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PubMed1999

Effect of filling gases on the backscatter from contrast microbubbles: theory and in vivo measurements.

Two surfactant-based contrast agents, ST44 and ST68, were produced according to US Patent # 5,352,436 and filled with either air, C4F10 (perfluorobutane) or SF6 (sulfur hexaflouride). Ten rabbits received i.v. injections of each agent/gas combination with 5 repetitions of each dose (range: 0.005-0.13 mL/kg). A custom-made 10-MHz cuff transducer was placed around the surgically exposed distal aorta and audio Doppler signals were acquired in vivo. Quantitative in vivo dose responses were calculated off-line using spectral power analysis and compared to a theoretical model of microbubble dissolution and enhancement. For qualitative comparisons, 10 rabbits were imaged pre- and postcontrast administration (dose: 0.1 mL/kg) in gray-scale and colour. All agent/gas combinations produced marked Doppler enhancement with air bubbles enhancing least of all (p < 0.0001) and ST68-SF6 best of all (maximum: 27.6 +/- 2.04 dB; p < 0.012). There were no significant differences between other agent/gas combinations (0.30 < p < 0.70). Theoretical enhancement was within 1 order of magnitude of the experimental observations (i.e., deviations of up to 10 dB). The duration of contrast enhancement was 1-2 min for air-filled bubbles, 3-5 min for SF6-filled bubbles and more than 7 min for C4F10-filled bubbles. In conclusion, ST68-SF6 microbubbles produced most in vivo enhancement of the agent/gas combinations studied. Theory matched the measurements within an order of magnitude.

Animals↗

PubMedDate not supplied

Technical factors that influence the determination of microbubble transit rate during contrast echocardiography.

The calculation of mean microbubble transit rate (MMTR) during contrast echocardiography provides information regarding the flow through and blood volume of a vascular system. Several technical factors can impact on the accuracy of MMTR determination. In this study, with computer simulation and in vitro and in vivo data, we systematically examined four such factors: the relationship between microbubble concentration versus videointensity, the size of the region of interest and the sampling rate used to derive time-intensity plots, and the method of deriving MMTR (direct numeric calculation vs use of a mathematic model). The results indicate that the effect of these technical factors on the estimation of MMTR can be significant.

Albumins↗

PubMedDate not supplied

Transpulmonary transit of microbubbles during contrast echocardiography: implications for estimating cardiac output and pulmonary blood volume.

We postulated that the pulmonary transit rate of sonicated albumin microbubbles, which have an intravascular rheology similar to that of red blood cells, would be directly proportional to cardiac output (CO) and inversely proportional to pulmonary blood volume (PBV). Accordingly, 4 ml of Albunex ultrasound contrast agent (0.5 billion/ml of 4.3 mu bubbles) was injected into the right atrium of six dogs (Group I) during simultaneously performed two-dimensional echocardiography, and the time between the initial appearance of the bubbles in the right and left ventricle, respectively, was measured. CO was either increased (by intravenous infusion of 15 micrograms/kg/min of dobutamine) or decreased (by producing left ventricular ischemia or by administering 2 mg of intravenous propranolol) in a random order and microbubbles were injected again. At each stage, thermodilution CO was measured. There was a close linear relation between CO and pulmonary transit rate of Albunex in each dog with the correlation coefficient ranging from 0.79 to 0.99, with a mean of 0.92. Pulmonary blood volume was derived in each dog from the reciprocal of the slope of the regression between CO and pulmonary transit rate and varied from 106 to 261 ml in the six dogs with a mean value of 178 +/- 64 ml. There was excellent interobserver and intraobserver correlation (r = 0.99 each) for determining the pulmonary transit rate of Albunex. The reproducibility of pulmonary transit rate estimation from repeated contrast injections at the same hemodynamic state in another group of six dogs (Group II) was also good (r = 0.99). It is concluded that the pulmonary transit rate of Albunex ultrasound contrast agent can be used to assess directional changes in CO and to measure pulmonary blood volume. This method may have clinical applications.

