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In monitoring of recanalization and in sonothrombolysis, contrast-enhanced ultrasound (CEUS) is applied in extended time protocols. As extended use may increase the probability of unwanted effects, careful safety evaluation is required. We investigated the safety profile and beneficial effects of CEUS in a reperfusion model. Wistar rats were subjected to filament occlusion of the right middle cerebral artery (MCA). Reperfusion was established after 90 minutes, followed by recombinant tissue-type plasminogen activator (rt-PA) treatment and randomization to additional CEUS (contrast agent: SonoVue; 60 minutes). Blinded outcome evaluation consisted of magnetic resonance imaging (MRI), neurologic assessment, and histology and, in separate experiments, quantitative 3D nano-computed tomography (CT) angiography (900 nm(3) voxel size). Nano-CT revealed severely compromised microcirculation in untreated animals after MCA reperfusion. The rt-PA partially improved hemispheric perfusion. Impairment was completely reversed in animals receiving rt-PA and CEUS. This combination was more effective than treatment with either CEUS without rt-PA or rt-PA and ultrasound or ultrasound alone. In MRI experiments, CEUS and rt-PA treatment resulted in a significantly reduced ischemic lesion volume and edema formation. No unwanted effects were detected on MRI, histology, and intracranial temperature assessment. This study shows that CEUS and rt-PA is safe in the situation of reperfusion and displays beneficial effects on the level of the microvasculature.

Accurate assessment of stroke is critical for patient prognosis and selection of appropriate treatment regimens in order to optimize patient outcomes. Advanced neurosonologic techniques are straightforward, portable, and cost-effective, representing significant advantages over other noninvasive imaging modalities for monitoring of the hemodynamic status of acute ischemic stroke. Ultrasound findings acquired both early (<3 h from onset of stroke) and later (6-24 h after stroke) have demonstrated feasibility and validity for the detection of stenosis/occlusion of key intracranial structures, such as the middle cerebral artery, and for immediate and unambiguous indication of flow velocities, particularly when contrast enhancement is used. In addition, the target of thrombolysis can be identified and localized, and the success of therapy monitored, by transcranial ultrasound. Finally, transcranial ultrasound can be used to gauge the appropriateness of more complex and costly imaging studies, thereby optimizing utilization of health care resources., (Copyright 2008 S. Karger AG, Basel.)

Objective: The immediate hemodynamic effects of contrast agents are well documented. Less is known about their longer-lasting effects. We investigated the later effect of iopromide on the neurovascular coupling mechanism after the performance of cerebral or coronary angiography. Neurovascular coupling is a fine-tuned and reliable mechanism adapting cerebral blood flow to cortical activity. When performing a visual stimulation and measuring the resultant flow velocity change in the posterior cerebral artery transcranial Doppler has been used to determine vascular integrity., Methods: The visually evoked blood flow velocity response in the posterior cerebral artery was measured with transcranial Doppler before, 1-2 h after and the day after angiography. The overshoot of the flow velocity response and the stable flow velocity level at the end of the stimulation phase were used to compare the different conditions., Results: A significantly diminished overshoot was found 1-2 h after angiography only in patients undergoing cerebral angiography. The stable blood flow velocity levels at the end of the stimulation phase remained unchanged in all cases., Conclusions: Our finding demonstrates effects of contrast media on dynamic blood flow regulation of the cerebral vasculature 1-2 h after application of direct contrast agent suggesting a possible concentration effect of the contrast agent. However, since the relative blood flow velocity increase under stable blood flow conditions remained constant, this dynamic alteration does not cause a reduction in cerebral blood flow., (Copyright 2003 S. Karger AG, Basel)

