(Radiology. 2001;219:823-827.)
© RSNA, 2001
Echo-enhanced Transcranial Color-coded US: Clinical Usefulness of Intravenous Infusion versus Bolus Injection of SH U 508A1
Thilo Hölscher, MD,
Felix Schlachetzki, MD,
Albrecht Bauer, MD,
Ludger Rosin, MD,
Birgit Götz, MS and
Ulrich Bogdahn, MD
1 From the Department of Neurology, University of Regensburg, Universitätsstrasse 84, D-93053 Regensburg, Germany (T.H., F.S., L.R., B.G., U.B.); and the Department of Clinical Development Diagnostics, Schering, Berlin, Germany (A.B.). Received January 25, 2000; revision requested March 30; final revision received October 31; accepted December 12. Address correspondence to T.H. (e-mail: thilo.hoelscher@klinik.uni-regensburg.de).
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ABSTRACT
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Twelve patients with insufficient transcranial Doppler signal underwent transcranial color-coded ultrasonography before and after administration of SH U 508A with different modes of administration. Clinically useful enhancement time after bolus injection was surpassed by that after standard infusion (1 mL/min), whereas further prolongation was observed after individualized infusion. Intravenous infusion of SH U 508A provides a prolonged useful enhancement compared with that after bolus injection.
Index terms: Arteries, US, 13.12988 • Brain neoplasms, US, 10.30, 10.12988 • Microbubbles, 13.12988 • Ultrasound (US), contrast media, 13.12988 • Ultrasound (US), Doppler studies, 13.12988
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INTRODUCTION
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Transcranial color-coded ultrasonography (US) is a tool with which to evaluate and monitor pathologic conditions of the parenchyma and vasculature of the central nervous system (1). Insufficient study conditions due to the absorption and scattering of ultrasound by the acoustic-bone window frequently require the use of echo-enhancing agents. SH U 508A (Levovist; Schering, Berlin, Germany) is an approved galactose-based microbubble echo-enhancing agent for transcranial US. The recommended mode of administration of SH U 508A has been bolus injection with an average rate of 1–2 mL/sec, which results in an average signal enhancement of 20–30 dB during 2–3 minutes (2). Therefore, the echo-enhancing effect lasts for only a brief time in relation to the duration of the entire study, which limits its clinical usefulness.
The purpose of this study was to clarify whether the clinically useful echo enhancement time could be extended by means of continuous intravenous infusion of SH U 508A.
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Materials and Methods
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Patient Evaluation and Visualization of Vessel Segments
Between March and August 1997, 12 consecutive patients (eight men and four women; mean age, 52 years; age range, 18–77 years) with insufficient Doppler signal retrieved at transtemporal or transnuchal color-coded US were enrolled in this study. The main diagnostic indications were suspected stenoses in the intracranial arteries or vascularization of intracranial tumors (Table). The patients were accepted for the trial according to the following criteria: Each patient (a) was scheduled to undergo vascular Doppler US in intracranial arteries or tumor vasculature and (b) had diagnostically insufficient Doppler signal. All patients gave their written informed consent, and the study was approved by the local ethics committee, according to the declarations of Helsinki (1995) and Tokyo (1998).
The following vessel segments were evaluated for bilateral depiction with color Doppler US through the transtemporal bone window: (a) middle cerebral artery (M1–M3 segment, n = 6), (b) anterior cerebral artery (A1–A3 segment, n = 6), (c) posterior cerebral artery (P1–P3 segment, n = 6), (d) internal carotid siphon (n = 2), (e) posterior communicating artery (n = 2), and (f) distal basilar artery (n = 1). A total of 23 vessel segments were evaluated. Visualization of vessel segments was evaluated before administration of SH U 508A and after bolus injection, standard infusion, or individualized infusion of the contrast material. The vessel segments were evaluated on-line by the investigator and at least one of the other coauthors, by consensus. The investigator was not blinded to the type of contrast material administered. Adverse events after administration of SH U 508A—such as thermal sensations or pain at the injection site, anaphylactic reactions, or cardiopulmonary side effects—were monitored by the investigator throughout the entire study and 24 hours thereafter. In case of unexpected toxicity reactions, the study protocol provided for interruption of the infusion or the procedure at any time.
