ONTraC presentation Plus random slides after (28 MB)

1. ONTraC presentation Plus random slides after (28 MB) Note: this presentation contains custom animation and with some slides you need to wait until this takes effect With particular thanks to Dr James Isbister of Sydney, Australia

2. Blood Transfusion: An expensive & potentially hazardous alternative to Blood Management John Freedman Director, Transfusion Medicine St Michael’s Hospital University of Toronto

3. I won’t keep you long As Henry VIII said to each of his 6 wives

4. Objectives of this presentation To gain an understanding of: • Risks of allogeneic transfusion • Infectious • Immunologic (TRALI, immunomodulation) • Errors • Blood conservation/transfusion alternatives • An Ontario approach to blood conservation

5. Blood will immerse you in a world of horror unlike any you've experienced before. Brace yourself for a nightmarish battle against the bloodthirsty minions of an ancient, forgotten god bent on wiping humanity from the face of the earth WWW.BLOOD.COM With thanks to Dr James Isbister, Sydney, SABM 2005

6. Blood הואבדםהבשרנפשכי ויקרא Leviticus 17 (‘the life/soul of the flesh is in the blood’) Blood transfusion: other than as a scarce and expensive resource, who cares? Adverse effects Errors 1:18,000 units to wrong pt

7. Patientsthink blood transfusion is special and beneficial, but have difficulty accepting small risks they can’t control. Blood Donorsbelieve their contribution is a gift to the community that will be used appropriately and safely Cliniciansthink blood is ordinary, take blood transfusion for granted, benefit is assumed and risks regarded as minimal. Governmentsview blood as a commodity and transfusion medicine as an expensive support service which should be regulated and funded in a cost-effective manner. Blood transfusion

9. 1997 Krever Commission: Recommendation #9: “It is recommended that ….. promote appropriate use of, and alternatives to, blood components and blood products.” 1996 Gallup Poll indicates that only 7% of respondents would want to receive donated blood; 82% think patients should have the right to make final decision

10. Virus TTI Residual risk HIV1:10 million HCV1:3 million HBV1:72,000 (no NAT) HTLV 1:1.1 million Per unit Risk of death from: (actuarial tables) MVA 1: 9,000 Home accident 1: 10,000 Murdered in Canada 1: 85,000 General anaesthesia 1: 20-50,000 Lightning 1: 3,000,000 Chiavetta et al, CMAJ, 169:67-73, 2003

11. bacterial contamination bacterial survival in component febrile reaction severe reaction fatality 106 105 104 102 103 Bacterial contamination Standard collection pouch Skin fragment

12. Bacterial contamination of platelets N plt type % positive Blajchman (1995) 15,838 RDP 0.04% Risk of receiving BCP 50-250-fold > combined risk from virus TTI. Estimated that BCP kill ≈15 Canadians/yr

13. The BSE threat, vCJD & transfusion UK

14. vCJD (variant Creutzfeldt-Jakob) First case in UK in 1996; annual increase; ? peaked 167 cases of vCJD worldwide; 1 in Canada Human cases about 5 yrs after BSE epidemic Growth hormone, corneas, --- ?No transfusion-transmitted cases Currently no screening test for vCJD Geographic exclusion criteria for donor exclusion 2003 1994 Llewelyn et al: Lancet 363:417-421, 2004 Peden et al: Lancet 364:527-529, 2004

15. TRALI: Transfusion-related acute lung injury leading cause of transfusion-related death Anti-leukocyte antibody, usually in the donor blood product

16. TRALI cases: Canada • Age – median 68 years, range 16-94 years • Sex – female 45%, male 55% • Blood pressure – 30% hypotension, 24% hypertension, • 75% perioperative (CVS), haem/onc, trauma patients

17. TRALI: • New acute lung injury; bilateral pulmonary infiltrates • Within 6 hours of plasma-containing transfusion • Acute respiratory distress • . ●Hypoxemia • PaO2 of 30 – 50 torr; • PaO2/FIO2 <300 mm Hg; • O2 saturation < 90% on room air • Fever (1 to 2 oC) • No evidence of circulatory overload

18. TRALI: • often difficult to know if X-ray image that of noncardiogenic pulmonary edema • Rales and diminished breath sounds • Normal jugular venous pressure • Normal/low pulmonary wedge pressure • Does not respond to diuretics • Hypotension does not respond to intravenous fluids • Absent S3

