Impaired Cerebral Perfusion Research Articles

Reinforcement of Transdural Angiogenesis: A Novel Approach to Treating Ischemic Stroke With Cerebral Perfusion Impairment.

Cerebral hypoperfusion plays a critical role in early neurological deterioration and long-term outcomes in patients with acute ischemic stroke, which remains a major global health challenge. This review explored transdural angiogenesis as a promising therapeutic strategy to restore cerebral perfusion in patients with ischemic stroke. The multiple burr hole procedure has been preliminarily used as an indirect revascularization method to induce transdural arteriogenesis. Theoretically, its efficacy could be enhanced by combining it with angiogenic boosters, such as erythropoietin. Recent clinical and preclinical studies have revealed that this combination therapy promotes angiogenesis and arteriogenesis, leading to successful revascularization across the dura mater and improved cerebral blood flow. This strategy may be particularly beneficial for high-risk patients with recurrent ischemic events, such as those with moyamoya disease or intracranial arterial occlusion, representing an effective strategy when conventional medical treatments are insufficient. This review highlights the potential of transdural angiogenesis enhancement as a novel intervention for ischemic stroke, offering an alternative to thrombolysis or endovascular treatment, particularly in acute stroke patients with impaired cerebral perfusion. This approach has the potential to bridge the treatment gap for patients outside the therapeutic window for acute stroke interventions. Although further research is required to refine this technique and validate its efficacy in broader clinical settings, early results have revealed promising outcomes at reducing stroke-related complications and improving patient prognosis. This review indicates that this novel strategy may offer hope for managing ischemic stroke and related conditions associated with significant cerebral hypoperfusion.

Impaired iron metabolism and cerebral perfusion patterns in unilateral middle cerebral artery stenosis or occlusion: Insights from quantitative susceptibility mapping

Background and purposeCerebral hypoperfusion caused by stenosis or occlusion of the middle cerebral artery (MCA) may be followed by impaired iron metabolism. We explored the association between iron changes of gray matter (GM) nuclei subregions and different cerebral perfusion patterns in patients with chronic unilateral middle cerebral artery (MCA) stenosis or occlusion using quantitative susceptibility imaging (QSM). MethodsSixty-one patients with unilateral MCA stenosis or occlusion were recruited and scored with Alberta-Stroke-Program-Early-CT-Score (ASPECTS) based on relative cerebral blood flow (rCBF) measurements to calculate the number of corresponding hypoperfusion subregions, and then divided into an extensive-hypoperfusion group (EH group), regional-hypoperfusion group (RH group), and normal-perfusion group (Control group) accordingly. The measured magnetic susceptibility of GM nuclei subregions was compared between the lesion and contralateral side for each group and among the three groups. Correlation analysis was performed to assess the relationships of magnetic susceptibility of GM nuclei with mean rCBF, National-Institutes-of-Health-stroke-scale (NIHSS) and modified-Rankin-scale (mRS) scores. ResultsMagnetic susceptibility in the putamen (PU) and globus pallidus (GP) at the lesion side was higher in the EH and RH groups compared with the contralateral side (all P < 0.05). Susceptibility in the lesion side PU and GP showed negative correlations with mean rCBF and positive correlations with NIHSS and mRS scores (all P < 0.05). ConclusionOur findings demonstrate that chronic cerebral hypoperfusion might be one cause of cerebral abnormal iron metabolism. In addition, magnetic susceptibility of PU and GP seems to be correlated with stroke scale scores, suggesting that iron deposition may play an important role in neurologic deficits after ischemic stroke.

A Review of Sturge-Weber Syndrome Brain Involvement, Cannabidiol Treatment and Molecular Pathways.

Sturge-Weber syndrome (SWS) is a rare congenital neurocutaneous disorder typically caused by a somatic mosaic mutation in R183Q GNAQ. At-risk children present at birth with a capillary malformation port-wine birthmark. The primary diagnostic characteristic of the disorder includes leptomeningeal enhancement of the brain, which demonstrates abnormal blood vessels and results in impaired venous drainage and impaired local cerebral perfusion. Impaired cerebral blood flow is complicated by seizures resulting in strokes, hemiparesis and visual field deficits, hormonal deficiencies, behavioral impairments, and intellectual disability. Therefore, anti-seizure medication in combination with low-dose aspirin is a common therapeutic treatment strategy. Recently published data indicate that the underlying mutation in endothelial cells results in the hyperactivation of downstream pathways and impairment of the blood-brain barrier. Cannabidiol (CBD) has been used to treat medically refractory seizures in SWS due to its anti-seizure, anti-inflammatory, and neuroprotective properties. Pilot research suggests that CBD improves cognitive impairment, emotional regulation, and quality of life in patients with SWS. Recent preclinical studies also suggest overlapping molecular pathways in SWS and in CBD, suggesting that CBD may be uniquely effective for SWS brain involvement. This review aims to summarize early data on CBD's efficacy for preventing and treating epilepsy and neuro-cognitive impairments in patients with SWS, likely molecular pathways impacted, and provide insights for future translational research to improve clinical treatment for patients with SWS.

