Can J Anesth/J Can Anesth DOI 10.1007/s12630-013-0106-5
SPECIAL ARTICLE
From the Journal archives: The red blood cell storage lesion: past, present, and future Keyvan Karkouti, MD
Received: 23 October 2013 / Accepted: 19 December 2013 Canadian Anesthesiologists’ Society 2014
Editors’ Note: Classics Revisited Key Articles from the Canadian Journal of Anesthesia Archives: 1954-2013 As part of the Journal’s 60th anniversary Diamond Jubilee Celebration, a number of seminal articles from the Journal archives are highlighted in the Journal’s 61st printed volume and online at: www.springer.com/12630. The following article was selected on the basis of its novelty at the time of publication, its scientific merit, and its overall importance to clinical practice: Purdy FR, Tweeddale MG, Merrick PM. Association of mortality with age of blood transfused in septic ICU patients. Can J Anaesth 1997; 44: 1256-61. Dr. Keyvan Karkouti provides expert commentary on the historical significance of this article questioning the safety of transfusing red blood cells nearing the end of their 42 day shelf life. Hilary P. Grocott MD, Editor-in-Chief Donald R. Miller MD, Former Editor-in-Chief
Purpose This retrospective observational study was performed to determine if the age of transfused units of red blood cells (RBCs) was related to mortality. The study included 31 transfused patients admitted to the intensive care unit during 1992 with severe sepsis (i.e., sepsis associated with organ dysfunction, hypoperfusion, or hypotension). Principal findings Nineteen of 31 patients (61%) died. On average, non-survivors received older RBC units than survivors. In non-survivors, the median age of the units was 24 days (range 7-36 days), whereas the median age in survivors was 21 days (range 5-35 days). Analyzing outcomes according to different age categories revealed that survivors received 85% of units that were less than ten days old, whereas non-survivors received 76% of units that were more than 20 days old. These differences were statistically significant (P \ 0.0001). Conclusions The authors concluded that the duration of storage of RBCs is directly related to the risk of mortality among transfused patients with severe sepsis. Recognizing the limitations of their small retrospective study that did not adjust for confounders, they also stated that further studies are needed to confirm or refute this association.
Article summary Authors Purdy FR, Tweeddale MG, Merrick PM. Citation Can J Anaesth 1997; 44: 1256-61. The past K. Karkouti, MD (&) Department of Anesthesia and Pain Management, Toronto General Hospital, University Health Network, University of Toronto, 200 Elizabeth St. 3EN, Toronto, ON M5G 2C4, Canada e-mail: [email protected] K. Karkouti, MD Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada
A major advance in transfusion medicine within the past century was the development of storage mediums that maintain red blood cell (RBC) functionality and viability during prolonged (currently up to 42 days) cold storage, thereby allowing for the provision of a stable blood supply. At the time of the publication of the study by Purdy et al. in 1997,1 it was well recognized that RBCs undergo a series
123
K. Karkouti
of progressive biochemical and morphological changes during storage that alter their functionality and viability.2 Collectively, these changes have been labelled the RBC storage lesion, but it was not known whether these changes had any deleterious clinical effects. In fact, even though RBC transfusions were (and continue to be) one of the most commonly prescribed medical interventions, this issue was considered neither contentious nor portentous until studies such as that by Purdy et al. raised important questions about the relative safety of transfusing older RBC units to susceptible patients. This lack of attention was well illustrated by the paucity of studies cited by Purdy et al. in support of their hypothesis and findings. One cited study in 23 critically ill patients found an inverse association between the age of transfused RBCs and gastric intramucosal pH as a measure of tissue oxygen delivery;3 these results have not been reproducible by more recent studies.4-6 Two other studies – one observational (reference 3 in the Purdy article) and one pre-clinical (reference 7 in the Purdy article) – seem to have been published only in abstract form. Thus, the primary finding of Purdy et al. – that the duration of storage of transfused RBCs is directly linked to the risk of mortality in critically ill patients – was noteworthy not only for its novelty, but also for highlighting a potentially important clinical issue with major societal implications. If fresh RBCs have clinical advantages over older units, then it would follow that we should limit RBC storage duration to the number of days that would avoid or minimize complications arising from the storage lesion. It is, however, generally recognized that any reduction in the allowable RBC storage duration would severely hamper blood inventory management and cause blood supply problems.
