European Journal of Vascular & Endovascular Surgery
Volume 25, Issue 1 , Pages 23-28, January 2003

Ultrasound contrast-agent improves imaging of lower limb occlusive disease

Departments of 1Vascular Surgery and 2Radiology, Rigshospitalet, Copenhagen, Denmark

Accepted 7 October 2002.

*Please address all correspondence to: J. P. Eiberg, Department of Vascular Surgery, Rigshospitalet 3111, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark.

Article Outline

Abstract 

Objectives: to evaluate if ultrasound contrast-agent infusion could improve duplex-ultrasound imaging of peripheral arterial disease (PAD) and increase the agreement with digital subtraction arteriography (DSA). Design: prospective and consecutive study. Material: of 60 consecutive PAD patients, 15 were found to have an inconclusive duplex-ultrasound scan of the trifurcation and were included in the study. All 15 patients (53% male) were scheduled for DSA, all being candidates for vascular surgery due to claudication (n = 3, 20%), rest pain (n = 5, 33%) and tissue loss (n = 7, 47%). Methods: on the day before DSA, a duplex-ultrasound scan of the trifurcation was performed. If the duplex-ultrasound scan was found inconclusive, it was repeated during continuous ultrasound contrast-agent infusion. DSA was performed unaware of the duplex-ultrasound results and served as the gold standard. Results: after contrast-agent administration, the number of inconclusively diagnosed segments was significantly reduced by 26 (70%), from 37 to 11(p < 0.001). In 19 segments (73%) contrast-agent infusion changed the diagnosis in accordance with the DSA (p < 0.05). Values of sensitivity and positive predictive value were improved from 0.20 (0.04–0.62) to 0.47 (0.26–0.69) and 0.50 (0.10–0.91) to 0.80 (0.49–0.93), respectively. Specificity and negative predictive value were unchanged. Agreement between duplex-ultrasound and DSA were improved from poor (κ = 0.18 (95% CI: 0–0.82)) to moderate (κ = 0.45 (0.17–0.74)) (p = 0.44). Conclusion: ultrasound contrast-agents improve the diagnostic ability of duplex-ultrasound when scanning difficult arterial segments in patients suffering from PAD.

Eur J Vasc Endovasc Surg 25, 23–28 (2003)

Keywords:  Ultrasonography, Duplex-ultrasound scanning, Doppler, Ultrasound contrast-agent, Levovist®, Peripheral arterial diseases, Vascular surgery, Angiography, Lower limb occlusive disease

 

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Introduction 

In most vascular centres, digital subtraction arteriography (DSA) is the preferred “gold standard” for diagnostic imaging prior to arterial reconstruction, although invasive and associated with a small but constant risk of major complications of 2%.1 Within the last decade, duplex-ultrasound arterial scanning has increasingly been used in examination of peripheral arterial disease (PAD). Diagnostic imaging in PAD can be obtained both above and below the knee and comparative studies have demonstrated that the diagnostic ability of duplex-ultrasound is similar to that of digital subtraction arteriography (DSA).2, 3, 4, 5, 6, 7 Though sensitivity and specificity are close to 100%, a small but not negligible percentage of patients are poorly imaged with duplex-ultrasound.2, 5, 8

Duplex-ultrasound of the trifurcation in PAD is difficult, and suboptimal visualization commonly occurs–probably due to the small size and deep course of the vessels as well as low inflow pressure in patients with multilevel occlusive disease.

These technical limitations have been challenged by the introduction of ultrasound contrast-agents, having the capability to increase the strength of the returning signal. In the few available clinical studies, ultrasound contrast-agents were found to increase the signal to noise ratio from the iliac, femoral, renal and intracranial arteries–although the clinical impact is largely uncertain.9, 10, 11 No studies yet have compared contrast-agent enhanced duplex-ultrasound with DSA in PAD-patients nor evaluated continuous contrast-agent infusion.

The aim of the present study was to prospectively assess the augmentation of diagnostic ability after ultrasound contrast-agent infusion in patients with PAD, all being possible candidates for arterial reconstruction.

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Material and methods 

Patients 

During a 10-month period, 60 legs of 60 consecutive patients had a routine duplex-ultrasound scanning of the lower limb performed due to PAD (SVS-ISCVS category 3–5).12 Of these, 15 patients had an inconclusive duplex-ultrasound scanning of the trifurcation and were enrolled in the study. All patients were possible candidates for elective surgery and scheduled as inpatients for a routine arteriography. Patients characteristics are listed in Table 1.

