1. Eastern Maine Medical Center
Is Patient Blood Management Safe?
Irwin Gross, M.D.
Eastern Maine Medical Center

2. Disclosures
None relevant to this presentation

3. Is Patient Blood Management Safe?
After all, transfusion is part of PBM
Is Transfusion Safe?

4. What Does “Safe” Mean
Protected from or not exposed to danger or risk
Free from risk, hurt, injury, or danger
Dependable, trustworthy
Does transfusion pop into your head when you hear the word “safe”?

5. So Let’s First Answer the Question: Is Transfusion Safe?
Transfusions are:
Not free from risk, hurt, or injury
Includes disease transmission, immunomodulation (TRIM), hemolytic and allergic transfusion reactions, ALI, TACO, and others
Not dependable or trustworthy
Allogeneic blood transfusion cannot be depended upon to achieve the desired outcome

6. UNSAFE AT ANY HEMOGLOBIN? The Inherent Dangers of Blood Transfusions

7. Question 1 A) Circulatory overload
Potential risks of red cell transfusion include all of the following except:
A) Circulatory overload
B) Immunomodulation
C) Warm auto-immune hemolytic anemia
D) Non-hemolytic febrile transfusion reaction

8. storage lesion, TRIM, SIRS, thrombosis, lack of efficacy
Adverse effects of RBC transfusion contrasted with other risks.Risk is depicted on a logarithmic scale.
Risks of:
storage lesion, TRIM, SIRS, thrombosis, lack of efficacy
Adverse effects of RBC transfusion contrasted with other risks.Risk is depicted on a logarithmic scale. Shaded bars represent the risk per RBC unit transfused, and unshaded bars represent the risk for fatality per person per year for various life events. During 2007 through 2008, HIV incidence in blood donors was 3.1 per 100 000 person-years. Residual risk was estimated as 1:1 467 000 transfused blood components or 6.8 per 10 million transfused components (10). During 2007 through 2008, HCV incidence in blood donors was 5.1 per 100 000 person-years with residual risk estimate of 0.87 per million transfused blood components (1:1 149 000) or 8.7 per 10 million transfused components (10). For 2006 to 2008, HBV incidence in blood donors was 3.41 to 3.43 per 100 000 person-years. The estimated residual risk for HBV was 1 in 282 000 to 1 in 357 000 transfused blood components (11) or 2.8 per million to 3.6 per million transfused blood components. In a recently published, large, prospective study with active recipient surveillance, the rate of TRALI occurrence in 2009 was 0.81 (95% CI, 0.44 to 1.49) per 10 000 transfused blood components or 8.1 per 100 000 transfused blood components (12). Although the literature has a wide range of TRALI risk estimates (1, 13–16), we have selected the rate reported in this recent prospective study. Three studies of TACO have produced similar results. In a study of 901 intensive care unit patients, 6% of patients who received transfusions developed TACO. Median units transfused were 2 RBCs and 3 overall (including plasma and platelets) (17). The rate per transfused RBC unit was 2 to 3 per 100. In 382 patients undergoing hip and knee replacement, 1% developed TACO after surgery (18). In a study of patients having total hip and knee arthroplasty, 8% developed fluid overload necessitating diuretic use and 4% of patients who did not receive transfusions developed fluid overload, leading to a TACO estimate of 4% (19). In published studies from the late 1990s, the risk for fatal hemolysis was estimated to range from 1.3 to 1.7 per million (5.9 to 7.7 per 10 million) transfused RBC units in 1 report (20) and 1 per 1 800 000 or 8.5 per 10 million in a second report (21). More recently, transfusion-related fatalities due to hemolysis reported to the U.S. Food and Drug Administration averaged 12.5 deaths per year from 2005 to 2010 (22). With 15 million RBC units transfused per year, the estimated risk for death due to hemolysis is 1:1 250 000 or 8 per 10 million RBC units. Fever (febrile nonhemolytic transfusion reactions) was estimated to be 1.1% with prestorage leukoreduction and 2.15% with poststorage leukoreduction (23). Death from medical error as reported by the Institute of Medicine was 1.3 to 2.9 per 1000 hospital admissions (24). Life-threatening transfusion reaction, defined as reactions requiring major medical intervention (for example, vasopressors, intubation, or transfer to an intensive care unit), occurred in 1:139 908 transfusions or 7.1 per million transfusions (1). Fatal motor vehicle accidents were estimated at 13.1 per 100 000 persons in 2008 or 1.3 per 10 000 persons (25). The rate of firearm homicide (which excludes suicide) was 4 per 100 000 persons in 2008 (25). Fatal falls were estimated at 8.2 deaths per 100 000 persons in 2008 (25). Lightning fatalities ranged from 0.02 per million (2 per 100 million) persons in California and Massachusetts to 2.0 per million persons in Wyoming (0 risk in Hawaii, Rhode Island, and Alaska) (26). The odds of being killed on a single airline flight on the 30 airlines with the best accident rates were 1 per 29.4 million. Among the 25 airlines with the worst accident records, rates were 1.7 per million per flight (27). Modified from Dzik and colleagues (2002) (28). HBV = hepatitis B virus; HCV = hepatitis C virus; RBC = red blood cell; TACO = transfusion-associated circulatory overload; TRALI = transfusion-related acute lung injury.
Carson J L et al. Ann Intern Med doi: /
©2012 by American College of Physicians

