Update on Transfusion Practice Where’s the Evidence?

1. Update on Transfusion PracticeWhere’s the Evidence? Connie Lorette Calvin, PhD, CRNA, APRN Northeastern University

2. Richard Lower (1631-1691) Performed the first transfusion (animal to animal) in 1665 Lamb to human 1667 History

3. 1667 Jean Baptist Denis • Lambs blood • Calves blood

4. 1774 – Lavoisier - Role of oxygen in respiration Priestley – RBC as oxygen carriers 1818 - first human to human transfusion James Blundell

5. 1900 – Landsteiner A-B-O 1902– Sturli & DeCastello AB 1940-Landsteiner Rh typing Karl Landsteiner1930 Nobel Prize Laureate

6. Lewisohn’s Method of Transfusion1913Blood is collected in a citrated flask….…...and immediately transfused.

7. Enculturation of Transfusion • Blood is a “life giving force” • 1-800-save a life

8. 1971 - 1987 • Red cell transfusion more than doubled • Platelet transfusion grew 50 fold • Risk of hepatitis transmission was approximately 1/100 U transfused • HIV / AIDS • Is transfusion beneficial

9. Transfusion Trigger • Hemoglobin 10gm/dl • Hematocrit 30% • Blood loss of 15% of circulating blood volume • Clinical presentation • Risk:Benefits

10. “Safest Blood” • Voluntary blood donation – self exclusion • Surrogate tests • NAT • Does transfusion of banked blood improve outcome for patients?

11. Infectious Risk of Transfusion

12. Infectious Risk of Transfusion

13. Troublesome Events! • Alloimmunization (platelets – Leukocytes - RBC) • HLA – antigens • Granulocyte – platelet – RBC specific • Allergic reactions • Febrile reactions • ABT – related mortality • TRALI – TAS – HTRs – TTI • What are the costs of these?

14. Mean annual # of ABT related deaths from 3 leading causes Eleftherios et al., 2010

15. TRALI -Transfusion Related Acute Lung Injury • All plasma containing blood products • Non-cardiogenic pulmonary edema • 1-2 hours post-transfusion • Dyspnea -cough - fever • Misdiagnosed - TACO • Volume overload • Cardiogenic pulmonary edema • Multiparous donors • HLA sensitization

16. Hemolytic Transfusion Reactions • ABO • ABO antigens and/or antibodies to other RBC antigens. • Acute = 24 hours • Delayed > 24 hours • Non-ABO • RBC antibodies • Jkb, Jka, Kell, Fya, Fyb, E, Jsa, I

17. Percent of HTR deaths ABO versus Non-ABO Eleftherios et al., 2010

18. Transfusion Associated Sepsis • Bacterial contamination • Platelets – highest • Decreased with single-donor • Organisms • Staphylococcus epidermidis • E-coli • Staphylococcus aureus • Bacillus cereus

19. Transfusion Related Immunomodulation - TRIM • APCs and plasma • Non-specific immunosuppression • Antigen-specific immunosuppression • Impaired T-cell mediated immunity • Decreased macrophage • Altered cytokine • Renal allografts – better outcomes • Tumor recurrence • Reduction in survival • WBCs – HLA – CD4 – Helper T-cell

20. Leukocyte Reduction • Non-hemolytic transfusion reactions • CMV transmission • HLA alloimmunization • Capraro et al. • Infection rate • 90-day mortality • Length of ICU stay

21. Benefits???

22. Oxygen Transports • Blood flow - CO • Arterial O2 content • DO2 = CO X CaO2 • Transportation • Hemoglobin • Plasma • DO2 = CO X (%Sat X 1.39 X [Hb])

23. Impact of Anemia • CRIT • NNE • Lowest hct on bypass = increased mortality and incidence of heart failure • However blood transfusions = increased need for mechanical and inotropic support • Nadir hgb following MI predicts mortality • Aronson et al. 2007

24. Adaption to Anemia • Shift in oxyhemoglobin dissociation curve • Right -  synthesis 2,3-DPG • Hemodynamic alterations • CO • Microcirculatory alterations • Vascular tone • Renin-angiotensin-aldosterone system

25. Impact of Preop Anemia on Postop Adverse Events • Cardiac surgical patients n=5065 • Low preop hgb = Comorbidities = adverse cardiac events • Anemia = adverse postop neurologic and renal outcomes • Kulier et al. 2007 • Preoperative anemia and intraoperative blood transfusion were both independent risk factors for adverse outcomes. • Incidence increased significantly as a function of numbers of units of RBCs transfused