Albumins↗

PubMedDate not supplied

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.

Animals↗

PubMed2002

Assessment of myocardial viability in prior myocardial infarction by intravenous bolus microbubble injection: a new time domain index to estimate regional relative myocardial blood volume.

We tested whether the duration of myocardial opacification by harmonic power Doppler imaging after intravenous bolus microbubble injection (with a definition of "the end of opacification") would reflect the remaining vascular bed in infarcted segments. In 28 patients with previous myocardial infarction and 20 control patients, we performed harmonic power Doppler imaging after intravenous bolus injection of 1.5 g of Levovist. Using multiframe trigger mode in which 4 consecutive frames were imaged at every sixth end systole, which formed 1 "burst," we recorded anterior/septal and inferior/posterior walls separately on the center of each apical view with individual boluses. The duration of segmental opacification was measured as the number of "bursts" in which color signals persisted until the fourth frame. The duration was similar between the anterior/septal and inferior/posterior walls (13 +/- 3 vs 13 +/- 3 bursts, not significant) in the control group. In myocardial infarction patients, the duration was significantly shorter in the infarcted than in the control segments (6 +/- 6 vs 14 +/- 3 bursts, P < .001) and their ratio and difference exhibited significant correlations (r = 0.82, P < .001 and r = 0.91, P < .001, respectively) with the activity ratio on thallium Tl 201 single-photon emission computed tomography at rest. Thus, the duration of opacification by harmonic power Doppler imaging after intravenous bolus microbubble injection, the measurement of which was standardized by using multiframe trigger mode, may be useful in assessing regional myocardial viability in patients with previous myocardial infarction.

Aged↗

PubMed2006

Intravascular fluorocarbon-stabilized microbubbles protect against fatal anemia in rats.

It has earlier been hypothesized that intravascular microbubbles, derived from a dodecafluoropentane (DDFP) emulsion, can transport physiologically significant amounts of oxygen in the animal body. To test this notion, anesthetized oxygen breathing rats were rendered severely anemic by bleeding and volume replacement. Rats treated with 0.014 ml/kg of DDFP in a 2% emulsion had normal circulatory parameters and behaved normally when waking up from anesthesia while controls died during anesthesia. Oxygen-breathing intact rats given 0.01 ml/kg of DDFP had muscle oxygen tensions which, for about 2.5 hours, exceeded those of controls by 50-100%. It was further verified in vitro that DDFP-derived microbubbles can exchange oxygen with a surrounding aqueous medium. Extrapolation from these experiments indicates that less than 1 ml of DDFP, in emulsion-form, could provide for the resting oxygen consumption of an adult person. This suggests various therapeutic uses of the emulsion.

Anemia↗

PubMedDate not supplied

Gelatin encapsulated nitrogen microbubbles as ultrasonic contrast agents.

Gelatin encapsulated nitrogen microbubbles were effective ultrasonic contrast agents in in vitro phantom and in vivo rabbit V2 carcinoma studies. Intra-arterial injection of 80-micrometer gelatin encapsulated nitrogen microbubbles appeared to improve tumor visualization by rim enhancement, which persisted for several minutes.

Aerosols↗

PubMed2000

Pulse inversion imaging of liver blood flow: improved method for characterizing focal masses with microbubble contrast.

RATIONALE AND OBJECTIVES: To create a microbubble contrast image of vessels that lie below the resolution of an ultrasound system, a technique is required that detects preferentially the agent echo, rejecting that from tissue. Harmonic imaging exploits the nonlinear behavior of microbubbles but forces a compromise between image sensitivity and axial resolution. The authors describe and evaluate a new method that overcomes this compromise and improves contrast imaging performance: pulse inversion imaging. METHODS: Sequences of pulses of alternate phase are transmitted into tissue and their echoes summed. A prototype scanner equipped with pulse inversion was used to image phantoms and 16 patients with focal liver masses. RESULTS: Pulse inversion images show contrast sensitivity and resolution superior to that of harmonic images. Vessels can be imaged at an incident power sufficiently low to avoid destroying the agent, allowing unique visualization of tumor vasculature. Distinct patterns were seen in hemangiomas, metastases, and hepatocellular carcinomas. CONCLUSIONS: Pulse inversion imaging is an improved bubble-specific imaging method that extends the potential of contrast ultrasonography.

