613807 research-article2015
SCVXXX10.1177/1089253215613807Seminars in Cardiothoracic and Vascular AnesthesiaVarghese and Jhang
Article
Blood Conservation in Cardiac Surgery: In Need of a Transfusion Revolution
Seminars in Cardiothoracic and Vascular Anesthesia 2015, Vol. 19(4) 293–301 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1089253215613807 scv.sagepub.com
Robin Varghese, MD1, and Jeffrey Jhang, MD1
Abstract Blood transfusion is the most common procedure in cardiac surgery. Increasing evidence exists that excess transfusions are harmful to patients. Transfusion reactions and complications, including infection, immune modulation, and lung injury, are known complications but underreported; hence, their significance is often disregarded. Furthermore, a number of randomized trials have shown that a restrictive transfusion strategy is equal to if not better than a liberal transfusion strategy. Despite the evidence for the use of restrictive transfusion triggers, its dissemination in the cardiac surgical community has met with resistance. In this review, we outline the risks of transfusion, compare restrictive and liberal transfusion strategies in cardiac surgery, and finally outline perioperative interventions to minimize transfusion in the cardiac surgical patient. Keywords blood loss, cardiac surgery, postoperative care, cardiopulmonary bypass, antifibrinolytics
Introduction Transfusion is the most common procedure performed in hospitals with departments of surgery accounting for a high percentage (20%) of the 13.8 million units of whole blood and red cells of all types transfused in the United States. In addition, a total of 2.2 million units of platelets, 3.9 million units of plasma, and 1.1 million units of cryoprecipitate were transfused in the United States according to the most recent available data from 2011.1 In patients with cardiovascular disease, a low preoperative hemoglobin (Hgb) or a significant amount of perioperative bleeding is associated with increased morbidity and mortality when compared with patients without cardiovascular risk.2 In cardiac surgery, an intraoperative Hgb level below 20% to 22% is associated with an increased risk of adverse outcomes such as stroke, renal failure, prolonged ventilation, and perioperative mortality.3-5 Red cell transfusions can be life saving and are frequently used to restore systemic oxygen carrying capacity and improve myocardial oxygen delivery.6 However, some studies show that transfusion does not improve oxygen consumption.7,8 Furthermore, a significant body of evidence has accumulated establishing that red cell transfusion has either a neutral effect or is an independent risk factor for increased morbidity, mortality, and length of stay. In 2014, there were about 51 000 transfusion reactions, which is a rate of 2.4 per 1000 units transfused.1 Other national hemovigilance programs report the rate of transfusion reactions to
be of the same order of magnitude.9 However, these numbers should be interpreted with caution because adverse reactions are underestimated as a result of underrecognition and underreporting, so that the actual rate is likely much higher. According to a National Summit of Overuse run by the Joint Commission, transfusion is one of the most overused procedures in medicine. Recently, many medical organizations have published guidelines to reduce unnecessary transfusions such as the British Committee for Standards in Haematology, Society of Critical Care Medicine, Society of Thoracic Surgeons, and AABB (formerly known as the American Association of Blood Banks).10-13 However, these guidelines have had modest success, and there is still significant interinstitutional variability in red cell transfusion practices. For example, a study at 798 sites in the United Kingdom observed that transfusion rates at sites performing coronary artery bypass grafting surgery varied from 7.8% to 92.8%,14 which suggests that education and enforcement of guidelines is necessary. There is a paradox: preoperative/intraoperative anemia is bad for cardiac surgical patient outcomes, and red cell 1
Icahn School of Medicine at Mount Sinai, NY, USA
Corresponding Author: Robin Varghese, Mount Sinai School of Medicine, 1 Gustave Levy Place, Box 1028, New York, NY 10011, USA. Email: [email protected]
Downloaded from scv.sagepub.com by guest on December 9, 2015
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Seminars in Cardiothoracic and Vascular Anesthesia 19(4)
transfusion is life saving and clinically useful in symptomatic patients; however, specific patient populations when transfused at specific Hgb values may not benefit or may be harmed by the transfusion. Therefore, the potential benefits of transfusion must be weighed against the harms of transfusion (an impendent risk factor for morbidity and mortality). In this review, we will examine the harmful effects of transfusions, costs, and finally strategies and their outcomes to minimize transfusions in cardiac surgical patients.
