EVIDENCE BASED RED CELL TRANSFUSION. Rana Samuel, MD DIRECTOR, PATHOLOGY AND LABORATORY MEDICINE VA WNY Health Care System

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1 EVIDENCE BASED RED CELL TRANSFUSION Rana Samuel, MD DIRECTOR, PATHOLOGY AND LABORATORY MEDICINE VA WNY Health Care System

2 HISTORY Blood transfusion works (ie: red cell transfusion saves lives). based on logic and anecdotal evidence. Blood transfusion works, but is risky: hemolytic transfusion reactions, including death. transmission of diseases: HIV, Hep C etc. other adverse effects of transfusion.

3 RISKS OF RED CELL TRANSFUSION EARLY COMPLICATIONS (occur during or within hours of transfusion; overall risk <1/1000 units) * 1. Hemolytic Tx reaction * 2. TRALI (Tx related acute lung injury) * 3. Circulatory overload * 4. Anaphylactic reaction 5. Allergic reaction 6. Febrile non-hemolytic reaction * may be fatal

4 RISKS OF RED CELL TRANSFUSION LATE COMPLICATIONS (occur days to months after transfusion; overall risk >1/100 units) * 1. Delayed hemolytic Tx reaction * 2. Iron overload * 3. IMMUNE SUPPRESSION - increased infections - increased cancer recurrence * 4. TRANSMITTED INFECTIONS - HIV - HCV - HBV * may be fatal

5 CURRENT VIEW (evidence based) Red cell transfusion offers no benefit to most patients, and often causes serious harm.

6 EVIDENCE Herbert PC et al: N Engl J Med 1999 Apr1;340(13): Multicenter prospective randomized controlled study critically ill adult patients admitted to ICU - Euvolemic after initial treatment - Hemoglobin < 9 g/dl - Randomized into 2 groups: - Restrictive Transfusion group (418 patients) - Liberal Transfusion group (420 patients)

7 TRICC TRIAL RESTRICTIVE TX GROUP LIBERAL TRANSFUSION GROUP Transfused if Hb < 7 g/dl Transfused if Hb < 10 g /dl Hb maintained at 7-9 g/dl Hb maintained at g/dl RESULTS: ALL OUTCOMES WERE EQUIVALENT OR BETTER IN THE RESTRICTIVE TRANSFUSION GROUP.

8 TRICC TRIAL OUTCOMES THAT WERE BETTER IN THE RESTRICTIVE TRANSFUSION GROUP OUTCOME RESTRICT TX LIBERAL TX P VALUE In hospital mortality 22.3 % 28.1 % day mortality < 55 yr 5.7 % 13 % 0.02 APACHE score < % 16.1 % 0.03 Myocardial infarction 0.07 % 2.9 % 0.02 CHF 5.3 % 10.7 % < 0.01

9 TRICC TRIAL OUTCOMES THAT WERE STATISTICALLY EQUIVALENT IN BOTH GROUPS OUTCOME RESTRICT TX LIBERAL TX P VALUE 30 day mortality 18.7 % 23.3 % cardiac patients 22.3% 22.9 % 0.69 Long-term mortality 22.7 % 26.5 % 0.23 Pneumonia 20.8 % 20.5 % 0.92 Other infections 10 % 11.9 % 0.38 Hospital LOS 34.8 days 35.5 days 0.58

10 There was no subset of patients that had a worse outcome with restrictive transfusion compared to liberal transfusion. ie: WITHOLDING blood did no harm. GIVING blood often did harm

11 EFFICACY OF RBC TRANSFUSION IN THE CRITICALLY ILL: A SYSTEMATIC REVIEW OF LITERATURE Marik PE and Corwin HL, Crit Care Med 2008;36: studies: association between RBC TX and: 1. Primary outcome: Mortality (18 studies) 2. Secondary outcome: Morbidity: - acquired infections (22 studies) - ARDS (6 studies) - Multiorgan dysfunction syndrome (3 studies) RESULTS: Risks of RBC TX > benefits: 42 of 45 studies Neutral (no difference in outcome): Benefit > risk: 2 of 45 studies in 1 subgroup of a single study (elderly patients with an acute MI and a Hct <30%,? euvolumic)