Ultrasound contrast agents (UCAs) have a distinct diagnostic impact on transcranial Doppler (TCD) and duplex sonography. In addition to the properties of the UCA and ultrasound imaging modes, the duration of contrast enhancement depends on the administration mode. Infusion of UCAs may be appropriate for prolonging the diagnostically useful time of elevated Doppler intensity. Five sedated dogs were investigated by TCD during infusion with SonoVue, a new UCA consisting of sulfur hexafluoride microbubbles. The infusion rate was varied, and the time-intensity curves were analyzed. Infusion rate of 70 ml/h provided a stable mean level of increased Doppler intensity up to 24 to 26 dB over baseline, whereas a rate of 35 ml/h did not result in a stable plateau (range 8-19 dB over baseline [5 minutes after starting time]). The maximum increases in Doppler mean intensity (18.2 dB [35 ml/h] and 25.6 dB [70 ml/h]) were significantly different (P = .025). Pharmacokinetic analysis of SonoVue during inflow (by exponential functional fitting of the time-mean intensity curves) and elimination (by linear regression analysis) revealed no dose-related differences. This study demonstrated a dose-dependent level of increased Doppler mean intensity within the brain circulation during infusion of SonoVue. Unlike the bell-shaped course of Doppler signal enhancement seen after bolus injection, infusion generates a stable plateau, which is an important prerequisite for more advanced contrast applications.

Background and Purpose: The authors investigated the safety and diagnostic potential of a new ultrasound contrast agent (SonoVue) using transcranial color-coded duplex sonography (TCCS)., Methods: Forty patients were enrolled in a multicenter, open-label (on-site), blind (off-site), randomized, dose-ranging crossover study. SonoVue was administered as an intravenous bolus injection of 4 different dosages (0.3, 0.6, 1.2, and 2.4 mL). Efficacy was evaluated as (1) off-site assessment of global quality of the Doppler investigation (based on color or power Doppler images and spectral analysis) at baseline and following each dose of SonoVue according to a 4-point scale (from very poor to excellent imaging of blood flow) and (2) duration of clinically useful signal enhancement and color or power Doppler visualization of blood flow. Additional on-site efficacy assessments performed following each dose of SonoVue included confidence in diagnosis and global consequences of contrast enhancement on diagnosis. Safety evaluations included clinical laboratory tests, neurological examination, injection site tolerability, and incidence of adverse events and their relationship to the study agent., Results: All doses of SonoVue significantly improved the global quality of Doppler examinations (P < .05). The median duration of clinically useful enhancement was dose related (P < .001) and ranged from 2 to 6 minutes at the highest dose. The administration of the contrast agent changed a nondiagnostic study to a diagnostic one in 66% of patients and increased the confidence in diagnosis in 74% of cases. No serious adverse events were recorded following SonoVue administration. The observed adverse reactions were all transient and mild in intensity., Conclusions: The results obtained from this multicenter study demonstrate that the administration of SonoVue to patients with ischemic cerebrovascular disease who undergo TCCS examination of cerebral vessels improves the visualization of intracranial arteries, providing a dose-dependent contrast enhancement and a clinically useful duration of signal enhancement related to the dose. During this multicenter study, SonoVue proved to be a safe and well-tolerated compound.

Background and Purpose: It is unclear which harmonic imaging mode (power Doppler or gray-scale imaging) is superior and which measuring method is the most robust for the description of brain perfusion., Methods: We performed an animal study on 6 beagles through the intact skull using a SONOS 5500 device and Optison injected intravenously in 3 different doses (0.15, 0.3, and 0.6 mL). Intensity versus heart-cycle plots for the brain parenchyma and the basal cerebral arteries were generated to evaluate the peak increase (PI) from baseline and the area under the curve (AUC)., Results: With harmonic gray-scale imaging, a homogeneous increase in echo contrast of the brain parenchyma was observed. The effect was dose dependent, resulting in a significant increase in PI as well as an insignificant increase of the AUC with 0.3 mL versus 0.15 mL contrast agent (P=0.03 and P=0.65, respectively; n=5). With harmonic power Doppler, injection of the 3 different doses resulted in a nonsignificant increase in PI and AUC P=0.17, n=6 for both). After normalization of the brain signal to the peak arterial signal in individual dogs, a significant increase could be demonstrated (P=0. 03 and P=0.01, respectively; n=6). The signal pattern of harmonic power Doppler was inhomogeneous, with stronger signal increases in the anterior part of the brain., Conclusions: Gray-scale imaging leads to a more homogeneous increase in echo contrast of the brain tissue and may be more suitable for displaying brain perfusion. The PI of the signal intensity seems the most robust parameter for the description of cerebral perfusion with both imaging modes under investigation.

