(Radiology. 1999;213:913-918.)
© RSNA, 1999
Optimal Protocol for Injection of Contrast Material at MR Angiography: Study of Healthy Volunteers1
Katsuhiko Mitsuzaki, MD,
Yasuyuki Yamashita, MD,
Ichiro Ogata, MD,
Yi Tang, MD,
Tomohiro Namimoto, MD and
Mutsumasa Takahashi, MD
1 From the Department of Radiology, Kumamoto University School of Medicine, 1-1-1 Honjo Kumamoto 860, Japan. Received July 15, 1998; revision requested August 6; final revision received February 16, 1999; accepted June 8. Address reprint requests to K.M. (e-mail: katsumit@kaiju.medic.kumamotou.ac.jp).
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Abstract
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Forty healthy volunteers, matched for age and body weight, underwent abdominal magnetic resonance angiography with gadopentetate dimeglumine administered by using a power injector. Injection rates were 0.3, 1.0, 2.0, or 3.0 mL/sec. Contrast material doses were 0.1 (single dose) or 0.2 (double dose) mmol/kg. Increased contrast enhancement in the aorta and minimum arteriovenous overlap can be achieved with high flow rate and double-dose injection.
Index terms: Aorta, MR, 94.129416, 94.12943 • Arteries, MR, 94.129416, 94.12943 • Magnetic resonance (MR), contrast enhancement, 94.129416, 94.12943 • Magnetic resonance (MR), vascular studies, 94.129416, 94.12943
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Introduction
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Intravenous gadolinium chelates used during magnetic resonance (MR) angiography help minimize flow artifacts, saturation effects, and long imaging times that can degrade time-of-flight MR angiograms acquired in the transverse plane. This technique allows excellent visualization of the abdominal and thoracic aorta and its branches during a single breath hold in a predetermined field of view (1–4). The contrast mechanism for gadolinium-enhanced MR angiography relies on the T1 shortening of blood that occurs in response to the administration of gadolinium chelates. Recently, use of MR systems with improved gradient performance has allowed a reduction in imaging times from 3–5 minutes to less than 30 seconds, which facilitates breath-hold MR angiography and eliminates respiratory artifacts (2–4). Contrast material is usually administered by means of rapid manual injection, although recent studies indicated better results with an automatic MR-compatible power injector (5,6). Even with these shorter acquisition times, administration of as much as 60 mL of gadolinium chelates was necessary to ensure sufficient arterial contrast (2,3). In a recent study by Ho et al (7) of moving-bed infusion-tracking MR angiography, they used a slow flow rate of 0.3 mL/sec for continuous injection of contrast material. This technique has the potential for use at peripheral MR angiography to cover from the aorta to below the knee after a single contrast material administration.
Theoretically, a low dose (0.1 mL per kilogram of body weight) of contrast material could help achieve adequate blood-to-background contrast if the central k-space data acquisition were performed at the critical time, such as at the peak arterial enhancement during the first pass of the contrast material through the circulation (8). Use of a low dose, however, means administration of a smaller volume of contrast material, which may place more constraints on the timing of contrast material administration. Findings in another study suggested that the volume of contrast material can be reduced without compromising image quality (9). Use of a low dose (0.1–0.2 mmol/kg) of contrast material is preferable, since the cost for contrast material decreases. To achieve the best results, an accurate method is needed to determine the window of arterial enhancement after venous injection. To our knowledge, however, the optimal contrast material injection rate and dose for MR angiography are as yet unexplored. In this study, we compared results with different contrast material injection protocols with a power injector at gadolinium-enhanced abdominal MR angiography in healthy volunteers. With use of a sequential, single-section, two-dimensional, axial, turbo fast low-angle shot (FLASH) sequence, we evaluated the injection rate, dose, and timing of acquisition that would provide maximum contrast and minimal arteriovenous overlap.
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Materials and Methods
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Volunteers
Gadolinium-enhanced MR angiography was performed in 40 healthy volunteers (12 men and 28 women; age range, 24–63 years; mean age, 53.7 years) who did not have heart disease or arteriosclerotic disease associated with dysfunction of cardiac output or circulation time. The institutional review board approved our study before it was initiated, and informed consent was obtained from all volunteers. The 40 volunteers were randomly assigned to one of eight equally sized groups; each group comprised five volunteers. The mean age and body weight (range, 55–76 kg) of the volunteers did not differ among the groups (Table 1).
