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Does Dopplersignal enhancement with Levovist® improve the diagnostic confidence of duplex scanning of the iliac arteries?—(A pilot study with correlation to intravascular ultrasound)
European Journal of Ultrasound 7 (1998) 159 – 165
Clinical paper
Does Dopplersignal enhancement with Levovist® improve the diagnostic confidence of duplex scanning of the iliac arteries? — (A pilot study with correlation to intravascular ultrasound) Katja C. Vogt *, Flemming Jensen, Torben V. Schroeder Departments of Vascular Surgery and Radiology, Rigshospitalet, Uni6ersity of Copenhagen, Blegdams6ej 9, DK-2100 Copenhagen, Denmark Received 24 September 1997; received in revised form 16 January 1998; accepted 25 January 1998
Abstract Objecti6e: To evaluate whether echo-enhancement with Levovist® improves the diagnostic confidence of duplex scanning of the iliac arteries. Methods: Sixteen patients admitted for either PTA (n =7) or femoro – femoral cross-over bypass (n=9) were examined with duplex scanning before and after Levovist® injection. The diagnostic confidence was noted before and after the echo-enhancement on a visual analog scale. The following day, intraoperatively, an IVUS examination of the iliac artery was performed. The agreement between duplex scanning before and after enhancement compared to IVUS was evaluated by k statistics, and sensitivity – specificity calculations. Results: The diagnostic confidence improved in 50% of the patients, remained unchanged in 44%, and deteriorated in one (6%) patient. The agreement with IVUS was moderate before enhancement (k= 0.48) and good after the enhancement (k = 0.63). Sensitivity rose from 64% (before) to 73% (after) Levovist®, while the specificity was unchanged (100%). These values are not as good as reported by others after fasting of the patients and comparing the results with arteriography. Conclusion: Levovist® improves the diagnostic confidence of duplex scanning, but marginally. In inconclusive duplex scannings echo-enhancement can supply decisive informations. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Echo-enhancement; Contrast agent; Duplex scanning; Intravascular ultrasound; Iliac artery
* Corresponding author. Tel.: +45 3545 3545; fax: + 45 3545 2303; e-mail: [email protected] 0929-8266/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0929-8266(98)00030-5
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K.C. Vogt et al. / European Journal of Ultrasound 7 (1998) 159–165
1. Introduction Duplex scanning is an established non-invasive method to visualize the iliac arteries (Jaeger et al., 1985; Kohler et al., 1987; Langsfeld et al., 1988; Legemate et al., 1989, 1991; Moneta et al., 1992; Rosfors et al., 1993; Currie et al., 1995; De Smet et al., 1996). It is mainly used as a follow-up examination after different interventions. It has not yet in our institution been able to replace arteriography as the method of choice for diagnostic purposes, as is the case in carotid artery disease (Zwolak, 1997). This is partly due to the deep location of the iliac arteries with overlying bowel gas as well as the tortousity of the vessels. The development of new ultrasound contrast agents, consisting of microbubbles, now capable of lung passage, seems a promising tool to improve the result of the duplex scanning by Doppler signal enhancement, thereby potentially replacing arteriography for iliac artery imaging. At this point the only results available, concerning the use of this new contrast agent, Levovist® in iliac arteries, are the results from phase III efficacy trials (Schwarz et al., 1994; Langholz et al., 1996). In these trials the echo-enhancement was used only when the initial duplex scanning was inconclusive or if the diagnostic confidence was low. No control procedure was used to evaluate the improved diagnostic confidence after Levovist® injection. We therefore wish to present the result of 16 patients, who had their iliac arteries examined by duplex scanning before and after echo-enhancement, and subsequently underwent intravascular ultrasound examination of the diseased artery.
2. Material Sixteen patients were admitted for either percutaneous transluminal angioplasty (PTA) of the iliac artery (n = 7) or for femoro – femoral crossover bypass (n =9) during the period from 20.11.96 to 25.6.97. The median age of the five women and 11 men was 65 (range: 46 – 76 years). One (6%) patient suffered diabetes. Ten (63%) patients were current smokers and six (37%) pa-
tients had ceased smoking recently. Ankelbrachial index (ABI) in the group of patients scheduled for PTA was in median 0.6 (0.34–0.9), while the ABI for the donorlimb in the group of patients scheduled for cross-over bypass was in median 0.5 (0.35–1.1). The indication for PTA was claudication in six (86%) cases, while one patient was without symptoms, but needed the PTA to ensure good inflow to a cross-over bypass. In the cross-over group 5 (56%) patients had no symptoms from their donorlimb, while four (44%) had claudication.
