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PubMed2004

Microbubble contrast-enhanced ultrasound in liver transplantation.

The use of liver transplantation for treatment of end-stage liver disease is now commonplace. The accurate assessment of the pre-transplant candidate and long-term follow-up of the posttransplant patient is vital in ensuring that the limited resource of donor livers is appropriately used. Ultrasound is accepted as playing an important role in this process. The advent of microbubble contrast enhanced ultrasound provides new opportunities in terms of improving diagnostic accuracy and obviating more invasive investigations with their associated patient morbidity and mortality. We present the current and developing applications of microbubble contrast-enhanced ultrasound in the field of liver transplantation.

Contrast Media↗

PubMed2004

Microbubbles and ultrasound: a bird's eye view.

Gas-filled microbubbles were initially used as ultrasound contrast agent because of their intravascular rheology, which is similar to that of red blood cells. Their transit through tissue can thus be quantified with ultrasound. More recently, these bubbles have been successfully used for molecular imaging by incorporating ligands on their surfaces that will adhere to cellular and other components within the microvasculature and can be detected by ultrasound. These bubbles have also been used for delivery of genes and drugs which can be released locally by disruption of the bubbles with high-energy ultrasound. Finally, bioeffects produced by localized ultrasound disruption of microbubbles have been shown to induce angiogenesis. This brief review will provide a bird's eye view of these applications.

Animals↗

PubMed2002

Correlation between myocardial perfusion abnormalities detected with intermittent imaging using intravenous perfluorocarbon microbubbles and radioisotope imaging during high-dose dipyridamole stress echo.

BACKGROUND: The clinical accuracy of myocardial contrast echocardiography (MCE) using intermittent harmonic imaging and intravenous perfluorocarbon containing microbubbles during dipyridamole stress has not been evaluated in a multicenter setting. HYPOTHESIS: The accuracy of dipyridamole stress contrast echo in the detection of coronary artery disease (CAD) using myocardial perfusion images is high in comparison with technetium-99 (99Tc) sestamibi single-photon emission computed tomography (MIBI SPECT) and increases the accuracy of wall motion data. METHODS: In 68 consecutive nonselected patients (46 men; mean age 66 years) from three different institutions in two countries. dipyridamole stress echo and SPECT with 99mTc MIBI were compared. Continuous intravenous (IV) infusion of perfluorocarbon exposed sonicated dextrose albumin (PESDA) (2-5 cc/min) was administered for baseline myocardial perfusion using triggered harmonic end systolic frames. Real-time digitized images were used for wall motion analysis. Dipyridamole was then injected in two steps: (1) 0.56 mg/kg for 3 min, (2) 0.28 mg/kg for 1 min, if the first step was negative for an inducible wall motion abnormality. After dipyridamole injection, myocardial contrast enhancement and wall motion were analyzed again by the same methodology. RESULTS: There were 35 patients with perfusion defects by SPECT. Wall motion was abnormal in 22, while MCE was abnormal in 32. Wall motion and MCE each had one false positive. The proportion of correctly assigned patients was significantly better with MCE than with wall motion (p = 0.03; chi square test). CONCLUSIONS: Myocardial contrast echocardiography, using intermittent harmonic imaging and intravenous perfluorocarbon containing microbubbles, is a very effective method for detecting coronary artery disease during dipyridamole stress echo.

Adult↗

PubMed2002

Correlation between microbubble contrast-enhanced color doppler sonography and immunostaining for Kupffer cells in assessing the histopathologic grade of hepatocellular carcinoma: preliminary results.

PURPOSE: The aim of this study was to determine the histopathologic grades of hepatocellular carcinomas (HCCs) on the basis of the presence of Kupffer cells, using color Doppler sonography with the liver-specific microbubble contrast agent Levovist. METHODS: Color Doppler sonograms generated by stimulated acoustic emission were obtained 7 minutes after intravenous injection of 5 ml of Levovist (300 mg/dl) in patients with histopathologically confirmed HCCs. CT scans were also obtained and evaluated, and hematoxylin and eosin staining for morphologic examination and immunostaining (anti-CD68) for detecting Kupffer cells were performed for confirmation of the sonographic findings. RESULTS: Eighteen tumors had a defect in the color Doppler signal (color void) that corresponded with the baseline gray-scale image of the tumor. On histopathologic examination, these 18 tumors were all found to be either poorly or moderately differentiated HCCs with either a marked reduction in the number of or the absence of Kupffer cells. The remaining 2 tumors showed color signals. Histopathologic examination of these 2 tumors disclosed well-differentiated components within the tumors, with Kupffer cells in the tumor tissue. CONCLUSIONS: Color Doppler sonography using a liver-specific microbubble ultrasound contrast agent appears to reflect the histopathologic features of HCCs and may thus be useful for differentiating liver tumors and determining a treatment strategy.

