Real-Time Cerebral Angiography: Sensitivity of a New Contrast-Specific Ultrasound Technique

Study Population

In a prospective study, patients scheduled for a cerebral contrast angiogram for any reason were asked to participate and were enrolled consecutively after providing written informed consent, according to local Institutional Review Board approval. Patients had to be 18 years of age or older and had to be scheduled for cerebral x-ray angiography for any clinical indication. Patients with a known history of severe emphysema, pulmonary vasculitis, history of pulmonary embolism, or chronic renal failure were excluded from the study

Sonography Devices and Study Design

Sonoline Elegra and a Sonoline Antares (Siemens, Erlangen, Germany) sonography systems were used for the transcranial studies. Both devices are equipped with 2.5-MHz phased-array transducers (2.5PL20, Elegra; PX4-1, Antares).

Each side of the head was imaged with the patient in a supine position and the transducer held at the temporal bone acoustic window. The goal was to assess the intracranial vessel segments of the middle cerebral artery (M1, M2, and M3), the anterior cerebral artery (A1 and A2), and the posterior cerebral artery (P1, P2, and P3) in an axial scanning plane.

Transcranial Ultrasound Angiography (tUSA)

Because the aim was to develop an imaging technique that enables visualization of the intracranial arteries with high spatial and temporal resolution with fewer artifacts in an angiographic view, the term “transcranial ultrasound angiography (tUSA)” was chosen. tUSA is based on a phase-inversion technique using high-resolution wideband harmonic imaging to detect UCA microbubbles. To minimize microbubble destruction as a result of high acoustic intensity imaging, the minimum output power was used depending on the quality of the bone window. The goal was to lower the acoustic power to a point at which known anatomic landmarks (ie, brain stem, third ventricle) could barely be seen. The transmit power ranged between 16% and 70% of maximum (mechanical index: 1.4 at 100% output power). In cases of sufficient to optimal bone windows, the transmit frequency was increased to a maximum of 2.0 MHz. This method of tUSA has been described in detail recently.¹²

UCA and UCA Administration

We used AF0150 perflexane lipid microspheres (Imagent; IMCOR Pharmaceutical, San Diego, Calif). Imagent was FDA approved for endocardial border delineation, but as of June 2005, the agent is no longer commercially available.

The agent was supplied as 200 mg of powder in a sealed vial. It was reconstituted by adding 10 mL of water and gently mixing. The resultant microbubble suspension encapsulated perfluorohexane vapor and nitrogen in a thin phospholipid membrane and contained 5 × 10⁸ microbubbles/mL with a mean diameter of 2–3 μm.

AF0150 was administered intravenously as a bolus injection into an antecubital or forearm vein by using a 20G catheter, followed by a 5-mL saline flush. The UCA bolus dose was 0.5 mL if the intracranial image quality was optimal, 1.0 mL if not optimal but clinically useful, and 2.0 mL if the image quality was insufficient (Table 1). The UCA dose injection was given twice, once for each hemisphere. Because the maximum allowable dose for this agent is 0.2 mL/kg, an average 70-kg adult can receive a total of 14 mL. If needed, up to 2 more UCA injections were allowed in this study.

Statistical Analysis

The visualization (yes/no) of the cerebral artery segments (MCA: M1, M2, M3, ACA: A1, A2, PCA: P1, P2, P3) was assessed by an experienced sonographer who was blinded to the cerebral x-ray angiography data. The presence of all cerebral artery segments was confirmed on all x-ray angiograms. The sensitivity of visualizing the segments was calculated using the x-ray angiogram as the “gold standard.” The 95% confidence intervals (CIs) were determined for each of these values using an exact binomial distribution.¹³

In addition to sensitivity, the interobserver agreement was also assessed. For the 24 of the 35 sonography studies for which videos of the studies were available, 2 physicians with little sonography training and an experienced sonographer evaluated the scans for bilateral visualization. All 3 readers were blinded to the tUSA and x-ray data. The sensitivity of visualization was calculated for all readers independently. The McNemar χ² test for paired proportions was used to determine the difference in sensitivities between pairs of readers. The Holm method was used to adjust for multiple comparisons.¹⁴

Overall Description

Thirty patients (21 women, 9 men) were studied with tUSA. The age ranged between 18 and 81 years of age with a mean age of 50 years. Three of 30 patients underwent 2 scans, and 1 patient underwent 3 scans. These 4 patients also underwent repeated neuroradiologic interventions, including preinterventional cerebral x-ray angiography, because of arteriovenous malformation treatment, as well as postinterventional angiography. The individual study conditions, based on the quality of the temporal bone window, were as follows: 7 of 35, optimal; 21 of 35, clinically useful; and 7 of 35, insufficient study quality. Ten of the 35 scans were performed using a Sonoline Elegra sonography scanner and the remaining 25 with a Sonoline Antares system. The total UCA volume per single case ranged between 1.0 and 8.0 mL, with a mean volume of 2.8 mL of contrast agent per patient. No serious adverse events were described as a result of UCA administration; in 2 of 35 cases, a mild, transient (<60 seconds) metallic taste was reported immediately after UCA injection, and in 1 case of 35, the tUSA study failed because of IV catheter misplacement.

Sensitivity

On the right hemisphere, the sensitivity to visualize the aforementioned vessel segments ranged between 0.788 (A2 segment) and 0.970 (P1 and P2 segments). The corresponding 95% CIs were 0.611–0.910 (A2 segment) and 0.842–0.999 (P1 and P2 segments).

For the left hemisphere, the results were comparable. The sensitivity ranged between 0.829 (A2 segment) and 0.971 (M1, P1, and P2 segments) with 95% CIs of 0.664–0.993 (A2 segment) and 0.851–0.999 (M1, P1, and P2 segments), respectively (Table 2). In both hemispheres, the highest sensitivities were seen in the proximal vessel segments (M1, P1, and A1 segments), whereas the lowest values were reached in the peripheral vessel segments (M3, P3, and A2). Among the latter, the sensitivity for A2 was slightly lower compared with M3 and P3 segments.

Interobserver Reliability

Twenty-four of 35 tUSA studies were videotaped. These tapes were used for interobserver reliability and to assess the difference between inexperienced and experienced observers. The sensitivities for the visualization by the 2 physicians with little sonography training and an experienced sonographer are shown in Table 3. No statistically significant differences in sensitivities were detected between any pairs of the 3 readers, thus indicating a high interobserver agreement of visualization.