During the course of the study, the Doppler signal after administration of SH U 508A was graded with the following scores: 0, unchanged; 1, slight increase; 2, considerable to optimal increase; 3, excessive increase with undesired effects despite use of an appropriate gain setting.
If a considerable to optimal increase (score of 2) was achieved, the contrast agent was clinically useful for the diagnosis. Each procedure was recorded on full-length S-VHS videotape and as a digital file on the hard drive. All data were acquired in the color mode.
Administration of SH U 508A
The study population was randomly assigned to one of two groups. Group 1 (n = 6) started with one intravenous bolus injection (2 mL/sec) of 4 g of SH U 508A (period 1) followed by a standard intravenous infusion (3 mL/min) of 4 g (period 2) after a wash-out phase of at least 10 minutes. Group 2 (n = 6) started with a standard infusion of 8 g (period 1) followed by an 8-g bolus injection after a wash-out phase of at least 10 minutes (period 2). In cases of diagnostic need (unclarified diagnostic question after bolus or standard administration) in both groups (n = 9), an optional infusion of 8 g of SH U 508A (period 3) was administered with an individually adapted infusion rate. The actual rate of the optional infusion was selected according to the results of signal enhancement after standard infusion, with the aim of a score of 2.
The SH U 508A suspension was administered via a flexible indwelling 20-gauge cannula in a cubital or forearm vein. The concentration of SH U 508A was 400 mg of microparticles per milliliter. Each vial contained 4 g of dry galactose granules; before administration, the dry galactose material was suspended in 8 mL of water for injection, vigorously shaken, and administered after 2 minutes of standing time (3). An interval of at least 10 minutes was selected between each administration, and the suspension was administered only when the signal returned to baseline.
The infusion rate was decreased in cases of excessive signal enhancement (blooming artifacts) or increased in cases of insufficient signal enhancement with standard infusion; the rate then remained unchanged during the entire study. An optional infusion was selected if the investigator had the impression that the diagnostic yield with SH U 508A could be improved with an individually adapted infusion rate.
US Examinations
US studies were performed with standard color duplex US systems (Sequoia 512, 3V2c phased-array transducer, Acuson, Mountain View, Calif; Sonoline Elegra, 2.5PL20 phased-array transducer, Siemens Medical Systems, Erlangen, Germany). Insonation was performed through transtemporal and transnuchal bone windows. The purpose of each study was to answer a specific clinical diagnostic question, which necessitated scanning of different intracranial planes; therefore, Doppler intensitometry could not be performed to quantify Doppler signal enhancement, since this would require use of a constant transducer position. Before the first administration of SH U 508A, the gain settings, transmit power, pulse repetition frequency, and other machine parameters were adapted individually for an optimal signal-to-noise ratio. These parameters remained unchanged during the entire study.
Statistical Analysis
All statistical evaluations were based on the times during the study when a score of 2 was achieved. All data were analyzed for the mean plus or minus the standard error of the mean and minimum and maximum values (range). The Wilcoxon paired-sample test (4) was performed as an overall comparison in which the individual clinically useful enhancement times (score of 2) for each administration mode were added. After addition of the data from both groups, statistical analysis was performed between the following pairs: (a) bolus injection versus standard infusion, (b) bolus injection versus individualized infusion, and (c) standard infusion versus individualized infusion. The Wilcoxon paired-sample test was also performed after visualization of vessel segments: The sum of segments detected with nonenhanced US was compared to that detected with SH U 508A–enhanced US for each administration mode.
