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Purpose Transfusion of allogeneic red blood cells (RBCs) is one of the main treatments of acute anemia secondary to blood loss and fluid resuscitation within the operating room. Decisions to transfuse blood are based largely on intermediate biological markers (hemoglobin, arterial oxygen saturation, blood pressure, heart rate) which may not accurately reflect inadequacy of tissue oxygen delivery.Based on experimental studies, we hypothesized that anemia-induced tissue hypoxia activates adaptive mechanisms which promote local vascular nitric oxide (NO) production to improve tissue perfusion and survival during acute anemia. Hemoglobin (Hb) oxidation to methemoglobin (MetHb) may be a byproduct of such local NO production. Therefore, we tested the hypothesis that MetHb is a biomarker of hypoxic-anemic stress during acute hemodilution associated with cardiopulmonary bypass. Methods With institutional ethics approval, routine laboratory arterial blood gas and co-oximetry values were obtained from 295 patients undergoing heart surgery during February 1 to September 30, 2010, and the values were assessed retrospectively. All samples with an arterial oxygen saturation value C90% were included (n = 1,421). The maximal change in Hb associated with hemodilution on cardiopulmonary bypass was determined within 48 hr of surgery (n = 180). A chart review was performed to determine the incidence of RBC transfusion and exogenous nitrate administration. All anonymous data were analyzed by linear regression to determine the relationship between Author contributions Gregory M.T. Hare designed the research, performed the research, contributed novel intellectual input, analyzed the data, and wrote the paper. Alexander Mu performed the research, contributed novel intellectual input, and analyzed the data. Alexander Romaschin designed the research, performed the research, contributed novel intellectual input, and analyzed the data. Nadine Shehata designed the research, performed the research, contributed novel intellectual input, and analyzed the data. W. Scott Beattie designed the research, performed the research, contributed novel intellectual input, analyzed the data, and wrote the paper. C. David Mazer designed the research, performed the research, contributed novel intellectual input, analyzed the data, and wrote the paper. Albert K.Y. Tsui contributed novel intellectual input, analyzed the data, and wrote the paper. RésuméObjectif La transfusion de globules rouges alloge´niques est l'un des principaux traitements de l'ane´mie aigues econdaire a`une perte sanguine et au remplissage liquidien en salle d'ope´ration. La de´cision de transfuser du sang repose essentiellement sur des marqueurs biologiques interme´diaires (he´moglobine, saturation en oxyge`ne du sang arte´riel, pression arte´rielle, fre´quence cardiaque) qui pourraient ne pas refle´ter avec pre´cision l'insuffisance d'apport d'oxyge`ne aux tissus. A`partir d'e´tudes expe´rimentales nous avons fait l'hypothe`se qu'une hypoxie tissulaire induite par l'ane´mie act...