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DOI: 10.1148/radiol.2203001628
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(Radiology. 2001;220:647-654.)
© RSNA, 2001

Experimental Studies

Continuous-Infusion Contrast-enhanced US: In Vitro Studies of Infusion Techniques with Different Contrast Agents1

Stefanie Kuntz-Hehner, MD, Jon Goenechea, MD, Christoph Pohl, MD, Thomas Schlosser, MD, Christian Veltmann, Christoph Lentz, MD, Stefan Lohmaier, Alexander Ehlgen, Heyder Omran, MD, Harald Becher, MD and Klaus Tiemann, MD

1 From the Departments of Cardiology (S.K.H., J.G., T.S., C.V., C.L., S.L., A.E., H.O., H.B., K.T.) and Neurology (C.P.), University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. Received October 26, 2000; revision requested November 24; revision received February 23, 2001; accepted April 12. S.K.H. supported by a research grant from the German Society of Cardiology, Düsseldorf, Germany. K.T. and C.P. supported by a research grant from BONFOR, Bonn, Germany. Address correspondence to K.T. (e-mail: k-tiemann@uni-bonn.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To evaluate the infusion properties of three ultrasonographic (US) contrast agents and to compare different infusion techniques for achieving constant signals during harmonic power Doppler US.

MATERIALS AND METHODS: In vitro studies were performed in a flow phantom. SH U 508A, NC100100, or FS069 was continuously infused at clinically usable doses and infusion rates. To assess agent-specific physical properties, these agents were administered by using a vertically fixed infusion pump and varying infusion start times. The contrast agents were administered by also using a horizontally oriented infusion pump that was either fixed or continuously rotated to homogenize the agent in the syringe.

RESULTS: With SH U 508A and NC100100, constant signals were achieved, regardless of the infusion modality used. Compared with conventional infusion, the continuous homogenization of SH U 508A, although not necessary for signal constancy, increased the agent’s usefulness (P < .05). With FS069, only continuous homogenization yielded constant signals (P < .001).

CONCLUSION: Continuous infusion of SH U 508A or NC100100 provided constant harmonic power Doppler US signals, regardless of the infusion modality used. Because of the special physical properties of FS069, only homogenization produced constant harmonic power Doppler US signals during continuous infusion of this agent.

Index terms: Contrast media, comparative studies • Contrast media, experimental studies • Experimental studies • Ultrasound (US), contrast media, **.129842, **.12988


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
With the development of transpulmonary stable microbubbles and harmonic imaging techniques, the noninvasive assessment of tissue perfusion is now feasible, as has been previously shown for imaging the myocardium (1–5), liver, kidney (6,7), and most recently, the brain (8). Most studies of tissue perfusion imaging have been performed with myocardial contrast material–enhanced echocardiography to demonstrate the feasibility of assessing myocardial perfusion. In previous clinical trials (9–12), echo contrast agents were administered mainly by using bolus injection and frequently caused image artifacts, such as acoustic shadowing and color blooming (13–15). In addition, in quantitative tissue perfusion approaches, each bolus may enable only one imaging plane to be examined, because ultrasonographic (US) contrast agents decay relatively fast in the bloodstream. Consequently, the time for clinically useful assessment of tissue perfusion is limited, particularly with myocardial contrast echocardiography (13,16).

Continuous infusion of the contrast agent by means of an infusion pump may overcome the limitations of bolus injection. It has been shown that the duration and usefulness of the resulting contrast enhancement can be greatly increased by using continuous infusion (13). This approach allows the clinician to adjust system settings (eg, time gain compensation and gain in terms of pulsed-wave Doppler studies) and to obtain different views of cardiac organs or, with abdominal US, even multiple organs. With continuous infusion, the infusion rate can be customized to individual patients and, thus, the bubble concentration can be titrated to achieve optimal enhancement, with the result of increased usefulness (17). Moreover, there has been considerable skepticism as to whether the greater contrast enhancement obtained with bolus injection obscures possible perfusion defects (18). Finally, most advanced clinical applications, such as the assessment of replenishment kinetics following US-induced destruction of microbubbles, require constant contrast enhancement during the entire study (17,19).

Because current transpulmonary echo contrast materials have specific physical properties, different agents might need different perfusion regimens to produce constant tissue contrast enhancement. Moreover, issues such as agent decay and inhomogeneity in the syringe need to be considered in the development of infusion techniques.