Insufficient ultrasound penetration through the temporal bone is a serious limitation of transcranial ultrasound diagnostics. In a phase I study, the authors studied safety and ultrasound enhancing potentials of the new transpulmonary ultrasound contrast agent SonoVue, which contains sulfur hexafluoride gas microbubbles stabilized by a phospholipid shell. Twelve healthy volunteers received four different doses of SonoVue (0.3 ml, 0.6 ml, 1.2 ml, and 2.4 ml) intravenously. The duration of ultrasound contrast enhancement was measured by transcranial Doppler sonography (TCD) and transcranial color-coded sonography (TCCS). Safety and tolerability was monitored during the study and for 24 hours after contrast agent administration. TCD: Duration of spectral enhancement (signal intensity of 5 dB over baseline) was observed dose-related (p < 0.0001; Friedman-test) for (0.3 ml) 136 +/- 63.4 seconds; (0.6 ml) 191 +/- 63.3 seconds; (1.2 ml) 314 +/- 88 seconds; (2.4 ml) 434 +/- 168 seconds [mean +/- SD]. Dependent on dosage, the peak signal amplification in TCD was significantly different (p < 0.001; Friedman-test) as well: (0.3 ml) 24.5 +/- 2.0 dB; (0.6 ml) 26.0 +/- 1.6 dB; (1.2 ml) 27.6 +/- 2.2 dB; (2.4 ml) 28.4 +/- 2.2 dB (mean +/- SD). TCCS: Mean time of optimal enhancement increased from 214 +/- 73 seconds (0.3 ml) to 356 +/- 14 seconds (2.4 ml) in a dose-dependent manner. In TCCS, signal amplification appeared to be stronger with increasing doses. Adverse events were not observed during the study. This investigation describes the ultrasound enhancing potential of SonoVue in the intracranial cerebral circulation. SonoVue proved to be well tolerated and provided a long-lasting ultrasound contrast enhancement that supports an optimal transcranial ultrasound diagnostic.

Harmonic imaging increases the signal-to-noise ratio in grey-scale imaging. With the use of ultrasound contrast agents (UCA), imaging of brain perfusion seems possible. The authors used an ultrasound system in connection with a 1.8/3.6-MHz harmonic sector transducer and an acoustic densitometry unit for quantification of ultrasound intensity in the thalamus (THAL), the temporoparietal white matter (TPWM), and the lateral fissure (LF). Ten milliliters of BY963, a spherosome-air-based UCA, was injected intravenously in 12 healthy volunteers. Time-intensity curves were calculated. Mean increase of intensity (standard deviation [SD]), mean area under the time-intensity curve (AUC) from baseline (SD), and mean transit time (MTT) (SD) in the region of LF, THAL, and TPWM were 2.2 +/- 1.7, 1.1 +/- 0.6, 0.9 +/- 0.9 dB and 16.7 +/- 22.7, 4.7 +/- 4.7, 3.7 +/- 6.3 as well as 11.1 +/- 3.5, 9.7 +/- 3.1, and 11.9 +/- 8.0, respectively. There was a statistically significant difference for mean AUC (p = 0.02) but none comparing mean intensity increase (p = 0.07) and MTT (p = 0.9). The authors' study indicates that different regions of the human brain show different time-intensity curves. These results suggest that it is possible to measure parameters closely related to perfusion in various regions of the adult human brain.

Objective: To evaluate the influence of different Doppler system settings on time-intensity curves after ultrasound contrast agent (UCA) bolus injection. This is important for the comparison of different UCAs., Methods: Six sedated dogs were investigated with a transcranial Doppler system and Doppler power, sample volume size and high pass filter settings were modified during the procedure. Mean time intensity curves were determined and peak values of mean intensity as well as the decrease in Doppler intensity were compared for the different system settings. Three different UCAs were used (SonoVue(TM), BY963 and Levovist(TM))., Results: The Doppler time intensity curves showed a typical two phase decrease with a distribution phase alpha and an elimination phase beta with all three UCAs. Altering the system settings had a significant effect on the mean peak Doppler intensity for SonoVue(TM) (P=0.02) but not for BY963 or Levovist(TM) (P=0.07 and P=0.39, respectively), due to high variation of the Levovist(TM) and BY963 intensity values. There were no significant differences between the alpha slopes of BY963 and Levovist(TM) (P=0.96), or the beta slope of Levovist(TM) and SonoVue(TM) (P=0.62), when the results of all system settings were combined., Conclusion: Different Doppler system settings show no significant influence on the decrease of mean Doppler intensity, but have a significant effect on peak intensity.