Transfusion-Related Adverse Outcomes Infectious Risk of Transfusion When it comes to blood transfusion, the general public has significant safety concerns about transfusion-transmitted viral infections because of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), but the truth is that the blood banking community has significantly reduced the risk of transfusion-transmitted infections by requiring donor history screening, serological testing, and highly sensitive nucleic acid testing. The approximate residual risk of transmission of HIV is 1 in 2.1 million, HBV is 1 in 1.1 million, HBV is 1 in 1.9 million, and human T-lymphotropic virus is 1 in 3 million.15,16 To help put this in perspective, this risk is of the same order of magnitude as dying by lightning strike or in an airplane crash. However, the blood banking community has not performed as well in reducing the risk of bacterial contamination and noninfectious hazards of transfusion. Bacterial contamination is one of the leading causes of transfusion-related mortality. Platelets are best stored in plasma (or plasma and additive solution) at room temperature (20°C-24°C), which provides optimal conditions for proliferation of bacteria. Therefore, the Food and Drug Administration (FDA) limits the shelf life of platelets to a maximum of 5 days. Unfortunately, platelets are quarantined 2 out of 5 days for bacterial culture readings prior to being released for patient use. Bacteria, predominantly skin flora, can be cultured from single donor apheresis platelet units as frequently as 1 in 1500 to 5000 units, but many of these units test positive before leaving quarantine. The risk of bacterial contamination and clinical sepsis caused by transfusion of a culture-negative platelet unit poses the greatest danger and is thought to affect 1 in 75 000 transfusions.16,17 Contamination of red cell units is less common because skin flora do not optimally grow at 1°C to 6°C, and red cells are not routinely cultured. The recent FDA approval of pathogen-inactivated platelets is a major step in improving the safety of platelets by reducing the infectivity of viral particles and bacteria as well as other nucleic acid–based pathogens. To perform pathogen
inactivation, amotosoralen is added to platelets collected in additive solution, and then the unit is exposed to ultraviolet light to create covalent bonds between the amotosoralen and nucleic acid base pairs, thereby preventing nucleic acid transcription. A related method that is in development includes riboflavin: UV light exposure leads to single-strand breaks. These inactivation methods are anticipated to be marketed for plasma, platelets collected in plasma, and red cells in the near future.17 Other organisms previously not of great focus are now receiving greater attention such as Chagas disease (Trypanosoma cruzi), malaria (Plasmodium spp), babesiosis (Babesia spp), dengue virus, chikungunya virus, and variant Creutzfelt-Jacob disease.
Serious Noninfectious Risks of Transfusion The United Kingdom’s hemovigilance program and the United States Center for Disease Control National Healthcare Safety Network Hemovigilance Module monitor the adverse outcomes associated with transfusion.18 Less-serious reactions such as allergic reactions and febrile nonhemolytic transfusion reactions are the most frequent types of reaction.19 However, the more severe noninfectious transfusion reactions caused the most fatalities out of the 176 fatalities reported to the FDA from 2010 to 2014.20 Transfusion-related acute lung injury (TRALI) accounted for 72 (41%) of the deaths, transfusion-associated circulatory overload (TACO) for 38 (22%), non-ABO hemolytic transfusion reactions for 25 (14%), and bacterial contamination for 15 (8%). TRALI classically presents as the acute (within 6 hours) onset of respiratory distress and hypoxemia after the transfusion of a plasma-containing blood component that resembles an acute respiratory distress (ARDS)-like picture. Other diagnostic criteria include the absence of elevated left atrial pressures, absence of preexisting acute lung injury, and a chest X-ray showing pulmonary infiltrates, classically “white out.” The current understanding of TRALI is that anti-HLA (human leukocyte antigens) or antigranulocyte antibodies in donor plasma activates recipient white blood cells, resulting in pulmonary injury and an ARDS-like clinical picture. In most patients, TRALI is transient, but it can cause significant morbidity and mortality. The risk of TRALI is estimated at 1 in 63 000 transfusions, with a higher incidence in patients who receive components containing the most plasma (ie, plasma > platelets > red cells > cryoprecipitate). Efforts to reduce this risk have focused on reducing plasma collected from individuals immunized against HLA and granulocytes—that is previously pregnant women; the production of an all-male donor plasma inventory has been a very common strategy throughout the United States and the United Kingdom, and testing for HLA antibodies from
Downloaded from scv.sagepub.com by guest on December 9, 2015