The present The objective of RBC storage is to provide functional and viable RBCs for patients requiring transfusion, and various additives and cold storage have been used to achieve this objective. The difficulty is that stored RBCs continue to be metabolically active and undergo morphological changes that are similar to the process of in vivo aging, with the difference being that all of the biochemical and cellular by-products remain in the supernatant, engulfing the surviving cells. Numerous pre-clinical studies have confirmed that during storage there is a progressive increase in the concentrations of lactate, K?, cytokines, free hemoglobin, and free iron, as well as a decrease in adenosine triphosphate, 2,3-diphosphoglycerate, and S-nitrosohemoglobin.2,7,8 Moreover, recent proteomic studies have shown that RBC membrane integrity is progressively compromised via degradation and
123
aggregation of the band 3 protein, which reduces RBC deformability, increases RBC fragility, and promotes the formation of hemoglobin-laden microvesicles that expose the pro-coagulant phospholipid phosphatidylserine.2,9 Altogether, these changes are thought to be responsible for the long-recognized reductions in RBC functionality and viability that occur as a function of storage duration.10,11 Nevertheless, using an arbitrary threshold of C 70% RBC survival at 24 hr post transfusion as a minimum requirement for considering stored RBCs efficacious and suitable for transfusion,10 the allowable storage period was increased from a maximum of 21 days in the 1940s to the current 42 days. Little consideration was given to whether transfusing better functioning and more viable fresh RBCs has any clinical advantages over transfusing older blood. Even now, the U.S. Food and Drug Administration’s requirement for approving new RBC products is that 24-hr RBC recovery studies must show with 95% confidence that more than 70% of the units will have a 24-hr RBC recovery of[ 75%.A Thus, the inherent presumption in this requirement is that the approximately 25% of nonviable RBCs in every older unit (that are removed from the circulation within one to two hours of transfusion)10-12 are of no clinical consequence when transfused. Since the publication of the study by Purdy et al., however, determining the clinical significance of the RBC storage lesion has become a matter of considerable interest. It has moved beyond the realm of pre-clinical studies to become the focus of numerous clinical studies and commentaries, no less than five recent (since 2009) systematic reviews,13-17 and three relatively large multicentre randomized trials, two of which are currently ongoing. The systematic reviews considered 21-27 of the clinical studies, and all but one of the reviews concluded that the studies did not support the hypothesis that transfusion of older RBCs is worse than that of fresh RBCs. The review by Wang et al. was the only one that found a significant association between transfusion of older RBCs and mortality,17 but this review included several studies that are ‘‘evidently confounded’’.16 Despite the conclusions of these reviews, no firm conclusions can be drawn from existing studies owing to important limitations in their design or analyses. One recently published double-blinded randomized controlled trial (hence not included in these reviews) that included 377 premature infants found no difference in any of the measured outcomes among those who received fresh RBCs [B seven days old as stated by protocol; mean 5.1 (SD 2.0) days in the trial] vs older RBCs [standard practice as stated by protocol; mean 14.6 (SD 8.3) days in the trial].18 It must be pointed out, however, that this trial was limited to A Blood Products Advisory Committee. Information available from URL: http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4355B1_1). htm (accessed October 20, 2013).