The purpose of this study was twofold: to evaluate the infusion properties of three US contrast agents that are either currently under development or already approved for clinical use and to evaluate different infusion techniques.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Flow Phantom
In vitro studies were performed by using a flow phantom designed for testing echo contrast agents in laminar steady flow conditions (45 mL/min). The flow circuit was sourced by a 5-L reservoir filled with a blood analog controlled to 37°C. Continuous homogenization of the blood analog was performed by using a magnetic stirrer (RHM 71; Gerhart, Bonn, Germany). A microfilter with a mesh size of 40 µm (model D734; Diteco, Mirandola, Italy) was fixed at the outlet of the reservoir to avoid contamination of the circuit. The blood analog was pneumatically driven through the flow circuit by means of a gear pump (MCP-Z Process; Ismatec, Glattbrugg-Zurich, Switzerland). The pump served as a mixing chamber, which provided fast and homogeneous mixing of the upstream-infused contrast agent. Different infusion modalities were used.

US imaging was performed downstream of the mixing chamber by using a Plexiglas tank that contained a polyethylene tube with an inner diameter of 8 mm. For attenuation and for adaptation of the acoustic properties to a physiologic US wave propagation velocity of 1,540 m/sec, the tank was filled with castor oil. In addition, a rough rubber mat was placed in the bottom of the tank. The position of the ultrasound transducer was 8 cm above the tube, with an insonation angle of 85° to avoid reverberation artifacts. To avoid recirculation of the contrast agent, two dialysis cartridges (Hemofilter 14; Gambro Dialysatoren, Hechingen, Germany) were interposed into the flow circuit downstream of the insonation area to filter the blood analog. The efficiency of the filter process with each contrast agent was assessed by using a second ultrasound transducer behind the filter section (Fig 1).



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  		Figure 1. Diagram of the flow phantom. Contrast agents were delivered to the infusion port upstream of the mixing chamber.

 
US Device
A commercially available US machine (HDI-5000; Advanced Technology Laboratory, Bothell, Wash) equipped with a phased-array sector transducer (P4-2) that transmits the ultrasound beam at a mean frequency of 1.67 MHz and receives the beam at a mean frequency of 3.3 MHz was used to perform harmonic power Doppler US. Intermittent scanning at 1 Hz was performed to avoid bubble destruction from frame to frame. The pulse repetition frequency was kept at 1,500 Hz for imaging with NC100100 (Sonazoid; Nycomed-Amersham, Oslo, Norway) and FS069 (Optison; Molecular Biosystems, San Diego, Calif, distributed by Mallinckrodt, St Louis, Mo) and was set to 2,500 Hz for imaging with SH U 508A (Levovist; Schering, Berlin, Germany). For all contrast agents, the dynamic range was set to the highest level possible, the sensitivity was set high, and the mechanical index was set to 1.3. Line density was high for SH U 508A and medium for NC100100 and FS069. Gain settings were adjusted to avoid background noise and system saturation during the contrast-enhanced studies. The maximum strength of the signal (in decibels) never exceeded the dynamic range. The focus was set at the bottom of the tube. A sector size of the color box that covered the entire cross-sectional area of the tube was chosen. The harmonic power Doppler US images were digitally stored as raw data prior to scan conversion.

Infusion Setup
With each infusion setup, the contrast agents were continuously delivered to the flow phantom by means of a dedicated infusion pump (Braun Perfusor; Braun Melsungen, Melsungen, Germany) that contained a 10-mL syringe (Omnifix; Braun Melsungen). The outlet of the syringe was connected to the infusion port of the flow phantom either directly, with a three-way stopcock and an 18-gauge needle, or by means of special 50-cm connector tubing (Medrad, Indianola, Pa). To evaluate the infusion properties of the three transpulmonary contrast agents—SH U 508A, NC100100, and FS069—we compared the following infusion modalities:

Vertical syringe technique.—All three contrast agents were administered by using a vertically fixed infusion pump. The outlet of the syringe pointed upward and was directly connected to the infusion port of the flow phantom with a three-way stopcock and an 18-gauge needle, without connection tubing. The infusion was started either immediately after fixation of the syringe at the infusion pump or with a delay of 5 or 10 minutes after filling and fixation. This infusion setup was designed to investigate the possible flotation of the microbubbles in the vertically oriented syringe over time, which would result in variable harmonic power Doppler US signal strengths. We hypothesized that a delay in starting the infusion would result in stronger harmonic power Doppler US signals at the beginning and a rapid decrease in signal strength at the end of infusion, with the final result of bolus-like kinetics of the time-signal curve. Therefore, each infusion was performed, with varying infusion start times, until the syringe was completely emptied.

Horizontal syringe technique.—In the horizontal syringe setup, the previously described infusion pump was oriented horizontally. Infusion was started immediately after fixation of the syringe. To evaluate the possible effects of connection tubing (as used in clinical scenarios) on the constancy of contrast enhancement, the syringe was fixed to the infusion port either directly, with a three-way stopcock and an 18-gauge needle, or through special 50-cm connector tubing (Medrad). These measurements were performed only with SH U 508A and NC100100.