Relationship between hemoglobin and specific cognitive domain among older adults using network analysis

Objectives Hemoglobin (Hgb) is associated with cognitive function, with low and high levels of Hgb leading to impaired cerebral oxygenation and perfusion. Yet, current studies focused on understanding the association between Hgb and cognitive function without consideration for each cognitive domain. Thus, this study aims to identify and visualize potentially interactive associations between Hgb and specific cognitive domains among older adults. Method This is a secondary data analysis using Wave II data from the National Social Life, Health, and Aging Project (NSHAP) and included 1022 older adults aged between 65 and 85 years. The network structure of three different models was estimated to understand the association between specific cognitive domains and Hgb in a mixed graphical model using the R-package ‘mgm’. Model 1 did not adjust for any covariates, Model 2 adjusted for age and gender, and Model 3 adjusted for all covariates. Results Among all cognitive domains, the visuospatial (edge weight = 0.06–0.10) and memory domains (0.04–0.07) were associated with Hgb in all three models Though not present in Model 3, the attention domain was associated with Hgb in Model 1 and Model 2 (0.08–0.11). In addition, the predictability of Hgb was the highest (8.1%) in Model 3. Conclusion Findings from this study suggest that cognition should be considered as a multidimensional construct, and its specific cognitive domain should be carefully assessed and managed in relation to Hgb among older adults.

Intracranial Pressure, Autoregulation, and Cerebral Perfusion in Infants With Nonsyndromic Craniosynostosis at the Time of Surgical Correction

BACKGROUND AND OBJECTIVE: Although an increased intracranial pressure (ICP) is a known problem in children with syndromic craniosynostosis, it remains unclear whether elevated ICP and impaired cerebral perfusion exist in nonsyndromic synostosis and should be defined as targets of primary treatment. This study aimed to investigate ICP, cerebral autoregulation (CAR), and brain perfusion in infants with nonsyndromic craniosynostosis at first surgical intervention. METHODS: Forty-three infants were prospectively included. The patients underwent perioperative measurement of mean arterial blood pressure, ICP, and brain perfusion before and after cranial vault decompression. Physiological parameters with possible influences on ICP and autoregulation/brain perfusion were standardized for age. CAR was assessed by the pressure reactivity index (PRx), calculated using the mean arterial blood pressure and ICP. RESULTS: Biparietal decompression was performed in 29 infants with sagittal synostosis (mean age, 6.1 ± 1.3 months). Fronto-orbital advancement was performed in 10 and 4 infants with metopic and unilateral coronal synostosis, respectively (mean age, 11.6 ± 2.1 months). An elevated ICP (&gt;15 mm Hg) was found in 20 of 26 sagittal (mean, 21.7 ± 4.4 mm Hg), 2 of 8 metopic (mean, 17.1 ± 0.4 mm Hg), and 2 of 4 unilateral coronal synostosis cases (mean, 18.9 ± 2.5 mm Hg). Initial ICP was higher in sagittal synostosis than in metopic/coronal synostosis (P = .002). The postdecompression ICP was significantly reduced in sagittal synostosis cases (P &lt; .001). The relative cerebral blood flow and blood flow velocity significantly increased after decompression. Impaired CAR was found in infants with a mean ICP &gt;12 mm Hg (PRx, 0.26 ± 0.32), as compared with those with a mean ICP ≤ 12 mm Hg (PRx, −0.37 ± 0.07, P = .001). CONCLUSION: Contrary to common belief, an elevated ICP and significantly impaired CAR can exist early in single suture synostosis, particularly sagittal synostosis. Because an influence of raised ICP on long-term cognitive development is known in other diseases, we suggest that preventing increased ICP during the phase of maximal brain development may be a goal for decompressive surgery, at least for sagittal synostosis cases.

