Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
1999-03-19
2001-10-16
Jaworski, Francis J. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C600S458000
Reexamination Certificate
active
06302845
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to the field of ultrasound imaging and methods of utilizing ultrasound contrast agents containing microbubbles, and more particularly to the use of such ultrasound contrast agents to accomplish noninvasive sub-harmonic aided pressure estimation inside the human body, especially in the cavities of the heart and in major vessels (e.g., the portal vein).
BACKGROUND OF THE INVENTION
Diagnostic ultrasound has become a very successful modality in clinical radiology because ultrasound imaging and measurement can provide noninvasive, real-time cross-sectional images and parameter estimations of soft tissue structures and blood flow without ionizing radiation. The advantages of noninvasive methods of imaging and measurement over invasive methods of imaging and measurement include the following: 1) the patient is not subjected to a general procedure involving penetrating the body nor is the patient subjected to the risks associated with an invasive imaging procedure, such as catherization; 2) where imaging and measurement are necessary to assess a patient's condition, noninvasive imaging and measurement are less dangerous alternatives, particularly when the patient's clinical condition is too unstable to permit an invasive procedure; 3) noninvasive imaging and measurement may better enable treating physicians and surgeons to provide an earlier and more focused method of intervention, thereby leading to a safer avenue and an earlier timetable for stabilization of critically ill patients, and 4) noninvasive imaging and measurement can significantly reduce the cost of clinical examinations.
Currently there are no methods available for direct noninvasive measurement of internal cavity pressure. Noninvasive pressure estimation in the cavities of the heart and in major vessels (e.g., the portal vein) would provide clinicians with a valuable tool for assessing patients with valvular heart disease, congestive heart failure and various vascular diseases. Measurement of cavity pressure is important in determining blood flow in the cardiovascular system. Accurate pressure estimation is a key parameter in assisting minute-to-minute settings for patients in intensive care settings. Such measurements would inform the physician of altered physiologic states caused by disease, especially where pressure has become abnormally high or abnormally low. These pressure measurements may be especially useful in emergency settings.
Some microbubble-based ultrasound contrast agents are particularly well suited for pressure measurements because their substantial compressibility enables the microbubbles to vary significantly in size in response to changes in pressure. Pressure changes in turn affect reflectivity of microbubbles after intravenous injection of a contrast agent. It is known that the diagnostic capabilities of ultrasound imaging can be improved by intravenous injection of ultrasound contrast agents (Ophir, J. and Parker, K. J. Contrast Agents in Diagnostic Ultrasound.
Ultrasound Med Biol
15: 319-325, 1989; Goldberg, B. B., Liu, J. B. and Forsberg, F. Ultrasound Contrast Agents: A Review.
Ultrasound Med Biol
20: 319-333, 1994). Most contrast agents consist of microbubbles of less than 10 &mgr;m in diameter in order to circulate through capillaries (Needleman, L. and Forsberg, F. Contrast Agents in Ultrasound.
Ultrasound Quarterly
13: 121-138, 1996). Such microbubbles can significantly enhance the backscatter from blood. Moreover, the nonlinear properties of these microbubbles can be used to create new harmonic and subharmonic imaging modalities (Schrope, B. A., and Newhouse, V. L., Second Harmonic Ultrasound Blood Perfusion Measurement.
Ultrasound Med Biol
19: 567-579, 1993; Shi, W. T., Forsberg, F. and Goldberg, B. B. Subharmonic Imaging with Gas-filled Microbubbles,
J Acoust Soc Am
101, 3139 (abstract), 1997) for detection of blood flow in small or even capillary blood vessels surrounded by stationary or moving tissue.
Contrast microbubbles are often stabilized with a coating of surfactants or with encapsulating elastic shells. (de Jong, N., Hoff, L., Skotland, T. and Bom, N. Absorption and Scatter of Encapsulated Gas Filled Microspheres: Theoretical Considerations and Some Measurements.