3. Method All patients were examined with duplex scanning the day before the intervention. The IVUS examination was performed during the intervention. The patients admitted for PTA had the diseased iliac artery examined, while the patients admitted for femoro–femoral cross over bypass had their donor iliac artery examined. Informed consent was obtained from all patients according to the Helsinki declaration II, and the use of IVUS in the iliac arteries was approved by the local ethical committee. Permission to use Levovist® (Schering AG, Berlin) for the visualisation of arteries and veins had been granted by the National Board of Health. Duplex scanning: The patients were examined in the supine position using a B and K 3535 color duplex scanner (B and K Medical, Copenhagen) and a 3.5 MHz curved phased array tranducer. Doppler spectra were obtained routinely from four positions: the proximal and distal part of the common and external iliac arteries. If a stenosis was present in between these locations, as indicated by the colour flow map, a Doppler spectrum from this site was also obtained. The peak systolic velocity (psv) and the end diastolic velocity (edv) from each site were noted along with information on spectral broadening. A stenosis of 50% or more was defined as a ratio of more than two between the psv in the stenosis and psv in a normal part of the same arterial segment (Jaeger et al., 1985; Kohler et al., 1987; Langsfeld et al., 1988; Moneta et al., 1992; Rosfors et al., 1993).
K.C. Vogt et al. / European Journal of Ultrasound 7 (1998) 159–165
The diagnostic confidence was subjectively evaluated and noted on a visual analog scale from 0–5. (5: excellent, 4: good, 3: reasonable, 2: poor, 1: miserable, 0: no diagnostic confidence). An evaluation of four or five would be clinical sufficient and no further examinations would have been nescessary. Zero to two would have demanded an arteriography, pressure measurement or IVUS examination in a clinical setting. While three could be sufficient along with other clinical informations. After the above described routine duplex scanning, 10 ml’s of 300mg/ml Levovist® was injected into a peripheral arm vein as a bolusinjection. Levovist® is an ultrasound echo-enhancement agent, which consists of a galactose suspension generating gaseous micro-bubbles only a few mm in size, that are able to survive passage through lung capillaries. The micro-bubbles are stabilized by thin membranes of palmitic acid (0.1%). After the injection the duplex scanning was repeated, obtaining Doppler spectra from the same positions, as well as from positions not clearly visualized at the first scanning. The diagnostic confidence was noted again. The patients were not routinely fasted before the examinations. IVUS: The intravascular ultrasound (IVUS) was performed with a 20 MHz transducer mounted in the tip of an 8 F catheter (CVIS Cardiovascular Imaging Systems, Sunnyvale, CA). The catheter was introduced either through the arterial sheath used for the angioplasty in patients scheduled for PTA, or through an arteriotomy of the common femoral artery in patients undergoing femoro – femoral bypass surgery. The catheter was advanced retrograde into the aorta and then slowly retracted while producing transsectional images displayed on a monitor and stored on a S-VHS video recorder. Moreover, in the PTA-patients the position of the transducer was recorded under fluoroscopy. In the operated patients the length from the bifurcation or from the ostium of the internal iliac artery to a lesion site was measured on the retracted part of the catheter, in order to define the location of the stenosis.
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The IVUS equipment enabled off-line measurement of the free lumen area and the mediabounded area, and the ratio between these two areas yielded the degree of stenosis, Fig. 1 (Vogt et al., 1997).
4. Results The diagnostic confidence of the examinations were evaluated on a visual scale from zero to five before and after echo-enhancement, Fig. 2. In all the diagnostic confidence improved in 50% of the patients, remained unchanged in 44% and deteriorated in one (6%) patient. In three of the patients submitted for PTA the diagnostic confidence was improved, due to total visualization of the iliac arteries, which was not possible in these patients before Levovist® injection. However, the conclusion of the examination was unchanged (tight stenosis). In the group of patients submitted for cross over bypass surgery the diagnostic confidence improved in five patients, remained unchanged in three and deteriorated in one patient after Levovist®. The latter was due to too high insonation angle at the examination after Levovist®. The echo-enhancement changed the conclusion in one patient, in whom a stenosis was diagnosed after obtaining additional Doppler spectra from a now better visualized part of the artery. In another patient the primary duplex scanning was inconclusive due to lack of visualization of the proximal part of the common iliac artery. After echo-enhancement the entire artery was visualized and no stenosis was found. Ten (63%) of the patients had a stenosis of more than 50% as evaluated by IVUS and one patient had a short occlusion of the iliac artery. The agreement with duplex scanning before and after echo-enhancement can be seen in Fig. 3. All together the sensitivity and specificity of duplex scanning, using IVUS as the gold standard, was 64 and 100% before Levovist®, and 73 and 100% after Levovist®. The k values were 0.48 before and 0.63 after Levovist®, corresponding to moderate and good agreement, according to the categories defined by Landis and Koch (1977).
