British Journal of Radiology (2006) 79, 44-51
© 2006 British Institute of Radiology
doi: 10.1259/bjr/23954854
Diagnostic efficacy of SonoVue®, a second generation contrast agent, in the assessment of extracranial carotid or peripheral arteries using colour and spectral Doppler ultrasound: a multicentre study
P S Sidhu, FRCR1,
P L Allan, FRCR2,
F Cattin, MD3,
D O Cosgrove, FRCR4,
A H Davies, MD5,
D D Do, MD6,
S Karakagil, MD7,
J Langholz, MD8,
D A Legemate, MD, PhD9,
A Martegani, MD10,
J-B Llull, MD11,
C Pezzoli, PhD12 and
A Spinazzi, MD11
1 Department of Radiology, King's College Hospital, Denmark Hill, London SE5 9RS, UK, 2 Department of Radiology, Edinburgh Royal Infirmary, Edinburgh, Lothian, UK, 3 CHU de Besancon, Service de Radiologie B, Boulevard Fleming, F-25030 Besancon, Belgium, 4 Department of Imaging, Royal Postgraduate Medical School, Hammersmith Hospitals Trust, Du Cane Road, London W12 OHS, UK, 5 Department of Surgery, Imperial College School of Science, Technology & Medicine, Charing Cross Hospital, Fulham Palace Road, London W6 8RP, UK, 6 Inselspital-Division of Angiology, Department of Internal Medicine, University of Berne, Freiburgstarsse 10, 3010 Berne, Switzerland, 7 Department of Surgery, Uppsala University Hospital, Akademiska sjukhuset, 75185 Uppsala, Sweden, 8 Schwerpunktpraxis für Angiologie, Wilsnacker Stra
e 14, 10559, Berlin, Germany, 9 Department of Vascular Surgery, Academic Medical Centre, Meibergdreef 9, NL-1105 AC DE Amsterdam, The Netherlands, 10 Servizio di Radiologia, Ospedale Valduce, Via Dante Alighieri, 11, 22100 Como, Italy, 11 Bracco Diagnostics Inc., 107 College Road East Princeton, Princeton, NJ 08540, USA and 12 Bracco Imaging SpA, Via E. Folli 50, 20134 Milan, Italy
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Abstract
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The purpose of this study was to demonstrate the improvement in diagnostic quality and diagnostic accuracy of SonoVue® microbubble contrast-enhanced ultrasound (CE-US) versus unenhanced ultrasound imaging during the investigation of extracranial carotid or peripheral arteries. 82 patients with suspected extracranial carotid or peripheral arterial disease received four SonoVue doses (0.3 ml, 0.6 ml, 1.2 ml and 2.4 ml) with Doppler ultrasound performed before and following each dose. Diagnostic quality of the CE-US examinations was evaluated off-site for duration of clinically useful contrast enhancement, artefact effects and percentage of examinations converted from non-diagnostic to diagnostic. Accuracy, sensitivity and specificity were assessed as agreement of CE-US diagnosis evaluated by an independent panel of experts with reference standard modality. The median duration of clinically useful signal enhancement significantly increased with increasing SonoVue doses (p
0.002). At the dose of 2.4 ml of SonoVue, diagnostic quality evaluated as number of inconclusive examinations significantly improved, falling from 40.7% at baseline down to 5.1%. Furthermore, SonoVue significantly (p<0.01) increased the accuracy, sensitivity and specificity of assessment of disease compared with baseline ultrasound. SonoVue increases the diagnostic quality of Doppler images and improves the accuracy of both spectral and colour Doppler examinations of extracranial carotid or peripheral arterial disease.
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Introduction
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Colour and spectral Doppler ultrasound examination of the peripheral [1, 2] and extracranial carotid [3, 4] arterial systems is a well established non-invasive method of assessment of arterial disease. Frequently, Doppler ultrasound replaces conventional angiography with the associated cost savings and reduction in patient morbidity [5–8]. However, Doppler ultrasound does not always provide a full diagnostic assessment and there is no alternative but to seek confirmatory evidence of arterial disease with conventional angiography and increasingly with helical CT angiography and MR angiography [9–12]. A number of factors preclude a full Doppler ultrasound examination of a vessel: heavily calcified plaque causes acoustic shadowing, a deep-seated artery returns a poor echo-signal and vessel tortuosity precludes a satisfactory Doppler angle for accurate velocity measurements. In order to improve the diagnostic capability of a Doppler ultrasound examination of the peripheral and carotid arteries, introducing an echo-enhancing agent would be expected to facilitate visualization of difficult arteries, thus overcoming inherent problems associated with ultrasound, and ultimately reducing unnecessary invasive and expensive diagnostic procedures.