In each volunteer, contrast material (Magnevist; Schering, Osaka, Japan) was administered with an automatic MR-compatible power injector (Spectris model SRM 230; MedRad, Pittsburgh, Pa) with an injection rate of 0.3 (groups 1 and 2), 1.0 (groups 3 and 4), 2.0 (groups 5 and 6), or 3.0 (groups 7 and 8) mL/sec. The doses of gadopentetate dimeglumine used in these study groups were 0.1 (single dose: groups 1, 2, 4, and 6) or 0.2 (double dose: groups 3, 5, and 7) mmol/kg (Table 1). To reduce viscosity, the contrast material was warmed to 37°C before injection.
Imaging Procedure
All MR images were obtained with a 1.5-T superconducting unit with a 25 mT/m maximum gradient capability (Magnetom Vision; Siemens Medical Systems, Erlangen, Germany) with a body phased-array coil. Sequential, transverse, two-dimensional, turbo FLASH imaging was performed (repetition time msec/echo time msec/inversion time msec = 5.0/2.3/300 with 15° flip angle and 1-cm section thickness). The turbo FLASH sequence was selected since it yields low signal intensity in nonenhanced blood (ie, there is no appreciable flow-related enhancement).
Venous access was achieved with a 21-gauge peripheral intravenous catheter in the antecubital fossa or forearm. The volunteers were instructed not to hold their breath during the acquisition period. A bolus injection of gadopentetate dimeglumine was followed by a 15-mL saline solution flush, both infused at the same injection rate with the power injector. From the beginning of contrast material injection, imaging was performed at the level of the porta hepatis at 1-second intervals for 180 seconds (Fig 1).
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Figure 1a. Timing study performed with a contrast material dose of 0.2 mmol/kg at an injection rate of 3 mL/sec in a 36-year-old healthy volunteer. (a-f) Sequential transverse turbo FLASH images were obtained at 1-second intervals for 120 seconds at the level of the porta hepatis. (a) The initial image, acquired at the start of the injection, demonstrates no enhanced vessels. (b) At 15 seconds after injection, enhancement is seen in the aorta (arrow). (c) At 30 seconds after injection, enhancement is seen in the portal vein (arrow) and inferior vena cava (IVC) (arrowhead). (d) At 45 seconds after injection, increased signal intensity is seen in the portal vein and hepatic parenchyma. (e) At 62 seconds after injection, increased signal intensity is seen in the IVC (arrow). (f) At 118 seconds after injection, high signal intensity continues in the aorta, portal vein, and IVC.
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Figure 1b. Timing study performed with a contrast material dose of 0.2 mmol/kg at an injection rate of 3 mL/sec in a 36-year-old healthy volunteer. (a-f) Sequential transverse turbo FLASH images were obtained at 1-second intervals for 120 seconds at the level of the porta hepatis. (a) The initial image, acquired at the start of the injection, demonstrates no enhanced vessels. (b) At 15 seconds after injection, enhancement is seen in the aorta (arrow). (c) At 30 seconds after injection, enhancement is seen in the portal vein (arrow) and inferior vena cava (IVC) (arrowhead). (d) At 45 seconds after injection, increased signal intensity is seen in the portal vein and hepatic parenchyma. (e) At 62 seconds after injection, increased signal intensity is seen in the IVC (arrow). (f) At 118 seconds after injection, high signal intensity continues in the aorta, portal vein, and IVC.
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Figure 1c. Timing study performed with a contrast material dose of 0.2 mmol/kg at an injection rate of 3 mL/sec in a 36-year-old healthy volunteer. (a-f) Sequential transverse turbo FLASH images were obtained at 1-second intervals for 120 seconds at the level of the porta hepatis. (a) The initial image, acquired at the start of the injection, demonstrates no enhanced vessels. (b) At 15 seconds after injection, enhancement is seen in the aorta (arrow). (c) At 30 seconds after injection, enhancement is seen in the portal vein (arrow) and inferior vena cava (IVC) (arrowhead). (d) At 45 seconds after injection, increased signal intensity is seen in the portal vein and hepatic parenchyma. (e) At 62 seconds after injection, increased signal intensity is seen in the IVC (arrow). (f) At 118 seconds after injection, high signal intensity continues in the aorta, portal vein, and IVC.