Adult↗

PubMed2003

Value of contrast-enhanced power Doppler sonography using a microbubble echo-enhancing agent in evaluation of small breast lesions.

PURPOSE: The purpose of this study was to prospectively evaluate the usefulness of contrast-enhanced power Doppler sonography (PDUS) using a microbubble echo-enhancing agent in differentiating between malignant and benign small breast lesions. PATIENTS AND METHODS: Between July 1, 2000, and September 30, 2001, we performed gray-scale sonographic examination of patients in whom diagnostic sonography or screening mammography had revealed solid breast lesions measuring less than 2 cm in the largest dimension. The patients were then examined on PDUS before and after injection of a microbubble contrast agent. The sonographic findings for all 3 techniques, as well as the morphologic features of the Doppler signals for each patient before and after injection of the contrast agent on PDUS, were independently assessed. Each lesion was classified as "benign" or "malignant" on the basis of specific criteria for sonographic interpretation. A hemodynamic study was performed in which time-transit profiles of the Doppler signals on contrast-enhanced PDUS were generated using a computer-assisted program, and the results for each patient were compared with the findings of a histopathologic examination of surgical specimens. RESULTS: Thirty-six patients (35 women and 1 man) with a mean age of 43.5 years (range, 18-69 years) were evaluated. The tumors ranged from 4 to 19 mm in the largest dimension. Histopathologic examination revealed that 19 tumors were benign and 17 were malignant. For morphologic diagnosis of the malignant lesions, the sensitivity of gray-scale sonography was 100%, compared with 29% for PDUS without contrast enhancement. The specificity of gray-scale sonography was 47%, compared with 74% for PDUS without contrast enhancement. Contrast-enhanced PDUS had a sensitivity of 71% and a specificity of 58%. The diagnostic accuracy was 72% for gray-scale sonography, 53% for PDUS without contrast enhancement, and 64% for contrast-enhanced PDUS. The time-transit profiles of the hemodynamic study did not reveal a statistically significant difference in the accuracy rates of contrast-enhanced PDUS between benign and malignant breast lesions. CONCLUSIONS: Compared with PDUS without contrast enhancement, contrast-enhanced PDUS provides better visualization of the morphology of vascular Doppler signals that is characteristic of malignancy and therefore has a higher sensitivity and diagnostic accuracy, albeit a lower specificity. In differentiating between benign and malignant small breast lesions, contrast-enhanced PDUS can be helpful when used with gray-scale sonography and PDUS without contrast enhancement.

Adolescent↗

PubMed1977

Ultrasonic contrast study to indentify stomach tap water microbubbles.

In ultrasound scanning of the left upper quadrant of the abdomen, it is important to identify stomach contents which may appear as a cyst if the content is fluid or as a solid mass if the content is fluid with suspended food particles. By giving the patient a drink of two or three ounces of freshly drawn water, multiple strong echoes are produced from the fundus and the body of the stomach because of the microbubbles contained in recently agitated tap water and the microbubbles produced by the mixing effect of swallowing. These strong echoes will cause a "cystic" or "mass-like" appearance produced by the stomach contents to disappear. Thus, a false positive diagnosis is easily and rapidly avoided. The portion of the pancreas behind the stomach may also become more obvious. If the mass or cyst persists, the diagnosis of an abnormality is confirmed.

Diagnosis, Differential↗

PubMed2002

On the parameters affecting the sensitivity of MR measures of pressure with microbubbles.

Recently, it has been suggested that gas encapsulated distensible microbubbles may serve as pressure probes in the MR field through the relationship between bubble size and 1/T(2) or 1/T(*)(2). Currently, in vivo application of this technique is hindered by the ability of T(2) or T(*)(2) to detect pressure changes that are clinically relevant. This work identifies and characterizes, through numerical simulations, the set of parameters which optimize the ability of this technique to detect small pressure changes. Results show that when the bubbles do not interact magnetically, the T(2)- and T(*)(2)-based measurements of pressure are strongly influenced by the bubble size at atmospheric pressure, static magnetic field strength, magnitude of the susceptibility difference between the encapsulated gas and plasma, bubble volume fraction, and the refocusing interval. In particular, to detect clinically relevant pressure changes, microbubbles need to be approximately 2-3 microm in radius, distributed at a volume fraction of 0.15%, and have a volumetric magnetic susceptibility difference of at least 34 ppm.

Blood Pressure↗

PubMed2002

Quantitative microbubble enhanced transrectal ultrasound as a tool for monitoring hormonal treatment of prostate carcinoma.

