Acute
anemia increases the risk for perioperative morbidity and mortality in
critically ill patients who experience blood loss and fluid
resuscitation (
hemodilution). Animal models of acute
anemia suggest that
neuronal nitric oxide synthase (nNOS)-derived
nitric oxide (NO) is adaptive and protects against
anemia-induced mortality. During acute
anemia, we have observed a small but consistent increase in
methemoglobin (MetHb) levels that is inversely proportional to the acute reduction in Hb observed during
hemodilution in animals and humans. We hypothesize that this increase in MetHb may be a
biomarker of
anemia-induced tissue
hypoxia. The increase in MetHb may occur by at least two mechanisms: (1) direct
hemoglobin oxidation by increased nNOS-derived NO within the perivascular tissue and (2) by increased
deoxyhemoglobin (DeoxyHb)
nitrite reductase activity within the vascular compartment. Both mechanisms reflect a potential increase in NO signaling from the tissue and vascular compartments during
anemia. These responses are thought to be adaptive; as deletion of nNOS results in increased mortality in a model of acute
anemia. Finally, it is possible that prolonged activation of these mechanisms may lead to maladaptive changes in redox signaling. We hypothesize, increased MetHb in the vascular compartment during acute
anemia may reflect activation of adaptive mechanisms which augment NO signaling. Understanding the link between
anemia, MetHb and its treatments (transfusion of stored blood) may help us to develop novel treatment strategies to reduce the risk of
anemia-induced morbidity and mortality.