Adult↗

PubMed2004

Perfectly monodisperse microbubbling by capillary flow focusing: an alternate physical description and universal scaling.

In a recent work [Phys. Rev. Lett. 87, 274501 (2001)], a method to produce monodisperse microbubbles was described. The physics of the phenomenon was explained in terms of the absolute instabilities of a gas microjet formed when a liquid stream which surrounds a coflowing gas stream is forced through a small orifice. Now, a much more consistent physical picture to describe the phenomenon which corrects prior assumptions is presented. Consequently, a much simpler and universal scaling law for the microbubble size is finally obtained which involves the orifice diameter and the gas/liquid flow rates ratio only. All data shown in prior works, together with newly obtained data sets, have been analyzed anew. These are in remarkable agreement with the here proposed scaling law.

Journal Article↗

PubMed2005

Drag reduction by microbubbles in turbulent flows: the limit of minute bubbles.

Drag reduction by microbubbles is a promising engineering method for improving ship performance. A fundamental theory of the phenomenon is lacking, however, making actual design quite haphazard. We offer here a theory of drag reduction by microbubbles in the limit of very small bubbles, when the effect of the bubbles is mainly to normalize the density and the viscosity of the carrier fluid. The theory culminates with a prediction of the degree of drag reduction given the concentration profile of the bubbles. Comparisons with experiments are discussed and the road ahead is sketched.

Journal Article↗

PubMed2006

Interaction and fragmentation of pulsed laser induced microbubbles in a narrow gap.

We investigate the interaction dynamics of an existing stable microbubble B1 and another laser induced nearby expanding microbubble B2 in a thin ink sheet between two glass slices. The fast expanding B2 causes anistropic compression of B1 with a forward penetrating jet. In the subsequent expansion stage of B1, the gas associated with jet protrusion to the opposite edge of B1 and the nonuniform surrounding flow field induce necking with transverse inward jetting from the side lobes, which further interact with the axial jet and lead to the final fragmentation into smaller bubbles. At small interbubble distance, the backward interaction from B1 first leads to the pointed pole of the expanding B2 and then a backward jetting during its collapsing. The strong interaction can merge the two bubbles with complicated asymmetric intermediated patterns.

Journal Article↗

PubMed2002

Dynamics and fragmentation of thick-shelled microbubbles.

Localized delivery could decrease the systemic side effects of toxic chemotherapy drugs. The unique delivery agents we examine consist of microbubbles with an outer lipid coating, an oil layer, and a perfluorobutane gas core. These structures are 0.5-12 microm in radius at rest. Oil layers of these acoustically active lipospheres (AALs) range from 0.3-1.5 microm in thickness and thus the agents can carry a large payload compared to nano-scale drug delivery systems. We show that triacetin-based drug-delivery vehicles can be fragmented using ultrasound. Compared with a lipid-shelled contrast agent, the expansion of the drug-delivery vehicle within the first cycle is similar, and a subharmonic component is demonstrated at an equivalent radius, frequency, and driving pressure. For the experimental conditions explored here, the pulse length required for destruction of the drug-delivery vehicle is significantly greater, with at least five cycles required, compared with one cycle for the contrast agent. For the drug-delivery vehicle, the observed destruction mechanism varies with the initial radius, with microbubbles smaller than resonance size undergoing a symmetric collapse and producing a set of small, equal-sized fragments. Between resonance size and twice resonance size, surface waves become visible, and the oscillations become asymmetrical. For agents larger than twice the resonance radius, the destruction mechanism changes to a pinch-off, with one fragment containing a large fraction of the original volume.

