Use of ultrasound contrast in the diagnosis of carotid artery occlusion

Transcription

1 Use of ultrasound contrast in the diagnosis of carotid artery occlusion J. M. Escribano Ferrer, MD, J. Juan Samsó, PhD, J. Royo Serrando, MD, V. Fernández Valenzuela, MD, S. Bellmunt Montoya, MD, and M. Matas Docampo, MD, Barcelona, Spain Objective: The purpose of this study was to evaluate the use of an echo-enhancing agent in patients with carotid artery occlusion to improve the sensitivity and specificity of carotid color flow ultrasonography. Method: Between January 1997 and December 1998, a prospective study involving 85 cases of carotid artery occlusion in 84 patients was carried out. After a baseline duplex ultrasonography (DU) diagnosis, a second (DU) along with an echo-enhancement agent (SHU-508-A [Levovist]) study was carried out (echo enhancement ultrasonography diagnosis [DUEE]). In 82 cases, a contrast angiography was performed to confirm the diagnosis, whereas in the other three cases the diagnoses were confirmed with surgery. Results: From the 85 internal carotid artery occlusions diagnosed at the initial DU examination, seven came out to be false occlusions in the DUEE examination (8,2%). There was a 100% correlation of the cases between the DUEE examination and the contrast angiography in the 82 cases in which this had been done. In three of the cases, the diagnosis was confirmed surgically because these displayed severe stenoses according to the DUEE studies in symptomatic patients, and so they required urgent treatment. Conclusions: The DUEE study is a potent diagnosis tool that allows the differentiation between true carotid artery occlusions and pseudo-occlusions. (J Vasc Surg 2000;31:736-41) There are numerous publications on the reliability of the duplex ultrasonography (DU) in the diagnosis of carotid artery occlusion Although in the first references the accuracy is very different according to the authors and, in general, is inferior to 85% 1-5 in more recent publications and after the important contribution of the color duplex scanning, the overall accuracy has been placed between 92% and 100% However, Berman et al 6 reported a small series. Kirsch et al 9 and Mattos et al 7 present a retrospective review in which only 15% to 20% of the cases of occlusion (those with patients who had undergone DU and contrast angiography [CA]) were apt for the study. Other authors differentiate the studied series on the basis of the good quality of the DU explorations. 8,10 From Vall d Hebron Hospital. Competition of interest: nil. Reprint requests: Dr J. M. Escribano Ferrer, Vall d Hebron Hospital, Vascular Surgery Staff, Calle/Laforja no. 26, atico 2a, Barcelona 08006, Spain. Copyright 2000 by The Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter /2000/$ /1/ doi: /mva It is precisely in those technically difficult cases when the use of echo-enhancing agents becomes particularly relevant. Sitzer et al 11 obtained a reduction of the uninterpretable cases from 21% to 6% after contrast application in the studied series. The evaluation of carotid occlusion is difficult not only because of the presence of calcified plaques or other local factors (eg, the postoperative cicatricial fibrosis, which makes the penetration of ultrasound scans difficult), but also because of the low volume of flow in the carotid near occlusion and the limited capacity of DU to detect low velocities The use of echo-enhancement agents is recommended to minimize the number of these examinations. This practice results in a smaller number of CA examinations to be performed, thus reducing the incidence of severe complications associated with CA, which could be as high as 1.2%. 17 METHODS Between January 1, 1997, and December 31, 1998, a prospective study involving 2576 DU studies was carried out. From that number, 1300 studies were initial examinations (50,4%), and 1276 studies were consecutive examinations. The 100 diagnoses of carotid artery occlusions resulting from those first 736

