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The Good, The Bad and the … Old(?): Making Sense of the Red Cell Age Debate

This article explores the importance of transfusion medicine and challenges faced in the transfusion of red cells. It discusses current data, future directions, and potential future challenges in the field. The article also examines the quality of evidence-based medicine and presents conclusions based on existing research.

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The Good, The Bad and the … Old(?): Making Sense of the Red Cell Age Debate

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  1. The Good, The Bad and the … Old(?):Making Sense of the Red Cell Age Debate Daniel N. Cohen, M.D.,Ph.D. Vanderbilt University Medical Center Department of Pathology 26 July 2013 : [31 August 2010]

  2. Importance of Transfusion Medicine • Every 2 seconds someone in the U.S. needs blood • 14,650,000 PRBCs in 2007. • 30,000,000 all transfused products • 5,000,000 recipients • U.S. population eligible to give blood… • Less than 38%

  3. Public attention Tennessean, 28 July 2010

  4. Challenges to Transfusionof Red Cells • Red cell storage lesion: Biochemistry, structural biology • Current data • Trials recruiting • Future directions • Future challenges • Pt safety, economics, EBM

  5. Quality of Evidence Based Medicine 1. Meta-Analysis 2. Systematic Review/Guideline 3. Randomized Controlled Trial 4. Cohort Study 5. Case Control Study 6. Case Series/Case Report 7. Animal Research/Lab Data 8. Anecdote, epiphenomenalism Modified from, BA Sastre, VUMC & hiru.mcmaster.ca/ebm

  6. A spark • 6000+ pts studied, Cincinnati, – retrospective observational, mortality index, complications, no biochemical ends.

  7. Koch et al. 2008 ↑ Complications Koch et al 2008, NEJM

  8. Koch et al. 2008 ↑Mortality Koch et al 2008, NEJM

  9. Koch et al. 2008 Complications

  10. Koch et al. 2008 The Rub – W.S. Koch et al 2008, NEJM

  11. Koch et al. 2008 The Conclusions • Adamson JW editorial (NEJM 2008) • 1) Generalizable? The median age of the patients in the study was 70 years , defined w/coexisting illnesses. • 2) The surgery required cardiopulmonary bypass. Bypass machine and red cells interaction? particularly deleterious if the red cells have been stored for 3 or 4 weeks, instead of 1 or 2? What about no bypass? • 3) Second, in any surgical setting, would the complete avoidance of blood transfusions (or as complete as possible) lead to even better outcomes?

  12. Current Data ~45 observational, retrospective studies (Cardiac surgery, critical care, trauma, colorectal surgery.) Problems for all (confounders): • Transfusion volume ≈ worse outcomes (underlying clinical factors) • ↑ volume, ↑ likelihood of older units • ø randomization, ø r/o confounders (unrecognized or recognized) • No std def. “storage duration” • Mean ([2+40]/2 = 21)?, Max?, proportion (>14d ↓DPG)? • Leukoreduced vs not – unknown clinical signif. • Primary endpoints and analysis plan (w/ 2º analysis) defined PRIOR and stated in publication. Avoid post hoc (cherry picking)

  13. The Storage “Lesion” • Metabolic • ↓pH ↑H+, ↓ATP ↓GTP, ↓DPG, ↓GSH, ↓NADH, ↓ NADPH • Enzymatic (↓ w/leuko) • Loss surf. Glycans (sticky) • Lysolipids • Protein damage • Oxidative • Band III damage* • Decoration of proteins (B9 and neo-Ag) • HgbA1C vs. ε-lysines • Oxidized lipids – micro vesicles – inflammatory trigger • Lysolipids – TRALI – neutrophil priming • Physiologic • Shape change (↓ deformability, ↓ capillary flow) • Membrane loss (PS) • Lysis (apoptosis, etc.) Right Rise ↑[H+]= ↓pH Adapted from: Hess Transf & Aphersis Sci. 2010 *Band III binds PS and PIP2

  14. Combating the storage lesion(30 minutes) after first separation • Helium • (99.9999%) • 1ppm • (Ar, N2 less effective) Zolla & D'Alessandro. 2013. Journal of Blood Transfusion. 896537. http://dx.doi.org/10.1155/2013/896537

  15. Deoxygenation hemoglobin A=kCL500-600 nm absorbance Before deoxygenation After deoxygenation Zolla & D'Alessandro. 2013. Journal of Blood Transfusion. 896537. http://dx.doi.org/10.1155/2013/896537

  16. Decreased hemolysis at 42 days Zolla & D'Alessandro. 2013. Journal of Blood Transfusion. 896537. http://dx.doi.org/10.1155/2013/896537

  17. Morphology less disrupted Zolla & D'Alessandro. 2013. Journal of Blood Transfusion. 896537. http://dx.doi.org/10.1155/2013/896537

  18. Clinical Trials.gov • Red Cell Storage Duration Study (RECESS) 2012-2014 • Complex cardiac, goal 300 pts, >18 yrs • NCT00991341 • Mechanisms NCT01541319, Physiology NCT01274390 • <11d vs >20d, ΔMODS • Age of Red Blood Cells in Premature Infants Study (ARIPI) <1250 g • NCT00326924 • <7d vs std (aliquots same PRBC unit for shelf life (2-42d) • NEC, retinopathy of newborn, bronchopulmonary displasia, intraventricular hemorrhage at 90d.