Occipital Artery to Middle Cerebral Artery Direct Bypass: A Salvage Revascularization Technique for Ischemic Moyamoya Disease

The main treatment for moyamoya disease (MMD) is revascularization surgery. Most bypasses use the superficial temporal artery (STA) as the donor vessel. However, even if the STA-middle cerebral artery (MCA) bypass is functioning, the affected hemisphere can continue to be symptomatically malperfused. We sought to assess the efficacy of salvage direct revascularization surgery using the occipital artery (OA) as a donor vessel in patients with ischemic MMD who experience continued cerebral malperfusion despite previous successful STA-MCA bypass. We retrospectively analyzed the cerebrovascular databases of 2 surgeons and described patients in whom the OA was used as the donor vessel for direct revascularization. Seven patients were included (5 women). Previous STA-MCA bypasses were direct (n= 2), indirect (n= 3), or combined/multiple (n= 2). The mean (SD) interval between STA-MCA and OA-MCA procedures was 29.2 (13.1) months. Despite an intact STA-MCA bypass in all 7 cases, all 7 patients had recurrent symptoms and demonstrated residual impaired cerebral perfusion. All 7 patients underwent successful OA-MCA direct revascularization. Follow-up perfusion imaging was obtained for 6 of 7 patients. All 6 of these patients demonstrated improved cerebral blood flow to the revascularized hemispheres. All 7 patients demonstrated clinical improvement. Patients with ischemic MMD who have continued symptoms and cerebral malperfusion despite previous successful STA-MCA bypass present a challenging clinical scenario. Our series highlights the potential utility of the OA-MCA direct bypass as a salvage therapy for these patients.

Effects of asymptomatic cerebral artery stenosis of anterior circulation and establishment of collateral circulation on cognition

ObjectiveThe purpose of this study is to investigate how cognition is affected by asymptomatic cerebral artery stenosis (CAS) of the anterior circulation and its related collateral circulation. Methods102 patients with CAS of the anterior circulation and 52 controls were enrolled from January 1, 2019 to June 30, 2022. Patients with CAS of anterior circulation were further divided into different subgroups according to the degree of stenosis, cerebral perfusion, and collateral circulation. A series of neuropsychological scales were used to evaluate the participant’s cognitive function, activities of daily living, and neuropsychiatric symptoms (such as memory, execution, psychomotor speed, etc.). The data were analyzed using T-test, F-test, chi-square test, rank sum test, and other statistical methods, moreover, the quantitative data were further examined for trends. The relationship between the degree of CAS, cerebral perfusion, collateral circulation, and the outcome of the cognitive test was investigated using Spearman correlation analysis. ResultsCompared to controls, there were severe impairments of global cognition, psychomotor speed/execution, memory, attention, activities of daily living, and more neuropsychiatric symptoms in patients with anterior circulation CAS (p < 0.05), and these impairments got worsened with the aggravation of CAS (p < 0.05). The global cognition, psychomotor speed / executive function, memory function, and daily living ability were impaired both in the cerebral perfusion-compensated group and decompensated group(p < 0.05), while there was no statistically significant difference between the two groups (p > 0.05). With the aggravation of CAS, the proportion of poor collateral formation increased, and this difference was statistically significant (P < 0.01). The degree of stenosis, cerebral perfusion, and collateral circulation establishment of anterior circulation CAS was correlated with global cognition, memory, psychomotor speed, execution, attention, activities of daily living, and neuropsychiatric symptoms (all p < 0.01). ConclusionCognitive impairment and the percentage of inadequate collateral circulation development rise as stenosis progresses in patients with anterior circulation CAS. The decline in global cognitive function was accompanied by impairments in psychomotor speed / executive function, memory function, attention, and daily living skills, as well as the aggravation of neuropsychiatric symptoms, especially in patients with impaired cerebral perfusion and poor collateral circulation formation.

Identification of hypoxia-related genes and exploration of their relationship with immune cells in ischemic stroke

