1. Anemia in the ICU: An Evidence Based Approach Andrew F. Shorr, MD, MPH Walter Reed Army Medical Center

2. Overview What is current transfusion practice? What are the risks of transfusion? Is there an optimal hemoglobin? Are there alternatives to the use of pRBCs?

3. Transfusion in the U.S. 12 million units given each year Common indications –Bleeding –Ischemia –Resuscitation –? Any indication

4. Costs of Transfusion Some estimates range from $100-$150/ unit Earlier studies fail to account for –Costs of nursing time –Costs of additional testing –Costs of reactions More recent estimates: –$250-$300/ unit pRBC Cantor, et al. Blood 1998; 16: 2364.

5. Cost of Transfusion Cost of pRBCs changing –Leukoreduction –Nucleic Acid Testing (NAT) Estimated increase in cost over next several years: $50-$100/unit New total cost to healthcare system --> at least $60 million

6. Transfusion in the ICU Retrospective review of patients in ICU > 1 week 85% received pRBCs Average transfusion: 9.5 units Indications for transfusion –No clear indication:29% –Low Hct:19% Average daily blood loss from phlebotomy: 70 ml/day Corwin, et al. CHEST 1995; 108: 767.

7. Transfusion in the ICU Practice survey in Canada 76% of all Canadian CCM MD participated Queried regarding –Current transfusion practice in ICU –Presented with hypothetical cases Hebert, et al. Crit Care Med 1998; 26: 482.

8. Transfusion in the ICU Academic physicians had a lower threshold than non-academic MDs (p<0.001) Once a threshold was reached, > 90% of MDs transfused 2 units

9. Transfusion in the ICU On average, pRBCs used in the ICU –Are at least 2 weeks old –Lack sufficient 2,3 DPG –Have diminished O2 carrying capacity –Remain in the circulation for only a short time

10. Risks of Transfusion Infection Transfusion reaction Immunomodulatory Volume-related

11. Blood Borne Infections

12. Blood and the Immune System Despite filters, WBCs remain in pRBCs Transfusion promotes cytokine release Alters cellular immunity: –Decreased: CD4 cells, NK cells, IL-2 production –Increases: B cells, CD8 suppressor cells, PGE2

13. Blood and the Immune System Design: Prospective, observational study Subjects: CABG patients Comparisons: transfused vs. no transfusion intraoperatively Measurements: IL-6, BPI n=136 Fransen et al. CHEST 1999; 116: 1233.

14. Blood and the Immune System

15. Do the immune effect of blood have clinical implications?

16. Transfusion and Outcomes Design: Retrospective Subjects: Colorectal cancer resection Comparison: transfused vs. non-transfused Endpoints: hospital charges and LOS Controlled for multiple confounders (comorbidity, age, gender, ICU admission, etc) n=487 Vamvakas et al, Arch Pathol Lab Med 1998; 122: 145. Colorectal Cancer

17. Transfusion and Outcome After controlling for confounders, each unit transfusion increased charges by 2.0% (p <0.001)

18. Transfusion and Outcome Design: Case-control Subjects: s/p CABG Endpoints: Nosocomial pneumonia n= 45 cases and 90 controls Leal-Noval, et al. Crit Care Med 2000; 28: 935 Nosocomial pneumonia after pRBC in CABG

19. Transfusion and Outcome

20. Transfusion and Outcomes Design: Prospective, multicenter, observational study Subjects: CABG patients Measurement: Initial ICU Hct Endpoints: MI, need for IABP for CHF, all adverse outcomes n=2,202 Spiess et al. J Thorac CV Sgy 1998;116: 460. Ischemia post-CABG

21. Transfusion and Outcome

22. Transfusion and Outcomes Multivariate analysis to control for confounders –Association with higher risk with higher Hct consistent –Initial Hct most significant predictor of adverse outcome (OR 2.22) Conclusion –“There is no rationale for transfusion to an arbitrary level after CABG.”

23. Transfusion and Outcomes Carotid Endarterectomy Evaluated impact of transfusion on ischemic events (Stroke and MI) n=1114 1980- 1985 1990- 1995 p CVA/MI6.6%5.5%<0.001 Age65.970.4<0.001 ASA > 379.2%93.6%<0.001 % AODM9.0%14.8%0.003 % CAD36.0%42.2%0.04 % Transfused72.9%8.7%<0.001 pRBC units transfused 1.100.27<0.001 Kober et al. Mayo Clin Proc 2001; 76: 369-376.

24. Transfusion and Outcome Design: Prospective observational study Subjects: Trauma patients at major trauma center Controlled for ISS, GCS, age, gender, race Measurements: SIRS, ICU admission, death n=9,539 Trauma Malone, et al. SCCM 2001, A138.

