Effects of red-cell storage duration on patients undergoing cardiac surgery.

BACKGROUND: Some observational studies have reported that transfusion of red-cell units that have been stored for more than 2 to 3 weeks is associated with serious, even fatal, adverse events. Patients undergoing cardiac surgery may be especially vulnerable to the adverse effects of transfusion. METHODS: We conducted a randomized trial at multiple sites from 2010 to 2014. Participants 12 years of age or older who were undergoing complex cardiac surgery and were likely to undergo transfusion of red cells were randomly assigned to receive leukocyte-reduced red cells stored for 10 days or less (shorter-term storage group) or for 21 days or more (longer-term storage group) for all intraoperative and postoperative transfusions. The primary outcome was the change in Multiple Organ Dysfunction Score (MODS; range, 0 to 24, with higher scores indicating more severe organ dysfunction) from the preoperative score to the highest composite score through day 7 or the time of death or discharge. RESULTS: The median storage time of red-cell units provided to the 1098 participants who received red-cell transfusion was 7 days in the shorter-term storage group and 28 days in the longer-term storage group. The mean change in MODS was an increase of 8.5 and 8.7 points, respectively (95% confidence interval for the difference, -0.6 to 0.3; P=0.44). The 7-day mortality was 2.8% in the shorter-term storage group and 2.0% in the longer-term storage group (P=0.43); 28-day mortality was 4.4% and 5.3%, respectively (P=0.57). Adverse events did not differ significantly between groups except that hyperbilirubinemia was more common in the longer-term storage group. CONCLUSIONS: The duration of red-cell storage was not associated with significant differences in the change in MODS. We did not find that the transfusion of red cells stored for 10 days or less was superior to the transfusion of red cells stored for 21 days or more among patients 12 years of age or older who were undergoing complex cardiac surgery. (Funded by the National Heart, Lung, and Blood Institute; RECESS ClinicalTrials.gov number, NCT00991341.).

Age of transfused blood in critically ill adults.

BACKGROUND: Fresh red cells may improve outcomes in critically ill patients by enhancing oxygen delivery while minimizing the risks of toxic effects from cellular changes and the accumulation of bioactive materials in blood components during prolonged storage. METHODS: In this multicenter, randomized, blinded trial, we assigned critically ill adults to receive either red cells that had been stored for less than 8 days or standard-issue red cells (the oldest compatible units available in the blood bank). The primary outcome measure was 90-day mortality. RESULTS: Between March 2009 and May 2014, at 64 centers in Canada and Europe, 1211 patients were assigned to receive fresh red cells (fresh-blood group) and 1219 patients were assigned to receive standard-issue red cells (standard-blood group). Red cells were stored a mean (±SD) of 6.1±4.9 days in the fresh-blood group as compared with 22.0±8.4 days in the standard-blood group (P<0.001). At 90 days, 448 patients (37.0%) in the fresh-blood group and 430 patients (35.3%) in the standard-blood group had died (absolute risk difference, 1.7 percentage points; 95% confidence interval [CI], -2.1 to 5.5). In the survival analysis, the hazard ratio for death in the fresh-blood group, as compared with the standard-blood group, was 1.1 (95% CI, 0.9 to 1.2; P=0.38). There were no significant between-group differences in any of the secondary outcomes (major illnesses; duration of respiratory, hemodynamic, or renal support; length of stay in the hospital; and transfusion reactions) or in the subgroup analyses. CONCLUSIONS: Transfusion of fresh red cells, as compared with standard-issue red cells, did not decrease the 90-day mortality among critically ill adults. (Funded by the Canadian Institutes of Health Research and others; Current Controlled Trials number, ISRCTN44878718.).

Effect of fresh red blood cell transfusions on clinical outcomes in premature, very low-birth-weight infants: the ARIPI randomized trial.

