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Canadian Journal of Anesthesia/Journal canadien d'anesthésie

20-11-2023 | Reports of Original Investigations

Assessing the impact of different heparin dosing regimens for cardiopulmonary bypass on anticoagulation: the HepDOSE pilot study

Authors: Thar Nyan Lwin, MBBS, MMed, FANZCA, Rahul Mudannayake, MBBS, BSc, FRCA, Stephen MacDonald, MPhil, Joseph E. Arrowsmith, MD, FRCP, FRCA, FFICM, Christiana Burt, BChir, MA (cantab), FRCA, LLM, RCPathME, Martin Besser, MD, MRCP, FRCPath, MA, Florian Falter, MD, FRCA, FFICM, PhD

Published in: Canadian Journal of Anesthesia/Journal canadien d'anesthésie

Abstract

Purpose

It has been suggested that a larger heparin dose during cardiopulmonary bypass (CPB) is associated with reduced perioperative coagulopathy and thromboembolic complications. We investigated the effect of different heparin doses during routine elective cardiac surgery. Our primary outcomes include blood loss and transfusion and secondary outcomes investigate the effects on coagulation biomarkers.

Methods

In this prospective pilot trial, we allocated 60 patients undergoing cardiac surgery on CPB in a single tertiary cardiac centre into three groups to receive an initial dose of 300, 400, or 500 units (U) per kilogram of intravenous heparin prior to the commencement of CPB. Blood was sampled after induction of anesthesia, at 30 and 60 min of CPB, and three minutes after heparin reversal with protamine. Samples were analyzed for fibrinopeptide A (FPA), fibrinopeptide B (FPB), D-dimer, and thrombin-antithrombin (TAT) complexes. Postoperative blood loss and transfusion was measured for the first 24-hr period after surgery.

Results

The total mean (95% CI) administered heparin dose in the 300 U·kg⁻¹, 400 U·kg⁻¹, and 500 U·kg⁻¹ groups were 39,975 (36,528 to 43,421) U, 43,195 (36,940 to 49,449) U and 47,900 (44,807 to 50,992) U, respectively. There were no statistically significant differences in FPA, FPB or D-dimer levels at the measured time intervals. There was a trend towards lower TAT levels while on CPB with greater heparin dosing, which was statistically significant after the administration of protamine. The clinical significance appears to be negligible, as there is no difference in overall blood loss and amount of packed red blood cell transfusion or other blood product transfusion.

Conclusion

This pilot study indicates that, while larger heparin dosing for routine cardiac surgery results in subtle biochemical changes in coagulation, there is no demonstrable benefit in postoperative blood loss or transfusion requirements.

Shore-Lesserson L, Baker RA, Ferraris VA, et al. The Society of Thoracic Surgeons, The Society of Cardiovascular Anesthesiologists, and The American Society of ExtraCorporeal Technology: clinical practice guidelines-anticoagulation during cardiopulmonary bypass. Ann Thorac Surg 2018; 105: 650–62. https://doi.org/10.1016/j.athoracsur.2017.09.061 CrossRefPubMed

Lax M, Pesonen E, Hiippala S, Schramko A, Lassila R, Raivio P. Heparin dose and point-of-care measurements of hemostasis in cardiac surgery-results of a randomized controlled trial. J Cardiothorac Vasc Anesth 2020; 34: 2362–8. https://doi.org/10.1053/j.jvca.2019.12.050 CrossRefPubMed

Paparella D, Yau TM, Young E. Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. An update. Eur J Cardiothorac Surg 2002; 21: 232–44. https://doi.org/10.1016/s1010-7940(01)01099-5 CrossRefPubMed

Besser MW, Klein AA. The coagulopathy of cardiopulmonary bypass. Crit Rev Clin Lab Sci 2010; 47: 197–212. https://doi.org/10.3109/10408363.2010.549291 CrossRefPubMed

Falter F, MacDonald S, Matthews C, Kemna E, Cañameres J, Besser M. Evaluation of point-of-care ACT coagulometers and anti-Xa activity during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2020; 34: 2921–7. https://doi.org/10.1053/j.jvca.2020.06.027 CrossRefPubMed

Miles LF, Coulson TG, Galhardo C, Falter F. Pump priming practices and anticoagulation in cardiac surgery: results from the global cardiopulmonary bypass survey. Anesth Analg 2017; 125: 1871–7. https://doi.org/10.1213/ane.0000000000002052 CrossRefPubMed

Despotis GJ, Joist JH, Hogue CW Jr, et al. More effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT. Thromb Haemost 1996; 76: 902–8. CrossRefPubMed

Okita Y, Takamoto S, Ando M, et al. Coagulation and fibrinolysis system in aortic surgery under deep hypothermic circulatory arrest with aprotinin: the importance of adequate heparinization. Circulation 1997; 96: 376–81.

