1. Blood Conservation in Cardiopulmonary Bypass 서울대학교병원 김경환

2. Introduction A minority of patients in cardiac surgery (15~20%) consume more than 80% of the blood products. Blood must be viewed as a scarce source that carries risks and benefits. Careful review of available published evidence can provide guidelines.  As CABG became accepted surgical intervention, there was concern that the nation’s entire blood supply might be consumed by cardiac surgery alone. –Tector et al. Reduction of blood usage in open heart surgery. Chest 1976;4:283-287.

3. ACC/AHA guideline

4. Risks of blood transfusion Infection –HIV, HBV, HCV, bacterial infection Immunologic reactions –Febrile nonhemolytic transfusion reaction (1%) –Anaphylactic transfusion reaction (1/20000~50000) –ABO mismatch –Hemolysis (1/60000) –Death (1/600000) –Transfusion-related acute lung injury (1/2000) –Posttrasfusion purpura (rare) –Leukocyte-related target organ injury (2%)

5. Transfusion on CPB (1) class IIa (level of evidence C) –During CPB with moderate hypothermia, transfusion of red cells for a hemoglobin of 6.0 g/dl or less is reasonable. –In high risk patients, higher hemoglobin is needed. stroke history, DM, cerebrovascular ds, carotid stenosis –Transfusion : reasonable in case of patient-related factors: age, severity of illness, cardiac function, critical end organ ischemia massive or active blood loss Lab: abnormal EKG, elevated cardiac enzyme etc…

6. Transfusion on CPB (2) Transfusion during CPB: associated poor outcomes In Cleveland clinic, 15,000 operations using CPB –strong association between the use of transfusions and postoperative infection –If for transfusion, notify to staff surgeons.

8. Postoperative considerations  Class IIa –After cardiac operations with hemoglobin 6 g/dl or less, red blood cell transfusion is reasonable and can be life-saving. –Transfusion in patients of hemoglobin below 7.0 g/dl is reasonable, but no high-level evidence supports this recommendation

9. Comprehensive Approach for blood conservation !! NovoVI I Autotransfusion Ultrafiltration Special CPB circuit

10. Topics Introduction Autologous blood donation Red cell saving with cell savor Retrograde autologous priming Ultrafiltration  Heparin bonded circuit Drugs: Aprotinin, NovoSeven Conclusions

11. Autotransfusion

12. Inexpensive simple method for providing fresh blood that is essentially free of risk from transmission of disease, allergic reaction, alloimmunization, and blood banking mishaps.

13. Should be deferred from autoTf Evidence of infection and bacteremia Scheduled for AS surgery Unstable angina, High grade left main ds AMI or CVA with 6m Active seizure disorder (within last 3m) Significant cardiopulmonary disease without optimal medical Mx Cyanotic heart ds Uncontrolled hypertension

14. Erythropoietin High-dosage erythropoietin regimen of 300 U/kg IV load, maintenance 500 U/kg subcutaneously every other day, supplemented by IV iron, folate, vit C. → Hct increases of 2~3%/day within 5~7 days –Effective even in hemolysis from perivalvular prosthetic leaks (endogenous Epo levels & erythropoiesis would be maximized) –Cost: 4,000 US dollars

15. Red cell scavenging

16. heparin10000-100000 IU/ 1L NS

18. Intraop blood scavenging Final Hct 70% Revoming freeHb, coagulation factors, debris, other plasma components Concerns: –Bacteria, malignant cells, certain drugs –Topical hemostatics: Avitene, Surgicel

19. Retrograde autologous priming

20. Retrograde Autologous Priming (RAP)

23. During RAP Process … Minimum systolic BP of 100 mmHg during entire RAP After ACT reached 400 seconds Exclusion: –Age: 80 years old –Exclusion for comparison of homologous transfusion LV dysfunction(EF<30%) Aorta surgery TCA case

