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(Radiology. 1999;211:427-431.)
© RSNA, 1999

Experimental Studies

Effect of US Contrast Agents on Spectral Velocities: In Vitro Evaluation1

Michelle L. Melany, MD, Edward G. Grant, MD, Shella Farooki, MD, David McElroy, BS and Carolyn Kimme-Smith, PhD

1 From the Department of Radiological Sciences, University of California, Los Angeles, Medical Center, 10833 Le Conte Ave, M/C 172115, Los Angeles, CA 90095-1721 (M.L.M., S.F., D.M., C.K.S.), and the Department of Radiology, West Los Angeles Veterans Affairs Medical Center, Los Angeles, Calif (E.G.G.). Received June 10, 1998; revision requested July 27; revision received August 17; accepted October 14. Address reprint requests to M.L.M.


   Abstract
TOP
 Abstract
Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To evaluate the effect of ultrasonographic (US) contrast agents on measurements of peak velocity with spectral Doppler US in stenotic and nonstenotic flow states.

MATERIALS AND METHODS: Nonpulsatile flow was established in a flow phantom with 0%, 50%, 75%, and 90% stenoses. SH U 508A, perflenapent emulsion, and perfluorohexane emulsion were the contrast agents evaluated. Before and after administration of each contrast agent, two peak velocity measurements obtained proximal to, at the site of, and distal to the stenosis in each vessel model were averaged. The percentage difference in peak velocity after contrast agent administration was calculated for each site interrogated. The mean, SD, and coefficient of variation of the percentage difference in peak velocity were calculated.

RESULTS: Percentage differences in peak velocity after contrast agent administration at different sample volume sites were not significantly different irrespective of the degree of stenosis or the contrast agent evaluated.

CONCLUSION: The contrast agents evaluated do not produce a statistically significant increase in peak velocity. If this result is corroborated in clinical practice, contrast agents can be used without reevaluating existing Doppler US thresholds for stenosis.

Index terms: Blood, flow dynamics, 9*.129842 • Blood vessels, stenosis or obstruction, 9*.721 • Ultrasound (US), contrast media, 9*.12988 • Ultrasound (US), Doppler studies, 9*.12984


   Introduction
TOP
 Abstract
 Introduction
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Most ultrasonographic (US) contrast agents enhance images by producing differences in acoustic impedance between the agent and the surrounding medium (1). This process leads to improved backscattering (echogenicity) in perfused tissue, as well as in vascular structures. Contrast agents can improve visualization of macroscopic vessels with both color and spectral Doppler imaging (2). Potential clinical uses include enhanced visualization of Doppler signals that are weak secondary to depth or attenuation (3). Examples include superior identification of the intracranial vessels with transcranial Doppler US and enhancement of the native renal arteries in patients suspected of having renal artery stenosis (4,5).

Spectral Doppler imaging plays a critical role in diagnosis of vascular pathologic conditions. The presence of plaque or clinically important stenosis disturbs normal laminar flow patterns; the result is turbulence and an increase in the velocity of blood flow through the stenotic region. The severity of vascular stenosis is related to alterations in spectral indexes such as peak systolic velocity, end-diastolic velocity, and various velocity ratios. For high-grade stenoses, peak systolic velocity is thought to be the parameter that is the most accurate indicator of the degree of vessel narrowing (6).

There is controversy in the literature about whether US contrast agents produce an increase in the detected peak systolic velocity. An increase in the maximum Doppler shift of 17%–45% has been reported (7). Some authors maintain that observed increases in peak velocity measurements represent an artifact produced by contrast agents. Other investigators believe that these higher velocities represent real, but weak, signals that were undetected without the use of contrast agents and may be more conspicuous in cases of clinically important stenosis (6,8). It is necessary to determine if an elevation of velocity is found with some or all contrast agents. If an elevation of peak velocity is present, it is essential to investigate whether this phenomenon is reproducible and whether it represents a real finding or an artifact. This information could have a great effect on the future clinical use of US contrast agents because US diagnosis of many diseases, such as renal artery and carotid artery stenosis, is based on peak systolic velocity measurements.

Therefore, an experiment was undertaken to determine whether there is a statistically significant increase in peak velocity, above the baseline variation in Doppler peak velocity measurements due to operator and equipment variability, in stenotic and nonstenotic flow states after the administration of three US contrast agents.


   MATERIALS AND METHODS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
The experiment was performed with a Doppler US flow phantom (ATS Laboratories, Bridgeport, Conn) composed of a tissue-mimicking rubber-based material with a propagation velocity of 1,450 m/sec and an attenuation of 0.5 dB/cm/MHz. The model consists of four flow channels simulating superficial vasculature. The simulated vessels are located 15 mm below the scanning surface. Each vessel model is 8 mm in diameter and has an intrinsic stenosis of 0%, 50%, 75%, or 90% area of occlusion. A scanning well built into the phantom permits the use of water as the acoustic coupling agent.