Ischemic stroke (IS) is a major threat to human health, and it is the second leading cause of long-term disability and death in the world. Impaired cerebral perfusion leads to acute hypoxia and glucose deficiency, which in turn induces a stroke cascade response that ultimately leads to cell death. Screening and identifying hypoxia-related genes (HRGs) and therapeutic targets is important for neuroprotection before and during brain recanalization to protect against injury and extend the time window to further improve functional outcomes before pharmacological and mechanical thrombolysis. First, we downloaded the GSE16561 and GSE58294 datasets from the NCBI GEO database. Bioinformatics analysis of the GSE16561 dataset using the limma package identified differentially expressed genes (DEGs) in ischemic stroke using adj. p. values < 0.05 and a fold change of 0.5 as thresholds. The Molecular Signature database and Genecards database were pooled to obtain hypoxia-related genes. 19 HRGs associated with ischemic stroke were obtained after taking the intersection. LASSO regression and multivariate logistic regression were applied to identify critical biomarkers with independent diagnostic values. ROC curves were constructed to validate their diagnostic efficacy. We used CIBERSORT to analyze the differences in the immune microenvironment between IS patients and controls. Finally, we investigated the correlation between HRGs and infiltrating immune cells to understand molecular immune mechanisms better. Our study analyzed the role of HRGs in ischemic stroke. Nineteen hypoxia-related genes were obtained. Enrichment analysis showed that 19 HRGs were involved in response to hypoxia, HIF-1 signaling pathway, autophagy, autophagy of mitochondrion, and AMPK signaling pathway. Because of the good diagnostic properties of SLC2A3, we further investigated the function of SLC2A3 and found that it is closely related to immunity. We have also explored the relevance of other critical genes to immune cells. Our findings suggest that hypoxia-related genes play a crucial role in the diversity and complexity of the IS immune microenvironment. Exploring the association between hypoxia-related critical genes and immune cells provides innovative insights into the therapeutic targets for ischemic stroke.

Abnormal cerebral blood flow and brain function in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) lead to impaired cerebral blood perfusion, which leads to changes in brain function and affects the cognitive function of patients. In this study, cerebral blood flow (CBF) was used to evaluate the effect of T2DM on cerebral perfusion, and functional connectivity (FC) analysis was further used to explore whether the FC between the abnormal CBF region and the whole brain was changed. In addition, amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) were used to investigate the changes in spontaneous activity and connectivity strength of the brain network. We recruited 40 T2DM patients and 55 healthy controls (HCs). They underwent 3D-T1WI, rs-fMRI, arterial spin labeling (ASL) sequence scans and a series of cognitive tests. Cognitive test scores and brain imaging indicators were compared between the two groups, and the relationships among laboratory indicators, cognitive test scores, and brain imaging indicators were explored in the T2DM group. Compared to HCs, The CBF values of Calcarine_L and Precuneus_R in the T2DM group were lower. The DC value of Paracentral_Lobule_L and Precuneus_L, and the ALFF value of Hippocampus_L in the T2DM group were higher. In addition, the CBF values of Calcarine_L was negatively correlated with fasting insulin and HOMA_IR. This study found that there were regions of cerebral hypoperfusion in T2DM patients, which are associated with insulin resistance. In addition, we found abnormally elevated brain activity and enhanced functional connectivity in T2DM patients, which we speculated was the compensatory mechanism of brain neural activity.

Late Decrease in Cerebral Blood Flow in Bacterial Meningitis: More than a Simple Normalization of Acute Inflammatory Vessel Wall Architecture?

Acute bacterial meningitis is a disease with an overwhelmingly high mortality rate and high incidence of adverse neurological sequelae and poor neurological recovery amongst survivors. Amongst the numerous complications of bacterial meningitis, the presence of cerebrovascular disease represents a severe disease form. Vascular involvement during bacterial meningitis has long been established by numerous pathological and angiographic studies. Cerebrovascular changes known to occur in bacterial meningitis ranging from narrowing of large arteries by vasospasm to critical stenosis/obliteration of small to medium sized arteries/arterioles by vasculitis. Not surprisingly, alterations in CBF velocities have commonly been described during the inflammatory process and may represent an important component of brain injury during meningitis. In accordance with previous studies observing a biphasic cerebral flow pattern characterized by an early but transient increase in flow velocity, mostly due to reflexive vasospasm, and later by a sustained decrease in flow velocity, likely attributable to stenotic vasculitis, cerebral ischemia is a notable complication of bacterial meningitis during the advanced disease phase. Impaired cerebral perfusion during the late stages of disease may result from a variety of factors that contribute to a vital component of cerebral injury in bacterial meningitis. The pathogenesis of cerebral ischemia with progression of disease course is less clearly understood but may involve a complex interaction between inflammatory processes, systemic dysfunction, energy impairment, neuronal damage and intracranial pressure, factors of which we aim to more precisely understand and assign a more definite contributory role in the development of cerebrovascular ischemic consequences with advanced stages of bacterial meningitis.