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Varghese and Jhang female platelet donors is now increasingly being implemented. These risk mitigations have decreased the number of TRALI cases by nearly 30%. Patients experiencing TACO typically present with dyspnea, orthopnea, or hypoxemia as a result of pulmonary edema, and it occurs in up to 8% of transfusions. Transfusion contributes to positive fluid balance, increased hydrostatic pressure, and the development of pulmonary edema. Elderly patients, pediatric patients, patients with a history of congestive heart failure or on hemodialysis, and women are at the greatest risk. However, patients without these risk factors can also develop TACO. Transfusing units slowly or splitting units into 2 aliquots transfused over a longer period of time, monitoring patients closely, and judiciously administering diuretics may be useful in preventing TACO when higher-risk patients are identified. Although ABO-incompatible transfusions are uncommon, they still account for 13 (8%) of the 176 FDAreported fatalities from 2010 to 2014.20 In the United Kingdom, 10 ABO incompatible transfusions were reported in 2014; there were no deaths, but 1 patients suffered major morbidity, and 9 were not harmed.9 Linden et al21 performed an analysis of errors reported to the New York State Department of Health and estimated that the rate of erroneous red cell administration is 1 in 19 000 units, the rate of ABO-incompatible transfusion is 1 in 38 000 units, and fatal acute hemolytic transfusion reaction is 1 in 1.8 million. The most frequent error leading to a fatality was transfusion to someone other than the intended recipient often because of failure to perform positive identification of the patient or unit. The rate of severe, life-threatening, or fatal error reported to the US hemovigilance program was 17.5 per 100 000 total blood components transfused from 2010 to 2012.18
Transfusion-Associated Immune Modulation Blood transfusions are known to be associated with immune suppression, and this has been known since the early days of transplantation. Overall, studies related to transfusion-related immune modulation have demonstrated that transfusions generally have beneficial to neutral effects on rejection and have minimal negative effects on the outcomes in kidney transplantation.22 In addition, additional reports of adverse effects of transfusion on the recurrence rate of resected colon cancer and postoperative infections have been reported.23,24 The mechanism of this effect has not been elucidated, but it is hypothesized that infusion of foreign antigens or cellular material may induce tolerance or that white cells mediate this effect.25 van de Watering26 has previously demonstrated that transfusion of leukodepleted red blood cells decreased mortality overall and infections in those patients who received more than 3 transfusions when compared with nonleuokodepleted
units. Bilgin et al27 and Wallis et al28 have also demonstrated the same findings of decreased infections and decreased in-hospital mortality with leukodepletion. For this reason, as well as reducing HLA alloimmunization and reducing CMV infection, provision of universally prestorage leukodepleted red cells is a very common practice in blood banks throughout the United States.
The Red Cell Storage Lesion Packed red cells, which can be stored for up to 42 days in additive solution at 1°C to 6°C, undergo biochemical and physical changes during storage that lead to the production of neutrophil-activating bioreactives, production of procoagulant microparticles, promotion of bacterial proliferation by non–transferrin-bound iron, scavenging of nitric oxide by nitrosylation of free Hgb, accumulation of cytokines and chemokines released by white blood cells, activation of the innate immune system, and loss of red cell deformability.29 Observational studies and animal studies have suggested that the age of red cells may explain why red cell transfusions are associated with poorer outcomes. Qu and Triulzi30 have reviewed more than 40 such studies that provide conflicting evidence and have concluded that most of the studies are single-center, retrospective studies that are underpowered and are subject to significant bias. Observational data are likely to be biased because sicker patients tend to receive more red cells and these red cells are more likely to have been stored for a longer term because a first-in first-out (FIFO) is most often used as an inventory management strategy. Therefore, several recent randomized controlled trials (RCTs) have been of tremendous help in establishing the best evidence on whether providing “fresh” red cells improves morbidity and mortality compared with standard blood bank inventory management (ie, FIFO). The effect of red cell storage on premature, low-birthweight neonates was assessed in the Age of Red Blood Cells in Premature Infants (ARIPI) study, which was a double-blind RCT that compared a group that received red cells stored for 7 days or less to a standard blood bank practice. The study did not detect a difference in the primary outcomes of major neonatal morbidities (necrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy, intraventricular hemorrhage) and mortality.31 The Age of Blood Evaluation (ABLE) trial was a RCT conducted at 64 sites in Canada and Europe that enrolled 1219 critically ill patients admitted to intensive care units to receive standard issue (mean = 22.0 ± 8.4 days) versus fresh red cells (mean = 6.1 ± 4.9 days).32 Patients were transfused according to a restrictive strategy (
