scholarly journals A Meta-Analytic Comparison of Cerebral Blood Flow As Measured By MRI in Children with Sickle Cell Disease Versus Healthy Controls

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1391-1391
Author(s):  
Melanie E. Fields ◽  
Kristin Guilliams ◽  
Dustin Ragan ◽  
Lauren H. Yaeger ◽  
Monica L. Hulbert ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Sickle Cell Disease ◽  
Literature Search ◽  
Meta Analysis ◽  
Cerebral Oxygen ◽  
Healthy Controls ◽  
Cell Disease ◽  
Older Children ◽  
Study Heterogeneity

Abstract Stroke and its neurocognitive sequelae are devastating complications of sickle cell disease (SCD). Cerebral blood flow (CBF), a measure of tissue specific blood flow in the brain, is a key part of cerebral metabolism, and can provide insight into the pathophysiology of the neurologic complications of SCD. Previous work suggests that CBF is elevated in SCD patients compared to healthy controls (HC). Elevated CBF likely represents a compensatory mechanism to maintain cerebral oxygen delivery and metabolism in the setting of decreased arterial oxygen content secondary to chronic anemia. Previous studies are limited by small sample size and variations in imaging technique, making meta-analysis an alluring method for obtaining large numbers of participants to determine and compare population norms. Therefore, we performed a systematic meta-analysis to establish normal CBF values as measured by arterial spin labeled perfusion MR imaging (ASL) in pediatric HC and SCD populations, hypothesizing that CBF would be elevated in children with SCD when compared to a HC cohort. A systematic literature search was performed in 02/2014 for the HC cohort, and 06/2014 for the SCD cohort in Medline, Embase, and CINAHL. Whole brain cerebral blood flow (WB-CBF) measurements obtained by ASL in participants from 1 - 18 years (yr) were necessary for inclusion in both cohorts, and a diagnosis of hemoglobin SS or hemoglobin S-Beta thalassemia null for inclusion in the SCD cohort. ASL is the preferred imaging modality for CBF in pediatrics because ASL non-invasively measures CBF without the use of an exogenous contrast agent or ionizing radiation exposure. Data was excluded from the HC cohort if a medical disorder known to affect CBF was reported. Analysis included determination of mean WB-CBF values weighted by the inverse variance with 95% confidence intervals (CI) stratified by mean age, which was categorized as 1-9 yr and 9-18 yr secondary to known CBF changes throughout development. Statistical heterogeneity, or between-study variability, was assessed with Cochrane's Χ2 and I2. An I2 value greater than 30% was used as the threshold for analysis with a random-effects model. A funnel plot of the effect estimates versus the sample size for each individual study was used to assess for publication bias. Metaregression was used to determine the contribution of covariates to between-study heterogeneity in measurements of WB-CBF. All analyses were performed with STATA 13.1 (College Station, Texas) using the METAN software package. The literature search produced 155 articles for HC patients, and 12 articles for SCD patients; 8 publications met the inclusion and exclusion criteria for the HC cohort (89 children) and 4 publications for SCD cohort (92 children). Between the ages of 1 – 9 yr, mean WB-CBF in HC children was 67.6 ml/100 g/min (95% CI 37.9, 97.2), and mean WB-CBF in children with SCD was 117.0 ml/100 g/min (95%CI 48.7, 185.4). Between the ages of 10 – 18 yr, mean WB-CBF in HC children was 60.8 ml/100 g/min (95% CI 37.7, 83.9), and mean WB-CBF in children with SCD was 68.4 ml/100 g/min (95% CI 50.5, 86.3) (figures 1 and 2). The difference between the two cohorts is not statistically significant because of overlapping CI. The CochraneÕs X2 was significant with a p < 0.001 in all 4 analysis, with the I2 for each analysis ranging from 93.1% - 98.9%, indicating significant between-study heterogeneity. Mean age, ASL labeling technique, MRI vendor, and magnet strength, were not significant predictors of between-study heterogeneity within the HC cohort after controlling for multiple comparisons with the Bonferroni correction. Metaregression analysis of the SCD cohort could not be performed secondary to insufficient number of studies. Visual inspection of funnel plots did not provide evidence of publication bias. Mean WB-CBF as determined by meta-analysis in younger SCD patients is higher than mean WB-CBF in HC children, with little difference seen in older children. These findings suggest that younger children with SCD require increased compensation via elevated CBF to maintain cerebral oxygen metabolism when compared to older children. The significant between-study heterogeneity and wide CI illustrate a need to standardize the ASL technique for CBF measurement within pediatric HC and SCD populations, and the importance of including an age-matched control population when measuring CBF in SCD children. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mechanisms of Stroke in Sickle Cell Disease: Sickle Erythrocytes Decrease Cerebral Blood Flow in Rats After Nitric Oxide Synthase Inhibition

