Christy K. Holland

Gauging the likelihood of cavitation from short-pulse, low-duty cycle diagnostic ultrasound

Although no deleterious effects form diagnostic ultrasound have been reported in epidemiologic studies and surveys of widespread clinical usage (Ziskin and Petitti 1988), the conditions for the onset of transient cavitation must be investigated in the total evaluation of potential risks associated with diagnostic ultrasound applications. An extension of the results from the approximate theory developed by Holland and Apfel (1989) is applied in this paper to a population of nuclei to predict the onset of cavitation in host fluids with physical properties similar to those of biological fluids. From this analysis and from results of recent in vitro cavitation experiments, an index is developed which can gauge the likelihood of substantial microbubble growth in the presence of short-pulse, low-duty cycle diagnostic ultrasound.

Thresholds for transient cavitation produced by pulsed ultrasound in a controlled nuclei environment

Transient cavitation is a discrete phenomenon that relies on the existence of stabilized nuclei, or pockets of gas within a host fluid, for its genesis. A convenient descriptor for assessing the likelihood of transient cavitation is the threshold pressure, or the minimum acoustic pressure necessary to initiate bubble growth and subsequent collapse. An automated experimental apparatus has been developed to determine thresholds for cavitation produced in a fluid by short tone bursts of ultrasound at 0.76, 0.99, and 2.30 MHz. A fluid jet was used to convect potential cavitation nuclei through the focal region of the insonifying transducer. Potential nuclei tested include 1-microns polystyrene spheres, microbubbles in the 1- to 10-microns range that are stabilized with human serum albumin, and whole blood constituents. Cavitation was detected by a passive acoustical technique that is sensitive to sound scattered from cavitation bubbles. Measurements of the transient cavitation threshold in water, in a fluid of higher viscosity, and in diluted whole blood are presented. These experimental measurements of cavitation thresholds elucidate the importance of ultrasound, host fluid, and nuclei parameters in determining these thresholds. These results are interpreted in the context of an approximate analytical theory for the prediction of the onset of cavitation.

Ultrasound-enhanced thrombolysis using Definity® as a cavitation nucleation agent

Ultrasound has been shown previously to act synergistically with a thrombolytic agent, such as recombinant tissue plasminogen activator (rt-PA) to accelerate thrombolysis. In this in vitro study, a commercial contrast agent, Definity, was used to promote and sustain the nucleation of cavitation during pulsed ultrasound exposure at 120 kHz. Ultraharmonic signals, broadband emissions and harmonics of the fundamental were measured acoustically by using a focused hydrophone as a passive cavitation detector and used to quantify the level of cavitation activity. Human whole blood clots suspended in human plasma were exposed to a combination of rt-PA, Definity and ultrasound at a range of ultrasound peak-to-peak pressure amplitudes, which were selected to expose clots to various degrees of cavitation activity. Thrombolytic efficacy was determined by measuring clot mass loss before and after the treatment and correlated with the degree of cavitation activity. The penetration depth of rt-PA and plasminogen was also evaluated in the presence of cavitating microbubbles using a dual-antibody fluorescence imaging technique. The largest mass loss (26.2%) was observed for clots treated with 120-kHz ultrasound (0.32-MPa peak-to-peak pressure amplitude), rt-PA and stable cavitation nucleated by Definity. A significant correlation was observed between mass loss and ultraharmonic signals (r = 0.85, p < 0.0001, n = 24). The largest mean penetration depth of rt-PA (222 microm) and plasminogen (241 microm) was observed in the presence of stable cavitation activity. Stable cavitation activity plays an important role in enhancement of thrombolysis and can be monitored to evaluate the efficacy of thrombolytic treatment.

Bioeffects Considerations for Diagnostic Ultrasound Contrast Agents

Diagnostic ultrasound contrast agents have been developed for enhancing the echogenicity of blood and for delineating other structures of the body. Approved agents are suspensions of gas bodies (stabilized microbubbles), which have been designed for persistence in the circulation and strong echo return for imaging. The interaction of ultrasound pulses with these gas bodies is a form of acoustic cavitation, and they also may act as inertial cavitation nuclei. This interaction produces mechanical perturbation and a potential for bioeffects on nearby cells or tissues. In vitro, sonoporation and cell death occur at mechanical index (MI) values less than the inertial cavitation threshold. In vivo, bioeffects reported for MI values greater than 0.4 include microvascular leakage, petechiae, cardiomyocyte death, inflammatory cell infiltration, and premature ventricular contractions and are accompanied by gas body destruction within the capillary bed. Bioeffects for MIs of 1.9 or less have been reported in skeletal muscle, fat, myocardium, kidney, liver, and intestine. Therapeutic applications that rely on these bioeffects include targeted drug delivery to the interstitium and DNA transfer into cells for gene therapy. Bioeffects of contrast‐aided diagnostic ultrasound happen on a microscopic scale, and their importance in the clinical setting remains uncertain.