Ultrasonics
30: 95-103, 1996). The materials on the bubble surface will greatly influence the response of the contrast microbubbles to hydrostatic pressure changes. De Jong and colleagues investigated the effect of the static ambient pressure on the size change of Albunex® (Molecular Biosystems Inc., San Diego, Calif.) and Quantison™ (Andaris Ltd., Nottingham, UK) microbubbles. (de Jong, N., Ten Cate, F. J., Vletter, W. B. and Roelandt, J. R. T. C. (1993). Quantification of Transpulmonary Echocontrast Effects. Ultrasound Med Biol 19: 279-288; de Jong, N. (1996). Improvements in Ultrasound Contrast Agents.
IEEE Eng Med Biol Mag
15: 72-82). Most of the Albunex encapsulated microbubbles shrunk and disappeared due to over-pressure, while the Quantison gas-filled microparticles were insensitive to pressure changes due to their rigid shells.
The reflectivity of microbubble contrast agents at the transmit frequency has been found to vary with the hydrostatic blood pressure. Videodensity variations measured during a cardiac cycle in both the ventricles and especially in the left ventricle indicated a large pressure dependence for microbubbles based on sonicated albumin. (Shapiro, J. S., Reisner, S. A., Lichtenberg, G. S. and Meltzer, R. S. Intravenous Contrast Echocardiography with Use of Sonicated Albumin in Humans: Systolic Disappearance of Left Ventricular Contrast after Transpulmonary Transmission.
J Am Coll Cardiol
7: 1603-1607, 1990; de Jong et al. Quantification of Transpulmonary Echocontrast Effects.
Ultrasound Med Biol
19: 279-288, 1993). This was further confirmed by Gottlieb et al. in an in vitro model. (Gottlieb, S., Ernst, A. and Meltzer, R. S. Effect of Pressure on Echocardio-graphic Videodensity from Sonicated Albumin: An in vitro Model.
J Ultrasound Med
14: 101-108, 1995). The effect of hydrostatic pressure on the acoustic transmittance of an Albunex microbubble suspension was studied by Brayman et al (1996), who found that the acoustic transmittance increased with hydrostatic pressure. (Brayman, A. A., Azadniv, M., Miller, M. W. and Meltzer, R. S. Effect of Static Pressure on Acoustic Transmittance of Albunex Microbubble Suspensions.
J Acoust Soc Am
99: 2403-2408, 1996). This effect could be caused by the destruction of many of the microbubbles at a pressure comparable to those produced in the heart. The reflectivity of some other agents such as Levovist® (Schering A G, Berlin, Germany) was reported to be less sensitive to pressure changes. (Schlief, R. Galactose-based Echo-enhancing agents in
Ultrasound Contrast Agents,
edit by Barry B. Goldberg, Martin Dunitz Ltd, London. pp 75-82, 1997).
There are many interesting bubble oscillations which span the range of possible frequency emissions from subharmonics (as well as ultraharmonics) through higher harmonics (Lauterborn, W. Numerical Investigation of Nonlinear Oscillations of Gas Bubble in Liquids.
J Acoust Soc Am
59: 283-293, 1976). Subharmonic oscillation (or ultraharmonic oscillation) of a free bubble occurs only when the exciting acoustic signal exceeds a certain threshold level (Prosperetti, A. Nonlinear Oscillations of Gas Bubble in Liquids: Transient Solutions and the Connection between Subharmonic Signal and Cavitation,
J Acoust Soc Am
57: 810-821, 1975; Prosperetti, A. Application of the Subharmonic Threshold to the Measurement of the Damping of Oscillating Gas Bubbles.
J Acoust Soc Am
61: 11-16, 1977; Leighton, T. G.,
The Acoustic Bubble.
Academic Press, London, Great Britain, 1994), while the generation of higher harmonics is a continuous process and occurs to various degree for all levels of excitation. Eller and Flynn estimated the threshold acoustic pressure required for subharmonic generation from a spherical bubble driven by a sinusoidal p
Forsberg Flemming
Goldberg Barry B.
Raichlen Joel S.
Shi William Tao
Jaworski Francis J.
Thomas Jefferson University
Weber, Esq. Clifford Kent
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