Prognostic implications of volume status assessed by blood volume analysis in ambulatory heart failure.

The prognostic implications of intravascular volume status assessed by blood volume analysis (BVA) in ambulatory heart failure (HF) remain uncertain. The incremental benefits of assessing volume status, beyond the well-established filling pressures, in predicting HF outcomes are unknown.

Magnitude and precision of absolute blood volume estimated during hemodialysis.

Background: Management of body fluid volumes and adequate prescription of ultrafiltration (UF) remain key issues in the treatment of chronic kidney disease patients.Objective: This study aims to estimate the magnitude as well as the precision of absolute blood volume (Vb) modeled during regular hemodialysis (HD) using standard data available with modern dialysis machines.Methods: The estimation utilizes a two-compartment fluid model and a mathematical optimization technique to predict UF-induced changes in hematocrit measured by available on-line techniques. The method does not rely on a specific hematocrit sensor or a specific UF or volume infusion protocol and uses modeling and prediction tools to quantify the error in Vb estimation.Results: The method was applied to 21 treatments (pre-UF body mass: 65.57±13.44 kg, UF-volume: 3.99±1.14 L) obtained in ten patients (4 female). Pre-HD Vb was 5.4±0.53 L with an average coefficient of variation of 9.8% (range 1 to 22%). A significant moderate correlation was obtained when Vb was compared to a different method applied to the same data set (r = 0.5). Specific blood volumes remained above the critical level of 65 mL/kg in 17 treatments (80.9%).Conclusion: The method offers the opportunity to detect critical blood volumes during HD and to judge the quality and reliability of that information based on the precision of the Vb estimate.

Haematocrit monitoring and blood volume estimation during continuous renal replacement therapy.

BACKGROUND: Continuous haemoglobin, venous blood oxygen saturation, and haematocrit (Hct) monitoring is currently not applied during continuous renal replacement therapy (CRRT). Such Hct monitoring enables estimation of changes in blood volume as percentage change (ΔBV%) from therapy start time and is incorporated into intermittent haemodialysis machines but not CRRT machines despite its potential to optimise fluid management in CRRT patients. METHODS: To overcome this problem, we used a standalone monitor (CRIT-LINE®IV, Fresenius Medical Care, Concord, USA) with an associated in-line blood chamber (CRIT-LINE®IV Blood Chamber, Fresenius Medical Care, Concord, USA) and designed our own adaptor connection piece (TekMed and Morriset, Melbourne and Brisbane, Australia) to allow these readings at the vascular access outflow and recorded data for estimated Hct and derived ΔBV% during CRRT. RESULTS: We report on this technique with an illustrative case example and 12 h of CRRT data on the fluid loss rate prescribed, hourly net patient fluid loss (range: 0-308 mL/h), mean arterial pressure, norepinephrine dose (range: 5-14 mcg/min), estimated continuous Hct and ΔBV%, and the otherwise undetected diagnosis of an approximate 15 % decrease in blood volume during the CRRT. CONCLUSION: We have described a technical CRRT circuit modification that can facilitate a previously unavailable assessment of fluid shifts during CRRT. Further application in clinical trials is now possible.

Manual erythroexchange in sickle cell disease: multicenter validation of a protocol predictive of volume to exchange and hemoglobin values.

Manual erythroexchange (MEEX) was proven to be effective and safe in the management of sickle cell disease (SCD). The goal is to quickly reduce the percentage of hemoglobin S (HbS%). A national survey of the Italian Society for Thalassemia and Hemoglobinopathies (SITE) observed a great variability among MEEX protocols none of which were found to be predictive of the values of HbS% and hemoglobin (Hb) after the exchange. Two equations to estimate the HbS% and Hb values to be obtained after MEEX were developed based on the results of the MEEX procedures in place in the centers participating in the present study. A standard protocol was subsequently defined to evaluate the volumes to exchange to obtain the target values of HbS% and Hb. The protocol was tested in 261 MEEX performed in SCD patients followed in the 5 participating centers that belong to the Italian Hemoglobinopathy Comprehensive Care Network, with the support of the SITE. The results showed a correlation between the estimated and measured values of HbS% and Hb (Rp 0.95 and 0.65 respectively, p < 0.001). A negligible bias was found for the prediction of HbS% and a bias of 1 g/dl for Hb. From consecutive MEEX, a rate of increase of HbS% between two exchanges of around 0.4% per day (p < 0.001) was measured. This protocol was shown to be effective and safe, as all patients reached the target value of HbS%. All the MEEX procedures were carried out with single venous access. No adverse events or reactions such as hypotension or electrolyte imbalance were reported nor were any complaints concerning the procedures received from patients.

