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Red Cell In Vivo Recovery and Survival Studies

Red Cell In Vivo Recovery and Survival Studies. Richard J. Davey, MD The Methodist Hospital, Houston TX Blood Products Advisory Committee May 1, 2008. Evolution of Labeling and Evaluation Criteria. 1947: Ross proposes 70% red cell survival at 24 hours as a minimum recovery

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Red Cell In Vivo Recovery and Survival Studies

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  1. Red Cell In Vivo Recovery and Survival Studies Richard J. Davey, MD The Methodist Hospital, Houston TX Blood Products Advisory Committee May 1, 2008

  2. Evolution of Labeling and Evaluation Criteria • 1947: Ross proposes 70% red cell survival at 24 hours as a minimum recovery • 1950: Gray and Sterling describe 51Cr as a red cell label • 1967: Fisher describes 99mTc as a red cell label • 1985: Minimum survival raised to 75% following FDA workshop • 1989: AuBuchon refines use of 111In as a red cell label • 1998: Minimum survival ≥ 75%: SD ≤ 9% based on historical data • 2004: Current criteria based on historical data, BPAC

  3. Characteristics of an Ideal Red Cell Radiolabel • Minimal preparative manipulation of red cells • Specific for red cells • Nontoxic to the cell • Nontoxic to the recipient • No metabolism by red cells • No elution from the cell • Radioactive half-life appropriate for the duration of the study • No relabeling of other cells

  4. Characteristics of Commonly Used Red Cell Radiolabels Characteristic51Cr 99mTc111In Half-life 27.7 days 6.0 hours 2.8 days Elution 1% day 4% hour 4% day Major γ-photon 320 keV 140 keV 173,247 keV emissions Suitable for imaging No Yes Yes

  5. Technical Steps for Labeling Red Cells with 51Cr • A suitable sample of red cells stored under experimental condition is chosen. For autologous studies, ~ 15ml is used. • An amount of 51Cr is used to insure minimum adequate counts throughout the study (~ 4000 counts/sample: 5 to 20 μCi) • After incubation with test red cells, unbound 51Cr is removed • An appropriate standard is prepared for blood volume determination • Labeled red cells are infused into a peripheral vein and exact volume of infused material is determined

  6. Technical Steps for Labeling Red Cells with 51Cr • Samples are drawn from opposite arm. Several early samples are drawn for 100% survival determination. • Samples counted in duplicate and corrected for elution.

  7. Early Loss of Labeled, Stored Red Cells After Infusion

  8. Zero-Time Determination by Direct Red Cell Mass Measurement (99m Tc) and by Back-Extrapolation (51 Cr)

  9. Partial List of Red Cell Products Evaluated Using Red Cell Recovery Studies • New plastics and plasticizers • New anticoagulant/preservatives • Filtration devices and leukoreduced products • Irradiated red cells • “Undercollected” red cell units • Pathogen inactivation procedures • Enzymatic removal of A and B antigens

  10. Effect of Prestorage Irradiation on 24-hour Posttransfusion Red Cell Recovery Storage Interval 21 Days1 28days1 42 Days2 Radiation dose 20 Gy 20 Gy 30 Gy Control Irrad. Cont. IrradCont. Irrad. Potassium (mEq/L) 36.6 63.4 47.7 69.4 42.6 78.1 ATP (μM/g Hb) 3.6 3.2 3.8 3.5 2.1 1.9 RBC 24 hr recovery (%) 90.4 82.2 85.0 80.7 78.4 68.5 1. Friedman et al. Transfusion 1991;31:50S 2. Davey et al. Transfusion 1992:32:525-8

  11. Evolution of Labeling and Evaluation Criteria • 1947: Ross proposes 70% red cell survival at 24 hours as a minimum recovery • 1950: Gray and Sterling describe 51Cr as a red cell label • 1967: Fisher describes 99mTc as a red cell label • 1985: Minimum survival raised to 75% following FDA workshop • 1989: AuBuchon refines use of 111In as a red cell label • 1998: Minimum survival ≥ 75%: SD ≤ 9% based on historical data • 2004: Current criteria based on historical data, BPAC