CONTEXT: Even though red blood cells (RBCs) are lifesaving in neonatal intensive care, transfusing older RBCs may result in higher rates of organ dysfunction, nosocomial infection, and length of hospital stay. OBJECTIVE: To determine if RBCs stored for 7 days or less compared with usual standards decreased rates of major nosocomial infection and organ dysfunction in neonatal intensive care unit patients requiring at least 1 RBC transfusion. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized controlled trial in 377 premature infants with birth weights less than 1250 g admitted to 6 Canadian tertiary neonatal intensive care units between May 2006 and June 2011. INTERVENTION: Patients were randomly assigned to receive transfusion of RBCs stored 7 days or less (n = 188) vs standard-issue RBCs in accordance with standard blood bank practice (n = 189). MAIN OUTCOME MEASURES: The primary outcome was a composite measure of major neonatal morbidities, including necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia, and intraventricular hemorrhage, as well as death. The primary outcome was measured within the entire period of neonatal intensive care unit stay up to 90 days after randomization. The rate of nosocomial infection was a secondary outcome. RESULTS: The mean age of transfused blood was 5.1 (SD, 2.0) days in the fresh RBC group and 14.6 (SD, 8.3) days in the standard group. Among neonates in the fresh RBC group, 99 (52.7%) had the primary outcome compared with 100 (52.9%) in the standard RBC group (relative risk, 1.00; 95% CI, 0.82-1.21). The rate of clinically suspected infection in the fresh RBC group was 77.7% (n = 146) compared with 77.2% (n = 146) in the standard RBC group (relative risk, 1.01; 95% CI, 0.90-1.12), and the rate of positive cultures was 67.5% (n = 127) in the fresh RBC group compared with 64.0% (n = 121) in the standard RBC group (relative risk, 1.06; 95% CI, 0.91-1.22). CONCLUSION: In this trial, the use of fresh RBCs compared with standard blood bank practice did not improve outcomes in premature, very low-birth-weight infants requiring a transfusion. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00326924; Current Controlled Trials Identifier: ISRCTN65939658.

The role of comparative effectiveness research in transfusion medicine clinical trials: proceedings of a National Heart, Lung, and Blood Institute workshop.

Comparative effectiveness research (CER) is the study of existing treatments or ways to deliver health care to determine what intervention works best under specific circumstances. CER evaluates evidence from existing studies or generates new evidence, in different populations and under specific conditions in which the treatments are actually used. CER does not embrace one research design over another but compares treatments and variations in practice using methods that are most likely to yield widely generalizable results that are directly relevant to clinical practice. Treatments used in transfusion medicine (TM) are among the most widely used in clinical practice, but are among the least well studied. High-quality evidence is lacking for most transfusion practices, with research efforts hampered by regulatory restrictions and ethical barriers. To begin addressing these issues, the National Heart, Lung, and Blood Institute convened a workshop in June 2011 to address the potential role of CER in the generation of high-quality evidence for TM decision making. Workshop goals were to: 1) evaluate the current landscape of clinical research, 2) review the potential application of CER methods to clinical research, 3) assess potential barriers to the use of CER methodology, 4) determine whether pilot or vanguard studies can be used to facilitate planning of future CER research, and 5) consider the need for and delivery of training in CER methods for researchers.

Clinical trial opportunities in hemostasis and thrombosis: NHBLI State-of-the-Science symposium.

Clinical trials in hemostasis and thrombosis (HT) are needed to guide medical practice and future research. Providing public support for trials that could have the greatest impact on clinical care has been a major challenge. The National Heart, Lung and Blood Institute (NHLBI) convened a State-of-the-Science meeting in Bethesda on September 14th and 15th, 2009 to identify Phase II and III clinical trials in HT that could have critical impact on healthcare. An oversight committee composed of representatives of the NHLBI and three experienced extramural investigators chose chairs of subcommittees representing six broad areas of investigation in adult and pediatric HT. Chairs were charged with identifying important, feasible proposals. Nineteen trial concepts were presented at this public meeting, followed by open commentary from members of an independent external panel chosen to evaluate the trials and from symposium participants from the wider scientific community. Descriptions of two important clinical trial concepts from each of the six subcommittees are provided in the Supporting Information. Phase II-III clinical trials that could have high impact include studies for treatment of venous thromboembolism (TE) in children and in adults, the potential utility of statins in prophylaxis of TE, prophylaxis of adults with severe hemophilia, management of heparin-induced thrombocytopenia (HIT) and of primary immune thrombocytopenia (ITP). The external panel also provided recommendations concerning infrastructure and approach that could improve the conduct of studies including: development of core organizations with expertise in design of clinical trials, biostatistics, and contract development; funding based on output and milestones; and enhanced investment in coordinating centers.

