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PubMed1994

Effects of left ventricular pressure on sonicated albumin microbubbles: evaluation using an isolated rabbit heart model.

OBJECTIVES: We used an isolated, crystalloid-perfused rabbit heart model to test the hypothesis that the phasic changes in left ventricular contrast are due to bubble compression and decompression during systole and diastole, respectively. BACKGROUND: Contrast enhancement of the left ventricular cavity has been shown to decrease during ventricular systole. This phenomenon has been attributed to pressure-induced microbubble destruction. Such destruction, if confirmed, would severely confound the quantitative interpretation of contrast echocardiographic data. METHODS: A fixed volume of contrast solution (5% human albumin and Albunex, approximately 400:1 ratio) was introduced into a latex balloon placed within the left ventricular cavity of an isolated paced rabbit heart preparation (n = 12). Instantaneous left ventricular pressure was measured using a high fidelity microtip catheter and digitized on-line. The beating heart was placed in a water tank, and ultrasound images were obtained using a 7.5-MHz transducer and were recorded and digitized off-line at 12 frames/s. Simultaneously, the pacing signal was used for gated on-line acquisition of end-diastolic frames. A simple theoretic model based on surface tension physical principles was used to predict changes in bubble size and, consequently, the reflection intensity in response to the measured changes in left ventricular pressure. RESULTS: We found that under peak left ventricular systolic pressures ranging from 89 to 155 mm Hg, 1) end-diastolic videointensity decreased by 8 +/- 6% (mean +/- SD) over 25 consecutive heart beats; and 2) intracyclic variations in measured videointensity were in close agreement with the theoretic calculations: 80.1 +/- 2.9% versus 80.2 +/- 4.6% of diastolic videointensity at systole. CONCLUSIONS: The major cause of systolic decrease in contrast enhancement is periodic bubble compression (as opposed to bubble destruction) induced by high systolic pressures. The minor progressive decrease in end-diastolic videointensity reflects the degree of instability of Albunex microbubbles under left ventricular pressures. However, the clinical impact of these destructive effects is likely to be only minor because of the rapid transit of microbubbles through the left heart chambers and myocardial microcirculation.

Albumins↗

PubMed2006

Microbubble-induced increase in ablation of liver tumors by high-intensity focused ultrasound.

We studied the possibility of using high-intensity focused ultrasound (HIFU) together with a microbubble agent to treat hepatocellular carcinoma. Development of liver tumors in rats was induced by administration of Dimethylnitrosamin (100ppm). Rats with liver tumors were anesthetized, underwent laparotomy, and were given the microbubble agent Levovist or saline intravenously. After the injection, the liver was exposed to HIFU for 30s (2.18MHz, 600W/cm(2), 40mm in diameter). Immediately after HIFU exposure, ultrasound images of the HIFU area were evaluated. Then the liver was excised and the volume of coagulated tissue was measured. The mean volumes of hyperechoic areas after HIFU were as follows (mm(3), Levovist versus saline: 355.3+/-180.7 versus 47.4+/-35.6, P<0.001, n=13). The volumes of liver tissue coagulated by HIFU were as follows (mm(3), Levovist versus saline: 275.3+/-120.0 versus 60.1+/-23.6, P<0.001, n=13). On microscopic examination of areas exposed to HIFU, implosion cysts were seen, and many cancer cells were found to have been destroyed completely (loss of cell membranes or nuclei). In conclusion, the microbubble agent Levovist can increase the volume of tissue coagulated by HIFU.

Journal Article↗

PubMed1997

Improved Doppler echocardiographic assessment of the left atrial appendage by peripheral vein injection of sonicated albumin microbubbles.

We evaluated the usefulness of peripherally injected sonicated albumin microbubbles in transesophageal echo-Doppler cardiographic assessment of the left atrial appendage in 19 patients (age 61 +/- 19 [range 21 to 86] years; 12 [63%] women). Multiplane transesophageal echocardiography was performed before and after intravenous injection of sonicated albumin, and the left atrial appendage image and Doppler flow signal quality were assessed by a grading system of 0 to 3+ (0 = poor, 1 + = adequate, 2+ = good, and 3+ = excellent). Microbubbles appeared in the left atrium in 15 (79%) of 19 patients and completely opacified the left atrial appendage in 7 (37%) of 19 patients. Left atrial appendage maximal and minimal areas by planimetry were similar before and after contrast injection, although image quality improved in 13 (68%) of 19 patients (echocardiographic grade 1.8 +/- 0.6 vs 2.6 +/- 0.5, p< 0.001). Similarly, left atrial appendage peak emptying and peak filling Doppler flow velocities did not change before and after contrast injection, although Doppler flow signal quality improved in 12 (63%) of 19 patients (Doppler grade 1.6 +/- 0.5 vs 2.1 +/- 0.8, p < 0.05). Overall, contrast injection improved left atrial appendage echocardiographic or Doppler quality in 16 (84%) of 19 patients. Thus peripheral vein injection of sonicated albumin microbubbles can improve the assessment of left atrial appendage structure and function by transesophageal echocardiography.

