Background and Purpose Pulsed color Doppler imaging of cerebrovascular structures permits rapid visual identification of the intracranial vessels. In some patients, however, the clinical utility of transcranial ultrasound examinations is limited by poor tissue penetration and inadequate imaging of vessels. This phase-two clinical trial evaluates whether administration of an echocontrast agent in such ultrasound-refractory patients enhances image acquisition enough to yield meaningful diagnostic impressions.
Methods This is a phase-two clinical trial of safety and efficacy of the “galactose/palmitic acid–based microbubble preparation” Levovist injection (Berlex Laboratories). Thirty subjects with clinical indications for cerebrovascular imaging but refractory to transcranial Doppler studies were enrolled in a nonrandomized, single-center study. Echocontrast agent was administered intravenously in a tiered-dose protocol. Safety was determined by clinical and laboratory monitoring for 18 to 24 hours. Efficacy of contrast enhancement was determined by comparisons between each patient’s precontrast (control) and postcontrast images.
Results No significant patient discomfort, side effects, or adverse reactions occurred that were due to the intravenous administration of the echocontrast agent. Optimal image enhancement was obtained using the 300-mg/mL concentration (3 g bolus) of contrast. Visualization of both individual arterial segments and/or the entire circle of Willis was demonstrated. Clinical confidence of diagnostic impressions was achieved in 77% (23/30) of subjects.
Conclusions The transpulmonary ultrasound contrast agent (Levovist injection) was easily administered and found to be safe in the 30 patients studied and increased the diagnostic utility of transcranial ultrasound in 77% of the patients studied.
Transcranial color Doppler imaging (color-coded real-time sonography) is an emerging diagnostic method that allows noninvasive imaging of intracranial vascular structures. The visual imaging added by this method permits exact localization of the Doppler sample volume, therefore allowing more rapid visual identification of the intracranial vessels in question and shortening examination time. In that vascular lesions represent the primary application of transcranial Doppler examinations, the addition of an imaging capability offers clear advantages, if the problems of poor ultrasound penetration and resultant poor resolution can be overcome. Ultrasound contrast-enhancing agents may accomplish this.
Ultrasound imaging depends on the acoustic interface between tissue and on the acoustic reflection within those tissues. Ultrasound contrast agents help by increasing the reflection of blood through the addition of microscopic bubbles of air. Previous commercial echocontrast agents, such as shaken saline or sonicated radiographic contrast media, are limited to right-heart contrast because the microbubbles formed cannot pass through the filtration of the lungs. Feasibility of transcranial signal enhancement with galactose-based microparticles was first demonstrated by Ries et al1 in 1991 in an animal model. This galactose-based sonographic contrast agent is characterized by microbubbles that are capable of traversing the cardiopulmonary circulation after intravenous injection, providing enhanced Doppler signals in the intracranial blood vessels. Three recent studies have reported its effectiveness in increasing Doppler signal intensity and improving signal-to-noise ratio and, thus, fine resolution.2 3 4
Goldberg et al,2 in a series of experiments using dogs, rabbits, and woodchucks, demonstrated that the intravenous contrast agent enhanced both color and spectral Doppler signals and was nontoxic and effective over a prolonged period, allowing for adequate analysis of the areas of interest. Bogdahn et al3 recently published information on 10 patients in a phase-two study on contrast-enhanced transcranial color-coded real-time sonography. The procedure was well tolerated, with no significant side effects or subject discomfort, and allowed detection of supratentorial arteries, deep cerebral veins, and, through the foramen magnum, the entire vertebrobasilar system.
Ries and colleagues4 evaluated Doppler spectral signal augmentation but not image enhancement using Levovist injection. Their study, which included 20 patients, suggested that galactose-based echocontrast was safe and demonstrated enhancement of insufficient native spectral signals in transcranial Doppler examinations.
The present study is a phase-two, open-label, single-site, nonrandomized study to examine the efficacy of this agent; that is, did the administration of this galactose-based intravenous sonographic contrast agent add to the diagnostic value of the procedure?
Subjects and Methods
This is the first US study of the intravenous echocontrast agent Levovist in patients undergoing Doppler ultrasonographic imaging examination of the carotid and intracranial arteries. The objective was to determine safety, patient acceptance, and extent of enhancement of blood pool echogenicity in patients. This open-label, nonrandomized study was conducted in 30 patients at one center (Scripps Clinic and Research Foundation). Each patient was to serve as his or her own control, and efficacy was to be evaluated from the color Doppler imaging. Inclusion criteria specified that each patient clinically had required a diagnostic ultrasound study of the carotid or intracranial arteries and exhibited suboptimal baseline color Doppler images of the vessel(s) in question, that is, the study performed was inadequate for diagnostic purposes. All subjects had to be at least 18 years of age, medically stable, and not pregnant if female. All subjects gave informed written consent approved by our hospital institutional review board. Patients were excluded if they had a history of galactosemia or galactokinase deficiency, were unable to give proper informed consent, or were found to have any unstable vascular or other disease or had received any contrast material within the preceding 44 hours.