Multifrequency Analysis of Single Inductive Coil Measurements Across a Gel Phantom Simulation of Internal Bleeding in the Brain.

The present study is part of an ongoing effort to develop a simple diagnostic technology for detecting internal bleeding in the brain, which can be used in lieu or in support of medical imaging and thereby reduce the cost of diagnostics in general, and in particular, would make diagnostics accessible to economically disadvantaged populations. The study deals with a single coil inductive device to be used for detecting cerebral hemorrhage. It presents a first-order experimental study that examines the predictions of our recently published theoretical study. The experimental model employs a homogeneous cylindrical phantom in which internal head bleeding was simulated by way of a fluid inclusion. We measured the changes in amplitude and phase across the coil with a network vector analyzer as a function of frequency (100-1,000 MHz), volume of blood simulating fluid, and the site of the fluid injection. We have developed a new mathematical model to statistically analyze the complex data produced in this experiment. We determined that the resolution for the fluid volume increase following fluid injection is strongly dependent on frequency as well as the location of liquid accumulation. The experimental data obtained in this study supports the predictions of our previous theoretical study, and the statistical analysis shows that the simple single coil device is sensitive enough to detect changes due to fluid volume alteration of two milliliters. Bioelectromagnetics. 2020;41:21-33 © 2019 Bioelectromagnetics Society.

Can cone-beam CT tumor blood volume predicts the response to chemoembolization of colorectal liver metastases? Results of an observational study.

PURPOSE: To determine whether intraprocedural C-arm cone-beam CT (CBCT) parenchymal blood volume (PBV) can predict the response of colorectal cancer liver metastases (CRCLM) 2 months after irinotecan drug-eluting bead (DEBIRI) chemoembolization. MATERIALS AND METHODS: This single-center observational study was compliant with the Helsinki Declaration and approved by our institutional review board. Thirty-four consecutive CRCLM patients referred for DEBIRI chemoembolization were enrolled between March 2015 and December 2016. Tumor size was assessed at baseline and 2 months after DEBIRI chemoembolization by multidetector CT (Response Evaluation Criteria in Solid Tumors RECIST 1.0), and PBV was measured before and after DEBIRI chemoembolization. Two independent readers reviewed all data. We determined the potential correlation (Spearman's rank correlation) between intraprocedural PBV values and tumor response at 2 months. The relationship between tumor response and PBV was studied using a mixed model. A logistic regression model was applied to study the relationship between patient "Responder/Non-responder" and PBV. RESULTS: There was a strong correlation between baseline PBV or the percent change of PBV and the 2-month tumor response (rho = - 0.8587 (p = 0.00001) and rho = 0.8027 (p = 0.00001), respectively). The mixed model showed that an increase of 1 ml/1000 ml in PBV of a tumor before DEBIRI chemoembolization led to a 0.54 mm decrease in diameter (p < 0.005). A 1% decrease in PBV after DEBIRI chemoembolization resulted in tumor shrinkage of 0.75 mm (p < 0.005). The logistic regression model showed that patients with a 1% smaller mean decrease of PBV after DEBIRI chemoembolization had a 10% lower likelihood of achieving disease control (OR = 0.9, 95% confidence interval (CI) = 0.81-1; p = 0.0493). CONCLUSION: Intraprocedural PBV may predict tumor response to DEBIRI chemoembolization. KEY POINTS: • There is a strong relationship between the parenchymal blood volume (PBV) of colorectal liver metastases before DEBIRI chemoembolization and tumor response at 2 months. • Higher PBV values before DEBIRI chemoembolization correlate with greater tumor shrinkage, but only if the PBV decreases by more than 70% after DEBIRI chemoembolization. • Each increase of 1% in the mean decrease of PBV after DEBIRI chemoembolization resulted in a 10% lower likelihood of achieving disease control (OR = 0.9, 95% confidence interval (CI) = 0.81-1; p = 0.0493).

