Elevated Cerebral Blood Oxygen Extraction in Non-Transfused Sickle Cell Disease Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1387-1387
Author(s):  
Adam M Bush ◽  
Matthew Borzage ◽  
Soyoung Choi ◽  
Thomas Coates ◽  
John C Wood
Keyword(s):  
Sickle Cell Disease ◽  
Metabolic Rate ◽  
Sickle Cell ◽  
Oxygen Extraction Fraction ◽  
Oxygen Extraction ◽  
Cell Disease ◽  
T2 Relaxation ◽  
Hemoglobin S ◽  
Cerebral Metabolic Rate ◽  
Extraction Fraction

Abstract Introduction Chronic Transfusion Therapy (CTT) has been successful in decreasing stroke frequency in patients with sickle cell disease (SCD). Despite this, indication for CTT is largely based on empirical evidence and the mechanisms by which CTT protects the brain remain unclear. CTT improves oxygen carrying capacity and lowers hemoglobin S%, but the corresponding impact on cerebral blood flow(CBF), cerebral metabolic rate (CMRO2), and oxygen extraction fraction (OEF) is unknown. Understanding the impact of these competing influences in non-transfused (NT) and chronically transfused (CT) SCD patients will inform stroke prevention. Thus, we measured CBF, CMRO2, and OEF, in NT and CT patients with SCD using magnetic resonance imaging (MRI). Methods All patients were recruited with informed consent or assent and this study was approved by the CHLA IRB. Fourteen (6 NT, 8 CT) patients with SCD and 12 healthy ethnicity matched controls (CTL) were studied. Exclusion criteria included pregnancy, previous stroke, acute chest or pain crisis hospitalization within one month. Complete blood count and hemoglobin electrophoresis were performed. Arterial oxygen saturation (SaO2) was measured via peripheral pulse oximetery. CaO2 was calculated as the product of hemoglobin, SaO2 and the oxygen density of hemoglobin (1.36 ml/g). Phase contrast imaging of the carotid and vertebral arteries was used to measure global CBF. T2 Relaxation Under Spin Tagging (TRUST) was used to measured T2 relaxation of blood within the sagittal sinus. T2 relaxation was converted to SvO2 via previously validated calibration curves. OEF represented the difference of SaO2 andSvO2 divided bySaO2. CMRO2 was calculated as the product of CBF and OEF. High resolution, 3D, T1 weighted images were used for brain volume calculation using BrainSuiteñ software. Results Table 1 summarizes the results. Hemoglobin and oxygen content were well matched between transfused and non transfused SCD patients. Cerebral metabolic rate was also nearly identical in the two groups. However, CT patients exhibited 25% higher CBF than NT SCD patients, allowing them to have a normal oxygen extraction fraction ~30%. In contrast, OEF in NT SCD patients was abnormally high (37.8%), suggesting a decreased extraction reserve. Total oxygenation index (TOI) by NIRS also trended lower in NT SCD patients, consistent with the greater oxygen extraction and lower cerebral venous saturations observed. Abstract 1387. TableCTL (reference)NTCTp value (NT vs CT)Hemoglobin (g/dl)13.5 ± 1.229.7 ± 1.259.7 ± 1.05nsCaO2 (umol O2/ml)9.85 ± .996.84 ± 1.176.95 ±.71nsCMRO2 (umol O2/100g/min)193.1 ± 44.9239.7 ± 35.3238.6 ± 38.3nsCBF (ml/100g/min)70.0 ± 12.8101.5 ± 16.6127.1 ± 23.5< 0.05OEF (%)30.0 ± 7.137.8. ± 3.0629.7 ± 7.53< 0.05NIRS TOI56.0 ± 4.0948.5 ± 4.2153.5 ± 8.760.076SvO2 (%)65.6 ± 6.856.2 ± 5.267.1 ± 6.7< 0.05 Discussion: Chronically transfused SCD patients achieve normal brain oxygenation metrics (SvO2, OEF, and NIRS) but require very high CBF to achieve this balance (lowering flow reserve). In contrast, NT SCD patients have smaller increases in CBF but require greater oxygen extraction to meet cerebrovascular demands (lowering extraction reserve). Hemoglobin S mediate changes in oxygen dissociation, blood viscosity, red cell deformability and microvascular damage potentially mediate these differences but their interplay is complicated and requires further study. Disclosures Coates: novartis: Consultancy, Honoraria, Speakers Bureau; shire: Consultancy, Honoraria; apo pharma: Consultancy, Honoraria; acceleron: Consultancy, Honoraria.

