Optimal blood management as priority route in cardiac surgery

Introduction. Generating manifold publications over decades, research continues assessing the burden of perioperative bleeding, preoperative anaemia and red blood component (RBC) transfusion in cardiac surgical patients. The past decade is witnessing a trend towards limited RBC transfusion. Nevertheless, the risk and justification of a restrictive or liberal transfusion strategy in cardiac surgery remain a matter of debate.

Aim — a description of evidence estimating the impact of bleeding, preoperative anaemia, red-cell transfusion and restrictive vs. liberal strategies on the risk of mortality and other adverse events in adults with cardiac surgery.

Methods. Relevant evidence was mined in PubMed for the period 2012–2019. The query phrases were: cardiac surgery [кардиохирургия], bleeding [кровотечение], preoperative anaemia [предоперационная анемия], red-cell transfusion [переливание эритроцитов], restrictive and liberal transfusion strategy [рестриктивная и либеральная трансфузионная стратегия]. The review includes 18 studies describing outcomes related to bleeding, preoperative anaemia of varying severity and variant-volume RBC transfusion in patients with cardiac surgery. Nine studies comparatively assessed the cardiac surgical clinical outcomes under restrictive and liberal transfusion strategies. A total of 24 full texts have been analysed, one randomised clinical trial (RCT) summary, one retrospective trial summary and one meta-analysis review. Additional studies of concern to discussion have also been considered.

Results. One prospective and four retrospective studies evaluated the effect of perioperative bleeding on the risk of subsequent adverse events in patients with cardiac surgery. Three prospective, five retrospective studies and one RCT revealed the association of red-cell transfusion with adverse outcomes. Five retrospective studies exposed a link between preoperative anaemia and reason for RBC transfusions. Six retrospective studies found an independent association between the risk of postoperative complications and mortality in patients having cardiac surgery and preoperative anaemia. Eight RCTs and one meta-analysis of seven RCTs presented comparative data on clinical outcomes of restrictive and liberal transfusion strategies in patients after heart surgery.

Conclusion. Preoperative anaemia, haemorrhage and donated component transfusion independently contribute to the risk of serious postoperative complications and death unifying in the “deadly triad” of cardiac surgery. RBC transfusions are integrally indicative of the aid quality in cardiac surgery reflecting the success of blood management system in the hospital. Leveraging a good patient blood management practice at all treatment steps to involve a multispecialty blood-team approach can significantly improve patient outcomes at a higher cost efficiency.

1. Thiele R.H., Raphael J. A 2014 Update on coagulation management for cardiopulmonary bypass. Semin Cardiothorac Vasc Anesth. 2014; 18(2): 177–189. DOI: 10.1177/1089253214534782.

2. Karkouti K., Ho L.T.S. Preventing and managing catastrophic bleeding during extracorporeal circulation. Hematology Am Soc Hematol Educ Program. 2018; 2018(1): 522–529. DOI: 10.1182/asheducation-2018.1.522.

3. Braga D.V., Brandão M.A.G. Diagnostic evaluation of risk for bleeding in cardiac surgery with extracorporeal circulation. Rev Lat Am Enfermagem. 2018; 26: e3092. DOI: 10.1590/1518-8345.2523.3092.

4. Pereira K.M.F.S.M., de Assis C.S, Cintra H.N.W.L., et al. Factors associated with the increased bleeding in the postoperative period of cardiac surgery: A cohort study. J Clin Nurs. 2019; 28(5–6): 850–861. DOI: 10.1111/jocn.14670.

5. Carson J.L., Brooks M.M., Abbott J.D., et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J. 2013; 165(6): 964–971.e1. DOI: 10.1016/j.ahj.2013.03.001.

6. Colson P.H, Gaudard P., Fellahi J.L., et al. Active bleeding after cardiac surgery: A prospective observational multicenter study. PLOS One. 2016; 11(9): e0162396. DOI: 10.1371/journal.pone.0162396.

7. Liu W., Xi Z., Gu C., et al. Impact of major bleeding on the risk of acute kidney injury in patients undergoing off-pump coronary artery bypass grafting. J Thorac Dis. 2018; 10(6): 3381–3389. DOI: 10.21037/jtd.2018.05.98.

8. Lobacheva G.V. Risk factors for early complications and their correction in patients after open heart surgery. Abstract of the dissertation of doctor of medical sciences. Moscow; 2000: 46 р. (In Russian).