The patients were admitted to the General Clinical Research Center of Scripps Research Institute. Researchers conducted continuous electrocardiographic and electroencephalographic recordings, blood pressure monitoring, and various blood and urine studies before, during, and after contrast administration for a period of up to 18 to 24 hours.
The sonographic agent used in these experiments was a galactose-based microbubble preparation: Levovist injection (Berlex Laboratories). A suspension was prepared by mixing the dry granulate with sterile water for injection at the time of administration. The palmitic acid stabilizes the microbubbles that form when dissolved gas is adsorbed to the surface of the microparticle. Ninety-nine percent of the microparticles to which the microbubbles are adsorbed are <8 μm in diameter, and 50% are <2 μm. Concentrations of 200, 300, and 400 mg/mL in a dosage volume of 10, 10, and 7.5 mL, respectively, were available for intravenous administrations. Investigators were free to explore ascending tiered-dose ranges by repeated injections subject to a single dose maximum of 3 g and a total dose exposure per patient not to exceed 14 g, per protocol (actual range, 5 to 8.4 g). All the injections were through an antecubital vein, and the injection rate of contrast was 1 to 2 mL/s through an 18- to 20-gauge indwelling catheter with a three-way stopcock. The injection was followed by a 5-mm flush of saline to clear the injection line. In all 30 patients, a minimum of two injections were performed; 9 subjects were given three injections, and 1 subject was given four.
Extracranial and Intracranial Ultrasound Technique
Color-coded Doppler and spectral Doppler recordings were performed using ATL Ultra Mark 9. Linear-array transducers of 5 MHz and 7.5 MHz were used for the extracranial evaluation, and a 2.25-MHz phased-array transducer was used for the intracranial imaging. The intracranial studies were performed through transforamenal approaches using the transtemporal, transorbital, and transforamen magnum protocols with procurement of coronal and axial information (see Otis and Ringelstein5 for protocol details). All the information was recorded on permanent written records and stored on videotape.
Baseline sonographic images were based on the best possible images attainable for the patient (not necessarily the maximum enhancement seen). Because the contrast injection can increase the signal-to-noise ratio, the investigator was free to adjust instrument settings as needed to optimize the image after the contrast administration.
Thirty separate patients were examined (14 men, 16 women). There were 71 injections and 11 different arteries of interest examined. The average patient age was 64.3 years (range, 25 to 84 years). Symptoms prompting evaluation were 11 cerebrovascular accidents, 7 transient ischemic attacks, 4 memory changes, 3 asymptomatic carotid stenoses, 3 amaurosis fugax, 1 bilateral visual loss, and 1 aneurysm in addition to 3 arteriovenous malformations (AVMs) found by other diagnostic studies. The risk factors included 12 patients with coronary artery disease, 11 with hypertension, 6 with peripheral vascular disease, 4 with elevated cholesterol and/or lipids, 2 with diabetes mellitus, and 1 who was a heavy smoker (Table 1⇓). No technical problems were encountered injecting the agent, and the procedure itself was relatively simple.
All 30 subjects tolerated the injections without significant side effects or serious adverse experiences. No clinically significant electrocardiographic or electroencephalographic changes were observed. There were no clinically significant changes in mean values for laboratory parameters at 30 minutes and 24 hours after examination. Patients with mild adverse experiences included 4 with taste perversion, 1 with injection site reaction, 1 with a sensation of cold, 1 with pain sensation on injection, 1 with headache, 1 with paroxysmal atrial tachycardia, 1 with supraventricular tachycardia, and 1 with a convulsion. The last 2 patients’ symptoms were not felt to be due to the contrast material. The patient with supraventricular tachycardia had had these same symptoms on multiple occasions in the past. The second patient had a long history of seizures and failed to take his usual anticonvulsant medicine the night before the study (Table 1⇑).
For all subjects, 200 mg/mL of contrast enhancement was only moderate and was inadequate in most cases. The dose that provided the best image was 10 mL of 300 mg/mL of contrast. Injections with 400 mg/mL added little additional value and usually increased color artifacts. Color artifacts were noted during the first few seconds of signal enhancement, requiring gain adjustment.
Mean time to contrast appearance was 9.4 seconds, but it varied widely (range, 3 to 24 seconds), especially between intracranial and extracranial vessels. Average time of appearance of contrast material in the extracranial carotid artery was approximately 3 seconds, whereas the time taken for contrast to appear in the middle cerebral artery after antecubital injection was approximately 8 seconds. However, this also varied greatly depending on the adequacy of the temporal window access. The majority of patients with suboptimal precontrast studies had inadequate bony windows, ie, skull bone thickness. We also found considerable variation from one temporal window to another in the same subjects. Other variables were inadvertent Valsalva maneuvers made by the patient, which increased transient time, and unavoidable variations in the rate of injection. Although every attempt was made to have a rapid bolus injection, injection rate varied from 1 to 2 mL/s. Also, small amounts of contrast material may remain within the injected vein and be released into the general circulation after muscular movement by the patient. The end of contrast enhancement was defined as the return of the image to its precontrast appearance despite changes in gain adjustment. Average duration of enhancement was 142.1 seconds, with a range of 30 to 460 seconds (Table 2⇓).