Key article from the journal archives
premature infants, limiting its external generalizability, and the standard practice arm still received relatively fresh blood; only 12 infants received RBCs that were exclusively more than 14 days old.18 There is also one randomized trial that has been recently completed, and two others that are in progress at this time. The Age of Blood Evaluation Study (ABLE; ISRCTN44878718), which has just been completed, planned on randomizing 2,510 intensive care unit patients to receive either fresh RBCs (B seven days old) or older RBCs (standard blood bank procedure of using the oldest units first, irrespective of the age). The primary outcome was 90day mortality; the results of this study have not yet been reported. The Red Cell Storage Duration Study (RECESS; NCT00991341) is randomizing 1,696 cardiac surgery patients to either fresh RBCs (\ 11 days old) or older RBCs ([ 20 days old). The primary outcome is a change from baseline in the multi-organ dysfunction score at seven days postoperatively. The Standard Issue Transfusion Versus Fresher Red Blood Cell Use in Intensive Care (TRANSFUSE; NCT01638416) is randomizing 5,000 intensive care unit patients to oldest vs freshest available RBCs, with 90-day mortality being the primary outcome. While these studies are substantially more robust than existing studies, their ability in detecting the potential harms of older RBCs is limited by the age distribution of available RBCs at the study sites, such that very few patients will receive RBCs that are nearing the end of their shelf life, which is when they are most likely to be harmful to the recipient.19
duration is based on post-transfusion viability criteria that seem to be almost purely arbitrary. As early as 1947, Ross observed that the ‘‘loss of viability of stored erythrocytes proceeds at a very constant rate in blood stored in any given preservative’’, and ‘‘in adopting the arbitrary value of 70% post-transfusion survival as a minimum requirement for satisfactory transfusion properties, we do not wish to imply that blood providing cells of this viability is as satisfactory as blood in which a greater percentage or all of the cells are viable.’’10 Then again in 1999, Hogman and Meryman stated that, ‘‘This criterion, which focuses on the proportion of RBCs still circulating, tends to distract attention from the converse that, in a unit of stored RBCs nearing the end of its shelf life, 25% of the cells are not circulating and must be removed from the circulation via the reticuloendothelial system. Assuming that the average unit contains 1.5 9 1012 RBCs, a four-unit transfusion will contain this number of nonviable cells to be dealt with by a mere 1011 phagocytes, a possible basis for at least a transient decrease in the immune system.’’ They go on to state, ‘‘It seems curious that more emphasis has not been placed on the quality and the clinical benefits of a transfusion as a function of storage duration.’’2 While there is now more emphasis on this critically important issue, we are in many ways no closer to the answer than we were in 1999 or even in 1947. It is time to redouble our efforts in determining whether transfusing older RBCs, particularly those that are nearing the end of their 42-day shelf life, is safe for our patients.
The future
Key points
Although much has been learned about the RBC storage lesion since the study by Purdy et al. was published, several fundamental questions remain unanswered. What is the temporal pattern of the changes that RBCs undergo during storage, and at what point do they become clinically significant? Which changes are clinically important, and what is their mechanism of injury? Does transfusion of older RBCs affect all patients similarly, or are there conditions or clinical situations that predispose patients to their potential harmful effects? To definitively answer these questions, randomized controlled trials that are adequately powered to investigate the relevant outcomes in susceptible patient groups will be required, but further pre-clinical and observational studies must first be completed to inform the proper design of such trials. The above list does not include another important question – Does the storage age of RBCs matter? It has been clearly illustrated but rarely factually stated that it does matter, which is why maximum allowable storage duration exists. The problem is that the maximum storage
•
•
•
•
Modern storage mediums maintain viability of RBCs when cold-stored for up to 42 days, but the RBCs and the storage medium itself undergo a series of progressive changes that may have deleterious effects in transfused patients. The study by Purdy et al. was one of the first to observe an association between the duration of RBC storage and increased risk of mortality in critically ill patients. Since then, numerous studies (but not all) have found that patients who receive older blood have worse outcomes than those who receive fresh blood, but owing to important limitations in study design and analysis, their findings are inconclusive. Large multicentre trials are underway to elucidate the clinical significance of the storage-related changes, but they are unlikely to provide a definitive answer due to insufficient power and not targeting susceptible patients. Recent pre-clinical studies have advanced our understanding of the storage lesion and potential
123
K. Karkouti
mechanisms of injury in transfused patients. Ultimately, data from multiple sources – including from mechanistic pre-clinical studies as well as observational and randomized trials – will be required to elucidate the clinical significance of the RBC storage lesion and to inform clinical practice. Conflicts of interest
None.