Monte Carlo Analysis of Optical Interactions in Reflectance and Transmittance Finger Photoplethysmography.

Photoplethysmography (PPG) is a non-invasive photometric technique that measures the volume changes in arterial blood. Recent studies have reported limitations in developing and optimising PPG-based sensing technologies due to unavailability of the fundamental information such as PPG-pathlength and penetration depth in a certain region of interest (ROI) in the human body. In this paper, a robust computational model of a dual wavelength PPG system was developed using Monte Carlo technique. A three-dimensional heterogeneous volume of a specific ROI (i.e., human finger) was exposed at the red (660 nm) and infrared (940 nm) wavelengths in the reflectance and transmittance modalities of PPG. The optical interactions with the individual pulsatile and non-pulsatile tissue-components were demonstrated and the optical parameters (e.g., pathlength, penetration depth, absorbance, reflectance and transmittance) were investigated. Results optimised the source-detector separation for a reflectance finger-PPG sensor. The analysis with the recorded absorbance, reflectance and transmittance confirmed the maximum and minimum impact of the dermis and bone tissue-layers, respectively, in the formation of a PPG signal. The results presented in the paper provide the necessary information to develop PPG-based transcutaneous sensors and to understand the origin of the ac and dc components of the PPG signal.

Rodent Cerebral Blood Volume (CBV) changes during hypercapnia observed using Magnetic Particle Imaging (MPI) detection.

Magnetic Particle Imaging (MPI) is a rapidly developing imaging modality that directly measures and maps the concentration of injected superparamagnetic iron oxide nanoparticles (SPIOs). Since the agent does not cross the blood-brain barrier, cerebral SPIO concentration provides a direct probe of Cerebral Blood Volume (CBV). Here we provide an initial demonstration of the ability of MPI to detect functional CBV changes (fCBV) by monitoring SPIO concentration during hypercapnic manipulation in a rat model. As a tracer detection method, MPI offers a more direct probe of agent concentration and therefore fCBV than MRI measurements in which the agent is indirectly detected through perturbation of water relaxation time constants such as T2∗. We found that MPI detection could measure CBV changes during hypercapnia with high CNR (CNR = 50) and potentially with high temporal resolution. Although the detection process more closely resembles a tracer method, we also identify evidence of physiological noise in the MPI time-series, with higher time-series variance at higher concentration levels. Our findings suggest that CBV-based MPI can provide a detection modality for hemodynamic changes. Further investigation with tomographic imaging is needed to assess tomographic ability of the method and further study the presence of time-series fluctuations which scale with signal level similar to physiological noise in resting fMRI time-courses.

Blood flow, volume and arterio-venous passages in induced mammary tumours of the rat.