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Figure 1d. Timing study performed with a contrast material dose of 0.2 mmol/kg at an injection rate of 3 mL/sec in a 36-year-old healthy volunteer. (a-f) Sequential transverse turbo FLASH images were obtained at 1-second intervals for 120 seconds at the level of the porta hepatis. (a) The initial image, acquired at the start of the injection, demonstrates no enhanced vessels. (b) At 15 seconds after injection, enhancement is seen in the aorta (arrow). (c) At 30 seconds after injection, enhancement is seen in the portal vein (arrow) and inferior vena cava (IVC) (arrowhead). (d) At 45 seconds after injection, increased signal intensity is seen in the portal vein and hepatic parenchyma. (e) At 62 seconds after injection, increased signal intensity is seen in the IVC (arrow). (f) At 118 seconds after injection, high signal intensity continues in the aorta, portal vein, and IVC.
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Figure 1e. Timing study performed with a contrast material dose of 0.2 mmol/kg at an injection rate of 3 mL/sec in a 36-year-old healthy volunteer. (a-f) Sequential transverse turbo FLASH images were obtained at 1-second intervals for 120 seconds at the level of the porta hepatis. (a) The initial image, acquired at the start of the injection, demonstrates no enhanced vessels. (b) At 15 seconds after injection, enhancement is seen in the aorta (arrow). (c) At 30 seconds after injection, enhancement is seen in the portal vein (arrow) and inferior vena cava (IVC) (arrowhead). (d) At 45 seconds after injection, increased signal intensity is seen in the portal vein and hepatic parenchyma. (e) At 62 seconds after injection, increased signal intensity is seen in the IVC (arrow). (f) At 118 seconds after injection, high signal intensity continues in the aorta, portal vein, and IVC.
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Figure 1f. Timing study performed with a contrast material dose of 0.2 mmol/kg at an injection rate of 3 mL/sec in a 36-year-old healthy volunteer. (a-f) Sequential transverse turbo FLASH images were obtained at 1-second intervals for 120 seconds at the level of the porta hepatis. (a) The initial image, acquired at the start of the injection, demonstrates no enhanced vessels. (b) At 15 seconds after injection, enhancement is seen in the aorta (arrow). (c) At 30 seconds after injection, enhancement is seen in the portal vein (arrow) and inferior vena cava (IVC) (arrowhead). (d) At 45 seconds after injection, increased signal intensity is seen in the portal vein and hepatic parenchyma. (e) At 62 seconds after injection, increased signal intensity is seen in the IVC (arrow). (f) At 118 seconds after injection, high signal intensity continues in the aorta, portal vein, and IVC.
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Contrast Enhancement Evaluation
Contrast enhancement was evaluated by means of a user-defined region of interest over the central portion of the aorta, portal vein, and IVC. The regions of interest were placed by one investigator (K.M.). Noise was measured on each image with use of a cursor positioned just ventral to the anterior abdominal wall. Areas with prominent ghosting were not included. The size of the cursor was chosen to include a large representative portion of the vessels. The signal-to-noise ratio (SNR) was derived by dividing the signal intensity values of the vessels by the corresponding SD of noise. A curve indicating SNR versus time was generated by using the software on the MR system. For each injection protocol, we evaluated the peak enhancement time (delay from the start of infusion of contrast medium to peak enhancement); peak SNR value (peak enhancement value); and 80% signal intensity duration in the aorta (duration of enhancement above 80% of peak enhancement), portal vein, and IVC. The mean value for each set of results was calculated from the individual data.
Statistical Analysis
One-way analysis of variance for comparison among various injection rates was used for statistical analysis. For each injection protocol, a Student t test was used to compare results with a single or double dose to evaluate the significance of differences in peak enhancement time; peak value of SNR; and 80% signal intensity duration in the aorta, portal vein, and IVC. A P value of less than .05 was considered to indicate a statistically significant difference.
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Results
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Administration of contrast material with the automatic power injector was uneventful in all 40 volunteers. No remarkable subcutaneous extravasation of contrast material was noted.