Clinical review: Canadian National Advisory Committee on Blood and Blood Products--Massive transfusion consensus conference 2011: report of the panel.

In June 2011 the Canadian National Advisory Committee on Blood and Blood Products sponsored an international consensus conference on transfusion and trauma. A panel of 10 experts and two external advisors reviewed the current medical literature and information presented at the conference by invited international speakers and attendees. The Consensus Panel addressed six specific questions on the topic of blood transfusion in trauma. The questions focused on: ratio-based blood resuscitation in trauma patients; the impact of survivorship bias in current research conclusions; the value of nonplasma coagulation products; the role of protocols for delivery of urgent transfusion; the merits of traditional laboratory monitoring compared with measures of clot viscoelasticity; and opportunities for future research. Key findings include a lack of evidence to support the use of 1:1:1 blood component ratios as the standard of care, the importance of early use of tranexamic acid, the expected value of an organized response plan, and the recommendation for an integrated approach that includes antifibrinolytics, rapid release of red blood cells, and a foundation ratio of blood components adjusted by results from either traditional coagulation tests or clot viscoelasticity or both. The present report is intended to provide guidance to practitioners, hospitals, and policy-makers.

Proceedings of a consensus conference: Risk-Based Decision Making for Blood Safety.

Blood safety decision making has become increasingly complex, and a framework for risk-based decision making is, thus, needed. The purpose of this consensus conference was to bring together international experts in an effort to develop the foundations for such a framework. These proceedings are described with a view to making available to the transfusion medicine community the considerable amount of information and insight that was presented and that emerged through debate by the experts, panel members, and delegates.

The Age of Blood Evaluation (ABLE) randomized controlled trial: study design.

Red blood cells (RBCs) are transfused to treat anemia and to maintain oxygen delivery to vital organs during critical illness. Laboratory and observational studies have raised the possibility that prolonged RBC storage may adversely affect clinical outcomes. Compared with RBCs stored less than 1 week, there are no clinical data demonstrating that RBCs stored longer remain as effective at carrying or releasing oxygen, and observational studies have risen to possibility that prolonged RBC storage might result in harm to vulnerable patients requiring blood transfusions. The "Age of Blood Evaluation" (ABLE) study (ISRCTN44878718) is a double-blind, multicenter, parallel randomized controlled clinical trial. It will test the hypothesis that the transfusion of prestorage leukoreduced RBCs stored for 7 days or less (fresh arm) as compared with standard-issue RBCs stored, on average, 15 to 20 days (control arm) will lead to lower 90-day all-cause mortality and reduced morbidity in critically ill adults. We include adults in intensive care units (ICUs) who (1) have had a request for a first RBC unit transfusion during the first 7 days of ICU admission and (2) have an anticipated requirement for ongoing invasive and noninvasive mechanical ventilation exceeding 48 hours. Enrolled patients are randomized at the time of transfusion to receive either standard-issue RBC units or RBCs stored 7 days or less issued by the local hospital transfusion service. The primary outcome is 90-day all-cause mortality. Secondary outcomes include ICU and hospital mortality, organ failure, and serious nosocomial infections. With 2510 patients, we will be able to detect a 5% absolute risk reduction (from 25% to 20%). The ABLE study is currently enrolling patients in 23 university-affiliated and community-hospital ICUs across Canada; sites in France and United Kingdom are expected to start recruitment in 2011. Regardless of the results, ABLE study will have significant implications on the duration of RBC storage. A negative trial will reassure clinicians and blood bankers regarding the effectiveness and safety of standard-issue RBCs. A positive trial will have significant implications with respect to inventory management of RBCs given to critically ill adults with a high risk of mortality and will also prompt research to better understand the RBC storage lesion in the hopes of minimizing its clinical consequences through the development of better storage methods.

A multidisciplinary "think tank": the top 10 clinical trial opportunities in transfusion medicine from the National Heart, Lung, and Blood Institute-sponsored 2009 state-of-the-science symposium.