In 23 of the 30 patients (76.7%), there was a change from initial diagnosis or confirmation of suspected diagnosis from the precontrast study. No enhancement at all was seen in only 1 subject. Four patients were evaluated for patency of the internal carotid artery, ie, an incomplete vessel was noted and/or there was uncertainty as to possible patency because of low flow. Patency was confirmed in these 4 subjects after contrast injection. Five patients with total occlusion of the internal carotid artery were examined for intracranial collaterals. All five postcontrast examinations were able to demonstrate collateral circulation either through the anterior or posterior communicating artery (Fig 1⇓). Four patients were evaluated for possible vascular dementia. One had bilateral high-grade internal carotid artery stenosis and was shown to have excellent intracranial collateral flow, and 2 of the remaining 3 were examined for small-vessel disease and found to have no stenosis; the fourth provided inadequate study despite three tier-dosed contrast injections. Six additional patients were evaluated for intracranial stenosis as the cause of their stroke (1 middle cerebral artery, 1 ophthalmic artery, 1 carotid siphon, 1 basilar artery, and 2 for integrity of the circle of Willis). For all 6 patients, arteries in question were adequately visualized after contrast injection, establishing a firm diagnosis. That is, the artery was patent, and no stenosis was demonstrated. One patient with a suspected dissection in the vertebral artery was studied. No dissection was seen before contrast; after contrast, some narrowing was noted, but a specific diagnosis of dissection could not be made. Three patients were evaluated for possible small plaque ulceration, 2 in the internal carotid artery and 1 in the common carotid artery. In 1 of the 3 patients, contrast injection added to the diagnostic certainty. Five patients were examined because they had no temporal window access to the circle of Willis. In all 5 patients, the circle of Willis was adequately evaluated after contrast (Fig 2⇓). Three patients with an AVM were evaluated. In 2 patients, the exact size and measurement of the AVM was obtained; more importantly, contrast injection permitted localization of these abnormal vessels so that the vascular dynamics could be studied (Fig 3⇓). In the third patient, there was no additional information obtained after contrast. In 1 patient, a 2-mm aneurysm in the middle cerebral artery was not visualized either before or after contrast. The results are tabulated in Table 3⇓.
Transcranial Doppler sonography was first described by Aaslid et al6 in 1982 and has proven to be a reliable and reproducible method of assessing intracranial vessels. More recently, ultrasonic improvements have led to morphological imaging of the vessels by color-coded real-time sonography.7 8 9 10 11 12 13 However, there are technical limitations inherent in Doppler imaging methods. Most notably, it is difficult to detect low-grade stenosis and weak signals seen in the case of extremely reduced blood flow and with high-grade stenosis and cerebral vasospasm.14 15 Intracranial imaging is further limited by the high degree of ultrasound reflection and absorption by the skull, whereby much of the emitted energy is lost.16 Because of this, many artifacts are produced as a result of the high ultrasound emission energy needed. This increased scattering of the ultrasonic beam with its subsequent large sample volume leads to limited spatial resolution and insufficient signal-to-noise ratio. This recently developed galactose-based contrast agent may help solve these problems by increasing the reflected ultrasound.
Previous studies by Goldberg et al,2 Bogdahn et al,3 and Ries et al4 have shown that this galactose-based contrast agent has the ability to enhance both color and spectral Doppler signals over a clinically useful period and improves flow sensitivity and resolution of the vessels in question. The increased ability of this agent to detect flow in large and small vessels intracranially should aid in the demonstration of stenosis, the differentiation of totally from partially occluded blood vessels, and the evaluation of small peripheral vessels for vasospasm. These previous studies already have demonstrated the ability to record flow or visualize the large basal cerebral arteries as well as peripheral branches, parenchyma, and veins. This study was designed to answer specific clinical questions to demonstrate efficacy. Admittedly, in the majority of patients the change in diagnosis was from uncertain to firmly established. The benefits of a definite diagnosis are difficult to measure quantitatively. However, an element of uncertainty in any diagnosis increases the likelihood of clinically inappropriate action, including unnecessary invasive procedures or surgery. In those patients in whom there was some question as to patency of the internal carotid artery, visualizing the vessel and establishing patency made them eligible for surgical versus medical treatment.17 In the patients in whom excellent intracranial collateralization was established, unnecessary angiography and surgery for reperfusion were avoided. The imaging experience in patients with AVM was most helpful in that in two cases the exact measurements of the AVM and small contributing vessels were easily demonstrated. This is of potential importance in the follow-up of those patients who undergo embolization or surgery.18 The study demonstrates the capability of the agent to display (1) segments of vessels that were otherwise undetectable, (2) flow where no flow was felt to be the case, (3) major portions of the circle of Willis when noncontrast studies were unable to adequately penetrate the skull, (4) collateral flow through the ophthalmic artery, (5) distal vertebrobasilar artery imaging where none could be performed before contrast agent injection, and (6) exact vessel localization in detection of AVMs. These capabilities can lead to the establishment of firm diagnoses that significantly influence clinical judgment and treatment.
- Received July 26, 1994.
- Revision received October 24, 1994.
- Accepted November 3, 1994.
- Copyright © 1995 by American Heart Association
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