SonoVue® is the trademark name of a new ultrasound contrast agent (BR1, Bracco, Italy) [13]. SonoVue is a suspension of phospholipid stabilized sulphur hexafluoride (SF6) microbubbles. When reconstituted with normal saline the product is stable at room temperature for several days, but should be used after reconstitution within 6 h as the product contains no preservative [14]. Reconstitution produces a high microbubble concentration (up to 5 x 108 microbubbles ml–1), a favourable size (90% of microbubbles smaller than 8.0 µm, mean diameter 2.5 µm) and strong echogenicity over the range of frequencies used in medical ultrasound examinations [15]. The microbubbles produced are not trapped in the capillary vasculature, and the use of SF6 (an innocuous gas) renders the microbubbles more resistant to pressure increases from the left ventricle of the heart, increasing microbubble survival. SonoVue demonstrates a maximum backscatter coefficient at about 3 MHz and an elimination half-life of approximately 6 min. More than 80% of the compound is exhaled via the lungs in 11 min [16].
The efficacy of SonoVue in extracranial carotid or peripheral arterial disease was evaluated in a multicentre study where the quality end-points were as follows: to ascertain the optimal dosage with regard to global quality of images, to assess the duration of microbubble contrast effect, to aid the interpretation of diagnostically difficult colour and spectral Doppler ultrasound examinations and to evaluate the potential of contrast-enhanced ultrasound (CE-US) to change a non-diagnostic ultrasound examination into a diagnostic examination. In a subset study population, the diagnostic accuracy, sensitivity and specificity of SonoVue enhanced Doppler investigations were evaluated in terms of agreement of CE-US examinations in comparison with other recognized diagnostic imaging modalities.
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Material and methods
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The overall study consisting of two (study A and B) parallel multicentre studies was aimed at investigating, with Doppler ultrasound and SonoVue, different vascular territories: renal, abdominal, cerebral, extracranial carotid or peripheral arteries, and the portal circulation.
We refer here to the results pertaining to extracranial carotid or peripheral arteries. Local Medical Ethics Committees granted approval for the study at each hospital site according to local legal requirements and the study was conducted in accordance with the Declaration of Helsinki and European Good Clinical Practice. All patients recruited gave written informed consent.
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Study population
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The study population comprised 82 male and female patients, over 18 years of age, with a suspected vascular pathology, referred for Doppler ultrasound investigations of carotid, iliac, femoral, popliteal or tibial arteries and for whom the observers could not make an interpretation with confidence at baseline unenhanced colour and spectral Doppler ultrasound examination. The main criteria for patient exclusion from the study were: severe congestive heart failure (New York Heart Association Class IV); unstable angina; severe cardiac arrhythmia; recent myocardial infarction; recent organ transplant or unstable neurological disease. Lactating women or women known or suspected to be pregnant were excluded. Patients were also excluded if they were critically ill, medically unstable or were in an intensive care setting. Patients receiving another investigational drug within 30 days prior to the study were not recruited.
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Study design
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The study was a multicentre, open-label (on-site), blinded (off-site), randomized, dose-ranging, cross-over study to compare four different doses of SonoVue (0.3 ml, 0.6 ml, 1.2 ml, and 2.4 ml) in Doppler ultrasound investigations of extracranial carotid (22 patients) or peripheral arteries (60 patients). Patients were randomized to one of four dose sequences, according to a randomization schedule with block size 4. The SonoVue doses were administered as an intravenous bolus injection over 20 s via a 20 gauge cannula (Introcan-W; Braun Melsungen AG, Germany) placed in the forearm. All centres employed the standard ultrasound machine used for routine colour Doppler ultrasound vascular examinations within the department. A variety of ultrasound machines were used, depending on the centre. Once the optimum colour and spectral Doppler ultrasound parameters were set for each patient at the baseline examination to extract maximum information (with the gain turned down to the lowest informative level), the parameters were unaltered for the remainder of the CE-US examination. For each patient, a vessel of interest was designated for further investigation, based on the vessel that would most likely drive the patient's diagnosis. Doppler ultrasound investigations of the designated vessel were performed at baseline and after each injection of SonoVue, with Super-Video Home System (S-VHS) videotape recording of images beginning 30 s prior to injection and continuing until the end of the microbubble contrast effect. At each time point, the designated vessel was studied first with either colour Doppler ultrasound or power Doppler ultrasound (only one mode was used for each patient depending on investigator choice), and then with spectral Doppler imaging. All SonoVue administration and imaging procedures were completed on the same day. The interval between administrations of the different doses was at least 10 min or until disappearance of the microbubble contrast effect from the previous administration.