25. Transfusion and Outcome

26. Use of pRBCs alters immune system Immune dysregulation has significant clinical correlates Multiple endpoints adversely affected by use of pRBCs But why are we transfusing anyway?

27. Optimal Hemoglobin Hemoglobin crucial for oxygen delivery O2 Delivery = C.O. x Sa02 x Hgb x 1.34 x 10 Originally thought that increasing delivery would improve outcomes (Shoemaker 1988) Multiple studies evaluated –Increasing CO with dobutamine –Increasing O2 carrying capacity with transfusion

28. Supraphysiologic O2 Delivery

29. Transfusion and Oxygen Delivery Subjects: 23 patients with septic shock Intervention: transfusion of 3u pRBCs Measurements: O2 uptake and gastric tonometry Results –No increase in O2 uptake with transfusion –Inverse association between gastric pH and age of blood (r=-0.71, p < 0.001) –No beneficial impact of transfusion in sepsis but at cost of splanchnic ischemia Marik P, et al. JAMA 1993; 269: 3024.

30. DPG and O 2 Carrying Fresh Blood Activated Blood 1-Week-Old Blood Hamasaki et al. Vox Sang 2000; 79:191-197.

31. Optimal Hemoglobin No evidence that increasing O2 delivery changes mortality in general ICU population May actually be harmful ATS position statement: –“We conclude that continued aggressive attempts to increase O2 delivery are unwarranted.”

32. Optimal Hemoglobin Clearly higher Hgb achieved via transfusion is not helpful and may be harmful Is there a lower threshold?

33. Transfusion Requirements in Critical Care Multicenter, RCT Subjects –Acutely ill in ICU, Hgb < 9.0 –Excluded if: chronic anemia, ongoing bleeding, admission after CABG Hebert et al. NEJM 1999; 340:409-17

34. Transfusion Requirements in Critical Care Randomized to 2 strategies Liberal strategy: –Maintain Hgb between 10-12 Restrictive strategy: –Maintain Hgb between 7-9 Endpoints –All cause mortality, MSOF –Predefined subgroups: age > 55, CAD, APACHE II > 20

35. Transfusion Requirements in Critical Care

36. p=0.02

37. Transfusion Requirements in Critical Care p=0.02

38. Transfusion Requirements in Critical Care Conclusions –Lower transfusion threshold was as effective as higher trigger –Lower threshold superior in some subgroups –Mechanism of worse outcomes with liberal strategy unclear (? promotes cytokine cascade, increased risk of ARDS)

39. Transfusion Requirements in Critical Care Editorial comment in NEJM “This study has made it clear that a single threshold for transfusion in all patients is not appropriate…… With this knowledge, more physicians will be able to follow the dictum “first do no harm,” and we will have a surplus of blood rather than a shortage.” Ely et al. NEJM 1999: 340: 468.

40. Alternatives to Transfusion Limited blood use policy Artificial hemoglobin Erythropoetin

41. Blood Policy (Police?) Enforce blood bank QA Eliminate routine ordering of labs Minimize frequency of lab testing Employ iSTAT system Attention to detail With this may be able to eliminate 20% of transfusions

42. Artificial Hemoglobin Several products –Biopure –HBOC –DCLHBG Current focus on cross-linked products –Increases half-life –No excessive oncotic pressure

43. Artificial Hemoglobin Potential advantages of cell-free HgB –No antigenicity –Unlimited supply –No disease transmission –Long storage –Better rheologic properties Demonstrated in vitro –Vasopressor –Corrects acidosis –Improves microvascular perfusion –Increases O2 delivery

44. Artificial Hemoglobin

46. Erythropoetin in Critical Illness Design: Prospective Subjects: MICU patients with and without sepsis Measurement: EPO level n=36 Rogiers et al. Inten Care Med 1997; 159.

47. Erythropoetin in Critical Illness

48. Efficacy of EPO in the Critically Ill Patient Multicenter DBRCT Subjects –Critically ill adults –Excluded if: underlying cancer, immunosuppressed, MSOF Intervention –rHuEPO vs placebo –rHuEPO given for at least 2 weeks –All subjects given FeSO 4 Corwin et al. CCM 1999; 27:2346-50.

49. Efficacy of EPO in the Critically Ill Patient Endpoints –Cumulative blood use –Ability to remain transfusion-free Indications for transfusion –Left to primary MD

50. EPO in the ICU Actual Transfusion Trigger No difference in trigger when stratified by study center

51. Efficacy of EPO in the Critically Ill Patient

53. Conclusions –EPO effective in critically ill patients –EPO clearly safe in ICU subjects –Optimal dose unknown –May be cost neutral –Attractive alternative

54. Conclusions Transfusions often over used Blood is not benign No clear transfusion trigger New options available