BACKGROUND: We quantified changes in prostate carcinoma vascularity treated with anti-androgens using color Doppler and power transrectal ultrasound in combination with microbubble contrast agent Levovist. METHODS: Thirty-six men with prostate carcinoma were studied at baseline and at intervals during treatment. At each attendance, Levovist((R)) (10 ml, 300 mg/ml) was given as an iv bolus. Using quantitative analysis, we calculated the pre-enhancement scores, arrival time, time to peak, peak value, and area under the time-enhancement curve (AUC). These were compared to pre-treatment values and serial PSA measurements. RESULTS: The pre-enhancement, peak value, and AUC each showed a marked response with reductions within one week. The average AUC declined to 68% +/- 9% (mean +/- standard error) by week 1, 56% +/- 9% by week 3, and 20% +/- 4% by week 6. A strong correlation with changes in the mean PSA (r = 0.95, P < 0.001) was also measured. In four patients, Doppler indices did not fall with PSA: two patients with the most marked discrepancy relapsed at 6 months. CONCLUSION: The vascular enhancement declined with therapy, similar to PSA. Microbubble enhanced ultrasound can show early response to treatment.

Androgen Antagonists↗

PubMed1999

Trajectory Analysis and Collision Efficiency during Microbubble Flotation.

The hydrodynamic interaction between a rising bubble and a sedimenting particle during microbubble flotation is considered. The effects of attractive van der Waals forces and attractive or repulsive electrostatic forces are included. A mathematical model is presented which is used to perform a trajectory analysis and to calculate collision efficiencies between the bubble and particle. It is shown that collision efficiencies and the nature of the bubble-particle interactions are strongly dependent on the relative strengths of the van der Waals and electrostatic forces and on the lengthscales over which these forces act. It is demonstrated that optimal operating conditions can be suggested to achieve efficient microbubble flotation by correctly accounting for the interaction of van der Waals, electrostatic, and hydrodynamic forces. Copyright 1999 Academic Press.

Journal Article↗

PubMed2002

Detection of an occult hepatocellular carcinoma using ultrasound with liver-specific microbubbles.

The radiological surveillance of cirrhosis to detect the development of hepatocellular carcinoma (HCC) is problematic because no highly sensitive and specific imaging investigation is available. Ultrasound is typically the first modality used but is less accurate than other imaging modalities. We report the first case of a patient with cirrhosis in whom US imaging with liver-specific microbubbles detected an HCC prior to its detection by MR. The use of liver-specific microbubble US contrast agents is an exciting development in the detection of HCC in chronic liver disease and may help to rectify some of the shortcomings of US.

Aged↗

PubMed1996

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.

Animals↗

PubMed2005

Computer-assisted quantitative assessment of power Doppler US: effects of microbubble contrast agent in the differentiation of breast tumors.

RATIONALE AND OBJECTIVES: To objectively quantify the effects of a microbubble contrast agent to differentiate breast tumors with power doppler ultrasound and to compare these results with color doppler ultrasound (CD US). METHODS: In 47 patients a microbubble contrast agent was injected intravenously. Computer-assisted quantitative assessment of the color pixel density was performed to evaluate the increase in Doppler signals. Results were compared to previously published results of a color Doppler ultrasound study. RESULTS: Peak color pixel density at contrast-enhanced power Doppler ultrasound was higher for carcinomas than for benign tumors (P < 0.03). Time to peak enhancement was shorter in carcinomas than in benign tumors (P < 0.01). For both parameters, diagnostic accuracy of power Doppler ultrasound was 69 and 78%, and for color Doppler ultrasound 62 and 76%, respectively. CONCLUSIONS: Quantitative assessment of contrast-enhanced power Doppler ultrasound showed significant differences in malignant and benign breast tumors. Diagnostic accuracy of contrast-enhanced power Doppler ultrasound was higher compared to color Doppler ultrasound.

Adult↗

PubMed2004

Ultrasound attenuation by encapsulated microbubbles: time and pressure effects.

Ultrasound (US) contrast agents (UCA) consist of artificial encapsulated microbubbles filled with low-diffusivity gas. This study evaluated, both experimentally and theoretically, the behavior of a cloud of encapsulated microbubbles while the surrounding pressure was modified within the physiological range. The theoretical analysis included calculation of US attenuation caused by a bubble cloud. The radius and gas content of each bubble were determined from a solution of a diffusion problem. Shell permeability and rigidity were taken into account. Both experiments and theory demonstrated that, for fixed ambient pressures, higher pressures result in increased rate of attenuation decay. Pulsatile ambient pressure induces pulsations of attenuation of the same frequency. In general, theoretical predictions are in good agreement with experimental data.

Acoustics↗

PubMed2000

Ex vivo delineation of placental angioarchitecture with the microbubble contrast agent Levovist.