PO-04-033 CARDIONEUROABLATION IN A WOMAN WITH ICTAL-INDUCED CARDIAC ASYSTOLE

Ictal-induced cardiac bradyarrhythmia and asystole is a rare phenomenon. The exact mechanism of ictal-induced cardiac bradyarrhythmia and asystole remains unclear. It was postulated that stimulation of central autonomic network during ictal episode may trigger an abrupt burst of hypervagotonia. Prolonged episode of cardiac bradyarrhythmia and asystole may result in syncope or death due to impairment of cerebral perfusion. The role of cardioneuroablation (CNA) in this condition has not been well-described in the literature. To describe a case of successful CNA in a patient with ictal-induced bradyarrhythmia and asystole. n/a A 47-year-old female has a 1.5-year history of intractable focal epilepsy and COVID-19 infection. She started having multiple episodes of seizures following a mild COVID-19 infection. Electroencephalogram (EEG) and brain MRI revealed right temporal onset seizures without structural lesions. Due to ongoing uncontrolled seizures with multiple semiologies despite multiple anti-epileptic drugs, she was admitted to Epilepsy Monitoring Unit for seizure classification. Her ictal EEGs (Figure 1) showed onset of ictal rhythm in the right temporal region with episodes of severe sinus bradycardia (15-30 bpm) and sinus pauses (15-16 seconds). Telemetry tracings demonstrated PP interval slowing with PR interval prolongation prior to the pauses consistent with a vagally-mediated mechanism. Cardiac electrophysiology team recommended CNA for treating the episodes of ictal-induced bradyarrhythmia and asystole. 3D anatomic maps of the right atrium (RA) and left atrium (LA) were created using CARTO system (Biosense Webster). Right superior ganglionated plexus (RSGP) was localized with fractionation mapping and intracardiac echocardiography guidance. RSGP was targeted from the RA using an irrigated radiofrequency catheter with power limit of 25 W. Post-ablations of RSGP, her heart rate increased from 60 - 99 bpm. Additional lesions were delivered from the LA site but no additional heart rate increase was not seen. An implantable loop recorder was implanted post-ablation procedure. During follow-up of 8 months, she had recurrent focal epilepsy, but no bradyarrhythmias or asystole was noted on her loop recorder. Resting heart rates at long-term follow up were between 70 - 100 bpm. This case highlights the utility of CNA in patient with ictal-induced cardiac bradyarrhythmia and asystole. CNA may be an approach to avoid permanent pacemakers in this population.

Correlation between Glasgow Coma Scale with central venous pressure and near-infrared spectroscopy in patients with acquired brain injury in the intensive care unit of Adam Malik Hospital Medan

Abstract Background Acquired brain injury (ABI) is caused by trauma or nontrauma to the brain after birth. Increased intracranial pressure in patients with traumatic or nontraumatic brain injury affects the cerebral perfusion pressure. After traumatic brain injury, there is an increase in air content in the brain and an increase in volume of blood flow to the brain, which can cause increased intracranial pressure, herniation of brain tissue, impaired cerebral perfusion, and brain damage. Most patients with traumatic brain injury die from uncontrolled increases in intracranial pressure. Near-infrared spectroscopy (NIRS) and central venous pressure (CVP) monitoring are also associated with cerebral perfusion. This study aimed to determine the relationship between the Glasgow Coma Scale (GCS) scores and CVP and NIRS values in patients with ABI. Methods This prospective analytical study used a cross-sectional design to compare GCS scores with CVP and NIRS values in patients with traumatic and nontraumatic brain injury in the intensive care unit (ICU) of Haji Adam Malik Hospital Medan. GCS, CVP, and NIRS descriptive data in patients with brain injury were presented in terms of mean and standard deviation if the data were normally distributed, or median (interquartile range) values if the data were not normally distributed. The relationship between GCS scores and CVP and NIRS values was assessed using the Pearson correlation test if the data were normally distributed, or the Spearman test if the data were not normally distributed. Results In this study, the mean GCS score and CVP values were 7.04 ± 2.69 and 5.63 ± 25.82 mmHg, respectively. The right tissue oxygen saturation (StO2) was 55.61% ± 18.72%, and the left StO2 was 57.57% ± 17.48% with normally distributed data. There was no correlation between GCS scores and CVP values (P = 0.829), and no correlation between moderate GCS scores and right and left StO2 (P = 0.343; P = 0.121); however, there was a significantly strong positive correlation between severe GCS scores and right and left StO2 (P = 0.028, r = 0.656; P = 0.005, r = 0.777). Conclusion There was no significant correlation between GCS scores and CVP values, and no correlation between moderate GCS scores and NIRS values; however, there was a significantly strong positive correlation between severe GCS scores and NIRS values in patients with ABI at the ICU of Haji Adam Malik Hospital Medan.

