Parenteral irons versus transfused red blood cells for treatment of anemia during canine experimental bacterial pneumonia

Abstract

Background No studies have been performed comparing intravenous iron with transfused red cells (RBC) for treating anemia during infection. In a previous report, transfused older RBC increased free iron release and mortality in infected animals when compared to fresher cells. We hypothesized that treating anemia during infection with transfused fresh RBC, with minimal free iron release, would prove superior to intravenous iron therapy. Methods Purpose-bred-beagles (n=42) with experimental S. aureus pneumonia rendered anemic were randomized to be transfused RBCs stored for 7-days or one of two intravenous iron preparations (7mg/kg), iron sucrose, a widely-used preparation, or ferumoxytol, a newer formulation that blunts circulating iron levels. Results Both irons increased the alveolar-arterial-oxygen gradient at 24–48-hours (p=0.02–0.001), worsened shock at 16-hours (p=0.02– p=0.003 respectively), and reduced survival (transfusion 56%; iron sucrose 8%, p=0.01; ferumoxytol 9%, p=0.04). Compared to fresh RBC transfusion, plasma iron measured by non-transferrin-bound iron (NTBI) levels increased with iron sucrose at 7, 10, 13, 16, 24 and 48-hours, (p=0.04 to p<0.0001) and ferumoxytol at 7, 24 and 48-hours (p=0.04 to p=0.004). No significant differences in cardiac filling pressures or performance, hemoglobin or cell free hemoglobin were observed. Conclusions During canine experimental bacterial pneumonia, treatment of mild anemia with intravenous iron significantly increased free iron levels, shock, lung injury, and mortality compared to transfusion of fresh RBC. This was true for iron preparations that do or do not blunt circulating free iron level elevations. These findings suggest that treatment of anemia with intravenous iron during infection should be undertaken with caution.

Impact of different standard red blood cell storage temperatures on human and canine RBC hemolysis and chromium survival

“…The clinical consequences of delayed hemolysis with release of CFH and NTBI are unknown, but increased risks by promoting bacterial growth during infection or through nitric oxide scavenging worsening coronary syndromes, respectively, have been proposed. 6,11,26 In contrast to 7-day-old RBCs, RBCs transfused after 35 days at 4 C and 6 C showed superior survival at 24, 48, and 72 hours when compared to RBCs stored at 2 C. The apparently improved recovery occurred despite the increased hemolysis in the storage bags after 35 days and the higher NTBI and CHF for 72 hours after transfusion. We attribute the discrepancy to a storage-induced artifact affecting the 51 Cr assay.…”

“…The clinical consequences of delayed hemolysis with release of CFH and NTBI are unknown, but increased risks by promoting bacterial growth during infection or through nitric oxide scavenging worsening coronary syndromes, respectively, have been proposed. 6,11,26 …”

“…[3][4][5] The increased hemolysis after prolonged storage and release of cell-free hemoglobin (CFH) and non-transferrin-bound iron (NTBI) may increase transfusion risks in subgroups such as patients with invasive bacterial infections. 6 At present, prospective clinical trials have not demonstrated a clear survival benefit for patients who receive fresher blood, although trial arms have been limited to RBC storage for 7 to 10 days versus 18 to 22 days, and included few RBCs close to the 42-day limit. 3 Evidence to date has been insufficient to change storage guidelines.…”

Ferroportin inhibition attenuates plasma iron, oxidant stress, and renal injury following red blood cell transfusion in guinea pigs

“…Excess iron (Fe 3+ ) transported into the circulation immediately binds to and eventually saturates transferrin protein, causing non–transferrin‐bound iron (NTBI) accumulation once transferrin saturations exceed 75% to 80% . Posttransfusion NTBI concentrations may be associated with RBC refrigerator storage duration in humans, and iron has been shown to contribute to infection virulence and mortality in animal models . Additionally, free iron is a labile toxicant that contributes to the generation of reactive oxygen species, lipid peroxides, and cellular injury .…”

“…6 Posttransfusion NTBI concentrations may be associated with RBC refrigerator storage duration in humans, 3,7 and iron has been shown to contribute to infection virulence and mortality in animal models. 8,9 Additionally, free iron is a labile toxicant that contributes to the generation of reactive oxygen species, lipid peroxides, and cellular injury. 6 Nonetheless, other well-conducted studies in humans have challenged these concepts in acute transfusion with endotoxemia.…”