  19. Clinical Trials.gov II • Age of Blood Evaluation (ABLE) Study (Canada) • <8d vs. std oldest first (2-42 d) (non-inferiority design) • All cause mortality at 90d • Storage Lesion in Banked Blood Due to Disruption of Nitric Oxide (NO) Homeostasis • NCT01137656 Univ Pittsburgh • 5-10d vs 35-42d • Examine RBC rupture in vivo forearm blood flow measurements ± Ach

  20. Clinical Trials.gov III • Age of blood in traumatic brain injury • NCT00141674 • U British Columbia • Not published. • Informing fresh versus standard Issue red cell management • ISRCTN08118744 • Australia, Canada, United States of America • Target 24,400 pts • Jan 2012 – Sept 2014 • McMaster, CA

  21. 2013-2014 • RECESS – Cardiac procedures (USA) • ARIPI – premature infants (Canada) • ABLE – ICU patients (Canada) • INFORM – Effects of tranfusing fresh versus std issue RBCs, in-hospital mortality

  22. ARIPI Study Design 2009 Fergusson D, et al.2009. Transfus Med Rev. 23(1):55-61

  23. ARIPI Study Execution 2012

  24. ARIPI 2012 JAMA • 6 Canadian institutions • May 2006- June 2011 • 377 children • 189 standard RBC issue • 188 fresh <7 days • Death, BPD, retinopathy, NEC, IVH • Monitoring for >90 days after stay

  25. ARIPI Design and Stats • 450 infants to detect 0.05% difference 80% power (2-tailed) with absolute decrease 15% • Assumption 10% non-compliance • IRB approved • Readjusted sample size to 372 with interim analysis (non-compliance 4%)

  26. ARIPI Distrubtion groups • Avg. age of each individual transfusion & • Weighted avg. age by volume transfused • Mean 5.1 d Mean 14.6 d Fergusson et al JAMA. 2012;308(14):1443-1451.

  27. ARIPI Transfusion Data Fergusson et al JAMA. 2012;308(14):1443-1451.

  28. ARIPI: Primary Outcomes Fergusson et al JAMA. 2012;308(14):1443-1451.

  29. ARIPI: Infectious outcomes Fergusson et al JAMA. 2012;308(14):1443-1451.

  30. ARIPI: Conclusions • In conclusion, the transfusion of fresh RBCs did not improve clinical outcomes in high-risk, premature, very low-birth-weight infants. We thus do not recommend any changes to storage time practices for the provision of RBCs to infants admitted to neonatal intensive care.

  31. Conclusions • RECESS, ABLE, INFORM – In progress • Deoxygenation of pRBCs reduces the storage lesion • Red Blood cell age does not influence low birthweight neonatal infectious outcomes Is the storage lesion clinically significant?