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Results
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Two of the 12 patients were not included in the subanalysis of visualization of vessel segments, owing to insufficient signal retrieval after administration of SH U 508A (patient 4) and insonation through transnuchal windows (patient 5). Patient 4 was not included in the subanalysis of clinically useful enhancement time owing to insufficient signal retrieval.
Safety
No adverse effects were observed in the 12 cases. The intravenous bolus injections and intravenous infusions were well tolerated. No technical problems concerning the preparation and administration of SH U 508A occurred.
Visualization of Vessel Segments
Ten of the 12 patients were evaluated for visualization of vessel segments (Fig 1). In nine of the 10 patients (no signals were retrieved before administration of contrast material in patient 9), a mean of 8.7 ± 1.5 (SD) (range, 0–17) vessel segments were identified before administration of SH U 508A. After bolus injection in all 10 patients, a mean of 18.6 ± 0.9 (range, 14–23) vessel segments were observed (P 
.005). During standard infusion, the number of vessel segments visualized increased to a mean of 19.5 ± 0.85 (range, 16–23). In nine of 10 patients with individualized infusion conditions (no optional infusion in patient 7), a mean of 19.4 ± 0.84 (range, 16–23) vessel segments were identified. Statistical significance was observed in the comparison of bolus injection with standard infusion (P = .04), but differences were not significant in the comparisons of bolus injection with individualized infusion (P .05) and standard with individualized infusion (identical values).
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Figure 1. Bar graph depicts the total number of vessel segments (vertical axis) visualized per patient (horizontal axis) after precontrast transcranial color-coded US (light gray bars) and postcontrast transcranial color-coded US with bolus injection (black bars), standard infusion (white bars), and individualized infusion (dark gray bars) of SH U 508A. In comparison with bolus injection at postcontrast imaging in all cases, infusion did not lead to a decrease in the number of vessel segments visualized. In five of 10 patients, results with standard and individualized infusion were superior to those with bolus injection. No differences were observed between the standard or individualized infusion.
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Clinically Useful Enhancement Time
In group 1, period 1, clinically useful enhancement after intravenous bolus administration of 4 g of SH U 508A varied between 45 and 200 seconds (mean, 113.8 seconds ± 25.7). In group 2, period 2, clinically useful enhancement with intravenous bolus administration of 8 g of SH U 508A varied between 30 and 226 seconds (mean, 124.4 seconds ± 36.2).
After intravenous standard infusion (rate, 3 mL/min) of SH U 508A, clinically useful enhancement was prolonged to a mean of 311 seconds ± 128.1 (range, 70–930 seconds) in group 1 (4 g) and to a mean of 422 seconds ± 66.1 (range, 182–586 seconds) in group 2 (8 g).
Individualized infusion (individual infusion rate) of 8 g of SH U 508A resulted in a mean clinically useful enhancement time of 1,011.4 seconds ± 168.8 (range, 425–1,381 seconds) in group 1 and a mean of 539.5 seconds ± 141.7 (range, 285–920 seconds) in group 2 (Figs 2, 3).
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Figure 2. Bar graph depicts clinically useful enhancement time (vertical axis) after administration of SH U 508A for each patient (horizontal axis). In all but one case, standard infusion (black bars) prolonged the enhancement time in comparison with bolus injection (gray bars), whereas a further increase was achieved after individualized infusion (white bars) in eight of nine cases.
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Figure 3a. Patient 3. Glioblastoma multiforme. (a) Sagittal gadolinium-enhanced (gadopentetate dimeglumine, Magnevist; Berlex Laboratories, Wayne, NJ) T1-weighted (repetition time, 10 msec; echo time, 4 msec; acquisition time, 6 minutes 46 seconds; one signal acquired; field of view, 251.0; matrix, 256 x 256) magnetization-prepared rapid gradient-echo three-dimensional magnetic resonance image depicts the tumor. (b) Precontrast, b-mode, transverse transcranial color-coded US scan depicts the tumor (arrow). (c) Postcontrast US scan was obtained after the standard infusion of SH U 508A (3 mL/min). (d) Postcontrast US scan obtained after individualized infusion shows a typical Doppler spectrum in the inferior venous sinus. (e) Later postcontrast US scan shows atypical flow pattern in tumor vessels.