OBJECTIVE: The aim of this study was to delineate placental vasculature with the microbubble contrast agent Levovist (99.9% galactose and 0.1% palmitic acid; Schering AG, Berlin, Germany), with the ultimate goal of delineating placental vascular anatomy in utero. STUDY DESIGN: A placental lobule from each of 11 term human placentas was perfused on the fetal side of the circulation under physiologic conditions. Randomly assigned dose-concentration combinations of Levovist were administered through a chorionic artery into the corresponding placental lobule, and the resultant echoenhancement with power Doppler imaging was recorded for digital analysis. Interplacental variability was corrected for by averaging the results of three injections at each dose-concentration combination. RESULTS: Echoenhancement was seen at all dose-concentration combinations in the injected lobule but not in adjacent control lobules. The three dose-concentration combinations that achieved optimal maximal integrated intensity and duration of action for both chorionic vessel and villus enhancement were 100 microL/kg of 400-mg/mL Levovist, 200 microL/kg of 400-mg/mL Levovist, and 400 microL/kg of 200-mg/mL Levovist. CONCLUSION: Microbubble contrast injection into the fetal vasculature enabled power Doppler imaging echoenhancement both in chorionic vessels and within the villus tree. We speculate that fetal injection of contrast agent may be applied to the delineation of placental lesions or areas of interfetal transfusion, although its applicability will be hindered by the need for fetal blood sampling.

Blood Vessels↗

PubMed2001

Detection of prostate cancer with a microbubble ultrasound contrast agent.

The diagnosis of prostate cancer is currently limited by the low sensitivity and specificity of systematic conventional grey-scale ultrasonography. We assessed contrast-enhanced colour Doppler ultrasonography by means of a microbubble ultrasound contrast agent to detect tumour vascularity and improve the diagnosis of prostate cancer. The use of a microbubble ultrasound contrast agent for transrectal colour Doppler targeted biopsy significantly improved the detection of prostate cancer compared with systematic biopsy following conventional grey-scale ultrasonography (p<0.001). Contrast-agent enhanced colour Doppler imaging may allow for limited targeted biopsies (five or less), which reduces costs and morbidity.

Adult↗

PubMed2000

Predicting the acoustic response of a microbubble population for contrast imaging in medical ultrasound.

Although the behavior of a bubble in an acoustic field has been studied extensively, few theoretical treatments to date have been applied to simulate the acoustic response of a real population of variably sized microbubbles in a finite-width sound beam. In this paper, we present a modified Trilling equation for single bubble dynamics that has been solved numerically for different conditions. Radiated waveforms from a large number of such bubbles are combined, reflecting their size distribution and location and the shape of a real acoustic beam. The resulting time-domain pressure waveforms can be compared with those obtained experimentally. The dependence of second-harmonic radiation on incident focal amplitude at different frequencies is presented. This model is particularly suited to the study of interaction between a medical ultrasound beam and microbubble contrast agents in aqueous media.

Acoustics↗

PubMed2001

Inhibition of carotid artery neointimal formation with intravenous microbubbles.

Because therapeutic gene products such as synthetic antisense oligodeoxynucleotides (ODN) bind to albumin-coated microbubbles, we sought to determine whether IV perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles could target their delivery to the carotid artery following balloon injury. In 5 pigs, the concentration of ODN taken up within the carotid vascular wall was found to be significantly increased when the IV antisense (ODN) was administered bound to PESDA (ODN-PESDA), and while transcutaneous low-frequency (20 kHz) ultrasound was applied over the carotid artery. Based on these results, a chronic model was then developed, in which 21 pigs received either IV ODN-PESDA, ODN alone, or control, following carotid balloon injury. At 30 days following balloon injury, percent area stenosis was only 8 +/- 2% in the ODN-PESDA groups compared to 19 +/- 8% and 28 +/- 3% in the other groups (p < 0.01). IV PESDA may be a method of noninvasively targeting the delivery of therapeutic genes.

Animals↗

PubMed1999

Erosion of artificial endothelia in vitro by pulsed ultrasound: acoustic pressure, frequency, membrane orientation and microbubble contrast agent dependence.

The erosion of cells from fibroblast monolayers simulating the vascular endothelium by 20 micros pulses of ultrasound at 500 Hz PRF was studied in relation to the peak negative acoustic pressure (P-; 0.0-2.5 MPa), ultrasound (US) frequency (1.0, 2.1 or 3.5 MHz), orientation of the monolayer (i.e., simulating the sites of ultrasound entry/exit from a blood vessel) and the presence or absence of a microbubble contrast agent (3 Vol% Albunex). The a priori hypotheses were that erosion of the monolayers would: 1. arise due to insonation treatment, 2. arise as a consequence of cavitation activity and, thus, increase with increasing P- at constant frequency, and decrease with increasing frequency at constant P-, 3. be significantly increased by the presence of a microbubble contrast agent, and 4. have a weak dependence on monolayer orientation. The data support these hypotheses. Under the most severe exposure conditions used, most of the affected cells appeared to have been lysed; however, a substantial number of viable cells were dislodged from the monolayer surface.

Acoustics↗