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Fig. 1. IVUS image of an iliac artery with an eccentric soft plaque. (A) The transducer (t), creates a black area in the center of the trans- sectional view. The lumen (l) is bordered by the intima, which is thickened by soft plaque (p) in the right part of the artery. The media (m) is represented by a black ring outside the intima. An artefact (a) is caused by a wire from the transducer. (B) The outer and inner lining of the intima have been marked. The area of the lumen and the media-bound area are calculated and shown in the lower left corner of the picture, along with the degree of stenosis and diameter reduction, which have been calculated from these two areas.
The duration of the enhancement ranged from 1.5 to 4 min (median 2 min). None of the patients experienced any side ef-
fects from the Levovist® injection. There were no complications in relation to the IVUS examination.
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Fig. 2. Visual analog scales showing the diagnostic confidence before and after echo-enhancement for the PTA patients (A) and the cross-over patients (B)
5. Discussion In the limited number of studies on Levovist® echo-enhancement and iliac duplex scanning (Schwarz et al., 1994; Langholz et al., 1996) the indication for echo-enhancement has been inconclusive duplex scanning. In the present study we administered Levovist® to 16 consecutive patients examined by duplex scanning either before PTA or cross over bypass. In some of the patients, especially the candidates for PTA, a conclusion was easily obtained before enhancement. It is therefore not surprising that the diagnostic confidence was unchanged in some of the patients, since the tight stenoses were easily found without Levovist® injection. However, the damped signal distal to a stenosis might prevent visualization of that particular part of the artery and additional stenoses might be overlooked. Echo-enhancement could facilitate the detection of such additional lesions. Another part of the iliac arteries, difficult to visualize, is the transition between the common and the external iliac artery. Due to the curved nature of this part of the arteries it is often difficult to obtain an acceptable insonation angle and keeping the whole segment in focus at the same time. It is our impression that echo-enhancement facilitates this part of the examination. In the donor iliac arteries the diagnostic confidence is often rather low due to findings of minor
changes in PSV but not to the level of a haemodynamically significant stenosis. In these patients a total visualization of the arteries might reveal segments not detected before Levovist® with a little higher PSV and this might change the conclusion of the examination. When evaluating a possible improvement of the diagnostic confidence before and after echo-enhancement, it is important, to confirm the diagnosis by another examination technique. We therefore examined all the patients with IVUS on the day after the duplex scanning, during revascularization. IVUS produces transsectional images of the artery at a high resolution. The luminal area and the mediabounded area can be outlined and measured, and the degree of stenosis thereby calculated (Fig. 1). The method has been shown to have an excellent agreement with histology (Gussenhoven et al., 1989; Nishimura et al., 1990; Di Mario et al., 1992), and a reasonable agreement with arteriography at least before PTA (Tabbara et al., 1991; Gerritsen et al., 1993; De Scheerder et al., 1994). We believe in the superiority of IVUS compared to arteriography, which is known to overlook especially eccentrically distributed plaques in the iliac arteries (Thiele and Strandness, 1983). It should be taken into consideration however, that both arteriography and IVUS yields anatomical measurements, while duplex scanning yields functional informations,
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Fig. 3. The agreement between duplex scanning and intravascular ultrasound(IVUS), before (A) and after (B) echo-enhancement.