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Assessments
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Four independent experienced readers, paired for each of the studies (A and B) and unaffiliated with the study sites performed an off-site assessment of the recorded ultrasound images. These readers were blinded to study agent dose (whether baseline or post-dose), and patient information, including results of other imaging procedures. The S-VHS videotape recordings were divided into sets consisting of four post-injection images, one for each of the four SonoVue injection doses, plus the baseline images. Within each image set, an assigned random code number determined the order of presentation of patient images to the off-site readers. The off-site readers were provided with the identification of the vessel under investigation for each video sequence. Following completion of these unpaired assessments, the baseline and corresponding post-injection images for each dose of SonoVue in each patient were then assessed in matched pairs. For patients with an available reference diagnostic modality (conventional angiography, MR angiography or CT angiography) from which a diagnosis could be ascertained (on-site), a committee of three experienced physicians (Accuracy Review Committee) unaffiliated with the study sites compared the diagnosis obtained by the off-site assessments of Doppler ultrasound images with the diagnosis obtained with the reference modality.
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Diagnostic quality
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Duration of clinically useful signal enhancement, defined as the time from appearance until disappearance of a microbubble contrast effect of sufficient intensity to be diagnostically or clinically useful, was assessed and documented by each off-site observer subjectively during review of the video recordings of the individual examinations.
Incidence and duration of artefactual microbubble contrast effects (shadowing, blooming and saturation effects) were assessed following each dose of SonoVue. Artefacts were defined as follows: a shadowing effect appeared as an obscured image and/or Doppler spectrum, blooming appeared as the presence of colour in an area without flow, while a saturation effect appeared as a noisy Doppler spectrum with artificially high velocities [17]. Duration was evaluated from the actual time of appearance to the disappearance of shadowing and/or blooming and/or saturation effects. Each of the artefacts was evaluated at their maximal effect in accordance with the following three-point scale: 0=no artefactual effect; 1=artefactual effect not compromising the image analysis; 2=artefactual effect compromising the image analysis.
Assessment of inconclusive Doppler examinations was performed on each baseline or post-injection video clip where off-site readers had to assess if a diagnosis was possible or not and, in patients where it was possible, make a diagnosis based on a pre-defined check list.
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Diagnostic accuracy
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Diagnostic accuracy was assessed for baseline and for the clinically recommended dose of SonoVue only (2.4 ml).
Assessment of agreement was carried out by an Accuracy Review Committee, based on a comparison of the diagnosis recorded by each of the off-site blinded readers from the Doppler ultrasound investigations with the diagnosis from the reference imaging modality. The following four-point scale was used: 1=full agreement; 2=basic agreement (differences in details but leading to the same diagnostic conclusion); 3=partial agreement (differences in details possibly leading to a different diagnostic conclusion); 4=disagreement.
Sensitivity and specificity
For the evaluation of the diagnostic performance of SonoVue CE-US in terms of sensitivity and specificity, it was necessary to further define agreement with the reference modality in terms of detection/exclusion (presence/absence) of particular lesions in the investigated vessels for each study patient. An independent experienced radiologist, not previously involved in these studies, was asked to classify the Doppler ultrasound off-site diagnoses and the reference modality diagnoses according to the following predetermined list of possible diagnoses for the designated vessel of interest: (1) no abnormality; (2) abnormality present: (a) stenosis > 50% or occlusion; (b) atheromatous plaque; (c) arteriovenous malformation; (d) aneurysm; (e) vessel displacement/compression due to extrinsic space-occupying mass; (f) collaterals or collateralization of normal vessels; (g) arterial wall dissection; (h) other. Sensitivity was defined as the proportion of patients with a matching abnormality in the vessel of interest using Doppler ultrasound and patients with an abnormality in the vessel of interest using the reference standard. Specificity was defined as the proportion of patients with no abnormality in the vessel of interest using Doppler ultrasound and patients with no abnormality in the vessel of interest using the reference standard.