24. Retrograde Autologous Priming (RAP)

25. Patient Characteristics Control Group RAP Group Age(yrs) 41±15 46 ±17 Female 28/50(56%) 19/37(51.3%) BSA(m 2 ) 1.64 ±0.18 1.64 ±0.16 Preop hct(%) 39.5±4.3 39.1±4.9 CPB(min) 105.5±58.1 174.0±84.7 ACC(min) 51.1±43.1 107.2±55.4 Kim, KJTCS 2005;38:821-7

26. RAP Volume Removed(ml)

27. Postoperative Chest Tube Drainage(ml) * P<0.05 * *

28. Ultrafiltration

29. Ultrafiltration in Cardiac Surgery

31. Pre-bypass UF, CUF circuit CUF: conventional UF

32. Prebypass UF Following addition of blood to CPB circuit, ultrafiltrate removal is initiated, and volume replacement with a balanced electrolyte solution is titrated to maintain a minimum reservoir level. Reduce bradykinin, FXIII, prekallikrein, HMWK Eliminate initial drop in blood pressure commonly seen with initiation of CPB Reduce edema, cardiac impairment and pulmonary dysfunction –Nagashima et al. ATS 2000;70:1901-06 –Nagatsu et al. Japanese JTCS 1995;48:281-85

33. Z-BUF circuit

34. Z-BUF Removal of large volume of ultrafiltrate and the subsequent replacement of volume with a balanced electrolyte solution. Water soluble inflammatory mediators are removed from circulation during ultrafiltration. Journois et al: removal of TNF, IL-10, myeloperoxidase, C3a

35. MUF circuit

36. MUF in adults Effectiveness is thought to diminish as the patient size increases. Little clinical impact? –Grunenfelder et al. EJCTS 2000;17:77-83 –Tassani et al. J CT Vasc Anesth 1999;13:285-91 Significant morbidity reduction? –Luciani et al. Circulation 2001;104:1253-1259

37. Heparin bonded circuit

38. Biomaterial-dependent strategies to minimize blood activation from CPB Biomembrane mimicry: phosphorylcholine Heparin-coated circuits Surface with modified protein adsorption

39. What is coating ? Like wax on the surface of your car, it protects and keep out unwanted deposits. Similarly the surface of plastics in Perfusion products are bonded with Carmeda or Trillium to prevent platelets and protein deposits Trillium surface Wax Paint

40. Heparin coating Ionic bonding –Gott shunt, Duraflo II Dispersion –KIST shunt Covalent bonding –Carmeda,Trillium “Burst effect”

41. Carmeda and Trillium bonded surface mimics the blood vessels, it reduces blood activation 1. P latelets sticks onto the wall of an artificial surface 2. Carmeda and Trillium bonded surface is less reactive to blood Blood flow

42. Uncoated oxygenator fiber Carmeda or Trillium™ coated fiber Massive platelet deposition Less platelet deposition

43. How Do The Coatings Compare to Natural Blood Vessels Heparin BondedNegatively Charged Hydrophilicity Carmeda®Yes – covalent (non-leaching) Yes Trillium™Yes – covalent (non- leaching) Yes Duraflo® IIYes – ionic (leaching)Yes Xcoating ™No Yes Smart®No Yes Safeline®No Yes Bioline®Yes – ionic+ covalent (some leaching) Yes

44. Comparison of two heparin-coated CPB circuits with reduced systemic anticoagulation in routine CABG Carmeda BioActive Surface system Duraflo II coating system Ovrum E. J Thorac Cardiovasc Surg. 2001;121(2):324-30.