The phantom was connected with plastic tubing to a pump that generated nonpulsatile flow. A flowmeter was used to set the pump to the same flow rate for each experiment (Fig 1). Heparinized porcine blood was used for the experiments because of the similar composition of porcine blood and human blood. Each contrast agent was tested by using a single porcine donor for that experiment. Blood was changed for each contrast agent investigated.



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  		Figure 1. Photograph shows the flow pump and flowmeter (left side of image) connected with plastic tubing to the flow phantom (right side of image), which has a scanning well and four channels.

 
The contrast agents tested were SH U 508A (Levovist; Schering, Berlin, Germany), perflenapent emulsion (EchoGen; Sonus Pharmaceuticals, Bothell, Wash), and perfluorohexane emulsion (Imagent; Alliance Pharmaceutical, San Diego, Calif) in concentrations of 200 mg/mL, 20 mg/mL, and 1 mg/mL, respectively. The amount of each agent injected was proportional to the dose given to human patients. Multiple injections were necessary for SH U 508A. Only a single injection was necessary for perflenapent and perfluorohexane because the enhancement persisted for the duration of the experiment. The agents were handled according to instructions from the respective pharmaceutical companies. Once each agent was prepared and activated, it was then introduced into the porcine blood that was flowing in the phantom.

All experiments were performed with the same US unit (HDI 3000; Advanced Technology Laboratories, Bothell, Wash) and the same 4–7-MHz linear-array broadband transducer. The measurements were all made by one sonologist (E.G.G.). The sample volume was 3 mm, and the angle of interrogation was 60°. The gain was adjusted only after administration of the contrast agent; this procedure was necessary to produce a satisfactory spectral image from which to derive peak velocity measurements. Gray-scale imaging was used because it allowed better demonstration of flowing blood in the simulated vessel than did color Doppler imaging. Blooming artifact degraded image quality when color Doppler imaging was used.

Before and after administration of each agent, two angle-adjusted peak velocity readings were recorded proximal to, at the site of, and distal to the stenosis in all three of the stenotic vessel models. Two peak velocity readings were recorded as well in the normal (0% stenosis) vessel model before and after contrast agent administration. Spectral tracings were observed for 4 seconds, and intrinsic software (High Q; Advanced Technology Laboratories) was used to decrease the intraobserver variability and inherent operator bias that occur with manual determination of peak velocity. This software provides automatic calculation and display of values for specified Doppler US parameters including peak velocity (Fig 2).



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  		Figure 2a. Spectral Doppler images show the peak systolic velocity (PSV) and end-diastolic velocity (EDV) measured proximal to the stenosis in the 75% stenosis vessel model. (a) Before contrast agent administration, the peak velocity is 39.9 cm/sec. (b) After contrast agent administration, the peak velocity is 35.9 cm/sec. The gray-scale image shows enhancement in the phantom.

 


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  		Figure 2b. Spectral Doppler images show the peak systolic velocity (PSV) and end-diastolic velocity (EDV) measured proximal to the stenosis in the 75% stenosis vessel model. (a) Before contrast agent administration, the peak velocity is 39.9 cm/sec. (b) After contrast agent administration, the peak velocity is 35.9 cm/sec. The gray-scale image shows enhancement in the phantom.

 
The two peak velocity measurements derived with these methods were averaged for each interrogation site before and after administration of each agent. All results were then calculated as the percentage difference in average peak velocity after contrast agent administration. Statistical analysis was performed with BMDP statistical software (Cork, Ireland) by using analysis of variance with the Tukey test (1 df). A P value of less than .05 was used to indicate a statistically significant difference. The mean, SD, and coefficient of variation of the percentage difference in peak velocity were calculated with different variables (eg, site of sample volume, type of contrast agent, degree of stenosis) held constant.


   RESULTS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Table 1 gives the percentage difference in peak velocity after contrast agent administration for each agent at each sample volume site and each degree of stenosis. Negative values indicate a decrease in velocity, whereas positive values indicate an increase in velocity. The percentage differences in peak velocity proximal to, at the site of, and distal to the stenosis were not significantly different (P = .35, P = .26, and P = .32, respectively) irrespective of the degree of stenosis (50%, 75%, or 90%). Furthermore, the percentage differences in peak velocity proximal to, at the site of, and distal to the stenosis were not significantly different (P = .27, P = .16, and P = .50, respectively) irrespective of the contrast agent evaluated.