which is a limitation of this comparison. In this study two stenoses visualized by IVUS were not found by duplex scanning. In one of the patients the insonation angle at one location after Levovist® was 68°, which might have prevented correct velocity measurement. Problems with insonation angle should naturally not arise with an experienced examinator, but the limited time of enhancement after a single dose of Levovist® precludes fine adjustment of angle and other settings, if the whole iliac arterial segment is to be visualized and measured within approximately 2 m. Additional injections or slowly infusion of the substance is possible and might be justified if the Doppler spectra obtained at the first examination after Levovist® injection are suboptimal. In the other patient, with a stenosis on the IVUS examination, not visualized by duplex scanning, the stenosis was situated just at the angle between the common and the external iliac artery. Reviewing the locations where the Doppler spectra were obtained, this particular area was not analysed neither before nor after echo-enhancement. Our overall sensitivity was 64% (before) and 73% (after) Levovist®, while the specificity was 100%, unchanged by echo enhancement. These sensitivities are not as good as those reported by other authors, preparing the patients by fasting for 6–12 h, and comparing the result to arteriography. Sensitivities of 83 – 92% for detecting significant stenosis were obtained in these studies (Kohler et al., 1987; Legemate et al., 1989, 1991; Moneta et al., 1992; Currie et al., 1995; De Smet et al., 1996). Whiteley et al. (1995) used an iso-
osmotic bowel preparation in order to avoid bowel gas and reached sensitivities of 93%. The higher sensitivities, compared to our results, might simply reflect our limited expertice in duplex scanning of the iliac arteries, but it could also reflect, that the visualization after fasting is better than what can be obtained by echo-enhancement. Another factor could be, that some of the less pronounced stenoses were missed by arteriography. Legemate et al. (1991) comparing duplex scanning with both pressure measurements and arteriography, found that both arteriography and duplex scanning missed some of the less pronounced lesions diagnosed by pressure measurements. For scheduled duplex scanning examinations fasting or bowel preparation seems possible non-invasive alternatives to Levovist® injection. But not all duplex scannnings are planned, and starvation for 12 h is unacceptable for diabetics.
6. Conclusion Levovist® seems to be a safe ultrasound contrast agent, which may improve the diagnostic confidence of duplex scanning of the iliac arteries. The indication for using Levovist® should be an inconclusive duplex scanning, where fasting of the patient is impossible or impractical. A dosage of 10 ml’s of 300mg/ml Levovist® offers good enhancement, but supplementary injections may be necessary due to the short duration of the contrast enhancing effect.
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Acknowledgements This study was supported by the Velux Foundation and by Minister Erna Hamilton’s Foundation for Science and Art.
References Currie IC, Jones AJ, Wakeley CJ, Tennant WG, Wilson YG, Baird RN, Lamont PM. Non-invasive aortoiliac assessment. Eur J Vasc Endovasc Surg 1995;9:24–8. De Scheerder I, De Man F, Herregods MC, Wilczek K, Barrios L, Raymenants E, Desmet W, De Geest H, Piessens J. Intravascular ultrasound versus angiography for measurement of luminal diameters in normal and diseased coronary arteries. Am Heart J 1994;127:243–51. De Smet AAEA, Ermers EJM, Kitslaar PJEHM. Duplex velocity characteristics of aortoiliac stenoses. J Vasc Surg 1996;23:628–36. Di Mario C, The SHK Madretsma S, van Suylen RJ, Wilson RA, Bom N, Serruys PW, Gussenhoven EJ, Roelandt JRTC. Detection and characterisation of vascular lesions by intravascular ultrasound: an in vitro study correlated with histology. J Am Soc Echocardiogr 1992;5:135 – 46. Gerritsen GP, Gussenhoven EJ, The SHK Pieterman H, v.d Lugt A, Li W, Bom N, van Dijk LC, Du Bois NAJJ, van Urk H. Intravascular ultrasound before and after intervention: In vivo comparison with angiography. J Vasc Surg 1993;18:31 –40. Gussenhoven EJ, Essed CE, Frietman P, van Egmond F, Lance´e CT, van Kappellen WH, Roelandt J, Serruys PW, Gerritsen GP, van Urk H, Bom N. Intravascular ultrasonic imaging: histological and echographic correlation. Eur J Vasc Surg 1989;3:571–6. Jaeger KA, Phillips DJ, Martin RL. Non-invasive mapping of lower limb arterial lesions. Ultrasound Med Biol 1985;11:515–21. Kohler TR, Nance DR, Cramer MM, Vanderburghe N, Strandness DE. Duplex scanning for the diagnosis of aorto-iliac and femoropopliteal disease: a prospective study. Circulation 1987;76:1074–80. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;3:159 – 74.
