EDITORIAL Fresh blood or old blood? How shall we manage the inventories?

T

he morphologic and functional changes that red blood cells (RBCs) undergo as they age, both during in vivo circulation and during refrigerated storage in nutrient anticoagulant solutions, have been recognized for a long time. Studies in the 1940s and 1950s, for example, showed that older cells lose their biconcave disc shape1 and their enzyme activity, particularly in glycolytic pathways, is reduced.2 Whether the changes in stored cells persist after transfusion also attracted attention. In this regard, the reduction in enzyme concentrations appears to be reversible, since there is evidence that 2,3-disphosphoglycerate (2,3-DPG) is restored in transfused cells thereby reversing the abnormal shift of the oxygen dissociation curve that is a feature of stored blood.3 While the return of intraerythrocytic 2,3-DPG levels to normal occurs within hours after transfusion, other changes were shown to take longer. For example, while the decreased performance of the RBC sodium-potassium pump is repaired after transfusion, the return to normal intraerythrocytic electrolyte concentrations takes several days.4 The possibility that restoration of some features of the RBC internal milieu might influence posttransfusion survival was also raised during the earlier studies. Investigators from the University of Washington Medical School and what was then the King County Central Blood Bank in Seattle studied the in vivo fate of RBCs, which were transfused after a period of refrigerated storage in anticoagulant solutions. They observed that changes during storage, particularly with regard to carbohydrate metabolism and adenosine triphosphate concentration, were not the same as changes during the natural senescence of the RBCs. They coined the term “storage lesion” and went on to show in animal and human studies using blood stored in ACD that metabolic failure in stored RBCs was not permanent.4 They concluded, “The biochemical storage lesion of the erythrocyte has been shown to be rapidly reversible, once the erythrocyte is introduced into active circulation.”5 Follow-up studies examining if such a bold conclusion was justified are limited. Subsequently, interest in the in vivo, posttransfusion, performance of RBCs has taken a number of different directions. For example, appreciation for the dissimilarities between older and younger RBCs prompted studies at the National Institutes of Health (NIH) exploring the likelihood that younger cells would survive longer after transfusion, thereby increasing the transfusion interval in TRANSFUSION 2013;53:3032-3035. 3032

TRANSFUSION Volume 53, December 2013

chronically transfusion-dependent patients and reducing their risk for iron overload. While clinical benefit proved elusive, the investigators showed that “neocytes,” harvested during continuous flow centrifugation, enjoyed a posttransfusion mean half-life that was significantly longer than that of older cells6 (which, out of deference to the NIH team’s terminology, this editorialist will in future refer to as “paleocytes”). Posttransfusion survival is also a central licensing issue, since the Food and Drug Administration stipulates RBC recovery standards when the agency evaluates new products in categories such as additive solutions, apheresis equipment, and pathogen reduction processes. The specialized methods available to confidently follow the fate of transfused RBCs are, however, limited to a few laboratories with experience in techniques such as radiolabeling and differential agglutination. It is not surprising, then, given the relative convenience of sampling aliquots of stored RBCs over time, that more attention has been devoted to identifying in vitro changes as a basis from which to predict in vivo survival, rather than following in vivo survival of a small cohort of transfused cells. During the course of the in vitro studies, a broad array of morphologic and biochemical changes has been demonstrated. A recent mini-symposium in TRANSFUSION added to the accumulating evidence for abnormalities in stored RBCs. For example, nitric oxide homeostasis is abnormal,7 and there is a risk for both complement activation8 and release of RBC-derived microparticles.9 Against the background of accumulating awareness of the broad extent of the storage lesion, questions continue to be raised about the functionality of RBCs used for transfusion. In partial answer, many retrospective studies have concluded that blood transfusion, particularly with older units, puts patients at an increased risk for complications. Despite most of the evidence weighing on the side of older units increasing the likelihood of adverse events, some critics have reservations about premature conclusions from observational studies on patients who, despite sharing similar diagnoses, were not consistently compared to untransfused controls. Furthermore, they point out that transfusion policies were not always identical during the periods under review. The limitations to drawing firm conclusions prompted the author of a recent, rigorous meta-analysis to suggest that the issue is at “equipoise.”10 Opinion is, however, not at equipoise, as evidenced by the emphatic opinion of the authors of another meta-analysis that “older stored blood is associated with significantly increased risk of death.”11