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  		TABLE 1. Percentage Differences in Peak Velocity after Contrast Agent Administration
 
Table 2 summarizes the mean, SD, and coefficient of variation of the percentage difference in peak velocity after contrast agent administration. The absolute value of the percentage difference in peak velocity was used in cases in which there was a decrease in velocity. Baseline values (n = 12) of the mean, SD, and coefficient of variation were derived from percentage differences in peak velocity obtained with all three agents at sites where there was no stenosis; these values were based on all measurements from the 0% stenosis model (n = 3) and all measurements proximal to the stenosis in the 50%, 75%, and 90% stenosis models (n = 9) for each of the three agents. The same statistical values were calculated for all three agents at the site of the stenosis (n = 9) and distal to the stenosis (n = 9). Finally, the same statistical values were calculated for each agent at the site of and distal to the stenosis (n = 6). All three agents demonstrated similar mean peak velocity differences.


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  		TABLE 2. Mean, SD, and Coefficient of Variation of Percentage Difference in Peak Velocity after Contrast Agent Administration
 

   DISCUSSION
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In the United States, the only US contrast agents currently approved by the Food and Drug Administration are human albumin (Albunex; Molecular Biosystems, San Diego, Calif) (8) and human albumin microspheres with octofluoropropane gas (Optison; Molecular Biosystems) (9), both of which are approved only for cardiac use. There are, however, numerous trials in progress with other agents that will likely receive Food and Drug Administration authorization for broader diagnostic radiology applications in the near future.

There is debate in the literature about a possible artifactual increase in peak velocity caused by US contrast agents (6,7,10). Should these agents be used to diagnose vascular stenoses, the presence or absence of an important increase in detected peak velocity after contrast agent administration must be determined. If contrast agents elevate velocity, studies must be performed to investigate whether this elevation represents actual high-velocity flow that was undetected without the use of contrast agents or whether the velocity increase is an artifact caused by the contrast agent. If the velocity elevation represents real flow or an artifact that is reproducible, then revision of the current velocity criteria for diagnosing vascular stenoses may be necessary when contrast agents are used. If the velocity increase is artifactual and not reproducible, then contrast agents may not be useful for the specific indication of determining the degree of stenosis. US contrast agents may, however, be useful in other areas of vascular diagnosis, such as determining the patency versus occlusion of vessels and stents (11,12).

The accuracy of Doppler US measurements is known to be operator and equipment dependent. For Doppler US to be clinically useful, the expected range of variability in Doppler US measurements must be determined. The inter- and intraobserver variabilities of peak velocity measurements with conventional (nonenhanced) spectral Doppler US are reported to be as high as 16% (13). Whyman et al (14) investigated interobserver variability in a femoral artery flow phantom and found an error in estimation of percentage stenosis of ±20%. Throughout the study, these investigators used the same US scanner and transducer with a fixed angle of interrogation and sample volume size; however, the Doppler gain was adjusted as needed. In other studies, the variability of Doppler US flow estimates due to both equipment and operator factors has been 10%–26% (15,16). In our study, there was no statistically significant velocity increase with US contrast agents above the baseline variability in Doppler US flow measurements reported in the literature.

Sources of variability in obtaining peak systolic velocity measurements can be classified into three broad categories: (a) factors pertaining to the blood and blood vessels (eg, blood viscosity, flow turbulence, vessel size and depth); (b) equipment factors (eg, transducer beam pattern, transducer frequency, manufacturer); and (c) factors pertaining to the Doppler US technique (eg, sample volume size, sample volume placement, angle correction, gain, transducer motion) (17,18). In our experiment, sources of variability that were not controlled included factors inherent in human acquisition of Doppler US measurements, such as sample volume placement, gain, and transducer motion.

Forsberg et al (7) noted an increase in maximal Doppler shift of 20%–45% in an in vivo experiment in a rabbit aorta model. These authors acknowledged that the cardiac output could rise as a reaction to the arrival of the contrast agent bolus in this small animal model and that this increase in the ejection fraction could result in an increase in the flow velocity. To determine whether this increase in cardiac output and ejection fraction was in fact the cause of the elevation in maximal Doppler shift, Forsberg et al (7) performed an in vitro experiment. They generated pulsatile flow in a flow phantom and found only a 17% increase in Doppler shifts. This percentage variation in velocity is within the range of baseline variability in obtaining Doppler US measurements reported in the literature. These authors used equipment from four different manufacturers in their experiments. The contributions of intra- and interobserver variability and equipment factors to the 17%–45% variation in Doppler US measurements are unable to be determined from their article.