Blood ◽  
1997 ◽  
Vol 89 (12) ◽  
pp. 4591-4599 ◽  
Author(s):  
James A. French ◽  
Dermot Kenny ◽  
J. Paul Scott ◽  
Raymond G. Hoffmann ◽  
James D. Wood ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Vascular Endothelium ◽  
Cell Disease ◽  
Cerebral Microvessels ◽  
Doppler Flowmetry ◽  
Cranial Window

Abstract The etiology of stroke in sickle cell disease is unclear, but may involve abnormal red blood cell (RBC) adhesion to the vascular endothelium and altered vasomotor tone regulation. Therefore, we examined both the adhesion of sickle (SS)-RBCs to cerebral microvessels and the effect of SS-RBCs on cerebral blood flow when the nitric oxide (NO) pathway was inhibited. The effect of SS-RBCs was studied in the rat cerebral microcirculation using either a cranial window for direct visualization of infused RBCs or laser Doppler flowmetry (LDF ) to measure RBC flow. When fluorescently labeled human RBCs were infused into rats, SS-RBCs had increased adhesion to rat cerebral microvessels compared with control AA-RBCs (P = .01). Next, washed SS-RBCs or AA-RBCs were infused into rats prepared with LDF probes after pretreatment (40 mg/kg intravenously) with the NO synthase inhibitor, N-ω-nitro-L-arginine methyl ester (L-NAME), or the control isomer, D-NAME. In 9 rats treated with systemic L-NAME and SS-RBCs, 5 of 9 experienced a significant decrease in LDF and died within 30 minutes after the RBC infusion (P = .0012). In contrast, all control groups completed the experiment with stable LDF and hemodynamics. Four rats received a localized superfusion of L-NAME (1 mmol/L) through the cranial window followed by infusion of SS-RBCs. Total cessation of flow in all observed cerebral microvessels occurred in 3 of 4 rats within 15 minutes after infusion of SS-RBCs. We conclude that the NO pathway is critical in maintaining cerebral blood flow in the presence of SS-RBCs in this rat model. In addition, the enhanced adhesion of SS-RBCs to rat brain microvessels may contribute to cerebral vaso-occlusion either directly, by disrupting blood flow, or indirectly, by disturbing the vascular endothelium.

Therapeutic Efficacy of Semisynthetic Supra Perfusion Resuscitation Fluids, EAF Peg Alb and EAF Peg Hb, Are Differentiated By Their Cerebral Effects in Animal Models of Sickle Cell Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 773-773
Author(s):  
Craig A Branch ◽  
Min-Hui Cui ◽  
Sangeetha Thangaswamy ◽  
Nicholas Branch ◽  
Seetharama Acharya
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Oxygen Delivery ◽  
Therapeutic Efficacy ◽  
Systemic Circulation ◽  
Cerebral Oxygen ◽  
Cremaster Muscle ◽  
Cell Disease ◽  
The Brain