BACKGROUND: In September 2009, the National Heart, Lung, and Blood Institute convened the State-of-the-Science Symposium in Transfusion Medicine to identify Phase II and/or III clinical trials that would provide important information to advance transfusion medicine. STUDY DESIGN AND METHODS: Seven multidisciplinary subcommittees developed proposals in the following areas: 1) platelet (PLT) product use, 2) neonatal and/or pediatric transfusion practice, 3) surgical transfusion practice, 4) intensive care unit and/or in trauma transfusion practice, 5) plasma and/or cryoprecipitate product use and therapeutic apheresis practice, 6) red blood cell (RBC) product use and/or blood conservation management, and 7) medical transfusion practice or blood donor studies. The committees consisted of transfusion medicine specialists, hematologists, cardiovascular surgeons, anesthesiologists, neonatologists, critical care physicians, and clinical trial methodologists. Proposals were presented and an external panel evaluated and prioritized each concept for scientific merit, clinical importance, and feasibility. RESULTS: Twenty-four concepts were presented by the subcommittees. Ten concepts addressed four areas deemed most important: 1) PLT transfusion strategies to prevent and/or mitigate bleeding in neonates and patients with hematologic malignancies, 2) RBC transfusion trigger strategies to improve overall outcomes in different patient populations, 3) evaluation of optimal plasma:PLT:RBC ratios in trauma resuscitation, and 4) pathogen inactivation of PLTs to improve PLT transfusion safety. CONCLUSIONS: The proposal themes not only represent inquiries about the indications for transfusion, but also epitomize the lack of consensus when clinical practice lacks a strong evidence base. Ultimately, the purpose of this publication is to provide a "blueprint" of ideas for further development rather than endorse any one specific clinical trial design.

Clinical trial opportunities in Transfusion Medicine: proceedings of a National Heart, Lung, and Blood Institute State-of-the-Science Symposium.

The use of blood products to support patients undergoing the large variety of medical and surgical interventions requiring such support has continued to escalate very significantly over time. Relevantly, significant practice variation in the use of blood products exists among practitioners and institutions, largely because of the lack of robust clinical trial data, in many instances, which are critical for providing practitioners with evidence-based guidelines for appropriate blood product utilization. Recognizing this gap, the National Heart, Lung, and Blood Institute recently established a State-of-the-Science Symposium to help define areas of clinical trial research that would enhance the opportunity for developing appropriate practice guidelines for both Transfusion Medicine and Hemostasis/Thrombosis. Such a Symposium was held in September 2009 to identify important clinical trial research issues in these 2 subject areas of endeavor. The aims of this Symposium were to specifically identify phase 2 and 3 clinical trials that, if conducted over the next 5 to 10 years, could impact the treatment of patients with hemostatic and other disorders as well as to optimize the use of blood products in patients who need such interventions. This article reports on the deliberations that were held relating to the various clinical trial concepts developed by 7 Transfusion Medicine subcommittees. This Symposium generated a rich assortment of clinical trial proposals that will undergo further refinement before final implementation into pilot or full randomized clinical trials. The various proposals identified many opportunities for clinical trial research and most importantly underscored the ongoing need for well-developed evidence-based clinical trial research in the field of Transfusion Medicine.

Warm autoimmune hemolytic anemia: recent progress in understanding the immunobiology and the treatment.

Autoimmune hemolytic anemia (AIHA) is defined as a condition associated with the increased destruction of red blood cells (RBCs) associated with the presence of IgG anti-RBC autoantibodies. The etiology underlying the pathogenesis of such autoantibodies is still uncertain. In the present article, we will discuss the postulated mechanisms that produce a breakdown of immunologic tolerance leading to warm AIHA including the possible roles of RBC autoantigens and the complement system, the lack of effective presentation of autoantigens, functional abnormalities of B and T cells resulting in polyclonal lymphocyte activation and alteration of cytokine production, and the role of immunoregulatory T cells. Because warm AIHA is a relatively rare clinical entity, current recommended therapeutic strategies for patients with warm AIHA are mainly based on results from small cohort studies. Clinicians must also balance the risk of withholding RBC transfusions against the possible benefit of ameliorating the hemoglobin level with such transfusions particularly in critically ill patients with warm AIHA. Glucocorticoids are the first-line treatment for patients with warm AIHA resulting in an 80% clinical response after 3 weeks of treatment. The latter, however, also may cause adverse events such as excessive weight gain, neuropsychiatric disorders, endocrine, or cardiovascular events. Splenectomy should be considered for patients who do not show a satisfactory response to glucocorticoids and may offer a success rate of up to 70% in patients with idiopathic warm AIHA. Rituximab treatment in patients with refractory warm AIHA has been well tolerated with an overall median response rate of approximately 60%. Danazol, intravenous immunoglobulin, alemtuzumab, as well as other immunosuppressive drugs have also been successfully used in patients with warm AIHA, refractory to glucocorticoids, splenectomy, and rituximab.