SCVXXX10.1177/1089253215613807Seminars in Cardiothoracic and Vascular AnesthesiaVarghese and Jhang
Article
Blood Conservation in Cardiac Surgery: In Need of a Transfusion Revolution
Seminars in Cardiothoracic and Vascular Anesthesia 2015, Vol. 19(4) 293–301 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1089253215613807 scv.sagepub.com
Robin Varghese, MD1, and Jeffrey Jhang, MD1
Abstract Blood transfusion is the most common procedure in cardiac surgery. Increasing evidence exists that excess transfusions are harmful to patients. Transfusion reactions and complications, including infection, immune modulation, and lung injury, are known complications but underreported; hence, their significance is often disregarded. Furthermore, a number of randomized trials have shown that a restrictive transfusion strategy is equal to if not better than a liberal transfusion strategy. Despite the evidence for the use of restrictive transfusion triggers, its dissemination in the cardiac surgical community has met with resistance. In this review, we outline the risks of transfusion, compare restrictive and liberal transfusion strategies in cardiac surgery, and finally outline perioperative interventions to minimize transfusion in the cardiac surgical patient. Keywords blood loss, cardiac surgery, postoperative care, cardiopulmonary bypass, antifibrinolytics
Introduction Transfusion is the most common procedure performed in hospitals with departments of surgery accounting for a high percentage (20%) of the 13.8 million units of whole blood and red cells of all types transfused in the United States. In addition, a total of 2.2 million units of platelets, 3.9 million units of plasma, and 1.1 million units of cryoprecipitate were transfused in the United States according to the most recent available data from 2011.1 In patients with cardiovascular disease, a low preoperative hemoglobin (Hgb) or a significant amount of perioperative bleeding is associated with increased morbidity and mortality when compared with patients without cardiovascular risk.2 In cardiac surgery, an intraoperative Hgb level below 20% to 22% is associated with an increased risk of adverse outcomes such as stroke, renal failure, prolonged ventilation, and perioperative mortality.3-5 Red cell transfusions can be life saving and are frequently used to restore systemic oxygen carrying capacity and improve myocardial oxygen delivery.6 However, some studies show that transfusion does not improve oxygen consumption.7,8 Furthermore, a significant body of evidence has accumulated establishing that red cell transfusion has either a neutral effect or is an independent risk factor for increased morbidity, mortality, and length of stay. In 2014, there were about 51 000 transfusion reactions, which is a rate of 2.4 per 1000 units transfused.1 Other national hemovigilance programs report the rate of transfusion reactions to
be of the same order of magnitude.9 However, these numbers should be interpreted with caution because adverse reactions are underestimated as a result of underrecognition and underreporting, so that the actual rate is likely much higher. According to a National Summit of Overuse run by the Joint Commission, transfusion is one of the most overused procedures in medicine. Recently, many medical organizations have published guidelines to reduce unnecessary transfusions such as the British Committee for Standards in Haematology, Society of Critical Care Medicine, Society of Thoracic Surgeons, and AABB (formerly known as the American Association of Blood Banks).10-13 However, these guidelines have had modest success, and there is still significant interinstitutional variability in red cell transfusion practices. For example, a study at 798 sites in the United Kingdom observed that transfusion rates at sites performing coronary artery bypass grafting surgery varied from 7.8% to 92.8%,14 which suggests that education and enforcement of guidelines is necessary. There is a paradox: preoperative/intraoperative anemia is bad for cardiac surgical patient outcomes, and red cell 1
Icahn School of Medicine at Mount Sinai, NY, USA
Corresponding Author: Robin Varghese, Mount Sinai School of Medicine, 1 Gustave Levy Place, Box 1028, New York, NY 10011, USA. Email: [email protected]
Downloaded from scv.sagepub.com by guest on December 9, 2015
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Seminars in Cardiothoracic and Vascular Anesthesia 19(4)
transfusion is life saving and clinically useful in symptomatic patients; however, specific patient populations when transfused at specific Hgb values may not benefit or may be harmed by the transfusion. Therefore, the potential benefits of transfusion must be weighed against the harms of transfusion (an impendent risk factor for morbidity and mortality). In this review, we will examine the harmful effects of transfusions, costs, and finally strategies and their outcomes to minimize transfusions in cardiac surgical patients.