Peak Enhancement Time
Peak enhancement time in the aorta with the 0.3 mL/sec injection protocol was 35–43 seconds (mean: single dose, 39 seconds; double dose, 38 seconds), with 1.0 mL/sec was 23–30 seconds (mean: single dose, 26 seconds; double dose, 25 seconds), with 2.0 mL/sec was 20–26 seconds (mean: single dose, 23 seconds; double dose, 24 seconds), and with 3.0 mL/sec was 17–22 seconds (mean: single dose, 20 seconds; double dose, 19 seconds). As the injection rate increased, the peak enhancement time in the aorta occurred significantly earlier (P < .001) (Fig 2), but no significant difference was found in the peak enhancement time in the aorta between single and double doses with the same injection protocol. No significant differences in the peak enhancement time in the portal vein were found among the 1.0, 2.0, and 3.0 mL/sec injection protocols. With the 0.3 mL/sec protocol, however, the peak enhancement time in the portal vein was significantly delayed (P < .05) (Fig 3). Similarly, no significant differences in peak enhancement time in the IVC were found among the injection protocols (Fig 4). Furthermore, peak enhancement times in the aorta, portal vein, and IVC were not significantly different with the double dose compared with the single dose (Figs 3, 4).
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Figure 2. Bar graph depicts peak enhancement time in the aorta with each injection protocol. As injection rate increased, peak enhancement time in the aorta was earlier (P < .001), but no difference was found with single dose (black bars) or double dose (gray bars) with the same injection rate. The significant difference (P < .001) was seen between the 0.3 mL/sec injection rate and the other injection rates with both single and double doses. Data above each bar indicate the mean peak enhancement time in the aorta with each injection protocol. Error bars indicate the SEM.
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Figure 3. Bar graph depicts peak enhancement time in the portal vein with each injection protocol. Differences among the injection rate protocols were significant with only 0.3 mL/sec; the time was significantly delayed with that rate (P < .05). Differences were not significant between the single dose (black bars, P = .15) or double dose (gray bars, P = .18). Data above each bar indicate the mean peak enhancement time in the portal vein with each injection protocol. Error bars indicate the SEM.
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Figure 4. Bar graph depicts peak enhancement time in the IVC with each injection protocol (single dose, black bars; double dose, gray bars). Differences among the injection rate and dose protocols were not significant (single dose, P = .99; double dose, P = .95). Data above each bar indicate the mean peak enhancement time in the IVC with each injection protocol. Error bars indicate the SEM.
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Differences in Interval between Arterial and Venous Peak Times
With a double dose, differences in the interval between the peak enhancement time in the aorta and that in the portal vein were not significant among the injection rates. With a single dose, however, differences among the injection rates were significant (P < .05) (Table 2). With each injection rate for the interval between the peak enhancement times in the aorta and IVC, the interval became significantly longer as the rate became higher (P < .001). These results suggest that arteriovenous overlap could be diminished by using a high-rate injection protocol, even though the duration of arterial enhancement is shortened.
Peak SNR in the Aorta, Portal Vein, and IVC
Peak SNR in the aorta became significantly higher as the injection rate increased (P < .05). With a single dose, peak SNR in the aorta with the 0.3 mL/sec injection protocol was 39.9 msec (T1 = 150 msec), with 1.0 mL/sec was 41.6 (T1 = 147 msec), with 2.0 mL/sec was 43.6 (T1 = 133 msec), and with 3.0 mL/sec was 55.0 (T1 = 74 msec). With a double dose, peak SNR in the aorta with the 0.3 mL/sec injection protocol was 41.4 (T1 = 148 msec), with 1.0 mL/sec was 43.6 (T1 = 138 msec), with 2.0 mL/sec was 46.6 (T1 = 105 msec), and with 3.0 mL/sec was 58.2 (T1 = 66 msec) (Fig 5). However, the increase in peak SNR with a double dose in the aorta was marginal compared to that with a single dose. Although the peak SNRs in the portal vein and IVC were not affected by the injection rate of contrast material, higher peak SNRs were obtained with a double dose (Figs 6, 7).
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Figure 5. Bar graph depicts the peak SNR in the aorta with each injection protocol. As the injection rate increased, the value became significantly higher, but the difference in increase between a double dose (gray bars) and a single dose (black bars) was marginal. Differences were significant between the 0.3, 1.0, or 2.0 mL/sec rates and the 3.0 mL/sec rate with the single dose (P < .05). With the double dose, differences were significant between the 0.3 or 1.0 mL/sec rate and the 3.0 mL/sec rate (P < .05) but not between the 2.0 and 3.0 mL/sec injection rates. Data above each bar indicate the mean peak SNR in the aorta. Error bars indicate the SEM.
