Ultrasound Contrast Agent Dose Research Articles

Pediatric contrast-enhanced ultrasound: optimization of techniques and dosing.

When performing contrast-enhanced ultrasound (CEUS), ultrasound (US) scanner settings, examination technique, and contrast agent dose and administration must be optimized to ensure that high-quality, diagnostic and reproducible images are acquired for qualitative and quantitative interpretations. When carrying out CEUS in children, examination settings should be tailored to their body size and specific indications, similar to B-mode US. This review article details the basic background knowledge that is needed to perform CEUS optimally in children, including considerations related to US scanner settings and US contrast agent dose selection and administration techniques.

Spectrum, Applicability and Diagnostic Capacity of Contrast-Enhanced Ultrasound in Pediatric Patients and Young Adults afterIntravenous Application - A Retrospective Trial.

Purpose: To investigate the spectrum, applicability and diagnostic capacity of intravenous contrast-enhanced ultrasound imaging (CEUS) in a pediatric population. Materials and Methods: From 08/2005 to 11/2015, n = 40 pediatric patients and young adults from 0 - 26 years (Ø 11.4 ± 7.5) and 3.0 - 85.3 kg (Ø 40.8 ± 25.6) with n = 55 investigations received n = 79 IV applications of ultrasound contrast agent (UCA). UCA dose and side effects were documented. Scanned organs were the liver (n = 42), spleen (n = 9), kidney (n = 3), and testis (n = 1). Histology, surgery or reference imaging was compared to CEUS and clinical follow-up. Results: The UCA dose < 20 kg was 0.4 ± 0.3 ml, (0.05 ± 0.02 ml/kg) and > 20 kg was 1.0 ± 0.4 ml (p< 0.0001) (0.02 ± 0.01 ml/kg, p< 0.0001). Adverse effects occurred in 2/79 applications (2.5 %). Agreement CEUS/gold standard resulted in 32/34 investigations. For liver diagnostics (gold standard: MRI, CT, histology, serology), n = 11 malignant and n = 15 benign focal liver lesions were included. The specificity was 100 % (95 % CI: 0.77 - 1.00), the sensitivity was 82 % (95 % CI: 0.48 - 0.98), the positive predictive value was 100 % (95 % CI: 0.69 - 1.00) and the negative predictive value was 88 % (95 % CI: 0.62 - 0.98, p< 0.0001). In n = 2 reference imaging misdiagnosed and CEUS was in accordance with clinical follow-up. All splenic/renal lesions were diagnosed correctly. In n = 1 an insufficient testicular perfusion was ruled out. The observation time was 30.4 ± 30.5 months. Conclusion: CEUS is a well-tolerated and diagnostically equivalent modality in pediatric care, providing fundamental advantages compared to currently approved imaging modalities for these age groups.

Focused ultrasound simultaneous irradiation/MRI imaging, and two-stage general kinetic model.

Many studies have investigated how to use focused ultrasound (FUS) to temporarily disrupt the blood-brain barrier (BBB) in order to facilitate the delivery of medication into lesion sites in the brain. In this study, through the setup of a real-time system, FUS irradiation and injections of ultrasound contrast agent (UCA) and Gadodiamide (Gd, an MRI contrast agent) can be conducted simultaneously during MRI scanning. By using this real-time system, we were able to investigate in detail how the general kinetic model (GKM) is used to estimate Gd penetration in the FUS irradiated area in a rat's brain resulting from UCA concentration changes after single FUS irradiation. Two-stage GKM was proposed to estimate the Gd penetration in the FUS irradiated area in a rat's brain under experimental conditions with repeated FUS irradiation combined with different UCA concentrations. The results showed that the focal increase in the transfer rate constant of K trans caused by BBB disruption was dependent on the doses of UCA. Moreover, the amount of in vivo penetration of Evans blue in the FUS irradiated area in a rat's brain under various FUS irradiation experimental conditions was assessed to show the positive correlation with the transfer rate constants. Compared to the GKM method, the Two-stage GKM is more suitable for estimating the transfer rate constants of the brain treated with repeated FUS irradiations. This study demonstrated that the entire process of BBB disrupted by FUS could be quantitatively monitored by real-time dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

Evaluation of Dose Distribution of Molecular Delivery After Blood-Brain Barrier Disruption by Focused Ultrasound with Treatment Planning