OBJECTIVE: To study blood flow, vascular volume and arterio-venous passages in induced mammary tumours of the rat to characterize parameters possibly responsible for tumour hyponutrition. METHOD: Dimethylbenzanthracene-induced mammary tumours in Sprague-Dawley rats were studied. Regional blood flow was studied by use of the radioactive microsphere tracer technique using 141Cerium-labelled 15µm spheres coinjected into the left cardiac ventricle with 125Iodine-labelled 25µm spheres. Blood volume was studied by use of 125Iodine- or 99mTechnetium-labelled human serum albumin, the latter allowing autoradiography of tumour sections for visualization of flow and volume. RESULTS: Twenty-seven rats with 170 tumours had a mean tumour blood flow of 48 and 67mL×min-1×100g-1 using 15 and 25µm sphere data, respectively, indicating a significant passage through vessels between 15 and 25µm. The lungs showed a "nominal bronchial" blood flow of 260 and 135mL×min-1×100g-1 for the 15 and 25µm spheres, respectively, indicating pulmonary trapping, particularly of small spheres passing the systemic circulation in vessels larger than 15µm. There was a positive correlation between the total tumour blood flow within individual rats and trapped spheres of both dimensions in the lungs, indicating shunts also larger than 25µm. Normal tissues disclosed only small differences in regional blood flow as measured by the two spheres. Blood volume was studied in 20 rats with 120 tumours, with a vascular volume of 3.6mL×100g-1 representing a blood turnover >15 times/min. Blood volume co-localized with perfusion as seen in autoradiographs. CONCLUSION: In induced rat mammary tumours, a high fraction of blood, 28%, passes arterio-venous vessels between 15 and 25µm and there also exist passages >25µm. These findings indicate that the functional capacity of the tumour vascular bed might be impaired, adding to the abnormal microenvironment of tumours.

Observer variability of reference tissue selection for relativecerebral blood volume measurements in glioma patients.

OBJECTIVES: To assess observer variability of different reference tissues used for relative CBV (rCBV) measurements in DSC-MRI of glioma patients. METHODS: In this retrospective study, three observers measured rCBV in DSC-MR images of 44 glioma patients on two occasions. rCBV is calculated by the CBV in the tumour hotspot/the CBV of a reference tissue at the contralateral side for normalization. One observer annotated the tumour hotspot that was kept constant for all measurements. All observers annotated eight reference tissues of normal white and grey matter. Observer variability was evaluated using the intraclass correlation coefficient (ICC), coefficient of variation (CV) and Bland-Altman analyses. RESULTS: For intra-observer, the ICC ranged from 0.50-0.97 (fair-excellent) for all reference tissues. The CV ranged from 5.1-22.1 % for all reference tissues and observers. For inter-observer, the ICC for all pairwise observer combinations ranged from 0.44-0.92 (poor-excellent). The CV ranged from 8.1-31.1 %. Centrum semiovale was the only reference tissue that showed excellent intra- and inter-observer agreement (ICC>0.85) and lowest CVs (<12.5 %). Bland-Altman analyses showed that mean differences for centrum semiovale were close to zero. CONCLUSION: Selecting contralateral centrum semiovale as reference tissue for rCBV provides the lowest observer variability. KEY POINTS: • Reference tissue selection for rCBV measurements adds variability to rCBV measurements. • rCBV measurements vary depending on the choice of reference tissue. • Observer variability of reference tissue selection varies between poor and excellent. • Centrum semiovale as reference tissue for rCBV provides the lowest observer variability.

Intraprocedural Parenchymal Blood Volume Is a Predictor of Treatment Response for Chemoembolization in Hepatocellular Carcinoma: Results of a Prospective Study.

PURPOSE: To evaluate cone-beam parenchymal blood volume (PBV) before and after embolization as a predictor of radiographic response to transarterial chemoembolization in unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A phase IIa prospective clinical trial was conducted in patients with HCCs > 1.5 cm undergoing chemoembolization; 52 tumors in 40 patients with Barcelona Clinic Liver Criteria stage B disease met inclusion criteria. Pre- and postembolization PBV analysis was performed with a semiquantitative best-fit methodology for index tumors, with a predefined primary endpoint of radiographic response at 3 months. Analyses were conducted with Wilcoxon signed-rank tests and one-way analysis of variance on ranks. RESULTS: Mean tumoral PBV measurements before and after embolization were 170 mL/1,000 mL ± 120 and 0 mL/100 mL ± 130, respectively. Per modified Response Evaluation Criteria In Solid Tumors, 25 tumors (48%) exhibited complete response (CR), 13 (25%) partial response (PR), 3 (6%) stable disease (SD), and 11 (21%) progressive disease (PD). Statistically significant changes in median PBV (ΔPBV) were identified in the CR (P = .001) and PR (P = .003) groups, with no significant difference observed in SD (P = .30) and PD groups (P = .06). A statistically significant correlation between ΔPBV and tumor response was established by one-way analysis of variance on ranks (P = .036; CR, 200 mL/100 mL ± 99; PR, 240 mL/100 mL ± 370; SD, 64 mL/100 mL ± 99; PD, 88 mL/100 mL ± 129). CONCLUSIONS: Intraprocedural PBV can be used as a predictor of response in index HCC tumors of > 1.5 cm.

