Reduced oxygen extraction efficiency in sickle cell anemia patients with evidence of cerebral capillary shunting.
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ABSTRACT:
SUBMITTER: Juttukonda MR
PROVIDER: S-EPMC7922746 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Blood transfusions are the mainstay of stroke prevention in pediatric sickle cell anemia (SCA), but the physiology conferring this benefit is unclear. Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) are elevated in SCA, likely compensating for reduced arterial oxygen content (CaO2). We hypothesized that exchange transfusions would decrease CBF and OEF by increasing CaO2, thereby relieving cerebral oxygen metabolic stress. Twenty-one children with SCA receiving chronic transfusion therapy (CTT) underwent magnetic resonance imaging before and after exchange transfusions. Arterial spin labeling and asymmetric spin echo sequences measured CBF and OEF, respectively, which were compared pre- and posttransfusion. Volumes of tissue with OEF above successive thresholds (36%, 38%, and 40%), as a metric of regional metabolic stress, were compared pre- and posttransfusion. Transfusions increased hemoglobin (Hb; from 9.1 to 10.3 g/dL; P < .001) and decreased Hb S (from 39.7% to 24.3%; P < .001). Transfusions reduced CBF (from 88 to 82.4 mL/100 g per minute; P = .004) and OEF (from 34.4% to 31.2%; P < .001). At all thresholds, transfusions reduced the volume of peak OEF found in the deep white matter, a location at high infarct risk in SCA (P < .001). Reduction of elevated CBF and OEF, both globally and regionally, suggests that CTT mitigates infarct risk in pediatric SCA by relieving cerebral metabolic stress at patient- and tissue-specific levels.
| S-EPMC5833262 | biostudies-literature
Project description:Neurologic complications are common in patients with sickle cell anemia (SCA), but conventional tools such as MRI and transcranial Doppler ultrasonography (TCD) do not fully assess cerebrovascular pathology. Cerebral tissue oximetry measures mixed oxygen saturation in the frontal lobes (SCT O2 ) and provides early prognostic information about tissue at risk of ischemic injury. Untreated patients with SCA have significantly lower SCT O2 than healthy controls that declines with age. Hydroxyurea is effective in preventing many SCA-related complications, but the degree to which it preserves normal neurophysiology is unclear. We analyzed participants enrolled in the Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154), which enrolled participants initiating hydroxyurea using individualized dosing (new cohort) and those previously taking hydroxyurea (old cohort) and was designed to monitor the long-term benefits of hydroxyurea. Cerebral oximetry was performed at baseline and annually. For the new cohort (median starting age = 12 months, n = 55), mean baseline SCT O2 was normal before starting hydroxyurea (mean 65%, 95% CI 58-72%) and significantly increased after 2 years (mean 72%, 95% CI 65-79%, p < .001). The SCT O2 for patients receiving long-term hydroxyurea (median age = 9.6 years) was normal at study entry (mean 66%, 95% CI 58-74%) and remained stable across 2 years. Both cohorts had significantly higher SCT O2 than published data from predominantly untreated SCA patients. Cerebral oximetry is a non-invasive method to assess cerebrovascular pathology that complements conventional imaging. Our results indicate that hydroxyurea suggests protection against neurophysiologic changes seen in untreated SCA.
| S-EPMC8858025 | biostudies-literature
Project description:Moyamoya is a bilateral, complex cerebrovascular condition characterized by progressive non-atherosclerotic intracranial stenosis and collateral vessel formation. Moyamoya treatment focuses on restoring cerebral blood flow (CBF) through surgical revascularization, however stratifying patients for revascularization requires abilities to quantify how well parenchyma is compensating for arterial steno-occlusion. Globally elevated oxygen extraction fraction (OEF) secondary to CBF reduction may serve as a biomarker for tissue health in moyamoya patients, as suggested in patients with sickle cell anemia (SCA) and reduced oxygen carrying capacity. Here, OEF was measured (TRUST-MRI) to test the hypothesis that OEF is globally elevated in patients with moyamoya (n = 18) and SCA (n = 18) relative to age-matched controls (n = 43). Mechanisms underlying the hypothesized OEF increases were evaluated by performing sequential CBF-weighted, cerebrovascular reactivity (CVR)-weighted, and structural MRI. Patients were stratified by treatment and non-parametric tests applied to compare study variables (significance: two-sided P < 0.05). OEF was significantly elevated in moyamoya participants (interquartile range = 0.38-0.45) compared to controls (interquartile range = 0.29-0.38), similar to participants with SCA (interquartile range = 0.37-0.45). CBF was inversely correlated with OEF in moyamoya participants. Elevated OEF was only weakly related to reductions in CVR, consistent with basal CBF level, rather than vascular reserve capacity, being most closely associated with OEF.