The permeability of the blood-brain barrier (BBB) can be enhanced by focused ultrasound (FUS) in localized regions with applications of ultrasound contrast agent (UCA). The purpose of this study was to evaluate the dose distribution of Evans blue (EB) in the targeted brain by sonication with treatment strategy. FUS exposure was applied with an ultrasound frequency of 1 MHz, a 5% duty cycle and a repetition frequency of 1 Hz. Single sonication with two doses of UCA and two sonications at the same location or an interval of 3 mm to induce BBB disruption for assessing dose distribution. The permeability of the BBB was measured quantitatively based on EB extravasation. Gadolinium deposition was monitored by contrast enhanced MR imaging for dose distribution of the focal plane. Hematoxylin and eosin staining was performed for histologic observation. No significant difference was found for EB in the focal regions between the single sonication with UCA at a dose of 300 μL/kg and repeated sonication with UCA at a lower dose of 150 μL/kg. There was a sharper dose distribution in the brain with repeated sonication at the same location, compared with the brain receiving two sonications at an interval of 3 mm. Compared with a single sonication with UCA at a dose of 150 μL/kg, the histologic evaluation of the sonicated regions indicated that more erythrocytes were seen in the brain treated with single sonication at a higher dose of 300 μL/kg or repeated sonication at a dose of 150 μL/kg. This study demonstrated that the dose distribution of molecular delivery could be regulated by sonication with treatment planning.

Efficiency of drug delivery enhanced by acoustic pressure during blood&amp;ndash;brain barrier disruption induced by focused ultrasound

PurposeWe evaluated the delivery efficiency of intravenously injected large molecular agents, before and after disruption of the blood–brain barrier (BBB-D), induced by focused ultrasound (FUS) using various acoustic parameters.Materials and methodsMale Sprague-Dawley rats were injected intravenously with Evans blue (EB) before or after BBB-D induction by pulsed FUS. We used a 1.0 MHz pulsed FUS with four acoustic power settings and an ultrasound contrast agent (UCA) at four different doses to induce BBB-D resulting from cavitation. The permeability of the BBB was assessed quantitatively based on the extravasation of EB. Contrast enhanced magnetic resonance imaging (MRI) was used to monitor the gadolinium deposition associated with FUS. Histological analysis was performed to examine tissue damage.ResultsThe accumulation of EB in rat brain was found to be dependent on acoustic power and UCA dosage, regardless of whether EB administration occurred before or after FUS-induced BBB-D. Administration of EB followed by sonication resulted in greater EB extravasation than that for rats subjected to sonication prior to EB injection. To reduce tissue damage, EB extravasation was enhanced by first administering EB by intravenous injection, followed by sonication at reduced acoustic power or UCA dosage. The normalized signal intensity change in rat brains that received the same dose of UCA and sonicated after gadolinium injection was significantly greater than in rats undergoing sonication followed by gadolinium administration. Moreover, contrast enhanced MRI showed a more precise distribution of gadolinium in the brain when gadolinium was administered before sonication.ConclusionWe demonstrated that a compound administered prior to sonication treatment promotes extravasation of the sonicated region. Thus, it is possible to optimize ultrasound parameters for lower sonication and reduced UCA doses, to induce BBB-D while minimizing damage to normal brain tissue.

Microbubble-enhanced functional changes in arteries induced by pulsed high-intensity focused ultrasound exposure

The purpose of this study is to investigate the dose-dependent effects of ultrasound contrast agent (UCA) on the changes of peak systolic velocity (PSV) and pulsatility index (PI) in the arteries of 24 male Sprague-Dawley rats. The rats were sonicated with 1.0-MHz pulsed high-intensity focused ultrasound (HIFU) at two acoustic powers, 15W and 30W, with UCA present at four concentrations (0, 150, 300, and 450μL/kg). Ultrasound imaging was used to localize and to monitor the pulsed-HIFU exposure. The mean PSV of blood flow, as measured by Doppler ultrasound imaging, increased immediately in the arteries where UCA has been administrated at all four doses after pulsed-HIFU at 15W. However, the normalized PSV change decreased with each injected dose of UCA at 30W. Furthermore, the normalized pulsatility index changes increased as the injected dose of UCA increased at two acoustic powers. No obvious changes were found in terms of histological structures and temperature rise at the vessel wall. Our results demonstrated that the response of the artery to pulsed-HIFU was dependent on UCA dose at the same acoustic power. The value of normalized PSV change was minimal and the normalized PI change reached a maximum when the UCA dose was at the highest dose of UCA (450μL/kg) with the two acoustic powers.