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Langholz J, Wanke M, Petry J, et al. Echo-enhanced ultrasound imaging of leg arteries with Levovist® (SH U 508 A) — multicenter trial results. Angiology 1996;47(2):37–49. Langsfeld M, Nepute J, Hershey FB, Thorpe L, Auer AI, Binnington B, Hurley JJ, Peterson GJ, Schwartz R, Woods JJ Jr. The use of deep duplex scanning to predict hemodynamically significant aortoiliac stenoses. J Vasc Surg 1988;7:395 – 9. Legemate DA, Teeuwen C, Hoeneveld H, Eikelboom BC. The potential of duplexscanning to replace aorto-iliac and femoro-popliteal angiography. Eur J Vasc Surg 1989;3:49– 54. Legemate DA, Teeuwen C, Hoeneveld H, Eikelboom BC. Value of duplex scanning compared with angiography and pressure measurement in the assessment of aortoiliac arterial lesions. Br J Surg 1991;78:1003 – 8. Moneta GL, Yeager RA, Antonovic R, Hall LD, Caster JD, Cummings CA, Porter JM. Accuracy of lower limb extremity arterial duplex mapping. J Vasc Surg 1992;15:275– 84. Nishimura RA, Edwards WD, Warnes CA, Reeder GS, Holmes DR, Tajik AJ, Yock PG. Intravascular ultrasound imaging: in vitro validation and pathologic correlation. J Am Coll Cardiol 1990;16:145 – 54. Rosfors S, Eriksson M, Høglund N, Johansson G. Duplex ultrasound in patients with suspected aorto – iliac occlusive disease. Eur J Vasc Surg 1993;7:513 – 7. Schwarz KQ, Becher H, Schimpfky C, Vorwerk D, Bogdahn U, Schlief R. Doppler enhancement with SH U 508A in multiple vascular regions. Radiology 1994;193:195 – 201. Tabbara M, White R, Cavaye D, Kopchok G. In vivo comparison of intravascular ultrasound and angiography. J Vasc Surg 1991;14:496 – 504. Thiele BL, Strandness DE Jr. Accuracy of angiographic quantification of peripheral atherosclerosis. Prog Cardiovasc Dis 1983;26(3):223– 36. Vogt KC, Just S nJ, Rasmussen JG, Schroeder TV. Prediction of outcome after femoropopliteal balloon angioplasty by intravascular ultrasound. Eur J Endovasc Surg 1997;13:563 – 8. Whiteley M, Harris R, Horrocks M. Aortoiliac segment examination with colour flow duplex — a pilot study using Klean Prep. to improve image quality. Eur J Vasc Endovasc Surg 1995;10:192 – 7. Zwolak RM. Carotid endarterectomy without angiography: are we ready? Vasc Surg 1997;31(1):1 – 9.
Clinical paper
Does Dopplersignal enhancement with Levovist® improve the diagnostic confidence of duplex scanning of the iliac arteries? — (A pilot study with correlation to intravascular ultrasound) Katja C. Vogt *, Flemming Jensen, Torben V. Schroeder Departments of Vascular Surgery and Radiology, Rigshospitalet, Uni6ersity of Copenhagen, Blegdams6ej 9, DK-2100 Copenhagen, Denmark Received 24 September 1997; received in revised form 16 January 1998; accepted 25 January 1998
Abstract Objecti6e: To evaluate whether echo-enhancement with Levovist® improves the diagnostic confidence of duplex scanning of the iliac arteries. Methods: Sixteen patients admitted for either PTA (n =7) or femoro – femoral cross-over bypass (n=9) were examined with duplex scanning before and after Levovist® injection. The diagnostic confidence was noted before and after the echo-enhancement on a visual analog scale. The following day, intraoperatively, an IVUS examination of the iliac artery was performed. The agreement between duplex scanning before and after enhancement compared to IVUS was evaluated by k statistics, and sensitivity – specificity calculations. Results: The diagnostic confidence improved in 50% of the patients, remained unchanged in 44%, and deteriorated in one (6%) patient. The agreement with IVUS was moderate before enhancement (k= 0.48) and good after the enhancement (k = 0.63). Sensitivity rose from 64% (before) to 73% (after) Levovist®, while the specificity was unchanged (100%). These values are not as good as reported by others after fasting of the patients and comparing the results with arteriography. Conclusion: Levovist® improves the diagnostic confidence of duplex scanning, but marginally. In inconclusive duplex scannings echo-enhancement can supply decisive informations. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Echo-enhancement; Contrast agent; Duplex scanning; Intravascular ultrasound; Iliac artery