Table 1. Patients characteristics of the study- and reference-population.
CharacteristicsStudyReferencep value
Median age (range), years72 (51–87)71 (41–89)n.s.
Male sex8 (53%)65 (68%)n.s.
Ankle blood pressure (range), mmHg50 (25–100)60 (0–170)n.s.
Ankle-brachial pressure index (range)0.36 (0.18–0.62)0.40 (0–1.13)n.s.
Symptoms
Claudication (SVS/ISCV: 3)3 (20%)23 (25%)
Rest pain (SVS/ISCV: 4)5 (33%)30 (33%)n.s.1
Tissue loss (SVS/ISCV: 5)7 (47%)39 (42%)
Diabetes (type I and II)6 (40%)31 (34%)n.s.
End stage renal disease (in dialysis)1 (7%)2 (2%)n.s.
1p-value was calculated for differences in proportions (claudication/rest pain/tissue loss).

n.s.: Not significant.

In order to compare the study-group with the background PAD-population, a recent published series of 94 PAD-patients served as a reference-group.13 The local ethical committee approved the study and informed consent was obtained form each patient.

Colour duplex-ultrasound arterial scanning 

The same physician performed all duplex-ultrasound examinations on the day before arteriography. For descriptive reasons, the trifurcation was divided into four individual segments: the tibioperoneal trunk and the origin (the most proximal first centimetre) of the three crural arteries–the anterior tibial artery, the posterior tibial artery and the peroneal artery. The examination of the trifurcation was only considered conclusive if all four segments could be identified–either by detection of a colour signal or by identification of a vessel-wall if the segment was occluded. Before and after contrast-agent administration all four arterial segments were classified as significantly diseased (diameter reduction 50% and occlusions), nonsignificantly diseased (diameter reduction < 50%) or inconclusive. In order to separate significant from non-significant stenosis, a peak-systolic velocity ratio >2.5 was used (the peak systolic velocity across the stenosis divided by the peak systolic velocity just proximal to the stenosis).14, 15, 16 When the examination of the trifurcation was found to be inconclusive on the first duplex-ultrasound scanning, an ultrasound contrast-agent (Levovist®) was administrated and the trifurcation re-examined.

All patients were scanned resting on the side using a colour duplex ultrasound system (Elegra, Siemens, Issaquah, WA, U.S.A.) and a 7.5 MHz linear array transducer. Velocity measurements were made in areas where the colour-image suggested velocity increase or turbulence or when the B-mode image suggested diameter changes. All velocities were obtained from the centre-stream of the vessels with an angel of insonation between 30° and 60°.

Ultrasound contrast-agent 

Levovist® (Schering AG, Berlin, Germany) is a galactose-based echo-enhancing contrast-agent (99.9% galactose, 0.1% palmitic acid). When mixed with water, it generates a milky gaseous suspension of micro-bubbles only a few mm in size (median diameter of 2 μm, 95% smaller than 8 μm).17 After intravenous injection, the micro-bubbles are capable of passing through the lung-capillaries and reaching the systemic circulation. When Levovist® is injected intravenously, the micro-bubbles act as highly effective back-scatters of ultrasound, significantly increasing the strength of the returning signal. Most commonly, Levovist® is administrated as a bolus-injection giving a relative short duration of peak-enhancement of approximately 1–2 min. In order to overcome this limitation, a bolus of 2 ml Levovist® (300 mg/ml) was followed by a continuous infusion (1 ml/min) of 11.5 ml (total dose = 4 g) using an automated injector system (Medrad Pulsar, Medrad Inc., Indianola, U.S.A.) giving approximately 12–14 min of optimal enhancement.

Following intravenous injection, the Levovist® micro-bubbles dissolve in the bloodstream and galactose is subject to insulin-independent glucose metabolism, mainly in the liver. Levovist® is generally non-toxic, but should logically not be given to patients suffering form galactosaemia. Levovist® is hyperosmotic and should be avoided in patients with critical cardiac failure and pulmonary fluid retention (NYHA stage IV). Even after repeated administrations of the diagnostic dose at short intervals, there is no risk of neither acute nor systemic intoxication. No allergic reactions are described in the available literature.