Funding sources K. Karkouti is supported in part by a merit award from the Department of Anesthesia, University of Toronto.
References 1. Purdy FR, Tweeddale MG, Merrick PM. Association of mortality with age of blood transfused in septic ICU patients. Can J Anaesth 1997; 44: 1256-61. 2. Hogman CF, Meryman HT. Storage parameters affecting red blood cell survival and function after transfusion. Transfus Med Rev 1999; 13: 275-96. 3. Marik PE, Sibbald WJ. Effect of stored-blood transfusion on oxygen delivery in patients with sepsis. JAMA 1993; 269: 3024-9. 4. Fernandes CJ Jr, Akamine N, De Marco FV, De Souza JA, Lagudis S, Knobel E. Red blood cell transfusion does not increase oxygen consumption in critically ill septic patients. Crit Care 2001; 5: 362-7. 5. Walsh TS, McArdle F, McLellan SA, et al. Does the storage time of transfused red blood cells influence regional or global indexes of tissue oxygenation in anemic critically ill patients? Crit Care Med 2004; 32: 364-71. 6. Smith MJ, Stiefel MF, Magge S, et al. Packed red blood cell transfusion increases local cerebral oxygenation. Crit Care Med 2005; 33: 1104-8. 7. Donadee C, Raat NJ, Kanias T, et al. Nitric oxide scavenging by red blood cell microparticles and cell-free hemoglobin as a mechanism for the red cell storage lesion. Circulation 2011; 124: 465-76.
123
8. Bennett-Guerrero E, Veldman TH, Doctor A, et al. Evolution of adverse changes in stored RBCs. Proc Natl Acad Sci USA 2007; 104: 17063-8. 9. Bosman GJ, Werre JM, Willekens FL, Novotny VM. Erythrocyte ageing in vivo and in vitro: structural aspects and implications for transfusion. Transfus Med 2008; 18: 335-47. 10. Ross JF, Finch CA, Peacock WC, Sammons ME. The in vitro preservation and post-transfusion survival of stored blood. J Clin Invest 1947; 26: 687-703. 11. Ebaugh G Jr, Emerson CP, Ross JF. The use of radioactive chromium 51 as an erythrocyte tagging agent for the determination or red cell survival in vivo. J Clin Invest 1953; 32: 1260-76. 12. Luten M, Roerdinkholder-Stoelwinder B, Schaap NP, de Grip WJ, Bos HJ, Bosman GJ. Survival of red blood cells after transfusion: A comparison between red cells concentrates of different storage periods. Transfusion 2008; 48: 1478-85. 13. Zimrin AB, Hess JR. Current issues relating to the transfusion of stored red blood cells. Vox Sang. 2009; 96: 93-103. 14. Lelubre C, Piagnerelli M, Vincent JL. Association between duration of storage of transfused red blood cells and morbidity and mortality in adult patients: myth or reality? Transfusion 2009; 49: 1384-94. 15. Triulzi DJ, Yazer MH. Clinical studies of the effect of blood storage on patient outcomes. Transfus Apher. Sci 2010; 43: 95106. 16. Vamvakas EC. Meta-analysis of clinical studies of the purported deleterious effects of ‘‘old’’ (versus ‘‘fresh’’) red blood cells: are we at equipoise? Transfusion 2010; 50: 600-10. 17. Wang D, Sun J, Solomon SB, Klein HG, Natanson C. Transfusion of older stored blood and risk of death: a meta-analysis. Transfusion 2012; 52: 1184-95. 18. Fergusson DA, Hebert P, Hogan DL, et al. Effect of fresh red blood cell transfusions on clinical outcomes in premature, very low-birth-weight infants: the ARIPI randomized trial. JAMA 2012; 308: 1443-51. 19. 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.
