PURPOSE: Clinical studies demonstrate that anemia increases the risk of morbidity and mortality. Tissue hypoxia is an attractive but incompletely characterized candidate mechanism of anemia-induced organ injury. Physiological responses that optimize tissue oxygen delivery (nitric oxide synthase-NOS) and promote cellular adaptation to tissue hypoxia (hypoxia inducible factor-HIF) may reduce the risk of hypoxic organ injury and thereby improve survival during anemia. The presence of vascular diseases would likely impair the efficacy of these physiological mechanisms, increasing the risk of anemia-induced organ injury. In all cases, biological signals that indicate the activation of these adaptive mechanisms could provide an early and treatable warning signal of impending anemia-induced organ injury. Thus, we review the evidence for tissue hypoxia during acute hemodilutional anemia and also explore the novel hypothesis that methemoglobin, a measurable byproduct of increased NOS-derived nitric oxide (NO), may serve as a biomarker for "anemic stress". SOURCE: Published peer-reviewed studies provided the main source of information. Data from experimental studies were reassessed to derive the relationship between hemodilution (reduced hemoglobin concentration) and increased methemoglobin levels. PRINCIPAL FINDINGS: Active physiological mechanisms (sympathetic nervous system) are required to maintain optimal tissue oxygen delivery during hemodilutional anemia. Despite these responses, tissue hypoxia occurs during acute hemodilution, as demonstrated by a decrease in tissue PO(2) and an increase in hypoxic cellular responses (NOS, HIF). Optimal tissue oxygen delivery may be compromised further when cardiovascular responses are impaired. The positive correlation between decreased hemoglobin concentration (Hb) and an increase in methemoglobin levels in acutely anemic animals supports the hypothesis that anemia-induced increases in tissue NOS activity could promote methemoglobin formation. Methemoglobin may be a measurable byproduct of NO-mediated Hb oxidation. CONCLUSIONS: Evidence continues to demonstrate that anemia increases morbidity and mortality, possibly via hypoxic mechanisms. A potential strategy for assessing "anemic stress" was derived from experimental data based on a readily measurable biomarker, methemoglobin. New methods for measuring real-time hemoglobin and methemoglobin levels in patients may provide the basis to translate this idea into clinical practice. Further mechanistic studies are required to determine if the impact of reduced tissue oxygen delivery and activation of hypoxic cellular mechanism can be linked to measurable changes in biomarkers and clinical outcomes in acutely anemic patients.
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