45. Clinical results favorable in both groups,

46. Pharmacologic Intervention

47. Medications ass with bleeding Aspirin: Irreversible platelet inhibition by blocking platelet cyclooxygenase Heparin: Inhibition of factors II and X, both direct and indirect thrombocytopenia mostly antibody-mediated (HIT) Coumadin: Multiple factor deficiency by blocking gamma-carboxylation Vitamin K–dependent factors Antibiotics: Multiple factor deficiency owing to vitamin K malabsorption Multiple drugs: Thrombocytopenia owing to bone marrow inhibition of platelet production

48. Acquired ds with  risk of bleeding ESRD/uremia Liver disease Malabsorption SLE Amyloid Malignancy

49. Herbs with adverse effects GarlicIncreased bleeding GingerPlatelet dysfunction Hypertension GingkoIncreased bleeding Platelet dysfunction GinsengHypertension LicoriceHypertension

50. Antifibrinolytics Epsilon-aminocaproic acid (Amicar): forms a complex with plasminogen through lysine-binding sites, thus blocking their adhesion to fibrin Tranexamic acid (Cyklokapron): forms a complex with plasminogen through lysine-binding sites, thus blocking their adhesion to fibrin Aprotinin (Trasylol): Serine protease inhibitor with an antifibrinolytic effect carried by the inhibition of plasmin and kallikrein Protection of platelet GP Ib, reducing thrombin-mediated consumption of the platelets

51. Antifibrinolytic agents (Class I) –High dose aprotinin (level of evidence A) Is indicated to reduce total blood loss to limit reexploration in high risk pts. Benefits of use should be balanced against risk of renal function –Low dose aprotinin (level of evidence A) Indicated to reduce the number of patients requiring transfusion and to reduce the total blood loss after cardiac surgeries –Transamine : lysin analogue (level of evidence A) Indicated to reduce the number of patients requiring transfusion and to reduce the total blood loss after cardiac surgeries Less potent blood sparing drugs and the safety profile is less well studied compared with aprotinin. Limits transfusion_drug

52. Safety of aprotinin –May be associated with thrombotic risk, especially renal dysfunction –FDA suggestions should be used with caution only for patients in whom the benefits of the drug outweighs the risks, mostly of renal dysfunction and of hypersensitivity –Renal dysfunction: its affinity for the proximal renal tubules –D’Ambra et al. Higher rate of renal dysfunction in patients undergoing valve surgery esp. DM (16% vs. 5%) –Kincaid et al. In CABG, combination with ACE inhibitors was associated with increased rate of ARF (OR 2.9) Limits transfusion_drug

53. High dose aprotinin vs. low dose  SNUH (Kim et al, 2008) –28 patients, prospective randomized –Compare the risks and effects on bleeding and inflammatory response. Limits transfusion_drug

54. No difference on transfusion requirement No difference on renal dysfunction

55. NovoSeven Recombinant factor VIIa (rFVIIa) (Bagsvaerd, Denmark) First used to decrease hemorrhage in hemophilia A or B In 1999, US FDA licensed rFVIIa for this purpose and in 2005 it was further approved for surgical procedures in the same patient group, and for patients with factor VII (FVII) deficiency. Although off-label use of rFVIIa has been reported in cardiac surgery.

56. NovoSeven Relatively little is known about the molecular mechanisms by which rFVIIa induces the formation of a stable hemostatic plug. –no direct effect on hemostatic plug formation, but exerts an effect by enhancing thrombin generation at sites of tissue injury.

57. NovoSeven –When vessel injury occurs in normal subjects, subendothelial cells that express TF are exposed to the blood. –The resulting TF-FVIIa complex catalyzes the conversion of factor X into its active form (Xa) leading to thrombin formation and platelet activation.

59. NovoSeven (1)prophylactically, with an aim of reducing postoperative bleeding (2)as a "rescue" therapy in hemorrhage refractory to other treatments

60. NovoSeven, Cost…. –A single 90 µg/kg dose of rFVIIa to an 80 kg patient costs $4,500. –may be offset against the costs of multiple transfusions, length of hospital stay, or even death. –multicenter trials, and cost-effectiveness analyses should be a part of any future trial involving rFVIIa.

62. Conclusions  With improving technology, awareness of blood conservation techniques, and better pharmacologic agents, a multidisciplinary approach to blood conservation can make bloodless heart surgery possible.  Using a team approach that both optimizes and integrates the use of each of these measures, the use of homologous blood can be markedly reduced in a majority of cardiac surgical patients.