Blood volume measurement using cardiovascular magnetic resonance and ferumoxytol: preclinical validation.

BACKGROUND: The hallmark of heart failure is increased blood volume. Quantitative blood volume measures are not conveniently available and are not tested in heart failure management. We assess ferumoxytol, a marketed parenteral iron supplement having a long intravascular half-life, to measure the blood volume with cardiovascular magnetic resonance (CMR). METHODS: Swine were administered 0.7 mg/kg ferumoxytol and blood pool T1 was measured repeatedly for an hour to characterize contrast agent extraction and subsequent effect on Vblood estimates. We compared CMR blood volume with a standard carbon monoxide rebreathing method. We then evaluated three abbreviated acquisition protocols for bias and precision. RESULTS: Mean plasma volume estimated by ferumoxytol was 61.9 ± 4.3 ml/kg. After adjustment for hematocrit the resultant mean blood volume was 88.1 ± 9.4 ml/kg, which agreed with carbon monoxide measures (91.1 ± 18.9 ml/kg). Repeated measurements yielded a coefficient of variation of 6.9%, and Bland-Altman repeatability coefficient of 14%. The blood volume estimates with abbreviated protocols yielded small biases (mean differences between 0.01-0.06 L) and strong correlations (r2 between 0.97-0.99) to the reference values indicating clinical feasibility. CONCLUSIONS: In this swine model, ferumoxytol CMR accurately measures plasma volume, and with correction for hematocrit, blood volume. Abbreviated protocols can be added to diagnostic CMR examination for heart failure within 8 min.

High-frequency oscillatory ventilation guided by transpulmonary pressure in acute respiratory syndrome: an experimental study in pigs.

BACKGROUND: Recent clinical studies have not shown an overall benefit of high-frequency oscillatory ventilation (HFOV), possibly due to injurious or non-individualized HFOV settings. We compared conventional HFOV (HFOVcon) settings with HFOV settings based on mean transpulmonary pressures (PLmean) in an animal model of experimental acute respiratory distress syndrome (ARDS). METHODS: ARDS was induced in eight pigs by intrabronchial installation of hydrochloric acid (0.1 N, pH 1.1; 2.5 ml/kg body weight). The animals were initially ventilated in volume-controlled mode with low tidal volumes (6 ml kg- 1) at three positive end-expiratory pressure (PEEP) levels (5, 10, 20 cmH2O) followed by HFOVcon and then HFOV PLmean each at PEEP 10 and 20. The continuous distending pressure (CDP) during HFOVcon was set at mean airway pressure plus 5 cmH2O. For HFOV PLmean it was set at mean PL plus 5 cmH2O. Baseline measurements were obtained before and after induction of ARDS under volume controlled ventilation with PEEP 5. The same measurements and computer tomography of the thorax were then performed under all ventilatory regimens at PEEP 10 and 20. RESULTS: Cardiac output, stroke volume, mean arterial pressure and intrathoracic blood volume index were significantly higher during HFOV PLmean than during HFOVcon at PEEP 20. Lung density, total lung volume, and normally and poorly aerated lung areas were significantly greater during HFOVcon, while there was less over-aerated lung tissue in HFOV PLmean. The groups did not differ in oxygenation or extravascular lung water index. CONCLUSION: HFOV PLmean is associated with less hemodynamic compromise and less pulmonary overdistension than HFOVcon. Despite the increase in non-ventilated lung areas, oxygenation improved with both regimens. An individualized approach with HFOV settings based on transpulmonary pressure could be a useful ventilatory strategy in patients with ARDS. Providing alveolar stabilization with HFOV while avoiding harmful distending pressures and pulmonary overdistension might be a key in the context of ventilator-induced lung injury.