9. Christensen M.C., Krapf S., Kempel A., von Heymann C. Costs of excessive postoperative hemorrhage in cardiac surgery. J Thorac Cardiovasc Surg. 2009; 138(3): 687–693. DOI: 10.1016/j.jtcvs.2009.02.021.

10. Koch C.G., Khandwala F., Li L., et al. Persistent effect of red cell transfusion on health-related quality of life after cardiac surgery. Ann Thorac Surg. 2006; 82(1): 13–20. DOI: 10.1016/j.athoracsur.2005.07.075.

11. Rawn J.D. Blood transfusion in cardiac surgery: A silent epidemic revisited. Circulation. 2007; 116(22): 2523–2524. DOI: 10.1161/CIRCULATIONAHA.107.739094.

12. Sniecinski R.M., Levy J.H. Bleeding and management of coagulopathy. J Thorac Cardiovasc Surg. 2011; 142(3): 662–667. DOI: 10.1016/j.jtcvs.2011.03.015.

13. Koch C.G., Li L., Duncan A.I., et al. Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting. Crit Care Med. 2006; 34(6): 1608–1616. DOI: 10.1097/01.CCM.0000217920.

14. Spiess B.D. Transfusion of blood products affects outcome in cardiac surgery. Semin Cardiothorac Vasc Anesth. 2004; 8(4): 267–281. DOI: 10.1177/108925320400800402.

15. Karkouti K., Wijeysundera D.N., Beattie W.S. Risk associated with preoperative anemia in cardiac surgery: A multicenter cohort study. Circulation. 2008; 117(4): 478–484. DOI: 10.1161/CIRCULATIONAHA.107.718353.

16. Weltert L., D’Alessandro S., Nardella S., et al. Preoperative very short-term, high-dose erythropoietin administration diminishes blood transfusion rate in offpump coronary artery bypass: A randomized blind controlled study. J Thorac Cardiovasc Surg. 2010; 139(3): 621–627. DOI: 10.1016/j.jtcvs.2009.10.012.

17. Society of Thoracic Surgeons Blood Conservation Guideline Task Force, Ferraris V.A., Brown J.R., et al. 2011 update to the Society of thoracic surgeons and the Society of cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011; 91: 944–982. DOI: 10.1016/j.athoracsur.2010.11.078.

18. Murphy G.J., Reeves B.C., Rogers C.A., et al. Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation. 2007; 116(22): 2544–2552. DOI: 10.1161/CIRCULATIONAHA.107.698977.

19. Hung M., Besser M., Sharples L.D., et al. The prevalence and association with transfusion, intensive care unit stay and mortality of pre-operative anaemia in a cohort of cardiac surgery patients. Anaesthesia. 2011; 66(9): 812–818. DOI: 10.1111/j.1365-2044.2011.06819.x.

20. von Heymann C., Sander M., Foer A., et al. The impact of an hematocrit of 20 % during normothermic cardiopulmonary bypass for elective low risk coronary artery bypass graft surgery on oxygen delivery and clinical outcome — A randomized controlled study [ISRCTN35655335]. Crit Care. 2006; 10: R58. DOI: 10.1186/cc4891.

21. Reeves B.C., Murphy G.J. Increased mortality, morbidity, and cost associated with red blood cell transfusion after cardiac surgery. Curr Opin Anaesthesiol. 2008; 21(5): 669–673. DOI: 10.1097/ACO.0b013e32830dd087.

22. Hajjar L.A., Vincent J., Galas F.R.B.G., et al. Transfusion requirements after cardiac surgery: The TRACS randomized controlled trial. JAMA. 2010; 304(14): 1559–1567. DOI: 10.1001/jama.2010.1446.

23. Ranucci M., Baryshnikova E., Castelvecchio S., et al. Major bleeding, transfusions, and anemia: The deadly triad of cardiac surgery. Ann Thorac Surg. 2013; 96(2): 478–485. DOI: 10.1016/j.athoracsur.2013.03.015.

24. Al-Attar N., Johnston S., Jamous N., et al. Impact of bleeding complications on length of stay and critical care utilization in cardiac surgery patients in England. J Cardiothorac Surg. 2019; 14(1): 64. DOI: 10.1186/s13019-019-0881-3.

25. Pasrija C., Ghoreishi M., Whitman G., et al. Mitigating the risk: Transfusion or reoperation for bleeding after cardiac surgery. Ann Thorac Surg. 2020; 110(2): 457–463. DOI: 10.1016/j.athoracsur.2019.10.076.

26. Petrou A., Tzoka T., Tzimas P., et al. Mortality associated with standard prescription transfusions in cardiac surgery. Hippokratia. 2018; 22(2): 68–74.

