Plasma methemoglobin as a potential biomarker of anemic stress in humans

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.

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 ≥ 90% 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 Hb and MetHb. A Wilcoxon Signed Rank Test and Student's t test were used to determine changes in Hb, MetHb, and carboxyhemoglobin (CarboxHb) levels. All data are presented as mean and significance was assigned at P < 0.05.

A significant decrease in Hb [118 (20) g x L(-1) vs 94 (18) g x L(-1)] was associated with an increase in MetHb [0.88 (0.22)% vs 0.95 (0.24)%] (P < 0.001 for both), but not CarboxHb [1.08 (0.47)% vs 1.08 (0.49)%]. Regression analysis revealed a significant relationship between the change in Hb and MetHb (F = 40.3; P < 0.001) but not between the change in Hb and CarboxyHb (F = 0.2; P = 0.694). This correlation was not influenced by RBC transfusion or exogenous nitrate use.

A negative correlation was observed between the change in Hb and MetHb in patients undergoing cardiac surgery and cardiopulmonary bypass. These data support the previously unreported hypothesis that MetHb may be a marker of anemic stress associated with reduced tissue perfusion during acute hemodilution in humans. Further prospective studies are needed to determine if these changes in MetHb are linked to adverse outcomes in patients undergoing cardiac surgery.