Albumins↗

PubMed2002

Physical principles of microbubble ultrasound contrast agents.

Early contrast agents could not achieve left-sided cardiac opacification because these microbubbles could not traverse the pulmonary circulation and remain intact. The specific shell material and gas used determine the properties of individual microbubbles, including fragility, persistence, and resonance. Persistence, perhaps the most important property of a microbubble, has been achieved by second-generation agents through the use of shells or surfactants and by substituting high-density, high molecular weight gas for air. Today's agents readily achieve opacification, not only of the cardiac chambers but also of the myocardium. Refinements in contrast agents and in the instrumentation for their detection are primarily responsible for these improvements.

Contrast Media↗

PubMed2000

Stimulated acoustic emission: pseudo-Doppler shifts seen during the destruction of nonmoving microbubbles.

The purpose of this study was to evaluate the appearance and the characteristics of stimulated acoustic emission (SAE) as an echo contrast-specific color Doppler phenomenon with impact on myocardial contrast echocardiography (MCE). Stationary microbubbles of the new contrast agent SH-U 563A (Schering AG) were embedded within a tissue-mimicking gel material. Harmonic power Doppler imaging (H-PDI), color Doppler and pulse-wave Doppler data were acquired using an HDI-5000 equipped with a phased-array transducer (1.67/3.3 MHz). In color Doppler mode, bubble destruction resulted in random noise like Doppler signals. PW-Doppler revealed short "pseudo-Doppler" shifts with a broadband frequency spectrum. Quantification of SAE events by H-PDI demonstrated an exponential decay of signal intensities over successive frames. A strong linear relationship was found between bubble concentration and the square root of the linearized H-PDI signal for a range of concentrations of more than two orders of magnitude (R = 0.993, p < 0.0001). Intensity of the H-PDI signals correlated well with emission power (R = 0.96, p = 0.0014). SAE results from disintegration of microbubbles and can be demonstrated by all Doppler imaging modalities, including H-PDI. Intensity of SAE signals is influenced by the applied acoustic power and correlates highly with the concentration of microbubbles. Because intensity of SAE signals correlates highly with echo contrast concentrations, analysis of SAE signals might be used for quantitative MCE.

Acoustics↗

PubMed1999

Pressure dependence of subharmonic signals from contrast microbubbles.

Noninvasive pressure estimation in heart cavities and in major vessels would provide clinicians with a valuable tool for assessing patients with heart and vascular diseases. Some microbubble-based ultrasound contrast agents are particularly well suited for pressure measurements because their substantial compressibility enables microbubbles to vary significantly in size in response to changes in pressure. Pressure changes should then affect reflectivity of microbubbles after intravenous injection of a contrast agent. This has been demonstrated with a galactose-based contrast agent using 2.0-MHz ultrasound tone bursts. Preliminary results indicate that, over the pressure range of 0-186 mmHg, the subharmonic amplitude of scattered signals decreases by as much as 10 dB under optimal acoustic settings and the first and second harmonic amplitudes decrease by less than 3 dB. An excellent correlation between the subharmonic amplitude and the hydrostatic pressure suggests that the subharmonic signal may be utilized for noninvasive detection of pressure changes.

Contrast Media↗

PubMed2000

Ultrasonic characterization of the nonlinear properties of contrast microbubbles.

The nonlinear properties of microbubble contrast agents have been used to create contrast-specific imaging modalities such as harmonic imaging and subharmonic imaging. Thus, a better understanding of the nonlinear performance of contrast microbubbles may enhance the diagnostic capabilities of medical ultrasound (US) imaging. The first and second harmonic, the 1/2 order subharmonic and the 3/2 order ultraharmonic components in spectra of scattered signals from Optison microbubbles insonified at 2 and 4 MHz have been investigated using an in vitro laboratory pulse-echo system. The development of these signal components over time is quite different for 2-MHz insonification compared to 4-MHz insonification. Scattered subharmonic and ultraharmonic signals are much more time-dependent than first and second harmonic echoes. The dependence of the first and second harmonic, subharmonic and ultraharmonic components on acoustic pressure for 2-MHz insonification is similar to that for 4-MHz insonification. The first and second harmonic components increase linearly with acoustic pressure (in double logarithmic scales) and the subharmonic and ultraharmonic amplitudes undergo rapid growths in the intermediate acoustic pressure range and much slower increases at both lower and higher acoustic pressures.

