Liver-specific imaging with SHU 563A: diagnostic potential of a new class of ultrasound contrast media.

The purpose of this study was to evaluate the imaging properties and diagnostic potential of the novel polymeric ultrasound contrast agent SHU 563 A. After i. v. injection, the agent circulates in the blood pool for about 10 min and is then subsequently sequestered by the RES cells predominantly in the liver. The acoustic emission capabilities enable a very sensitive detection during the blood pool phase and after uptake in the RES cells, contributing to differential diagnosis as well as detection of liver lesions. During a multicenter study, 28 patients with liver lesions were examined. In all patients the results were compared to baseline ultrasound and Contrast enhanced Spiral CT. With respect to lesion size and location, very good agreement between SHU 563 A ultrasound and Spiral CT was achieved. Additional lesions could be shown in the RES phase by SHU 563 A enhanced ultrasound. 26 further patients were examined in other indications. The results in all 54 patients indicate good safety and tolerance of SHU 563 without limitations for diagnostic use. SHU 563 A enhanced ultrasound adds significantly to the detection and delineation of focal liver lesions by improving conspicuity due to RES based contrast after uptake.

Wideband harmonic imaging: a novel contrast ultrasound imaging technique.

A novel ultrasonic imaging method, wideband harmonic imaging, for nonlinear imaging of microbubble contrast agents is evaluated. In wideband harmonic mode, two pulses of alternate phase are send out. The image is then processed from the sum of both pulses, resulting in an image of nonlinear scatterers such as microbubbles. A prototype ultrasound system, Siemens Elegra, was evaluated with in vitro investigations and animal trials, using conventional, harmonic and wideband harmonic settings with the galactose based ultrasound contrast agent Levovist. Wideband harmonic imaging offers superior sensitivity for ultrasound contrast agents compared to conventional imaging and harmonic imaging. At low transmit power settings (MI 0. 1-0.5) the nonlinear response is already sufficient to generate a image of the blood pool distribution of Levovist in the rabbit kidney including the microvasculature, with clear delineation of vessels and perfused parenchyma. At high transmit amplitudes, nonlinear tissue response reduced the apparent image contrast between contrast agent and tissue. The results suggest that wideband harmonic imaging is currently the most sensitive contrast imaging technique, maintaining highest spatial resolution. This may add to image quality and offer new clinical potential for the use of ultrasound contrast agents such as Levovist.

Improved imaging of liver metastases with stimulated acoustic emission in the late phase of enhancement with the US contrast agent SH U 508A: early experience.

PURPOSE: To see whether stimulated acoustic emission (SAE) in the liver parenchyma in the late phase of enhancement with SH U 508A increases the conspicuity of occult metastases at ultrasonography (US). MATERIALS AND METHODS: Eighteen patients with known hypo- or hypervascular hepatic metastases underwent US after SH U 508A administration, after a delay of at least 5 minutes, to ensure decay of blood pool enhancement. In 16 patients with visible metastases, conspicuity was compared on registered SAE and gray-scale scans by two blinded readers and by using computerized analysis of relative gray-scale and color Doppler conspicuity scores inside and outside the lesion. In nine patients, areas suspected of being involved but without definite gray-scale masses were imaged in the same way. Paired sections were analyzed by two blinded readers looking for parenchymal color defects without corresponding gray-scale masses; nine control images from three healthy volunteers were also included. RESULTS: Intense, transient parenchymal SAE was seen in all subjects. All metastases appeared as areas of reduced or absent signal. The conspicuity score was 80% for SAE versus 9% for gray-scale US (P < .001, Wilcoxon signed rank test). SAE-specific defects were seen in all patients but in none of the volunteers. Metastases seen on SAE but undetectable on gray-scale images were proved in three patients. CONCLUSION: SAE with SH U 508A improves the conspicuity of metastases. SAE-specific defects may reveal isoechoic or subtle metastases.

Stimulated acoustic emission to image a late liver and spleen-specific phase of Levovist in normal volunteers and patients with and without liver disease.

Quantitative studies were performed to investigate liver- specific uptake of the microbubble Levovist, using stimulated acoustic emission (SAE), which can detect microbubbles even when stationary or slow-moving. These comprised studies of biodistribution comparing the liver and kidney in five normal volunteers, reproducibility in 34 patients, comparison between cirrhotics and controls (n = 9 each) and maximal depth of effect at different frequencies (180 measurements in 31 patients). Stimulated acoustic emission lasted beyond 30 min, with strongly liver-specific properties in each volunteer and was highly reproducible. No difference in the amount of SAE in the superficial liver was seen between cirrhotic and normal livers, but attenuation was higher in cirrhotics. This demonstrates a frequency-dependent effect on liver SAE penetration. We conclude that the liver uptake of Levovist lasts over 30 min, is reproducible, occurs even where diffuse liver disease is present and can be used to assess tissue attenuation in a novel fashion.