27. Delaney M., Stark P.C., Suh M., et al. Massive transfusion in cardiac surgery: The impact of blood component ratios on clinical outcomes and survival. Anesth Analg. 2017; 124(6): 1777–1782. DOI: 10.1213/ANE.0000000000001926.

28. Galas F.R., Almeida J.P., Fukushima J.T., et al. Blood transfusion in cardiac surgery is a risk factor for increased hospital length of stay in adult patients. J Cardiothorac Surg. 2013; 8: 54. DOI: 10.1186/1749-8090-8-54.

29. Kinnunen E.M., Zanobini M., Onorati F., et al. The impact of minor blood transfusion on the outcome after coronary artery bypass grafting. J Crit Care. 2017; 40: 207–212. DOI: 10.1016/j.jcrc.2017.04.025.

30. Paone G., Likosky D.S., Brewer R., et al. Transfusion of 1 and 2 units of red blood cells is associated with increased morbidity and mortality. Ann Thorac Surg. 2014; 97(1): 87–93, discussion: 93–94. DOI: 10.1016/j.athoracsur.2013.07.020.

31. Koster A., Zittermann A., Börgermann J., et al. Transfusion of 1 and 2 units of red blood cells does not increase mortality and organ failure in patients undergoing isolated coronary artery bypass grafting. Eur J Cardiothorac Surg. 2016; 49(3): 931–936. DOI: 10.1093/ejcts/ezv252.

32. Hogervorst E.K., Rosseel P.M., van de Watering L.M., et al. Intraoperative anemia and single red blood cell transfusion during cardiac surgery: An assessment of postoperative outcome including patients refusing blood transfusion. J Cardiothorac Vasc Anesth. 2016; 30(2): 363–372. DOI: 10.1053/j.jvca.2015.10.021.

33. Huang D., Chen C., Ming Y., et al. Risk of massive blood product requirement in cardiac surgery: A large retrospective study from 2 heart centers. Medicine. 2019; 98(5): e14219. DOI: 10.1097/MD.0000000000014219.

34. Klein A.A., Collier T.J., Brar M.S., et al. The incidence and importance of anaemia in patients undergoing cardiac surgery in the UK — the fi rst Association of Cardiothoracic Anaesthetists national audit. Anaesthesia. 2016; 71(6): 627–635. DOI: 10.1111/anae.13423.

35. Vlot E.A., Verwijmeren L., van de Garde E.M.W., et al. Intra-operative red blood cell transfusion and mortality after cardiac surgery. BMC Anesthesiol. 2019; 19(1): 65. DOI: 10.1186/s12871-019-0738-2.

36. von Heymann C., Kaufner L., Sander M., et al. Does the severity of preoperative anemia or blood transfusion have a stronger impact on long-term survival after cardiac surgery? J Thorac Cardiovasc Surg. 2016; 152(5): 1412–1420. DOI: 10.1016/j.jtcvs.2016.06.010.

37. LaPar D.J., Hawkins R.B., McMurry T.L., et al. Preoperative anemia versus blood transfusion: Which is the culprit for worse outcomes in cardiac surgery? J Thorac Cardiovasc Surg. 2018; 156(1): 66–74.e2. DOI: 10.1016/j.jtcvs.2018.03.109.

38. Miceli A., Romeo F., Glauber M., et al. Preoperative anemia increases mortality and postoperative morbidity after cardiac surgery. J Cardiothorac Surg. 2014; 9: 9050. DOI: 10.1186/1749-8090-9-137.

39. Koch C.G., Sessler D.I., Mascha E.J., et al. A randomized clinical trial of red blood cell transfusion triggers in cardiac surgery. Ann Thorac Surg. 2017; 104(4): 1243–1250. DOI: 10.1016/j.athoracsur.2017.05.048.

40. Garg A.X., Badner N., Bagshaw S.M., et al. Safety of a restrictive versus liberal approach to red blood cell transfusion on the outcome of AKI in patients undergoing cardiac surgery: A randomized clinical trial. J Am Soc Nephrol. 2019;30(7): 1294–1304. DOI: 10.1681/ASN.2019010004.

41. Mazer C.D., Whitlock R.P., Fergusson D.A., et al. Restrictive or liberal redcell transfusion for cardiac surgery. N Engl J Med. 2017; 377(22): 2133–2144. DOI: 10.1056/NEJMoa1711818.