A new method for the assessment of endothelial function with peripheral arterial volume.

BACKGROUND: Currently, many methodological approaches have been developed to assess peripheral endothelial function. However, a development of the noninvasive and automated technique for routinely assessing endothelial function is still required. We evaluated the potential value of a new method to measure peripheral endothelial function with reactive hyperemia peripheral arterial volume (RH-PAV) in patients with chest pain. METHODS: We used a novel oximeter-like probe to detect the peripheral arterial volume (PAV) of the finger and compared it with brachial flow-mediated dilation (FMD) performed in 93 consecutive patients with chest pain. The RH-PAV index was defined as the ratio of the digital pulse volume during reactive hyperemia relative to the baseline. RESULTS: Ninety-three patients (53 men, 58 ± 5 years) completed the study, and 53 patients demonstrated coronary artery disease (CAD) following scheduled coronary angiography. There was a moderate linear relationship between PAV and FMD (r = 0.69, p < 0.01). Similar to FMD, PAV was more impaired in patients who have more cardiovascular risk factors (CRFs). The subjects with CAD had lower PAV and FMD, compared with those without CAD (1.05 ± 0.23 VS. 1.41 ± 0.37, p < 0.01; 6.7% ± 2.9% VS. 10.4% ± 2.9%, p < 0.01, respectively), and the relationships between FMD and PAV were also significant in both CAD (r = 0.54, p < 0.01) and non-CAD (r = 0.62, p < 0.01) patients. CONCLUSIONS: Endothelial function of digital artery assessed with the novel PAV method demonstrated a profile similar to that of brachial artery measured with FMD. The hyperemia PAV was decreased by factors which were considered to impair endothelial function, suggesting that PAV has the potential to be a novel method to study endothelial function.

Challenge of intravascular volume assessment in acute ischemic stroke.

INTRODUCTION: Retrospective data indicates that dehydration in acute ischemic stroke patients may be common, even though these patients frequently have elevated blood pressure. We sought to evaluate clinical and laboratory measures of intravascular volume status compared to more objective measures using ultrasound measurements of the inferior vena cava (IVC). METHODS: This was a prospective observation study of acute ischemic stroke patients in the emergency department. Patients with NIH stroke scale ≥4 within 12 h of symptom onset were included. A trained ultrasonographer performed bi-dimensional imaging of the IVC with passive respiration to determine the percent inspiratory collapse and maximum diameter. We defined low intravascular volume as >50% IVC collapse and a maximal diameter < 2.1 cm. Analysis was limited to patients with confirmed ischemic stroke. RESULTS: There were 42 patients, of whom 31 had confirmed acute ischemic stroke. The mean age was 65 ±â€¯15 years, 52% were female, and 71% were hypertensive. The median NIH stroke scale score was 7 (IQR 5-15). Based on IVC ultrasound, low intravascular volume was present in 63% (95% CI 44-80%) of patients. A higher proportion of hypertensive patients had low intrasvascular volume (72% vs. 33%). There was poor correlation between IVC assessment of intrasvascular volume and blinded clinician assessment or laboratory markers of dehydration. CONCLUSION: The majority of ED acute ischemic stroke patients in this sample were hypertensive and demonstrated low intravascular volume based on IVC ultrasound.

Fluid Responsiveness After CArdiac Surgery (FRACAS): A Prospective Observational Study Using Peripheral Near-Infrared Spectroscopy.

