From the perspectives of disease transmission and sterility maintenance, the world's blood supplies are generally safe. However, in multiple clinical settings, red blood cell (RBC) transfusions are associated with adverse cardiovascular events and multiorgan injury. Because ∼85 million units of blood are administered worldwide each year, transfusion-related morbidity and mortality is a major public health concern. Blood undergoes multiple biochemical changes during storage, but the relevance of these changes to unfavorable outcomes is unclear. Banked blood shows reduced levels of S-nitrosohemoglobin (SNO-Hb), which in turn impairs the ability of stored RBCs to effect hypoxic vasodilation. We therefore reasoned that transfusion of SNO-Hb-deficient blood may exacerbate, rather than correct, impairments in tissue oxygenation, and that restoration of SNO-Hb levels would improve transfusion efficacy. Notably in mice, administration of banked RBCs decreased skeletal muscle pO 2 , but infusion of renitrosylated cells maintained tissue oxygenation. In rats, hemorrhage-induced reductions in muscle pO 2 were corrected by SNO-Hb-repleted RBCs, but not by control, stored RBCs. In anemic awake sheep, stored renitrosylated, but not control RBCs, produced sustained improvements in O 2 delivery; in anesthetized sheep, decrements in hemodynamic status, renal blood flow, and kidney function incurred following transfusion of banked blood were also prevented by renitrosylation. Collectively, our findings lend support to the idea that transfusions may be causally linked to ischemic events and suggest a simple approach to prevention (i.e., SNO-Hb repletion). If these data are replicated in clinical trials, renitrosylation therapy could have significant therapeutic impact on the care of millions of patients.ethyl nitrite | hemoglobin cysbeta93 | nitric oxide | storage lesion

Disruption of microvascular blood flow is a common cause of tissue hypoxia in disease, yet no therapies are available that directly target the microvasculature to improve tissue oxygenation. Red blood cells (RBCs) autoregulate blood flow through S‐nitroso‐hemoglobin (SNO‐Hb)‐mediated export of nitric oxide (NO) bioactivity. We therefore tested the idea that pharmacological enhancement of RBCs using the S‐nitrosylating agent ethyl nitrite (ENO) may provide a novel approach to improve tissue oxygenation. Serial ENO dosing was carried out in sheep (1–400 ppm) and humans (1–100 ppm) at normoxia and at reduced fraction of inspired oxygen (FiO2). ENO increased RBC SNO‐Hb levels, corrected hypoxia‐induced deficits in tissue oxygenation, and improved measures of oxygen utilization in both species. No adverse effects or safety concerns were identified. Inasmuch as impaired oxygenation is a major cause of morbidity and mortality, ENO may have widespread therapeutic utility, providing a first‐in‐class agent targeting the microvasculature.

Banked blood exhibits impairments in nitric oxide (NO)‐based oxygen delivery capability, reflected in rapid depletion of S‐nitrosohemoglobin (SNO‐Hb). We hypothesized that transfusion of even freshly‐stored blood used in pediatric heart surgery would reduce SNO‐Hb levels and worsen outcome. In a retrospective review (n = 29), the percent of estimated blood volume (% eBV) replaced by transfusion directly correlated with ventilator time and inversely correlated with kidney function; similar results were obtained in a prospective arm (n = 20). In addition, an inverse association was identified between SNO‐Hb and postoperative increase in Hb (∆Hb), reflecting the amount of blood retained by the patient. Both SNO‐Hb and ∆Hb correlated with the probability of kidney dysfunction and oxygenation‐related complications. Further, regression analysis identified SNO‐Hb as an inverse predictor of outcome. The findings suggest that SNO‐Hb and ∆Hb are prognostic biomarkers following pediatric cardiopulmonary bypass, and that maintenance of red blood cell‐derived NO bioactivity might confer therapeutic benefit.

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