Contrast Media↗

PubMed1997

Usefulness of stable microbubble test of tracheal aspirate for the diagnosis of neonatal respiratory distress syndrome.

OBJECTIVES: To compare the overall accuracy of the stable microbubble test (SM test) with measurement of level of surfactant protein A (SP-A) of tracheal aspirate for the diagnosis of respiratory distress syndrome (RDS). METHODOLOGY: Tracheal aspirates were obtained from neonates on ventilatory support. The SM test was carried out on specimens of tracheal aspirate immediately after collection. Levels of SP-A in tracheal aspirates were determined by enzyme-linked immunosorbent assay (ELISA) method. The results of the SM test and SP-A level of the tracheal aspirates were compared against the clinical diagnosis of RDS based on clinical, radiological and bacteriological findings. RESULTS: Both the median microbubble counts (6 microbubbles/mm2, range = 0-90) and median SP-A levels (100 micrograms/L, range = 0-67447) of infants with RDS were significantly lower than those of infants with no obvious lung pathology (P < 0.0001), and pneumonia (P < 0.0001). The SM test of tracheal aspirates had higher overall accuracy for the diagnosis of RDS than measurement of SP-A levels (94.6% vs 82.4%). When the receiver operating characteristic (ROC) curves of both tests for RDS were compared, the area under the ROC curve of the SM test was larger (0.9689) than that of the SP-A method (0.8965). CONCLUSIONS: This study showed that the SM test of tracheal aspirate was a useful bedside diagnostic test for RDS. It could be carried out at any time after birth on infants requiring ventilatory support.

Cross-Sectional Studies↗

PubMed2000

Kramers-Kronig relations applied to finite bandwidth data from suspensions of encapsulated microbubbles

In this work, the Kramers-Kronig (K-K) relations are applied to experimental data of resonant nature by limiting the interval of integration to the measurement spectrum. The data are from suspensions of encapsulated microbubbles (Albunex) and have the characteristics of an ultrasonic notch filter. The goal is to test the consistency of this dispersion and attenuation data with the Kramers-Kronig relations in a strict manner, without any parameters from outside the experimental bandwidth entering in to the calculations. In the course of reaching the goal, the artifacts associated with the truncation of the integrals are identified and it is shown how their impacts on the results can be minimized. The problem is first approached analytically by performing the Kramers-Kronig calculations over a restricted spectral band on a specific Hilbert transform pair (Lorentzian curves). The resulting closed-form solutions illustrate the type of artifacts that can occur due to truncation and also show that accurate results can be achieved. Next, both twice-subtracted and lower-order Kramers-Kronig relations are applied directly to the attenuation and dispersion data from the encapsulated microbubbles. Only parameters from within the experimental attenuation coefficient and phase velocity data sets are used. The twice-subtracted K-K relations produced accurate estimates for both the attenuation coefficient and dispersion across all 12 data sets. Lower-order Kramers-Kronig relations also produced good results over the finite spectrum for most of the data. In 2 of the 12 cases, the twice-subtracted relations tracked the data markedly better than the lower-order predictions. These calculations demonstrate that truncation artifacts do not overwhelm the causal link between the phase velocity and the attenuation coefficient for finite bandwidth calculations. This work provides experimental evidence supporting the validity of the subtracted forms of the acoustic K-K relations between the phase velocity and attenuation coefficient.

Journal Article↗

PubMed2002

Coupled dynamics of translation and collapse of acoustically driven microbubbles.