9. Is PBM Safe? Putting it in Context: the Questions We Need to Answer
Does PBM reduce the likelihood of transfusion?
Which transfusions carry greater risk than benefit?
Why is there so much variation in transfusion rates?
Can a transfusion be “appropriate” yet avoidable?
Do transfusions “work” ?
Do the clinical management strategies that allow us to avoid transfusions (PBM) carry more benefit than risk compared to transfusion alone?
Is PBM safer than a transfusion-only strategy?
(Benefit / Risk) PBM Strategy* > (Benefit / Risk) Transfusion
*may include transfusion

10. Is PBM Safe? The Questions We Need to Ask
Is PBM Safe? Putting it in Context: the Questions We Need to Answer
Does PBM reduce the likelihood of transfusion?
Which transfusions that carry greater risk than benefit?
Why is there so much variation in transfusion rates?
Can a transfusion be “appropriate” yet avoidable?
Do transfusions “work”
Do the clinical management strategies that allow us to avoid transfusion carry more benefit than risk compared to transfusion alone?
(Benefit / Risk) PBM Strategy > (Benefit / Risk) Transfusion

11. EMMC Annual Red Cell Transfusions: 1994 -2013

12. Is PBM Safe? Putting it in Context: the Questions We Need to Answer
Does PBM reduce the likelihood of transfusion?
Which transfusions carry greater risk than benefit?
Why is there so much variation in transfusion rates?
Can a transfusion be “appropriate” yet avoidable?
Do transfusions “work”
Do the clinical management strategies that allow us to avoid transfusion carry more benefit than risk?
(Benefit / Risk) PBM Strategy > (Benefit /Risk) Transfusion

13. Why Do We Transfuse Red Cells? O2 Delivery or Consumption?
DO2 - VO2 relationship & DO2 CRIT
We transfuse to ensure we are meeting the oxygen needs at a tissue level. Delivery of oxygen beyond the ability of the tissues to use that oxygen does not yield additional benefit. VO2 – DO2 relationship. Three different conditions are shown: individuals 1 and 2 differ in their
metabolic demand, i.e. oxygen consumption (VO2) which is held constant despite a decrease (arrowheads) in
oxygen supply (DO2). At a critical threshold of DO2 (DO2 CRIT) which is reached sooner in individual 2 than
in individual 1, VO2 begins to fall rapidly. Individual 3 represents a particular condition: above DO2 CRIT, VO2 –
DO2 relationship does not plateau as under physiologic conditions. In contrast, VO2 continues to increase with
increasing DO2 even in a range of DO2 that would be largely sufficient to meet metabolic demands
under normal conditions and demonstrates therefore a ‘‘supply-dependency’’ indicating an oxygen debt.
This situation may be found in critical illness such as sepsis.
If DO2 is >
DO2 CRIT
Tx unlikely to benefit
© Elsevier
Modified from: Madjdpour & Spahn. Best Pract Res Clin Anaesthesiol 2007

14. Chionodraco rastrospinosus
Optimize Oxygenation and Hemodynamics: A Lesson from the Ocellated Icefish
Ocellated Icefish lives in deep water off the coast of Antarctica
Clear, colorless blood without hemoglobin
Survives on oxygen dissolved in its plasma
Cardiac output is 5 times usual for fish that size
At cold temperatures more dissolved oxygen
Low metabolic rate
To help drive home the importance of hemodynamics and oxygenation, I’ve enlisted the help of the ocellated icefish
Chionodraco rastrospinosus
Safest approach:
Optimize hemodynamics
Optimize oxygenation
Reduce metabolic demand