Transfusion-Related Adverse Outcomes Infectious Risk of Transfusion When it comes to blood transfusion, the general public has significant safety concerns about transfusion-transmitted viral infections because of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), but the truth is that the blood banking community has significantly reduced the risk of transfusion-transmitted infections by requiring donor history screening, serological testing, and highly sensitive nucleic acid testing. The approximate residual risk of transmission of HIV is 1 in 2.1 million, HBV is 1 in 1.1 million, HBV is 1 in 1.9 million, and human T-lymphotropic virus is 1 in 3 million.15,16 To help put this in perspective, this risk is of the same order of magnitude as dying by lightning strike or in an airplane crash. However, the blood banking community has not performed as well in reducing the risk of bacterial contamination and noninfectious hazards of transfusion. Bacterial contamination is one of the leading causes of transfusion-related mortality. Platelets are best stored in plasma (or plasma and additive solution) at room temperature (20°C-24°C), which provides optimal conditions for proliferation of bacteria. Therefore, the Food and Drug Administration (FDA) limits the shelf life of platelets to a maximum of 5 days. Unfortunately, platelets are quarantined 2 out of 5 days for bacterial culture readings prior to being released for patient use. Bacteria, predominantly skin flora, can be cultured from single donor apheresis platelet units as frequently as 1 in 1500 to 5000 units, but many of these units test positive before leaving quarantine. The risk of bacterial contamination and clinical sepsis caused by transfusion of a culture-negative platelet unit poses the greatest danger and is thought to affect 1 in 75 000 transfusions.16,17 Contamination of red cell units is less common because skin flora do not optimally grow at 1°C to 6°C, and red cells are not routinely cultured. The recent FDA approval of pathogen-inactivated platelets is a major step in improving the safety of platelets by reducing the infectivity of viral particles and bacteria as well as other nucleic acid–based pathogens. To perform pathogen
inactivation, amotosoralen is added to platelets collected in additive solution, and then the unit is exposed to ultraviolet light to create covalent bonds between the amotosoralen and nucleic acid base pairs, thereby preventing nucleic acid transcription. A related method that is in development includes riboflavin: UV light exposure leads to single-strand breaks. These inactivation methods are anticipated to be marketed for plasma, platelets collected in plasma, and red cells in the near future.17 Other organisms previously not of great focus are now receiving greater attention such as Chagas disease (Trypanosoma cruzi), malaria (Plasmodium spp), babesiosis (Babesia spp), dengue virus, chikungunya virus, and variant Creutzfelt-Jacob disease.
Serious Noninfectious Risks of Transfusion The United Kingdom’s hemovigilance program and the United States Center for Disease Control National Healthcare Safety Network Hemovigilance Module monitor the adverse outcomes associated with transfusion.18 Less-serious reactions such as allergic reactions and febrile nonhemolytic transfusion reactions are the most frequent types of reaction.19 However, the more severe noninfectious transfusion reactions caused the most fatalities out of the 176 fatalities reported to the FDA from 2010 to 2014.20 Transfusion-related acute lung injury (TRALI) accounted for 72 (41%) of the deaths, transfusion-associated circulatory overload (TACO) for 38 (22%), non-ABO hemolytic transfusion reactions for 25 (14%), and bacterial contamination for 15 (8%). TRALI classically presents as the acute (within 6 hours) onset of respiratory distress and hypoxemia after the transfusion of a plasma-containing blood component that resembles an acute respiratory distress (ARDS)-like picture. Other diagnostic criteria include the absence of elevated left atrial pressures, absence of preexisting acute lung injury, and a chest X-ray showing pulmonary infiltrates, classically “white out.” The current understanding of TRALI is that anti-HLA (human leukocyte antigens) or antigranulocyte antibodies in donor plasma activates recipient white blood cells, resulting in pulmonary injury and an ARDS-like clinical picture. In most patients, TRALI is transient, but it can cause significant morbidity and mortality. The risk of TRALI is estimated at 1 in 63 000 transfusions, with a higher incidence in patients who receive components containing the most plasma (ie, plasma > platelets > red cells > cryoprecipitate). Efforts to reduce this risk have focused on reducing plasma collected from individuals immunized against HLA and granulocytes—that is previously pregnant women; the production of an all-male donor plasma inventory has been a very common strategy throughout the United States and the United Kingdom, and testing for HLA antibodies from
Downloaded from scv.sagepub.com by guest on December 9, 2015
295