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Figure 6. Bar graph depicts peak SNR in the portal vein with each injection protocol. Differences were not significant as the injection rate increased. The increase with a double dose (gray bars) was marginally higher than that with a single dose (black bars) with each injection protocol, but the difference was not significant (single dose, P = .78; double dose, P = .24). Data above each bar indicate the mean peak SNR in the portal vein with each injection protocol. Error bars indicate the SEM.
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Figure 7. Bar graph depicts peak SNR in the IVC with each injection protocol. Differences were not significant as the injection rate increased. The increase with a double dose (gray bars) was marginally higher than that with a single dose (black bars) with each injection protocol, but the difference was not significant (single dose, P = .82; double dose, P = .76). Data above each bar indicate the mean peak SNR in the IVC with each injection protocol. Error bars indicate the SEM.
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80% Signal Intensity Duration in the Aorta
As the injection rate increased with both the single and double dose, the 80% signal intensity duration became significantly shorter (P < .001) and was shortest with the 3.0 mL/sec injection protocol (single dose, approximately 11 seconds; double dose, approximately 18 seconds). With the double dose, the duration of arterial enhancement of 80% signal intensity lengthened significantly (P < .05) with all but 2.0 mL/sec injection rates. With the slow infusion rate (0.3 mL/sec), enhancement of the aorta was lowest (Fig 8), and significant (P = .005) arteriovenous overlap was seen.
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Figure 8. Bar graph depicts the duration of 80% signal intensity in the aorta with each injection protocol. As the injection rate increased, the duration became significantly shorter with both the single dose (black bars) and double dose (gray bars) (P < .001). Differences were significant within the 0.3 (*), 1.0 (**), and 3.0 (***) mL/sec injection protocols with the single and double doses (P < .05). Data on each bar indicate the mean duration of 80% signal intensity in the aorta with each injection protocol. Error bars indicate the SEM.
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Discussion
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Previously, slow infusion of a gadolinium chelate was used with a non–breath-hold image acquisition technique for contrast material–enhanced MR angiography. With the development of fast MR imaging technology, three-dimensional imaging can be performed in a single breath hold (2–12). A single-dose, rapid-acquisition technique for gadolinium-enhanced MR angiography is being sought to minimize respiratory motion artifacts, eliminate contamination by venous enhancement, and decrease costs incurred by using contrast material. This type of technique would be preferable to the strategies involving use of higher doses and longer acquisition times that have recently become popular (1–3,10). Short imaging times allow data acquisition during the first pass of contrast material. To achieve high-contrast MR angiography, optimization of the contrast material injection protocol is of the utmost importance.
The quality of contrast-enhanced MR angiography depends on the timing of the contrast material bolus (2,3,6,11,12). If images are obtained too early, arterial enhancement will be insufficient because the gadolinium chelate has not yet entered the arterial system. If images are obtained too late, both arterial and venous enhancement may be seen, which renders interpretation difficult owing to overlap and identification errors. To achieve high intravascular signal intensities, injection of a compact bolus is necessary so that it reaches its peak value when low spatial frequencies are acquired in the central lines of k space (2,5,13,14). This optimization can be accomplished with use of a test bolus measurement obtained with an injection rate identical to that used for diagnostic contrast material administration. This enables correct adaptation of the bolus peak enhancement to the MR sequence to ensure reproducibly good image quality (3,6,9,11,12). An automatic MR bolus tracking device, as used in helical CT (15,16), is also under clinical exploration.
The introduction of MR-compatible automatic contrast material injectors promised an improvement in arterial signal intensity and diagnostic image quality. The advantages of automatic power injection, as opposed to manual injection, have been reported (5,6). Power injection helps ensure not only a reliable rate of delivery, with no delay between contrast material and saline solution, but also a constant rate of delivery regardless of catheter size.
