin doses required to institute cardiopulmonary bypass by performing a heparin dose response (HDR), measures heparin concentrations during bypass and calculates protamine doses based on residual heparin levels. Raymond et al. validated it, comparing it to a lab-based anti-Xa assay which demonstrated that heparin concentration rather than ACT was related to anti-Xa levels [2]. Murray et al. found similar correlations [3]. A number of studies report that Hepcon use results in higher total heparin and lower protamine doses than conventional management [4–10]. It has been suggested that this may cause less coagulation system activation, decreased bleeding and blood component therapy requirement.
Several studies have confirmed decreased coagulation system and inflammatory marker activation using Hepcon- guided therapy. Ohata et al. demonstrated significantly lower Interleukin-8 levels post-protamine and post-CPB [11], and Shigeta et al. noted that lower Hepcon-guided protamine doses attenuated platelet alpha-granule secretion during heparin neutralisation with better preservation of platelet aggregation to thrombin [5]. Volunteer studies confirmed protamine interfered with platelet aggregation and heparin attenuated aggregation to thrombin, but lower protamine concentrations compared to heparin restored thrombin-mediated aggregation [5]. Koster et al. measured various markers post-CPB noting that anti-Xa levels were significantly higher, and thrombin-antithrombin complexes (TATs), D-dimers, and neutrophil esterase levels lower, in their Hepcon-managed group [12]. In a subgroup of their 1995 study, Despotis et al. found significantly better preservation of clotting factors V and VIII, anti-thrombin III, and fibrinogen in their Hepcon group prior to protamine administration [7]. Several inflammatory markers were also significantly decreased in their Hepcon group. They also compared data in patients who bled excessively noting that respective D-dimer levels and plasmin-antiplasmin complexes (PAPs) had been higher, and Factor V, X and platelet counts lower pre-protamine [7].
But does this affect bleeding and blood component therapy requirement Neither Yamanishi et al. nor Sakaruda et al. found excessive bleeding in their Hepcon groups despite higher heparin and lower protamine doses [4,9]. Shigeta et al. similarly observed no difference in bleeding although Hepcon-management improved platelet preservation [5]. In a larger study investigating hemostatic-inflammatory activation, Koster et al. reported no differences in postoperative blood loss, or Red cells or FFP requirement in a Hepcon-guided group [12].
Other studies have shown decreases in postoperative bleeding and/or blood component therapy requirements. Ohata et al. found patients required less blood transfusion when protamine was given according to Hepcon heparin concentration [11]. Despotis et al. found that Hepcon use was associated with significantly less bleeding in the first 4 h, more rapid chest closure, and decreased requirement for ‘hemostatic intervention’ [6]. Whilst red cell use just failed to reach significance, FFP, platelets and cryoprecipitate requirements were all significantly less in the Hepcon group [6]. More recently Avidan et al. used Hepcon, thromboelastography and PFA-100 platelet function monitoring in combination comparing bleeding and blood component requirements with patients monitored using ‘rapidly available lab tests’. Both techniques were associated with similar bleeding to a retrospective case-control cohort, but blood and blood components requirements were less [13]. There were, however, no differences in outcomes between groups.
In contrast, Beholz et al. reported excessive bleeding using the Hepcon leading to increased autologous retransfusion requirement but no additional blood products [10], 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 [8].
Other protamine-titration monitors are available. The Hemocron RxDx device (ITC, Edison, NJ) quantifies heparin and protamine doses on a patient-specific basis. Its use also leads to higher heparin and lower protamine doses [14,15] but Shore-Lesserson et al. were unable to demonstrate effects on bleeding or blood, FFP or platelet transfusion requirement [15].
7. Clinical bottom line
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 blood component therapy requirement. Larger trials are required to investigate this further.
References
Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact Cardiovasc Thorac Surg 2003; 2:405–409.
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. Perfusion 2003; 18:269–276.
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. J Cardiothorac Vasc Anesth 1997; 11:24–28.
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. Kyobu Geka – Jpn J Thorac Surg 1997; 50:459–62. (in Japanese).
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. J Thorac Cardiovasc Surg 1999; 118:354–360.
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. J Thorac Cardiovasc Surg 1995; 110:46–54.
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. Thrombosis & Haemostasis 1996; 76:902–908.
Newsome J, Stipanovich K, Flaherty S. Comparison of heparin administration using the Rapidpoint Coag and Hepcon HMS. J Extra-Corporeal Technol 2004; 36:139–144.
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. Nippon Kyobu Geka Gakkai Zasshi-J Jpn Assoc Thorac Surg 1997; 45:836–840. (in Japanese).
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. Thorac Cardiovasc Surgeon 1999; 47:322–327.
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. Nihon Kyobu Geka Gakkai zasshi-Jpn J Thorac Cardiovasc Surg 1999; 47:600–606.
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. Anesthesiology 2002; 97:837–841.
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. Br J Anaesth 2004; 92:178–186.
Bennett KM, Briggins D, Zucker M, LaDuca F. A four-year experience with patient individualized heparin and protamine dosing using the Hemochron RxDx system. J Extra-Corporeal Technol 2001; 33:19–22.
Shore-Lesserson L, Reich DL, DePerio M. Heparin and protamine titration do not improve haemostasis in cardiac surgical patients. Can J Anaesth 1998; 45:10–18.(Khairul Anuar Abdul Aziz,)