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1
Department of General Internal Medicine, University of Bonn, Sigmund Freud
Str. 25, D-53105 Bonn, Germany.
2
Present Address: Department of Internal Medicine I, Klinikum
Saarbrücken, Winterberg 1, D-66119
Saarbrücken, Germany.
3
Department of Radiology, University of Bonn, D-53105 Bonn, Germany.
Received August 17, 2000;
accepted after revision July 17, 2001.
Address correspondence to P. Schiedermaier.
Abstract
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SUBJECTS AND METHODS. We performed color Doppler sonography at baseline and during IV Levovist infusion (4 g, 300 mg/min). First, we measured the duration of portal vein visualization during Levovist infusion in 15 patients in whom unenhanced color Doppler sonography failed to show the portal confluence from a subcostal view. This duration of improved portal conspicuity was termed "diagnostic window." We then compared in 30 patients enhanced color Doppler sonographic findings with conventional imaging methods, including portography (n = 14), helical CT (n = 4), or gadolinium-enhanced MR angiography (n = 12), and we recorded the investigator's confidence in the color Doppler sonographic result before and after Levovist infusion.
RESULTS. The diagnostic window achieved by the Levovist infusion was 13.6 ± 0.9 min. At baseline, color Doppler sonography was nondiagnostic in 19 patients. The diagnostic confidence level was low in all the remaining 11 patients. During Levovist infusion, color Doppler sonography remained nondiagnostic only in two of 30 patients. The confidence level was low in five patients and high in 23 patients. In 26 of these 28 patients, echo-enhanced color Doppler sonographic findings were confirmed by reference methods.
CONCLUSION. The continuous infusion of Levovist achieved a sufficient echo enhancement from the portal vascular bed and allowed a valid diagnostic color Doppler sonographic examination in portal hypertensive patients for whom color Doppler sonography would otherwise be nondiagnostic.
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The galactose-based transpulmonary sonographic microbubble contrast agent SH U 508A (Levovist; Schering, Berlin, Germany) increases the intensity of the Doppler echo [4]. The blood-pool enhancement after IV injection has been shown to improve the diagnostic confidence of color Doppler sonography for the portal vascular bed [5]. In practice, the usefulness of an IV bolus injection for an echo-enhanced sonographic examination of the portal vascular system is, however, limited to the short duration of the diagnostically useful signal increase of less than 5 min [6]. A preliminary study using continuous infusion of Levovist has recently been published. Albrecht et al. [7] found that an infusion provided a more uniform echo enhancement for up to 15 min in the femoral and carotid artery; however, this pilot study was performed on superficial vessels in healthy volunteers, and the results are not representative for deep abdominal vessels. We therefore examined the feasibility and the impact of a continuous Levovist infusion on the diagnostic value of primarily nondiagnostic portal vascular color Doppler sonography in patients with portal hypertension.
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Protocol 1
We included 15 patients (three women, 12 men; age 44 ± 18 years)
with known sinusoidal portal hypertension and in whom the confluence of the
portal vein was not visible by unenhanced color Doppler sonography in the
subcostal view. The patients underwent color Doppler sonography in the morning
after an overnight fast. All color Doppler sonographic examinations were
performed by one of the authors. We used a Duplex-Doppler device (SSH 140-A;
Toshiba Medical Systems, Neuss, Germany) with a 2.5 MHz convex probe
PVF—275MT (Toshiba Medical Systems). Immediately after the baseline
examination, we started the Levovist infusion (4 g, 300 mg/mL; 1 mL/min; total
volume, 13.3 mL) via an antecubital vein resulting in an infusion time of 11
min because approximately 2 mL remained in the infusion system. For the
infusion, we used a P 4000 infusion pump (IVAC Medical Systems, San Diego,
CA). We recorded the time (in min) during which the nonvisible confluence of
the portal vein became visible in the same subcostal view without changing the
transducer position (Fig.
1A,1B).
The diagnostic window of the Levovist infusion was defined as the time when
confluence of the portal vein was visible.
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Protocol 2
Thereafter, an additional 30 patients (10 women, 20 men; age 42 ± 15
years) with suspected or known portal hypertension were included in a
comparative analysis. Inclusion criteria were primarily nondiagnostic color
Doppler sonography as a result of insufficient color Doppler echo and the
clinical necessity of a subsequent reference method for portal imaging. We
assessed vascular patency solely by color Doppler sonography; neither power
nor spectral Doppler imaging was used. Color Doppler sonography was indicated
either to assess portal vascular patency (n = 6) before transjugular
intrahepatic portosystemic shunt (TIPS) insertion, shunt surgery, or
orthotopic liver transplantation, or to determine the extension of a
thrombosis in the portal system (i.e., stated in the patient's medical history
but not specified regarding its extension; n = 7), or to prove shunt
patency (surgical: one mesocaval, two splenorenal, one collaterocaval; TIPS:
four), or to differentiate a portal hypertension of unknown origin (i.e.,
clinical signs of portal hypertension without evidence of liver cirrhosis in
the patient's medical history; n = 9). Immediately after failure of
the basal examination, color Doppler sonography was repeated while we infused
Levovist, as described in protocol 1. A diagnostic confidence score (DCS) for
color Doppler sonography was assessed before and after Levovist infusion
according to the following scale: DCS 0, nondiagnostic; DCS 1, low diagnostic
confidence; DCS 2, high diagnostic confidence.