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Figure 3b. Patient 3. Glioblastoma multiforme. (a) Sagittal gadolinium-enhanced (gadopentetate dimeglumine, Magnevist; Berlex Laboratories, Wayne, NJ) T1-weighted (repetition time, 10 msec; echo time, 4 msec; acquisition time, 6 minutes 46 seconds; one signal acquired; field of view, 251.0; matrix, 256 x 256) magnetization-prepared rapid gradient-echo three-dimensional magnetic resonance image depicts the tumor. (b) Precontrast, b-mode, transverse transcranial color-coded US scan depicts the tumor (arrow). (c) Postcontrast US scan was obtained after the standard infusion of SH U 508A (3 mL/min). (d) Postcontrast US scan obtained after individualized infusion shows a typical Doppler spectrum in the inferior venous sinus. (e) Later postcontrast US scan shows atypical flow pattern in tumor vessels.
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Figure 3c. Patient 3. Glioblastoma multiforme. (a) Sagittal gadolinium-enhanced (gadopentetate dimeglumine, Magnevist; Berlex Laboratories, Wayne, NJ) T1-weighted (repetition time, 10 msec; echo time, 4 msec; acquisition time, 6 minutes 46 seconds; one signal acquired; field of view, 251.0; matrix, 256 x 256) magnetization-prepared rapid gradient-echo three-dimensional magnetic resonance image depicts the tumor. (b) Precontrast, b-mode, transverse transcranial color-coded US scan depicts the tumor (arrow). (c) Postcontrast US scan was obtained after the standard infusion of SH U 508A (3 mL/min). (d) Postcontrast US scan obtained after individualized infusion shows a typical Doppler spectrum in the inferior venous sinus. (e) Later postcontrast US scan shows atypical flow pattern in tumor vessels.
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Figure 3d. Patient 3. Glioblastoma multiforme. (a) Sagittal gadolinium-enhanced (gadopentetate dimeglumine, Magnevist; Berlex Laboratories, Wayne, NJ) T1-weighted (repetition time, 10 msec; echo time, 4 msec; acquisition time, 6 minutes 46 seconds; one signal acquired; field of view, 251.0; matrix, 256 x 256) magnetization-prepared rapid gradient-echo three-dimensional magnetic resonance image depicts the tumor. (b) Precontrast, b-mode, transverse transcranial color-coded US scan depicts the tumor (arrow). (c) Postcontrast US scan was obtained after the standard infusion of SH U 508A (3 mL/min). (d) Postcontrast US scan obtained after individualized infusion shows a typical Doppler spectrum in the inferior venous sinus. (e) Later postcontrast US scan shows atypical flow pattern in tumor vessels.
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Figure 3e. Patient 3. Glioblastoma multiforme. (a) Sagittal gadolinium-enhanced (gadopentetate dimeglumine, Magnevist; Berlex Laboratories, Wayne, NJ) T1-weighted (repetition time, 10 msec; echo time, 4 msec; acquisition time, 6 minutes 46 seconds; one signal acquired; field of view, 251.0; matrix, 256 x 256) magnetization-prepared rapid gradient-echo three-dimensional magnetic resonance image depicts the tumor. (b) Precontrast, b-mode, transverse transcranial color-coded US scan depicts the tumor (arrow). (c) Postcontrast US scan was obtained after the standard infusion of SH U 508A (3 mL/min). (d) Postcontrast US scan obtained after individualized infusion shows a typical Doppler spectrum in the inferior venous sinus. (e) Later postcontrast US scan shows atypical flow pattern in tumor vessels.