15. in patients whose VO2 is < DO2 at the time of transfusion
The Distribution of Benefit and Risk Modified from Goodnough LT, Shander A. Anesth and Anal 2012
Transfusion
in patients whose VO2 is < DO2 at
the time of transfusion

16. Is PBM Safe? Putting it in Context: the Questions We Need to Answer
Does PBM reduce the likelihood of transfusion?
Which transfusions carry greater risk than benefit?
Why is there so much variation in transfusion rates?
Can a transfusion be “appropriate” yet avoidable?
Do transfusions “work”
Do the clinical management strategies that allow us to avoid transfusion carry more benefit than risk?
(Benefit / Risk) PBM Strategy > (Benefit /Risk) Transfusion

17. Observed Variation in Hospital-Specific Transfusion Rates for Primary Isolated CABG Surgery With Cardiopulmonary Bypass During 2008 (N = 798 Sites)‏
Bennett-Guerrero, E. et al. JAMA 2010;304:

18. Variation in Transfusion by Surgeon and Hospital in CABG
Ann Thor Surg 2012

19. Variations in Blood Transfusion in Non-cardiac Surgery
RBC Transfusion rate range: 1.7% to 47.9%
FFP Transfusion rate range: 0% to 20.0%

20. Variation in Transfusion Rates: Cardiac and Non-Cardiac Surgery
Variation in transfusion rates due to:
Local culture and practice
Physician preference re: hemoglobin “trigger”
Variation in transfusion rates not due to differences in patient acuity
Transfused patients not necessarily that different than those not transfused
Some of the variation is due to differences in how patients’ blood is “managed”: anemia treatment, avoiding blood loss, inappropriate transfusion threshold

21. The Role of the Transfusion Threshold
Distribution of Pre-transfusion Hemoglobin: EMMC
6.8 g/dl
7.8 g/dl
7.0 g/dl
One way to reduce transfusions is to reduce the hgb threshold for transfusion and the number of units transfused

22. Is PBM Safe? Putting it in Context: the Questions We Need to Answer
Does PBM reduce the likelihood of transfusion?
Which transfusions carry greater risk than benefit?
Why is there so much variation in transfusion rates?
Can a transfusion be “appropriate” yet avoidable?
Do transfusions “work”
Do the clinical management strategies that allow us to avoid transfusion carry more benefit than risk?
(Benefit / Risk) PBM Strategy > (Benefit /Risk) Transfusion

23. Examples of “Appropriate but Avoidable”
A patient has signs and symptoms of tissue ischemia with significant anemia (e.g. hemoglobin < 7 g/dl)
Elective surgical patient with preoperative anemia that was not treated; surgery not delayed
Excessive surgical blood loss preventable through use of clinical interventions such as topical hemostatic agents or antifibrinolytic drugs (tranexamic acid, aminocaproic acid),intraoperative cell salvage
Excessive phlebotomy for diagnostic laboratory testing in an anemic ICU patient
Failure to use intravenous iron and ESAs in oncology patients

24. Appropriate but Avoidable
PBM is about:
Eliminating inappropriate (unnecessary) transfusions
Right product to the right patient at the right time
Appropriate clinical indications
Avoiding avoidable transfusions: failure to avoid avoidable transfusions harms patients
Stop the bleeding
Treat anemia
Avoid blood loss – surgical, procedural, phlebotomy
Optimize hemodynamics and oxygenation

25. Is PBM Safe? Putting it in Context: the Questions We Need to Answer
Does PBM reduce the likelihood of transfusion?
Which transfusions carry greater risk than benefit?
Why is there so much variation in transfusion rates?
Can a transfusion be “appropriate” yet avoidable?
Do transfusions “work”
Do the clinical management strategies that allow us to avoid transfusion carry more benefit than risk?
(Benefit / Risk) PBM Strategy > (Benefit / Risk) Transfusion
By work, we mean improve clinical outcomes

26. Question 2 A) Hemoglobin less than 10 g/dl
An appropriate threshold for considering transfusion in most adult patients over the age of 55 is:
A) Hemoglobin less than 10 g/dl
B) Hemoglobin less than 9 g/dl
C) Hemoglobin less than 8 g/dl
D) Hemoglobin less than 7 g/dl

27. The number needed to treat to prevent 1 death is 33
A restrictive transfusion trigger of < 7 g/dl in patients with critical illness or hemorrhage reduces morbidity and mortality
A less restrictive transfusion strategy was not effective
The number needed to treat to prevent 1 death is 33
Observational data indicate that hgb levels of 5-6 g/dl are well tolerated in normovolemic patients without affecting oxygen delivery