26. Efficacy of RBC transfusion • DO2 and utilization = improved outcomes • Delivery - Stored RBC • Low p50 – shift oxygen dissociation curve – left • Depletion 2,3, DPG • Depletion ATP • Oxygen utilization • Organ level • Hemodynamics and oxygen transport parameters

27. Anemia and Transfusion • Anemia predicts adverse outcomes • Current transfusion practice provides no benefit or is harmful • Ischemic complications were not decreased with blood transfusion • Murphy et al. 2007 • Patients who received blood that was stored for more than 2 weeks prior to transfusion had a statistically significant increase in in-hospital mortality, prolonged intubation, renal failure and sepsis or septicemia • Koch 2007

28. Storage LesionsBiochemical Changes • Lactate  = 1.6 - 30.1 mmol/L • pH  = 7.2 - 6.6 • 2,3-DPG  • ATP • GSH  • K+ = 3.9 - 78 mEq/L • SNO-Hb  • Ionized Calcium and magnesium = 0 • Free Hemoglobin 

29. Regulation of microvascular perfusion mediated by Hemoglobin + NO Low pO2 Low pH • Release • ATP 

30. Storage LesionsBiomechanical • Hemolysis • Membrane area  • Osmotic fragility • RBC adhesion • Deformability 

31. Storage LesionsOxidative • Hemoglobin oxidation • Hemoglobin denaturation • Lipid peroxidation • Bioactive Substance • Cytokines • Histamines • Lipids • Soluble HLA

32. Storage • Morphologic • Biochemical • Storage duration • Increased mortality • Increased length of stay in ICU/Hospital • Multiple organ failure • TRALI • Increased infections • Impaired tissue oxygen utilization

33. Benefits • Hemorrhagic shock • Critically ill do not tolerate anemia • Goal • Increase DO2 • Increase VO2

34. Efficacy of RBC Transfusion in the Critically Ill • RBC transfusion did not improve VO2 • RBC transfusion was not associated with improvements in clinical outcomes • RBC transfusion was associated with worse outcomes • Factors to identify patients who may benefit • Lack of efficacy related to • Adherence of stored RBCs • Nitric Oxide binding • Donor leukocytes • Inflammatory response • Decreased red cell deformability

35. Large Randomized Controlled Trials • Restrictive strategies vs. liberal strategies • Carson et al. 1996 • No data demonstrating that allogeneic RBCs increase oxygen carrying capacity • Hebert et al. 1997 • Mortality rate was doubled for patients receiving perioperative transfusion • Engoren et al. 2002 • The number of RBC units transfused is an independent predictor of worse clinical outcome • Corwin et al. 2004 • Corwin et al. 2007

36. Transfusion (1-2 U) Does Not Increase Oxygen Delivery!! • The influence of allogeneic RBC transfusion compared with 100% oxygen ventilation on systemic oxygen transport and skeletal muscle oxygen tension after cardiac surgery • O2 - not the blood transfusion increased tissue oxygen levels Suttner et al. (2004) anesth analg 99: 2-11

37. Rejuvenation • Post-storage metabolic manipulations • Mixture of pyruvate – inosine – phosphate – adenine • Rejuvesol (Cytosol Laboratory Inc) • 37°C incubation followed by cell washing [24] • Restored ATP • Elevated 2,3-DPG

38. Goals • Reduce hemolysis • Reduce dead-on-arrival RBC • Iron toxicity • Vasoconstriction via NO scavenging • Maintain deformability / prevent aggregation • Prevent capillary blockage • Maintenance of high ATP – 2,3, DPG – SNO-hb • Minimize oxidative damage • Prevent release, and/or remove bio-active substances • Prevention of TRALI • Leukoreduction, irradiation, pathogen-reduction, etc.

39. Hemoglobin Solutions • Limited duration of action • Half life 10 - 30 minutes • High colloidal osmotic pressure • 7 g/dL • Vasoactive properties • Oxygen affinity • Dissociation into dimers

40. Acute Normovolemic Hemodilution • Conserved RBC Mass • Improved Oxygenation • Preservation of Hemostasis

41. Other Autologous Transfusions • Intraoperative blood collection • Cell saver – shed blood • Postoperative blood collection • Shed blood

42. Recombinant Factor VIIa • Approved for hemophilia patients • Enhances thrombin generation on activated platelets • Cost – exorbitant $15,000.00 • Thrombotic complications

43. DDAVP • Dose: 0.3 mcg/kg over ½ hour • Release of factor VIII and vWF • Enhances platelet adhesion to the vessel wall • Shortens the prolonged aPTT and bleeding time