SPECIAL ARTICLE
From the Journal archives: The red blood cell storage lesion: past, present, and future Keyvan Karkouti, MD
Received: 23 October 2013 / Accepted: 19 December 2013 Canadian Anesthesiologists’ Society 2014
Editors’ Note: Classics Revisited Key Articles from the Canadian Journal of Anesthesia Archives: 1954-2013 As part of the Journal’s 60th anniversary Diamond Jubilee Celebration, a number of seminal articles from the Journal archives are highlighted in the Journal’s 61st printed volume and online at: www.springer.com/12630. The following article was selected on the basis of its novelty at the time of publication, its scientific merit, and its overall importance to clinical practice: Purdy FR, Tweeddale MG, Merrick PM. Association of mortality with age of blood transfused in septic ICU patients. Can J Anaesth 1997; 44: 1256-61. Dr. Keyvan Karkouti provides expert commentary on the historical significance of this article questioning the safety of transfusing red blood cells nearing the end of their 42 day shelf life. Hilary P. Grocott MD, Editor-in-Chief Donald R. Miller MD, Former Editor-in-Chief
Purpose This retrospective observational study was performed to determine if the age of transfused units of red blood cells (RBCs) was related to mortality. The study included 31 transfused patients admitted to the intensive care unit during 1992 with severe sepsis (i.e., sepsis associated with organ dysfunction, hypoperfusion, or hypotension). Principal findings Nineteen of 31 patients (61%) died. On average, non-survivors received older RBC units than survivors. In non-survivors, the median age of the units was 24 days (range 7-36 days), whereas the median age in survivors was 21 days (range 5-35 days). Analyzing outcomes according to different age categories revealed that survivors received 85% of units that were less than ten days old, whereas non-survivors received 76% of units that were more than 20 days old. These differences were statistically significant (P \ 0.0001). Conclusions The authors concluded that the duration of storage of RBCs is directly related to the risk of mortality among transfused patients with severe sepsis. Recognizing the limitations of their small retrospective study that did not adjust for confounders, they also stated that further studies are needed to confirm or refute this association.
Article summary Authors Purdy FR, Tweeddale MG, Merrick PM. Citation Can J Anaesth 1997; 44: 1256-61. The past K. Karkouti, MD (&) Department of Anesthesia and Pain Management, Toronto General Hospital, University Health Network, University of Toronto, 200 Elizabeth St. 3EN, Toronto, ON M5G 2C4, Canada e-mail: [email protected] K. Karkouti, MD Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada
A major advance in transfusion medicine within the past century was the development of storage mediums that maintain red blood cell (RBC) functionality and viability during prolonged (currently up to 42 days) cold storage, thereby allowing for the provision of a stable blood supply. At the time of the publication of the study by Purdy et al. in 1997,1 it was well recognized that RBCs undergo a series
123
K. Karkouti
of progressive biochemical and morphological changes during storage that alter their functionality and viability.2 Collectively, these changes have been labelled the RBC storage lesion, but it was not known whether these changes had any deleterious clinical effects. In fact, even though RBC transfusions were (and continue to be) one of the most commonly prescribed medical interventions, this issue was considered neither contentious nor portentous until studies such as that by Purdy et al. raised important questions about the relative safety of transfusing older RBC units to susceptible patients. This lack of attention was well illustrated by the paucity of studies cited by Purdy et al. in support of their hypothesis and findings. One cited study in 23 critically ill patients found an inverse association between the age of transfused RBCs and gastric intramucosal pH as a measure of tissue oxygen delivery;3 these results have not been reproducible by more recent studies.4-6 Two other studies – one observational (reference 3 in the Purdy article) and one pre-clinical (reference 7 in the Purdy article) – seem to have been published only in abstract form. Thus, the primary finding of Purdy et al. – that the duration of storage of transfused RBCs is directly linked to the risk of mortality in critically ill patients – was noteworthy not only for its novelty, but also for highlighting a potentially important clinical issue with major societal implications. If fresh RBCs have clinical advantages over older units, then it would follow that we should limit RBC storage duration to the number of days that would avoid or minimize complications arising from the storage lesion. It is, however, generally recognized that any reduction in the allowable RBC storage duration would severely hamper blood inventory management and cause blood supply problems.