We evaluated the effect of homogenization, as a special technique with the horizontally oriented syringe, on the constancy of harmonic power Doppler US signals. To homogenize the contrast agent in the syringe, the infusion pump was manually rotated 180° longitudinally along the vertical axis (about 20 times per minute) during continuous infusion. All three contrast agents were administered by using the previously described infusion pump, which was connected to the infusion port by means of a shortened 6-F, 12-cm-long catheter.

Straight tube technique.—We evaluated the straight tube technique, as a special modality for infusion of FS069, to assess the consistency of microsphere delivery over time, as previously described by Miller et al (16). Therefore, vertically oriented 3-mm-diameter extension tubing was filled with a total of 2.5 or 5.0 mL of FS069; the length of the tubing varied from 50 cm for 2.5 mL of FS069 to 100 cm for 5.0 mL of FS069. The outlet of the straight tube pointed upward and was directly connected to the infusion port of the flow phantom with a three-way stopcock and an 18-gauge needle. Another extension line connected the lower part of the straight tube to the infusion pump by way of a three-way stopcock. FS069 (2.5 or 5.0 mL) was introduced into the straight tube at the lowest injection port of the system, which was the distal three-way stopcock. To drive the microbubbles into the flow phantom, normal saline was continuously administered through the infusion pump at varying infusion rates—10, 20, and 30 mL/h. This infusion setup has been described by Miller et al (16).

Echo Contrast Agents
Three contrast agents were evaluated in the flow phantom: SH U 508A is a galactose-based US contrast agent composed of air-filled microbubbles, 99% of which are smaller than 7 µm. This agent also contains palmitic acid (0.1%) to stabilize the microbubbles for lung transit (9,12,13). We used a concentration of 400 mg/mL. Therefore, a total of 4 g of SH U 508A granules was suspended in 8 mL of sterile water that was agitated by hand, as recommended by the manufacturer. After preparation, the vial was left for 1–2 minutes to allow the solution to reach equilibrium. The 10-mL syringe was filled with a total of 8 mL of SH U 508A, and the infusion was started. For each infusion modality, one vial of SH U 508A (8 mL) was infused for 12 minutes at a rate of 40 mL/h.

NC100100 is a second-generation perfluorocarbon-filled contrast agent with a median microbubble diameter of 3.4 µm (20,21). For examinations in humans, the granules are diluted with 2 mL of saccharin solution. For in vitro studies, we used a 1:100 dilution—that is, 0.1 mL of NC100100 plus 10 mL of saccharin solution—to avoid system saturation and acoustic shadowing. To reduce additional agent decay due to dilution, the infusion was started immediately after preparation of the contrast agent. By using the vertical syringe setup, a total of 10 mL of diluted NC100100 was infused for 12 minutes at a rate of 50 mL/h. For the horizontal syringe (with and without an extension line) and homogenization setups, 10 mL of diluted NC100100 was infused for 10 minutes at a rate of 60 mL/h.

FS069 is a second-generation contrast agent that contains sonicated octafluoropropane-filled albumin microspheres. The microspheres have a mean size of 3.6–5.4 µm and are supplied in ready-to-use vials that contain 6.3–9.0 x 108 microspheres per milliliter (11,22). Prior to infusion, we resuspended FS069, as recommended by the manufacturer, by rolling the vial horizontally between the palms. Without further dilution, a total of 2.5 mL of FS069 was infused for 15 minutes at a rate of 10 mL/h during homogenization and for the vertical-syringe setup. As described for the straight tube technique, either 2.5 or 5.0 mL of FS069 was administered to the flow phantom for 20 minutes by means of continuous saline infusion, with the infusion rate varying between 10 and 30 mL/h.

Data Analyses and Statistics
Quantitative offline analyses of the raw data were performed prior to scan conversion by using calibrated software (HDI-Lab; Advanced Technology Laboratory) that takes machine settings into account. Before contrast material administration, a circular 8-mm-diameter region of interest was placed by one observer (J.G.) by using the background B-mode image as a reference for the cross-sectional area of the tube. The suggested regions of interest were routinely cross checked by another author (S.K.H.).

The mean (± SD) strength of the harmonic power Doppler US signals (in decibels) in each region of interest was calculated. Each data point of the resulting time-signal curve represented an average of 10 consecutive measurements at a sampling rate of 1 Hz—that is, one measurement per second was recorded for 10 successive seconds. This type of measurement was performed during three independent contrast agent infusions (average of three passes). Because of the digital acquisition time, we started the measurements at the beginning of every minute of infusion. For clarity, we abstained from additionally displaying SDs on the graphs.