Detecting blood-brain barrier disruption within minimal hemorrhage following transcranial focused ultrasound: A correlation study with contrast-enhanced MRI

Focused ultrasound combined with an intravascular ultrasound contrast agent can induce transient disruption of the blood-brain barrier, and the blood-brain barrier disruption can be detected by contrast-enhanced MRI. There is, however, no study investigating the ability of various MR methods to detect focused ultrasound-induced blood-brain barrier disruption within minimal hemorrhage. Sonication was applied to 15 rat brains with four different doses of ultrasound contrast agent (0, 10, 30, or 50 μL/kg), and contrast-enhanced T1-weighted spin echo, gradient echo images, and longitudinal relaxation rate mapping along with effective transverse relaxation time-weighted and susceptibility-weighted images were acquired. Volume-of-interest-based and threshold-based analyses were performed to quantify the contrast enhancement, which was then correlated with the ultrasound contrast agent dose and with the amount of Evans blue extravasation. Both effective transverse relaxation time-weighted and susceptibility-weighted images did not detect histology-proved intracranial hemorrhage at 10 μL/kg, but MRI failed to detect mild intracranial hemorrhage at 30 μL/kg. All tested sequences showed detectable contrast enhancement increasing with ultrasound contrast agent dose. In correlating with Evans blue extravasation, the gradient echo sequence was slightly better than the spin echo sequence and was comparable to longitudinal relaxation rate mapping. In conclusion, both gradient echo and spin echo sequences were all reliable in indicating the degree of focused ultrasound-induced blood-brain barrier disruption within minimal hemorrhage.

Real-time ultrasound image-monitored focal changes of the vascular function in rats by pulsed HIFU

It has been shown that B-mode ultrasound can be useful for the real-time visualization of high-intensity focused ultrasound (HIFU) treatment. The aim of this study is to demonstrate the real-time ultrasound observation of functional changes when a vessel is exposed to pulsed-HIFU in the presence of preformed microbubbles. Using in vivo experiments, 12 male Sprague-Dawley rats were sonicated by 1-MHz pulsed-HIFU in the presence of ultrasound contrast agent (UCA) at four doses (0, 150, 300, and 450 microL/kg). The microbubbles passing through the aorta can be discerned with B-mode imaging. The mean peak systolic velocity (PSV) of the blood flow, as measured by Doppler ultrasound imaging, increased in arteries when the low-dose UCA groups (0 and 150 microL/kg) were examined after pulsed-HIFU at 45 W, but decreased when the high-dose UCA groups (300 and 450 microL/ kg) were examined. Additionally, the normalized pulsatility index (PI) changes increased with the injected dose of UCA. The interactions between ultrasound and the microbubbles can be seen to change the tissue permeability of the drug. Thus, monitoring of PSV or PI might be useful as an online method to ensure the correct sonicated position and to indicate when drug delivery has occurred.

Pulse sequence and timing of contrast‐enhanced MRI for assessing blood–brain barrier disruption after transcranial focused ultrasound in the presence of hemorrhage

To optimize the timing of contrast-enhanced magnetic resonance imaging (MRI) that best indicates blood-brain barrier (BBB) disruption induced by focused ultrasound (FUS) along with an ultrasound contrast agent (UCA) and to verify that the contrast-enhanced spin-echo MRI sequence can indicate the degree and location of BBB disruption in the presence of hemorrhage better than a gradient-echo sequence. Sonication was applied to 12 rat brains with four different doses of UCA to cause variable degrees of hemorrhage. Two imaging sequences were performed to acquire T1-weighted (T1W) images at two time-points after the administration of a T1-shortening contrast agent. The contrast enhancement at the sonicated regions was quantified and correlated against Evans blue (EB) staining. The spin-echo T1W images at 10 minutes post-contrast enhancement showed the best correlation with EB staining in both quantity of EB extravasation (r = 0.812; P < 0.01) and spatial distribution (r = 0.528, P < 0.01). This capability was more robust than the gradient-echo sequence. Our results suggest that contrast-enhanced T1W spin-echo sequence acquired in the early phase post-contrast enhancement should be considered to monitor the degree and location of BBB disruption under the possibility of hemorrhage induced by FUS.