scholarly journals Reduced Cerebral Metabolic Rate of Oxygen in Adults with Sickle Cell Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 11-11
Author(s):  
Lena Vaclavu ◽  
Esben Thade Petersen ◽  
Ed T VanBavel ◽  
Charles BL Majoie ◽  
Aart J Nederveen ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Metabolic Rate ◽  
Sickle Cell ◽  
Carrying Capacity ◽  
Oxygen Extraction Fraction ◽  
Healthy Controls ◽  
Cell Disease ◽  
Whole Brain ◽  
Cerebral Metabolic Rate ◽  
Oxygen Carrying Capacity

Abstract Introduction: Cerebral blood flow (CBF) is increased in sickle cell disease (SCD) to compensate for chronic hemolytic anemia. Since the brain is strongly dependent on adequate oxygen levels, severe anemia may result in ischemia and silent cerebral infarctions (SCIs), which are present in the majority of patients with SCD. Besides CBF, the cerebral metabolic rate of oxygen (CMRO2), representing the cerebral oxygen consumption, can be measured using specialized MRI techniques. CMRO2 is dependent on CBF, OEF oxygen extraction fraction (OEF) and the hematocrit in the cerebral circulation. In order to maintain stable CMRO2 the OEF changes to compensate for fluctuations in CBF. Previous studies found either elevated or reduced rather than stable CMRO2 in SCD. To further explore the regulation of cerebral oxygenation in SCD, we measured CMRO2, OEF and CBF using MRI at rest and upon administration of acetazolamide (ACZ), a non-metabolic vasodilator. In addition, we related the CMRO2 to the prevalence and location of SCIs and to laboratory parameters of hemolysis. Methods: Adult SCD patients (HbSS/HbSβ0) without a history of stroke, and healthy age-, sex, and race-matched controls were recruited for this IRB-approved MRI study with ACZ-induced vasodilation and venous blood sampling. MRI images were acquired at 3T (Philips Healthcare, Best, NL). Sequences included 3D FLAIR with 1mm isotropic resolution for lesion evaluation, longitudinal and transverse relaxation times of blood (T1b and T2b) in the cerebral sagittal sinus using a T2 prepared tissue relaxation with inversion recovery sequence (T2-TRIR), and pseudo-continuous arterial spin labeling (ASL) for whole brain CBF measurements. T1b was used to correct ASL-based CBF values. T2b was converted to venous saturation (Yv) using a recently published SCD-specific model, which was calibrated in sickle blood rather than bovine blood. CBF was measured at baseline and 10 min post acetazolamide (ACZ) (16mg/kg intravenous infusion over 3min). Images were co-registered and quantified using the ExploreASL toolbox. CMRO2 was calculated as follows: CMRO2 = CBF * OEF * Ca, where CBF is the whole brain CBF map from ASL, OEF is the arteriovenous oxygen saturation (Y) difference (Ya-Yv/Ya) derived from T2 measurements, and Ca is the oxygen carrying capacity of blood calculated from hematocrit sampled immediately prior to MRI. Blood markers of hemolysis (reticulocyte count and bilirubin) were correlated to MRI hemodynamic markers using bivariate Spearman's rho (ρ). Group comparisons were tested using Student's t-tests. P values <0.05 were considered statistically significant. Results: As expected, CBF was significantly higher in patients with SCD (69 ± 16 mL/100g/min) compared to healthy controls (42 ± 4 mL/100g/min, P <0.001), whereas oxygen carrying capacity (Ca) was significantly lower in patients with SCD vs healthy controls due to lower hematocrit (485 ± 83 vs 794 ± 66 μmol O2/100ml blood, P=0.001). At baseline, mean CMRO2 was lower in patients with SCD compared to healthy controls (88 ± 20 vs 117 ± 18 μmol/100 g/min, P = 0.002), contrary to our hypothesis, indicating a reduced oxygen metabolism in patients with SCD. After acetazolamide, CMRO2 remained the same due to an increase in CBF (P<0.001) and a compensatory reduction in OEF. The reduction in OEF in patients with SCD and healthy controls (20 ± 7 vs 19 ± 6, respectively P= 0.76) indicates that OEF adjusts appropriately according to the increased flow. By mapping CMRO2 and the locations of SCIs, we found that lesions were most prevalent in the regions with the lowest CMRO2 corresponding to the deep white matter and borderzone regions, supporting an ischemic etiology of lesions. High hemolytic rate was associated with higher CMRO2 most likely due to an increased CBF. Conclusion: We observed reduced CMRO2 in patients with SCD compared to healthy controls due to low OEF. A reduced CMRO2 could pose a risk for ischemia, despite high flow rate delivering oxygen, because of low OEF. This is supported by the fact that the silent cerebral infarcts are located in regions with the lowest CMRO2. We postulate that patients with SCD have a reduced capacity to increase the OEF in regions with inadequate CBF resulting in local ischemia and local infarction. The pathogenesis of the reduced OEF remains unclear but could be related to arteriovenous shunting whereby there is insufficient time for oxygen to dissociate. Figure Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effect of ephedrine and phenylephrine on brain oxygenation and microcirculation in anaesthetised patients with cerebral tumours: study protocol for a randomised controlled trial

