Purpose T2 MRI oximetry can non-invasively determine oxygen saturation (Y) but requires empirical MR calibration models to convert the measured blood transverse relaxation (T2b) into Y. The accuracy of existing T2b models in the presence of blood disorders such as sickle cell disease (SCD) remains unknown. Methods A Carr Purcell Meiboom Gill T2 preparation sequence was used to make 83 whole blood measurements from 11 subjects with SCD in order to derive an ex-vivo hemoglobin S (HbS) T2b model. Forearm venous blood gas, sagittal sinus T2 (T2 Relaxation Under Spin Tagging) and total brain blood flow (phase contrast MRI) were measured in 37 healthy controls and 33 SCD subjects (age 24.6 ± 10.2 years). Cerebral oxygen saturation, extraction fraction and metabolic rate estimates were calculated using three separate T2b models. Cerebral and forearm oxygen extraction fraction were compared. Results Ex-vivo, SCD blood had greater saturation dependent relaxivity than control blood, with a weak dependence on HbS and no dependence on hematocrit. In-vivo, the HbS T2b model predicted Yv values with lowest coefficient of variation (compared to existing T2b models) and the strongest correlation with peripheral venous oximetry (r2=.29). The HbS T2b model predicted systematically higher Yv measurements in SCD patients (73 ± 5 and 61 ± 6, p<0.0001) which was mirrored by peripheral venous measurements (75 ± 20 and 45 ± 20, p<0.0001). Conclusion Cerebral and peripheral oxygen extraction are decreased in SCD patients, suggesting either blood flow is increased beyond metabolic demands or the presence of physiological arterial-venous shunting.

Stroke is common in children with sickle cell disease and results from an imbalance in oxygen supply and demand. Cerebral blood flow (CBF) is increased in patients with sickle cell disease to compensate for their anemia, but adequacy of their oxygen delivery has not been systematically demonstrated. This study examined the physiological determinants of CBF in 37 patients with sickle cell disease, 38 ethnicity matched control subjects and 16 patients with anemia of non-sickle origin. Cerebral blood flow was measured using phase contrast MRI of the carotid and vertebral arteries. CBF increased inversely to oxygen content (r2 = 0.69, p < 0.0001). Brain oxygen delivery, the product of CBF and oxygen content, was normal in all groups. Brain composition, specifically the relative amounts of grey and white matter, was the next strongest CBF predictor, presumably by influencing cerebral metabolic rate. Grey matter/white matter ratio and CBF declined monotonically until the age of 25 in all subjects, consistent with known maturational changes in brain composition. Further CBF reductions were observed with age in subjects older than 35 years of age, likely reflecting microvascular aging. On multivariate regression, CBF was independent of disease state, hemoglobin S, hemoglobin F, reticulocyte count and cell free hemoglobin, suggesting that it is regulated similarly in patients and control subjects. In conclusion, sickle cell disease patients had sufficient oxygen delivery at rest, but accomplish this only by marked increases in their resting CBF, potentially limiting their ability to further augment flow in response to stress.

Purpose We sought a human blood T2-oximetery calibration curve over the wide range of hematocrits commonly found in anemic patients applicable with T2 Relaxation Under Spin Tagging (TRUST). Methods Blood was drawn from 5 healthy control subjects. Ninety-three in vitro blood transverse relaxation (T2b) measurements were performed at 37° C over a broad range of hematocrits (10–55%) and oxygen saturations (14–100%) at 3T. In vivo TRUST was performed on 35 healthy African American control subjects and 11 patients with chronic anemia syndromes. Results 1/T2 rose linearly with hematocrit (r2 = 0.96), for fully saturated blood. Upon desaturation, 1/T2 rose linearly with the square of the oxygen extraction, (1−Y)2, and the slope was linearly proportional to hematocrit (r2= 0.88). The resulting bilinear model between 1/T2, (1−Y)2 and hematocrit had a combined r2 of 0.96 and a coefficient of variation of 6.1%. Using the in-vivo data, the bilinear model had significantly lower bias and variability than existing calibrations, particularly for low hematocrits. In-vivo Bland Altman analysis demonstrated clinically relevant bias that was −6% (absolute saturation) for hematocrits near 30% and rose to +6% for hematocrits near 45%. Conclusion This work introduces a robust bilinear calibration model that should be used for MRI oximetry.