The present The objective of RBC storage is to provide functional and viable RBCs for patients requiring transfusion, and various additives and cold storage have been used to achieve this objective. The difficulty is that stored RBCs continue to be metabolically active and undergo morphological changes that are similar to the process of in vivo aging, with the difference being that all of the biochemical and cellular by-products remain in the supernatant, engulfing the surviving cells. Numerous pre-clinical studies have confirmed that during storage there is a progressive increase in the concentrations of lactate, K?, cytokines, free hemoglobin, and free iron, as well as a decrease in adenosine triphosphate, 2,3-diphosphoglycerate, and S-nitrosohemoglobin.2,7,8 Moreover, recent proteomic studies have shown that RBC membrane integrity is progressively compromised via degradation and
123
aggregation of the band 3 protein, which reduces RBC deformability, increases RBC fragility, and promotes the formation of hemoglobin-laden microvesicles that expose the pro-coagulant phospholipid phosphatidylserine.2,9 Altogether, these changes are thought to be responsible for the long-recognized reductions in RBC functionality and viability that occur as a function of storage duration.10,11 Nevertheless, using an arbitrary threshold of C 70% RBC survival at 24 hr post transfusion as a minimum requirement for considering stored RBCs efficacious and suitable for transfusion,10 the allowable storage period was increased from a maximum of 21 days in the 1940s to the current 42 days. Little consideration was given to whether transfusing better functioning and more viable fresh RBCs has any clinical advantages over transfusing older blood. Even now, the U.S. Food and Drug Administration’s requirement for approving new RBC products is that 24-hr RBC recovery studies must show with 95% confidence that more than 70% of the units will have a 24-hr RBC recovery of[ 75%.A Thus, the inherent presumption in this requirement is that the approximately 25% of nonviable RBCs in every older unit (that are removed from the circulation within one to two hours of transfusion)10-12 are of no clinical consequence when transfused. Since the publication of the study by Purdy et al., however, determining the clinical significance of the RBC storage lesion has become a matter of considerable interest. It has moved beyond the realm of pre-clinical studies to become the focus of numerous clinical studies and commentaries, no less than five recent (since 2009) systematic reviews,13-17 and three relatively large multicentre randomized trials, two of which are currently ongoing. The systematic reviews considered 21-27 of the clinical studies, and all but one of the reviews concluded that the studies did not support the hypothesis that transfusion of older RBCs is worse than that of fresh RBCs. The review by Wang et al. was the only one that found a significant association between transfusion of older RBCs and mortality,17 but this review included several studies that are ‘‘evidently confounded’’.16 Despite the conclusions of these reviews, no firm conclusions can be drawn from existing studies owing to important limitations in their design or analyses. One recently published double-blinded randomized controlled trial (hence not included in these reviews) that included 377 premature infants found no difference in any of the measured outcomes among those who received fresh RBCs [B seven days old as stated by protocol; mean 5.1 (SD 2.0) days in the trial] vs older RBCs [standard practice as stated by protocol; mean 14.6 (SD 8.3) days in the trial].18 It must be pointed out, however, that this trial was limited to A Blood Products Advisory Committee. Information available from URL: http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4355B1_1). htm (accessed October 20, 2013).