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Statistical methods
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Demography
Demographics and other baseline characteristics were summarized using descriptive statistics.
Efficacy analysis
An analysis of variance (ANOVA) using ranked durations of clinically useful signal enhancement was performed to investigate overall differences between doses. Summary statistics, frequency distributions and cross-tabulations were elaborated for efficacy parameters, but no formal statistical analyses were performed. For the purposes of statistical summaries from the assessment by the Accuracy Review Committee, these data were further categorized as follows: agreement denoted full agreement or basic agreement, and disagreement denoted partial agreement or disagreement. Individual study results for diagnostic accuracy were analysed using McNemar's test of association between baseline and post-dose in the proportion of patients for whom agreement was recorded. For all analyses, a two-sided p-value was used to test for significance.
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Results
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Eighty-two patients (study A, n=43; study B, n=39), 49 male and 33 female subjects, median age of 71 years (range 41–87 years), with suspected extracranial carotid artery or peripheral vascular disease were recruited and received SonoVue for the assessment of diagnostic quality parameters. The diagnostic accuracy assessment was performed on 59 patients where final diagnosis made from a reference imaging modality (conventional angiography/CT angiography n=58 and MR angiography n=1) was available for assessment by the Accuracy Review Committee.
At Doppler examination 32 of 59 were found positive and 27 of 59 were negative for the presence of pathology.
Sensitivity and specificity were calculated in the subset of patients (n=46) where the reference standard with the pathology or no pathology in the vessel of interest was available for assessment (n=22 and 24 patients, respectively, for the two studies).
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Diagnostic quality
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Duration of signal enhancement
A statistically significant dose response was observed in the duration of clinically useful signal enhancement with a significant increase in the median duration across the doses (p<0.001 for 3 readers and p=0.002 for 1 reader). At the highest SonoVue dose of 2.4 ml, the average median duration of clinically useful signal enhancement was of 3.9 min, range 0.0–14.3 (Table 1
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Table 1. Duration of clinically useful signal enhancement in the two studies combined (A and B) from the off-site evaluation
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The pair of off-site reader assessments for each patient was combined by calculating the average duration of clinically useful signal enhancement.
Artefactual effects
Due to methodology which did not permit gain adjustment, a dose response was observed in the incidence and duration of artefactual contrast effects, with median values increasing up to a maximum of 3.6 min at the 2.4 ml dose. The most common artefactual effects were blooming in colour or power Doppler ultrasound (up to 92.9% with the 2.4 ml dose) followed by a saturation effect on spectral Doppler ultrasound. Both of these artefacts are related to the increase in Doppler signal intensity caused by the microbubble contrast agent (Figure 1). Shadowing was not reported to be a significant microbubble contrast artefactual effect by any of the four off-site readers.
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Figure 1. Illustration of the "blooming" artefact. (a) Following the administration of SonoVue 1.2 ml, extensive blooming at 36 s obscures the arterial anatomy precluding diagnostic interpretation. (b) Without adjustment of the ultrasound machine imaging parameters, at 63 s blooming has subsided and there is better delineation of the arterial anatomy.
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Assessment of inconclusive Doppler ultrasound examinations
Despite the limitations of the methodology used in this study, the results of the statistical analysis performed showed that, at the dose 2.4 ml, which is recommended for Doppler ultrasound of macrovasculature, SonoVue markedly decreased the number of baseline inconclusive Doppler ultrasound examinations (rated as "no diagnosis possible"). Considering the entire population, the percentage decreased from 40.7% to 7.4% (decrease=33.3%) while, in the patient population with a reference gold standard control, the percentage decreased from 45.8% to 5.1% (decrease=40.7%) (Figure 2).
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Figure 2. Bar chart diagram demonstrating the alteration in the number of inconclusive off-site Doppler ultrasound assessments at the dose of 2.4 ml of SonoVue (entire population: all patients in the study, n=82; population with ref. std: patients with the reference gold standard, n=46).