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For further analysis, the individual clinically useful enhancement times for each administration mode were added (group 1 plus group 2). After bolus injection, the overall mean clinically useful enhancement time was 118.6 seconds ± 20.5 (range, 30–226 seconds), whereas after standard infusion, the overall mean enhancement time was 361.5 seconds ± 74.7 (range, 70–930 seconds) (P .005). The overall mean clinically useful enhancement time with individualized infusion was 801.6 seconds ± 134.7 (range, 285–1,381 seconds) (P .008 in comparison with bolus injection). Standard versus individualized infusion revealed a preference for the individualized infusion mode (P .038).
In a comparison of the different amounts of SH U 508A administered in each group (group 1, 4 g of SH U 508A for bolus injection and standard infusion; group 2, 8 g for each administration mode), no preference was indicated for the high-dose group. For each gram of SH U 508A, the mean clinically useful enhancement time in group 1 was 28.45 seconds after bolus injection and 77.75 seconds after standard infusion; in group 2, the values were 15.55 and 52.75 seconds, respectively (differences were not significant).
The individualized infusion rates varied considerably within each group, depending on the individual study conditions. The slowest infusion was performed in patient 6 (suspected stenosis of the middle cerebral artery), with a rate of 0.75 mL/min. Clinically useful enhancement lasted 1,381 seconds in comparison with 182 seconds after standard infusion (3 mL/min). The maximum administration rate of 5 mL/min was administered in two cases. Patient 8 (suspected stenosis of the middle cerebral artery) experienced an increase in clinically useful enhancement time from 200 seconds after standard infusion to 425 seconds after optional administration. In patient 2 (central nervous system metastasis of a hepatocellular carcinoma), enhancement time with the optional infusion rate was not superior to that with the standard infusion rate.
The clinically useful enhancement time was more than 10 minutes in five of the nine patients who underwent individualized infusion and was more than 20 minutes in two of the five cases. After standard infusion, clinically useful enhancement continued after 10 minutes in one patient. We concluded that (a) the infusion rate must be adapted to achieve optimal enhancement over time; (b) SH U 508A is even more stable than expected (plasma half-life, 10–11 minutes); and (c) in most cases, 10 minutes are sufficient to allow identification of the vessel segments.
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Discussion
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Since the introduction of transcranial color-coded US by Furuhata et al in 1987 (5), transcranial color-coded US has proved to be a valid noninvasive bedside tool for vascular and parenchymal imaging of the brain (6–8). Absorption and scattering by the often unfavorable individual acoustic-bone windows, which results in a low signal-to-noise ratio, restrict the sensitivity of the method and thus reduce the clinical effect. Echo-enhancing agents, described by Gramiak et al (9) more than 25 years ago, improve signal backscattering by means of their high acoustic impedance. SH U 508A, as a transpulmonary-stable galactose-based agent, has been shown to achieve effective signal enhancement at transcranial Doppler US (10–12). Therefore, specific additional information may be extracted from US studies, such as quantification of vascularization of a central nervous system tumor (12).
Because of rapidly changing study conditions after intravenous bolus injection of SH U 508A, the neurosonologist is confronted by severe artifacts such as color blooming, shadowing artifacts, and low signal intensities, which restrict the clinically useful enhancement time. Constant administration of the agent should therefore lead to a steady-state concentration in the blood pool at a diagnostically useful level. Since a sufficiently extended enhancement time is required to answer the diagnostic questions (eg, tumor vascularization, venous sinus thrombosis), continuous intravenous infusion seems to be a plausible solution (13).