2 Volume 31, Number 4 Escribano et al 737 examinations are the subject of this study. This means an incidence of 100 carotid occlusions among 1300 (7.7%) cases, according to the DU. A protocol was designed by which the initial DU evaluation of the carotid artery occlusion had to be followed by a echo enhancement ultrasonography diagnosis (DUEE) study within a week. The DU and the DUEE were performed by staff members of the Vascular Laboratory from the Department of Angiology and Vascular Surgery. These staff members are also the authors of the study. Then, CAs had to be performed within a maximum period of 15 days after the last duplex examination. Angioneuroradiology staff physicians carried these out. Patients. From the 100 cases of DU diagnosis of carotid occlusion (99 patients), a second DU with an echo-enhancement agent (DUEE) was carried out in 87 patients (88 cases with a prediction of carotid occlusion). Twelve patients refused consent to the injection of Levovist. The mean age of the patients in the group was 67. There were 71 men and 16 women. The patients risk factors were those that are characteristic of atherosclerosis: 72% were smokers, 56% were hypertensive, 35.5% had dislipemia, and 33.5% had diabetes. Two thirds of the patients had some symptomatology related to carotid artery disease. There were 13 cases of amaurosis fugax, 28 cases of transient ischemic attack, and 15 cases of minor stroke. Color flow scanning. The DU evaluations were performed with the Philips 800-SD (Philips, Irving, Calif) using a 7.5-MHz probe. The diagnostic criterion to be followed was the absence of a Doppler signal inside the vessel lumen, followed by a secondary supportive criterion, such as the lack of color Doppler filling of the lumen or indirect Doppler s parameters, such as an increase in the resistance index of the common carotid. The echo-enhancement agent used was SHU- 508-A (Levovist). It is a 99.9% galactose/0.1% palmitic acid based agent that, on dissolution and agitation in sterile water, generates air-filled microbubbles with a palmitic acid coating and median diameter of 2 µm. It is stable across the pulmonary circulation, and it is useful to increase signal from the entire vascular pool. Galactose is an aldohexose found in milk, and it is metabolized in the liver with a half-life of 10 to 11 minutes. Palmitic acid is a normal constituent of blood, and SHU-508-A does not influence the normal circulating concentration. 18 The dose used was 2.5 g at a concentration of 300 mg/ml in 79 patients. The nine remaining patients required a second injection (400 mg/ml) to allow a reliable diagnosis. After an intravenous bolus injection, the time course of echo-enhancement was more than 4 minutes. Furthermore, the use of continuous infusion provided prolonged echo-enhancement until 7 minutes. 19 Carotid angiography. Finally, a CA was carried out according to the intra-arterial digital subtraction angiography technique with aortic arch and selective carotid artery catheterizations. Three of the cases were severe in neurologically unstable patients with crescendo transient ischemic attacks. These patients were operated on an urgent basis without a CA study, considering surgery an analogous method to CA to confirm or not the occlusion. From the 88 included cases, we have rejected the three patients for whom neither a CA nor surgery was performed; the patients had been diagnosed through the use of DUEE as having stenosis without hemodynamic significance. So it was decided not to continue the diagnostic battery. Database and statistical analysis. The 85 patients to whom a DU and a DUEE were performed have been considered as the population to be studied, confirming or rejecting the diagnosis of occlusion with a CA (n = 82) or surgery (n = 3) (Fig 1). Sensitivity, specificity, and positive predictive value were calculated for DU and DUEE, considering CA/surgery as the gold standard, using a 95% CI. Overall accuracy was calculated by dividing the true positives and true negatives by the total population. RESULTS From the 85 baseline diagnoses of occlusion found in the first DU examination, seven patients displayed patency in the DUEE. In 78 cases the diagnosis was occlusion. From these 85 cases, a CA was performed on 82 of the patients, confirming the internal carotid occlusion in 78 cases (four patency cases). In regard to the three patients on whom urgent carotid endarterectomy was performed because of their neurologic instability (with DUEE suggesting stenosis >90%), the patency of the internal carotid artery (ICA) was confirmed in all of them (CA/surgery: 78 occlusions, 7 ICA patencies). Table I analyzes the reliability of the examination using DUEE. The reference examination and the CA/surgery available to verify the reliability of the DUEE examination confirmed that the patients with a diagnosis of stenosis in the previous exploration were patients with false occlusions. In this case, not only is the predictive value of the examination 100%

3 738 Escribano et al April 2000 Table I. Validity of DUEE compared with CA/surgery CA/surgery Occlusion Stenoses DUUE Occlusion Stenoses Positive predictive value of the DUEE in the diagnosis of carotid artery occlusion: 100% (CI, 94.2%-100%). True positives =78, false positives = 0, false negatives = 0, true negatives = 7. Sensitivity = 100% (CI, 94%-100%); specificity = 100% (CI, 56%- 100%). Overall accuracy = 100%. CA, Carotid angiography; DUEE, echo enhancement ultrasonography diagnosis. Table II. Validity of the DU compared with CA/surgery CA/surgery Occlusion Stenoses DU Occlusion Stenoses Fig 1. Patients distribution. CA, Carotid angiography; DU, duplex ultrasonography; DUEE, echo enhancement ultrasonography diagnosis. Positive predictive value: 91.8% (CI, 83.2%-96.3%). True positives = 78, false positives = 7, true negatives and false negatives = 0. Sensitivity = 100% (CI, 94%-100%); specificity = 0% (CI, 0%- 44%). Overall accuracy = 91%. CA, Carotid angiography; DU, duplex ultrasonography. reliable, but also the risk of error due to chance is low (95% CI, 94.2%-100%). However, when we compare the results obtained using the DU with CA/surgery (Table II), the positive predictive value of the DU is 91.8% (95% CI, 83.2%-96.3%). Seven false occlusions (false positives) were obtained using the DU. DISCUSSION In spite of agreeing with other authors that the DU is an acceptable method to diagnose the ICA occlusion, even in the best series, there is a high substantial number of explorations in which a false diagnosis of occlusion, done with a DU, could lead these patients to miss the chance of improving the prognosis of their disease by means of surgical treatment. 17,20-22 In 1996, we began to experiment with Levovist, obtaining results that were comparable with those of other centers integrated into the same European multicentric study. 11,23 The study s main objective was to evaluate the correlation in the diagnosis of internal carotid stenosis between DUEE and CA. Among the various secondary objectives, we can emphasize the tolerance to the product. Included in the study were 255 patients from 20 different centers. The use of Levovist enabled a better assessment in cases where there was a deficient intensity Doppler signal (DU versus CA North American Symptomatic Carotid Endarterectomy Trial [NASCET]: C. Pearson: 0.004, P =.98 ; DUEE versus CA NASCET: C. Pearson: 0.32, P =.066). Nevertheless, in the cases where the Doppler signal was moderate or had an adequate intensity, the echo-enhancement did not offer any further benefit (DU versus CA NASCET: C. Pearson: 0.51, P =.0009; DUEE versus CA NASCET: C. Pearson: 0.52, P =.0009). Conclusions could not be obtained about the DUEE s efficiency in the diagnosis of carotid occlusion because the number of cases available was lower than that required to get any significant statistical data. Regarding the above mentioned secondary objective, some adverse effects of small or moderate intensity were reported in a 5,6% of the cases. The most common was local pain (1,2%) or paresthesia (1,2%) in the punctured areas. There have been no reports of serious adverse effects