Ultrasound contrast agents change the acoustic properties of brain tissue. This can be quantified with acoustic densitometry. In a dog model, the authors examined changes in acoustic impedance in the thalamic and parietal white-matter regions of the brain after intravenous injection of the spherosome containing an ultrasound contrast agent (BY963) filled with perfluoropentane gas. The authors examined six sedated mongrel dogs with a Hewlett-Packard Sonos 1500 device. BY963 filled with perfluoropentane (0.2 ml/kg body weight) was injected three times with a time interval between injections of 5 minutes. Time-dependent changes in mean acoustic impedance were calculated. The authors found a significant increase in peak acoustic impedance after fractional injection of 0.6 ml/kg body weight (3 x 0.2 ml/kg body weight) in the thalamus region up to 7.0 IU (p = 0.006). In the parietal white matter the increase in peak acoustic impedance was not significant (p = 0.06). Statistical comparison of the increase in peak acoustic impedance between placebo and BY963 injection in the thalamus region showed a significant difference after the first injection (p = 0.01) but showed no significance after the second and third injections. The authors concluded that thalamus and parietal white matter of the brain showed different accumulations of BY963.

Ultrasound contrast agents improve the signal-to-noise ratio of reflected ultrasound, enhancing the diagnostic value of transcranial Doppler (TCD). In dog studies, we investigated the time course of TCD signal amplitude after application of a phospholipid-containing ultrasound contrast agent (BY963) filled with different gases. The median time of Doppler amplitude enhancement exceeding 5 dB was determined using isoflurane-, isopentane-, trichlortrifluoroethane-, air-, argon-, and perfluoropentane-filled BY963 (69, 72, 75, 78, 88, and 245 seconds respectively). The decrease of time-intensity curve and the duration of signal enhancement showed significant differences comparing the different gases (p = 0.04 and 0.03, respectively). The time course of in vitro stability of BY963 agitated with the different gases measured by absorbance of light (500 nm) showed a retarded decay for perfluoropentane, a rapid decrease for air, isopentane, trichlortrifluoroethane, and argon, and a very rapid decrease using isoflurane. The time course of the different gases depended on the physiochemical properties (lipophilicity and the solubility in water) of the gas encoated in the phospholipid shell. Perfluoropentane-filled BY963 showed the highest in vitro stability and the longest duration of TCD enhancement compared with the other gases used.

Objectives: To study the effects of different colour imaging modes on the contrast-medium-enhanced image of the intracranial cerebral arteries., Methods: Twelve healthy volunteers were studied transcranially after administration of 10 ml BY963 successively with Power Doppler (p-TCCS) and with colour Doppler frequency imaging mode (f-TCCS) in a randomized order., Results: The latency time (mean+/-SD) from the injection until the signal enhancement in the middle cerebral artery was 17.1+/-5.8 s for p-TCCS and 17.8+/-4 s for f-TCCS, and the duration of the optimal diagnostically useful signal enhancement was 44.2+/-8.2 s and 40.2+/-12.6 s respectively., Conclusions: Based on the measured parameters, both imaging modes were of equal value. Theoretical differences in sensitivity of the two methods play no particular role facing the immense signal enhancement after echo contrast application.

Background and Purpose: Ultrasound attenuation caused by the skull is a major limitation of transcranial Doppler. Echocontrast agents (EAs) may solve this problem. The aim of the present study was to investigate the characteristics of a new echocontrast agent (BY963) containing air bubbles stabilized by phospholipids., Methods: Nine healthy volunteers received three different doses (2.5, 5.0, and 10 mL) of BY963 at an injection rate of 0.25 mL/s. The Doppler signal amplitude obtained from the middle cerebral artery was recorded with a 2-MHz pulsed-wave Doppler system. After complete decay of the signal enhancement, upward stroking of the veins of the upper arm was performed to evaluate the stability of the EA in the venous system., Results: A dose-dependent increase of at least 30 dB in the Doppler signal amplitude lasted 19 to 47, 35 to 64, and 48 to 126 heart cycles (68% range) after 2.5, 5.0, and 10 mL EA, respectively. In 6 cases, there was a biphasic increase in EA enhancement. Upward stroking of the forearm, in general 12 to 18 minutes after administration, caused a Doppler signal enhancement of at least 30 dB in 6 cases., Conclusions: Each injection of BY963 caused a diagnostically relevant Doppler signal enhancement. A considerable amount of EA remained stable in the venous system for at least 12 minutes. The biphasic dose-response fits to models of dilution-indicator theory and indicates free recirculation, as well as a nonlinear washout curve.