* Corresponding author. Tel.: +45 3545 3545; fax: + 45 3545 2303; e-mail: [email protected] 0929-8266/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0929-8266(98)00030-5
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1. Introduction Duplex scanning is an established non-invasive method to visualize the iliac arteries (Jaeger et al., 1985; Kohler et al., 1987; Langsfeld et al., 1988; Legemate et al., 1989, 1991; Moneta et al., 1992; Rosfors et al., 1993; Currie et al., 1995; De Smet et al., 1996). It is mainly used as a follow-up examination after different interventions. It has not yet in our institution been able to replace arteriography as the method of choice for diagnostic purposes, as is the case in carotid artery disease (Zwolak, 1997). This is partly due to the deep location of the iliac arteries with overlying bowel gas as well as the tortousity of the vessels. The development of new ultrasound contrast agents, consisting of microbubbles, now capable of lung passage, seems a promising tool to improve the result of the duplex scanning by Doppler signal enhancement, thereby potentially replacing arteriography for iliac artery imaging. At this point the only results available, concerning the use of this new contrast agent, Levovist® in iliac arteries, are the results from phase III efficacy trials (Schwarz et al., 1994; Langholz et al., 1996). In these trials the echo-enhancement was used only when the initial duplex scanning was inconclusive or if the diagnostic confidence was low. No control procedure was used to evaluate the improved diagnostic confidence after Levovist® injection. We therefore wish to present the result of 16 patients, who had their iliac arteries examined by duplex scanning before and after echo-enhancement, and subsequently underwent intravascular ultrasound examination of the diseased artery.
2. Material Sixteen patients were admitted for either percutaneous transluminal angioplasty (PTA) of the iliac artery (n = 7) or for femoro – femoral crossover bypass (n =9) during the period from 20.11.96 to 25.6.97. The median age of the five women and 11 men was 65 (range: 46 – 76 years). One (6%) patient suffered diabetes. Ten (63%) patients were current smokers and six (37%) pa-
tients had ceased smoking recently. Ankelbrachial index (ABI) in the group of patients scheduled for PTA was in median 0.6 (0.34–0.9), while the ABI for the donorlimb in the group of patients scheduled for cross-over bypass was in median 0.5 (0.35–1.1). The indication for PTA was claudication in six (86%) cases, while one patient was without symptoms, but needed the PTA to ensure good inflow to a cross-over bypass. In the cross-over group 5 (56%) patients had no symptoms from their donorlimb, while four (44%) had claudication.
3. Method All patients were examined with duplex scanning the day before the intervention. The IVUS examination was performed during the intervention. The patients admitted for PTA had the diseased iliac artery examined, while the patients admitted for femoro–femoral cross over bypass had their donor iliac artery examined. Informed consent was obtained from all patients according to the Helsinki declaration II, and the use of IVUS in the iliac arteries was approved by the local ethical committee. Permission to use Levovist® (Schering AG, Berlin) for the visualisation of arteries and veins had been granted by the National Board of Health. Duplex scanning: The patients were examined in the supine position using a B and K 3535 color duplex scanner (B and K Medical, Copenhagen) and a 3.5 MHz curved phased array tranducer. Doppler spectra were obtained routinely from four positions: the proximal and distal part of the common and external iliac arteries. If a stenosis was present in between these locations, as indicated by the colour flow map, a Doppler spectrum from this site was also obtained. The peak systolic velocity (psv) and the end diastolic velocity (edv) from each site were noted along with information on spectral broadening. A stenosis of 50% or more was defined as a ratio of more than two between the psv in the stenosis and psv in a normal part of the same arterial segment (Jaeger et al., 1985; Kohler et al., 1987; Langsfeld et al., 1988; Moneta et al., 1992; Rosfors et al., 1993).
