Cerebral Oxygen Delivery and Metabolic Rate in Chronically Anemic Subjects

Introduction:

In subjects with chronic anemia syndromes, such as sickle cell disease and major thalassemia, cerebral blood flow (CBF) has been shown to increase in compensation for the decreased oxygen content. In previous works using pseudo-continuous arterial spin labeling, our laboratory has demonstrated the phenomenon of venous outflow suggestive of physiological arteriovenous shunting in anemic subjects with high CBF and short microvascular transit time (Bush et al., 2018). In this study, we evaluated CBF, oxygen delivery (DO₂), oxygen extraction fraction (OEF) and cerebral metabolic rate (CMRO₂) in three subject groups: sickle cell disease (SCD), non-sickle anemia (ACTL) and healthy controls (CTL). We hypothesize that even though DO₂ is preserved in the presence of chronic anemia, due to physiological shunting, OEF and CMRO₂ are impaired in anemic subjects compared to controls.

Methods:

Three study groups of 50 SCD subjects, 27 ACTL subjects and 44 healthy controls were tested (Table 1). Oxygen content, DO₂, OEF and CMRO₂ were computed from the hemoglobin level, CBF from phase contrast MRI and venous saturation from TRUST MRI.

Results:

Table 2 shows the global DO₂, OEF and CMRO₂. As expected, anemic patients had approximately 50% higher CBF but similar DO₂ levels compared to healthy controls. Despite normal delivery, both CMRO₂ and OEF are significantly decreased in SCD and ACTL subjects.

Resting DO₂, whether entered as CBF and O₂ content separately or as their product, was the strongest predictor of the brain's metabolic rate, explaining approximately 21% of the variation in baseline CMRO₂. Even after controlling for the variations in delivery, our subjects still demonstrated significant differences based on disease state, with the lowest CMRO₂ in SCD patients, followed by ACTL and then healthy controls (p<0.01). After correcting for both DO₂ and disease state, CMRO₂ was independent of transfusion status, age, sex, hemolytic indices, fetal hemoglobin levels and mean corpuscular volume but remained directly proportional to hemoglobin (p=0.01) and platelets (p=0.01) with a combined r²=0.62.

Discussion:

Using a larger cohort, our results recapitulated the compensatory hyperemic response previously described in anemic subjects. Despite the ability to maintain a normal level of oxygen supply to the brain, these anemic patients had significantly lower cerebral metabolism, consistent with reports from two other laboratories (Vaclavu et al., 2019; Croal et al., 2019). We postulate that poor oxygen utilization is caused by non-nutritive perfusion or physiological arteriovenous shunting. This phenomenon has been previously characterized in SCD and other anemias with high CBF and reduced microvascular transit times. Microvascular oxygen unloading requires sufficient transit time in the capillaries network for efficient oxygen extraction, but transit times had been demonstrated to be significantly shorter in the presence of anemia due to compensatory hyperemia. In chronic anemia syndromes, the elevated CBF that preserves normal DO₂ shortens transit times and impairs oxygen unloading, leading to a decrease in OEF and CMRO₂ in both SCD and ACTL subjects.

The predictors of baseline CMRO₂ yielded interesting insights into the physiological impact of chronic anemia on cerebral oxygen availability and utilization. In acute normovolemic anemia, CMRO₂ is preserved despite declining O₂ carrying capacity. However, in our chronically anemic cohort, CMRO₂ was strongly proportional to resting DO₂; this result suggests that there is a divergence in physiological responses to acute versus chronic anemia. While DO₂ was the strongest predictor of CMRO₂, disease state, hemoglobin level and platelets remained in the multivariate model, confirming the roles of anemia, inflammation, and disease-specific factors in the modulating CMRO₂.

In summary, this report demonstrates impaired cerebral oxygen supply-demand matching in chronically anemic subjects. Cerebral hyperemia appears to simultaneously preserve DO₂ while diminishing OEF and CMRO₂. This observation may explain why absolute hemoglobin level remains the strongest predictor of poor neurovascular outcome in SCD patients, and raises questions regarding the proper hemoglobin target level for hydroxyurea and chronic transfusion therapy.

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