OBJECTIVES: To describe tissue oxygen saturation (StO2) in response to a vascular occlusion test using thenar eminence and forearm near-infrared spectroscopy (NIRS) and the association with volume responsiveness after cardiac surgery. DESIGN: Single-center, prospective, observational cohort study. SETTING: Cardiothoracic intensive care unit. PARTICIPANTS: Seventy-six post-cardiac surgical adults. INTERVENTIONS: Immediately before and 10 minutes after a 250-to-500 mL fluid bolus, StO2 was measured in response to a vascular occlusion test to calculate tissue deoxygenation (Rdes) and reoxygenation (Rres) rates. Concurrently, systemic hemodynamic, metabolic, and blood gas variables were collected. MEASUREMENTS AND MAIN RESULTS: A total of 203 boluses were captured using thenar NIRS and 141 boluses using forearm NIRS. Approximately 25% of boluses increased cardiac output by ≥15% (volume responders). Thenar and forearm Rdes decreased in responders, but increased (thenar) or remained unchanged (forearm) in nonresponders. A logistic regression model of the association among StO2, Rdes and Rres, and volume responsiveness was significant for thenar measurements (p = 0.001) with an area under the receiver operating characteristic of 0.69 (95% confidence interval: 0.62-0.75). It also was significant (p = 0.02) for forearm measurements, with an area under the receiver operating characteristic of 0.71 (0.62-0.79). Rdes was an independent variable in both instances (odds ratio 0.31 [0.14-0.69], thenar; odds ratio 0.60 [0.45-0.80], forearm). Thenar and forearm NIRS variables were correlated poorly with cardiac output, stroke volume, systemic oxygen delivery and consumption index, mixed venous, and central venous oxygen saturation (Spearman׳s coefficients, r = 0.17-0.46, p < 0.002). CONCLUSION: In post-cardiac surgical patients, thenar and forearm NIRS variables were associated with volume responsiveness although not achieving precision necessary for clinical management.

Quantitative vascular neuroimaging of the rat brain using superparamagnetic nanoparticles: New insights on vascular organization and brain function.

A method called Quantitative Ultra-Short Time-to-Echo Contrast Enhanced (QUTE-CE) Magnetic Resonance Imaging (MRI) which utilizes superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent to yield positive contrast angiograms with high clarity and definition is applied to the whole live rat brain. QUTE-CE MRI intensity data are particularly well suited for measuring quantitative cerebral blood volume (qCBV). A global map of qCBV in the awake resting-state with unprecedented detail was created via application of a 3D MRI rat brain atlas with 173 segmented and annotated brain areas. From this map we identified two distributed, integrated neural circuits showing the highest capillary densities in the brain. One is the neural circuitry involved with the primary senses of smell, hearing and vision and the other is the neural circuitry of memory. Under isoflurane anesthesia, these same circuits showed significant decreases in qCBV suggesting a role in consciousness. Neural circuits in the brainstem associated with the reticular activating system and the maintenance of respiration, body temperature and cardiovascular function showed an increase in qCBV with anesthesia. During awake CO2 challenge, 84 regions showed significant increases relative to an awake baseline state. This CO2 response provides a measure of cerebral vascular reactivity and regional perfusion reserve with the highest response measured in the somatosensory cortex. These results demonstrate the utility of QUTE-CE MRI for qCBV analysis and offer a new perspective on brain function and vascular organization.

High resolution CBV assessment with PEAK-EPI: k-t-undersampling and reconstruction in echo planar imaging.

PURPOSE: Achieving higher spatial resolution and improved brain coverage while mitigating in-plane susceptibility artifacts in the assessment of perfusion parameters, such as cerebral blood volume, in echo planar imaging (EPI)-based dynamic susceptibility contrast weighted cerebral perfusion measurements. METHODS: PEAK-EPI, an EPI sequence with interleaved readout trajectories and three different strategies for autocalibration-signal acquisition (inplace, dynamic extra and extra) is presented. Performance of each approach is analyzed in vivo based on flip angle variation induced dynamics, assessing temporal fidelity, temporal SNR and g-factors. All approaches are compared with conventional GRAPPA reconstructions. PEAK-EPI with inplace autocalibration-signal at R = 5 is then compared with the standard clinical EPI protocol in six patients, using two half-dose dynamic susceptibility contrast weighted cerebral perfusion measurements per subject. RESULTS: PEAK-EPI acquisition facilitates a substantial increase of spatial resolution at a higher number of slices per TR and provides improved SNR compared to conventional GRAPPA. High dependency of the resulting reconstruction quality on the type of autocalibration-signal acquisition is observed. PEAK-EPI with inplace autocalibration-signal achieves high temporal fidelity and initial feasibility is shown. CONCLUSION: The obtained high resolution cerebral blood volume maps reveal more detailed information than in corresponding standard EPI measurements and facilitate detailed delineation of tumorous tissue. Magn Reson Med 77:2153-2166, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Evaluation of an fMRI USPIO-based assay in healthy human volunteers.

