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Technical Developments |
1 From the Department of Radiology and Nuclear Medicine, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany (T.A., C.W.H., S.S., A.O., K.J.W.); the Department of Clinical Development, Schering, Berlin, Germany (A.B.); and Siemens US Group, Issaquah, Wash (M.I., P.L.v.B.). Received June 14, 1999; revision requested July 22; revision received October 12; accepted November 16. Address correspondence to T.A. (e-mail: t.albrecht@medizin.fu-berlin.de).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMaterials and MethodsResultsDiscussionREFERENCES |
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Index terms: Ultrasound (US), contrast media, 9*.129882
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMaterials and MethodsResultsDiscussionREFERENCES |
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When exposed to the ultrasound beam, microbubbles oscillate. These oscillations have a strong tendency to be resonant, and the resonance frequency of microbubble contrast agents happens to be within the frequency range of diagnostic US. With increasing transmit power, the bubbles show an increasingly nonlinear response (ie, the reflected signal contains frequencies that differ from the insonating frequency and the returned signal is thus distorted). These nonlinearities occur since less energy is required to expand the bubble than to compress it. The nonlinear signals contain overtones or harmonic and subharmonic signals at multiples and fractions of the insonating frequency (1–5). Previous studies used the second-harmonic signal, which occurs at twice the incident frequency for second-harmonic imaging (1,6).
When the energy of the insonating beam is further increased to mechanical indexes greater than approximately 0.3, the microbubbles are increasingly destroyed. The threshold for destruction is variable and depends on many factors, such as the nature and size of the bubble or the attenuation of the overlying tissue. Klibanov et al (7) found a threshold mechanical index for destruction of an air-based microbubble agent (Albunex; Mallinckrodt, St Louis, Mo) of 0.3 in vitro, and this corresponds well to our in vivo observations with the US contrast agent used in the current study (SH U 508A, Levovist; Schering, Berlin, Germany). The destruction is a very fast process, taking place during a single or a few ultrasound pulses, during which a strong and highly nonlinear signal is returned from the bubble. This process is called "stimulated acoustic emission" or "transient scattering." It can be used for imaging in color Doppler mode where it is displayed as a mosaic of randomly distributed pseudo–Doppler shifts that are independent of flow (8–12).
Both second-harmonic imaging and stimulated acoustic emission have been used for imaging in humans. Outside of the heart, this was mostly limited to color or power Doppler displays.
In this study, we evaluated the initial human results with a B-mode pulse- or phase-inversion technology that selectively displays nonlinear signals.
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Materials and Methods |
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TOPABSTRACTINTRODUCTIONMaterials and MethodsResultsDiscussionREFERENCES |
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If only stationary linear scatterers are insonated, the two pulses sent are returned to the transducer without distortion; therefore, the summation of two phase-inverted pulses results in a complete signal void. If nonlinear scatterers are encountered, however, each of the two pulses is distorted, and the summation of the pulses no longer results in a void but in a signal that is almost exclusively produced by nonlinearities (13) (Fig 1) (although moving linear scatterers will also produce some signal at phase-inversion US owing to the Doppler effect). The phase-inversion technique thus effectively constitutes a subtraction technique for stationary linear scatterers. Since microbubbles are very strong nonlinear scatterers, the phase-inversion technique is extremely sensitive to the presence of the bubbles in the insonated tissue and displays the bubbles preferentially (although tissue also has nonlinear properties, especially at high transmit power, so that a nonlinear image can also be obtained from tissue and can be used in tissue-harmonic imaging). The technique is particularly sensitive at high insonating amplitudes where stimulated acoustic emission occurs. As discussed previously, this produces a strong signal from the first pulse. The second pulse will not produce a response, since the bubble has been destroyed by the first pulse, and the summation of the two pulses will result in a particularly strong signal (Fig 1). When used for B-mode imaging enhanced with a microbubble contrast agent, the phase-inversion technique achieves strong B-mode enhancement of vessels and parenchyma of abdominal organs in animals (14).
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With the linear signal eliminated from the summed returned signal, a narrow frequency-domain filter is not required. Essentially, the entire bandwidth of the returned signal can be used; thus, spatial resolution with the phase-inversion technique is better than that with second-harmonic imaging.
Subjects
Three healthy volunteers (two women and one man; age range, 25–37 years; mean age, 29 years) and 36 consecutive patients (24 women and 12 men; age range, 31–82 years; mean age, 57 years) were prospectively included. The study was approved by our institutional ethics committee, and subjects gave informed written consent. In all cases, routine B-mode US of the abdomen was performed to assess anatomy and any potential pathologic condition before administration of the contrast agent.