We compared the diagnosis established by color Doppler sonography with the correlative imaging method. Correlative findings were obtained from digital subtraction angiographic portography (n = 14), helical CT (n = 4), or gadolinium-enhanced MR angiography (n = 12) and were interpreted by one of the authors, who was unaware of the color Doppler sonographic results. The interval between color Doppler sonography and subsequent reference methods ranged from 0 to 8 days, with a median of 5 days.
We performed digital subtraction angiographic portography on an Integris 3000 (Philips Medizinsysteme, Hamburg, Germany) after an injection of 35 mL of iopamidol (Solutrast 300; Byk Gulden, Konstanz, Germany) with a flow rate of 5 mL/sec via the superior mesenteric artery and the splenic artery. Helical CT (Somatom Plus 4; Siemens, Erlangen, Germany) included two phases, 20 and 70 sec after 150 mL of IV injected iopromid (Ultravist 300; Schering) (3 mL/sec). Scan parameters were 5 mm each for slice thickness, table movement, and reconstruction. MR angiography studies were performed on a 1.5 T system (Gyroscan ACS NT; Philips Medical Systems, Best, The Netherlands) equipped with 2 mT/m gradients with a slew rate of 23 mT/m per msec. The pulse sequence used was a three-dimensional fast low-angle shot sequence in which slab-reflective radiofrequency excitation is followed by a series of gradient-recalled echos. This 70-sec slice sequence was repeated three times with a dynamic resolution of 20 sec. Imaging parameters were as follows: TR/TE, 44-1.2; flip angle, 40°; in-plane resolution, 1.8 mm; field of view, 450 mm; matrix, 163 x 512. We injected 40 mL of gadopentetate dimeglumine (Magnevist; Schering) with a flow rate of 8 mL/sec. Data from each of the three acquisitions were processed with a maximum-intensity-projection algorithm.
Statistical Analysis
For statistical calculations we used a statistical analysis software
package (Statistical Package for the Social Sciences, Chicago, IL). Wilcoxon's
signed rank test compares diagnostic confidence scores before and after
Levovist infusion. Results are shown as mean ± standard deviation. A
p value of less than 0.05 (two-sided) is considered statistically
significant.
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Protocol 2
In accordance with the inclusion criteria, none of the patients had an
unenhanced color Doppler baseline sonogram that was diagnostic (DCS 2),
whereas color Doppler sonography was nondiagnostic (DCS 0) in 19 patients and
with a low confidence level (DCS 1) in 11 patients. While we infused Levovist,
DCS remained unchanged in two patients but increased in 28 patients
(Wilcoxon's signed rank test, p < 0.001); color Doppler sonography
was nondiagnostic in two patients (DCS 0), with a low confidence level in five
patients (DCS 1) and with a high confidence level in 23 patients (DCS 2). In
10 of 19 patients, a nondiagnostic color Doppler sonogram at baseline (DCS 0)
changed to a high confidence level (DCS 2) after echo enhancement.
In two of 28 patients, echo-enhanced color Doppler sonographic findings were different from those obtained by the reference methods. Color Doppler sonography and the reference method diverged in their interpretation of small and tortuous extrahepatic vessels (i.e., original portal vessels or spontaneous collateral vessels) and irregular intrahepatic venous vessels. In one patient, the color Doppler sonographic pattern of a jet stream in the portal vein, caused by compression of an enlarged head of the pancreas, suggested a prehepatic form of portal hypertension in color Doppler sonography but not in the CT scan.
Figure 2A,2B,2C shows how the Levovist infusion allowed the differentiation between total and subtotal portal vein thrombosis in a patient who presented with an acute variceal bleeding after TIPS insertion. Figure 3A,3B,3C shows the ability of contrast-enhanced color Doppler sonography to proof perfusion in a surgical splenorenal Cooley shunt that could not be detected by the unenhanced baseline examination.
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Various comparative studies confirmed color Doppler sonography as a reliable tool to depict the portal vascular anatomy and perfusion and the patency of artificial portosystemic shunts [2, 9,10,11,12,13]. However, color Doppler sonography is nondiagnostic in a considerable number of patients with portal hypertension because of insufficient B-mode images and poor color Doppler signals [3].
The galactose-based microbubble contrast agent Levovist increases Doppler echo intensity [4] and improves diagnostic confidence for the portal vascular system [5, 6]. However, the applicability of the bolus injection for portal vessels has two major limitations. First, the short signal enhancement of less than 5 min after the bolus injection does not allow the entire portal vascular system to be scanned, resulting in repeated injections [6]. Second, undesired artifacts during the peak echo enhancement after the injection, such as blooming, have a negative effect on the image quality and consequently on the diagnostic confidence. Both limitations might be overcome with a more prolonged application as suggested by Albrecht et al. [7]. However, these data were obtained in superficial vessels. The clinical feasibility of the continuous infusion for color Doppler sonography of deeply located abdominal vessels in terms of infusion rate, diagnostic window, and gain in diagnostic confidence remains to be established.