BMJ Open ◽  
2017 ◽  
Vol 7 (11) ◽  
pp. e018560 ◽  
Author(s):  
Klaus Ulrik Koch ◽  
Anna Tietze ◽  
Joel Aanerud ◽  
Gorm von Öettingen ◽  
Niels Juul ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Metabolic Rate ◽  
Transit Time ◽  
Oxygen Extraction Fraction ◽  
Oxygen Extraction ◽  
Brain Oxygenation ◽  
Cerebral Metabolic Rate ◽  
Arterial Blood ◽  
Extraction Fraction

IntroductionDuring brain tumour surgery, vasopressor drugs are commonly administered to increase mean arterial blood pressure with the aim of maintaining sufficient cerebral perfusion pressure. Studies of the commonly used vasopressors show that brain oxygen saturation is reduced after phenylephrine administration, but unaltered by ephedrine administration. These findings may be explained by different effects of phenylephrine and ephedrine on the cerebral microcirculation, in particular the capillary transit-time heterogeneity, which determines oxygen extraction efficacy. We hypothesised that phenylephrine is associated with an increase in capillary transit-time heterogeneity and a reduction in cerebral metabolic rate of oxygen compared with ephedrine. Using MRI and positron emission tomography (PET) as measurements in anaesthetised patients with brain tumours, this study will examine whether phenylephrine administration elevates capillary transit-time heterogeneity more than ephedrine, thereby reducing brain oxygenation.Methods and analysisThis is a double-blind, randomised clinical trial including 48 patients scheduled for surgical brain tumour removal. Prior to imaging and surgery, anaesthetised patients will be randomised to receive either phenylephrine or ephedrine infusion until mean arterial blood pressure increases to above 60 mm Hg or 20% above baseline. Twenty-four patients were allocated to MRI and another 24 patients to PET examination. MRI measurements include cerebral blood flow, capillary transit-time heterogeneity, cerebral blood volume, blood mean transit time, and calculated oxygen extraction fraction and cerebral metabolic rate of oxygen for negligible tissue oxygen extraction. PET measurements include cerebral metabolic rate of oxygen, cerebral blood flow and oxygen extraction fraction. Surgery is initiated after MRI/PET measurements and subdural intracranial pressure is measured.Ethics and disseminationThis study was approved by the Central Denmark Region Committee on Health Research Ethics (12 June 2015; 1-10-72-116-15). Results will be disseminated via peer-reviewed publication and presentation at international conferences.Trial registration numberNCT02713087; Pre-results. 2015-001359-60; Pre-results.

