1. Red Cell Transfusion in Critical Care Patients Alan Tinmouth, MD MSc University of Ottawa Centre for Transfusion Research, Ottawa Health Research Institute and the Ottawa Hospital November 2009

2. Objectives Review the seminal observational and randomized clinical trials evaluating red cell transfusions in the critically ill. Understand the limitations of the current evidence surrounding red cell transfusions. Understand the limits and benefits of alternatives / strategies to reduce the need for red cell transfusions.

3. Case 1 Hebert, Crit Care Med 2005; 33; 7.

4. Anemia in the critically ill is very common 95% anemic by 3 rd day in ICU 40 – 45% of patients will receive RBCs Average = 5 units RBC Vincent et al, JAMA 2002; Corwin et al, CCM 2004

5. RBC Transfusions in Critical Care and Cardiac Surgery in Canada, 1998-2000 Hutton et al. CJA 2005

6. Purpose of an RBC transfusion Increase O 2 delivery and consumption. Increase hemoglobin levels. Decrease morbidity and mortality.

7. The Role of Hemoglobin in O 2 Delivery (1) DO 2 = CO x (%sat x 1.39 x Hb) (2) CO = HR x stroke volume DO 2 = O 2 Delivery (ml/L) CO = Cardiac output(L/min) %Sat= % saturation of Hb Hb = Hemoglobin (g/L) 1.39 = O 2 carried in blood (ml/L)

8. Oxygen Delivery and RBC Transfusion VO 2 Delivery IndependentDelivery Dependent Critical DO 2 DO 2 At least 19 clinical studies evaluating impact RBCs on oxygen kinetics in humans Uniform increase in DO2 but not VO2 Hebert et al, CMAJ, 1997

9. Oxygen Delivery and Consumption following RBC transfusion Suttner et al. Anesth Analg 2004; 99: 2-11

10. Transfusion Requirements in Critical Care (TRICC) Hebert PC, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med. 1999;340(6):409-17 Purpose: To determine if a restrictive and liberal red cell transfusion strategy are equivalent in terms of effects on mortality and morbidity in volume resuscitated critically ill patients Hebert et al. NEJM 321: 151-156, 1999

11. Study design: Multicentre RCT Setting: 25 ICUs across Canada Study Population: Included Hb 3 unit transfusion in 12 hrs) Intervention: 7.0 g/dl vs 10.0 g/dl hemoglobin trigger Outcomes: 30 day all-cause mortality and organ failure TRICC Study Hebert et al. NEJM 321: 151-156, 1999

12. Hemoglobins over time Liberal strategy Restrictive strategy p<0.01 Hebert et al. NEJM 321: 151-156, 1999

13. Survival of all patients over 30 days Hebert et al. NEJM 321: 151-156, 1999 18.7% 23.3%

14. Survival of patients < 55 years of age Hebert et al. NEJM 321: 151-156, 1999

15. TRICC – Mortality and MODS OutcomesLiberal RestrictiveP-Value (n=420)(n=418) Mortality No.(%) 30-day 98 (23.3)78 (18.7)0.11 60-day111(26.5)95(22.8)0.23 ICU 68 (16)56 (13)0.29 Hospital118(28.1)93(22.3)0.05 Organ Dysfunction MODS8.8 ± 4.48.3 ± 4.60.10 MODS* 11.8 ± 7.710.7 ± 7.50.03 Change in MODS1.26 ± 4.300.79 ± 4.260.15 Hebert et al. NEJM 321: 151-156, 1999

16. Case 1 Hebert, Crit Care Med 2005; 33; 7.

17. ICU Responses 1997 and 2003 Hebert, Crit Care Med 2005; 33; 7.

18. RBC transfusions and risk of death Marik and Corwin, CCM 2008;36:2667

19. Can we trust these studies? Inferences from these studies are weakened because: Logic of transfusions always being harmful?? Retrospective with limited data Minimal adjustment for confounding factors Timing of RBCs unknown Trigger unknown…admission hematocrit/nadir hematocrit Main culprit: “Confounding by Indication” –higher acuity → more aggressive care

20. Adverse Effects Associated with Transfusion Fever Neutrophilia Flushing Proinflammatory Capillary leak TRALI / ARDS MOF Other adverse effects of leukocytes Thrombosis Impaired O 2 delivery Acidosis K+, Na+, NH4+ Hypothermia Glucose Plasticisers Jaundice Thrombosis ? ARDS RES Blockade Microvascular Pathology Hypotension Flushing Anxiety GIT Symptoms Pain Proinflammatory PLASMA Cleavage / activation of Plasma proteins BUFFY COAT RED CELLS 1.Impaired RBC survival 2.Reduced efficacy 3.Adverse effects Chemical, Metabolic & Physical Haemolysis Billirubin LDH Iron Cytokines Kinins Complement Histimine Microaggregates Procoagulants