4 Volume 31, Number 4 Escribano et al 739 attributable to Levovist. The drug was well tolerated even after multiple doses. However, because Levovist contains galactose, it should not be given to individuals with galactosemia. The three patients from the present study for whom a CA was not performed because they had <50% stenosis after the practice of the DUEE are included in the group of explorations with deficient intensity Doppler signal. These three patients have been following checkups in our department for their chronic limb ischemia, and they have not had any symptoms of cerebrovascular ischemia. In the annual control with DU + DUEE, there has not appeared any change in their diagnosis. There are calcified plaques followed by a kink that makes it difficult to follow the distal internal carotid to the lesion. The stenosis degree assessment and the evaluation of the distal internal carotid that is free of disease are achieved through the raise of gain given by Levovist, making any other confirmatory test unnecessary. (An example of suspicion of occlusion is in Fig 2, in a case of deficient Doppler signal.) In the European study, our center found an increased subjective diagnostic reliability in all doubtful cases (range, 15%-50%; mean, 28%) thanks to an increase in the signal of the Doppler s spectrum and the color Doppler of 20 to 25 db. Fürst et al 24 reported that the echo-enhancement produces overenhancement of color display (blooming effect). In contrast, power Doppler mode was not compromised by gain-related blooming artifacts. In the short studied series, they find a fair correlation between DUEE and CA. The echoenhancement applied to the color duplex allows the false negative rate to be lowered from 30% to 17% in the diagnosis of carotid occlusion. From our experience, the adjustment of the gains must also be done when using the power Doppler mode. (In Fig 3 it can be seen as a case of suspicion of occlusion assessed with power Doppler mode.) We thought, like Gerriets et al, 25 that the excessive increase of the gain color as well as the power Doppler can be easily reduced by lessening the insonation power and gain if necessary. In fact, modifying these parameters in the explorations with DU is a common practice because every patient has a different index of penetration of the ultrasounds, which often forces them to be modified to obtain a proper signal. On the other hand, the possible increase of velocity would be justified because of the better detection of high-velocity components. In accordance with Gerriets et al and Gutberlet et al, 26 this increased signal did not alter the Doppler s spectrum parameters. However, it is necessary to regulate the A B Fig 2. A, False occlusion with DU (using color Doppler scanning). B, DUEE shows patency of the ICA. DU, Duplex ultrasonography; DUEE, echo enhancement ultrasonography diagnosis; ICA, internal carotid artery. Doppler scan and the color gain carefully because the important increase in the signal makes the transmitted movement due to breathing, swallowing, pulsativity of nearby vessels, and superposition of external carotid branches and could be easily mistaken for a false color Doppler filling of the lumen of the vessel being studied. This is why we hope that new multifrequency probes incorporating the second harmonic echo Doppler modality solve these problems and improve even further the value of ultrasound potentiators. This method could distin-

5 740 Escribano et al April 2000 A B Fig 3. A, False occlusion with DU (using power Doppler scanning). B, DUEE shows patency of the ICA. DU, Duplex ultrasonography; DUEE, echo enhancement ultrasonography diagnosis; ICA, internal carotid artery. guish the echoes from the echo-enhancing agent and thereby suppress those echoes from solid tissue. 27 Although the present technology does not allow a proper study of the peripheral vascular tree yet, recent studies of application of harmonic mode in echocardiography have allowed the achievement of important advances in the study of the flow of the coronary arteries in the moving myocardium. 28 In conclusion, the use of echo-enhancement in the diagnosis of carotid artery occlusion has allowed us to obtain a positive predictive value of 100% in our series; we only have to use CA in exceptional cases. Levovist allows us to optimize the technically difficult explorations with a Doppler signal of deficient intensity, as well as to improve the detection of minimal flow and slow velocities in the narrowest stenosis. This contributes to the improvement of the already good accuracy that the DU has in these studies. The possibility of accurately diagnosing carotid artery occlusion in optimal DU studies will allow us to save money, reduce hospital bed occupancy, and lower our global morbidity-mortality rate. The good

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