Hemoglobin S Exhibits Distinct MRI Oximetry Calibration in Vitro

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4842-4842
Author(s):  
Adam M Bush ◽  
Thomas D. Coates ◽  
John C Wood
Keyword(s):  
Sickle Cell Disease ◽  
Oxygen Saturation ◽  
Sickle Cell ◽  
Model Fit ◽  
Oxygen Extraction Fraction ◽  
Cell Disease ◽  
Extraction Fraction ◽  
Gray Circle

Abstract Cerebral oxygen extraction fraction (OEF) is a powerful biomarker that could be used to stratify cerebrovascular morbidity in patients with sickle cell disease (SCD). Recently, several MRI intravascular oximetry techniques have demonstrated early feasibility in non-invasively quantitating OEF. Critical to this technique is the use of empirically derived calibrations that convert the measured magnetic relaxation property, T2, into oxygen saturation. Previous work demonstrated a strong hematocrit and saturation dependence on T2 and our prior work extended early results to hematocrit ranges common in patients with chronic anemia1. Despite improvements in calibration models, it remains an unanswered question whether the unique hemorheologic properties of hemoglobin S (HbS) containing red cells will give rise to fundamentally distinct magnetic properties compared to healthy, hemoglobin A (HbA) cells. Methods: All studies were performed on at CHLA under an IRB protocol with consent/assent. The blood of 11 subjects with sickle cell disease were studied (6 Male, 5 Female, aged 25.4 ± 14.5 years). Six had HbSS, three had HbSC, and two had HbSB0). Three of the subjects were on chronic transfusion therapy (2HbSS, 1 HbSB0). Two tablespoons of blood was drawn for the antecubital vein and stored at 4°C until analysis. For analysis, blood was placed in a custom built imaging apparatus and heated to 37° C. Oxygen level was measured with a hemoximeter and T2 was measured within a 3T Philips scanner. Following the T2 measurement blood was removed from the imaging apparatus and desaturated in a temperature controlled chamber using a membrane oxygenator and 5% CO2 and 95% N2 gas mixture. MRI T2 measurements and deoxygenation were repeated until a blood saturation level of ~30% was reached. T2 was measured with a phase cycled, CPMG sequence with 0, 4, 8 16 inversions pulse and a tau of 10ms. Monoexponetial fitting was used to derive T2. Results: Our previous work using a similar system and HbA blood demonstrated a highly reproducible relationship linking T2 to hematocrit and oxygen saturation (Y) as follows: R2= 1/T2 = A1*HCT*(1-Y)2 + A2*(1-Y)2 + A3*HCT + A4 where the coefficients A1, A2, A3, and A4 were fit to data from a broad range of hematocrit and oxygen saturation values. In blood from sickle cell patients, we found that the A1 and A3 terms were zero. Thus the calibration curve was essentially independent of hematocrit. Figure 1 shows the tight relationship between hematocrit and 1/T2 for HbA could not be reproduced in HbS blood. In Figure 2, 1/T2 maintained a tight relationship (R2=.981) with (1-Y)2. The slope of 1/T2 and (1-Y)2was higher in HbS blood compared to HbA. There was also a positive relationship between HbS% and the residual of (1-Y)2 and R2 however this is was a weak effect (R2=0.057). Discussion: We found that the T2 of HbS containing red cells is distinct from the healthy HbA containing cells. This work has clinical implications for intravascular MRI oximetry performed in patients with sickle cell disease2 in that neglecting the magnetic differences between HbA and HbS may result in a 9.5%± 2.8% average bias in absolute saturation at a HCT of 32% . Interestingly, we were unable find a difference across sickle phenotypes and only small differences in transfused vs nontransfused patients. We suspect that irreversibly sickled cells, even few in number, will greatly influence the local magnetic field and shorten the T2 of sickle blood. It remains to be shown whether the in vitro conditions of this experiment are applicable to in vivo condition more broadly. In-vivo cross-validation studies are ongoing. 1). Bush et al. MRM 2016 2). Jordan LC et al. Brain 2016 Jordan LC, Gindville MC, Scott AO, et al. Non-invasive imaging of oxygen extraction fraction in adults with sickle cell anaemia. Brain 2016;139(Pt 3):738-5 Figure 1 Light gray circle designate HbA samples and dark gray squares correspond to HbS. There was a tight linear relationship between HCT and 1/T2 in HbA cells that was not present in HbS cell. Figure 1. Light gray circle designate HbA samples and dark gray squares correspond to HbS. There was a tight linear relationship between HCT and 1/T2 in HbA cells that was not present in HbS cell. Figure 2 Light gray line designates previously published HbA model fit and dark gray squares correspond to HbS. 1/T2 was linearly dependent on (1-Y)2in HbS blood however the slope of this relationship was higher when compared to known relationship with HbA. Figure 2. Light gray line designates previously published HbA model fit and dark gray squares correspond to HbS. 1/T2 was linearly dependent on (1-Y)2in HbS blood however the slope of this relationship was higher when compared to known relationship with HbA. Disclosures Wood: World Care Clinical: Consultancy; Celgene: Consultancy; World Care Clinical: Consultancy; Vifor: Consultancy; Vifor: Consultancy; Ionis Pharmaceuticals: Consultancy; Ionis Pharmaceuticals: Consultancy; Celgene: Consultancy; AMAG: Consultancy; AMAG: Consultancy; Apopharma: Consultancy; Apopharma: Consultancy; Biomed Informatics: Consultancy; Biomed Informatics: Consultancy.