Digital subtraction arteriography 

In all patients the vessels from the aortic bifurcation to the pedal arteries were visualized using one of two standard angio-equipments: Integris 3000 (Philips, Best, The Netherlands) or Angiostar Plus (Siemens, Forchheim, Germany). Omnipaque 300 mg I/ml (Nycomed, Oslo, Norway) were used as contrast-agent. Ipsilateral puncture of the common femoral artery was performed. After demonstration of the iliac arteries the 5F catheter was withdrawn to external iliac artery in order to visualise the vessels of the leg and foot in patients with unilateral PAD. In case of bilateral PAD a standard bolus chase arteriography was performed. If the infrapopliteal vessels including the pedal arteries were insufficiently visualised, selective series were performed. The trifurcation was classified as described for the ultrasound technique. Segments were classified as non-diagnostic if no genuine or unnamed collateral vessels could be visualised due to inadequate contrast-agent opacification (“contrast underfilling”). The radiologist reading the arteriogram was unaware of the duplex findings.

Data analysis and statistics 

Results obtained by ultrasound and arteriography were recorded in similar diagrams. The paired-samples t-test was used to test differences before and after contrast-agent administration. When appropriate, the chi-squared-test or Fisher's exact test was used for comparison of categorical data, and the two-sample t-test for continuous data. Agreement between duplex and arteriography were compared using the kappa (κ) statistics to analyse the agreement beyond chance, and a z-test to test the difference between the agreements. A κ-value of 1 represents perfect agreement and a κ-value of 0 represents agreement by purely chance.18 A p-value < 0.05 was considered significant. Sensitivity and specificity were calculated by a two-way contingency table and presented with 95%-confidence interval in brackets.

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Results 

The study group (n = 15) was similar to the reference group with respect to age, sex, and the distribution in the SVS-ISCV categories (Table 1).

In these 15 patients with inconclusive segments, a total of 60 arterial segments were available for analysis. All 60 segments were found diagnostically visualized on DSA. After contrast-agent administration, the number of inconclusively diagnosed segments was significantly reduced by 26 (70%), from 37 to 11 (p < 0.001) (Fig. 1, Table 2).

Of these 26 segments, contrast-agent administration changed the diagnosis correctly in 19 segments (73%) and incorrectly in 7 (27%), using arteriography as the gold standard (p < 0.05) (Fig. 2).

Table 2. Data for the study population (15 patients, 60 segments).
DSA
+Disease−DiseaseInconcl.Total
Before Levovist® administration
Ultrasound
+Disease1102
−Disease417021
Inconcl.1621037
Total5 (21)18 (39)023 (60)
After Levovist® administration
Ultrasound
+Disease82010
−Disease930039
Inconcl.47011
Total17 (21)32 (39)049 (60)
Results of the conclusive segments only (bold figures)
Duplex-ultrasoundWithout contrast-agentWith contrast-agentp-value
Conclusively diagnosed segments23490.001
Inconclusively diagnosed segments37110.001
Sensitivity (95% CI)0.20 (0.04–0.62)0.47 (0.26–0.69)
Specificity (95% CI)0.94 (0.74–0.99)0.94 (0.80–0.98)
Positive predictive value (95% CI)0.50 (0.01–0.91)0.80 (0.49–0.94)
Negative predictive value (95% CI)0.81 (0.60–0.92)0.77 (0.62–0.87)
Agreement (κ) (95% CI)0.18 (0–0.82)0.45 (0.17–0.74)n.s.

There was disagreement between duplex and DSA after contrast administration in only seven segments: five segments were found to be normal on contrast-enhanced duplex-ultrasound, whereas DSA indicated occlusion and two segments, considered occluded on duplex, were normal on DSA (Fig. 2). Contrast-agent administration did not change the diagnosis in any segments assessed as conclusive on the primary non-enhanced duplex-ultrasound scanning.

Sensitivity and positive predictive value improved from 0.20 (0.04–0.62) to 0.47 (0.26–0.69) and 0.50 (0.10–0.91) to 0.80 (0.49–0.93), respectively. Specificity and negative predictive value remained virtually unchanged (Table 2).

Agreement between duplex-ultrasound and DSA for the diagnostically visualised segments, was improved from poor (κ = 0.18 (95% CI: 0–0.82)) to moderate (0.45 (0.17–0.74)) following contrast-agent administration, although this difference was not significant (p = 0.44) (Table 2).

The mean examination time, including both duplexultrasound examinations (enhanced and non-enhanced), preparation of contrast-agent and loading infusion pump was approximately 30 min. No complications or side effects were recorded following the contrastagent administration.