  32. Thank you, Questions?Comments/Discussion

  33. References • 1.     Aucar J. A., Isaak E. & Anthony D. (2009). The effect of red blood cell age on coagulation. Am. J. Surg. 198, 900-904.2.     Benjamin R. J., Dodd R. Y. (2008). Red-cell storage and complications of cardiac surgery. N. Engl. J. Med. 358, 2840-1; author reply 2841-2.3.     D'Alessandro A., Liumbruno G., Grazzini G. & Zolla L. (2010). Red blood cell storage: the story so far. Blood Transfus. 8, 82-88.4.     Dumont L. J., Yoshida T. & AuBuchon J. P. (2009). Anaerobic storage of red blood cells in a novel additive solution improves in vivo recovery. Transfusion 49, 458-464.5.     Edgren G., Kamper-Jorgensen M., Eloranta S., Rostgaard K., Custer B., Ullum H., Murphy E. L., Busch M. P., Reilly M., Melbye M., Hjalgrim H. & Nyren O. (2010). Duration of red blood cell storage and survival of transfused patients (CME). Transfusion 50, 1185-1195.6.     Eikelboom J. W., Cook R. J., Liu Y. & Heddle N. M. (2010). Duration of red cell storage before transfusion and in-hospital mortality. Am. Heart J. 159, 737-743.e1.7.     Fergusson D., Hutton B., Hogan D. L., LeBel L., Blajchman M. A., Ford J. C., Hebert P., Kakadekar A., Kovacs L., Lee S., Sankaran K., Shapiro S., Smyth J. A., Ramesh K., Bouali N. R., Tinmouth A. & Walker R. (2009). The age of red blood cells in premature infants (ARIPI) randomized controlled trial: study design. Transfus. Med. Rev. 23, 55-61.7.5 Fergusson DA, Hébert P, Hogan DL, LeBel L, Rouvinez-Bouali N, Smyth JA, Sankaran K, Tinmouth A, Blajchman MA, Kovacs L, Lachance C, Lee S, Walker CR, Hutton B, Ducharme R, Balchin K, Ramsay T, Ford JC, Kakadekar A, Ramesh K, Shapiro S. Effect of fresh red blood cell transfusions on clinical outcomes in premature, very low-birth-weight infants: the ARIPI randomized trial. JAMA. 2012 Oct 10;308(14):1443-51. 8.      Garay R., Senn N. & Ollivier J. P. (1994). Erythrocyte ion transport as indicator of sensitivity to antihypertensive drugs. Am. J. Med. Sci. 307 Suppl 1, S120-5.9.      Hess J. R. (2010). Conventional blood banking and blood component storage regulation: opportunities for improvement. Blood Transfus. 8 Suppl 3, s9-15.10.     Hess J. R. (2010). Red cell changes during storage. Transfus. Apher. Sci. 43, 51-59.11.     Hess J. R. (2010). Red cell storage. J. Proteomics 73, 368-373.12.     Hess J. R. (2006). An update on solutions for red cell storage. Vox Sang. 91, 13-19.13.     Jain R., Jarosz C. (2001). Safety and efficacy of AS-1 red blood cell use in neonates. Transfus. Apher. Sci. 24, 111-115.14.     Koch C. G., Li L., Sessler D. I., Figueroa P., Hoeltge G. A., Mihaljevic T. & Blackstone E. H. (2008). Duration of red-cell storage and complications after cardiac surgery. N. Engl. J. Med. 358, 1229-1239.15.     Lacroix J, Hébert P, Fergusson D, Tinmouth A, Blajchman MA, Callum J, Cook D, Marshall JC, McIntyre L, Turgeon AF; ABLE study group. The Age of Blood Evaluation (ABLE) randomized controlled trial: study design. Transfus Med Rev. 2011 25(3):197-205. 15.5 Lelubre C., Piagnerelli M. & Vincent J. L. (2009). Association between duration of storage of transfused red blood cells and morbidity and mortality in adult patients: myth or reality? Transfusion 49, 1384-1394.16.     Marik P. E., Corwin H. L. (2008). Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit. Care Med. 36, 2667-2674.17.     Offner P. J. (2004). Age of blood: does it make a difference? Crit. Care 8 Suppl 2, S24-6.18.     Shafer S. L. (2009). Notice of retraction. Anesth. Analg. 108, 1953.19.     Sparrow R. L. (2010). Red blood cell storage and transfusion-related immunomodulation. Blood Transfus. 8 Suppl 3, s26-30.20.     Spinella P. C., Carroll C. L., Staff I., Gross R., Mc Quay J., Keibel L., Wade C. E. & Holcomb J. B. (2009). Duration of red blood cell storage is associated with increased incidence of deep vein thrombosis and in hospital mortality in patients with traumatic injuries. Crit. Care 13, R151.21.     Steiner M. E., Assmann S. F., Levy J. H., Marshall J., Pulkrabek S., Sloan S. R., Triulzi D. & Stowell C. P. (2010). Addressing the question of the effect of RBC storage on clinical outcomes: The Red Cell Storage Duration Study (RECESS) (Section 7). Transfus. Apher. Sci. 43, 107-116.22.     Tinmouth A., Chin-Yee I. (2001). The clinical consequences of the red cell storage lesion. Transfus. Med. Rev. 15, 91-107.23.     Triulzi D. J., Yazer M. H. (2010). Clinical studies of the effect of blood storage on patient outcomes. Transfus. Apher. Sci. 43, 95-106.24.     Usry R. T., Moore G. L. & Manalo F. W. (1975). Morphology of stored, rejuvenated human erythrocytes. Vox Sang. 28, 176-183.25.     Vamvakas E. C. (2010). Meta-analysis of clinical studies of the purported deleterious effects of "old" (versus "fresh") red blood cells: are we at equipoise? Transfusion 50, 600-610.26.     Vandromme M. J., McGwin G.,Jr & Weinberg J. A. (2009). Blood transfusion in the critically ill: does storage age matter? Scand. J. Trauma. Resusc. Emerg. Med. 17, 35.27.     Vandromme M. J., McGwin G.,Jr & Weinberg J. A. (2009). Blood transfusion in the critically ill: does storage age matter? Scand. J. Trauma. Resusc. Emerg. Med. 17, 35.28.     Welsby I. J., Lockhart E., Phillips-Bute B., Campbell M. L., Mathew J. P., Newman M. F., Peterson E., Milano C. A. & Mark Stafford-Smith for members of the Cardiothoracic Anesthesiology Research Endeavors (C.A.R.E.), Department of Anesthesiology, Duke University Medical Center. (2010). Storage age of transfused platelets and outcomes after cardiac surgery. Transfusion .29.     Yoshida T., AuBuchon J. P., Tryzelaar L., Foster K. Y. & Bitensky M. W. (2007). Extended storage of red blood cells under anaerobic conditions. Vox Sang. 92, 22-31.30.     Zimrin A. B., Hess J. R. (2009). Current issues relating to the transfusion of stored red blood cells. Vox Sang. 96, 93-103.