In our study, it was necessary to adjust the gain after contrast agent administration because of the new signal-to-noise conditions imposed by the contrast material–enhanced image. For routine (nonenhanced) Doppler US measurement in the clinical setting, gain adjustments are necessary during periods in which signal-to-noise conditions result in the display of a suboptimal image or Doppler tracing. Increasing the gain increases the brightness of the Doppler spectra on the monitor. These amplified spectra result in an increase in perceived velocity when the peak velocity is manually determined, as well as when intrinsic software is used to determine peak velocity. Despite the contribution of gain adjustments to the variability in velocity measurements, spectral velocity measurements obtained with nonenhanced Doppler US have been used to diagnose vascular disease for more than a decade.

The gain was decreased after each injection of contrast agent (a single injection for perflenapent and perfluorohexane, multiple injections for SH U 508A). The gain was not increased to compensate for decreased contrast agent concentration over time as the experiment progressed. The reason why the gain was not increased was largely because, in our experimental model, the simulated vessels were located only 15 mm deep to the scanning surface and flowing blood was easily identified in the vessels with or without the contrast agent. The order in which the nonstenotic and stenotic vessel models were scanned after contrast agent administration varied from agent to agent. The purpose of this variation in scanning order was to eliminate the potential effect of decreasing contrast agent concentration over time on the peak velocity values obtained with different degrees of stenosis.

Forsberg et al (7) reported that a 15-dB reduction in gain brought their Doppler spectrum back to the baseline appearance. These authors noted elimination of contrast enhancement when they decreased the gain. In our experiment, the gain was decreased to minimize the artifact in the spectral display that was associated with excessive contrast enhancement in the superficial vessel model. Minimization of this artifact was achieved without loss of contrast enhancement with all of the contrast agents evaluated. With this technique, a statistically significant increase in peak velocity was not demonstrated with any of the contrast agents at any level of stenosis (Fig 2).

Petrick et al (6) used variable sound attenuators in their in vitro experiment to control for the effect of excessive increase in signal intensity from the contrast agent. The sound attenuators were used to simulate unfavorable examination conditions, which are an indication for US contrast agents. These authors concluded that, if the effect of excessive signal intensity is eliminated, the contrast agent (SH U 508A in their study) does not cause an increase in velocity.

Sponheim and Myhrum (10) used a flow phantom with nonpulsatile flow without sound attenuators. These authors concluded that the principal effect of the contrast agent (sonicated albumin [Infoson; Molecular Biosystems]) was signal enhancement. They described the importance of adjusting the instrument settings, including the gain, to obtain accurate velocity estimates with and without contrast agents. In our experimental model, optimal signal-to-noise conditions were achieved before and after contrast agent administration by manually decreasing the gain, the same method that would be used in the clinical setting with or without contrast agents.

In our study, no statistically significant differences in peak velocity were found in either the stenotic or nonstenotic vessel model. It is possible that, in the in vivo situation of eccentric stenoses secondary to atherosclerotic plaque, greater turbulence at the site of stenosis might produce different results. The parvus tardus waveform was not identified distal to the stenosis in either of the vessel models regardless of the degree of stenosis or the presence or absence of a contrast agent. Absence of this waveform was likely due to lack of compliance in the simulated vessels of the phantom.

In conclusion, our results do not substantiate the theory that US contrast agents elevate peak velocity. Elevation of peak velocity identified by other authors that was greater than that anticipated from the baseline variability in peak velocity measurements may have been caused by improper gain settings. No statistically significant differences in measured peak velocity were found when different US contrast agents or different degrees of stenosis were compared after contrast agent administration.Practical application: If these results are corroborated in human trials, revision of the current velocity criteria for diagnosing vascular stenosis when US contrast agents are used would likely not be necessary regardless of the contrast agent used or the degree of stenosis.


   Footnotes
 
9*. Vascular system, location unspecified Back

Author contributions: Guarantor of integrity of entire study, M.L.M.; study concepts, M.L.M., E.G.G.; study design, M.L.M., C.K.S.; definition of intellectual content, M.L.M.; literature research, M.L.M., E.G.G.; clinical studies, M.L.M., E.G.G., S.F.; experimental studies, M.L.M., E.G.G., C.K.S.; data acquisition, M.L.M., E.G.G., D.M., S.F.; data analysis, C.K.S., S.F., M.L.M.; statistical analysis, C.K.S.; manuscript preparation and editing, M.L.M., S.F.; manuscript review, M.L.M., S.F., E.G.G.


   References
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

  1. Needleman L, Forsberg F. Contrast agents in ultrasound. Ultrasound Q 1996; 13:121-138.
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This Article
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