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Assessment of diagnostic accuracy
The percentage of agreement between diagnosis from Doppler ultrasound investigations and diagnosis from the reference imaging modality in the entire patient population increased from 30.7% at baseline to 68.9% post-contrast (Table 2).
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Table 2. Diagnostic accuracy. Percentage agreement between diagnosis from Doppler ultrasound investigations (both unenhanced and SonoVue microbubble contrast-enhanced) and diagnosis from the reference standard in the entire population
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The change in agreement rates from baseline was statistically significant for three of the four off-site readers (range p<0.05–0.001). Furthermore, considering the subset of patients whose investigation was diagnostic and the reference standard imaging modality available, agreement between the Doppler ultrasound diagnosis and the diagnosis from the reference imaging modality further increased to 72.3% after microbubble contrast administration (Figure 3).
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Figure 3. (a) Baseline unenhanced colour and spectral Doppler ultrasound examination of a patient right lower limb. Insufficient information for a firm conclusion about patency of the anterior tibial artery. (b) Following the administration of 2.4 ml of SonoVue, clear depiction of a patent anterior tibial artery is seen (long arrow) with a large collateral artery seen in a superior position (short arrow). (c) Spectral Doppler contrast ultrasound confirms a monophasic abnormal arterial trace. (d) Corresponding arteriogram confirms the patent anterior tibial artery (long arrow) and the collateral artery (short arrow). Collateral arteries have formed around an occluded popliteal artery. (Courtesy of Dr J Langholz).
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Diagnostic performance, in terms of sensitivity and specificity, was assessed in the subset of patients (n=46) with an abnormality or no abnormality in the vessel of interest on the available reference gold standard examinations. In study A, in the eight patients with an abnormality in the carotid/peripheral vessel of interest on the reference standard modality, the sensitivity increased from 13% pre-contrast to 75% at the 2.4 ml dose for reader 1 and from 50% to 75% for reader 2 (Table 3).
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Table 3. Sensitivity and specificity of Doppler ultrasound investigations based on diagnosis from the reference gold standard
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In the 16 patients with no abnormality on the reference modality, specificity increased from a pre-contrast value of 0% to 85 % at 2.4 ml for reader 1 and from 31% to 75% for reader 2. In study B, in the nine patients with an abnormality on the reference modality, the sensitivity increased from 89% pre-contrast to 100% at the 2.4 ml dose for reader 3 and increased from 22% to 67% for reader 4. In the 13 patients with no abnormality on the reference modality, specificity increased from a pre-contrast value of 23% to 46% at 2.4 ml for reader 3 and from 8% to 85% for reader 4.
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Discussion
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Failure to obtain a diagnostic colour Doppler ultrasound examination of the extracranial carotid and peripheral arteries is typically a consequence of patient factors. Rather than abandon the colour Doppler ultrasound examination instituting another examination, with the implications of higher cost, the introduction of a microbubble contrast agent would enable the examiner to attempt to establish a conclusive diagnosis and reduce the amount of time necessary to perform a peripheral arterial examination. In the present study, a significant dose effect was observed for the duration of clinically useful signal enhancement for all four off-site readers; the average median duration of useful enhancement was of 3.91 min for the 2.4 ml dose. Due to a conservative approach in the study design, the incidence and duration of artefactual microbubble contrast effects also tended to increase with increasing dose. These artefacts can normally be limited by reducing the effective sensitivity of the system, by decreasing the colour or power and spectral Doppler ultrasound gains. Indeed, in order to maximize Doppler quality, gain settings for both colour or power and spectral Doppler ultrasound should be continuously adjusted as enhancement returns to baseline. However, in this study the protocol required that the level of the gain for both colour or power and spectral Doppler be set before the first injection of microbubble contrast and could not be modified after that. With gain adjustment, the duration of artefacts would have been greatly reduced if not completely eliminated and, as a result, the duration of clinically useful signal enhancement would have been increased. Moreover, now there is a tendency to use infusions rather than bolus injection of microbubble contrast during the investigation of vascular disease. This has been demonstrated to further improve the duration of useful enhancement and reduce artefactual effects in the extracranial carotid and peripheral arteries [18], in transcranial Doppler ultrasound [19] and in the portal vein [20, 21].