The Heart Is at Risk: Understanding Stroke-Heart-Brain Interactions with Focus on Neurogenic Stress Cardiomyopathy-A Review.

In recent years, it has been convincingly demonstrated that acute brain injury may cause severe cardiac complications-such as neurogenic stress cardiomyopathy (NSC), a specific form of takotsubo cardiomyopathy. The pathophysiology of these brain-heart interactions is complex and involves sympathetic hyperactivity, activation of the hypothalamic-pituitary-adrenal axis, as well as immune and inflammatory pathways. There have been great strides in our understanding of the axis from the brain to the heart in patients with isolated acute brain injury and more specifically in patients with stroke. On the other hand, in patients with NSC, research has mainly focused on hemodynamic dysfunction due to arrhythmias, regional wall motion abnormality, or left ventricular hypokinesia that leads to impaired cerebral perfusion pressure. Comparatively little is known about the underlying secondary and delayed cerebral complications. The aim of the present review is to describe the stroke-heart-brain axis and highlight the main pathophysiological mechanisms leading to secondary and delayed cerebral injury in patients with concurrent hemorrhagic or ischemic stroke and NSC as well as to identify further areas of research that could potentially improve outcomes in this specific patient population.

Sound out the impaired perfusion: Photoacoustic imaging in preclinical ischemic stroke.

Acoustically detecting the optical absorption contrast, photoacoustic imaging (PAI) is a highly versatile imaging modality that can provide anatomical, functional, molecular, and metabolic information of biological tissues. PAI is highly scalable and can probe the same biological process at various length scales ranging from single cells (microscopic) to the whole organ (macroscopic). Using hemoglobin as the endogenous contrast, PAI is capable of label-free imaging of blood vessels in the brain and mapping hemodynamic functions such as blood oxygenation and blood flow. These imaging merits make PAI a great tool for studying ischemic stroke, particularly for probing into hemodynamic changes and impaired cerebral blood perfusion as a consequence of stroke. In this narrative review, we aim to summarize the scientific progresses in the past decade by using PAI to monitor cerebral blood vessel impairment and restoration after ischemic stroke, mostly in the preclinical setting. We also outline and discuss the major technological barriers and challenges that need to be overcome so that PAI can play a more significant role in preclinical stroke research, and more importantly, accelerate its translation to be a useful clinical diagnosis and management tool for human strokes.

Effect of Voxelotor on Cerebral Perfusion and Cerebral Oxygen Metabolism in Adult Patients with Sickle Cell Disease; Preliminary Results of the Coverage Study