EDITORIAL

The answers to questions about the contribution of RBC storage age to posttransfusion morbidity and mortality might come from prospective, randomized clinical trials (RCTs) currently investigating a number of classes of patients, including those undergoing cardiac surgery, premature infants, and individuals admitted to intensive care units. At the time of this editorial, preliminary evidence from two of these studies did not show benefit to fresher blood. In a double-blind RCT, outcomes in premature infants were not improved by the use of fresher blood.12 In another pilot trial, similarly double blinded, randomized, and controlled, comparing fresher and older stored RBCs for critically ill and cardiac surgery patients, the investigators concluded that there was “insufficient evidence” to encourage the use of RBCs with a shorter storage time.13 If, however, subsequent reports confirm the superiority of fresher RBCs for certain categories of patients, managers at both blood centers and hospitals will need to reconsider the standard practices that govern how they manage their inventories. Given extensive literature, elsewhere, on inventory management, it is surprising that the discipline has gained relatively few advocates in blood banking. That is not to say the topic has been ignored entirely. A publication in TRANSFUSION in 1973 from authors at the Connecticut Red Cross Blood program described effective changes in distribution policy from their central inventory. Whereas the previous policy had been to ship the oldest units to hospitals, they proposed that fresher units “would be more acceptable for massive transfusions and potentially could be used in bypass operations.” Given the RCTs under way today, their remarks were prophetic. While their goal was to improve outdating, which they reduced from 11.9% to 9.2%, they emphasized the importance of “distributing blood on a date closer to its date of collection.”14 Blood bankers’ delayed interest in modernizing inventory management could be because the currently popular industrial approaches, such as just-in-time strategies, are ill-suited for both blood provider and hospital stocks of RBCs. Just-in-time, an outgrowth of queuing theory, is successful when costs are contained by maintaining smaller stocks and orders are met with a time delay that is reduced to a minimum. Given blood bankers’ experiences with surges in demand, plentiful inventories rather than minimal inventories are preferred, since any queue, such as an accumulation of transfusion orders as a result of a delay in restocking, is unacceptable. A recent scholarly review of supply chain management of blood products by authors at the Catholic University in Leuven, Belgium, served as a reminder that queue theory applications are not the only source of guidance for blood bankers.15 Blood bank RBCs are similar to drugs and also photographic films in that all belong to a perishable inventory. From an industry point of view, there are two

classes of perishability, fixed lifetime and random lifetime. While it is tempting to regard all RBCs as having a fixed storage lifetime, determined by their anticoagulant solution, that may not be the case with evidence emerging that some donors store better than others. This consideration could be further complicated if, for any category of patient requiring fresher units, some RBCs in hospital inventory could be regarded as perished after only 7 or 10 days of storage. Although these possibilities point to the need for a more sophisticated, and possibly costly, approach, blood bankers should not be discouraged by the prospect. Some investigators have argued that greater efficiency does not have to depend on “the adoption of more advanced and complex inventory management models.”16 They argued for well-trained staff, regular review of target stock levels, shared knowledge of provider and user inventories, diligent attention to first-in and first-out policies and electronic cross-matching. A recent international forum17 on inventory management was, in part, provoked by increasing concern for whether consideration should be given to the age of RBCs at the time of transfusion. The report, which included opinions from participants in some 30 countries, covered a number of topics, including ideal inventory levels, the age of RBCs both at distribution to hospitals and at transfusion, and integration between the provider and the user. The closest the group came to consensus was with regard to inventory management in that “first-in first-out” prevailed, except for a small group of patients earning “last-in first-out” candidacy. Intrauterine transfusion recipients and neonates were most often in this group. There was collaboration between provider and hospital when the providers were also responsible for the hospital transfusion service, but only a few other services were integrated; the New Zealand Blood Service, the Hong Kong Red Cross Blood Transfusion Service, and the Blood Services Group in Singapore were among them. The age of delivery of blood to the hospital ranged between 5 and 21 days and, in general, hospitals’ goal inventories were 5 to 7 days. In this issue of TRANSFUSION, Dzik and colleagues18 report, against a broad background of international experience, on the effects that reduced expiration dates for RBCs would have on hospital blood banking inventory management and maintenance. Their analyses are timely. If there is an increased risk for morbidity and mortality in patients transfused with older blood then, depending on the size of the categories of deserving patient, major replanning will be an imperative for both blood providers and hospitals. Much of this planning will have to be directed toward inventory management at both sites and its success will in part depend on the very integration between the two sites that the international forum found lacking. Volume 53, December 2013 TRANSFUSION

3033

EDITORIAL

A recent editorial in TRANSFUSION was entitled “Old blood bad? Either the biggest issue in transfusion medicine or a nonevent.”19 Even if subsequent studies do confirm that the pendulum has swung to the nonevent side, there are still cautionary notes. While the best outcome of the RCTs comparing fresh and old blood would be an unambiguous declaration that one of the two conditions is preferable or that there is no difference whatever, such conclusions could prove elusive. A computer simulation that took into account the pace at which the storage lesion developed and the various storage ages of RBCs transfused in the current RCTs prompted the investigator to warn that the studies might be insufficiently powered to provide an answer.20 For other reviewers of the RCT outcomes, the caveats are different. While they respected that the results in the RCT involving transfusion of premature infants were valid for the institutions where the study was performed, they cautioned against assuming that the results could be generalized to other locations where transfusion triggers and storage solutions were different.21 The results of the ongoing RCTs are certainly awaited with keen interest. Inventory managers should not, however, wait to be guided by future publications. Even if there are no hard and fast answers, such is the primacy of the precautionary principle that evidence-based practice could be trumped. Some clinicians may give weight exclusively to the observational, retrospective studies and opt for fresher RBCs regardless of negative outcomes in RCTs. Those who have urged closer collaboration between blood provider and hospital blood banks, and not exclusively in anticipation of shelf life becoming a consideration in ordering RBCs, should persist.16,22 A closer relationship could promote efficiencies, enhance patient safety, reduce outdating, improve availability, and facilitate benchmarking between hospitals.23 The article coauthored by Dzik and others from the Biomedical Excellence for Safer Transfusion Collaborative identifies clearly the factors that determine age of transfused RBCs and since neither blood providers nor blood users can control all of the factors, collaboration is imperative if inventory management is to keep pace with the sophistication demanded by current transfusion practice.