Administration of microbubble contrast resulted in an increase in agreement between colour Doppler ultrasound diagnosis and diagnosis from a reference imaging modality. This is of importance where full reliance can be placed on the results of a colour Doppler ultrasound examination in order to bypass angiography prior to any surgical procedure, particularly in carotid end-arterectomy surgery [5] where there is a small but significant morbidity attached to diagnostic angiography [22]. The effect of introducing a microbubble contrast agent, the "Doppler rescue" effect, has been successful in the imaging of the renal arteries [23], the hepatic artery in the liver transplant patient [24, 25] and the portal vein [20, 26, 27]. In the assessment of renal artery disease, using a galactose based microbubble contrast agent (LevovistTM; Schering AG, Berlin, Germany), visualization of the renal arteries improved from 65.7% to 78.3% (p<0.01) following the administration of microbubble contrast [23]. The use of SonoVue in the present study improved the ability of all the off-site readers, presented with a minimum amount of information, to make a confident interpretation of the underlying vascular disorder on the CE-US examination. On the baseline ultrasound examinations, a correct diagnosis confirmed by the standard of reference was achieved in 29.7% of studies, improving to 67.6% with the 2.4 ml dose of SonoVue. Moreover, if accuracy is evaluated in the subset of patient population with diagnostic examinations, a further increase in the percentage of agreement with reference gold standard is observed after SonoVue (72.3%) compared with unenhanced examinations. There was an overall improvement in sensitivity and specificity for all the off-site readers. The ability shown by SonoVue to improve the diagnostic information from a recorded ultrasound examination, having knowledge of the vessel of interest only, is remarkable since in the clinical practice the nature of any ultrasound examination is one of examiner-patient interaction, where the physician is allowed to develop an overall concept of the diagnosis. This would suggest that the use of a microbubble contrast agent as part of an on-site ultrasound assessment would improve the diagnostic ability to an even greater degree than what appeared under the investigational conditions of the present study.
One limitation of the current study is the level of sophistication of the ultrasound machines used. When this multicentre study was commenced, each centre was equipped with a "top-of-the-range" ultrasound machine, but during the course of the study introduction on the market of newer machines with digital capability, more sensitive to blood flow, was seen to improve vascular ultrasound diagnosis. Nevertheless, even with the improved capabilities of these newer ultrasound machines, problem patients will still exist and the need for "Doppler-rescue" with microbubble contrast will still be advantageous to reduce the need for further imaging. The quality and standard of the on-site colour Doppler ultrasound examinations were dependent on the experience of the examining sonographer, with likely variation between the centres involved in the study. Accepting centres with an established reputation for vascular ultrasound and ensuring that only the most experienced sonographers performed the examination minimized this variation. Not all of the patients had an acceptable standard of reference imaging examination, but even in the smaller number where this was available, addition of microbubble contrast improved the diagnostic capability of the colour Doppler ultrasound examination. The variation in the assessment of the baseline colour Doppler ultrasound examinations by the off-site investigators highlights the difficulties of ultrasound interpretation and the subjective nature of conclusions reached. However, addition of microbubble contrast, although not completely eliminating this subjectivity, dramatically improved the confidence in interpretation allowing the off-site investigator to establish the correct diagnosis more consistently.
In conclusion, at the dose of 2.4 ml of SonoVue, the duration of useful enhancement achieved, which may be further extended by adjustment of the ultrasound machine settings, allowed a sufficiently prolonged period to establish a definitive diagnosis avoiding further imaging. Further studies to evaluate the potential use of infusion methods of SonoVue administration are needed; these may have advantages over bolus methods of administration. The use of SonoVue allowed an improvement in diagnostic accuracy to be achieved in comparison with an accepted reference examination. The administration of 2.4 ml dose significantly produces an overall improvement in terms of diagnostic performance. Microbubble ultrasound contrast represents the next stage of development, following on from the introduction of duplex Doppler and colour Doppler ultrasound, in the improving the overall diagnostic capability of ultrasound in the vascular system.
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Acknowledgments
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We wish to thank Dr Franca Heiman for her statistical assistance.
Received for publication May 6, 2005.
Accepted for publication June 9, 2005.
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Abstract
Introduction
