Transfused older stored red blood cells improve the clinical course and outcome in a canine lethal hemorrhage and reperfusion model

Abstract

BACKGROUND In canine models, transfused older stored red blood cells (RBCs) hemolyze in vivo resulting in significantly increased intravascular cell free hemoglobin (CFH) and non-transferrin bound iron (NTBI). During canine bacterial pneumonia with septic shock, but not in controls, older stored RBCs were associated with significantly increased lung injury and mortality. It is unknown if in shock without infection transfusion of older RBCs will result in similar adverse effects. STUDY DESIGN AND METHODS Two-year-old purpose-bred beagles (n=12) were transfused similar quantities of either older (42-day) or fresher (7-day) stored universal donor canine RBCs 2.5 hours after undergoing controlled hemorrhage (55ml/kg). RESULTS With older transfused RBCs, CFH (p<0.0001) and NTBI (p=0.004) levels increased, but lung injury (p=0.01) and C-reactive protein levels (p=0.002) declined and there was a trend toward lower mortality (18% versus 50%). All 3 deaths after transfused fresher red cells resulted from hepatic fractures. Lowered exogenous norepinephrine requirements (p<0.05) and cardiac outputs (p<0.05) after older transfused RBCs were associated with increased CFH levels that have known vasoconstrictive nitric oxide scavenging capability. CONCLUSIONS In hemorrhagic shock, older RBCs altered resuscitation physiology but did not worsen clinical outcomes. Elevated CFH may lower norepinephrine requirements and cardiac outputs ameliorating reperfusion injuries. With hemorrhagic shock, NTBI levels persist in contrast to the increased clearance, lung injury, and mortality in the previously reported infection model. These preclinical data suggest that whereas iron derived from older RBCs promotes bacterial growth, worsening septic shock mortality during infection, release of CFH and NTBI during hemorrhagic shock is not necessarily harmful.

Haptoglobin or Hemopexin Therapy Prevents Acute Adverse Effects of Resuscitation After Prolonged Storage of Red Cells

“…Our findings are concordant with previous reports indicating that, compared to FRBCs, SRBCs undergo increased in vivo hemolysis within the first 24 hours after transfusion in animal models and humans 16,18–21,28,29 (Figure 1C and Supplemental Table I). We were surprised to observe that mice receiving FRBCs for resuscitation of hemorrhagic shock had a small but significantly higher MAP immediately after transfusion as compared to mice that received SRBCs 37,38 . Acidosis is associated with vessel dilatation and decrease in systemic peripheral resistance 39 .…”

“…Acidosis is associated with vessel dilatation and decrease in systemic peripheral resistance 39 . When SRBCs are transfused for resuscitation of hemorrhagic shock, the vasodilatory effect of acidosis during and immediately after transfusion might overwhelm any vasoconstrictor effect caused by NO-scavenging by cell-free hemoglobin 38,40 .…”

“…For example, we did not use intensive care therapeutic approaches such as mechanical ventilation or vasopressor therapy, forms of organ support that might be partly responsible for the lower mortality after hemorrhagic shock and SRBC-resuscitation seen in larger animal models such as the canine model used by Solomon and colleagues 38 . In addition, in this study, mice were resuscitated with PRBCs stored for 14 days (mimicking human blood stored for 35–42 days).…”

“…The last two studies did not examine patient subpopulations with comorbidities such as chronic renal disease or inflammation nor were they powered to examine patients who received transfusions with PRBCs that had been stored for longer periods, for example 30–42 days, when most red cell damage and hemolysis occurs 7,9 . It is likely that the risk of adverse outcomes after transfusion of stored blood will depend on the underlying disease and patient subpopulation in which transfusion occurs 20,38 . In previous preclinical studies, animals with bacterial infection that were transfused with SRBCs (42-days storage in dogs and 14-days storage in mice) had a significantly increased mortality compared to those transfused with FRBCs 20,21,52,53 .…”

A flow cytometric assessment of the lymphocyte immunophenotypes in dogs naturally infected with Babesia rossi

“…The traditional murine model of malaria has however been criticised and has deficiencies (17). There is a clear need to explore other possible animal models of haemoprotozoal disease that may offer the research community an opportunity to explore the immunology and pathogenesis as well as possible supportive therapeutic interventions for these diseases (18,19).…”