Rationale: Sickle cell disease is an inherited blood disorder characterized by vasoocclusive crises. Although hypoxia and pulmonary disease are known risk factors for these crises, the mechanisms that initiate vasoocclusive events are not well known. Objectives: To study the relationship between transient hypoxia, respiration, and microvascular blood flow in patients with sickle cell. Methods: We established a protocol that mimics nighttime hypoxic episodes and measured microvascular blood flow to determine if transient hypoxia causes a decrease in microvascular blood flow. Significant desaturations were induced safely by five breaths of 100% nitrogen. Measurements and Main Results: Desaturation did not induce change in microvascular perfusion; however, it induced substantial transient parasympathetic activity withdrawal in patients with sickle cell disease, but not controls subjects. Marked periodic drops in peripheral microvascular perfusion, unrelated to hypoxia, were triggered by sighs in 11 of 11 patients with sickle cell and 8 of 11 control subjects. Although the sigh frequency was the same in both groups, the probability of a sigh inducing a perfusion drop was 78% in patients with sickle cell and 17% in control subjects (P , 0.001). Evidence for sighinduced sympathetic nervous system dominance was seen in patients with sickle cell (P , 0.05), but was not significant in control subjects.Conclusions: These data demonstrate significant disruption of autonomic nervous system balance, with marked parasympathetic withdrawal in response to transient hypoxia. They draw attention to an enhanced autonomic nervous system-mediated sigh-vasoconstrictor response in patients with sickle cell that could increase red cell retention in the microvasculature, promoting vasoocclusion.Keywords: hypoxia; autonomic nervous system; respiration; vasoconstriction; sickle cell disease Sickle cell disease (SCD) is an inherited blood disorder that results from an amino acid substitution in the b globin chain of hemoglobin, producing sickle hemoglobin (HbS) (1, 2). HbS polymerizes when it releases oxygen to tissues, causing the normally flexible red blood cells to become rigid and to obstruct blood flow (3). The subsequent ischemia results in chronic organ damage and ultimately premature death (3-5). Although SCD is caused by a single amino acid substitution, significant variability in the frequency of overt sickling episodes has been reported among subjects with the same genotype, suggesting that other factors cause the transition from steady-state sickling to full vasoocclusive crisis (VOC).The specific factors that affect this transition are incompletely understood. Flexible, oxygenated, HbS-containing red blood cells (SRBC) traverse capillaries and release their oxygen. After HbS releases its oxygen, it polymerizes after a short delay and the SRBC become rigid (6). If the SRBC fail to escape the microvasculature within the delay time period, the SRBC become lodged. Thus, any factor that increases the SRBC transit time or shortens t...

Sickle cell disease (SCD) is the most common cause of stroke in childhood and results primarily from a mismatch of cerebral oxygen supply and demand rather than arterial obstruction. However, resting cerebral blood flow (CBF) has not been examined in the general African American population, in whom obesity, hypertension, cerebrovascular disease, and diminished cerebrovascular reserve capacity are common. To better understand the underlying physiological substrate upon which SCD is superimposed, we measured CBF in 32 young (age 28 ± 10 yr), asymptomatic African American subjects with and without sickle cell trait (n= 14). To characterize the effects of chronic anemia, in isolation of sickle hemoglobin we also studied a cohort of 13 subjects with thalassemia major (n= 10), dyserythropoetic anemia (n= 1), or spherocytosis (n= 2). Blood was analyzed for complete blood count, hemoglobin electrophoresis, cell free hemoglobin, and lactate dehydrogenase. Multivariate regression analysis showed that oxygen content was the strongest predictor of CBF (r(2)= 0.33,P< 0.001). CBF declined rapidly in the second and third decades of life, but this drop was explained by reductions in cerebral gray matter. However, age effects persisted after correction for brain composition, possibly representing microvascular impairment. CBF was independent of viscosity, hemoglobin S%, and body mass index. Hyperoxia resulted in reduced CBF by 12.6% (P= 0.0002), and CBF changes were proportional to baseline oxygen content (r(2)= 0.16,P= 0.02). These data suggest that these hemoglobin subtypes do not alter the normal CBF regulation of the balance of oxygen supply and demand.