Blood still kills: six strategies to further reduce allogeneic blood transfusion-related mortality.

After reviewing the relative frequency of the causes of allogeneic blood transfusion-related mortality in the United States today, we present 6 possible strategies for further reducing such transfusion-related mortality. These are (1) avoidance of unnecessary transfusions through the use of evidence-based transfusion guidelines, to reduce potentially fatal (infectious as well as noninfectious) transfusion complications; (2) reduction in the risk of transfusion-related acute lung injury in recipients of platelet transfusions through the use of single-donor platelets collected from male donors, or female donors without a history of pregnancy or who have been shown not to have white blood cell (WBC) antibodies; (3) prevention of hemolytic transfusion reactions through the augmentation of patient identification procedures by the addition of information technologies, as well as through the prevention of additional red blood cell alloantibody formation in patients who are likely to need multiple transfusions in the future; (4) avoidance of pooled blood products (such as pooled whole blood-derived platelets) to reduce the risk of transmission of emerging transfusion-transmitted infections (TTIs) and the residual risk from known TTIs (especially transfusion-associated sepsis [TAS]); (5) WBC reduction of cellular blood components administered in cardiac surgery to prevent the poorly understood increased mortality seen in cardiac surgery patients in association with the receipt of non-WBC-reduced (compared with WBC-reduced) transfusion; and (6) pathogen reduction of platelet and plasma components to prevent the transfusion transmission of most emerging, potentially fatal TTIs and the residual risk of known TTIs (especially TAS).

Extending the horizon for cell-based immunotherapy by understanding the mechanisms of action of photopheresis.

Most of the current cell-based immunotherapy protocols concentrate on immune stimulatory effects against certain pathogenic insults, such as cancer. In this article, a potential cell-based immunotherapeutic strategy to induce immune tolerance by infusion of apoptotic leukocytes is presented in conjunction with a review of newly understood mechanisms of action of photopheresis and relevant information about allogeneic transfusion-related immunomodulation. The scientific rationale is discussed by examining our understanding of the role of apoptosis in self-antigen tolerance, the interaction between apoptotic bodies and antigen-presenting cells, and the subsequent induction of T regulatory cells and clonal deletion of effector T cells. Previous data on transfusion-related immunomodulation are assembled to examine a possible link between the immunosuppressive effects obtained from photopheresis and those seen post allogeneic blood transfusion. Accumulating evidence appears to support the hypothesis that photopheresis and allogeneic blood transfusion may share a mechanism of action for the induction of immunosuppression, which suggests the potential of eliciting selective immune tolerance by giving the recipient a bolus of apoptotic cells. Such immunotherapy interventions could bring significant clinical benefit to patients undergoing transplant rejection or autoimmune-related disorders and deserve further investigation as well as validation studies.

Research opportunities for pathogen reduction/inactivation of blood components: summary of an NHLBI workshop.