Key article from the journal archives
premature infants, limiting its external generalizability, and the standard practice arm still received relatively fresh blood; only 12 infants received RBCs that were exclusively more than 14 days old.18 There is also one randomized trial that has been recently completed, and two others that are in progress at this time. The Age of Blood Evaluation Study (ABLE; ISRCTN44878718), which has just been completed, planned on randomizing 2,510 intensive care unit patients to receive either fresh RBCs (B seven days old) or older RBCs (standard blood bank procedure of using the oldest units first, irrespective of the age). The primary outcome was 90day mortality; the results of this study have not yet been reported. The Red Cell Storage Duration Study (RECESS; NCT00991341) is randomizing 1,696 cardiac surgery patients to either fresh RBCs (\ 11 days old) or older RBCs ([ 20 days old). The primary outcome is a change from baseline in the multi-organ dysfunction score at seven days postoperatively. The Standard Issue Transfusion Versus Fresher Red Blood Cell Use in Intensive Care (TRANSFUSE; NCT01638416) is randomizing 5,000 intensive care unit patients to oldest vs freshest available RBCs, with 90-day mortality being the primary outcome. While these studies are substantially more robust than existing studies, their ability in detecting the potential harms of older RBCs is limited by the age distribution of available RBCs at the study sites, such that very few patients will receive RBCs that are nearing the end of their shelf life, which is when they are most likely to be harmful to the recipient.19
duration is based on post-transfusion viability criteria that seem to be almost purely arbitrary. As early as 1947, Ross observed that the ‘‘loss of viability of stored erythrocytes proceeds at a very constant rate in blood stored in any given preservative’’, and ‘‘in adopting the arbitrary value of 70% post-transfusion survival as a minimum requirement for satisfactory transfusion properties, we do not wish to imply that blood providing cells of this viability is as satisfactory as blood in which a greater percentage or all of the cells are viable.’’10 Then again in 1999, Hogman and Meryman stated that, ‘‘This criterion, which focuses on the proportion of RBCs still circulating, tends to distract attention from the converse that, in a unit of stored RBCs nearing the end of its shelf life, 25% of the cells are not circulating and must be removed from the circulation via the reticuloendothelial system. Assuming that the average unit contains 1.5 9 1012 RBCs, a four-unit transfusion will contain this number of nonviable cells to be dealt with by a mere 1011 phagocytes, a possible basis for at least a transient decrease in the immune system.’’ They go on to state, ‘‘It seems curious that more emphasis has not been placed on the quality and the clinical benefits of a transfusion as a function of storage duration.’’2 While there is now more emphasis on this critically important issue, we are in many ways no closer to the answer than we were in 1999 or even in 1947. It is time to redouble our efforts in determining whether transfusing older RBCs, particularly those that are nearing the end of their 42-day shelf life, is safe for our patients.
The future
Key points
Although much has been learned about the RBC storage lesion since the study by Purdy et al. was published, several fundamental questions remain unanswered. What is the temporal pattern of the changes that RBCs undergo during storage, and at what point do they become clinically significant? Which changes are clinically important, and what is their mechanism of injury? Does transfusion of older RBCs affect all patients similarly, or are there conditions or clinical situations that predispose patients to their potential harmful effects? To definitively answer these questions, randomized controlled trials that are adequately powered to investigate the relevant outcomes in susceptible patient groups will be required, but further pre-clinical and observational studies must first be completed to inform the proper design of such trials. The above list does not include another important question – Does the storage age of RBCs matter? It has been clearly illustrated but rarely factually stated that it does matter, which is why maximum allowable storage duration exists. The problem is that the maximum storage
•
•
•
•
Modern storage mediums maintain viability of RBCs when cold-stored for up to 42 days, but the RBCs and the storage medium itself undergo a series of progressive changes that may have deleterious effects in transfused patients. The study by Purdy et al. was one of the first to observe an association between the duration of RBC storage and increased risk of mortality in critically ill patients. Since then, numerous studies (but not all) have found that patients who receive older blood have worse outcomes than those who receive fresh blood, but owing to important limitations in study design and analysis, their findings are inconclusive. Large multicentre trials are underway to elucidate the clinical significance of the storage-related changes, but they are unlikely to provide a definitive answer due to insufficient power and not targeting susceptible patients. Recent pre-clinical studies have advanced our understanding of the storage lesion and potential
123
K. Karkouti
mechanisms of injury in transfused patients. Ultimately, data from multiple sources – including from mechanistic pre-clinical studies as well as observational and randomized trials – will be required to elucidate the clinical significance of the RBC storage lesion and to inform clinical practice. Conflicts of interest
None.