Varghese and Jhang female platelet donors is now increasingly being implemented. These risk mitigations have decreased the number of TRALI cases by nearly 30%. Patients experiencing TACO typically present with dyspnea, orthopnea, or hypoxemia as a result of pulmonary edema, and it occurs in up to 8% of transfusions. Transfusion contributes to positive fluid balance, increased hydrostatic pressure, and the development of pulmonary edema. Elderly patients, pediatric patients, patients with a history of congestive heart failure or on hemodialysis, and women are at the greatest risk. However, patients without these risk factors can also develop TACO. Transfusing units slowly or splitting units into 2 aliquots transfused over a longer period of time, monitoring patients closely, and judiciously administering diuretics may be useful in preventing TACO when higher-risk patients are identified. Although ABO-incompatible transfusions are uncommon, they still account for 13 (8%) of the 176 FDAreported fatalities from 2010 to 2014.20 In the United Kingdom, 10 ABO incompatible transfusions were reported in 2014; there were no deaths, but 1 patients suffered major morbidity, and 9 were not harmed.9 Linden et al21 performed an analysis of errors reported to the New York State Department of Health and estimated that the rate of erroneous red cell administration is 1 in 19 000 units, the rate of ABO-incompatible transfusion is 1 in 38 000 units, and fatal acute hemolytic transfusion reaction is 1 in 1.8 million. The most frequent error leading to a fatality was transfusion to someone other than the intended recipient often because of failure to perform positive identification of the patient or unit. The rate of severe, life-threatening, or fatal error reported to the US hemovigilance program was 17.5 per 100 000 total blood components transfused from 2010 to 2012.18
Transfusion-Associated Immune Modulation Blood transfusions are known to be associated with immune suppression, and this has been known since the early days of transplantation. Overall, studies related to transfusion-related immune modulation have demonstrated that transfusions generally have beneficial to neutral effects on rejection and have minimal negative effects on the outcomes in kidney transplantation.22 In addition, additional reports of adverse effects of transfusion on the recurrence rate of resected colon cancer and postoperative infections have been reported.23,24 The mechanism of this effect has not been elucidated, but it is hypothesized that infusion of foreign antigens or cellular material may induce tolerance or that white cells mediate this effect.25 van de Watering26 has previously demonstrated that transfusion of leukodepleted red blood cells decreased mortality overall and infections in those patients who received more than 3 transfusions when compared with nonleuokodepleted
units. Bilgin et al27 and Wallis et al28 have also demonstrated the same findings of decreased infections and decreased in-hospital mortality with leukodepletion. For this reason, as well as reducing HLA alloimmunization and reducing CMV infection, provision of universally prestorage leukodepleted red cells is a very common practice in blood banks throughout the United States.
The Red Cell Storage Lesion Packed red cells, which can be stored for up to 42 days in additive solution at 1°C to 6°C, undergo biochemical and physical changes during storage that lead to the production of neutrophil-activating bioreactives, production of procoagulant microparticles, promotion of bacterial proliferation by non–transferrin-bound iron, scavenging of nitric oxide by nitrosylation of free Hgb, accumulation of cytokines and chemokines released by white blood cells, activation of the innate immune system, and loss of red cell deformability.29 Observational studies and animal studies have suggested that the age of red cells may explain why red cell transfusions are associated with poorer outcomes. Qu and Triulzi30 have reviewed more than 40 such studies that provide conflicting evidence and have concluded that most of the studies are single-center, retrospective studies that are underpowered and are subject to significant bias. Observational data are likely to be biased because sicker patients tend to receive more red cells and these red cells are more likely to have been stored for a longer term because a first-in first-out (FIFO) is most often used as an inventory management strategy. Therefore, several recent randomized controlled trials (RCTs) have been of tremendous help in establishing the best evidence on whether providing “fresh” red cells improves morbidity and mortality compared with standard blood bank inventory management (ie, FIFO). The effect of red cell storage on premature, low-birthweight neonates was assessed in the Age of Red Blood Cells in Premature Infants (ARIPI) study, which was a double-blind RCT that compared a group that received red cells stored for 7 days or less to a standard blood bank practice. The study did not detect a difference in the primary outcomes of major neonatal morbidities (necrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy, intraventricular hemorrhage) and mortality.31 The Age of Blood Evaluation (ABLE) trial was a RCT conducted at 64 sites in Canada and Europe that enrolled 1219 critically ill patients admitted to intensive care units to receive standard issue (mean = 22.0 ± 8.4 days) versus fresh red cells (mean = 6.1 ± 4.9 days).32 Patients were transfused according to a restrictive strategy (