  34. Hopewell, Omar et al. BMJ Open 2013;3:e002154. • “Most studies showed higher death rates when comparing patients who received RBCT with those who did not.” • “… observational studies [DO] show a consistently adverse effect of RBCT on mortality.” • “Whether this is a true effect remains uncertain…” […] this author emphasis

  35. Koch et al 2008. • Two groups even for number of RBCs obtained,

  36. Koch et al 2008. • Many complications unrelated, MI, VTach, VFib, Dissection, tamponade, Pneumonia, PE, deep sternal wound etc.

  37. Most Current Data:Cardiac Care RCTs • Outcomes: Post-op bleeding, feasability (retracted larger study from 2006) • Wasser et al. Brit J Haem, 1989 • <12hr vs 2-5 days (Wasser et al) • n = 237 • Bennett-Guerrero et al. Transfusion 2009 • I: Std vs. <22 days • II: 7 ± 4days vs 21 ± 4days • n = 43 • van de Watering et al. Transfusion 2006 46: 1712-18. Triulzi et al 2010

  38. Most Current Data:Trauma RCTs • Weinberg JA McGwin Griffth et al. J. Trauma 2008; 65:279-82. Triulzi et al 2010

  39. Most Current Data:Critical Care RCTs • Outcomes: Systemic VO2 and gastric VO2 by pHi (Fernandes et al. Crit Care 2001.) • PRBCs (1U) vs. albumin • n = 15 (10 test, 5 ctrl) • Test oxygenation immediately after transfusion – too small? too soon? • Gastric VO2 pHi (Walsh et al. Crit Care Med 2004.) • PRBCs, leukoreduced • ≤ 5 days vs. ≥ 20 days • T0 and T5 hr pHi, PCO2 gap, ABG, lactate • n = 22 • Sched or urgent! cardiac surgery and ICU pts (Herbert et al. Anesth Analg 2005.) • <8 day vs. std. (mean = 19d) Leukoreduced, clinicians blinded • n = 57 Triulzi et al 2010

  40. Most Current Data:Colorectal surgery RCTs • Zero, zilch, nada, zip. Triulzi et al 2010

  41. Most Current Data:Anaerobic Storage RCT (!) • Anaerobic conditions, Dartmouth (Dumont et al Transfusion 2009.) • 24hr RBC recovery (51Cr), lifespan (99mTc)at 6 wks and 9 wks post collection. • In vitro & in vivo • In vitro (d0, 6wk, 9wk) Hgb, Hct (PCV), WBC (post ↓), Na+, K+, Gluc, Lactate, pH, pCO2, pO2 • Morphology (SEM) • Anaerobic storage ↓ the # of non-viable cells by 1/3 • Recovery at 6 wks, 8% higher 24hr recovery • Recovery at 9 wks, like 6 wks control • Lifespan, no difference. • n = 8

  42. Current Data: Summary • 8 Cardiac • 2 RCTs, 6 observational • 1 RCT no effect, 1 not outcome not studied • 3 yes Old = Bad, 3 no • 7 Trauma (all observational) • 5 yes Old = Bad, 2 no • 7 Critical Care • 3 RCTs, 4 observational • 3 RCTs, no effect. • 2 yes Old = Bad, 2, no • 3 Colorectal surgery (all observational) • 1 yes Old = Bad, 2, no (yes 1 post hoc ) • “Danalysis” – adverse effects of storage • 4 RCTs : • no effect, 2 : equiv. • 20 Observational : • 11 yes, 9 no Triulzi et al 2010

  43. Most Current Data: Meta-analysis • Storage age question – “Odds ratio of adverse outcomes” : 1 = equivalent (not statistically significantly different) Odds ratio Vamvakas 2010 Transfusion

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