An improved theory for the prediction of microcavitation thresholds

An approximate analytical formulation is presented that allows for the calculation of acoustic pressure thresholds for transient cavitation over a variety of frequencies and host fluid parameters. Specifically, R.E. Apfels (1986) theory is extended to include an estimate of the time delay associated with the Laplace pressure, 2 sigma /R/sub 0/, where sigma is the surface tension and R/sub 0/ is the initial radius. Also presented is a correction factor for the time-averaged pressure difference, across the bubble wall during growth. An optimum size distribution of nuclei for the predisposition of a sample to microcavitation is exhibited. The role of transient cavitation in medical ultrasound is discussed.<<ETX>>

Direct evidence of cavitation in vivo from diagnostic ultrasound

Recent increases in the pressure output of diagnostic ultrasound scanners have led to an interest in establishing thresholds for bioeffects in many organs including the lungs of mammals. Damage may be mediated by inertial cavitation, yet there have been no such direct observations in vivo. To explore the hypothesis of cavitation-based bioeffects from diagnostic ultrasound, research has been performed on the thresholds of damage in rat lungs exposed to 4.0-MHz pulsed Doppler and color Doppler ultrasound. A 30-MHz active cavitation detection scheme complementing these studies provides the first direct evidence of cavitation in vivo from diagnostic ultrasound pulses.

Mechanical bioeffects from diagnostic ultrasound: AIUM consensus statements. American Institute of Ultrasound in Medicine.

Diagnostic ultrasonography has provided an incredible wealth of knowledge in medicine. Few would be willing to deny the impact this modality has had on patient care, particularly for women and children. With millions of ultrasound examinations performed each year, ultrasonography remains one of the fastest growing imaging modalities. This growth is due to its low cost, real-time image display, and, to no lesser extent, its apparent lack of bioeffects.

Thresholds for cavitation produced in water by pulsed ultrasound

The threshold for transient cavitation produced in water by pulsed ultrasound was measured as a function of pulse duration and pulse repetition frequency at both 0.98 and 2.30 MHz. The cavitation events were detected with a passive acoustic technique which relies upon the scattering of the irradiation field by the bubble clouds associated with the events. The results indicate that the threshold is independent of pulse duration and acoustic frequency for pulses longer than approximately 10 acoustic cycles. The threshold increases for shorter pulses. The cavitation events are likely to be associated with bubble clouds rather than single bubbles.

Ultrasound-enhanced thrombolysis with tPA-loaded echogenic liposomes

BACKGROUND AND PURPOSE Currently, the only FDA-approved therapy for acute ischemic stroke is the administration of recombinant tissue plasminogen activator (tPA). Echogenic liposomes (ELIP), phospholipid vesicles filled with gas and fluid, can be manufactured to incorporate tPA. Also, transcranial ultrasound-enhanced thrombolysis can increase the recanalization rate in stroke patients. However, there is little data on lytic efficacy of combining ultrasound, echogenic liposomes, and tPA treatment. In this study, we measure the effects of pulsed 120-kHz ultrasound on the lytic efficacy of tPA and tPA-incorporating ELIP (t-ELIP) in an in-vitro human clot model. It is hypothesized that t-ELIP exhibits similar lytic efficacy to that of rt-PA. METHODS Blood was drawn from 22 subjects after IRB approval. Clots were made in 20-microL pipettes, and placed in a water tank for microscopic visualization during ultrasound and drug treatment. Clots were exposed to combinations of [tPA]=3.15 microg/ml, [t-ELIP]=3.15 microg/ml, and 120-kHz ultrasound for 30 minutes at 37 degrees C in human plasma. At least 12 clots were used for each treatment. Clot lysis over time was imaged and clot diameter was measured over time, using previously developed imaging analysis algorithms. The fractional clot loss (FCL), which is the decrease in mean clot width at the end of lytic treatment, was used as a measure of lytic efficacy for the various treatment regimens. RESULTS The fractional clot loss FCL was 31% (95% CI: 26-37%) and 71% (56-86%) for clots exposed to tPA alone or tPA with 120 kHz ultrasound. Similarly, FCL was 48% (31-64%) and 89% (76-100%) for clots exposed to t-ELIP without or with ultrasound. CONCLUSIONS The lytic efficacy of tPA containing echogenic liposomes is comparable to that of tPA alone. The addition of 120 kHz ultrasound significantly enhanced lytic treatment efficacy for both tPA and t-ELIP. Liposomes loaded with tPA may be a useful adjunct in lytic treatment with tPA.

Passive cavitation imaging with ultrasound arrays

A method is presented for passive imaging of cavitational acoustic emissions using an ultrasound array, with potential application in real-time monitoring of ultrasound ablation. To create such images, microbubble emissions were passively sensed by an imaging array and dynamically focused at multiple depths. In this paper, an analytic expression for a passive image is obtained by solving the Rayleigh-Sommerfield integral, under the Fresnel approximation, and passive images were simulated. A 192-element array was used to create passive images, in real time, from 520-kHz ultrasound scattered by a 1-mm steel wire. Azimuthal positions of this target were accurately estimated from the passive images. Next, stable and inertial cavitation was passively imaged in saline solution sonicated at 520 kHz. Bubble clusters formed in the saline samples were consistently located on both passive images and B-scans. Passive images were also created using broadband emissions from bovine liver sonicated at 2.2 MHz. Agreement was found between the images and source beam shape, indicating an ability to map therapeutic ultrasound beams in situ. The relation between these broadband emissions, sonication amplitude, and exposure conditions are discussed.