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Hepatic vein transit time of an ultrasound contrast agent: simplified procedure using pulse inversion imaging

Departments of ¹Radiology and ²Otorhinolaryngology—Head and Neck Surgery, Rigshospitalet and ³Department of Radiology, Glostrup Hospital, University of Copenhagen, Denmark

Correspondence: Dr N Bang, Department of Radiology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK 2100 Copenhagen, Denmark

	Abstract

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The aim of this study was to ascertain whether a new ultrasound technique, namely pulse inversion imaging, could assess the arrival of a contrast agent in the hepatic veins, and to describe possible advantages of this procedure in determining transit time over a previously described method based upon spectral Doppler quantification. 15 subjects were scanned using pulse inversion imaging. A bolus injection of 2.5 g Levovist (Schering AG, Berlin, Germany) 300 mg ml^-1 was given into an antecubital vein. Median transit times of 16 s (range 14–20 s) were found in patients with liver cirrhosis (n=4), 22 s (range 16–27 s) in patients with focal liver lesions (n=8) and 31 s (range 30–32 s) in control subjects (n=3). The maximum interobserver variation was 2 s and the maximum intraobserver variation was 3 s (n=10). Transit time was assessed by both pulse inversion imaging and spectral Doppler quantification in six patients. Comparison of the two methods showed transit times within 2 s apart in five patients and within 5 s apart in one patient. In conclusion, it is possible to assess transit time using pulse inversion imaging. This method is simpler than a previously described method requiring computer analysis. Moreover, several liver veins can be assessed simultaneously. Different transit times were observed in different liver veins in two patients with liver tumours. A short transit time (<27 s) appears to be found only in patients with liver disease. After transit time assessment, it is possible to use the injected contrast agent for late phase imaging of the liver parenchyma.

	Introduction

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The aim of this study was to ascertain whether a new ultrasound technique, namely pulse inversion imaging, could assess the arrival of an echo enhancing agent in the hepatic veins, and to describe possible advantages of this procedure in determining transit time over a previously described method based upon spectral Doppler quantification [1]. This report contains the preliminary findings.

	Materials and methods

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We examined 12 patients with liver disease who were referred for an abdominal ultrasound examination with an echo enhancing agent. Four patients (age range 39–56 years) had hepatic cirrhosis (one had normal portal flow, two had reduced flow, one had retrograde flow) and eight patients (age range 46–70 years) had focal liver lesions (one patient with hepatocellular carcinoma, seven patients with metastases). As a control we examined an additional three patients (age range 65–73 years) with no history of hepatic or malignant disease during echo enhanced Doppler evaluation of the carotid arteries.

The liver veins were scanned in a transverse section in the epigastrium using the built-in pulse inversion technique optimized for contrast agent (mechanical index 0.7) using the Siemens Elegra (Issaquah, WA) ultrasound apparatus (software version 4.3) (Figure 1a). Patients were instructed to breathe normally during the investigation. Control cases had their carotid study performed with one ultrasound unit while another was used to simultaneously assess the transit time by performing abdominal scanning. Patients were not required to be fasting for inclusion in the study.

View larger version (115K): [in this window] [in a new window]   Figure 1. Ultrasound scan of the liver veins with pulse inversion imaging. Before injection of contrast agent a good view of the liver veins is obtained (a). Arrival of the contrast agent was seen as white reflections after 19 s in a right-sided liver vein (b) and after 28 s in the left liver vein (c). There was a hepatocellular carcinoma in the right liver lobe (not shown in this figure).

The interobserver variation in assessing transit time by pulse inversion imaging was estimated. The videotapes from 10 patients were reviewed by two observers (2 patients with different transit times in different hepatic veins and the 3 normal controls were not included in this part of the study). Observers were blinded to the diagnosis of the patients and to the results of the other observer. To estimate intraobserver variation, one of the observers, still blinded, reviewed the videotapes after a couple of months.

In six patients, two injections of Levovist were given at least 10 min apart to assess the transit time both by pulse inversion imaging and according to a previously described technique using analysis of spectral Doppler ultrasound of a hepatic vein (usually the middle hepatic vein) [1]. For the latter, a special computer program was created to make a quantitative analysis of the audio signals. The ultrasound scanner provides two audio signals (left and right). Using a digital signal processor evaluation board (Analog Devices ADDS-2106x SHARC; Analog Devices, Norwood, MA), these signals were digitized (16 bit, 16 kHz sampling rate) and a custom-made program calculated the root-mean-square (rms) value of both channels summed over intervals of 1 s. The rms data were presented in decibels relative to 50 mV. Separate files containing consecutive sequences of 120 measurements (2 min) were stored on the controlling PC for the left and right channel, together with a similar file containing the total signal. The total signal was based on the power sum of the left and right channel recordings. The arrival time was defined according to Albrecht et al [1] from the raw data curves. The results of the two techniques were later compared.

	Results

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Results regarding transit time analysis using the pulse inversion imaging technique are given in Figure 2. In the patients with liver cirrhosis, the median transit time was 16 s (range 14–20 s). In the patients with focal liver lesions, the median transit time was 22 s (range 16–27 s). The controls had median transit times of 31 s (range 30–32 s).

