Donated human red blood cells (RBC) are processed and stored in blood banks for up to 42 days. During storage, RBC undergo biochemical and biophysical changes: bioreactive substances from RBC breakdown and from the storage system itself accumulate over time. There continues to be concern that transfusion of this heterogeneous product produces adverse clinical effects. Four recently completed large randomized controlled trials (RCT) addressed clinical impacts of RBC storage age. These RCT found no significant deleterious effects of longer-stored RBC transfusion in contrast to earlier observational literature often associating longer-stored RBC with increased morbidity/mortality. In addition, there was a non-significant trend toward worse outcomes with shorter-stored RBC. However, these RCT did not individually address safety of RBC >35 days or include sufficient numbers of subjects receiving RBC at either storage age extreme (<7 days or >35 days) to identify effects of RBC transfusion at these limits. Finally, recent biomarker studies defining the evolving metabolomics age of RBC during storage suggest RBC transfused in the mid-storage window may be preferable to either shorter or longer storage age extreme. Conventional meta-analysis methodology combines multiple trials' data to reveal new information. However, meta-analyses of RBC storage age trials have been hampered by study variability and thus unable to analyze the impact of storage age extremes. The most powerful technique to explore the full implications of trial results is Individual Patient Data Meta-Analysis (IPDMA), which allows direct comparison of each subject's data and outcomes across trials. We propose performing IPDMA across the four RCTs of RBC storage age in a unique international collaboration to explore the relationship between age of transfused RBC and mortality/morbidity. We will identify and refine common data elements to extract comparable Individual Patient Data (IPD) from the 4 largest RCT: ABLE, RECESS, INFORM and TRANSFUSE. We will merge IPD from nearly 33,000 subjects, the largest number transfused with RBC at storage age extremes to date, to optimize comparison of outcomes, such as mortality. The primary analysis will use IPDMA to assess the effect of longer vs. shorter stored RBC on time to death through 28 days from the first RBC transfusion, preserving the benefits of randomization while increasing statistical power. We will also use IPDMA to explore the hypothesis that RBC transfusion at either storage extreme is associated with other adverse outcomes. We will additionally investigate whether mid-range storage duration RBC could be associated with better outcomes as suggested from metabolomics studies. If exploration of the combined datasets suggests either extreme of storage age is associated with worse clinical outcomes, then global blood bank RBC practice, storage methods and/or transfusion practice might be dramatically impacted. Secondly, if mid-range stored RBC are associated with fewer adverse clinical events, this would support the need to incorporate metabolomics in further studies of the impact of RBC transfusion.

Public Health Relevance

Red blood cells processed for transfusion to patients undergo refrigerated storage in the blood bank for up to 42 days. Although some prior basic science and clinical research have suggested that transfusion with red cells stored for a longer duration within this 42 day period can contribute to adverse clinical effects, all four recent large randomized clinical trials evaluating the effects of transfused red cell age found no evidence that longer storage age negatively affects patient outcomes. Since few patients in each study received the extremes of the shortest (?7 days) or longest (>35 days) stored red cells, we propose to combine individual patient data from each of these large study databases to evaluate the outcomes of the merged population of patients receiving the extremes of red cell storage compared to patients who received blood of other storage durations and to explore the relation between mortality and the exact age of red blood cells (in days) as a continuous time-line, an analysis that has not been done before.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Zou, Shimian
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University of Minnesota Twin Cities
Schools of Medicine
United States
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