12 Multiple studies: similar results 2008: (Koch CG, et al. N Engl J Med 358: ) Retrospective single center analysis of 6000 pts undergoing CABG or Valve surgery: Tx of older RBC units (> 14 days) = worse outcomes: Increased: - in-hospital mortality, (P= 0.004) - 1 yr mortality (P<0.001) - intubation >72 h (P<0.001) - sepsis (P=0.01) - renal failure (P=0.003) 2004: (Corwin HL, et al, Crit Care Med 32(1):39-52) Prospective multicenter observational cohort study, 4892 ICU pts: The # of RBC units transfused (but not the baseline Hb) is an independent predictor of worse outcome: - longer hospital stay - longer ICU stay - increased mortality

13 Multiple studies: similar results 2004: Shorr AF et al, Crit Care Med 32(3): Secondary analysis of a prospective multicenter observational cohort study, 4892 ICU pts without pneumonia at ICU admission who then required at least 48 h of mechanical ventilation: CONCLUSION: RBC transfusion increases the risk of developing VAP in ICU patients, with a positive dose response relationship. 2008: Rawn J. Curr Opin Anaesthesiol Oct;21(5):664-8 Review: The silent risks of blood transfusion. CONCLUSION: The benefits of blood transfusion have never been conclusively demonstrated, but evidence of transfusion-related harm continues to accumulate. Given the transfusion triggers that currently predominate in clinical practice it appears that clinical outcomes could significantly improve with more widespread adoption of restrictive transfusion strategies.

14 ?? WHATS GOING ON?? Q: Why is there no benefit from RBC Tx? A: Because current RBC Tx practice is unscientific (based on myths): MYTH 1: MYTH 2: MYTH 3: Anemia = low O2 delivery to tissues RBC Tx increases O2 delivery to tissues The Hb level correlates well with tissue oxygenation

15 MYTH 1: Anemia = low tissue O2 Anemia (defined as decreased red cell mass) in practice measured as decreased Hb. Compensatory mechanisms in normovolemic anemia maintain O2 delivery to the tissues: 1. decreased blood viscosity -> decreased vascular resistance -> increased venous return -> increased cardiac output (heart rate and stroke volume) 2. increased tissue O2 extraction (maintains tissue O2 to Hb 4.5 g/dl in healthy resting adults, 5 g/dl [Hct 15] in anesthetized adults) 3. increased tissue 2,3 DPG levels -> increased dissociation of O2 from Hb -> increased tissue O2 delivery

16 MYTH 2: RBC Tx increases tissue oxygenation NO evidence to prove this assumption. Indirect evidence that RBC transfusion DECREASES tissue oxygenation (therefore usually WORSE outcomes)! WHY? due to 1. the RBC STORAGE DEFECT 2. Increased blood viscosity

17 RBC STORAGE DEFECT VARIABLE CHANGE TIME COURSE EFFECT OUTCOME RBC 2,3 DPG Decreased Near 0 after 2-3 days Increased affinity of Hb for O2 (more tightly bound) Decreased O2 delivery to tissues RBC Nitric Oxide (NO) Decreased Very rapid (4 fold decrease within 3 hrs) 1. RBC unable to dilate capillaries Sluggish microcirculation 2. RBC suck up vascular & tissue NO vasoconstriction Decreased O2 delivery to tissues RBC SHAPE Flexible biconcave disc rigid spiky ball (Echinocyte) 5 10 d: spicules d: spherocyte RBC unable to deform and squeeze through capillaries Sluggish microcirculation Decreased O2 delivery to tissues

18 RBC STORAGE DEFECT VARIABLE CHANGE TIME COURSE EFFECT OUTCOME K+ RBC K+ decreases Rapid, progressive Hyperkalemia Cardiac and metabolic effects EC K+ increases LACTATE increases Progressive Pro-acidotic CELL FREE Hb increases Progressive Highly oxidative & cytotoxic, esp. to endothelial cells Proinflammatory and prothrombotic effects