View larger version (24K): [in this window] [in a new window]   Figure 2. Hepatic vein transit time (s) of an ultrasound contrast agent assessed by pulse inversion imaging in patients with no history of hepatic or malignant disease (a), in patients with liver cirrhosis (b) and in patients with focal liver lesions (c).

Comparison of transit times obtained by our method and by spectral Doppler analysis showed transit times within 2 s apart in five patients and within 5 s apart in one patient (Table 1).

	Discussion

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Pulse inversion is an option that is built-in on some new ultrasound machines. Two ultrasound pulses are sent, one of them phase inverted 180°, so that when added the reflections due to the linear behaviour of the tissue cancel out [3]. However, ultrasound contrast agents in particular behave in a non-linear fashion, so that the image resulting from an inversed pulse scanning will be dominated by the reflections from the contrast agent. It is a black and white imaging mode, in which the contrast agent appears as white reflections.

The major advantage of this pulse inversion technique is that arrival of the contrast agent in the hepatic veins can be directly seen and does not need subsequent computer analysis. The transit time will thus be apparent within a minute after the contrast agent is injected. Furthermore, movement caused by the patient breathing is not a significant problem with this method, as it may be with spectral Doppler studies if the Doppler gate is not kept constantly in the vein. We also experienced another problem with the spectral Doppler technique, namely that destruction of the air bubbles by the ultrasound beam in some cases produced spikes and this may influence the results. This phenomenon may explain the flat curves seen by Blomley et al [2].

An advantage of this method is that usually more than one hepatic vein can be visualized in the same scan plane. Since rapid transit time is also found in liver tumours [2], there may theoretically be different transit times in different liver veins. This was observed in two patients with liver tumours. One patient had a large hepatocellular carcinoma (Figures 1a–c) and one had a large solitary liver metastasis. This phenomenon has never been described before.

The transit times found in our study were in accordance with those obtained by others [1, 2]. All our patients with focal liver lesions had a transit time of up to 27 s. Blomley et al [2] found values less than 25 s in six out of seven patients with liver metastases, while their seven control subjects had values greater than 25 s. A maximum transit time of 20 s was found in patients with cirrhosis. In the study by Albrecht et al [1], all patients with cirrhosis had transit times of less than 24 s (mean 18.3 s). We found a median transit time of 31 s in control subjects, while Albrecht et al [1] found a mean arrival time at 49.8 s for 11 normal subjects, all values being at least 24 s.

The drawback of our method is that only the arrival time of the contrast agent can be noted, but not other variables such as time to peak or absolute peak enhancement. Since the arrival time seems to be of especial clinical value [1], this should not be a problem. Furthermore, an increased energy in the ultrasound beam when using the pulse inversion method and the spectral Doppler method could result in increased bubble destruction, which might influence, for example, absolute peak measurements.

The current results demonstrate that a short transit time detected by either of the two methods may indicate some kind of hepatic pathology. The techniques do not determine whether the shunting takes place within the liver or outside the liver, but the difference in transit times in different hepatic veins as observed in some of our patients suggests that at least part of the shunting is inside the liver.

In conclusion, pulse inversion imaging has been found to be more simple and to have certain advantages over spectral Doppler quantification in the assessment of the transit time of a bolus of an echo enhancing agent. A short transit time (less than 27 s) was found only in patients with liver disease. The bubbles of contrast agent are visualized directly as they arrive in the liver veins, allowing comparison of transit time in different liver veins. As transit time assessment is completed within 1 min from the bolus injection, it is possible to use the injected contrast agent for late phase imaging of the liver parenchyma [4]. Larger studies are required to determine the significance of transit time analysis in clinical practice.

	Acknowledgments

 
We thank Schering A/S Albertslund, Denmark, for supplying the Levovist used in this study.

Received for publication November 23, 2000. Revision received April 23, 2001. Accepted for publication May 1, 2001.

	References

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1. Albrecht T, Blomley MJ, Cosgrove DO, Taylor-Robinson SD, Jayaram V, Eckersley R, et al. Non-invasive diagnosis of hepatic cirrhosis by transit-time analysis of an ultrasound contrast agent. Lancet 1999;353:1579–83.[Medline]
2. Blomley MJ, Albrecht T, Cosgrove DO, Jayaram V, Eckersley RJ, Patel N, et al. Liver vascular transit time analyzed with dynamic hepatic venography with bolus injections of an US contrast agent: early experience in seven patients with metastases. Radiology 1998;209:862–6.[Abstract/Free Full Text]
3. Burns PN, Wilson SR, Simpson DH. Pulse inversion imaging of liver blood flow: improved method for characterizing focal masses with microbubble contrast. Invest Radiol 2000;35:58–71.[Medline]
4. Harvey CJ, Blomley MJ, Eckersley RJ, Heckemann RA, Butler-Barnes J, Cosgrove DO. Pulse-inversion mode imaging of liver specific microbubbles: improved detection of subcentimetre metastases. Lancet 2000;355:807–8.[Medline]

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