Albumins↗

PubMed2002

Enhancement characteristics of the microbubble agent Levovist: reproducibility and interaction with aspirin.

We investigated the reproducibility of Doppler enhancement indices following intravenous bolus injections of Levovist (Schering AG, Berlin) microbubbles. We also aimed to determine whether observations from animal studies suggesting that aspirin potentiates microbubble enhancement were reproducible in humans. In five healthy volunteers, time enhancement profiles of Doppler intensity following repeated bolus injections of Levovist were acquired from the common carotid artery, hepatic vein and kidney using spectral and power Doppler before and after oral aspirin (600 mg). Peak enhancement (PE), area under the curve (AUC) and decay slopes (lambda) were calculated. Hepatic vein contrast arrival time (AT) was determined subjectively. Well-defined carotid enhancement was seen in 19/20 injections. Reproducibility was high (r > 0.8). PE and AUG were unaffected by aspirin, but lambda was slightly reduced (P = 0.02). Renal power Doppler profiles were well defined (10/10) with no significant changes of AUC, PE or lambda after aspirin. Our study demonstrates good reproducibility of carotid spectral Doppler time intensitometry with Levovist in man. Aspirin does not have a significant effect on enhancement indices except carotid spectral Doppler decay. We conclude that aspirin is unlikely to potentiate microbubble enhancement, as seen in animal studies.

Adult↗

PubMedDate not supplied

Myocardial contrast enhancement after intravenous injection of sonicated albumin microbubbles: a transesophageal echocardiography dipyridamole study.

Myocardial opacification after intravenous injection of an echo-contrast agent is a major end point in contrast echocardiography, but it has not yet been obtained in human beings. We propose transesophageal contrast echocardiography as a clinical tool for the study of myocardial perfusion in human beings. Sonicated albumin microbubbles are bright ultrasound reflectors that cross the pulmonary vasculature after intravenous injection and show physiologic transit times through tissues. Transesophageal echocardiography uses ideal transducer frequency and acoustic window for in vivo detection of sonicated albumin microbubbles. We have studied 11 patients receiving peripheral vein bolus injection of sonicated albumin microbubbles during transesophageal echocardiography at baseline and during dipyridamole infusion. Images were recorded on videotape and digitized off-line. Quantitative measurements were made on 11 normally perfused myocardial segments by tracing a region of interest of greater than 100 pixels on frozen end-systolic frames, at baseline, and during dipyridamole infusion. Transpulmonary passage with full left ventricular cavity opacification was obtained in all injections. In 8 of 22 injections there was also transient left ventricular cavity attenuation. In all patients there was a marked opacification of the left ventricular outflow tract and aortic root. At baseline, mean signal intensity in the myocardium increased from 80 +/- 37 to 117 +/- 49 IU (p < 0.05) and during dipyridamole infusion increased from 84 +/- 28 to 146 +/- 36 IU (p < 0.001). The analysis of background-subtracted data showed that mean pixel intensity increased from baseline to dipyridamole contrast injection (from 37 +/- 15 to 62 +/- 19 IU; p < 0.01). The opacification of normally perfused left ventricular myocardium is feasible during transesophageal echocardiography because there is a significant increase in signal intensity versus background intensity. During dipyridamole infusion there is a further increase in signal intensity that probably reflects pharmacologically induced increase in myocardial blood flow.

Albumins↗

PubMed2005

Zeta potential of microbubbles in aqueous solutions: electrical properties of the gas-water interface.

Microbubbles are very fine bubbles and appropriate for the investigation of the gas-water interface electrical charge, because of their long stagnation, due to slow buoyancy, in the electrophoresis cell observation area. This study investigated the zeta potential of microbubbles in aqueous solutions and revealed that the bubbles were negatively charged under a wide range of pH conditions. The potential was positive under strong acidic conditions, and the inorganic electrolytes decrease the potential by increasing the amount of counterions within the slipping plane. OH(-) and H(+) are crucial factors for the charging mechanism of the gas-water interface, while other anions and cations have secondary effects on the zeta potential, because counterions are attracted by the interface charge. The addition of a small amount of propanol and butanol provided significant information for considering the mechanism of the gas-water interface charge. Even though these alcohols did not have any electrical charge, they had a strong effect on the gas-water interface charge and dispersed the zeta potential of the microbubbles in the aqueous solution. These alcohols tended to adsorb to the interface and affect the hydrogen-bonding network at the interface, so that it was concluded that the gas-water interface electrical charge must be related to the difference of the construction of the hydrogen-bonding network between the bulk water and the gas-water interface.