Faster injection rates may obviate unfavorable venous overlap (17). Kopka and colleagues (6) studied the optimal contrast material injection rate with a single dose at three-dimensional MR angiography with use of a power injector. In their study, SNR, contrast-to-noise ratio, and average relative vascular enhancement could be achieved with faster injection rates except 6 mL/sec. The contrast material bolus provided with this very rapid injection rate did not cover large parts of k space, which results in increased blurring of the vessel contours. They also suggest that a faster injection rate of 6 mL/sec seemed to exceed the threshold for optimal intravascular concentration of contrast material owing to excess shortening of T1 in the altered tissue, which results in a lower SNR. Furthermore, the injection time of the contrast material volume is drastically decreased to 3–5 seconds when an injection rate of 6 mL/sec is used, which leads to a short bolus that covers only 20%–30% of the entire k space. This lack of coverage can explain reduced image contrast, increased image blurring, and nonuniform vascular enhancement owing to amplitude modulation in the MR signal (18). They concluded that the optimal injection rate for examination of the abdominal aorta and its branches was 2 mL/sec (6).
Contrary to previous reports, Ho et al (7) used a slow infusion rate at moving-bed infusion-tracking MR angiography to maintain arterial enhancement for a long period. As pointed out by the authors, however, venous enhancement and uptake of contrast material in the surrounding tissue results in lowered vessel-to-background contrast. Furthermore, the degree of arterial enhancement is low with use of a slow infusion rate.
On the basis of findings in our volunteer study, we concluded that high-quality MR angiograms can be obtained with use of a two-dimensional turbo FLASH imaging technique by means of relatively rapid injection (2–3 mL/sec) of a relatively small amount of contrast material. Higher enhancement of the aorta without venous enhancement was obtained with a higher injection rate (T1 = 74 msec with 3.0 mL/sec vs T1 = 150 msec with 0.3 mL/sec with single dose). The duration of arterial enhancement obtained with a higher injection rate, however, was shorter than that obtained with a slower injection rate. The narrow window of optimal arterial enhancement available with a higher injection rate could be compensated for by use of a double dose, which can provide a wider window of optimal arterial enhancement than can a single dose. Furthermore, Maki et al (14) suggest that a nonuniform intravascular signal intensity within the central lines of k space proved to be the factor most responsible for degradation of image quality. The wide window of arterial enhancement (18–24 seconds) with double-dose injection could cover large parts of k space and fill the central portions of k space, which results in improved image quality. Therefore, the technique for contrast material injection should be optimized depending on the acquisition time. When the acquisition time is short (
15 seconds), high-quality MR angiograms could be obtained with a rapid injection rate with a relatively small amount of contrast material. When the acquisition time is long (>30 seconds), however, a large amount of contrast material might be required to maintain optimal arterial enhancement.
Peak enhancement time in the portal venous system was slightly delayed with the slower injection rate, but that in the IVC was independent of injection rate. Furthermore, the degree of enhancement in these venous systems depended mostly on the dose of contrast material. These results suggest that a larger amount of contrast material would produce better contrast at gadolinium-enhanced portography or venography.
A limitation of our study is that we used interindividual comparison of injection rates and doses instead of intraindividual comparison. Our results could be related to individual patient parameters such as body weight or circulation time rather than to injection rate and dose. However, the contrast material concentration was individually calculated depending on body weight, which largely decreased the influence of the contrast material. Our study subjects were healthy volunteers without heart disease or arteriosclerotic disease. In these patients, the peak time and peak SNR may differ. Another limitation of this study is that we did not perform quantitative and qualitative evaluation of MR angiograms obtained with these injection protocols.
In conclusion, we found that increased contrast enhancement in the aorta without venous enhancement was obtained with use of a higher injection rate for gadopentetate dimeglumine, but the optimal arterial enhancement duration was relatively short. Double-dose injection may prolong arterial enhancement time, but the increase in maximum contrast enhancement was slight.
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Acknowledgments
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The authors thank Kimihiko Ogata, PhD, for statistical analysis.
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Footnotes
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Abbreviations: FLASH = fast low-angle shot
IVC = inferior vena cava
SNR = signal-to-noise ratio
Author contributions: Guarantor of integrity of entire study, K.M.; study concepts, K.M., T.N.; study design, K.M.; definition of intellectual content, M.T.; literature research, K.M.; clinical studies, K.M.; data acquisition, K.M., I.O.; data analysis, K.M., Y.T.; statistical analysis, K.M.; manuscript preparation, K.M.; manuscript editing, K.M., Y.Y.; manuscript review, K.M., M.T.
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MR Angiography of the Hand Arteries
Angiology,
November 1, 2001;
52(11):
763 - 772.
[Abstract]
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Abstract
Introduction