Abstract Background: Extension Arm Facilitated (EAF) PEG Alb and EAF PEG Hb are low viscosity semisynthetic hybrid biopolymers which are isoviscous with conventional colloidal plasma expanders but are distinguished from them because they are supra perfusion resuscitation fluids (SPF's). These SPF's have longer half-life, are pseudoplastic and facilitate the production of NO in vivo by increasing shear thinning of RBC's. We recently tested two SPF's, EAF-P5K6 Alb and P3K6 Hb in WT mice, and in two Tg models of Sickle Cell Disease (SCD): the Berkley mouse (BERK), which is a severe anemic model exhibiting a high impairment of systemic blood flow, and in the NY1DD mouse which only exhibits extensive blood flow impairment when challenged with hypoxia followed by reoxygenation. Here we present a comparison of the systemic and cerebral effects of the EAF PEGgylated SPF's. Methods: A single intraperitoneal 10% top-load dose of either drug was given to WT, NY1DD or BERK mice. In NY1DD mice SPF's were administered after hypoxia at the beginning of reoxygenation (8% for 18 hours), while SPF's were given to WT or BERK mice under normoxia conditions. Three hours after the administration of drug, in vivo intra-vital microscopic observation of post-capillary venules in cremaster muscle was performed. In a separate group of WT and BERK animals, we employed MRI to examine the therapeutic efficacy of a single dose of the same SPF's by measuring cerebral blood flow (CBF) and sufficiency of cerebral oxygen delivery (B OLD MRI R esponse to a brief period of H yperO xia, BRHO) serially following treatment. Results: In NY1DD mice, EAF P5K6 Alb significantly attenuated hopoxia reoxygenation induced impairment of cremaster blood flow and associated vaso-occlusion, while EAF P3K6 Hb completely neutralized the experimentally induced sickle crisis. In BERK mice, both SPF's had comparable effects: the chronic state of vaso-occluison as observed in the cremaster muscle was eliminated completely by EAF P3K6-Hb. In MRI experiments in WT mice, both drug candidates resulted in increases in CBF, which resolved over 1 week. The increased CBF was accompanied by decreased BRHO consistent with a pseudo 'luxury perfusion' afforded by the accentuated delivery of oxygen. On the other hand, when BERK mice were treated with EAF P5K6 Alb or EAF P3K6 Hb, CBF trended lower, but with the Alb SPF, BRHO increased, and the Hb SPF, BHRO was unchanged, suggesting that the slightly reduced CBF led to increased O2 deficiency with the PEG-Alb, but not with the PEG-Hb. Conclusion : In WT mice, SPF's increase CBF in the brain where the facility to modify NO production is intact, resulting in over delivery of oxygen as confirmed by reductions in deoxy-Hb levels by BROH imaging, confirming supraperfusionary properties of the SPF's. In SCD animals, both SPF's attenuate muscle vaso-occlusion and restore blood flow. In addition, in experimentally induced sickle crisis (NY1DD), EAF P3K6 Hb maintained O2 level in the plasma and attenuate depolymerization of deoxyHb. In the severely anemic BERK mouse, EAF P5K6-Alb slightly attenuated CBF, likely due to reduced cerebral perfusion pressure (CPP), while O2 extraction increased suggesting that reduced CBF was detrimental to cerebral oxygen delivery. This effect was remediated when EAF P3K6-Hb is administered, which afforded additional oxygen to offset the losses due to reduced CBF. EAF P3K6 Hb led to slightly reduced CBF in NY1DD and BERK mice to levels approaching that obtained after administering EAF P5K6 Alb, but without inducing further oxygen debt. EAF P3K6 Hb appears to be the choice agent as this SPF facilitates increased delivery of O2 to hypoxic tissues thereby neutralizing painful crisis, and protects the brain from further ischemic insults. The influence of SCD on CBF by MRI is opposite to the decrease in blood flow observed in the systemic circulation. The infusion of SFA's increased flow in the systemic circulation, but reduced CBF in a disease dependent fashion. These divergent responses suggest the need for oxygen supplementation when developing SCD therapeutics. In particular, these studies suggest that high oxygen affinity PEG-Hb may have increased the therapeutic efficacy of this SPF by preventing the complete deoxygenation of HbS in the RBC. An antioxidant conjugated to the SFP, such as quercetin, could attenuate the hypoxia reoxygenation induced acute crisis and improve the efficacy of SCD therapeutics. Disclosures No relevant conflicts of interest to declare.

Relationship between skin microvascular reactivity, cerebral blood flow and hypoxaemia in children with sickle cell disease

2010 ◽  
Vol 95 (Suppl 1) ◽  
pp. A5.2-A5
Author(s):  
VS L'Esperance ◽  
F Kirkham ◽  
C Hill ◽  
S Cox ◽  
J Makani ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease ◽  
Microvascular Reactivity

Nifedipine Increases Cerebral Blood Flow in Sickle Cell Disease: A Case Study

1994 ◽  
Vol 9 (3) ◽  
pp. 337-338 ◽  
Author(s):  
Stephen Ashwal ◽  
Antranik Bedros ◽  
Joseph Thompson
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease

scholarly journals Assessment of Cerebral Blood Flow and Oxygen Extraction in Pediatric Sickle Cell Disease with Non-Invasive Diffuse Optical Spectroscopies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Seung Yup Lee ◽  
Eashani Sathilingam ◽  
Kyle R. Cowdrick ◽  
Rowan O. Brothers ◽  
Wilbur A. Lam ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Low Cost ◽  
Oxygen Extraction ◽  
Signal Quality ◽  
Cell Disease ◽  
Non Invasive