Background: Sickle cell disease (SCD) is characterized by hemolytic anemia and a hyperdynamic circulation resulting in impaired cerebral hemodynamics and perfusion, culminating in ischemic damage of the brain. SCD is strongly associated with overt strokes or silent cerebral infarctions (SCI) which have been related to elevated flow in the median cerebral artery in children measured by transcranial Doppler. Patients with SCD have an increased cerebral blood flow (CBF) to maintain adequate oxygen delivery (OD). Previously, we and others have demonstrated with special MRI techniques that despite the maintained OD, cerebral metabolic rate of oxygen (CMRO2) is reduced in SCD due to reduced oxygen extraction fraction (OEF), which in turn is strongly related to CBF and hemoglobin (Hb) level. Voxelotor is a small molecule that reversibly binds to Hb and increases its oxygen affinity, thereby decreasing Hb polymerization and sickling. The resulting decreased hemolytic anemia can potentially ameliorate cerebral hemodynamics and perfusion, the increased oxygen affinity may reduce the offloading of oxygen. The aim of our study is to assess the effects of voxelotor on markers of cerebral perfusion and oxygen metabolism. In addition, the effect of voxelotor on the hyperdynamic cardiac function was assessed. Methods: This single-arm, interventional trial is being conducted in a tertiary hospital in Amsterdam, The Netherlands. Adult SCD patients with the severe genotypes of HbSS and HbSβ0-thalassemia were eligible for inclusion. Other major inclusion criteria were: Hb ≤ 10.5 g/dL and in case of hydroxyurea use, a stable dose for at least 90 days. Major exclusion criteria were: regular transfusions or a transfusion within 90 days prior to inclusion, hospitalization for vaso-occlusive crisis ≤ 14 days before inclusion. At baseline and after 3 months of voxelotor treatment (1500 mg pd), MRI scans, echocardiography and laboratory assessments were performed. Time-encoded arterial spin labeling was performed to obtain CBF measurements, gray matter CBF was derived by using white matter and gray matter masks. T2 relaxation under spin tagging was performed in order to calculate OEF. Oxygen delivery and CMRO2 were calculated: formula, CBF x OD, with the OD calculated from OEF and oxygen content. Maximal tricuspid regurgitation velocity (TRVmax) was assessed by trans-thoracic echocardiography as a marker of hyperdynamic circulation. N-Terminal pro-B-type natriuretic peptide (NT-proBNP) was measured as a marker of cardiac stress/dilatation. Parametric data are presented with mean and SD and analyzed by a paired T-test and non-parametric data with median and IQR, and analyzed by a Wilcoxon signed-rank test. Results: Preliminary results of 15 patients (HbSS/HbSβ0-thalassemia, 11/4, mean age 38 years (SD 10), 4 female) who completed their 3 month follow-up are presented here. Upon 3 months of voxelotor treatment, Hb levels significantly increased, 7.6 g/dL, (IQR 6.9 - 8.2) compared to 10.0 g/dL (IQR; p < 0.001), and hemolysis significantly reduced, represented by reticulocyte count, bilirubin and LDH levels (p = < 0.05; Table 1). After 3 months of treatment also a significant increase in oxygen delivery from 6.4 to 8.2 ml O2/100g/min (p = 0.006) was observed, which was primarily due to the increased Hb levels. However, CBF and CMRO2 did not change significantly after 3 months of voxelotor treatment (Table 2) while OEF decreased significantly at 3 months as compared to baseline (from 28.9% to 23.2%, p = 0.002) (Table 2). No significant changes in NT-proBNP levels and TRVmax were observed (Table 1) although a significant decrease was observed in patients with NT-proBNP-levels >160 at baseline (213 (IQR 161 - 254) ng/L vs 152 (IQR 50 -163) ng/L; p = 0.028)). Conclusion: In this preliminary study, no changes in cerebral hemodynamics (CBF) and oxygen metabolic rate (CMRO2) were observed, despite an increased cerebral oxygen delivery due to improvement of Hb levels. CMRO2 remained unchanged as a result of diminished OEF, based on the calibration according to the Li-Bush model, most likely due to the increased oxygen affinity attributed to voxelotor. With respect to the cardiac measures of the circulatory state, no effect on NT-proBNP levels and TRVmax was observed although a significant decrease in NT-proBNP-levels was observed in a post-hoc analysis of patients with elevated NTproBNP levels at baseline. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venous Outflow and Parenchymal Hemorrhage: A Clogged Drain Problem?

Venous Outflow and Parenchymal Hemorrhage: A Clogged Drain Problem?

Early Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage Is Associated with Prior Global Cerebral Hypoperfusion

Early cerebral infarction (ECI) is an independent factor associated with poor outcome following aneurysmal subarachnoid hemorrhage (aSAH). We aimed to test the association between ECI and prior global impairment of cerebral perfusion. We performed a retrospective cohort study of consecutive patients admitted for aSAH in 2 centers. ECI was defined as any radiological cerebral infarction identified within 3days from the onset of bleeding and not related to aneurysm repair. Global impairment of cerebral perfusion was defined as clinical or transcranial Doppler signs of brain hypoperfusion together with circulatory failure or intracranial hypertension in keeping with guidelines. The association between ECI and prior occurrence of global impairment of cerebral perfusion was tested using binary logistic regression adjusted for confounders identified in the univariate analysis. Seven hundred fifty-three patients with aSAH were included. ECI was observed in 40 patients (5.3%; 95% CI=3.7%-6.9%). Prior global impairment of cerebral perfusion occurred in 90% of them (60% in-hospital) versus in 11% of patients without ECI (P<0.001). In the multivariate analysis, World Federation of Neurological Surgeons grade (OR=2.3, 95% CI= 1.5-3.6, P<0.001), global impairment of cerebral perfusion due to circulatory failure (OR=4.7, 95% CI=1.8-11, P= 0.001), or intracranial hypertension (OR=11.1, 95% CI=3.8-32.3, P<0.001) was an independent risk factor for ECI. Our study demonstrated that ECI is strongly associated with the prior occurrence of global impairment of cerebral perfusion, independent of World Federation of Neurological Surgeons grade. These patients may benefit from more intensive and systematic prevention of impaired cerebral perfusion, particularly in poor-grade patients.