42. Mazer C.D., Whitlock R.P., Fergusson D.A., et al. Six-month outcomes after restrictive or liberal transfusion for cardiac surgery. N Engl J Med. 2018; 379(13): 1224–1233. DOI: 10.1056/NEJMoa1808561.

43. Chen Q.H., Wang H.L., Liu L., et al. Effects of restrictive red blood cell transfusion on the prognoses of adult patients undergoing cardiac surgery: A meta-analysis of randomized controlled trials. Crit Care. 2018; 22(1): 142. DOI: 10.1186/s13054-018-2062-5.

44. Reeves B.C., Pike K., Rogers C.A., et al. A multicentre randomised controlled trial of Transfusion Indication Threshold Reduction on transfusion rates, morbidity and health-care resource use following cardiac surgery (TITRe2). Health Technol Assess. 2016; 20(60): 1–260. DOI: 10.3310/hta20600.

45. Nakamura R.E., Vincent J.L., Fukushima J.T., et al. A liberal strategy of red blood cell transfusion reduces cardiogenic shock in elderly patients undergoing cardiac surgery. J Thorac Cardiovasc Surg. 2015; 150(5): 1314–1320. DOI: 10.1016/j.jtcvs.2015.07.051.

46. Shehata N., Burns L.A., Nathan H., et al. A randomized controlled pilot study of adherence to transfusion strategies in cardiac surgery. Transfusion. 2012; 52(1): 91–99. DOI: 10.1111/j.1537-2995.2011.03236.x.

47. Shander A., Van Aken H., Colomina M.J., et al. Patient blood management in Europe. Br J Anaesth. 2012; 109(1): 55–68. DOI: 10.1093/bja/aes139.

48. Weltert L., Rondinelli B., Bello R., et al. A single dose of erythropoietin reduces perioperative transfusions in cardiac surgery: Results of a prospective single-blind randomized controlled trial. Transfusion. 2015; 55(7): 1644–1654. DOI: 10.1111 / trf.13027.

49. Yoo Y.C., Shim J.K., Kim J.C., et al. Effect of single recombinant human erythropoietin injection on transfusion requirements in preoperatively anemic patients undergoing valvular heart surgery. Anesthesiology. 2011; 115(5): 929–937. DOI: 10.1097/ALN.0b013e318232004b.

50. Spahn D.R., Schoenrath F., Spahn G.H., et al. Effect of ultra-short-term treatment of patients with iron defi ciency or anaemia undergoing cardiac surgery: A prospective randomised trial. Lancet. 2019; 393(10187): 2201–2212. DOI: 10.1016/S0140-6736(18)32555-8.

51. Urena M., Del Trigo M., Altisent O.A., et al. Combined erythropoietin and iron therapy for anaemic patients undergoing transcatheter aortic valve implantation: The EPICURE randomised clinical trial. EuroIntervention. 2017; 13(1): 44–52. DOI: 10.4244/EIJ-D-16-00591.

52. Pagano D., Milojevic M., Meesters M.I., et al. 2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery. Eur J Cardiothorac Surg. 2018; 53(1): 79–111. DOI: 10.1093/ejcts/ezx325.

53. Lako S., Dedej T., Nurka T., et al. Hematological changes in patients undergoing coronary artery bypass surgery: A prospective study. Med Arch. 2015; 69(3): 181–186. DOI: 10.5455/medarh.2015.69.181-186.

54. Salisbury A.C., Reid K.J., Alexander K., et al. Diagnostic blood loss from phlebotomy and hospital-acquired anemia during acute myocardial infarction. Arch Intern Med. 2011; 171(18): 1646–1653. DOI: 10.1001/archinternmed.2011.361.

55. Thavendiranathan P., Bagai A., Ebidia A., et al. Do blood tests cause anemia in hospitalized patients? The effect of diagnostic phlebotomy on hemoglobin and hematocrit levels. J Gen Intern Med. 2005; 20(6): 520–524. DOI: 10.1111/j.1525-1497.2005.0094.x.

56. Bokeria L.A., Samuilova D.Sh., Shvedunova V.N., et al. Hematological stress syndrome after radical correction of congenital heart defects in conditions of extracorporeal circulation. Russian Journal of Surgery. 2003; (2): 24–28. (In Russian).

57. Wu F., Chipman A., Pati S., et al. Resuscitative strategies to modulate the endotheliopathy of trauma: From cell to patient. Shock. 2019; 53(5): 575–584. DOI: 10.1097/SHK.0000000000001378.