In July 2008, a workshop sponsored by the Division of Blood Diseases and Resources of the National Heart, Lung, and Blood Institute (NHLBI) was convened to identify potential research opportunities that could advance our understanding of both the biologic and the clinical impact of the various available pathogen reduction/inactivation (PR/PI) methods of blood components (platelets [PLTs], red blood cells, and plasma) intended for allogeneic transfusion. These discussions resulted in consensus that, even though several PR/PI technologies have already been licensed and are being used in Europe and elsewhere for PLTs and plasma, concerns about possible side effects, particularly component quality and pulmonary toxicity, have impeded regulatory approval in North America (United States and Canada). Such concerns thus threaten to stall further development of these technologies. As a consequence, the NHLBI workshop participants focused on formulating a series of research-related recommendations to better understand, mitigate, and prevent these adverse effects. Other important issues identified included the need for a single method to inactivate pathogens in whole blood without damaging the various blood components; new ways to monitor the efficacy of treated components, including animal models to screen for safety; a better understanding of the effect of PR/PI-treated products on recipient alloimmunization, tolerance, and immune modulation; understanding the impact of PR/PI on various other noninfectious hazards of transfusion; and establishing methods to evaluate risk-benefit and cost-effectiveness, in particular with reference to emerging pathogens. The working group also discussed issues related to specific blood components, such as improving the process of clinical evaluation, investigating the impact of PR/PI on component storage lesions, understanding mechanisms that reduce component viability, and addressing the underlying resistance to the adoption of PR/PI-treated components. This communication summarizes the opinions of workshop participants on these issues and concludes with a list of areas for possible research that could advance the application of PR/PI methods to enhance the safety of the world's blood supplies.

Severe hemolytic anemia post-renal transplantation produced by donor anti-D passenger lymphocytes: case report and literature review.

The passenger lymphocyte syndrome (PLS), often associated with immune-mediated hemolytic anemia after solid organ and hematopoietic stem cell transplantation, is the result of concomitant transplantation of donor lymphocytes along with the donor allograft. Antibodies directed against recipient red blood cells (RBCs) are frequently found in ABO-mismatched solid organ transplants; however, passenger lymphocyte-mediated hemolysis due to Rh-incompatible antibodies has only rarely been reported. In this report, we present a case of severe hemolytic anemia related to the PLS in an ABO-matched renal allograft recipient. The recipient's blood type was A Rh(D) positive; and the donor, who had been previously alloimmunized, was A Rh(D) negative. The renal allograft recipient's hemoglobin abruptly decreased on postoperative day 12 in the setting of a newly positive direct antiglobulin test and anti-D antibodies in the plasma. The patient required intermittent RBC transfusions for ongoing hemolysis during the first 6 months post-renal transplant. Of all reported cases of anti-D-mediated PLS, our patient would seem to have been one of the most severe, as indicated by a nadir hemoglobin of 41 g/L and the need for 23 U of transfused RBCs. A hemolytic anemia occurring after organ transplantation should raise the possibility of donor-derived antibodies directed against the recipient RBCs. Passenger lymphocyte syndrome-associated hemolysis is occasionally severe as in our case, but can be effectively treated with compatible RBC transfusions.

Transfusion-related mortality: the ongoing risks of allogeneic blood transfusion and the available strategies for their prevention.

As the risks of allogeneic blood transfusion (ABT)-transmitted viruses were reduced to exceedingly low levels in the US, transfusion-related acute lung injury (TRALI), hemolytic transfusion reactions (HTRs), and transfusion-associated sepsis (TAS) emerged as the leading causes of ABT-related deaths. Since 2004, preventive measures for TRALI and TAS have been implemented, but their implementation remains incomplete. Infectious causes of ABT-related deaths currently account for less than 15% of all transfusion-related mortality, but the possibility remains that a new transfusion-transmitted agent causing a fatal infectious disease may emerge in the future. Aside from these established complications of ABT, randomized controlled trials comparing recipients of non-white blood cell (WBC)-reduced versus WBC-reduced blood components in cardiac surgery have documented increased mortality in association with the use of non-WBC-reduced ABT. ABT-related mortality can thus be further reduced by universally applying the policies of avoiding prospective donors alloimmunized to WBC antigens from donating plasma products, adopting strategies to prevent HTRs, WBC-reducing components transfused to patients undergoing cardiac surgery, reducing exposure to allogeneic donors through conservative transfusion guidelines and avoidance of product pooling, and implementing pathogen-reduction technologies to address the residual risk of TAS as well as the potential risk of the next transfusion-transmitted agent to emerge in the foreseeable future.

The age of red blood cells in premature infants (ARIPI) randomized controlled trial: study design.