Journal Article↗

PubMed2002

Bioeffects of myocardial contrast microbubble destruction by echocardiography.

BACKGROUND: Microbubble destruction during contrast echocardiography is known to cause capillary leaks and red blood cell extravasation in skeletal muscle. This study evaluated the biological effects of microbubble destruction on cardiac muscle. METHODS: Contrast echocardiography was performed in 36 rats randomized to receive either Definity or Optison at a mechanical index (MI) of 1.6, 1.2, or 0.8. Myocardial bioeffects were assessed by measuring left ventricular (LV) size and fractional area shortening and histopathology. In addition, blood samples for troponin T were drawn at baseline, postinfusion (30 minutes), day 1, day 4, and day 7. LV size and function were measured at baseline and immediately prior to euthanasia on day 7, after which the heart was removed and sectioned for histopathology. RESULTS: There was no statistical difference in LV size or function regardless of the contrast agent or MI, nor was there any histopathological evidence of myocardial damage. However, troponin T increased over time (F = 3.77, P = 0.012), peaking at 30 minutes and returning to normal by day 4. The difference between Definity and Optison was not statistically significant. However, troponin T values were higher at a higher MI (F = 5.01, P = 0.012). Of 12 rats imaged at a MI of 1.6, 9 (75%) had elevated troponin T as compared to 4 (33%) of 12 at a MI of 1.2. None of the 12 rats imaged at a MI of 0.8 had an elevated troponin T at any time point. CONCLUSIONS: Microbubble destruction at high acoustic power (MI 1.6) can cause mild troponin T elevations that are not associated with LV dysfunction or histopathological evidence of myocardial damage.

Albumins↗

PubMed1998

Correlation between quantitative angiographic lesion severity and myocardial contrast intensity during a continuous infusion of perfluorocarbon-containing microbubbles.

The purpose of this study was to determine whether quantitative measurements of myocardial videointensity (MVI) during continuous intravenous infusions of microbubbles could detect differences in coronary artery stenosis severity during dobutamine stress echocardiography. Coronary artery stenoses were created in seven dogs by progressively tightening a snare around the coronary artery. Intravenous infusions of perfluorocarbon microbubbles were given during dobutamine stress. The initial rate of myocardial contrast enhancement (slope), peak myocardial contrast (peak MVI) at the longest pulsing interval, and the product (slope * peak MVI) were compared as ratios in the stenosed versus adjacent normal perfusion beds. Twenty-two coronary stenoses were compared (range 16% to 80% in diameter). There was a strong correlation between both slope ratios and slope * peak MVI ratios and percent stenosis (r = -0.89 for both, p<0.001). The rate of contrast replenishment during a continuous infusion of microbubbles can be used to determine both the presence and severity of coronary stenoses during stress echocardiography.

Animals↗

PubMedDate not supplied

Ultrasound, microbubbles, and thrombolysis.

Although dissolution of thrombus using ultrasound has been attempted for over 25 years, the clinical use of this technique remains limited. The ability of microbubbles to potentiate ultrasound-induced thrombolysis has renewed interest in this technique, which recanalizes occluded vessels without the need for fibrinolytic therapy. In this article, the potential mechanisms by which ultrasound and microbubbles produce thrombus dissolution are explored. In vitro and in vivo studies using ultrasound alone and ultrasound in combination with microbubbles to cause thrombolysis are reviewed. Potential clinical implications of more recent findings are explored.

Animals↗

PubMed2001

Liver mass evaluation with ultrasound: the impact of microbubble contrast agents and pulse inversion imaging.

Liver mass evaluation includes two essential elements--lesion detection and lesion characterization. Both of these are greatly improved on sonography with the addition of contrast agents and the use of specialized imaging techniques, particularly pulse inversion imaging. Ultrasound contrast agents are comprised of tiny microbubbles of gas that interact with the ultrasound beam producing an enhancement of the Doppler signal from blood. Pulse inversion imaging allows preferential detection of the signal from the microbubble agents with suppression of the signal from background tissue. Two imaging techniques include a low mechanical index (MI) nondestructive method to show lesional vascularity and a high MI destructive mode that produces disruption of the bubbles in a single frame. The latter allows for quantitative assessment of the relative enhancement of a lesion as compared with the adjacent liver parenchyma, which is a reflection of the relative vascular volumes. Vascular imaging has shown characteristic and reproducible features of common liver masses, including hemangioma, focal nodular hyperplasia, hepatocellular carcinoma, and liver metastases. Delayed postvascular enhancement of the normal liver, a phenomenon that is unique to certain classes of microbubble contrast agents, allows detection of more and smaller malignant lesions than on baseline.