Contrast Agent Administration and Scanning Technique
Fifty-two intravenous injections (46 bolus injections and six infusions at 1 mL/min) of SH U 508A at a concentration of 400 mg/mL were administered, with a maximum of two injections per subject. The dose per injection was 2.5 g (n = 41) and 4 g (n = 11), respectively.
After administration of the contrast agent, the relevant body areas (liver, n = 39; right kidney, n = 31; spleen, n = 14; portal vein and/or its major branches, n = 19; renal artery, n = 17; hepatic artery, n = 17; aorta and inferior vena cava, n = 7; carotid artery, n = 6) were scanned successively with the B-mode phase-inversion technique. Large vessels and the kidney were scanned during the blood-pool phase (less than 5 minutes after initiation of the injection) of SH U 508A and the liver and spleen, in the late liver- or spleen-specific phase (more than 3 minutes after initiation of the injection) (10,11,15,16). For abdominal imaging, a 3.5-MHz wideband curved transducer was used. For the carotid arteries, a 7.5-MHz wideband linear transducer was used. We used parallel processing with high frame rates (nine or more frames per second), and scanning was continuous without triggering. A single focal zone was used, and its position was always adapted to the depth of the relevant anatomic site. When the liver was scanned, at least two different focal zone positions were applied, one for the superficial and one for the deep part of the organ.
In 21 subjects, mechanical indexes between 0.4 and 1.6 were compared for abdominal imaging. In all remaining cases (abdomen and carotid arteries), mechanical indexes greater than 1.0 were used.
In 15 subjects, different transmit center frequencies were compared. For abdominal imaging (n = 13), these ranged between 1.9 and 3.0 MHz and for the carotid arteries (n = 5), between 3.3 and 6.0 MHz. In all remaining subjects, 2.5 MHz (abdominal imaging) and 3.3 MHz (carotid arteries) were used.
Image Interpretation
All scans were recorded on super VHS videotape, and representative digital soft copy still images were obtained of each body area. Scans obtained with the phase-inversion technique were evaluated independently by two radiologists (C.W.H., T.A.) on the basis of the real-time scans and, if necessary, after review of videotapes and soft copy still images. Each observer graded the degree of enhancement on a scale from 0 to 3: 0, no enhancement; 1, mild enhancement; 2, moderate enhancement; 3, strong enhancement. A consensus score was calculated as the mean of the scores given by the two observers. If the observers disagreed by one score increment, the lower of the two scores was used for the consensus score. For parenchymal enhancement, the scores were defined as mild, only slight and/or patchy elevation of the parenchymal gray-scale level; moderate, elevation of the gray-scale level clearly visible and predominantly homogeneous in distribution; and strong, homogeneously bright gray or nearly white parenchyma. For large vessels, the scores were defined as mild, luminal gray level similar to surrounding tissue; moderate, lumen brighter than surrounding tissue; and strong, white or nearly white lumen longer than 2 cm.
The influence of the transmit amplitude was assessed as follows: Initial scanning was performed at the maximum mechanical index (1.3–1.6). The mechanical index was then gradually decreased to 0.4. At each mechanical index increment, the degree of enhancement was compared with that at the maximum mechanical index. The two observers assessed images by consensus that were obtained down to the mechanical index with which there was the same or almost the same degree of enhancement as at the maximum mechanical index and below which a substantial decrease in signal intensity occurred.
The influence of the transmit center frequency was assessed at the maximum mechanical index. The two observers assessed by consensus which frequency provided the strongest enhancement.
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Results |
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TOPABSTRACTINTRODUCTIONMaterials and MethodsResultsDiscussionREFERENCES |
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Influence of Transmit Amplitude
The intensity of enhancement was strongest at high transmit amplitudes (mechanical index of 1.0 or higher, Table 2), where bubble destruction and stimulated acoustic emission occurred. On the other hand, the enhancement was highly transient when scanning was performed at high amplitudes; an individual bubble population in the ultrasound beam then yielded enhancement of only two to three frames. This manifested itself in two ways.
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Second, in small vessels with slow flow (organ parenchyma) or in areas with stationary bubbles (late phase imaging of liver and spleen), there was marked enhancement on the first frame after the scanner was unfrozen, which rapidly decreased over the next two or three frames, and the enhancement usually disappeared by the third or fourth frame. Review of the images on the cine loop was extremely helpful to appreciate the enhancement. An effective way to circumvent the transience of the contrast agent effect was to continuously move the transducer through an organ so that a new area with undestroyed bubbles was scanned with each frame. It was important not to sweep too fast with this approach, as this would have produced flash artifacts as described later. Continuous movement of the transducer allowed us to obtain brightly enhanced sweeps of an entire organ. Again, use of the cine loop to review the sweeps was very useful as it allowed detailed inspection of all images acquired during the sweep.