Hirsh J, Anand SS, Halperin JL, Fuster V, American Heart Association. AHA scientific statement: guide to anticoagulant therapy: heparin: a statement for healthcare professionals from the American Heart Association. Arterioscler Thromb Vasc Biol 2001; 21: E9. https://doi.org/10.1161/hq0701.093520

10.

Miles LF, Burt C, Arrowsmith J, et al. Optimal protamine dosing after cardiopulmonary bypass: the PRODOSE adaptive randomised controlled trial. PLoS Med 2021; 18: e1003658. https://doi.org/10.1371/journal.pmed.1003658 CrossRefPubMedPubMedCentral

11.

Whitehead AL, Julious SA, Cooper CL, Campbell MJ. Estimating the sample size for a pilot randomised trial to minimise the overall trial sample size for the external pilot and main trial for a continuous outcome variable. Stat Methods Med Res 2016; 25: 1057–73. https://doi.org/10.1177/0962280215588241 CrossRefPubMed

12.

Boisclair MD, Lane DA, Philippou H, Sheikh S, Hunt B. Thrombin production, inactivation and expression during open heart surgery measured by assays for activation fragments including a new ELISA for prothrombin fragment F1 + 2. Thromb Haemost 1993; 70: 253–8. CrossRefPubMed

13.

Brister SJ, Ofosu FA, Buchanan MR. Thrombin generation during cardiac surgery: is heparin the ideal anticoagulant? Thromb Haemost 1993; 70: 259–62. CrossRefPubMed

14.

Apte G, Börke J, Rothe H, Liefeith K, Nguyen TH. Modulation of platelet-surface activation: current state and future perspectives. ACS Appl Bio Mater 2020; 3: 5574–89. https://doi.org/10.1021/acsabm.0c00822 CrossRefPubMed

15.

Koster A, Yeter R, Buz S, et al. Assessment of hemostatic activation during cardiopulmonary bypass for coronary artery bypass grafting with bivalirudin: results of a pilot study. J Thorac Cardiovasc Surg 2005; 129: 1391–4. https://doi.org/10.1016/j.jtcvs.2004.09.016 CrossRefPubMed

16.

Lander H, Zammert M, FitzGerald D. Anticoagulation management during cross-clamping and bypass. Best Pract Res Clin Anaesthesiol 2016; 30: 359–70. https://doi.org/10.1016/j.bpa.2016.07.002 CrossRefPubMed

17.

Garvin S, Fitzgerald D, Muehlschlegel JD, et al. Heparin dose response is independent of preoperative antithrombin activity in patients undergoing coronary artery bypass graft surgery using low heparin concentrations. Anesth Analg 2010; 111: 856–61. https://doi.org/10.1213/ane.0b013e3181ce1ffa CrossRefPubMedPubMedCentral

18.

Shuhaibar MN, Hargrove M, Millat MH, O'Donnell A, Aherne T. How much heparin do we really need to go on pump? A rethink of current practices. Eur J Cardiothorac Surg 2004; 26: 947–50. https://doi.org/10.1016/j.ejcts.2004.07.009 CrossRefPubMed

19.

Bull BS, Korpman RA, Huse WM, Briggs BD. Heparin therapy during extracorporeal circulation. I. Problems inherent in existing heparin protocols. J Thorac Cardiovasc Surg 1975; 69: 674–84.

20.

Palmer K, Ridgway T, Al-Rawi O, Poullis M. Heparin therapy during extracorporeal circulation: deriving an optimal activated clotting time during cardiopulmonary bypass for isolated coronary artery bypass grafting. J Extra Corpor Technol 2012; 44: 145–50. CrossRefPubMedPubMedCentral

21.

Delavenne X, Ollier E, Chollet S, et al. Pharmacokinetic/pharmacodynamic model for unfractionated heparin dosing during cardiopulmonary bypass. Br J Anaesth 2017; 118: 705–12. https://doi.org/10.1093/bja/aex044 CrossRefPubMed

22.

Sniecinski RM, Chandler WL. Activation of the hemostatic system during cardiopulmonary bypass. Anesth Analg 2011; 113: 1319–33. https://doi.org/10.1213/ane.0b013e3182354b7e CrossRefPubMed

23.

Chandler WL, Velan T. Plasmin generation and D-dimer formation during cardiopulmonary bypass. Blood Coagul Fibrinolysis 2004; 15: 583–91. https://doi.org/10.1097/00001721-200410000-00009 CrossRefPubMed

24.

Nossel HL, Ti M, Kaplan KL, Spanondis K, Soland T, Butler VP Jr. The generation of fibrinopeptide A in clinical blood samples: evidence for thrombin activity. J Clin Invest 1976; 58: 1136–44. https://doi.org/10.1172/jci108566 CrossRefPubMedPubMedCentral

25.

Davies GC, Sobel M, Salzman EW. Elevated plasma fibrinopeptide A and thromboxane B2 levels during cardiopulmonary bypass. Circulation 1980; 61: 808–14. https://doi.org/10.1161/01.cir.61.4.808 CrossRefPubMed

26.