CONFLICT OF INTEREST The author reports no conflicts of interest or funding sources.

Merlyn H. Sayers, MBBCh, PhD e-mail: [email protected] Carter BloodCare Bedford, TX The University of Texas Southwestern Medical Center Dallas, TX

3034

TRANSFUSION Volume 53, December 2013

REFERENCES 1. Rapoport S. Dimensional, osmotic, and chemical changes of erythrocytes in stored blood. I. Blood preserved in sodium citrate, neutral, and acid citrate-glucose (ACD) mixtures. J Clin Invest 1947;26:591-615. 2. Allison AC, Burn GP. Enzyme activity as a function of age in the human erythrocyte. Br J Haematol 1955;1: 291-303. 3. Beutler E, Wood L. The in vivo regeneration of red cell 2,3diphosphoglyceric acid (DPG) after transfusion of stored blood. J Lab Clin Med 1969;74:300-4. 4. Gabrio B, Finch C, Linde W, et al. Erythrocyte preservation. I. The relation of the storage lesion to in vivo erythrocyte senescence. J Clin Invest 1954;33:242-6. 5. Gabrio B, Finch C, Stevens A. Erythrocyte preservation. II. A study of extra-erythrocyte factors in the storage of blood in acid-citrate-dextrose. J Clin Invest 1954;33:247-51. 6. Bracey A, Klein H, Chambers S, et al. Ex vivo selective isolation of young red blood cells using the IBM-2991 cell washer. Blood 1983;61:1058-71. 7. Kim-Shapiro DB, Lee J, Gladwin MT. Storage lesion: role of red cell breakdown. Transfusion 2011;51:844-51. 8. Weinberg JA, Barnum SR, Patel RP. Red blood cell age and potentiation of transfusion-related pathology in trauma patients. Transfusion 2011;51:867-73. 9. Jy W, Ricci M, Shariatmadar S, et al. Microparticles in stored red blood cells as potential mediators of transfusion complications. Transfusion 2011;51:886-93. 10. Vamvakas EC. Meta-analysis of clinical studies of purported deleterious effects of “old” (versus “fresh”) red blood cells: are we at equipoise? Transfusion 2010;50:600-10. 11. Wang D, Sun J, Solomon SB, et al. Transfusion of older stored blood and risk of death: a meta-analysis. Transfusion 2012;52:1184-95. 12. Fergusson D, Hébert P, Hogan D, et al. Effect of fresh red blood cell transfusions on clinical outcomes in premature, very low-birth-weight infants. JAMA 2012;308:1443-51. 13. Hébert P, Chin-Yee I, Fergusson D, et al. A pilot trial evaluating the clinical effects of prolonged storage of red cells. Anesth Analg 2005;100:1433-8. 14. Katz AJ, Morse EE. Distribution of fresher blood in a statewide blood program. Transfusion 1973;13:324-7. 15. Beliën J, Forcé H. Supply chain management of blood products: a literature review. 2010. [cited 2013 Aug 9]. Available from: https://lirias.kuleuven.be/bitstream/ 123456789/318525/1/KBI_1127.pdf 16. Stanger S, Yates N, Wilding R, et al. Blood inventory management: hospital best practice. Transfus Med Rev 2012;26:153-63. 17. Devine DV, Sher GD, Reesink HW, et al. Inventory management. Vox Sang 2010;98:e295-e363. 18. Dzik WH, Beckman N, Murphy MF, et al. Factors affecting red blood cell storage age at the time of transfusion. Transfusion 2013;53:3110-9.

EDITORIAL

19. Warkentin TE, Eikelboom JW. Old blood bad? Either the biggest issue in transfusion medicine or a nonevent. Transfusion 2012;52:1165-7. 20. Pereira A. Will clinical studies elucidate the connection between the length of storage of transfused red blood cells and clinical outcomes? An analysis based on the simulation of randomized controlled trials. Transfusion 2013;53: 34-40.

21. Patel RM, Josephson CD. Storage age of red blood cells for transfusion of premature infants. JAMA 2013;309: 544-5. 22. Sayers M, Centilli J. What if shelf life becomes a consideration in ordering red blood cells? Transfusion 2012;52: 201-6. 23. Chapman J. Unlocking the essentials of effective blood inventory management. Transfusion 2007;47:190S-6S.

Volume 53, December 2013 TRANSFUSION

3035

Fresh blood or old blood? How shall we manage the inventories?

Fresh blood or old blood? How shall we manage the inventories? - PDF Download Free
50KB Sizes 0 Downloads 0 Views