19. TRALI patients • 17% died • 48% mechanical ventilation (70% of those who died) • Donor α-leukocyte antibodies in 63% α-PMN in 54% of those who died vs in 25% of patients who recovered; sicker patients also frequently received components containing α-HLA, particularly class II

20. Donors • Overall, 18 % of donors had anti-HLA (29% female vs 7% male) • 9 % of donors had anti-PMN (equal frequency female & male) • ?? Remove suspect donors from the donor pool; • ?? Remove female blood donors • Many donors implicated had donated many times before (in one case >200 times) without a previously reported TRALI reaction

21. Donor blood products with α-leukocyte antibodies implicated in TRALI cases

22. Antibody to WBC TRALI Pulmonary damage Ag/Ab reaction Capillary leak syndrome C’ activation Pulmonary endothelial damage Leukosequestration Pulmonary endothelium primed PMN sequester on EC, adhere, cytoskeletal change, rigid, trapped in microvasculature Immunogenic TRALI: Classical theory, anti-leukocyte antibody, but antibody not always found. Activation of EC Hyper-reactive PMN adhesion molecules chemokines Silliman et al: Non-immunogenic TRALI.2 stage process. i. Susceptible patient: sepsis, surgery, trauma, ii. Transfusion Release enzymes PMN primed 2 1 • Transfusion: • BRMs: • Lipids (Lyso-PCs) • Cytokines • Antibodies • Susceptible patient • Sepsis • Surgery (CPB) • Trauma

23. 1Susceptible pt: sepsis, surgery, trauma • Activated EC • Chemokines • Adhesion molecules on EC O2- Capillary leak 2Transfusion (BRM) Lipids (lyso-PCs) Cytokines (antibodies, microvesicles, cell fragments) Attraction Tethering Firm Adhesion Activation EC damage Primed PMN Rigid Trapped . in mv Hyper-reactive enzymes Pulmonary endothelium TRALI Lung damage

24. Transfusion-induced immunomodulation • Renal allograft survival [Opelz & Terasaki, 1981] • Graft one year survival rates • 23% in patients not transfused • 87% in patients receiving > 10 transfusions transfusion-induced immunosuppression (allogeneic leukocytes)

25. Transfusion-induced immunomodulation(due to allogeneic leukocytes)Some potential mechanisms: • Clonal deletion or anergy (of CTLs) • Induction of suppressor cells • Production of antiidiotypic antibody • Suppression of NK cell activity • Polarization of cytokine response

26. Infections & perioperative transfusion 10/16 observational studies and 4/5 randomized trials showed statistically significant reduction in postoperative infections with autologous versus allogeneic transfusions. Even more true for no transfusion versus allogeneic transfusion

27. In various surgical settings, no variable was more consistently associated with postoperative infection than was perioperative allogeneic transfusion • For each allogeneic RBC unit given, 1.5 fold increase in nosocomial infection. • Translates into potential morbidity, mortality and LOS. (Koval et al, J Orthop Trauma, 1997, 11:260)

28. SHOT, UK, annual report 2000-01 Adverse effects of transfusion TRALI 4.8% TTI 1.9% TA-GvHD 0.3% PTP 1.0% Delayed HTR 12.7% Acute HTR 11.7% IBCT 67.6% Incorrect blood component transfused (IBCT): “Wrong blood” is, without exception, an avoidable error

29. SHOT 1996/97 to 2001/01 • Blood centre 2% • Transfusion laboratory 28% • Collection, administration 55% • Prescription, sampling, request 13% • Other 1% • Unknown<1% . 68% Wards

30. CBS Projections: Collections vs Demands

31. Cost of Blood Transfusion (in US$, 1998) Mean Overall Cost: $491-$545 per unit. • Overhead = facility cost • Variable direct labour = lab technologists, phlebotomists, nurses • Fixed direct labour = administrators, etc. • Direct material = supplies, blood, tests Ontario blood budget: $420 million per year . Cremieux P-Y, Barrett B, Anderson K, Slavin MB. J Clin Oncol 18:2755, 2000