Liver vascular transit time analyzed with dynamic hepatic venography with bolus injections of an US contrast agent: early experience in seven patients with metastases.

Spectral Doppler intensitometry to study transit of a bolus of an ultrasonographic (US) contrast agent in the hepatic veins was performed in seven patients suspected of having liver metastases and seven control subjects. All control subjects had a late response (rise time, > 25 seconds; time to peak intensity, > 45 seconds), whereas six of seven patients had an early response (rise time, < 25 seconds; time to peak intensity, < 45 seconds) (P < .01).

[3-dimensional echo-enhanced transcranial Doppler ultrasound diagnosis]. / Dreidimensionale echosignalverstärkte transkranielle Doppler-Ultraschalldiagnostik.

Echo-enhancing agents improve the signal intensity of transcranial Doppler signals, enabling a novel approach of three-dimensional transcranial vascular imaging by Doppler ultrasound. The basic principle, system requirements and early clinical results with a custom built system are described. Transcranial color Doppler imaging was performed through the temporal bone acoustic window. During i.v. administration of the transpulmonary stable, galactose-based echo-enhancer Levovist (Schering) the video output of the ultrasound scanner was digitized and the spatial position of the recorded frames was simultaneously registered using a mechanical position sensor. After automatic segmentation of the color information, the 3D datasets were reconstructed offline using a Unix-based workstation (Silicon Graphics). Visualization was achieved by maximum intensity projection or surface visualization techniques. Administration of Levovist resulted in good enhancement of the vascular Doppler signal intensity, enabling acquisition of a 3D dataset of the complete circle of Willis with an imaging window of approximately 3-5 min for one i.v. injection. The vascularity of tumors could be recorded as a 3D dataset and further analyzed. The power Doppler technique with echoenhancement proved a valuable tool for 3D dataset recording. 3D datasets clearly facilitated the diagnosis of the vascular anatomy and lesion vascularity and provided additional information on localization of feeders, vascular displacement and extent of tumor vascularity.

A mathematical model for the assessment of hemodynamic parameters using quantitative contrast echocardiography.

A mathematical model for the assessment of hemodynamic parameters using quantitative echocardiography is presented. The method involves the intravenous injection of an ultrasonic echo contrast agent. The relative enhancement of the backscattered ultrasound intensity is measured as a function of time (the time-intensity curve). From this measurement, the volume flow rate (cardiac output) and the mixing volume are calculated. Relevant acoustic properties of the ultrasound contrast agent are discussed. An in vitro experiment is performed to corroborate the theory presented.

Prolongation and optimization of Doppler enhancement with a microbubble US contrast agent by using continuous infusion: preliminary experience.

PURPOSE: To investigate whether continuous infusion of an echo-enhancing contrast agent for up to 15 minutes can provide uniform and prolonged enhancement. MATERIALS AND METHODS: Six volunteers each received one bolus and three infusions of a microbubble contrast agent over 6-15 minutes at (a) a standard rate (mean, 2.08 mL/min), (b) a fast rate at twice the standard rate, and (c) a slow rate at half the standard rate. Spectral Doppler intensitometry of the femoral artery was performed for all infusions. Spectral Doppler ultrasound (US) scans of the femoral artery and color Doppler US scans of the carotid artery were subjectively assessed. RESULTS: All infusions provided an equilibrium plateau of constant prolonged enhancement starting after 1-2 minutes and lasting until the end of the infusion. Enhancement at the plateau was +13 dB (slow rate), +17.1 dB (standard rate), and +18.3 dB (fast rate) compared with baseline. Saturation artifacts with infusions were markedly fewer than those with bolus injections. Dose effectiveness (duration of enhancement that measured at least 7.5 dB per gram of contrast agent) was markedly improved with the infusions, from 0.8 min/g for the bolus to 2.6 min/g for the slow infusion. CONCLUSION: Continuous infusion of the microbubble contrast agent provided prolonged and uniform enhancement of Doppler signals and improved image quality by minimizing saturation artifacts.

Assessment of fetal and placental blood flow in primates using contrast enhanced ultrasonography.