Ultrasound contrast agents (UCAs) are improving the signal-to-noise ratio of the reflected ultrasound so that Doppler frequency spectra can be recorded even under poor sonographic conditions. This is of particular diagnostic value in transcranial Doppler sonography. Depending on specific pharmacologic properties, echo-contrast agents may cause different increase and duration in Doppler signal amplitude. We used a dog model to study the temporal profile of Doppler signal amplitude after application of a phospholipid-containing echo-contrast agent (BY 963). In addition, we compared it with a contrast agent containing albumin (Albunex). Spherosome suspension BY 963 resulted in a dose-dependent increase in the duration of ultrasound amplification (Doppler enhancement of 1 mL, 3 mL and 10 mL of BY 963 per animal: 62.4 +/- 8.4, 72.8 +/- 9.2 and 67.7 +/- 4.2 s, respectively, n = 6). Detection of BY 963 in the extracranial jugular vein demonstrated that the UCA passes through the cerebral microcirculation (cerebral transit time was 2.2 +/- 0.2 s, n = 4). The signal enhancement lasted longer using the spherosome suspension compared with the albumin-containing solution (77.2 +/- 11.6 and 31.1 +/- 3.7 s, respectively, n = 6), and the maximum increase in intensity was more pronounced (27.0 +/- 2.0 and 17.5 +/- 2.2 dB, respectively, n = 6).

Background and Purpose: Transcranial ultrasound diagnostics are particularly hindered by insufficient ultrasound penetration through the temporal bone. The use of ultrasonic contrast media to enhance the Doppler signal is an important step toward the solution of this problem. In the present study we investigated the tolerability and the diagnostic value of a new intravenous transpulmonary ultrasonic contrast medium, BY963., Methods: In two phase I studies, 8 healthy volunteers received a spherosome suspension containing a phospholipid as the active ingredient. The intravenous injection was performed in three doses (2.5, 5, and 10 mL) at four different injection rates (0.25, 0.5, and 1 mL/s and bolus). The duration and degree of the signal enhancement were measured by two transcranial ultrasonic procedures presently used in clinical practice: transcranial Doppler sonography (TCD) and transcranial color-coded sonography (TCCS). The assessment of tolerability was based on chemical laboratory parameters and hemodynamic data (heart rate, blood pressure, electrocardiogram) and on questionnaires relating to general well-being., Results: BY963 was tolerated without complications. All 38 administrations of the echo contrast medium produced a marked increase in the TCD signal (> 30 dB) in the intracranial basal cerebral arteries. To obtain the optimum time window for diagnostic use, higher doses with slower injection rates are advantageous. The duration of optimal contrasting was 42 to 68 seconds (TCD) and 12 to 132 seconds (TCCS), depending on the method and mode of administration. Bolus injections gave rise to an increased incidence of color artifacts., Conclusions: BY963 significantly improves intracranial Doppler imaging while being well tolerated. The signal enhancement lasts long enough for TCCS to display all basal cerebral arteries after just one injection.

Background: Patent foramen ovale as a possible stroke risk factor can be diagnosed with transcranial Doppler sonography (TCD) by detecting intravenous contrast medium crossing from the right to the left atrium. The present study evaluates the reliability of this method., Summary of Report: We performed TCD and transesophageal echocardiography simultaneously in 50 patients using galactose microbubbles. We observed bubble signals passing the middle cerebral artery in 7 patients less than 20 seconds after injection; we found positive TCD tests in 14 patients using the Valsalva maneuver. With transesophageal echocardiography patent foramen ovale could be detected in 15 patients (sensitivity, 0.93; specificity, 1; P < .01)., Conclusions: TCD with echo contrast is a reliable screening tool for patent foramen ovale. A standardized procedure including the Valsalva maneuver is essential to prevent false-negative results.