Dose-dependent relationship between intra-procedural hypoxaemia or hypocapnia and postoperative delirium in older patients

BackgroundPrevious studies indicated an association between impaired cerebral perfusion and post-procedural neurological disorders. We investigated whether intra-procedural hypoxaemia or hypocapnia are associated with delirium after surgery. MethodsInpatients ≥60 yr of age undergoing anaesthesia for surgical or interventional procedures between 2009 and 2020 at an academic healthcare network in the USA (Massachusetts) were included in this hospital registry study. The primary exposure was intra-procedural hypoxaemia, defined as peripheral oxygen saturation <90% for >2 cohering min. The co-primary exposure was hypocapnia during general anaesthesia, defined as end-tidal carbon dioxide pressure ≤25 mm Hg for >5 cohering min. The primary outcome was delirium within 7 days after surgery. ResultsOf 71 717 included patients, 1702 (2.4%) developed postoperative delirium, and hypoxaemia was detected in 2532 (3.5%). Of 42 894 patients undergoing general anaesthesia, 532 (1.2%) experienced hypocapnia. The occurrence of either hypoxaemia (adjusted odds ratio [ORadj]=1.71; 95% confidence interval [CI], 1.40–2.07; P<0.001) or hypocapnia (ORadj=1.77; 95% CI, 1.30–2.41; P<0.001) was associated with a higher risk of delirium within 7 days. Both associations were dependent on the magnitude, and increased with event duration (ORadj=1.03; 95% CI, 1.02–1.04; P<0.001 and ORadj=1.01; 95% CI, 1.00–1.01; P=0.005, for each minute increase in the longest continuous episode, respectively). There was no association between occurrence of hypercapnia and postoperative delirium (ORadj=1.24; 95% CI, 0.90–1.71; P=0.181). ConclusionsIntra-procedural hypoxaemia and hypocapnia were dose-dependently associated with a higher risk of postoperative delirium. These findings support maintaining normal gas exchange to avoid postoperative neurological disorders.

Prenatal consequences of ­congenital heart disease on brain development

In fetuses with complex congenital heart disease (CHD), impaired brain growth and brain development starts in utero. A complex interplay between heart, brain, body and placenta takes place in the second and third trimesters of pregnancy. Altered fetal cardiovascular hemodynamics due to differnt types of CHD lead to altered cerebral, body and placental perfusion, all factors contributing to maturational delay of body and brain development. Impaired cerebral perfusion, oxygenation and nutritive energy supply affects brain growth and leads to a brain developmental delay of 3–4 weeks until birth. Comparable to the altered brain development in preterm infants, similar pathogenic mechanisms lead to an encephalopathy of CHD on a micro- and macrostructural level. After birth palliative or corrective cardiac surgery is needed, which further contributes to the brain maturational delay with consequences on the neurodevelopmental outcome.

A cervical compartment syndrome impairs cerebral circulation in post-thyroidectomy hemorrhage: data from an animal model.

Post thyroidectomy hemorrhage is a potentially life-threatening complication. As the mechanism leading to hypoxemic brain damage and death is still unknown, our aim was to examine the underlaying pathophysiology in an animal model. A series of experiments was performed in our established model for post thyroidectomy hemorrhage in 6 pigs. First, post thyroidectomy hemorrhage was simulated with an artificial increase of cervical compartment pressure. Second, spontaneous bleeding into the cervical compartment was initiated. Primary outcome measure is the correlation between cerebral oxygenation and cervical compartment pressure. With an increase in cervical compartment pressure apnea could be detected in all experiments. A significant 24.2% (9.5-34.4%) decrease of cerebral oxygenation at time of apnea (47.0%; 38.0-65.0%) compared to baseline values (63.5%; 56.0-74.0%; P=0.043) occurred due increase of cervical compartment pressure concurrent with an impaired cerebral perfusion. Apnea occurred about 200 sec after a 10% decrease of cerebral oxygenation, but 35 sec before a 10% decrease of peripheral oxygenation. Spontaneous bleeding into the cervical compartment causes an increase of cervical compartment pressure reaching levels of the mean arterial blood pressure 56.0 (35.0-72.0) mmHg. Peripheral hypoxemia occurs with relevant delay in time after decrease of cerebral perfusion and cerebral hypoxemia, therefore cerebral hypoxemia seems to be causal for a central apnea. With this evidence of impaired cerebral perfusion and cerebral hypoxemia due to an increased cervical compartment pressure we can disprove the historic theory of tracheal collapse due to a compressive hematoma in post thyroidectomy hemorrhage. A cervical compartment syndrome seems to be causal, not only for brain hypoxemia but also an additional laryngo-pharyngeal mucosal edema.