Ultrasonographic contrast agents that stay within the vascular space and do not cross the placenta may permit differentiation between the maternal and fetal portions of the placenta and may be clinically useful for diagnosis of placental abnormalities. This study was performed to assess the effects of Levovist (Schering AG, Berlin) on the placental circulation and to determine whether hemodynamic effects on the fetus occur. Ten studies were performed in five pregnant macaques (median weight, 9.15 kg; range, 6.15 to 11 kg; median gestational age, 121 days; range, 34 days to term) under anesthesia. Gray scale, color, and duplex Doppler sonographic scans of the fetus and placenta were acquired using a 5 MHz curved array transducer. Fetal heart rate, resistive index, and systolic-diastolic ratios were measured in the fetal middle cerebral artery, aorta, umbilical artery, and uterine artery before and after administration of contrast agent. The following dose regimen was tested: 5 ml of physiologic saline solution followed by 0.1 ml/kg of 300 mg/ml Levovist (diagnostic dose), 0.5 ml/kg of 400 mg/ml Levovist (maximum dose), and 5 ml physiologic saline solution. The order of diagnostic dose and maximal dose was randomized among animals. Color enhancement of the basal portions of the placenta was documented after administration of contrast agent. Heart rate and middle cerebral artery systolic-diastolic ratio did not change between baseline and injections. A 7% decrease of the resistive index from baseline to maximum dose was measured in the uterine artery (not significant). A 7.7% decrease in the systolic-diastolic ratio from baseline to maximum dose was recorded in the umbilical artery. However, an identical change was measured after saline solution was injected. The resistive index in the aorta increased by 2.6% from baseline to maximum dose, a change that was not significant (P > 0.5). Ultrasonographic contrast enhancement of the maternal circulation in placenta is demonstrated to be without significant effects on the fetal circulation as measured in this limited population.

An investigation of the relationship between ultrasound echo enhancement and Doppler frequency shift using a pulsatile arterial flow phantom.

RATIONALE AND OBJECTIVES: Based on the echo-enhancing effect of microbubbles, various agents have been developed to improve the diagnostic confidence in patients with inadequate Doppler signals. In the clinical trials of the echo enhancer Levovist, there were a few isolated cases in which the maximum flow velocities of the enhanced Doppler spectra appeared to higher than the velocities in the nonenhanced baseline spectra. This raised the concern that echo enhancement could give a false indication of maximum flow velocity. This study investigated whether a systematic association between echo enhancement and velocity shift exists. METHODS: A pulsatile flow phantom that simulated the elasticity of blood vessels and the acoustic attenuation of extravascular tissue was used to compare enhanced with unenhanced Doppler spectra under accurately reproducible flow conditions. The experiments were carried out with varied sound attenuation and evaluated with dedicated spectral analysis software that included a special averaging tool. RESULTS: Levovist enhanced the Doppler signal by 16 to 31 dB, and the enhanced and unenhanced power spectra presented identical distribution of spectral power density under all flow conditions. CONCLUSIONS: The measurements gave no evidence that echo enhancement with Levovist falsifies the Doppler measurement of flow velocity.

Hemodynamic effects of microbubble echo contrast.

The dose-related hemodynamic effects of an active (bubble-rich) echo contrast agent were compared with those of a bubble-free contrast agent and saline solution to determine whether the microbubbles contained in the echo contrast agent are truly passive indicators in the circulation or whether they actively alter the hemodynamic state independent of the volume and osmotic loading associated with such injections. The study population consisted of 13 fully instrumented open-chest mongrel dogs. Four hundred ninety-two bolus injections were made of three different types: active contrast agent (Levovist, Schering AG, Berlin) (n = 333), saline solution (n = 112), and bubble-free contrast agent (n = 47). Levovist was administered in five dose ranges spanning 0.013 to 0.341 gm/kg and, like the saline solution, was administered in bolus volumes of 0.053 to 1.136 ml/kg. For each injection type, the percent change in hemodynamic parameters after administration of the bolus were calculated on the basis of the dose or volume of the injectate. Audio Doppler signal intensity was used to document the presence of bubbles in the injectate. Statistical significance was defined at the p = 0.05 level; clinical significance was defined as a greater than 15% change in a hemodynamic parameter. Statistically, but not clinically, significant changes were noted in almost all hemodynamic parameters regardless of injection type, and at all dose and volume ranges. Although statistically significant, injection of an active contrast agent in the human dose range resulted in a < 5% change in hemodynamic parameters. High doses of a contrast agent (active or bubble-free) increased the left atrial pressure and had associated changes in peripheral vascular hemodynamics because of the osmotic load. Clinically significant increases (> 15%) in pulmonary artery pressure and pulmonary vascular resistance were unique to the active contrast agent at high dose ranges. Standard doses of the active contrast agent changed the hemodynamics by less than 5% in healthy dogs. Transient clinically significant increases in pulmonary artery pressure and pulmonary vascular resistance are a unique side effect to high dose bolus injections of microbubble echo contrast agent.