Effect of ultrasound contrast agent dose on the duration of focused-ultrasound-induced blood-brain barrier disruption

It has been shown that focused ultrasound (FUS) is capable of noninvasive and reversible disruption of the blood-brain barrier (BBB) at target regions when applied in the presence of ultrasound contrast agent (UCA). The purpose of this study was to investigate the effects of UCA dose on the reversibility of BBB disruption induced by the same acoustical power of FUS. Sonications were applied at an ultrasound frequency of 1 MHz with a 5% duty cycle and a repetition frequency of 1 Hz. The brains of 66 male Sprague-Dawley rats were subjected to sonications with three doses of UCA. BBB integrity was evaluated via femoral vein injection of Evans Blue (EB) while the rats were anesthetized. The relationship between UCA dose and the region of EB extravasation was evaluated at an acoustic power of 1.43 W. The BBB disruption, as indexed by the amount of EB extravasation, was the largest immediately after the sonications. The quantity of Evans blue extravasation decreased as a function of time at various UCA doses. This study demonstrates that the appropriate dose of UCA not only enhance the BBB opening but also effectively aid in controlling the duration of BBB disruption.

Gas body destruction reduces the effective circulating dose of ultrasound contrast agent infused in rats.

Glomerular capillary hemorrhage (GCH) in rat kidney provides a model system for assessing in vivo gas body efficacy in diagnostic or therapeutic applications of ultrasound. Two diagnostic ultrasound machines were utilized: one monitored the second‐harmonic B mode contrast‐enhancement of the left kidney and the other exposed the right kidney for GCH production. Definity contrast agent was infused at 5 μl/kg/min for 300 s during shams and 1.5‐MHz intermittent exposures at 2.3‐MPa peak rarefactional pressure amplitude in groups of five rats. The left kidney image brightness enhancement, indicative of circulating gas body dose, was 18.4 au (decompressed arbitrary units) in shams with no GCH in histology. Exposure of the right kidney with a normal 1‐s image interval induced 68.4% GCH but reduced the left kidney enhancement to 3.3 au, which implies substantial gas body destruction. Decreased exposure with 10‐s interval reduced right kidney GCH (P′<0.001) but only to 30.3% while ameliorating gas body destruction with 13.1‐au left kidney enhancement. The effective in vivo gas body dose in rats may be reduced greatly due to gas body destruction in the small animal, complicating extrapolation to similar conditions of human exposure. [Work supported by NIH grant EB00338.]

Effects of Acoustic Parameters and Ultrasound Contrast Agent Dose on Focused-Ultrasound Induced Blood-Brain Barrier Disruption

Previously, it was shown that low-intensity focused ultrasound pulses applied along with an ultrasound contrast agent results in temporary blood-brain barrier (BBB) disruption. This effect could be used for targeted drug delivery in the central nervous system. This study examined the effects of burst length, pulse repetition frequency (PRF), and ultrasound contrast agent dose on the resulting BBB disruption. One hundred nonoverlapping brain locations were sonicated through a craniotomy in experiments in 26 rabbits (ultrasound frequency: 0.69 MHz, burst: 0.1, 1, 10 ms, PRF: 0.5, 1, 2, 5 Hz, duration: 20 s, peak negative pressure amplitude: 0.1 to 1.5 MPa, Optison dosage 50, 100, 250 μl/kg). For each sonication, BBB disruption was evaluated using contrast-enhanced magnetic resonance imaging. The BBB disruption threshold (the pressure amplitude yielding a 50% probability for BBB disruption) was determined using probit regression for the three burst lengths tested. Tissue effects were examined in light microscopy for representative locations with similar amounts of contrast enhancement from each group. While changing the PRF or the Optison dosage did not result in a significant difference in the magnitude of the BBB disruption ( p > 0.05), reducing the burst length resulted in significantly less contrast enhancement ( p < 0.01). The BBB disruption thresholds were estimated to be 0.69, 0.47 and 0.36 MPa for 0.1, 1 and 10 ms bursts, respectively. No difference was detected in histology between any experimental groups. This data suggests that over the range of parameters tested, BBB disruption is not affected by PRF or ultrasound contrast agent dose. However, both the BBB disruption magnitude and its threshold depend on the burst length. (E-mail: njm@bwh.harvard.edu)

OP25.01: First trimester combined screening: prospective evaluation of performance in an OSCAR setting