19 RBC STORAGE DEFECT VARIABLE CHANGE TIME COURSE Inflammatory and prothrombotic Cytokines Platelet microparticles & WBC membrane fragments EFFECT Increased Progressive Increased: - ARDS, - SIRS, - Immunosupression OUTCOME Increased: - Infections - Organ failure - Cancer recurrence - Death Increased Progressive As above As above ATP Decreased Progressive Loss of membrane structure and integrity

20 MYTH 3: Hg level reflects tissue oxygenation In a euvolemic patient, Hb level reflects only the degree of anemia, NOT the tissue oxygenation. If dehydrated/hypovolemic: Hb level is artifactually high (ie: patient may be anemic, but Hb level appears normal) If overhydrated/hypervolemic: patient may have a normal red cell mass, but the Hb level appears low (in the anemic range) *****

21 Guideline: first do no harm! Acute blood loss: rapid loss of up to 1.5 to 2 liters (30 40 % of blood volume) -> rapid infusion of crystalloids (order Type & Screen)-> assess clinically: Vital signs stable: treat the cause of blood loss, no RBC Tx; continue to monitor Unstable or symptomatic (Hypotension, tachycardia, dyspnea etc): rule out causes other than anemia, and treat specifically (pressors, diuretics, oxygen etc). Unstable/symptomatic and no other likely cause: Tx 1 unit of prbc and re-evaluate clinically the need for each additional unit. Acute blood loss > % of blood volume: - as above, but often require blood Tx.

22 GUIDELINE: first do no harm! CHRONIC ANEMIA: DO NOT TRANSFUSE. - Determine and treat the cause of the anemia (polypectomy, hysterectomy, iron, vit B 12, erythropoietin etc.) - If non-responsive to treatment: Is patient symptomatic? symptoms and/or signs of cardiovascular or cerebrovascular compromise (hypotension, tachycardia, dyspnea, dizziness, angina). If no: DO NOT TRANSFUSE Is patient euvolemic? (Give fluids first: see if symptoms resolve). Is another etiology more likely (than anemia) for the symptoms: If yes: DO NOT TRANSFUSE.

23 RBC Tx Guidelines Chronic anemia: determine cause and treat. Chronic anemia not responsive to specific treatment: No signs and symptoms: do not Tx. Continue to monitor. Hypotension, tachycardia, dyspnea, dizziness: ensure euvolemia and re-evaluate. If still symptomatic, and no other causes of S&S: Tx one unit and re-evaluate clinically the need for each additional unit.

24 THE TEAMWORK CHALLENGE: LOOK FOR EVIDENCE THAT: - RBC Tx increases tissue O2 delivery - RBC Tx improves patient outcomes in euvolemic patients. rana.samuel@va.gov

25 ?? WHY IS THIS A SUITABLE TOPIC FOR DISCUSSION AT ANNUAL RC MEET?? - Because our role can (and does) go beyond ensuring compliance with rules and regulations. - Because the VA nationally wants to transition to best evidence based practice - Because I want to tap into the phenomenal collective experience and expertise represented here

26 PROOF THAT EDUCATION AND UTILIZATION REVIEW ARE EFFECTIVE: 25% less prbc usage (04 08 avg: 800 units/yr, 09 avg: 600 units/yr) 40% decrease in Transfusion costs (1.1 million -> 660,000 $) BLOOD PRODUCTS TRANSFUSED FY RBC FFP PLT SINGLES PLT PHERESIS CRYO AUTO PRODUCTS DIRECTED PRODUCTS ST QTR/2007 2ND QTR 3RD QTR 4TH QTR 1ST QTR/2008 2ND QTR 3RD QTR 4TH QTR 1ST QTR/2009 2ND QTR 3RD QTR 4TH QTR RBC FFP PLT SINGLES PLT PHERESIS CRYO AUTO PRODUCTS DIRECTED PRODUCTS

27 THANK YOU! Q s?