| S-EPMC6125968 | biostudies-literature
Project description:BackgroundElevated cerebral fractional tissue oxygen extraction (cFTOE) is an adaptation to anemia of prematurity (AOP). cFTOE ≥0.4 is associated with brain injury in infants ≤30 weeks. This longitudinal study sought to investigate the utility of cFTOE in the evaluation of AOP.MethodsInfants ≤30 weeks estimated gestational age (EGA) underwent weekly hemoglobin, cerebral saturation, and pulse oximetry recordings from the second through 36 weeks post-menstrual age (PMA). Recordings were excluded if they were under 1 h or if hemoglobin was not measured within 7 days of recording. Mean cFTOE was calculated for each recording. Statistical analysis used linear mixed-effects modeling and receiver operating characteristic analysis.Results144 recordings from 39 infants (mean EGA 27.6 ± 2.2 weeks, BW 1139 ± 286 g) were included of whom 39% (15/39) were transfused. The mean recording length was 2.8 ± 1.3 h. There was a significant negative correlation between hemoglobin and cFTOE (R = -0.423, p ≤.001). In a multivariate model, adjusting for EGA, PMA, and patent ductus arteriosus treatment the AUC was 0.821. A critical increase in cFTOE occurred at a hemoglobin level of 9.6 g/dL.ConclusionsAOP is associated with a critical increase in cFTOE that occurs at a significantly higher hemoglobin level than standard clinical thresholds for transfusion.
| S-EPMC7180102 | biostudies-literature
Project description:Cerebral ischemia is a significant source of morbidity in children with sickle cell anemia; however, the mechanism of injury is poorly understood. Increased cerebral blood flow and low hemoglobin levels in children with sickle cell anemia are associated with increased stroke risk, suggesting that anemia-induced tissue hypoxia may be an important factor contributing to subsequent morbidity. To better understand the pathophysiology of brain injury, brain physiology and morphology were characterized in a transgenic mouse model, the Townes sickle cell model. Relative to age-matched controls, sickle cell anemia mice demonstrated: (1) decreased brain tissue pO2 and increased expression of hypoxia signaling protein in the perivascular regions of the cerebral cortex; (2) elevated basal cerebral blood flow , consistent with adaptation to anemia-induced tissue hypoxia; (3) significant reduction in cerebrovascular blood flow reactivity to a hypercapnic challenge; (4) increased diameter of the carotid artery; and (5) significant volume changes in white and gray matter regions in the brain, as assessed by ex vivo magnetic resonance imaging. Collectively, these findings support the hypothesis that brain tissue hypoxia contributes to adaptive physiological and anatomic changes in Townes sickle cell mice. These findings may help define the pathophysiology for stroke in children with sickle cell anemia.
| S-EPMC5363475 | biostudies-literature
Project description:Sickle cell disease (SCD) is caused by a single amino acid mutation in hemoglobin, causing chronic anemia and neurovascular complications. However, the effects of chronic anemia on oxygen extraction fraction (OEF), especially in deep brain structures, are less well understood. Conflicting OEF values have been reported in SCD patients, but have largely attributed to different measurement techniques, faulty calibration, and different locations of measurement. Thus, in this study, we investigated the reliability and agreement of two susceptibility-based methods, quantitative susceptibility mapping (QSM) and complex image summation around a spherical or a cylindrical object (CISSCO), for OEF measurements in internal cerebral vein (ICV), reflecting oxygen saturation in deep brain structures. Both methods revealed that SCD patients and non-sickle anemia patients (ACTL) have increased OEF in ICV (42.6% ± 5.6% and 30.5% ± 3.6% in SCD by CISSCO and QSM respectively, 37.0% ± 4.1% and 28.5% ± 2.3% in ACTL) compared with controls (33.0% ± 2.3% and 26.8% ± 1.8%). OEF in ICV varied reciprocally with hematocrit (r 2 = 0.92, 0.53) and oxygen content (r 2 = 0.86, 0.53) respectively. However, an opposite relationship was observed for OEF measurements in sagittal sinus (SS) with the widely used T2-based oximetry, T2-Relaxation-Under-Spin-Tagging (TRUST), in the same cohorts (31.2% ± 6.6% in SCD, 33.3% ± 5.9% in ACTL and 36.8% ± 5.6% in CTL). Importantly, we demonstrated that hemoglobin F and other fast moving hemoglobins decreased OEF by TRUST and explained group differences in sagittal sinus OEF between anemic and control subjects. These data demonstrate that anemia causes deep brain hypoxia in anemia subjects with concomitant preservation of cortical oxygenation, as well as the key interaction of the hemoglobin dissociation curve and cortical oxygen extraction.
| S-EPMC9248375 | biostudies-literature
Project description:PurposeTo evaluate different T2 -oxygenation calibrations for estimating venous oxygenation in people with sickle cell anemia (SCA).MethodsBlood T2 values were measured at 3 T in the internal jugular veins of 12 healthy volunteers and 11 SCA participants with no history of stroke, recent transfusion, or renal impairment. T2 -oxygenation relationships of both sickled and normal blood samples were calibrated individually and compared with values generated from published models. After converting venous T2 values to venous oxygenation, whole-brain oxygen extraction fraction and cerebral metabolic rate of oxygen were calculated.ResultsSickle blood samples' oxygenation values calculated from our individual calibrations agreed well with measurements using a blood analyzer, whereas previous T2 calibrations based on normal blood samples showed 13%-19% underestimation. Meanwhile, oxygenation values calculated from previous grouped T2 calibration for sickle blood agreed well with experimental measurement on averaged values, but showed up to 20% variation for several individual samples. Using individual T2 calibrations, the whole-brain oxygen extraction fraction and cerebral metabolic rate of oxygen of SCA participants were 0.38 ± 0.08 and 172 ± 42 µmol/min/100 g, respectively, which were comparable to those values measured on healthy volunteers.ConclusionOur results confirm that sickle blood T2 values not only depend on the hematocrit and oxygenation values, but also on other hematological factors. The individual T2 calibrations minimized the effect of heterogeneity of sickle blood between different SCA populations and improved the accuracy of T2 -based oximetry. The measured oxygen extraction fraction and cerebral metabolic rate of oxygen of this group of SCA participants were found to not differ significantly from those of healthy individuals.