The Doppler kinetics of microbubble echo contrast.

The right and left heart kinetics of a saccharide-based microbubble echo contrast agent were measured in 11 anesthetized dogs using Doppler intensity as a measure of microbubble concentration while controlling for the dose administered, weight of the subject and cardiac output. A two-phase Doppler time-intensity curve was noted in all vascular regions. A brief first pass effect (phase 1) was found to depend on the contrast dose, cardiac output and subject size. This was followed by a much longer nearly steady-state elevation in the Doppler intensity compared with baseline (phase 2). The kinetics of phase 2 were found to be the same in all vascular distributions and independent of cardiac output. The phase 2 kinetics depend on the contrast dose, subject size and elimination characteristics of the contrast agent. The clinically important conclusions are: (1) the magnitude of Doppler enhancement and duration of the contrast effect can be predicted using the simple formulas presented; (2) the flow-dependent portion of the arterial contrast effect is effectively over only a few seconds after intravenous injection; and (3) the kinetics of phase 2 are the same throughout the body.

[Ultrasound contrast media. New perspectives in ultrasound diagnosis]. / Ultraschallkontrastmittel. Neue perspektiven in der ultraschalldiagnostik.

Ultrasound contrast agents have recently proven to be clinically useful in many different areas and with many different ultrasound modalities. B-mode contrast echocardiography and delineation of cavities with ultrasound contrast agents are already accepted. Based on the contrast agent Echovist, assessment of tubal patency is possible with hysterosalpingo contrast sonography (HyCoSy). A new generation of transpulmonary, stable ultrasound contrast agents such as Levovist offer potential for various Doppler applications. Ultrasound contrast agents act as signal enhancers in Doppler examinations and therefore help to overcome the limitations of insufficient Doppler signal intensity. Recently, clinical studies have shown [correction of shown.] Doppler examinations to have many clinical benefits. Contrast agents are useful in the assessment of high-grade stenosis or the delineation of small vessels and under difficult conditions. Ultrasound contrast agents also create new applications: analysis of tumor vascularization and delineation of the transcranial venous system are possible with contrast enhancement. Future developments in contrast-specific scanning ("harmonic imaging") and new contrast agents, including organ-specific contrast agents, are expected to make a significant impact in the years to come.

Color doppler ultrasound of liver lesions: signal enhancement after intravenous injection of the ultrasound contrast agent Levovist.

Patients with focal liver lesions (hemangioma, focal nodular hyperplasia, adenoma, hepatocellular carcinoma, metastatic lesions, focal fatty lesion) received the ultrasound contrast agent Levovist (300 mg/mL and 400 mg/mL) intravenously. This ultrasound contrast agent (a suspension of micrometer-sized microparticles of galactose and microscopic gaseous bubbles) can pass through the lungs without impairment. After the administration of Levovist, increased color flow signals were detected in the liver. Five of 6 patients with metastatic liver lesions showed previously undetected blood flow in the rim of the tumor. In 4 patients with hepatocellular carcinoma, enhanced signal intensity was observed in the vessels of the rim and in 3 of those patients in the center of the tumor. One patient with adenoma and one patient with focal nodular hyperplasia showed signal enhancement in the central area of the tumor. No signal enhancement was observed in hemangiomas, a focal fatty lesion, or in a carcinoid metastatic lesion. Levovist increased the echointensity of normal and tumor vessels in liver lesions. This new ultrasound contrast agent led to the detection of tumor vessels previously not detectable by conventional color flow imaging.

Doppler enhancement with SH U 508A in multiple vascular regions.

PURPOSE: To determine the magnitude and duration of peripheral vascular and cardiac Doppler signal enhancement after intravenous administration of contrast agent SH U 508A. MATERIALS AND METHODS: Suboptimal cardiac or peripheral vascular Doppler examinations were evaluated. A total of 75 intravenous bolus injections were made in 30 patients. Spectral audio Doppler intensity was measured throughout the duration of contrast effect. RESULTS: No clinically relevant adverse effects were noted, and Doppler enhancement was apparent in all cases. The diagnostic confidence of the investigators when scored before and after Doppler enhancement improved from 35% to 91% (P < .05). Doppler intensity increased more than 16 dB in all vascular regions investigated (P < .05). The contrast effect lasted for more than 120 seconds in the peripheral vascular and cardiac groups at equivalent doses. CONCLUSION: Intravenously administered SH U 508A is effective in markedly increasing cardiac, femoral arterial, and transcranial (cerebral arterial) Doppler signal intensity. The effect improves the clinical diagnostic confidence in cases of suboptimal unenhanced Doppler examinations.