K.C. Vogt et al. / European Journal of Ultrasound 7 (1998) 159–165
The diagnostic confidence was subjectively evaluated and noted on a visual analog scale from 0–5. (5: excellent, 4: good, 3: reasonable, 2: poor, 1: miserable, 0: no diagnostic confidence). An evaluation of four or five would be clinical sufficient and no further examinations would have been nescessary. Zero to two would have demanded an arteriography, pressure measurement or IVUS examination in a clinical setting. While three could be sufficient along with other clinical informations. After the above described routine duplex scanning, 10 ml’s of 300mg/ml Levovist® was injected into a peripheral arm vein as a bolusinjection. Levovist® is an ultrasound echo-enhancement agent, which consists of a galactose suspension generating gaseous micro-bubbles only a few mm in size, that are able to survive passage through lung capillaries. The micro-bubbles are stabilized by thin membranes of palmitic acid (0.1%). After the injection the duplex scanning was repeated, obtaining Doppler spectra from the same positions, as well as from positions not clearly visualized at the first scanning. The diagnostic confidence was noted again. The patients were not routinely fasted before the examinations. IVUS: The intravascular ultrasound (IVUS) was performed with a 20 MHz transducer mounted in the tip of an 8 F catheter (CVIS Cardiovascular Imaging Systems, Sunnyvale, CA). The catheter was introduced either through the arterial sheath used for the angioplasty in patients scheduled for PTA, or through an arteriotomy of the common femoral artery in patients undergoing femoro – femoral bypass surgery. The catheter was advanced retrograde into the aorta and then slowly retracted while producing transsectional images displayed on a monitor and stored on a S-VHS video recorder. Moreover, in the PTA-patients the position of the transducer was recorded under fluoroscopy. In the operated patients the length from the bifurcation or from the ostium of the internal iliac artery to a lesion site was measured on the retracted part of the catheter, in order to define the location of the stenosis.
161
The IVUS equipment enabled off-line measurement of the free lumen area and the mediabounded area, and the ratio between these two areas yielded the degree of stenosis, Fig. 1 (Vogt et al., 1997).
4. Results The diagnostic confidence of the examinations were evaluated on a visual scale from zero to five before and after echo-enhancement, Fig. 2. In all the diagnostic confidence improved in 50% of the patients, remained unchanged in 44% and deteriorated in one (6%) patient. In three of the patients submitted for PTA the diagnostic confidence was improved, due to total visualization of the iliac arteries, which was not possible in these patients before Levovist® injection. However, the conclusion of the examination was unchanged (tight stenosis). In the group of patients submitted for cross over bypass surgery the diagnostic confidence improved in five patients, remained unchanged in three and deteriorated in one patient after Levovist®. The latter was due to too high insonation angle at the examination after Levovist®. The echo-enhancement changed the conclusion in one patient, in whom a stenosis was diagnosed after obtaining additional Doppler spectra from a now better visualized part of the artery. In another patient the primary duplex scanning was inconclusive due to lack of visualization of the proximal part of the common iliac artery. After echo-enhancement the entire artery was visualized and no stenosis was found. Ten (63%) of the patients had a stenosis of more than 50% as evaluated by IVUS and one patient had a short occlusion of the iliac artery. The agreement with duplex scanning before and after echo-enhancement can be seen in Fig. 3. All together the sensitivity and specificity of duplex scanning, using IVUS as the gold standard, was 64 and 100% before Levovist®, and 73 and 100% after Levovist®. The k values were 0.48 before and 0.63 after Levovist®, corresponding to moderate and good agreement, according to the categories defined by Landis and Koch (1977).
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Fig. 1. IVUS image of an iliac artery with an eccentric soft plaque. (A) The transducer (t), creates a black area in the center of the trans- sectional view. The lumen (l) is bordered by the intima, which is thickened by soft plaque (p) in the right part of the artery. The media (m) is represented by a black ring outside the intima. An artefact (a) is caused by a wire from the transducer. (B) The outer and inner lining of the intima have been marked. The area of the lumen and the media-bound area are calculated and shown in the lower left corner of the picture, along with the degree of stenosis and diameter reduction, which have been calculated from these two areas.
The duration of the enhancement ranged from 1.5 to 4 min (median 2 min). None of the patients experienced any side ef-
fects from the Levovist® injection. There were no complications in relation to the IVUS examination.