Carcinoma, Hepatocellular↗

PubMed2001

Myocardial cavitational activity during continuous infusion and bolus intravenous injections of perfluorocarbon-containing microbubbles.

The 20-MHz component of broadband noise from inertial cavitation within the anterior myocardium of an open-chest dog was recorded during intravenous infusions or injections of perfluorocarbon-containing microbubbles during insonation with a 1.7-MHz harmonic transducer. Intramyocardial cavitational activity was evident even at a mechanical index of 0.2, but it increased significantly as frame rate and mechanical index were increased. The amount of myocardial contrast intensity produced by the microbubbles was increased by variables that reduced cavitational activity (eg, reducing frame rate to 1 every cardiac cycle or decreasing mechanical index). At a mechanical index of 0.2, myocardial contrast could still be observed at 10-Hz frame rates. These results confirm that intramyocardial cavitational activity is present during ultrasound imaging of microbubbles; imaging techniques that reduce cavitational activity increase the magnitude of myocardial contrast.

Animals↗

PubMed2001

Radiofrequency spectral analysis of attenuated ultrasound signals in experiments with echo contrast microbubbles.

Conventional gray-scale myocardial contrast echocardiography cannot distinguish perfused but attenuated from nonperfused myocardium because both may appear similar at low image intensity. We hypothesized that with radiofrequency spectral analysis of attenuated ultrasound signals, the harmonic-to-fundamental frequency ratio of the peak power spectrum (HFR(P)) could determine the presence of contrast microbubbles. We measured frequency responses of Optison microbubbles at defined degrees of ultrasound signal attenuation with different formulations of silicone (55D, 80A, and 3M); gray-scale intensities of Optison plus water compared with degassed water were analyzed at different attenuation settings (-25, -32, and -44 dB, respectively). HFR(P) values of Optison plus water were significantly higher than reference values of degassed water at each attenuation setting (55D, -14 +/- 2 dB versus -30 +/- 2 dB, P <.001; 80A, -19 +/- 2 dB versus -30 +/- 3 dB, P <.01; 3M, -22 +/- 2 dB versus -30 +/- 3 dB, P <.05), even though conventional videodensitometric analysis could not distinguish them. HFR(P) analysis objectively detects microbubbles in clinically relevant conditions of attenuation.

Contrast Media↗

PubMed2002

Ultrasound-mediated transfection of canine myocardium by intravenous administration of cationic microbubble-linked plasmid DNA.

We tested the hypothesis that targeted disruption of cationic microbubble-linked plasmid DNA, using diagnostic ultrasound, may aid transfection of large animal myocardium. Plasmid DNA encoding for CAT (pCAT, chloramphenicol acetyltransferase) was bound to a novel cationic microbubble containing MRX-225 for intravenous administration, and 16 dogs in 4 groups variously received this conjugate or plasmid only, or were exposed to ultrasound. Histochemical staining and enzyme-linked immunosorbent assay analysis showed CAT activity in the myocardium of only those animals that received microbubble-linked DNA and were exposed to ultrasound. Thus, disruption of cationic-linked, low-dose plasmid systems by diagnostic ultrasound may facilitate transfection of large animal hearts.

Amino Acid Transport Systems, Basic↗

PubMed1987

Saline microbubbles monitoring sonography-assisted abscess drainage.

The objective of this study was to assess the use of saline microbubbles as a sonographic contrast medium in monitoring abscess drainage. Seven abscesses were localized and drained with sonographic guidance. Four were in the brain and three were small abscesses in the liver, the subhepatic region, and the pancreas. After aspiration of the purulent material, irrigation with saline produced a highly echogenic sonographic pattern that was free of artifacts and distinctly different from the abscess contents and capsule, and the surrounding parenchyma. In one case, previously unsuspected loculation was detected, requiring repositioning of the needle for complete drainage. All abscesses were resolved and no untoward effects, such as sepsis, were encountered. In one additional patient, microbubble sonographic evaluation was used to monitor the progress of an abscess in which a percutaneous catheter was placed. Saline microbubbles may be used as a sonographic contrast medium to monitor sonography-assisted abscess drainage.

Abdomen↗