  12. FDA Requirements for Approval of Red Blood Cell Products • Total 20 or more evaluable 24-hour recoveries • Minimum two laboratories • Sample mean ≥ 75% • Sample standard deviation ≤ 9% • One-sided 95% lower confidence limit for the proportion of successes must be >70% with success threshold for individual recovery ≥ 75%. • A successful trial can have no more than 3 of 24 RBC recoveries below 75% • Hemolysis < 1% at end of storage • Comparison, control vs. test: ATP, 2,3 DPG, pH, glucose, lactate

  13. The Problem With “Old” Blood

  14. Mechanisms of Morbidity and Mortality: The Red Cell Storage Lesion Storage Lesion • Decreased 2,3 DPG • Increased rigidity • High PA I level Poor O2 transport • High CD 40 Inflammation • NO depletion Thrombosis • Increase in IL-10 • Decrease in TNF-α

  15. Depletion of 2,3 DPG

  16. Loss of RBC Deformability

  17. Storage Depletes RBC Nitric Oxide Bioactivity

  18. Outcomes: Liberal vs. Restrictive Transfusions Outcome MeasureRestrictive (n=418) Liberal (n=420) p value (Hb: 7.0-9.0) (Hb: 10.0-12.0) Death (# / %) 30 day 78 (18.7) 98 (23.3) 0.11 ICU 56 (13.4) 68 (16.2) 0.29 Hospital 93 (22.2) 118 (28.1) 0.05 Length of stay – days ICU 11.0 ± 10.7 11.5 ± 11.3 0.53 Hospital 34.8 ± 19.5 35.5 ± 19.4 0.58 Hebert PC, et al. New Engl J Med 1999;340:409.

  19. Factors Associated With Postoperative Morbidity Post-CABG VariableOdds RatioUpper CLLower CLp value Transfusion PRBC, units 1.73 1.67 1.80 <.0001 Preoperative Higher BMI 1.05 1.04 1.07 <.0001 Abnormal LVEF 1.62 1.33 1.98 <.0001 Peripheral vasc. disease 1.54 1.21 1.95 .0004 Previous stroke 1.55 1.14 2.11 . 0051 “Perioperative RBC transfusion is the single factor most reliably associated with postoperative morbid events” Koch GC et al. Crit Care Med 2006;34;1608

  20. Hypothesis • Serious complications and mortality after cardiac surgery may increase when red cell units are transfused after they have been stored for more than 2 weeks • Patients underwent coronary-artery bypass grafting, cardiac-valve surgery, or a combination of the two procedures • 6002 patients studied from June 30, 1998 to January 30, 2006 • All serious morbid events evaluated • When blood was ordered for transfusion, the blood bank provided the oldest available matching unit for each request (FIFO) • Median time of storage was 15 days

  21. Conclusions • Patients given older blood: • Greater in-hospital mortality (2.8% vs. 1.7%, P < 0.004) • More likely to need prolonged ventilatory support (9.7% vs. 5.6%, P<0.001) • More likely to have renal failure (2.7% vs. 1.6%, P < 0.003) • Increased sepsis (4.0% vs. 2.8%, P < 0.01) • Increased multisystem organ failure (0.7% vs. 0.2%, P < 0.007)

  22. Red Cell Recoveries in Clinical Trials: Where Should We Set the Bar? • Technical labeling procedures are well established and performed by skilled laboratories • Prudent to be cautious in liberalizing threshold value • Do not want to set bar so highas to lead to unnecessary trial failures. (67.3% historical success rate for liquid products @ 75% threshold value) • Do not want to set the bar so lowas to have almost 100% success. (99.9% historical success for liquid products @ 67% threshold) • Alternatives: • 70% threshold value = 95.5% historical success (liquid storage) • 72 -73% threshold value? Davey RJ. Editorial. Transfusion. In press.

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