32. Costs incurred in provision of blood • Recruitment and collections • Infectious disease testing • Manufacturing, shipping, handling, labelling • Pre-transfusion testing • Transfusion costs • Post-transfusion sequelae • Regulatory and legal costs

33. Hospital charges • Blood type ABO $ 156 • Blood type Rh 85 • Antibody screen 182 • Crossmatch, immediate spin 350 • Crossmatch, antiglobulin (Coombs) 391 • Red cell antigen screening, per antigen 108 • Fresh frozen plasma thawing 156 • Crypoprecipitate pooling 43 • Handling 86 • Surcharge 15% Zeger, Jabbour (USC): Transfusion-free medicine and surgery, 2005, Blackwell

34. COSTS: Adult open heart surgery Jabbour, 2005

35. It is clear that: 1) the demand for blood outweighs the supply 2) there are real risks associated with blood transfusion 3) blood is not ‘free’

36. Blood transfusion is a lot like marriage. It should not be entered into lightly, unadvisedly or wantonly, or more often than is absolutely necessary. [Beal RW: Aust N Z J Surg 46:309, 1976]

37. Blood is Good?????

38. 1960 1971

39. Blood • Enough • In the right place • At the right time • And not too much Most people in this room will depart Earth as a result of not maintaining one or more of these functions of the blood J Isbister, SABM 2005

41. Blood Conservation: Aims Management • Allogeneic transfusion avoidance • Transfusion reduction

42. Goals: Minimize Anemia and Avoid Allogeneic Blood Transfusion. Risk Anemia (Reduced Hematocrit) Allogeneic Transfusion Transfusion has risks, but bleeding to death is fatal !

43. Anemia is common: 30% patients preop In the ICU, most patients anemic at time of admission. Hb typically declines by at least 0.5 g/dL/day in first 3 d of ICU stay. Continues to decline if sepsis/severe illness. These patients particularly may be at risk from anemia (cardiovascular, respiratory, metabolic compromise). Etiology of anemia multifactorial: phlebotomy, GI bleeding, coagulopathy, blood loss from vascular procedures, renal failure, nutritional deficiencies, marrow suppression, impaired erythropoietin response, etc

44. Blood Conservation?? Office of the Director of Medical Services “I need you to find a radically innovative new way to keep everything exactly the same”

45. Blood conservation approaches in surgery Autologous blood (PAD, cell salvage, ANH) Erythropoietin (EPO, Eprex) Other pharmacologics (e.g. antifibrinolytics) Fibrin glues (e.g. Tisseel) Hemostatic/harmonic scalpels Blood substitutes Controlled hypotension; positioning Minimally invasive surgery Transfusion trigger (level of Hb) rFVIIa etc

46. Preoperative Autologous Donation (PAD) in primary hip surgery:No PAD, 29% had allogeneic transfusionPAD, 6% had allogeneic transfusion(B Feagan; 2001/2002); 28 Ontario sites; 3352 pts Is blood conservation approach effective in avoiding allogeneic transfusion?

47. Pre-operative EPO for Orthopaedic Surgery Feagan BG et al. Ann Intern Med 133:845-854, 2000. Allogeneic Blood Transfusions 45% in placebo group 23% in low dose EPO (p<0.003) 11% in high dose EPO (p< 0.001) Significant requirement for supplemental iron Monitor serum ferritin, transferrin saturation

48. Initial Hb level predictive of transfusion. Hb pre-op% transfused < 130 53 % > 130 20 % But, if Hb done in PAF < 130 > 130 BC Capital Health Region EPO Iron B12, folate 15% 5%

49. Transfusion trigger:How much Hb do you need? Operative mortality increases with untreated anemia. Preop Hb Mortality < 60 g/L 62% 61 - 80 33% 81 - 100 0% > 100 7% Carson, Am J Surg 170:6A:32S, 1995 Adjusting for APACHE II score: Post-op,2.5X increase inodds of death for each 10 g/L decrease in Hb below 80 g/L (Carson et al: Transfusion 42:812, 2002)

50. Crude in-hospital survival rate of patients with different preoperative haemoglobin concentrations . Preoperative haemoglobin >100g/L . Preoperative haemoglobin ≤100g/L So level of Hgb important, but at what trigger should one transfuse? Lancet, Vol 369, May 18, 2002 .