We compared the clinically useful enhancement time achieved with standard intravenous bolus administration versus that with intravenous infusion of SH U 508A. Independent of the individual diagnostic question, the enhancement time after standard infusion (rate, 3 mL/min) was significantly superior to that with the bolus injection (P .005). Comparable prolongation of the enhancement time was achieved with the individualized infusion (P .008), which was superior to the standard infusion (P .038) and resulted in an almost sevenfold increase in the enhancement time in comparison with bolus administration. The great variation in individualized infusion rate from 0.75 to 5.00 mL/min reflects the individual quality of the transtemporal bone windows. In our experience, higher infusion rates lead to a clinically useful enhancement time comparable to that with an extended bolus injection mode. We encountered another problem in transcranial color-coded US: Higher infusion rates helped clearer delineation of peripheral vessel segments, but blooming artifact was then seen in the basal circle of Willis (Fig 4). To delineate the vessel’s main stems, however, the infusion rate must be reduced, which leads to a loss of Doppler signal in the periphery. This phenomenon may be due to the lack of stability of SH U 508A.
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Figure 4a. Patient 6. Exclusion of suspected stenosis of the middle cerebral artery. (a) Precontrast, c-mode, transverse transcranial color-coded US scan depicts the circle of Willis and vessel segments. ACA = anterior cerebral artery, CS = contralateral skull, MCA = middle cerebral artery, PCA = posterior cerebral artery. (b) Postcontrast image was obtained after bolus injection of SH U 508A.
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Figure 4b. Patient 6. Exclusion of suspected stenosis of the middle cerebral artery. (a) Precontrast, c-mode, transverse transcranial color-coded US scan depicts the circle of Willis and vessel segments. ACA = anterior cerebral artery, CS = contralateral skull, MCA = middle cerebral artery, PCA = posterior cerebral artery. (b) Postcontrast image was obtained after bolus injection of SH U 508A.
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To compare visualization of vessel segments, those of 10 of 12 patients were visualized with both pre- and postcontrast conditions. The number of segments identified was significantly increased on postcontrast compared with precontrast studies (P .005). No significant differences were observed in the comparison of bolus injection with standard (P .043) or individualized (P .05) infusion. In comparison with bolus injection, infusion does not result in a significant decrease in visualization of vessel segments (14).
In a study of acute and chronic adverse effects of SH U 508A in several species, results were negative for local tolerance, embryotoxicity, and mutagenicity (15). The long-term studies in beagles showed no significant differences between the physiologic effects of SH U 508A or saline. Detailed histologic investigations showed no signs of any abnormalities due to the contrast agent. The most frequent adverse events during or after administration of SH U 508A are transient thermal sensations, such as warmth or localized coldness, and localized pain. These effects may be regarded as nonspecific reactions related to intravenous administration itself, independent from the substance administered. Contraindications for administration of SH U 508A are galactosemia and severe heart insufficiency (New York Heart Association classification IV).
None of the study patients was excluded from the study because of a known contraindication. No adverse events were observed in any of the 12 patients after bolus injection or infusion of SH U 508A. These results demonstrate that intravenous infusion is as safe as bolus injection.
The administration of SH U 508A as an infusion was safe and well tolerated. At transcranial color-coded US enhanced with SH U 508A, intravenous infusion led to a significantly prolonged clinically useful enhancement time in comparison with bolus injection. A further increase in the enhancement time was achieved by individually adapting the infusion rate. No loss of visualization of vessel segments was associated with the two infusion modes, and no untoward toxicity was observed.
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FOOTNOTES
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Author contributions: Guarantors of integrity of entire study, T.H., U.B., A.B.; study concepts, A.B., U.B.; study design, A.B.; literature research, T.H., F.S.; clinical studies, T.H., F.S., U.B.; data acquisition, T.H., F.S., L.R.; data analysis/interpretation, T.H., U.B., A.B.; statistical analysis, T.H., B.G.; manuscript preparation, T.H.; manuscript definition of intellectual content, T.H., F.S., U.B., A.B.; manuscript editing, T.H.; manuscript revision/review, T.H., U.B., A.B.; manuscript final version approval, T.H., U.B.
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ABSTRACT
INTRODUCTION