Pressure gradients drive the motion of microbubbles relative to liquids in which they are suspended. Examples include the hydrostatic pressure due to a gravitational field, and the pressure gradients in a sound field, useful for acoustic levitation. In this paper, the equations describing the coupled dynamics of radial oscillation and translation of a microbubble are given. The formulation is based on a recently derived expression for the hydrodynamic force on a bubble of changing size in an incompressible liquid [J. Magnaudet and D. Legendre, Phys. Fluids 10, 550-556 (1998)]. The complex interaction between radial and translation dynamics is best understood by examination of the added momentum associated with the liquid motion caused by the moving bubble. Translation is maximized when the bubble collapses violently. The new theory for coupled collapse and translation dynamics is compared to past experiments and to previous theories for decoupled translation dynamics. Special attention is paid to bubbles of relevance in biomedical applications.

Acoustics↗

PubMed2003

Liver microbubble transit time compared with histology and Child-Pugh score in diffuse liver disease: a cross sectional study.

BACKGROUND: A previous pilot study showed that early arrival time of a microbubble in a hepatic vein is a sensitive indicator of cirrhosis. AIM: To see if this index can also grade diffuse liver disease. PATIENTS: Thirty nine fasted patients with histologically characterised disease were studied prospectively. Nine patients had no evidence of liver fibrosis, 10 had fibrosis without cirrhosis, and 20 had cirrhosis (five Child's A, seven Child's B, and eight Child's C). METHODS: Bolus injections of a microbubble (Levovist; Schering, Berlin) were given intravenously, followed by a saline flush. Time intensity curves of hepatic vein and carotid artery spectral Doppler signals were analysed. Hepatic vein transit time (HVTT) was calculated as the time after injection at which a sustained signal increase >10% of baseline was seen. Carotid delay time (CDT) was calculated as the difference between carotid and hepatic vein enhancement. RESULTS: Diagnostic studies were achieved in 38/39 subjects. Both HVTT and CDT became consistently shorter with worsening disease, as follows (means (SD)): HVTT: no fibrosis 44 (25) s, fibrosis 26 (8) s, Child's A 21 (1) s, Child's B 16 (3) s, and Child's C 16 (2) s; CDT: no fibrosis 31 (29) s, fibrosis 14 (6) s, Child's A 8 (1) s, Child's B 4 (4) s, and Child's C 3 (3) s. These differences were highly significant (p<0.001, ANOVA comparison). A HVTT <24 s and a CDT <10 s were 100% sensitive for cirrhosis (20/20 and 18/18, respectively) but not completely specific: 2/8 subjects with fibrosis had CDT values <10 s and 3/9 had HVTT <24 s. CONCLUSION: This minimally invasive test shows promise not only in diagnosing cirrhosis but also in assessing disease severity.

Adult↗

PubMed1996

Renal cortical perfusion in rabbits: visualization with color amplitude imaging and an experimental microbubble-based US contrast agent.

PURPOSE: To evaluate an experimental microbubble-based ultrasound (US) contrast agent (Imagent US, formulation AF0150) in the kidney to help identify focal perfusion abnormalities. MATERIALS AND METHODS: Six incremental doses (0.007-0.2 mL/kg) of contrast material were injected intravenously in six New Zealand rabbits (3.1-3.5 kg), with experimental focal renal ischemia in five kidneys. Unenhanced and contrast material-enhanced color amplitude and gray-scale images of the kidney were analyzed for changes in mean pixel intensity. Kidneys were harvested and examined pathologically. RESULTS: On contrast-enhanced color amplitude images, mean pixel intensity increased significantly in cortex and medulla at every dose level (P < .0005) (with doses as low as 0.007 mL/kg), and differences were significant in cortical peak intensity and duration of enhancement with incremental increases in dose (P < .006). On contrast-enhanced gray-scale images, renal cortical enhancement reached statistical significance only at the highest dose (0.2 mL/kg). Duration of gray-scale tissue enhancement was not dose related. Color mean pixel intensity markedly increased in areas of normally perfused kidney (P = .002) but remained essentially unchanged in ischemic areas (P = .34). CONCLUSIONS: Color Doppler and gray-scale images enhanced with this microbubble-based US contrast agent depict renal cortical perfusion clearly in rabbits.

Animals↗

PubMed1998

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.

Adult↗