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Fig. 2. Visual analog scales showing the diagnostic confidence before and after echo-enhancement for the PTA patients (A) and the cross-over patients (B)
5. Discussion In the limited number of studies on Levovist® echo-enhancement and iliac duplex scanning (Schwarz et al., 1994; Langholz et al., 1996) the indication for echo-enhancement has been inconclusive duplex scanning. In the present study we administered Levovist® to 16 consecutive patients examined by duplex scanning either before PTA or cross over bypass. In some of the patients, especially the candidates for PTA, a conclusion was easily obtained before enhancement. It is therefore not surprising that the diagnostic confidence was unchanged in some of the patients, since the tight stenoses were easily found without Levovist® injection. However, the damped signal distal to a stenosis might prevent visualization of that particular part of the artery and additional stenoses might be overlooked. Echo-enhancement could facilitate the detection of such additional lesions. Another part of the iliac arteries, difficult to visualize, is the transition between the common and the external iliac artery. Due to the curved nature of this part of the arteries it is often difficult to obtain an acceptable insonation angle and keeping the whole segment in focus at the same time. It is our impression that echo-enhancement facilitates this part of the examination. In the donor iliac arteries the diagnostic confidence is often rather low due to findings of minor
changes in PSV but not to the level of a haemodynamically significant stenosis. In these patients a total visualization of the arteries might reveal segments not detected before Levovist® with a little higher PSV and this might change the conclusion of the examination. When evaluating a possible improvement of the diagnostic confidence before and after echo-enhancement, it is important, to confirm the diagnosis by another examination technique. We therefore examined all the patients with IVUS on the day after the duplex scanning, during revascularization. IVUS produces transsectional images of the artery at a high resolution. The luminal area and the mediabounded area can be outlined and measured, and the degree of stenosis thereby calculated (Fig. 1). The method has been shown to have an excellent agreement with histology (Gussenhoven et al., 1989; Nishimura et al., 1990; Di Mario et al., 1992), and a reasonable agreement with arteriography at least before PTA (Tabbara et al., 1991; Gerritsen et al., 1993; De Scheerder et al., 1994). We believe in the superiority of IVUS compared to arteriography, which is known to overlook especially eccentrically distributed plaques in the iliac arteries (Thiele and Strandness, 1983). It should be taken into consideration however, that both arteriography and IVUS yields anatomical measurements, while duplex scanning yields functional informations,
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Fig. 3. The agreement between duplex scanning and intravascular ultrasound(IVUS), before (A) and after (B) echo-enhancement.
which is a limitation of this comparison. In this study two stenoses visualized by IVUS were not found by duplex scanning. In one of the patients the insonation angle at one location after Levovist® was 68°, which might have prevented correct velocity measurement. Problems with insonation angle should naturally not arise with an experienced examinator, but the limited time of enhancement after a single dose of Levovist® precludes fine adjustment of angle and other settings, if the whole iliac arterial segment is to be visualized and measured within approximately 2 m. Additional injections or slowly infusion of the substance is possible and might be justified if the Doppler spectra obtained at the first examination after Levovist® injection are suboptimal. In the other patient, with a stenosis on the IVUS examination, not visualized by duplex scanning, the stenosis was situated just at the angle between the common and the external iliac artery. Reviewing the locations where the Doppler spectra were obtained, this particular area was not analysed neither before nor after echo-enhancement. Our overall sensitivity was 64% (before) and 73% (after) Levovist®, while the specificity was 100%, unchanged by echo enhancement. These sensitivities are not as good as those reported by other authors, preparing the patients by fasting for 6–12 h, and comparing the result to arteriography. Sensitivities of 83 – 92% for detecting significant stenosis were obtained in these studies (Kohler et al., 1987; Legemate et al., 1989, 1991; Moneta et al., 1992; Currie et al., 1995; De Smet et al., 1996). Whiteley et al. (1995) used an iso-
osmotic bowel preparation in order to avoid bowel gas and reached sensitivities of 93%. The higher sensitivities, compared to our results, might simply reflect our limited expertice in duplex scanning of the iliac arteries, but it could also reflect, that the visualization after fasting is better than what can be obtained by echo-enhancement. Another factor could be, that some of the less pronounced stenoses were missed by arteriography. Legemate et al. (1991) comparing duplex scanning with both pressure measurements and arteriography, found that both arteriography and duplex scanning missed some of the less pronounced lesions diagnosed by pressure measurements. For scheduled duplex scanning examinations fasting or bowel preparation seems possible non-invasive alternatives to Levovist® injection. But not all duplex scannnings are planned, and starvation for 12 h is unacceptable for diabetics.
6. Conclusion Levovist® seems to be a safe ultrasound contrast agent, which may improve the diagnostic confidence of duplex scanning of the iliac arteries. The indication for using Levovist® should be an inconclusive duplex scanning, where fasting of the patient is impossible or impractical. A dosage of 10 ml’s of 300mg/ml Levovist® offers good enhancement, but supplementary injections may be necessary due to the short duration of the contrast enhancing effect.
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Acknowledgements This study was supported by the Velux Foundation and by Minister Erna Hamilton’s Foundation for Science and Art.
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