Review The red cell storage lesion(s): of dogs and men Harvey G. Klein Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, United States of America
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The advent of preservative solutions permitted refrigerated storage of red blood cells. However, the convenience of having red blood cell inventories was accompanied by a disadvantage. Red cells undergo numerous physical and metabolic changes during cold storage, the "storage lesion(s)". Whereas controlled clinical trials have not confirmed the clinical importance of such changes, ethical and operational issues have prevented careful study of the oldest stored red blood cells. Suggestions of toxicity from meta-analyses motivated us to develop pre-clinical canine models to compare the freshest vs the oldest red blood cells. Our model of canine pneumonia with red blood cell transfusion indicated that the oldest red blood cells increased mortality, that the severity of pneumonia is important, but that the dose of transfused red blood cells is not. Washing the oldest red blood cells reduces mortality by removing senescent cells and remnants, whereas washing fresher cells increases mortality by damaging the red blood cell membrane. An opposite effect was found in a model of haemorrhagic shock with reperfusion injury. Physiological studies indicate that release of iron from old cells is a primary mechanism of toxicity during infection, whereas scavenging of cellfree haemoglobin may be beneficial during reperfusion injury. Intravenous iron appears to have toxicity equivalent to old red blood cells in the pneumonia model, suggesting that intravenous iron and old red blood cells should be administered with caution to infected patients.
stored refrigerated blood was accompanied by a drawback. Red cells clearly changed during cold storage as documented by a number of in vitro measurements of size, shape, enzyme content, rheology, and filterability4. Furthermore, modern tools can now detect thousands of changes in red cell metabolomics that occur within a few weeks of refrigerated storage5. The critical question, however, concerns the clinical importance of these changes. For much of the 20th century, a major challenge in RBC transfusion involved efforts to extend component shelf life without sacrificing quality and efficacy. Early investigators settled on RBC recovery and survival in vivo at the end of storage as the key measure of RBC quality. The US Food and Drug Administration, which licenses RBCs, containers and storage solutions, relies primarily on two surrogate measures of efficacy and safety: 24-hour recovery and survival of >75% of radiochromium-labelled RBCs, and haemolysis of
©
SI M
Sr l
TI
Se rv
The advent of preservative solutions permitted refrigerated storage of red blood cells. However, the convenience of having red blood cell inventories was accompanied by a disadvantage. Red cells undergo numerous physical and metabolic changes during cold storage, the "storage lesion(s)". Whereas controlled clinical trials have not confirmed the clinical importance of such changes, ethical and operational issues have prevented careful study of the oldest stored red blood cells. Suggestions of toxicity from meta-analyses motivated us to develop pre-clinical canine models to compare the freshest vs the oldest red blood cells. Our model of canine pneumonia with red blood cell transfusion indicated that the oldest red blood cells increased mortality, that the severity of pneumonia is important, but that the dose of transfused red blood cells is not. Washing the oldest red blood cells reduces mortality by removing senescent cells and remnants, whereas washing fresher cells increases mortality by damaging the red blood cell membrane. An opposite effect was found in a model of haemorrhagic shock with reperfusion injury. Physiological studies indicate that release of iron from old cells is a primary mechanism of toxicity during infection, whereas scavenging of cellfree haemoglobin may be beneficial during reperfusion injury. Intravenous iron appears to have toxicity equivalent to old red blood cells in the pneumonia model, suggesting that intravenous iron and old red blood cells should be administered with caution to infected patients.
stored refrigerated blood was accompanied by a drawback. Red cells clearly changed during cold storage as documented by a number of in vitro measurements of size, shape, enzyme content, rheology, and filterability4. Furthermore, modern tools can now detect thousands of changes in red cell metabolomics that occur within a few weeks of refrigerated storage5. The critical question, however, concerns the clinical importance of these changes. For much of the 20th century, a major challenge in RBC transfusion involved efforts to extend component shelf life without sacrificing quality and efficacy. Early investigators settled on RBC recovery and survival in vivo at the end of storage as the key measure of RBC quality. The US Food and Drug Administration, which licenses RBCs, containers and storage solutions, relies primarily on two surrogate measures of efficacy and safety: 24-hour recovery and survival of >75% of radiochromium-labelled RBCs, and haemolysis of