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Discussion 

For the first time, we have demonstrated that an ultrasound contrast-agent (Levovist®) significantly reduces the number of inconclusive scans in the trifurcation–known as one of the most problematic arterial segments when visualising PAD. Contrastagent administration significantly improves the diagnostic ability of duplex-ultrasound in inconclusive segments with 73%, when using DSA as the gold standard. Additionally, sensitivity, positive predictive value and agreement with DSA were improved following contrast-agent administration.

Following ultrasound contrast-agent administration, five segments originally considered inconclusive were erroneously classified as normal–although occluded on DSA. This phenomenon can be explained by either a disadvantage of the enhanced ultrasound technique, or as a known limitation in DSA when visualising multilevel diseased arteries below the knee. It's well known when visualising vessels distal to multiple occlusive lesions, that the resulting low contrast-agent concentration (“contrast underfilling”) can make patent vessels look occluded on arteriography.19 Though, DSA was considered representing the truth, a small proportion of patent runoff vessels being invisible on DSA has previously been described when comparing DSA with magnetic resonance arteriography (MRA).20 Additionally, DSA of the trifurcation is connected with a moderate interobserver variation.2 Thus, DSA could be questioned as the gold standard when visualising vessels below the knee, especially in patients with multilevel occlusive disease. In these cases, contrast-agent-enhanced duplex-ultrasound could serve as a valuable alternative or supplement to DSA having the possibility to increase the limb salvage rate by detecting DSA invisible runoff.

When visualising PAD in most vascular regions, the duration of a single contrast-agent injection is often too short for an ultrasound examination and therefore of limited clinical relevance. In the present study, an infusion-pump was used, giving a relative long period of stable diagnostic enhancement of 12–14 min. Moreover, with continuous infusion, blooming and shadowing in the early phase of the enhancement, as seen after a single bolus injection, is avoided. Due to a remote control, continually scanning was possible independently of infusion start and bolus administration.

The available literature addressing ultrasound contrast-agent in PAD is very limited, especially when evaluating arteries below the knee. In the iliac arteries, Vogt et al. demonstrated a marginal improvement in the diagnostic confidence of duplex-ultrasound after a single injection of Levovist®, using intravascular ultrasound as the reference.11 A subgroup of a phase III study from 1993 investigated Levovist® in PAD patients using a visual analogue scale, and found the number of suboptimal duplex scans reduced after Levovist® injection.21

Although cost-benefit analysis was not the purpose of the study, the costs of a single dose (4 g) ultrasound contrast-agent (Levovist®) were approximately 135$ (1145 Dkr.), being comparable with the cost of iodinated contrast-agent used for a routine DSA. In the diagnostic workup of PAD, using duplex-ultrasound as the primary imaging modality, supplementary use of ultrasound contrast-agent can potentially reduce the number of patients needing a diagnostic arteriography. Because duplex-ultrasound, with and without contrast-agent enhancement, is non-invasive and well tolerated, no additional costs compared to DSA are required for post procedural observation and treatment of possible complications. Besides the economical aspect of replacing some DSA procedures with contrast-agent enhanced duplex-ultrasound, patients' discomfort and risk can possibly be reduced as well as the radioactive exposure to both staff and patients.

Although not addressed in this study, ultrasound contrast-agents may be beneficial in several vascular regions besides the trifurcation when arterial insonation is inadequate: e.g. in obese and oedematous patients being generally difficult visualize due to a suboptimal signal to noise ratio and in diabetic and uremic patients with a high attenuation of the ultrasound waves due to highly calcified vessels.22 The high proportions of females in the study-population could possibly be a result of a sex-linked higher circumference of the calf. In further studies, factors such as BMI should be accounted.

In conclusion, ultrasound contrast-agents can improve the diagnostic ability of duplex-ultrasound when scanning difficult arterial segments in patients suffering from PAD. By lowering the number of inconclusive duplex scans, ultrasound contrast-agents have the potential to expand the indications for noninvasive assessment of PAD. In selected cases, contrast-enhanced duplex scanning may allow visualisation of patent runoff vessels which are invisible on arteriography, improving the opportunity for limb salvage surgery. In the future, ultrasound contrastagents should be a more common supplement to the non-invasive diagnostic armamentarium when evaluating patients with PAD.

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Acknowledgements 

This study was supported by grants from the Danish Medical Research Council and the Kathrine and Vigo Skovgaards Foundation.

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PII: S1078-5884(03)70181-6

doi:10.1053/ejvs.2002.1796

European Journal of Vascular & Endovascular Surgery
Volume 25, Issue 1 , Pages 23-28, January 2003

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