58. Ospina-Tascón G.A., Umaña M., Bermúdez W., et al. Combination of arterial lactate levels and venous-arterial CO 2 to arterial-venous O2 content difference ratio as markers of resuscitation in patients with septic shock. Intensive Care Med. 2015; 41(5): 796–805. DOI: 10.1007/s00134-015-3720-6.

59. Jacob M., Chappell D., Becker B.F. Regulation of blood fl ow and volume exchange across the microcirculation. Crit Care. 2016; 20(1): 319. DOI: 10.1186/s13054-016-1485-0.

60. Kanoore Edul V.S., Ince C., Dubin A. What is microcirculatory shock? Curr Оpin Crit Care. 2015; 21(3): 245–252. DOI: 10.1097/MCC.0000000000000196.

61. Tsui A.K, Dattani N.D., Marsden P.A., et al. Reassessing the risk of hemodilutional anemia: Some new pieces to an old puzzle. Can J Anaesth. 2010; 57(8): 779–791. DOI: 10.1007/s12630-010-9329-x.

62. Hare G.M., Mu A., Romaschin A., et al. Plasma methemoglobin as a potential biomarker of anemic stress in humans. Can J Anaesth. 2012; 59(4): 348–356. DOI: 10.1007/s12630-011-9663-7.

63. Hare G.M.T., Han K., Leshchyshyn Y., et al. Potential biomarkers of tissue hypoxia during acute hemodilutional anemia in cardiac surgery: A prospective study to assess tissue hypoxia as a mechanism of organ injury. Can J Anaesth. 2018; 65(8): 901–913. DOI: 10.1007/s12630-018-1140-0.

64. Creteur J., Neves A.P., Vincent J.L. Near‐infrared spectroscopy technique to evaluate the effects of red blood cell transfusion on tissue oxygenation. Critical Care. 2009; 13(Suppl. 5): S11. DOI: 10.1186/cc8009.

65. Nielsen N.D., Martin-Loeches I., Wentowski C. The effects of red blood cell transfusion on tissue oxygenation and the microcirculation in the intensive care unit: A systematic review. Transfus Med Rev. 2017; 31(4): 205–222. DOI: 10.1016/j.tmrv.2017.07.003.

66. Cabrales P., Ortiz D., Friedman J.M. NO supplementation for transfusion medicine and cardiovascular applications. Future Sci OA. 2015; 1(1): FSO51.DOI: 10.4155/fso.15.51.

67. Bordbar A., Johansson P.I., Paglia G., et al. Identifi ed metabolic signature for assessing red blood cell unit quality is associated with endothelial damage markers and clinical outcomes. Transfusion. 2016; 56(4): 852–862. DOI: 10.1111/trf.13460.

68. Yurkovich J.T., Zielinski D.C., Yang L., et al. Quantitative time-course metabolomics in human red blood cells reveal the temperature dependence of human metabolic networks. J Biol Chem. 2017; 292(48): 19556–19564. DOI: 10.1074/jbc.M117.804914.

69. Helms C.C., Gladwin M.T., Kim-Shapiro D.B. Erythrocytes and vascular function: Oxygen and nitric oxide. Front Physiol. 2018; 9: 125. DOI: 10.3389/fphys.2018.00125.

70. Barshtein G., Arbell D., Yedgar S. Hemodynamic functionality of transfused red blood cells in the microcirculation of blood recipients. Front Physiol. 2018; 9: 41. DOI: 10.3389/fphys.2018.00041.

71. D’Alessandro A., Reisz J.A., Zhang Y., et al. Effects of aged stored autologous red blood cells on human plasma metabolome. Blood Adv. 2019; 3(6): 884–896. DOI: 10.1182/bloodadvances.2018029629.

72. Baron-Stefaniak J., Leitner G.C., Küntzel N.K.I. Transfusion of standard-issue packed red blood cells induces pulmonary vasoconstriction in critically ill patients after cardiac surgery — A randomized, double-blinded, clinical trial. PLoS One. 2019; 14(3): e0213000. DOI: 10.1371/journal.pone.0213000.

73. Yoshida T., Prudent M., D’alessandro A. Red blood cell storage lesion: Causes and potential clinical consequences. Blood Transfus. 2019; 17(1): 27–52. DOI: 10.2450/2019.0217-18.

74. Aksel’rod B.A., Balashova E.N., Bautin A.E., et al. Clinical use of erythrocytecontaining components of donated blood. Gematologiya i Transfusiologiya. 2018; 63(4): 372–435. DOI: 10.25837/HAT.2019.62.39.006. (In Russian).