Physical principles of microbubbles for ultrasound imaging and therapy.

Microbubble ultrasound contrast agents have been in clinical use for more than two decades, during which time their range of applications has increased to encompass echocardiography, Doppler enhancement, perfusion studies and molecular imaging, as well as a number of therapeutic applications, including drug delivery, gene therapy, high-intensity focused ultrasound treatments and sonothrombolysis. The aim of this article is to review the different types of microbubble agents, their physical behaviours and the mechanisms underlying their effectiveness in imaging and therapeutic applications.

Hypoxia due to shunts in pig lung treated with O2 and fluorocarbon-derived intravascular microbubbles.

RATIONALE: Earlier work has shown that experimental conditions calling for improved tissue oxygenation could be assisted by i.v. infusion of a dodecafluoropentane emulsion (DDFPe) forming oxygen-transporting microbubbles. OBJECTIVES: The present work investigated the effect of DDFPe on hypoxia due to experimental shunts in the pig lung. METHODS: Nineteen O(2) breathing, anesthetized pigs had glass beads administered into the trachea so as to significantly depress arterial oxygen tension (PaO(2)). PaO(2) was recorded for up to 12 hrs while 0.1 ml/kg DDFPe was administered 1-3 times. MAIN RESULTS: The animals were divided into two groups based on arterial oxygen saturation (SaO(2)) after shunt induction, combined with oxygen breathing: the "SaO(2) >90% group" (n=6) and the "SaO(2) <90% group" (n=13). In the "SaO(2) <90% group," the PaO(2) increased stepwise with each infusion from 56.6+/-2.9 to 88.6+/-14.6 mmHG (P

Incidence, time course, and characteristics of microbubble formation during radiofrequency ablation of pulmonary veins with an 8-mm ablation catheter.

BACKGROUND: Microbubble formation during pulmonary vein (PV) radiofrequency (RF) ablation of atrial fibrillation (AF) occurs relatively frequently. Prior studies have shown that microbubble formation may be associated with an increased risk of complications. However, the incidence, time course, and temperature characteristics of microbubble formation during AF ablation with an 8-mm catheter have not been prospectively described in humans. METHODS: We studied 46 (30 men, age 56+/-10 years) patients with AF who underwent RF ablation of PVs between January 2005 and December 2005 using an 8F, 8-mm Biosensetrade mark ablation catheter (Biosense-Webster, Diamond Bar, CA, USA). All patients underwent continuous intracardiac echocardiography (ICE). Microbubble patterns were classified as either type 1 (intermittent, scattered microbubble formation) or type 2 (explosive shower of dense microbubbles). Formation of any microbubbles was detected by ICE and the time, PV location, and electrode temperature were recorded. RESULT: A total of 1,479 (32+/-13, range 12-73) RF lesions were delivered to 167 veins. Twenty (2%) lesions were classified as type 2. Since the number of lesions resulting in type 2 bubbles was very small, only type 1 lesions were included in the final analysis. Thirty-nine (85%) patients had at least one lesion associated with bubble formation during ablation (mean: 7+/-7 lesions, range 1-28 lesions). Twenty-three percent (327) of the RF lesions resulted in bubble formation. RF generator power setting during lesions resulting in bubble formation was lower than lesions which did not result in bubble formation (47.9+/-7.4 W vs 49.7+/-7.1 W, P<0.001). Logistic regression analysis revealed a significant negative correlation (P<0.001) between RF generator power settings and a positive correlation between the generator temperature settings and formation of bubbles (both P<0.02). However, the maximum temperature attained was not different between lesions resulting in bubble formation (n=327) and those which did not result in bubble formation (n=1,139). Fifty-three (16%) of the lesions associated with bubble formation occurred within 2-10 seconds after RF was begun. Bubble formation was significantly more frequent in left superior PVs compared to the other PVs (left superior PV 27.3% left inferior PV 18.6%, right superior PV 20.5%, and right inferior PV 18.8%, P=0.005, left superior PV vs other PVs, P<0.001) even after adjustment for the other factors including generator power settings and the temperature setting. CONCLUSION: Bubble formation is common during RF ablation of PV with 8-mm tip catheter and can occur as early as 2 seconds after starting RF. RF generator power is negatively correlated with bubble formation while generator temperature settings are positively correlated with formation of bubbles. Microbubble formation is also more frequent with ablation of the left superior PV probably due to better catheter contact in that area.

Microbubble production in an in vitro cardiopulmonary bypass circuit ventilated with xenon.

Xenon, as an anaesthetic gas, has the potential to be used in an increasing range of applications. However, its use in cardiopulmonary bypass (CPB) has not yet progressed from the rat model due to concerns that its relative insolubility may cause microbubble formation and/or expansion in the micro-vasculature of the patient. An in vitro CPB circuit was designed to create and measure gaseous microbubbles over a range of temperature gradients, pressure drop and gas tensions. We were able to demonstrate that our test circuit did not produce any significant microbubbles and that, under normal physiological blood pressures, a fixed gas bubble in connection with the circuit did not grow in the presence of Xe.

Forced linear oscillations of microbubbles in blood capillaries.

A theoretical investigation of the forced linear oscillations of a gas microbubble in a blood capillary, whose radius is comparable in size to the bubble radius is presented. The natural frequency of oscillation, the thermal and viscous damping coefficients, the amplitude resonance, the energy resonance, as well as the average energy absorbed by the system, bubble plus vessel, have been computed for different kinds of gas microbubbles, containing air, octafluropropane, and perflurobutane as a function of the bubble radius and applied frequency. It has been found that the bubble behavior is isothermal at low frequencies and for small bubbles and between isothermal and adiabatic for larger bubbles and higher frequencies, with the viscous damping dominating over the thermal damping. Furthermore, the width of the energy resonance is strongly dependent on the bubble size and the natural frequency of oscillation is affected by the presence of the vessel wall and position of the bubble in the vessel. Therefore, the presence of the blood vessel affects the way in which the bubble absorbs energy from the ultrasonic field. The motivation of this study lies in the possibility of using gas microbubbles as an aid to therapeutic focused ultrasound treatments.

Microbubble contrast agents for echocardiography: rationale, composition, ultrasound interactions, and safety.

Imaging the small blood vessels within the myocardium, which contains only a small fraction of the total coronary blood volume, is a significant challenge for ultrasound imaging. Recent advances in microbubble design and ultrasound technology have improved our ability to image the microcirculation. It is essential to understand the fundamentals of microbubble behavior in an ultrasound field and how it impacts technology and safety.

Effect of coupled oscillations on microbubble behavior.

Ultrasound contrast agents are encapsulated microbubbles whose nonlinear acoustic scattering signatures have been the foundation of their use in diagnostic imaging. The coupled oscillations of microbubbles along their lines of center are investigated theoretically using radial equations in the monopole approximation and an energy balance, which is obtained for the system. Coupled microbubble pairs of different initial radii are investigated numerically relative to the normal modes for the linearized system. For microbubble pairs of different size bubbles driven below the mode of the smaller bubble and above the mode of the larger bubble, it is shown that oscillations of the smaller agent are affected substantially more by the coupling than those of the larger one. For separation distances of 10 and 500 microns, a difference of approximately 10 dB occurs in the second harmonic output of a 1.0-micron radius agent coupled with a 2.2-micron radius agent forced at 2.0 MHz and 0.3 MPa. The subharmonic spectral peak is shown to decrease approximately 19 dB for the coupling of 1.5- and 2.2-micron radius agents at 10- and 500-micron distances under the same acoustic forcing conditions. These coupling effects on the radiated pressure and its spectral power are highlighted for contrast agent imaging applications.