Muedra V, Bonanad S, Gómez M, Villalonga V, Sánchez F, Llopis JE. Relationships between antithrombin activity, anticoagulant efficacy of heparin therapy and perioperative variables in patients undergoing cardiac surgery requiring cardiopulmonary bypass. Perfusion 2011; 26: 487–95. https://doi.org/10.1177/0267659111412999 CrossRefPubMed

27.

Chandler WL, Velan T. Estimating the rate of thrombin and fibrin generation in vivo during cardiopulmonary bypass. Blood 2003; 101: 4355–62. https://doi.org/10.1182/blood-2002-08-2400 CrossRefPubMed

28.

Sato H, Yamamoto K, Kakinuma A, Nakata Y, Sawamura S. Accelerated activation of the coagulation pathway during cardiopulmonary bypass in aortic replacement surgery: a prospective observational study. J Cardiothorac Surg 2015; 10: 84. https://doi.org/10.1186/s13019-015-0295-9 CrossRefPubMedPubMedCentral

29.

Riedel T, Suttnar J, Brynda E, Houska M, Medved L, Dyr JE. Fibrinopeptides A and B release in the process of surface fibrin formation. Blood 2011; 117: 1700–6. https://doi.org/10.1182/blood-2010-08-300301 CrossRefPubMedPubMedCentral

30.

Rimpo K, Tanaka A, Ukai M, Ishikawa Y, Hirabayashi M, Shoyama T. Thrombin-antithrombin complex measurement using a point-of-care testing device for diagnosis of disseminated intravascular coagulation in dogs. PLoS One 2018; 13: e0205511. https://doi.org/10.1371/journal.pone.0205511 CrossRefPubMedPubMedCentral

31.

Ruhl H, Berens C, Winterhagen A, Müller J, Oldenburg J, Potzsch B. Label-free kinetic studies of hemostasis-related biomarkers including D-dimer using autologous serum transfusion. PLoS One 2015; 10: e0145012. https://doi.org/10.1371/journal.pone.0145012 CrossRefPubMedPubMedCentral

32.

Eisenberg PR, Lucore C, Kaufman L, Sobel BE, Jaffe AS, Rich S. Fibrinopeptide A levels indicative of pulmonary vascular thrombosis in patients with primary pulmonary hypertension. Circulation 1990; 82: 841–7. https://doi.org/10.1161/01.cir.82.3.841 CrossRefPubMed

33.

Ainle FN, Preston RJ, Jenkins PV, et al. Protamine sulfate down-regulates thrombin generation by inhibiting factor V activation. Blood 2009; 114: 1658–65. https://doi.org/10.1182/blood-2009-05-222109 CrossRef

34.

Meesters MI, Veerhoek D, de Jong JR, Boer C. A Pharmacokinetic model for protamine dosing after cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2016; 30: 1190–5. https://doi.org/10.1053/j.jvca.2016.04.021 CrossRefPubMed

35.

Goedhart AL, Gerritse BM, Rettig TC, et al. A 0.6-protamine/heparin ratio in cardiac surgery is associated with decreased transfusion of blood products. Interact Cardiovasc Thorac Surg 2020; 31: 391–7. https://doi.org/10.1093/icvts/ivaa109

36.

Mahmood S, Bilal H, Zaman M, Tang A. Is a fully heparin-bonded cardiopulmonary bypass circuit superior to a standard cardiopulmonary bypass circuit? Interact Cardiovasc Thorac Surg 2012; 14: 406–14. https://doi.org/10.1093/icvts/ivr124 CrossRefPubMedPubMedCentral

Title: Assessing the impact of different heparin dosing regimens for cardiopulmonary bypass on anticoagulation: the HepDOSE pilot study
Authors: Thar Nyan Lwin, MBBS, MMed, FANZCA
Rahul Mudannayake, MBBS, BSc, FRCA
Stephen MacDonald, MPhil
Joseph E. Arrowsmith, MD, FRCP, FRCA, FFICM
Christiana Burt, BChir, MA (cantab), FRCA, LLM, RCPathME
Martin Besser, MD, MRCP, FRCPath, MA
Florian Falter, MD, FRCA, FFICM, PhD
Publication date: 20-11-2023
Publisher: Springer International Publishing
Published in: Canadian Journal of Anesthesia/Journal canadien d'anesthésie
Print ISSN: 0832-610X
Electronic ISSN: 1496-8975
DOI: https://doi.org/10.1007/s12630-023-02645-6

Keynote Webinar | Spotlight on Diet and Diabetes

Springer Medicine

Assessing the impact of different heparin dosing regimens for cardiopulmonary bypass on anticoagulation: the HepDOSE pilot study

Abstract

Purpose

Methods

Results

Conclusion

Keynote Webinar | Spotlight on Diet and Diabetes

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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