Objectives: The study was performed to assess whether hemodynamic effects on the fetus occur in late-pregnancy mice when ultrasound contrast agent (UCA) (SonoVue TM ) is used for clinical applications in obstetrical ultrasonography. Methods: Sixty late-pregnancy mice (Wister mice, median weight, 300 (range, 260–330) g; median gestational age, 19 (range, 16–21) days) were selected and divided into three experimental groups – Group A, the control group, were injected with physiologic saline solution, Group B were injected with a diagnostic dose of UCA − 0.06 mg/kg body weight – and Group C were injected with a high dose of UCA − 12 mg/kg. From each group a random selection of one mouse was made and it was examined by ACUSON Sequoia 512 with contrast pulse sequencing (CPS) technology. Maternal and fetal heart rate, pulsatility index (PI), resistance index (RI), and systolic: diastolic ratios (S/D) were measured in the fetal middle cerebral artery, umbilical artery, and uterine artery before and after administration of UCA or physiologic saline solution. Results: There were no significant differences in maternal and fetal heart rate, PI, RI, and S/D ratios in the fetal middle cerebral artery, umbilical artery and uterine artery between the different dosage groups of UCA or physiologic saline solution (ANOVA, P > 0.05). A significant decrease in the maternal and fetal heart rate, measured in the uterine artery and in the fetal middle cerebral artery, before and after injection of UCA or physiologic saline solution was found (t-test, P 0.05). Conclusions: The SonoVue TM UCA did not produce any harmful fetal or placental effects in late pregnancy and was shown to be safe in this study. The decreases in maternal and fetal heart rates was probably caused by the stress of the procedure.

Quantitative evaluation of the use of microbubbles with transcranial focused ultrasound on blood–brain-barrier disruption

It has been shown that focused ultrasound (FUS) can disrupt the blood–brain barrier (BBB) noninvasively and reversibly at target locations when applied in the presence of ultrasound contrast agent (UCA). In this study, the dose-dependent effects of UCA on BBB disruption were investigated in the brains of 16 male Wistar rats sonicated by 1.0-MHz transcranial FUS, with the UCA present at four doses. The BBB disruption was evaluated quantitatively based on the extravasation of Evans blue (EB). The amount of EB extravasation in the brain increased with the quantity of UCA injected into the femoral vein prior to sonication. Moreover, the use of a suitable dose of UCA resulted in the BBB disruption being concentrated in the focal region instead of the entire brain. Our results indicate that injecting an appropriate quantity of UCA effectively increases and localizes the BBB disruption induced by transcranial FUS sonications.

Quantitative Evaluation of Focused Ultrasound with a Contrast Agent on Blood-Brain Barrier Disruption

The use of an ultrasound contrast agent (UCA) with focused ultrasound sonication has the potential to disrupt the blood-brain barrier (BBB) noninvasively and reversibly at target locations. This study investigated the effects of UCA dose and ultrasound pressure on BBB disruption. Sonications were applied at 1 MHz with a burst length of 10 ms, a 1% duty cycle and a repetition frequency of 1 Hz. The duration of the sonication was 30 s. In in vivo experiments, 16 male Wistar rats were sonicated in the presence of UCA at four doses (0, 30, 60 and 90 μL/kg). BBB integrity was evaluated by injecting Evans blue (EB) into the femoral vein of anesthetized rats. The relationship between UCA dose and the region of EB extravasation was evaluated at ultrasound pressures of 0.9 and 1.2 MPa. The BBB disruption, as quantified by the amount of EB extravasation, was significantly greater in rats injected with UCA at a dose of 60 or 90 μL/kg than at a dose of 0 or 30 μL/kg. The amount of EB extravasation increased monotonically with the quantity of UCA injected into the femoral vein before sonication. Furthermore, the BBB disruption could be enhanced in the focal region relative to the surrounding region with a higher dose of UCA (60 or 90 μL/kg). This study demonstrates that BBB disruption can be both increased and localized to the focal region by injecting an appropriate quantity of UCA before performing focused ultrasound sonications. (E-mail: winli@ntu.edu.tw)

MRA contrast bolus timing with ultrasound bubbles.

The purpose of this study was to determine the feasibility of using an ultrasound contrast agent test bolus to determine optimum bolus timing for three-dimensional (3D) gadolinium (Gd)-enhanced magnetic resonance angiography (MRA). Small test doses of ultrasound contrast agent (0.3 ml Optison) were injected intravenously followed immediately by a 20 ml saline flush. Arrival of the contrast agent was detected by spectral Doppler ultrasound (US). This technique was implemented in patients undergoing peripheral vascular MRA and carotid MRA. Arrival of the US contrast agent test bolus was readily detected by the change in amplitude of the Doppler spectrum and by a huge increase in the audio signal amplitude. This contrast travel time measurement accurately guided bolus timing for 3D Gd MRA. Bolus timing for 3D contrast-enhanced MRA can be performed using US, thereby eliminating the problems and MR scanner time required for injecting a test bolus of Gd contrast.