A plateau in signal strength (hereafter referred to as signal plateau) was defined when the differences in signal strength between at least five successive data points did not exceed 1 dB. When a plateau was reached, the mean signal plateau value (in decibels ± SD), plateau duration (in minutes), and systematic increase or decrease in signal plateau (in decibels per minute) were assessed for each contrast agent. If the time-signal curve did not reach a signal plateau, the mean peak signal strength (in decibels ± SD) and systematic increase or decrease in peak signal strength (in decibels per minute) were assessed.

Group comparisons were performed by using the Kruskal-Wallis test. A P value less than .05 was considered to indicate a statistically significant difference. Calculations were performed by using the most recent version of a computer software package (SPSS; SPSS, Chicago, Ill).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Vertical Syringe Technique
SH U 508A.—At immediate onset of the SH U 508A infusion after syringe fixation, constant harmonic power Doppler US signals were produced for a mean of 10.67 minutes ± 0.58 during continuous infusion. The time-signal curve revealed a signal plateau at a mean of 2.67 minutes ± 0.58 after infusion onset, and a mean harmonic power Doppler US value of 10.53 dB ± 0.15 was reached. With delayed infusion starts—5 and 10 minutes after syringe fixation—the time-signal curves showed similar kinetics: A plateau was reached at a mean of 2.67 minutes ± 0.58 after infusion onset, and enhancement lasted for a mean of 10.67 minutes ± 0.58. The signal plateau reached a mean value of 11.33 dB ± 0.49 with a 5-minute delay and 11.47 dB ± 0.12 with a 10-minute delay in the start of infusion, after fixation of the syringe to the infusion pump. According to the Kruskal-Wallis test results, there were no significant differences between the signal values obtained at infusion onset and those obtained after delayed infusion or in the mean signal plateau values obtained among the three infusion modalities. All three time-signal curves showed a slight increase in signal strength during the plateau: 0.07 dB/min at 0 minute, 0.05 dB/min at 5 minutes, and 0.06 dB/min at 10 minutes (Fig 2a).



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  		Figure 2a. Graphs illustrate the signal strengths at harmonic power Doppler US in the flow phantom achieved by using the vertical syringe setup for continuous infusion of (a) 8 mL of SH U 508A for 12 minutes at a rate of 40 mL/h, (b) 10 mL of NC100100 (1:100 dilution) for 12 minutes at a rate of 50 mL/h, and (c) 2.5 mL of FS069 for 15 minutes at a rate of 10 mL/h. {blacksquare} = immediate infusion onset (no delay), {bullet} = 5-minute infusion delay, {blacktriangleup} = 10-minute infusion delay. Each data point of the resulting time-signal curve represents an average of 10 consecutive measurements at a sampling rate of 1 Hz for three independent contrast agent infusions. Therefore, the signal strength at harmonic power Doppler US was assessed for 10 seconds at the beginning of every minute of infusion. For clarity reasons, we abstained from additionally displaying SDs on the graph. With continuous infusion of SH U 508A (in a) and NC100100 (in b), the time-signal curves reached a plateau at different infusion onset times. Continuous infusion of 2.5 mL of FS069 (in c), however, resulted in a relatively bolus-like kinetic of the time-signal curves, and constant harmonic power Doppler US signals were never observed.

 


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  		Figure 2b. Graphs illustrate the signal strengths at harmonic power Doppler US in the flow phantom achieved by using the vertical syringe setup for continuous infusion of (a) 8 mL of SH U 508A for 12 minutes at a rate of 40 mL/h, (b) 10 mL of NC100100 (1:100 dilution) for 12 minutes at a rate of 50 mL/h, and (c) 2.5 mL of FS069 for 15 minutes at a rate of 10 mL/h. {blacksquare} = immediate infusion onset (no delay), {bullet} = 5-minute infusion delay, {blacktriangleup} = 10-minute infusion delay. Each data point of the resulting time-signal curve represents an average of 10 consecutive measurements at a sampling rate of 1 Hz for three independent contrast agent infusions. Therefore, the signal strength at harmonic power Doppler US was assessed for 10 seconds at the beginning of every minute of infusion. For clarity reasons, we abstained from additionally displaying SDs on the graph. With continuous infusion of SH U 508A (in a) and NC100100 (in b), the time-signal curves reached a plateau at different infusion onset times. Continuous infusion of 2.5 mL of FS069 (in c), however, resulted in a relatively bolus-like kinetic of the time-signal curves, and constant harmonic power Doppler US signals were never observed.