| S-EPMC6879787 | biostudies-literature
Project description:In sickle cell disease (SCD), oxygen delivery is impaired due to anemia, especially during times of increased metabolic demand, and cerebral blood flow (CBF) must increase to meet changing physiologic needs. But hyperemia limits cerebrovascular reserve (CVR) and ischemic risk prevails despite elevated CBF. The cerebral metabolic rate of oxygen (CMRO2 ) directly reflects oxygen supply and consumption and may therefore be more insightful than flow-based CVR measures for ischemic risk in SCD. We hypothesized that adults with SCD have impaired CMRO2 at rest and that a vasodilatory challenge with acetazolamide would improve CMRO2 . CMRO2 was calculated from CBF and oxygen extraction fraction (OEF), measured with arterial spin labeling and T2 -prepared tissue relaxation with inversion recovery (T2 -TRIR) MRI. We studied 36 adults with SCD without a clinical history of overt stroke, and nine healthy controls. As expected, CBF was higher in patients with SCD versus controls (mean?±?SD: 74?±?16 versus 46?±?5?mL/100?g/min, P?<?.001), resulting in similar oxygen delivery (SCD: 377?±?67 versus controls: 368?±?42??mol O2 /100g/min, P = .69). OEF was lower in patients versus controls (27?±?4 versus 35?±?4%, P?<?.001), resulting in lower CMRO2 in patients versus controls (102?±?24 versus 127?±?20??mol O2 /100g/min, P = .002). After acetazolamide, CMRO2 declined further in patients (P?<?.01) and did not decline significantly in controls (P = .78), indicating that forcing higher CBF worsened oxygen utilization in SCD patients. This lower CMRO2 could reflect variation between healthy and unhealthy vascular beds in terms of dilatory capacity and resistance whereby dysfunctional vessels become more oxygen-deprived, hence increasing the risk of localized ischemia.
| S-EPMC7155077 | biostudies-literature
Project description:BackgroundIrregular, sporadic episodes of ischemic brain injury are known to occur in sickle cell anemia (SCA), resulting in overt stroke and silent cerebral infarction. Ongoing ischemia in other organs is common in SCA but has never been documented in the brain.ObjectiveTo test the hypothesis that acute silent cerebral ischemic events (ASCIEs) are frequent and potentially transient.DesignCross-sectional and cohort study of children with SCA screened by magnetic resonance imaging (MRI) of the brain for a randomized clinical trial.SettingClinical trial setting in tertiary care centers.PatientsAsymptomatic children with SCA without known stroke, neurologic injury, or epilepsy not receiving treatment with transfusions or hydroxyurea.Main outcome measureIncidence of ASCIEs calculated using single diffusion-weighted MRI scans (acute ischemic events that occurred within 10 days of the MRI).ResultsAcute silent cerebral ischemic events were detected on 1.3% of MRIs (10 of 771) in 652 children (mean age, 10.0 years), with an incidence of 47.3 events per 100 patient-years (95% CI, 22.7-87.2). Two of 10 children with ASCIEs had follow-up MRIs of the brain; only 1 had silent cerebral infarction in the same location as the previously detected ASCIE.ConclusionsChildren with SCA experience ongoing (chronic, intermittent) cerebral ischemia, sometimes reversible, far more frequently than previously recognized. The brain in SCA is at constant threat of ischemia.
| S-EPMC3677221 | biostudies-literature
Project description:The tight coupling between cerebral blood flow and neural activity is a key feature of normal brain function and forms the basis of functional hyperemia. The mechanisms coupling neural activity to vascular responses, however, remain elusive despite decades of research. Recent studies have shown that cerebral functional hyperemia begins in capillaries, and red blood cells (RBCs) act as autonomous regulators of brain capillary perfusion. RBCs then respond to local changes of oxygen tension (PO2) and regulate their capillary velocity. Using ex vivo microfluidics and in vivo two-photon microscopy, we examined RBC capillary velocity as a function of PO2 and showed that deoxygenated hemoglobin and band 3 interactions on RBC membrane are the molecular switch that responds to local PO2 changes and controls RBC capillary velocity. Capillary hyperemia can be controlled by manipulating RBC properties independent of the neurovascular unit, providing an effective strategy to treat or prevent impaired functional hyperemia.
| S-EPMC6541463 | biostudies-literature