Abstract WMP97: Regional Cerebral Oxygen Extraction is Elevated in Tissue at High Risk of Stroke in Pediatric Sickle Cell Disease

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Andria L Ford ◽  
Kristin P Guilliams ◽  
Melanie Fields ◽  
Dustin K Ragan ◽  
Cihat Eldeniz ◽  
...  
Keyword(s):  
High Risk ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Retrospective Cohort ◽  
Stroke Risk ◽  
Oxygen Extraction Fraction ◽  
Oxygen Extraction ◽  
Cell Disease ◽  
Heat Map ◽  
Spin Echo Sequence

Introduction: Children with sickle cell disease (SCD) are at high risk of stroke. Hemispheric oxygen extraction fraction (OEF) is a predictor of stroke in adults with carotid occlusion, but OEF has not been evaluated as a predictor of stroke in children with SCD. Hypothesis: OEF is elevated in SCD children compared to controls within a region at high risk of stroke as defined by an infarct heat-map created from a separate retrospective SCD cohort. Methods: A prospective MRI study enrolled 37 children aged 5-21: 17 with SCD and no stroke, 12 with SCD and silent infarcts (median infarct volume=0.3ml), and 8 sibling controls. None were on transfusions or had overt stroke history. Voxel-wise OEF was measured using an asymmetric spin echo sequence. In a separate retrospective cohort of 67 SCD children with overt and silent stroke, infarct regions on FLAIR were manually outlined and coregistered to an average T1 map to create an infarct heat-map (Fig A) which was used to define a “high risk” ROI (defined by >3% infarct density). This ROI was aligned to individual OEF maps from the prospective cohort (Fig B, average OEF map). OEF within the “high risk” ROI was compared between SCD children and controls; and between SCD children with and without infarction using Mann Whitney U tests. Results: The infarct heat-map from the retrospective cohort (Fig A) and the average OEF map from the prospective SCD cohort (Fig B) demonstrate striking co-localization of infarct density and elevated OEF. Within the “high risk” ROI, OEF was higher in SCD children compared to controls (39% [36, 46] vs. 23% [22, 27], p<0.0001 (Fig C). OEF within this “high risk” ROI did not differ between SCD children with and without infarcts (40% [38, 47] vs. 38% [35, 46], p=0.6). Conclusion: OEF in SCD children is elevated in the internal borderzone, a region with high stroke risk in SCD. Regional OEF may be a marker of cerebral metabolic stress that could be exploited to stratify stroke risk in this vulnerable population.

scholarly journals Regional oxygen extraction predicts border zone vulnerability to stroke in sickle cell disease