 


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  		Figure 2c. Graphs illustrate the signal strengths at harmonic power Doppler US in the flow phantom achieved by using the vertical syringe setup for continuous infusion of (a) 8 mL of SH U 508A for 12 minutes at a rate of 40 mL/h, (b) 10 mL of NC100100 (1:100 dilution) for 12 minutes at a rate of 50 mL/h, and (c) 2.5 mL of FS069 for 15 minutes at a rate of 10 mL/h. {blacksquare} = immediate infusion onset (no delay), {bullet} = 5-minute infusion delay, {blacktriangleup} = 10-minute infusion delay. Each data point of the resulting time-signal curve represents an average of 10 consecutive measurements at a sampling rate of 1 Hz for three independent contrast agent infusions. Therefore, the signal strength at harmonic power Doppler US was assessed for 10 seconds at the beginning of every minute of infusion. For clarity reasons, we abstained from additionally displaying SDs on the graph. With continuous infusion of SH U 508A (in a) and NC100100 (in b), the time-signal curves reached a plateau at different infusion onset times. Continuous infusion of 2.5 mL of FS069 (in c), however, resulted in a relatively bolus-like kinetic of the time-signal curves, and constant harmonic power Doppler US signals were never observed.

 
NC100100.—After immediate infusion onset, constant signals were seen after a mean of 3.67 minutes ± 0.58 of continuous infusion and reached a mean harmonic power Doppler US value of 10.70 dB ± 2.04. The mean duration of the signal plateau was 9.67 minutes ± 0.58, with a slight, nonsignificant decay in strength (-0.04 dB/min). With delayed infusion starts—5 and 10 minutes after syringe fixation—the time-signal curves showed similar kinetics: A signal plateau was reached at a mean of 3.33 minutes ± 0.58 after infusion onset with a 5-minute delay and at a mean of 2.67 minutes ± 0.58 after infusion onset with a 10-minute delay, and it lasted for a mean of 9.33 minutes ± 0.58 of continuous infusion. The signal plateau reached a mean value of 12.67 dB ± 1.45 with the 5-minute delay and 12.30 dB ± 0.79 with the 10 minute-delay, after fixation of the syringe to the infusion pump. According to Kruskal-Wallis test results, there were no significant differences between values obtained at infusion onset and those obtained after delayed infusion or in the mean signal plateau values obtained among the three infusion modalities. Time-signal curves for the 5- and 10-minute infusion delays showed a visible but not significant increase in signal strength during the plateau (0.07 dB/min with 5-minute delay; 0.03 dB/min with 10-minute delay) (Fig 2b).

FS069.—Immediate onset of FS069 infusion yielded a bell-shaped time-signal curve, with the highest values after 8 minutes of infusion and a maximum mean value of 17.85 dB ± 0.28. Afterward, the time-signal curve showed a decreasing slope until the infusion stopped after 15 minutes. With delayed infusion starts—5 and 10 minutes after filling and fixation of the syringe—the time-signal curves revealed a bolus-like kinetic with a steep increase; peak values were reached after 5 minutes of infusion and followed by a slow decrease. The peak signal strength reached a mean value of 22.36 dB ± 0.62 with the 5-minute infusion delay and of 22.08 dB ± 0.31 with the 10-minute delay (Fig 2c). Kruskal-Wallis test results indicated a significant group difference between values obtained at immediate infusion onset and those obtained with the two infusion delays (P < .05). Posthoc Dunn multiple comparisons test results revealed that the peak harmonic power Doppler US signals were significantly stronger with the 5- and 10-minute infusion delays than with immediate infusion (P < .05). There were no significant differences between the peak signal strengths achieved with the two infusion delays (Fig 2c).

Horizontal Syringe Technique
SH U 508A.—By infusing SH U 508A directly into the infusion port, we achieved constant harmonic power Doppler US signals at a mean of 3.00 minutes ± 1.00 after infusion onset. The signal strength reached a mean value of 10.43 dB ± 0.29 at the plateau of the time-signal curve and lasted for a mean of 10.33 minutes ± 0.58. Infusing SH U 508A through 50-cm connection tubing resulted in a slight, nonsignificant decay in harmonic power Doppler US signal strength, and a mean value of 9.73 dB ± 0.40 was reached. A signal plateau was achieved after a mean of 3.33 minutes ± 0.58 and lasted for a mean of 10.33 minutes ± 0.58. The time-signal curves for both infusion modalities showed a slight increase in signal plateau: of 0.09 dB/min with direct infusion and of 0.07 dB/min with infusion through the 50-cm connection tubing. During homogenization, constant signals were achieved at a mean of 3.33 minutes ± 0.58 after infusion onset, and a mean value of 11.60 dB ± 0.61 was reached. The signal plateau lasted a mean of 9.67 minutes ± 0.58, and there was a slight increase in strength of 0.07 dB/min (Fig 3a). As indicated by the Kruskal-Wallis test results, there were no significant differences between the signal plateau values obtained at onset and those obtained at delayed infusion among the three infusion modalities. However, we found a significant difference (P = .037) in signal plateau during homogenization, as compared with the signal plateau achieved by using the horizontally fixed syringe, with or without connection tubing (Fig 3a).