21. Consequences of Biochemical and BioMechanical Changes in Stored RBCs Left shift of oxygen- hemoglobin dissociation curve Loss of red blood cell deformability Increased RBC aggregation Increased RBC adhesion to endothelial cells Release of hypercoagulable microvessicles Increased NO scavenging Accumulation of cytokines Tinmouth. Transfusion 2006

22. Case 3 Hebert, Crit Care Med 2005; 33; 7.

23. TRICC and acuity of illness Hebert et al. NEJM 321: 151-156, 1999

24. Goal Directed Therapy in Early Sepsis Rivers et al. NEJM 2004; 345: 1368

25. Goal Directed Therapy in Early Sepsis Rivers et al. NEJM 2004; 345: 1368

26. Case 3

27. ICU Responses 1997 and 2003 Hebert, Crit Care Med 2005; 33; 7.

28. Case 2 Hebert, Crit Care Med 2005; 33; 7.

29. TRICC – Cardiovascular Disease Patients with Ischemic Heart Disease (n=257) Patients with cardiovascular diseases (n=357) Hebert et al. NEJM 321: 151-156, 1999

30. Complications during the ICU Stay ComplicationLiberal (n=420) Restrictive (n=418) P Values Cardiac No. (%)88 (21.0)55 (13.2)<0.01 Myocardial Infarction12 (2.9)3 (0.7)0.02 Pulmonary Edema45 (10.7)22 (5.3)<0.01 Angina9 (2.1)5 (1.2)0.28 Cardiac Arrest33 (7.9)29 (6.9)0.6 Pulmonary No. (%)122 (29.1)106 (25.4)0.22 ARDS48 (11.4)32 (7.7)0.06 Pneumonia86 (20.5)87 (20.8)0.92 Hebert et al. NEJM 321: 151-156, 1999

31. RBC transfusions in acute MI Wu. NEJM 2001; 345: 1230.

32. RBC transfusion in ACS Transfused patients were older, had more co- morbidities and higher mortality rates Rao. NEJM 2001; 345: 1230.

33. RBC transfusion in ACS Adjusted analysis showed higher mortality rate associated with transfusions –No associated with harm for nadir hct of 0.20-0,25 –Increased mortality for nadir hct > 0.30 Rao. NEJM 2001; 345: 1230.

34. Case 2 Hebert, Crit Care Med 2005; 33; 7.

35. ICU Responses 1997 and 2003 Hebert, Crit Care Med 2005; 33; 7.

36. Case 4 Walsh, Transf 2009; epub.

37. TRICC and mechanical ventilation Hebert et al. NEJM 321: 151-156, 1999

38. Case 4 Walsh, Transf 2009; epub.

39. Case 5 28 year old Jehova Witness. Peripartum hemorrage taken to OR and hysterectomy performed. Bleeding now controlled. Admitted to ICU post-op with Hgb 28 g/L. Treatment recommendations ?

40. Alternatives to Red Cell Transfusions Erythropoietin Iron replacement Folate Other –Factor VIIa for bleeding –Reduce phlebotomy – pediatric tubes

41. EPO in Critical Care – Part 1 Corwin, JAMA 2002; 288: 2827.

42. EPO in Critical Care – Part 1 EPO raised hemoglobin (13.2 g/L vs. 9.4 g/L) EPO resulted in 19% reduction in number of units RBCs transfused

43. EPO in Critical Care – part II EPO raised increased hemoglobin (16 g/L vs. 12 g/L, p < 0.001) and resulted in higher hemoglobin levels. No difference in transfusion rates with restrictive transfusion policy Corwin, NEJM 2007; 357: 965.

44. EPO in Critical Care – part II Thrombosis Mortality Corwin, NEJM 2007; 357: 965.

45. Conclusions In critical care patients, restrictive RBC transfusion strategy is not worse than liberal transfusion strategy –Patients not likely to benefit from RBC transfusion are only likely to be harmed Results of TRICC not generalizable to all critically ill patients –e.g. cardiac and bleeding patient Alternatives to transfusions also have adverse effects –“best transfusion is not simply transfusion not given”