In a pilot study, we determined the diagnostic window of the Levovist infusion as the time when a primarily obscured confluence of the portal vein was detectable by means of color Doppler sonography. Echo-enhanced color Doppler sonography was performed immediately after the baseline examination to rule out spontaneous improvement of visibility of the portal vein caused by variability of the bowel gas distribution. We chose an infusion rate of 300 mg/min that allowed us to inject one 4-g vial of Levovist in approximately 11 min. The Levovist dose and concentration were the lowest shown to have been effective by Albrecht et al. [7], and the infusion time equals the proven time of stability of Levovist. This infusion achieved a diagnostic window for the portal vein during a 13-min time interval. The portal vein was not detectable by gray-scale sonography throughout the observation time; only a color Doppler signal could be obtained during the Levovist infusion. A possible explanation could be that Levovist overcomes acoustic shadowing frequently caused by bowel gas.
This finding from the confluence of course cannot be transferred to the entire portal vascular system. Smaller and deeper located vessels may remain undetectable. The results from protocol 1 encouraged us to evaluate the clinical impact comparing the color Doppler sonographic diagnoses with the correlative findings. The continuous Levovist infusion enabled color Doppler sonography to establish a confirmed diagnosis in most patients, whereas without the infusion, this was not achieved in any of the patients at baseline conditions. Besides bowel shadowing, color Doppler sonography may be impaired by low blood flow volumes in small, irregular, and deeply located vessels. It is difficult to decide which phenomenon is causative in the individual patient. In general, in patients in whom a positive grayscale B-mode image can be obtained, the failure of color Doppler sonography is more likely a result of deeply located vessels and low blood flow volumes, whereas abdominal gas hinders both color Doppler sonography and B-mode imaging. In our study, Levovist probably improved color Doppler imaging in both conditions.
The use of echo-enhanced color Doppler sonography provides distinct advantages. It is noninvasive and less expensive than CT and MR imaging and can therefore be repeated at any time. In patients with an impaired renal function, a frequent complication from liver cirrhosis, sonography avoids the use of radio-contrast agents. Finally, with our experience, echo-enhanced color Doppler sonography seems to provide some advantages over reference methods in detecting small collaterals with very low blood flow velocities, in detecting retrograde or oscillating flow, and in interpreting jet phenomena using the color-coded velocity scale.
The changes in the diagnostic confidence from baseline, which were recorded by a single investigator, might be a possible source of interpretive bias. However, it is a consistent finding that the echo enhancement after Levovist injection results in an improved conspicuity of the portal vein and an increase in the investigator's confidence [5, 6].
To date, no prospective data have shown that power Doppler sonography is superior to conventional color Doppler sonography in the evaluation of the extrahepatic portal vascular system in patients with portal hypertension. Furthermore, in our experience, the use of power Doppler sonography in deep abdominal vessels is limited by artifacts, particularly in cirrhotic patients. We therefore refrained from a comparison between echo-enhanced color Doppler and power Doppler sonography in this study.
Prospective trials have already shown that the use of sonographic contrast media can provide additional information for the sonographic surveillance of patients with TIPS [14,15,16]. Observations from our limited number of patients with TIPS are well in line with the conclusion of these trials. In a small subgroup of patients, in whom the perfusion not only in the stent but also in the portal vascular system remains questionable, the prolonged echo enhancement achieved by the continuous Levovist infusion might have an additional benefit. In Figure 2A,2B,2C, we give a corresponding example of patients with obvious TIPS dysfunction in whom the additional information after contrast enhancement was that the portal vein thrombosis was subtotal with a slim perfusion remaining.
In contrast to what has been published about the bolus injection, in all of our patients, the infusion of one 4-g vial of Levovist was sufficient to accomplish the color Doppler sonographic examination and to avoid further invasive or expensive diagnostic procedures. It was not the aim of this feasibility study to estimate the percentage of patients in whom echo enhancement is necessary to establish a diagnosis by means of color Doppler sonography. This question can only be answered in a larger prospective trial. Further studies will also optimize infusion rates and intermittent injections for different vascular regions. Such study protocols, however, require adequate pump injectors.
In conclusion, the continuous infusion of Levovist provides an echo enhancement potent enough to visualize the portal vascular system and a prolongation of the observation period sufficient to assess the perfusion in the entire portal vascular system and to establish a valid diagnosis by means of color Doppler sonography. We therefore recommend the use of a continuous infusion of the sonographic contrast agent in all patients with portal hypertension in whom color Doppler sonography is primarily nondiagnostic.
Acknowledgments
We thank R. Fimmers, the Statistical Institute, University of Bonn, for
statistical advice; R. König, the Radiology
Department, University of Bonn, for preparing the pictures for publication;
and D. Bammer for her expert technical assistance.
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