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  		Figure 3a. Graphs illustrate the different infusion modalities during continuous infusion of (a) 8 mL of SH U 508A for 12 minutes at a rate of 40 mL/h and (b) 10 mL of NC100100 (1:100 dilution) for 10 minutes at a rate of 60 mL/h. {blacksquare} = horizontal syringe setup with tubing, {bullet} = horizontal syringe setup without tubing, {blacktriangleup} = manual homogenization. Each infusion modality was checked for immediate onset of continuous contrast agent infusion. With all three modalities, the time-signal curves reached a plateau during continuous infusion. Note that the homogenization of SH U 508A (P < .05) (in a) and to a lesser degree of NC100100 (P > .05) (in b), as compared with the conventional infusion technique, caused an increase in signal enhancement.

 


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  		Figure 3b. Graphs illustrate the different infusion modalities during continuous infusion of (a) 8 mL of SH U 508A for 12 minutes at a rate of 40 mL/h and (b) 10 mL of NC100100 (1:100 dilution) for 10 minutes at a rate of 60 mL/h. {blacksquare} = horizontal syringe setup with tubing, {bullet} = horizontal syringe setup without tubing, {blacktriangleup} = manual homogenization. Each infusion modality was checked for immediate onset of continuous contrast agent infusion. With all three modalities, the time-signal curves reached a plateau during continuous infusion. Note that the homogenization of SH U 508A (P < .05) (in a) and to a lesser degree of NC100100 (P > .05) (in b), as compared with the conventional infusion technique, caused an increase in signal enhancement.

 
NC100100.—After direct infusion of NC100100 into the infusion port, a signal plateau was achieved at a mean of 3.33 minutes ± 0.58 after infusion onset and lasted a mean of 7.67 minutes ± 0.58. The plateau reached a mean value of 12.47 dB ± 0.15, which was indicative of a slight decay—of 0.07 dB/min—in signal plateau. Infusing NC100100 through 50-cm connection tubing resulted in a mean signal plateau of 11.43 dB ± 1.27, with a slight increase of 0.07 dB/min during the plateau. A signal plateau was reached at a mean of 3.67 minutes ± 0.58 after infusion onset and lasted a mean of 7.33 minutes ± 0.58. While the infusion pump was manually rotated, a signal plateau was reached at a mean of 3.33 minutes ± 0.58 after infusion onset and lasted a mean of 7.67 minutes ± 0.58. Compared with the signals produced by using the infusion modalities without homogenization, slightly higher signals were achieved at harmonic power Doppler US with homogenization: A mean value of 13.07 dB ± 0.67 was reached during the plateau, with a slight decay in signal strength of 0.06 dB/min. As indicated by the Kruskal-Wallis test results, there were no significant differences between values obtained at infusion onset and those obtained at delayed infusion or in the mean strength of the signal plateaus produced among the three infusion modalities (Fig 3b).

FS069.—Owing to results that showed an obvious concentration gradient developing in the vertical syringe and to results of previous studies by Miller and co-workers (16), we abstained from performing FS069 US measurements with the horizontal syringe setup, with or without extension tubing. Only with homogenization were constant signals achieved during continuous infusion of FS069; this finding is concordant with previous clinical experience (18). Constant signals were seen after a mean of 5.33 minutes ± 0.58, and a mean signal strength of 15.99 dB ± 0.31 was reached. The mean plateau duration was 11.33 minutes ± 0.58, with a slight increase in signal strength of 0.06 dB/min (Fig 4).



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  		Figure 4. Graph illustrates the strengths of harmonic power Doppler signals in the flow phantom during continuous infusion of FS069. Manual homogenization ({blacksquare}) and straight tube ({bullet}) infusion techniques are compared. A total of 2.5 mL of FS069 was constantly infused at a rate of 10 mL/h. Only homogenization of the agent in the syringe during constant infusion resulted in a signal plateau at harmonic power Doppler US. There was a significant difference between the mean signal plateau achieved with homogenization (15.99 dB ± 0.31) and the mean maximum signal strength achieved by using the straight tube technique (8.88 dB ± 3.17) (P < .05).

 
In a second step, we compared the mean signal plateaus achieved with homogenization with those obtained with the straight tube technique by infusing the same amount of FS069 (2.5 mL) at the same rate (10 mL/h). As indicated by the Mann-Whitney test results, there was a significant difference between the mean signal plateau achieved with homogenization (15.99 dB ± 0.31) and the mean maximum signal strength achieved by using the straight tube technique (8.88 dB ± 3.17) (P < .05) (Fig 4). When the straight tube technique was used for constant infusion of FS069 into the flow phantom, the time-signal curves never reached a signal plateau. The strongest harmonic power Doppler US signals were observed during the administration of either 2.5 or 5.0 mL of FS069 by means of continuous saline infusion at the highest rate of 30 mL/h. This infusion rate resulted in a bolus-like kinetic of the time-signal curve, with a rapid increase to peak values after 5 minutes of infusion, followed by a rapid decrease in signal strength (Fig 5).



