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We have performed a series of studies over the course of a decade with a large animal model of shock and meta-analysis techniques to study transfusion trials. Although clinical trials have established the safety of the current practice of transfusing 18- to 22-day-old stored blood, observational studies have suggested that the oldest units (aged 35–42 days) when transfused have increased risks. These risks are dependent on host factors. Transfused older blood has increased hemolysis with the release of cell free hemoglobin (CFH) and iron. Subjects with infection may be harmed by transfusing iron which promotes bacterial growth. In situations where nitric oxide (NO) is important, such as coronary disease, CFH scavenging of NO may increase risk to patients.

The finding of toxicity in a meta-analysis of observational clinical studies of transfused longer stored red blood cells (RBC) and ethical issues surrounding aging blood for human studies prompted us to develop an experimental model of RBC transfusion. Transfusing older RBCs during canine pneumonia increased mortality rates. Toxicity was associated with in vivo hemolysis with release of cell-free hemoglobin (CFH) and iron. CFH can scavenge nitric oxide, causing vasoconstriction and endothelial injury. Iron, an essential bacterial nutrient, can worsen infections. This toxicity was seen at commonly transfused blood volumes (2 units) and was altered by the severity of pneumonia. Washing longer-stored RBCs mitigated these detrimental effects, but washing fresh RBCs actually increased them. In contrast to septic …