Introduction: Cerebral infarcts and associated cognitive impairments are a devastating consequence of sickle cell disease (SCD). While the underlying mechanisms are poorly understood, infarctions are thought to arise from anemia-induced microvascular perfusion abnormalities and subsequent reduced cerebrovascular reserve that is insufficient to meet tissue metabolic demands. Thus, quantification of abnormalities in microvascular cerebral blood flow (CBF) and oxygen extraction (OEF) may be useful in identifying infarct risk and monitoring therapeutic efficacy. Unfortunately, current modalities that quantify microvascular hemodynamics (e.g., PET, MRI) are prohibitively expensive, have limited availability, and require anesthesia in children &lt;6y, making them inappropriate as routine monitoring tools. Transcranial Doppler ultrasound (TCD) is currently the standard screening tool for overt stroke risk in pediatric SCD, but it only measures blood flow velocity in the large arteries, which is a poor surrogate for microvascular perfusion in sickle cell disease. Diffuse optical spectroscopies (specifically near-infrared frequency-domain spectroscopy, FDNIRS, and diffuse correlation spectroscopy, DCS) offer a low-cost, non-invasive alternative for bedside monitoring of tissue-level OEF and CBF. We previously demonstrated that FDNIRS/DCS are sensitive to elevations in resting-state OEF and CBF in children with sickle cell disease compared to healthy controls (Lee, Neurophotonics 2019), consistent with previous studies using MRI and PET. In this feasibility study, we demonstrate these optical techniques are sensitive to altered cerebral hemodynamics in sickle patients who are 1) undergoing chronic transfusion, and 2) experiencing vaso-occlusive pain episodes (VOE). Methods: To date, we have recruited 6 pediatric patients with sickle cell disease undergoing chronic transfusion (5 females and 1 male, 6 - 14 y, mean ± std hemoglobin change pre- to post-transfusion = 1 ± 0.8 g/dL) and 4 patients admitted to the Emergency department for VOE (2 females and 2 males, 8 - 18 y, mean±std hemoglobin on admission = 8.9 ± 1.6 g/dL). For the transfusion cohort, FDNIRS/DCS measurements were made immediately prior to the start of transfusion and again immediately upon completion. For the VOE cohort, FDNIRS/DCS measurements were made upon hospital admission. For all FDNIRS/DCS assessments, a custom sensor was manually held over right and left forehead to assess oxygen extraction fraction (OEF, %) and an index of microvascular cerebral blood flow (CBFi, cm2/s) (Lee, Neurophotonics 2019). Hemispheric results were averaged to yield a mean of each measured parameter. Total measurement time was less than 15 minutes. Results: In the cohort undergoing chronic transfusion, one patient data was excluded due to poor DCS signal quality. Of the remaining 5 patients, OEF and CBFi decreased after transfusion by a median of -6.4% and -30.0%, respectively (Fig 1A, B). The FDNIRS-measured OEF decrease is comparable to previous results with MRI (Guilliams, Blood 2017) that quantified both cortical OEF and CBF response to transfusion in a similarly aged cohort. However, the DCS-measured CBFi decrease is more prominent than previously reported (30% vs. 9%). The enhanced sensitivity of DCS to CBF in sickle cell disease was reported in our recent study and is likely attributed to the confounding influences of hematocrit on the DCS-measured CBFi (Sathialingam, Biomed Opt Exp 2020). In the cohort measured during VOE, one patient data was excluded due to poor FDNIRS data quality. Of the remaining 3 subjects, OEF was elevated compared to healthy controls and was on the upper range of values measured in a cohort of otherwise subjects with sickle cell disease who were without clinical complications and were measured as part of a separate study (Fig. 1C). Conclusion: These data demonstrate how FDNIRS/DCS may be used as a simple, low-cost tool for bedside assessment of cerebral hemodynamics in non-sedated sickle children that could be used to track brain health over time, particularly during periods thought to be prone to hemodynamic instability like transfusion or VOEs. Although ~20% of data was discarded in this dataset due to improper sensor positioning leading to poor signal quality, we have recently implemented real-time quality control feedback to ensure our data passes quality criteria. Disclosures Lam: Sanguina, Inc: Current equity holder in private company.

Sign in / Sign up

Export Citation Format

Share Document