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  		Figure 5. Graph illustrates the strengths of harmonic power Doppler signals in the flow phantom during continuous infusion of FS069 for 20 minutes with the straight tube technique. The signal values achieved by infusing 2.5 mL of FS069 at 10 ({square}), 20 ({lozenge}), and 30 ({triangleup}) mL/h and 5.0 mL of FS069 at 10 ({blacksquare}), 20 ({bullet}), and 30 ({blacktriangleup}) mL/h are depicted. Each data point of the resulting time-signal curve represents an average of 10 consecutive measurements at a sampling rate of 1 Hz for three independent contrast agent infusions. For clarity reasons, we abstained from additionally displaying SDs on the graph. Time-signal curves never reached a signal plateau despite continuous infusion of FS069. Note that the infusion rate had a profound effect on the shape of the time-signal curve, whereas the total contrast agent dose had a minor effect.

 
Delivering a total of 2.5 mL of FS069 by means of saline infusion at a rate of 10 or 20 mL/h resulted in the lowest strengths. Slightly and nonsignificantly stronger harmonic power Doppler US signals were produced during constant administration of 5.0 mL of FS069 at variable (10- or 20-mL/h) infusion rates. The rate of infusing normal saline to deliver FS069 to the flow phantom was the dependent variable for the shape of the time-signal curve, which revealed a kind of washout kinetic that was independent of the total amount of FS069 administered. The mean peak signal values at harmonic power Doppler US, as well as the mean signal durations, are shown in the Table.


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  		Parameters for Infusion of FS069 with the Straight Tube Technique

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
The performance of contrast-enhanced US previously depended on the application of intravenous bolus injection and resulted in substantial transient imaging artifacts, such as acoustic shadowing or color blooming (3,4). Thus, study results suggest that bolus kinetics might not be applicable to perfusion assessment (23–25). Newer concepts in contrast-enhanced US in particular require a constant concentration of the echo contrast agent for quantitative assessment of blood flow (15,17,19). Thus, we characterized the effects of different infusion modalities and different US contrast agents on contrast enhancement.

Continuous infusion of both SH U 508A and NC100100 with all of the described infusion modalities produced a plateau of constant contrast enhancement. Because SH U 508A has relatively high viscosity and the bubbles do not tend to rise rapidly in the syringe, there was only a slight, nonsignificant increase in signal strength with delayed infusion and the vertical syringe setup. Independently of the infusion modality, constant and prolonged enhancement was achieved 3 minutes after infusion onset and lasted until the end of infusion. Even when extension tubing was connected to the syringe, the conventional infusion setup used in clinical scenarios had a minor effect on signal plateau and duration. Our results are in good agreement with those of Albrecht et al (13), who observed the feasibility of continuous infusion of SH U 508A in a clinical pilot study on Doppler US enhancement. Albrecht et al (13) compared bolus injection with constant infusion of SH U 508A at three different infusion rates for the acquisition of spectral and color Doppler US scans of the femoral and carotid arteries. All infusions yielded a plateau of constant enhancement that started after 1–2 minutes and lasted until the end of infusion; however, the plateau duration was dependent on the infusion speed. Not only were the saturation artifacts with infusion fewer than those with bolus injection, but also the dose effectiveness was improved with continuous infusion.

Similar results were obtained with continuous infusion of NC100100. We achieved constant signal enhancement with all of the described infusion modalities, and a plateau of the time-signal curve was reached after 3 minutes and lasted until the end of infusion. Although the results of the vertical syringe setup might lead to the assumption that a minor degree of bubble flotation occurs within the syringe, floating bubbles seem to have a minor effect on signal constancy during continuous infusion of NC100100. In several clinical trials involving NC100100 for assessment of myocardial perfusion abnormalities, NC100100 was administered as a bolus injection and followed by a saline flush (26–28). Clinical data that indicate whether continuous infusion of NC100100 can provide prolonged contrast enhancement and thus improve the dose effectiveness of this agent are necessary.

In contrast to SH U 508A and NC100100, FS069 cannot be easily infused by using the conventional infusion setup, because the microspheres tend to float rapidly, if not in an agitated manner, and thus create a concentration gradient within the syringe. This concentration gradient has a marked effect on the total amount of microbubbles released over time during the continuous infusion of FS069. To overcome this limitation, several groups have tried to use solutions of this contrast agent, with FS069 diluted in normal saline. Saline bags containing the diluted contrast agent were used frequently. These bags were manually agitated to prevent microbubble flotation. However, it was difficult to maintain consistent myocardial opacification with this dilution infusion method, because the degree of manual manipulation of the diluent affected the microsphere delivery rate (16).