When scanning was performed at lower amplitude (mechanical index of less than 1.0), the intensity of the enhancement gradually decreased. Table 2 shows the threshold mechanical indexes below which there was a substantial reduction in the intensity of enhancement in comparison with that seen at the maximum mechanical index for the 21 subjects in whom different mechanical indexes were compared. This threshold was between 0.6 and 0.9 in 12 subjects and was 1.0 or more in nine. Even below these thresholds, however, considerable enhancement was seen in many patients. No substantial enhancement was seen on scans obtained at mechanical indexes below 0.5 in any of the subjects.
Despite the reduction in signal intensity at low amplitudes, visualization of small vessels (eg, in the kidney) was improved. This improvement resulted because the bubbles were not destroyed in larger vessels within the imaging plane before they reached the small vessels as happened at high amplitudes.
Influence of Transmit Center Frequency
Comparison of different transmit center frequencies for the 3.5-MHz transducer showed the strongest enhancement at 2.5 MHz. With this transducer, however, enhancement was observed at all frequencies used, and the difference between the frequencies was only minor. With the 7.5-MHz transducer, the strongest enhancement was seen at low transmit frequencies (
4 MHz), and it became gradually weaker as the frequency was increased beyond 4.0 MHz. No relevant differences were observed between 3.3 and 4.0 MHz.
Artifacts and Other Technical Factors
The enhancement was always strictly limited to the anatomic structure at question (vessel lumen or organ parenchyma) with no blooming artifacts.
Since the phase-inversion technology is dependent on frequency shifts between two consecutive pulses, it has Doppler properties and is therefore motion sensitive. This sensitivity applies to moving scatterers such as flowing microbubbles and to relative motion between the transducer and tissue; thus, vascular enhancement was stronger during systole than during diastole. Flash artifacts across the entire image occurred when the transducer sweep was rapid, but this was not the case when the sweep was performed more slowly. Also, no flash artifacts were observed with normal respiration or from referred cardiac pulsations in the left lobe of the liver.
Although we did not systematically evaluate the influence of depth on the enhancement, we observed a gradual decrease at depths greater than 10–12 cm from the skin. Enhancement was never seen beyond 15 cm, as the intensity of the US pulse at this depth was not sufficient to produce a strong nonlinear response. This insufficiency proved a limitation during scanning of the renal artery from the flank and of the liver in obese patients. On the basis of recorded images in 31 subjects, we retrospectively assessed if the entire liver could be enhanced. In five of the 31 subjects, we found that liver enhancement was incomplete, with a 2-cm band of insufficient enhancement beyond 11–13 cm due to limited penetration.
Enhancement was dependent on the position of the focal zone. Enhancement was most marked at a band approximately 6 cm wide centered around the focal zone, and it gradually decreased on either side of the band. Moving the focus to a different depth shifted this band of enhancement to other parts of the image, which allowed the entire image to be enhanced. This effect occurred since the maximum energy was deposited around the focal zone.
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Discussion |
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TOPABSTRACTINTRODUCTIONMaterials and MethodsResultsDiscussionREFERENCES |
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With regard to image quality, the B-mode phase-inversion technique has a number of favorable properties that are advantageous for vascular and parenchymal imaging. It has a spatial resolution superior to that of other modalities such as fundamental B-mode US or color and power Doppler US. In contrast to Doppler modalities, the phase-inversion technique is not subject to blooming and clutter artifacts, which occur under only extreme circumstances. Temporal resolution is also usually higher with the phase-inversion technique than with color Doppler techniques (except when a very small color box is used). The fact that two pulses are required for one phase-inversion image, however, reduces the frame rate by 50% in comparison with that for fundamental B-mode US. The parallel processing feature of the scanner we used, which doubles the frame rate without relevant loss of image quality, allowed us to scan at a frame rate of nine or more frames per second in all cases.
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FOOTNOTES |
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Author contributions: Guarantor of integrity of entire study, T.A.; study concepts, T.A., P.L.v.B.; study design, T.A.; definition of intellectual content, T.A., C.W.H.; literature research, T.A.; clinical studies, T.A., C.W.H., S.S., A.O., M.I., A.B.; data acquisition, T.A., C.W.H., S.S., A.O., M.I., A.B.; data analysis, T.A., C.W.H., S.S.; manuscript preparation, T.A., C.W.H.; manuscript editing, T.A., C.W.H., P.L.v.B., M.I., K.J.W.; manuscript review, T.A.
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TOPABSTRACTINTRODUCTIONMaterials and MethodsResultsDiscussionREFERENCES |
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