44. Conclusion • Benefits of transfusion are theoretical • Risks of transfusion are fact • Transfusion of allogeneic blood represents a major risk for immunosuppression and adverse outcome • Transfusion must be considered carefully • Accept lower transfusion thresholds • Alternatives to RBC transfusion

45. References Spiess BD. Blood transfusion: The silent epidemic. Ann Thorac Surg 2001;72:S1832-7. Gombotz H, Rehak PH, Shander A, Hofman A. Blood use in elective surgery: The Austrian benchmark study. Transfusion 2007;47:1468-80. Corwin HL, Carson JL. Blood transfusion-When is more really less? N Engl J Med 2007;356:1667-9.Shander A. Emerging risks and outcomes of blood transfusion in surgery. Semin Hematol. 2004:41(suppl):117-24. Brecher ME, Goodnough LT. The rise and fall of preoperative autologous blood donation. Transfusion 2001;41(12):1459-62. Sugai Y, Sugai K, Fuse A. Current status of bacterial contamination of autologous blood for transfusion. Transfus Apheresis Sci. 2001;24(3):255-9. Carson Jl, Duff A, Poses RM, et al. Effect of anaemia and cardiovascular disease on surgical mortality and morbidity. Lancet 1996;348:1055-60. Hébert PC, Wells G, Tweeddale M, et al. Does transfusion practice affect mortality in critically ill patients? Am J Respir Crit Care Med 1997:155:1618-23. Vincent JL, Baron JF, Reinhart K, et al. Anemia and blood transfusion in critically ill patients. JAMA 2002;288(12):1499-1507. Hébert PC, Wells G, Blajchman MA, et al. A Multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Eng J Med 1999;340(6);409-17. Ho J, Sibbald WJ, Chin-Yee IH. Effects of strorage on efficacy of red cell transfusion: When is it not safe? Crit Care Med 2003:31[suppl.]:S687-97. Opelz G, Sengar DPS, Mickey MR, et al. Effect of blood transfusions on subsequent kidney transplants. Transplan Proc. 1993;5:253-9. Blumberg N, Heal JM, Murphy P, et al. Association between transfusion of whole blood and recurrence of cancer. Br Med J. 1986;293:530-3. Blumberg N, Heal JM, Chuang C, et al. Further evidence supporting a cause and effect relationship between blood transfusion and cancer recurrence. Annm Surg. 1988;207:410-5. Blumberg N, Chuang-Stein C, Heal JM. The relationship of blood transfusion, tumor staging, and cancer recurrence. Transfusion. 1990;30:291-4.

46. Vamvakas EC. Possible mechanisms of allogeneic blood transfusion-associated postoperative infection. Trans Med Rev. 2002;16(2):144-60. Blumberg N, Heal SM. Universal leukocyte reduction of blood transfusion. Clin Inf Dis. 2007;45:1014-15. Vamvakas EC, Blajchman MA. Universal WBC reduction: The case for and against. Transfusion 2001;41:691-712. Capraro L, Kuitunen A, Vento AE, et al. Universal leukocyte reduction of transfused red cells does not provide benefit to patients undergoing cardiac surgery. J Cardiothor Vas Anes. 2007;21(2):232-6. Silliman CC, Boshkov LK, Mehdizadehkashi Z, et al. Transfusion related acute lung injury: epidemiology and a prospective analysis of etiologic factors. Blood 2003;101:454-62. Looney MR, Gropper MA, Matthay MA. Transfusion-related acute lung injury. Chest 2004;126:249-58. Kopko PM, Marshall CS, MacKenzie MR, et al. Transfusion-related acute lung injury: report of a clinical look-back investigation. JAMA 2002;287:1968-71. Vamvakas EC, Taswell HF. Long-term survival after blood transfusion. Transfusion 1994;34:471-7. Purdy FR, Tweeddale MG, Merrick PM. Association of mortality with age of blood transfused in septic ICU patients. Can J Anaesth 1997;44:1256-61. Moore FA, Moore EE, Sauaia A. Blood transfusion: An independent risk factor for postinjury multiple organ failure. Arch Surg 1997;132:620-5. Napolitano LM, Corwin HL. Efficacy of red blood cell transfusion in the critically ill. Crit Care Clin 2004;20:255-68. Engoren MC, Habib RH, Zacharias A, et al. Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg. 2002;74:1180-6. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT study: Anemia and blood transfusion in the criticallhy ill – current clinical practice in the United States. Crit Care Med 2004;32(1):39-52. Suttner S, Piper SN, Kumle B, et al. The influence of allogeneic red blood cell transfusion compared with 100% oxygen ventilation on systemic oxygen transport and skeletal muscle oxygen tension after cardiac surgery. Anesth Analg 2004;99:2-11.