Furthermore, the microbubbles, when diluted in the perfluorocarbon-deficient saline solution, tend to release their encapsulated gas volume rapidly and thereby lose effectiveness in a short time, as demonstrated in a study by Podell et al (22). A decrease of 50% backscatter was observed in a gas-deficient solution (60% air-saturated diluent) within only 90 seconds versus 6 minutes in a 100% air-saturated diluent. This microsphere instability can result in unacceptable variability in the measured acoustic properties, especially when the time after dilution is not controlled. On the other hand, conventional dripping bags act as a bubble trap owing to gravity and therefore do not seem to be useful for infusion. The combination of these limitations makes it impossible to predict the amount of contrast agent infused at any given time.

Therefore, an alternative infusion setup that makes use of the buoyant properties of FS069 microspheres was evaluated by Miller et al (16): The contrast agent was filled into a vertically oriented line and flushed with normal saline. This setup was found to reduce shadowing and the attenuation artifacts caused by bolus injection and thereby provide prolonged contrast enhancement. To evaluate the contrast enhancement constancy achieved by using the straight tube technique, Miller and co-workers (16) introduced a total of 2.5 or 5.0 mL of FS069 into the straight tube, with normal saline used as the vehicle for continuous administration of microbubbles, at three infusion rates.

At low infusion rates, constant signals were observed 5 minutes after infusion onset and lasted for 3–4 minutes; a slow decrease in signal strength followed. On the other hand, the highest saline infusion rates resulted in the typical wash in–washout enhancement pattern, which resembled a bolus curve with a rapid increase followed by a rapid decrease in signal strength. Miller et al (16) found that at slower saline flow rates, bigger FS069 microbubbles tended to develop faster than the following fluid could push through the straight tube; this resulted in a concentration of larger microbubbles at the head of the flow. Furthermore, as the line was depleted of larger microspheres, the mean diameter and concentration of the microspheres decreased; this resulted in a slow decay in signal at the end of infusion. Because gas exchange in the straight tube has to be considered, we do not believe that this method is ideal for myocardial perfusion assessment modalities, which require a steady state of contrast enhancement.

Because of difficulties in the continuous infusion of FS069, a major part of this study was focused on the evaluation of different setups for FS069 infusion to define the infusion properties of the agent and to design an infusion setup that is suitable for constant microbubble delivery. The flotation properties of FS069 microbubbles were clearly demonstrated in our experiments with the vertical syringe setup. When FS069 was infused immediately after the resuspension of the microbubbles, the resulting time-signal curve was less bolus like and showed relatively constant signals for 5 minutes. On the other hand, a short delay between the preparation and start of infusion resulted in a bolus-like shape of the curve with significantly higher peak values, followed by a fast decay in signal.

We built on our experience with FS069 infusion modalities and evaluated the effect of homogenization on signal constancy. With FS069, homogenization was the only infusion modality that resulted in a constant delivery of the agent during the entire infusion period. In addition, the highest peak signal values and highest signal values in the area under the curve were achieved by using this method. We therefore conclude that with FS069, homogenization during continuous infusion is required to achieve constant signals.

Practical application: The results of this study demonstrate that constant infusion of SH U 508A, NC100100, or FS069 into the vascular system is feasible. Because of the special physical properties of FS069, homogenization is a prerequisite to achieving constant signals during continuous infusion. Although with infusion of SH U 508A or NC100100, homogenization was not necessary to reach a signal plateau, homogenization improved the contrast enhancement achieved with SH U 508A infusion, as compared with the conventional infusion method. Whether the infusion modality used can markedly affect echo enhancement has to be evaluated with other US contrast agents.

We conclude that homogenization might be the superior technique for stable and maximal contrast enhancement with continuous infusion of FS069, whereas conventional infusion of SH U 508A or NC100100 is feasible for constant contrast enhancement.


   FOOTNOTES
 
2 **. Multiple body systems Back

Author contributions: Guarantors of integrity of entire study, S.K.H., K.T., J.G.; study concepts, K.T., J.G., H.B., S.K.H.; study design, K.T., C.P., J.G.; literature research, S.L., J.G., A.E., C.L.; experimental studies, J.G., C.V., S.L., C.L.; data acquisition, J.G., T.S., C.V., C.L.; data analysis/interpretation, S.K.H., C.P., J.G.; statistical analysis, C.P., J.G., C.L.; manuscript preparation, S.K.H.; manuscript definition of intellectual content, K.T., H.B., S.K.H.; manuscript editing, H.O., S.K.H.; manuscript revision/review, H.B., H.O.; manuscript final version approval, K.T., H.B., H.O. S.K.H. and J.G. contributed equally to this work.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

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