Funding sources K. Karkouti is supported in part by a merit award from the Department of Anesthesia, University of Toronto.
References 1. Purdy FR, Tweeddale MG, Merrick PM. Association of mortality with age of blood transfused in septic ICU patients. Can J Anaesth 1997; 44: 1256-61. 2. Hogman CF, Meryman HT. Storage parameters affecting red blood cell survival and function after transfusion. Transfus Med Rev 1999; 13: 275-96. 3. Marik PE, Sibbald WJ. Effect of stored-blood transfusion on oxygen delivery in patients with sepsis. JAMA 1993; 269: 3024-9. 4. Fernandes CJ Jr, Akamine N, De Marco FV, De Souza JA, Lagudis S, Knobel E. Red blood cell transfusion does not increase oxygen consumption in critically ill septic patients. Crit Care 2001; 5: 362-7. 5. Walsh TS, McArdle F, McLellan SA, et al. Does the storage time of transfused red blood cells influence regional or global indexes of tissue oxygenation in anemic critically ill patients? Crit Care Med 2004; 32: 364-71. 6. Smith MJ, Stiefel MF, Magge S, et al. Packed red blood cell transfusion increases local cerebral oxygenation. Crit Care Med 2005; 33: 1104-8. 7. Donadee C, Raat NJ, Kanias T, et al. Nitric oxide scavenging by red blood cell microparticles and cell-free hemoglobin as a mechanism for the red cell storage lesion. Circulation 2011; 124: 465-76.
123
8. Bennett-Guerrero E, Veldman TH, Doctor A, et al. Evolution of adverse changes in stored RBCs. Proc Natl Acad Sci USA 2007; 104: 17063-8. 9. Bosman GJ, Werre JM, Willekens FL, Novotny VM. Erythrocyte ageing in vivo and in vitro: structural aspects and implications for transfusion. Transfus Med 2008; 18: 335-47. 10. Ross JF, Finch CA, Peacock WC, Sammons ME. The in vitro preservation and post-transfusion survival of stored blood. J Clin Invest 1947; 26: 687-703. 11. Ebaugh G Jr, Emerson CP, Ross JF. The use of radioactive chromium 51 as an erythrocyte tagging agent for the determination or red cell survival in vivo. J Clin Invest 1953; 32: 1260-76. 12. Luten M, Roerdinkholder-Stoelwinder B, Schaap NP, de Grip WJ, Bos HJ, Bosman GJ. Survival of red blood cells after transfusion: A comparison between red cells concentrates of different storage periods. Transfusion 2008; 48: 1478-85. 13. Zimrin AB, Hess JR. Current issues relating to the transfusion of stored red blood cells. Vox Sang. 2009; 96: 93-103. 14. Lelubre C, Piagnerelli M, Vincent JL. Association between duration of storage of transfused red blood cells and morbidity and mortality in adult patients: myth or reality? Transfusion 2009; 49: 1384-94. 15. Triulzi DJ, Yazer MH. Clinical studies of the effect of blood storage on patient outcomes. Transfus Apher. Sci 2010; 43: 95106. 16. Vamvakas EC. Meta-analysis of clinical studies of the purported deleterious effects of ‘‘old’’ (versus ‘‘fresh’’) red blood cells: are we at equipoise? Transfusion 2010; 50: 600-10. 17. Wang D, Sun J, Solomon SB, Klein HG, Natanson C. Transfusion of older stored blood and risk of death: a meta-analysis. Transfusion 2012; 52: 1184-95. 18. Fergusson DA, Hebert P, Hogan DL, et al. Effect of fresh red blood cell transfusions on clinical outcomes in premature, very low-birth-weight infants: the ARIPI randomized trial. JAMA 2012; 308: 1443-51. 19. 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.