Neurology ◽  
2018 ◽  
Vol 90 (13) ◽  
pp. e1134-e1142 ◽  
Author(s):  
Melanie E. Fields ◽  
Kristin P. Guilliams ◽  
Dustin K. Ragan ◽  
Michael M. Binkley ◽  
Cihat Eldeniz ◽  
...  
Keyword(s):  
White Matter ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Border Zone ◽  
Oxygen Extraction Fraction ◽  
Oxygen Extraction ◽  
Cell Disease ◽  
Oxygen Utilization ◽  
Deep White Matter ◽  
Regional Vulnerability

ObjectiveTo determine mechanisms underlying regional vulnerability to infarction in sickle cell disease (SCD) by measuring voxel-wise cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen utilization (CMRO2) in children with SCD.MethodsParticipants underwent brain MRIs to measure voxel-based CBF, OEF, and CMRO2. An infarct heat map was created from an independent pediatric SCD cohort with silent infarcts and compared to prospectively obtained OEF maps.ResultsFifty-six participants, 36 children with SCD and 20 controls, completed the study evaluation. Whole-brain CBF (99.2 vs 66.3 mL/100 g/min, p < 0.001), OEF (42.7% vs 28.8%, p < 0.001), and CMRO2 (3.7 vs 2.5 mL/100 g/min, p < 0.001) were higher in the SCD cohort compared to controls. A region of peak OEF was identified in the deep white matter in the SCD cohort, delineated by a ratio map of average SCD to control OEF voxels. CMRO2 in this region, which encompassed the CBF nadir, was low relative to all white matter (p < 0.001). Furthermore, this peak OEF region colocalized with regions of greatest infarct density derived from an independent SCD cohort.ConclusionsElevated OEF in the deep white matter identifies a signature of metabolically stressed brain tissue at increased stroke risk in pediatric patients with SCD. We propose that border zone physiology, exacerbated by chronic anemic hypoxia, explains the high risk in this region.

Lead Neuropathy and Sickle Cell Disease

PEDIATRICS ◽  
1974 ◽  
Vol 54 (4) ◽  
pp. 438-441
Author(s):  
Gerald Erenberg ◽  
Steven S. Rinsler ◽  
Bernard G. Fish
Keyword(s):  
Case Report ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Lead Poisoning ◽  
Cell Disease ◽  
Hemoglobin S ◽  
Increased Risk ◽  
Rare Manifestation ◽  
Poisoning In Children

Four cases of lead neuropathy in children with hemoglobin S-S or S-C disease are reported. Neuropathy is a rare manifestation of lead poisoning in children, and only ten other cases have been well documented in the pediatric literature. The last previous case report of lead neuropathy was also in a child with hemoglobin S-S disease. The neuropathy seen in the children with sickle cell disease was clinically similar to that seen in the previously reported cases in nonsicklers, but differed in both groups from that usually seen in adult cases. It is, therefore, postulated that children with sickle cell disease have an increased risk of developing neuropathy with exposure to lead. The exact mechanism for this association remains unknown, but in children with sickle cell disease presenting with symptoms or signs of peripheral weakness, the possibility of lead poisoning must be considered.

scholarly journals Sickle Retinopathy in a Person with Hemoglobin S/New York Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-3 ◽  
Author(s):  
Donovan Calder ◽  
Maryse Etienne-Julan ◽  
Marc Romana ◽  
Naomi Watkins ◽  
Jennifer M. Knight-Madden
Keyword(s):  
New York ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Trait ◽  
Laboratory Diagnosis ◽  
Compound Heterozygote ◽  
Cell Disease ◽  
Hemoglobin S

A patient who presented with sickle retinopathy and hemoglobin electrophoresis results compatible with sickle cell trait was found, on further investigation, to be a compound heterozygote with hemoglobin S and hemoglobin New York disease. This recently reported form of sickle cell disease was not previously known to cause retinopathy and surprisingly was observed in a non-Asian individual. The ophthalmological findings, the laboratory diagnosis, and possible pathophysiology of this disorder are discussed. Persons diagnosed with sickle cell trait who present with symptoms of sickle cell disease may benefit from specific screening for this variant.

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