28. All cause mortality ; Pooled RR 2.91

29. 4% ABSOLUTE reduction in mortality (95% survival vs. 91%)
Randomized 961 patients with severe acute upper GI hemorrhage to restrictive (< 7 gm/dl) vs. liberal (< 9 gm/dl)
45% transfusion rate in restrictive group vs. 85% in liberal group
Further bleeding: 10% in restrictive; 16% in liberal group
4% ABSOLUTE reduction in mortality (95% survival vs. 91%)
So transfusion doesn’t always save lives

30. Drop in Hgb vs. Hgb Level
Study of 10,179 patients undergoing cardiac surgery
Composite outcome of death, stroke or renal failure
Increased risk of composite outcome independent of starting Hb associated with >50% drop from baseline Hb (OR 1.53, p=0.008)
RBC Tx
No Tx
Karkouti K et al. Transfusion 2008

31. Why Does its Seem Obvious that Transfusions “Work”
Confirmation bias
Transfusions usually given to very sick patients
If patient dies or does poorly, we blame the underlying illness
When they improve, we credit transfusion
We don’t question whether the transfusion contributed to their death in the first case or delayed their recovery in the second

32. Is PBM Safe? Putting it in Context: the Questions We Need to Answer
Does PBM reduce the likelihood of transfusion?
Which transfusions carry greater risk than benefit?
Why is there so much variation in transfusion rates?
Can a transfusion be “appropriate” yet avoidable?
Do transfusions “work”
Do the clinical management strategies that allow us to avoid transfusion carry more benefit than risk?
(Benefit / Risk) PBM Strategy > (Benefit / Risk) Transfusion

33. PBM Clinical Strategies
Restrictive transfusion threshold: Pre-transfusion hemoglobin of 6-8 g/dl
Already discussed some of these data
While anemia is associated with worse outcomes, transfusion does not improve outcomes in many cases
“Anemia is bad; transfusion may be worse”
Intravenous iron
Erythropoietic stimulating agents

34. IV Iron
Risk of Infection
Staphlococcus aureus

35. Infection not a pre-defined endpoint – unmeasured bias
No dose-response relationship
No difference in mortality or other SAE’s

36. Iron Administration and Infection: Data
EPIBACDIAL Study:
No association between IV iron and bacteremia or between ferritin level and bacteremia in 988 dialysis patients (Hoen)
Observational study of 2,547 peri-op patients undergoing elective TJA or hip fracture treated with IV iron:
No increased risk of infection but reduction in transfusion (Munoz) and shorter LOS (p=0.0001)
Non-randomized study comparing 302 CT surgery patients receiving IV iron vs. 561 receiving no IV iron
No difference in infection rates
Hoen B et al. J Am Soc Nephrol 1998; 9:
Munoz M et al. Transfusion 2014;54:
Torres S et al. Surgical Infections 7:4, 2006*

37. Question 3 Transfusion is associated with
A) No change in hospital acquired infections
B) A decrease in Hospital acquired infections
C) An increase in deep mediastinal wound infections only
D) An increase in most hospital acquired infections

38. The pooled risk of all serious infections was 16
The pooled risk of all serious infections was 16.9% in the liberal group but only 11.8% in the restrictive group
For trials with a restrictive hemoglobin threshold < 7 g/dl, the RR was 0.82; NNT to prevent one hospital acquired infection: 20

39. Must not look at risk of infection with IV iron in isolation Transfusion of red cells has an immunomodulatory effect Hemolysis of transfused red cells (as much as 30% in the first 24 hours) provides a source of iron in the form of both free iron and heme iron

40. S. aureus and Iron-regulated Surface Determinant (IsdB) .
Pathogen Mechanisms:
S. aureus and Iron-regulated Surface Determinant (IsdB) .
Host Specificity of Staphylococcus aureus.  S. aureus uses the iron-regulated surface determinant (Isd) group of proteins to acquire iron from hemoglobin. It secretes a hemolytic toxin that releases hemoglobin from red cells. The released hemoglobin then binds to the staphylococcal receptor, iron surface determinant B (IsdB) on the bacterial cell surface. Heme is extracted from hemoglobin and is transported across the cell wall and cytoplasmic membrane by other Isd proteins. After its release from heme, iron becomes available as a nutrient within the bacterial cell. The increased affinity of the S. aureus IsdB for human hemoglobin (Panel A) versus mouse hemoglobin (Panel B) accounts for the enhanced availability of iron and, in part, for the host specificity of S. aureus.
Lowy FD. N Engl J Med 2011;364:

41. Cancer Recurrence and VTE Risk
ESAs
Cancer Recurrence and VTE Risk

42. Bennett CL et al, JAMA. 2008;299 (8): 914-924
ESA and Cancer: Venous Thromboembolism and Mortality Risk in Cancer-Associated Anemia
Meta-analysis of mortality in 51 trials involving 13,611 patients and VTE in 38 trials involving 8172 patients
Overall odds ratio for mortality risk was 1.10 ( ); VTE risk was 1.57 ( )
8 studies from showed increased mortality or tumor progression among patients treated with ESA
Heavily influenced by the BEST (Breast Cancer Erythropoietin Survival) Trial in breast cancer
All targeted hemoglobin > 13 g/dL (3 targeted Hgb > 15 g/dL)
EPO receptors
Adenocarcinoma, breast
Bennett CL et al, JAMA. 2008;299 (8):

43. Glaspy J et al British Journal of Cancer 2010;102, 301-315
ESA and Cancer: Venous Thromboembolism and Mortality Risk Cancer-Associated Anemia
Meta-analysis of 60 controlled ESA trials (15,323 patients) involving cancer patients with anemia undergoing chemo and/or RT
Included studies not in the Bennett analysis
ESA use did not significantly affect mortality (60 studies: OR = 1.06) or disease progression (26 studies: OR = 1.01)
VTE risk was increased (44 studies: OR = 1.48)
Future randomized trials recommended –clinical equipoise
Glaspy J et al British Journal of Cancer 2010;102,

44. Adding EPO to Intense Dose - Dense Adjuvant Chemo for Breast Cancer: RCT
5 year follow-up No difference in survival
Moebus et al. JNCI. 2013; 105:14,

46. VTE risk does appear to be increased, at least with longer term ESA therapy, but this can be mitigated with thromboprophylaxis. What about cancer recurrence?

47. Editorial by Leyland-Jones on Moebus study
Background: Leyland-Jones was principal investigator for the Breast cancer Erythropoietin Survival Trial
Target Hgb was g/dL
ESA started at Hgb > 13 g/dL and continued for 12 months regardless of whether subjects still receiving chemo
If you exclude BEST from the Bennet and Bohlius analysis it changes the OR for mortality to include unity
Simply including the long-term survival data from BEST (beyond one year) instead of the published data changes the mortality OR to include unity
Editorial by Leyland-Jones concludes:
The concept of pushing hemoglobin to 14 g/dL is wrong
I remain to be convinced that ESAs have any negative effect on progression free survival
If one limits the analyses to trials where ESAs are prescribed within label, the evidence suggests very little, if any, impact on overall survival
Leyland –Jones B. JNCI. 2013; 105:14,

48. Influence of Transfusion on Colorectal Cancer Recurrence
Meta-analysis: 20,795 patients followed for average 59 months
Transfused (58%) vs. not transfused
OR for all cause mortality was 1.72
OR for combined recurrence-metastasis-death was 1.66
OR for post-op infection 3.27
Acheson A G, et al Ann Sur 2012;256:

49. Linder et al BJUI 2013 doi:10.1111/bju.12535
The Impact of Perioperative Transfusion on Survival after Nephrectomy for Non-metastatic Renal Cell Carcinoma
Retrospective database study of 2318 patients who underwent partial or radical nephrectomy
21% were transfused
Median follow-up 9.1 years
On multivariate analysis, transfusion associated with higher risk of death from any cause (HR 1.23; P= 0.02)
Dose response: increasing # of units associated with increased all-cause mortality
Linder et al BJUI 2013 doi: /bju.12535

50. Are overall clinical outcomes better or worse with PBM?
In Conclusion
Are overall clinical outcomes better or worse with PBM?
If they are the same or better, then PBM must be both as safe or safer and as effective or more effective than a transfusion only strategy

51. EMMC: 2006-2012 60 % reduction in transfused products
67 % reduction in transfusion reactions

52. PBM and Length of Stay at EMMC

53. CABG RBC Intra or Post op Transfusion* Rates by Quarter
*Received RBCs prior to POD4 until April 2006

54. Cardiac Surgical Site Infection Surveillance (EMMC)
1/1/1995 thru 9/30/2012
Association is not causality, but…

55. Outcome of Patients Who Refuse Transfusion After Cardiac Surgery
10 years

56. Outcome of Patients Who Refuse Transfusion After Cardiac Surgery

57. Thank You!