Despite recent trends in decreasing transfusion thresholds and the development of technologies designed to avoid allogeneic exposure, allogeneic red blood cell (RBC) transfusions remain an important supportive and life-saving measure for neonatal intensive care patients experiencing illness and anemia. Reluctantly, a number of laboratory and observational studies have indicated that the amount of time RBCs are stored can affect oxygen delivery to tissues. Consequently, older RBCs may result in higher rates of organ dysfunction, nosocomial infection, and lengths of stay. Because of such harmful effects, an evaluation of the association between age of blood and nosocomial infection and organ dysfunction is warranted. The aim of the study was to determine if RBCs stored for 7 days or less (fresh RBCs) compared to current standard transfusion practice decreases major nosocomial infection and organ dysfunction in neonates admitted to the neonatal intensive care unit and requiring at least one RBC transfusion. This study is a double-blind, multicenter, randomized controlled trial design. The trial will be an effectiveness study evaluating the effectiveness of stored vs fresh RBCs in neonates requiring transfusion. Neonatal patients requiring at least one unit of RBCs will be randomized to receive either (1) RBCs stored no longer than 7 days or (2) standard practice. The study was conducted in Canadian university-affiliated level III (tertiary) neonatal intensive care units. The primary outcome for this study will be a composite measure of major neonatal morbidities (necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia, intraventricular hemorrhage, and mortality). Secondary outcomes include individual items of the composite measure and nosocomial infection (bacteremia, septic shock, and pneumonia). The sample size calculations have been estimated based on the formula for 2 independent proportions using an alpha of .05, a (1-beta) of .80, and a 10% noncompliance factor. The baseline rate for our composite measure is estimated to be 65% as indicated by the literature. Assuming a 15% absolute risk reduction with the use of RBCs stored 7 days or less, our estimated total sample size required will be 450 (225 patients per treatment arm). The Age of Red Blood Cells in Premature Infants (ARIPI) trial is registered at the US National Institutes of Health (ClinicalTrials.gov) no. NCT00326924 and current controlled trials ISRCTN65939658.

New strategies for the optimal use of platelet transfusions.

Patients with severe thrombocytopenia are presumed to be at increased risk for bleeding, and consequently it has been standard practice for the past four decades to give allogeneic platelet transfusions to severely thrombocytopenic patients as supportive care. Platelet transfusions may be given either prophylactically to reduce the risk of bleeding, in the absence of clinical hemorrhage (prophylactic transfusions), or to control active bleeding when present (therapeutic transfusions). While no one would argue with the need for platelet transfusions in the face of severe bleeding, important questions remain about what constitutes clinically significant bleeding and whether a strategy of prophylactic platelet transfusions is effective in reducing the risk of bleeding in clinically stable patients. It is now uncommon for patients undergoing intensive chemotherapy or bone marrow transplantation to die of hemorrhage, but it is open to debate as to what degree platelet transfusions have been responsible for this change in outcome, given the many other advances in other aspects of supportive care. If a prophylactic strategy is followed, the optimal transfusion trigger or quantity of platelets to be transfused prophylactically per transfusion episode needs to be addressed in adequately powered clinical trials, but these remain highly controversial issues. This is because, until recently, there have been few high-quality, prospective, randomized clinical trial (RCT) data for evaluating the relative effects of different platelet transfusion regimens or platelet doses on clinical outcomes. Moreover, most of these RCTs have not used bleeding as the primary outcome measure. Two such studies on platelet dose have now been undertaken, the PLADO (Prophylactic PLAtelet DOse) and the SToP (Strategies for the Transfusion of Platelets) trials. Data from these RCTs are not contained in this overview, as these data have not yet been completely analyzed or submitted for peer review publication. In addition to the above, several recent observational studies have raised the possibility that there is not a clear association between the occurrence of a major clinical bleeding episode and the platelet count in thrombocytopenic patients. Such findings have led to the questioning of the efficacy of prophylactic platelet transfusions in all clinically stable patients, and whether a policy of therapeutic transfusions used only when patients have clinical bleeding might be as effective and safe for selected patients. At least two RCTs evaluating the relative value of prophylactic versus therapeutic platelet transfusions have been initiated in thrombocytopenic patients with hematological malignancies. One such study, known as the TOPPS (Trial of Prophylactic Platelets Study) study, is currently underway in the U.K.