PURPOSE: To present the testretest and contrast dose effect results of cerebral blood volume (CBV) functional MRI (fMRI) in healthy human volunteers using ferumoxytol (Feraheme), an ultrasmall-superparamagnetic iron oxide (USPIO) nanoparticle. MATERIALS AND METHODS: This was an open-label, two-period, fixed-sequence study in healthy young volunteers. In eight subjects, using a 3 Tesla field strength system, blood oxygen level dependent (BOLD) and CBV fMRI were acquired in response to a visual black-and-white checkboard stimulation paradigm using an escalating ferumoxytol dose design (250, 350, and 510 mg iron). Multiple outcome measures were analyzed including absolute percent signal change (|PSC|, primary endpoint), its contrast-to-noise ratio (CNR) and corresponding z-score, percent CBV change (ΔCBV) and respective CNR, concentration of Fe, and baseline CBV. RESULTS: The |PSC| in the visual cortex increased with ferumoxytol dose and was up to 3 × higher than BOLD fMRI. Test-retest reliability was comparable for BOLD and CBV fMRI. Intraclass correlation coefficients (ICCs) for |PSC| were 0.3 (one-sided 95% lower confidence limit = 0.00), 0.81 (0.47), 0.48 (0.00), and 0.3 (0.00) for BOLD and the 250-, 350-, and 510-mg doses of ferumoxytol, respectively. For ΔCBV, ICCs were 0.77 (0.37), 0.48 (0.00), and 0.49 (0.00) for 250 mg, 350 mg, and 510 mg, respectively. CONCLUSION: This work demonstrates that CBV fMRI techniques and endpoints are dose dependent, robust and have good test-retest repeatability. It also confirms previous findings that USPIO enhances sensitivity of fMRI stimulus-response endpoints. LEVEL OF EVIDENCE: 1 J. MAGN. RESON. IMAGING 2017;46:124-133.

Temporal evolution of perfusion parameters in brain metastases treated with stereotactic radiosurgery: comparison of intravoxel incoherent motion and dynamic contrast enhanced MRI.

Intravoxel incoherent motion (IVIM) is a magnetic resonance imaging (MRI) technique that is seeing increasing use in neuro-oncology and offers an alternative to contrast-enhanced perfusion techniques for evaluation of tumor blood volume after stereotactic radiosurgery (SRS). To date, IVIM has not been validated against contrast enhanced techniques for brain metastases after SRS. In the present study, we measure blood volume for 20 brain metastases (15 patients) at baseline, 1 week and 1 month after SRS using IVIM and dynamic contrast enhanced (DCE)-MRI. Correlation between blood volume measurements made with IVIM and DCE-MRI show poor correlation at baseline, 1 week, and 1 month post SRS (r = 0.33, 0.14 and 0.30 respectively). At 1 week after treatment, no significant change in tumor blood volume was found using IVIM or DCE-MRI (p = 0.81 and 0.41 respectively). At 1 month, DCE-MRI showed a significant decrease in blood volume (p = 0.0002). IVIM, on the other hand, demonstrated the opposite effect and showed a significant increase in blood volume at 1 month (p = 0.03). The results of this study indicate that blood volume measured with IVIM and DCE-MRI are not equivalent. While this may relate to differences in the type of perfusion information each technique is providing, it could also reflect a limitation of tumor blood volume measurements made with IVIM after SRS. IVIM measurements of tumor blood volume in the month after SRS should therefore be interpreted with caution.