Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
2000-06-19
2002-06-25
Jaworski, Francis J. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
Reexamination Certificate
active
06409671
ABSTRACT:
This invention relates to ultrasound imaging, more particularly to use of contrast agent-enhanced ultrasound imaging in the detection of local aberrations in perfusion and/or compliance of vasculated tissue.
Measurements of tissue perfusion, i.e. blood flow per unit of tissue mass, are of value in, for example, detection of regions of low perfusion, e.g. as a result of arterial stenosis, and in detection of abnormal growths such as tumours in tissues such as the liver, kidney, thyroid, prostate, testes and breast, tumour tissue typically having different vascularity from healthy tissue. Measurement of cardiac perfusion in order to identify any myocardial regions supplied by stenotic arteries is of particular importance.
Currently used methods for obtaining quantitative perfusion data utilise radioisotopic imaging techniques such as scintigraphy, positron emission tomography and single photon emission computed tomography. These techniques all involve injection of radioactive substances, with potential safety risks for both the patient and medical staff, and use of expensive imaging equipment; this inevitably prohibits their widespread use.
Ultrasound imaging is a relatively inexpensive and essentially non-invasive imaging technique which is increasingly used for diagnostic purposes. However, whilst ultrasound images, particularly images obtained using ultrasound contrast agents, may provide qualitative information as to whether particular organs or regions thereof are perfused or not, they do not readily permit quantification of levels of perfusion. In part this is because reduced perfusion is not necessarily accompanied by detectable vascular volume changes which would give rise to perfusion-related variations in the intensity of the backscattered ultrasound signal. Quantification of contrast agent concentration in a particular tissue region is itself an uncertain process which is inevitably imprecise given that the degree of attenuation of ultrasound irradiation by proximal intervening tissue cannot accurately be determined.
Wash-in kinetic studies following intravenous injection of a contrast agent bolus may in principle give information on tissue perfusion, but in practice the bolus waveforms lack the abrupt temporal changes needed for reliable observations to be made. Moreover, most perfusion changes are accompanied by distribution volume variations which counteract their temporal effect, so that the wash-in kinetics of intravascular tracers cannot give a precise measure of perfusion.
Accurate perfusion measurements with high spatial resolution are also made difficult by the substantial spacial heterogeneity of normally perfused tissue.
A variety of ultrasound Doppler techniques have been proposed for measuring the velocity of blood flow. Thus, for example, U.S. Pat. No. 5,211,169 (Prism Imaging, Inc.) discloses that Doppler signals may be analysed to obtain information in respect of movement of the heart and in respect of the more rapid movement of the blood pool; the latter information is used to determine changes in the size of the blood pool, thereby permitting calculation of heart function parameters such as the ejection fraction. Contrast agents are not used in this technique, return signals from the blood pool being generated by backscatter from red blood cells.
Similar Doppler velocity measurements may be used to detect tissue regions with reduced perfusion. Interpretation of the Doppler waveform must be made in such a way as to eliminate the effects of local anatomical detail such as vessel size and orientation, for example by calculating dimensionless indices such as the “resistance index”, “Pourcelot index” or “pulsatility index” by simple waveform analysis techniques. Analysis of these may permit detection of abnormal circulation on the basis that arterial pulsatility waveforms are different upstream and downstream of an arterial stenosis, thus the waveform undergoes characteristic changes when arterial resistance is increased, both as a result of the resistance changes per se and because the pressure distal to the stenosis causes increased local compliance through non-linear elastic mechanisms. In general, the arterial velocity pulsation waveform in a stenotic vessel is determined by factors such as the input pressure waveform (i.e. the systemic arterial pressure), the resistance of the stenosis, the compliance of vessels between the transducer and the stenosis, and the compliance of the distal vascular bed. The pattern of flow velocity change proximal to a stenosis is characterised by the effects of pulse wave reflection and tends to have a relatively high content of high frequencies, whereas the waveform distal to a stenosis tends to be low-pass filtered and phase shifted by the increased resistance and compliance. Such applications are, however, limited by the need for anatomical identification of the desired vessels, which must be “visible” and non-perpendicular to the irradiating ultrasound beam, and are only practicable in respect of measurements involving relatively large vessels.
The present invention is based on the finding that contrast agent-enhanced ultrasound imaging may be used to identify local aberrations in the perfusion and/or compliance of vasculated tissue by image analysis techniques which identify such aberrations through associated variations in waveforms representative of arterial pulsatility.
Thus according to one aspect of the present invention there is provided a method for detecting local aberrations in the perfusion and/or compliance of vasculated tissue within a human or non-human animal subject pretreated with an intravascularly administered ultrasound contrast agent, said method comprising the steps:
i) generating a sequence of ultrasound image data in respect of a region of interest in said vasculated tissue;
ii) processing said data to generate waveforms representative of arterial pulsatility; and
iii) analysing said waveforms for variations characteristic of local aberrations in tissue perfusion and/or compliance.
The invention further provides the use of an ultrasound contrast agent both as and in the manufacture of an image-enhancing composition for administration to the vascular system of a human or non-human animal subject in order to detect local aberrations in perfusion and/or compliance within said vascular system in accordance with the above-defined method.
Representative ultrasound imaging techniques which may be useful in accordance with the invention include fundamental B-mode imaging; harmonic B-mode imaging including reception of sub-harmonics and the second and higher harmonics; power Doppler imaging, optionally including selective reception of fundamental, harmonic or sub-harmonic echo frequencies; power Doppler imaging utilising loss of correlation or apparent Doppler shifts caused by changes in the acoustical properties of contrast agent microbubbles such as may be caused by spontaneous or ultrasound-induced destruction, fragmentation, growth or coalescence; pulse inversion imaging, optionally including selective reception of fundamental, harmonic or sub-harmonic echo frequencies, and also including techniques wherein the number of pulses emitted in each direction exceeds two; pulse inversion imaging utilising loss of correlation caused by changes in the acoustical properties of contrast agent microbubbles such as may be caused by spontaneous or ultrasound-induced destruction, fragmentation, growth or coalescence; pulse pre-distortion imaging, e.g. as described in 1997 IEEE Ultrasonics Symposium, pp. 1567-1570; ultrasound imaging techniques based on comparison of echoes obtained with different emission output amplitudes or waveform shapes in order to detect non-linear effects caused by the presence of gas bubbles; ultrasound imaging techniques where images are taken at different acoustic output levels such as one with high power and up to ten (e.g. two or three) images are taken at low power; and ultrasound imaging techniques based on comparison of echoes obtained with any of the above mentioned techniques,
Eriksen Morten
Frigstad Sigmund
Chisholm Robert F.
Jaworski Francis J.
Nycomed Imaging AS
Ronning, Jr. Royal N.
Ryan Stephen G.
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