Effects of Reduced Gadolinium-Based Contrast Agents (GBCA) Volumes on MRI Image Quality: An Experimental Phantom Study
1IsmaIl, N., 2*Bashah, F. a. a. aNd2ZakarIa, F.
ABSTRACT
Many recent studies focused on the patient’s safety from the administration of gadolinium-based contrast agents (GBCAs), their concentration, the dose of administration and their effects on the image quality. The present study was aimed at evaluating the effects of reduced GBCAs (gadobutrol and gadoterate meglumine) volume on the image quality by using phantoms. Eight (8) human brain mimicking phantom made of nickel chloride (NiCl2) doped agarose gel were added with 0.00500 ml (100% volume), 0.00350 ml (75% volume), 0.00250 ml (50% volume) and 0.00125 ml (25% volume) of gadobutrol, 0.0100 ml (100% volume), 0.0075 ml (75% volume), 0.0050 ml (50% volume) and 0.0025 ml (25% volume) of gadoterate meglumine. The phantoms were scanned using a 1.5-T and a 3 T-MRI system. Signal-to-noise ratio (SNR) and the contrast agents enhancement were evaluated quantitatively and qualitatively. The 50% volume of gadobutrol and gadoterate meglumine at 3 T showed greater enhancement when compared with 50% and 100% volumes of gadobutrol and gadoterate meglumine at 1.5 T. It can be concluded that the volume of gadobutrol and gadoterate meglumine contrast agents can be reduced when using a higher field system.
Keywords: Volumes; magnetic resonance imaging; contrast agent; gadolinium; image quality
1Department of Radiology, National Cancer Institute, Jalan P7, Presint 7, 62250 Putrajaya, Wilayah Persekutuan Putrajaya
2*Centre for Medical Imaging, Faculty of Health Sciences, Universiti Teknologi MARA Kampus Selangor, Bandar Puncak Alam, Selangor Darul Ehsan
*Corresponding Author: Bashah, F. A. A.
Email: [email protected] Tel: 03-32584483
Fax: 03-32584500 Received: 14 October 2020
Accepted for publication: 1 February 2021
Publisher: Malaysian Association of Medical Physics (MAMP) http://www.mamp.org.my/
https://www.facebook.com/MedicalPhysicsMalaysia
INTRODUCTION
Gadolinium-Based Contrast Agents (GBCA) is a paramagnetic contrast agent and widely used in Magnetic Resonance Imaging (MRI). GBCA is injected intravenously into the dorsal, cephalic and antecubital veins to enhance the visualization of normal and abnormal tissues. The GBCA molecules administered to increase the signal intensity at specific tissues (Fallenberg et. al. 2014) and allowing superior identification and diagnosis of the pathology. The recommended dosage of GBCA is based on body weight;
0.1 ml/kg of 0.5 M contrast for Gadoterate Meglumine (Dotarem, Guerbet, Aulnay-sous-Bois, France) and 0.1 ml/kg of 1.0 M contrast for Gadobutrol (Gadovist, Bayer Schering Pharma, Berlin, Germany) (Scott 2018). A similar recommendation is applied for all strengths of the MR system from 1.5 T to 7.0 T (Krautmacher et al.
2015; Noebauer-Huhmann & Szomolanyi 2015). Yet, recent studies had discovered that higher magnetic field strength required less concentration of GBCAs in human MR examination (Krautmacher et al. 2015; Noebauer- Huhmann & Szomolanyi 2015). The same amount of gadopentetate dimeglumine (0.1 mmol/kg) scanned with 3-T MRI system has been proven to exhibit higher contrast to noise ratio (CNR) and signal to noise ratio (SNR) of cerebral lesions compared to when scanned with a 1.5-T system (Krautmacher et al. 2015). Another recent study also recommended reducing the gadoterate meglumine volume to half (50%) in paediatric bone and soft tissue MR examinations using a 3T MR system. The results showed no significant difference in SNR and CNR between the half (50%) and full (100%) standard volume of GBCA when scanned with a 3T system (Colafati et.
al. 2018). Taking advantage of having a 3T system, it is possible to use less than the recommended volume of GBCA without degrading the image quality. However, reducing the GBCA volume for the purpose of MRI brain examination and its implication on the current healthcare cost has not yet been explored. Thus, the purpose of this study was to evaluate the effects of different volumes of the gadobutrol and gadoterate meglumine contrast agents on the image quality using a 1.5T and a 3T MRI system using laboratory-made phantoms.
EXPERIMENTAL METHODS
PHANTOM PREPARATION
MRI phantoms made from agarose powder and paramagnetic additives, nickel chloride (NiCl2) (Fig.
1), were chosen for this study due to the structural and electrical properties that mimic human brain (Kandada et al. 2012; Pomfret et al. 2013). Agarose gel is used as the main matrix due to its low viscosity, low melting point and low gelling property (Azhar et al. 2020). Apart from that, the agarose gel provides a T2 relaxation time that mimic human tissue (40 – 150 ms) while NiCl2 provides the T1 relaxation time nearer to human tissue (Hellerbach et al. 2013). Agarose is a polysaccharide extracted from seaweed genera gelidium and gracilaria and is widely used as the gelling agent in electrophoresis (Lee et al.
2012). The phantoms in this study were prepared by dissolving 6 g of agarose powder in 1000 ml of deionized water to obtain the 0.6% agarose gel concentration.
The NiCl2 preparation was performed at room temperature and no heating was necessary as this compound is easily soluble as shown in Fig. 2(b). An amount of 0.714 g of NiCl2 was dissolved in 1000 ml distilled water in order to obtain 0.3 mMol/dm3 concentration (a concentration near to the T1 relaxation of human tissues and blood) (Ohno et al. 2008;
Thangavel & Saritas 2017). The NiCl2 bottle was kept closed as the compound can be hydroscopic and distorts the weighing.
FIGURE 1 NiCl2 crystal (left), 50-ml centrifuge tube (middle) and agarose powder (right)
During the preparation, the agarose solution was stirred for approximately 1 minute using a magnetic stirrer at room temperature. The solution was then heated in a microwave oven for 9 minutes at the interval of 3 minutes until it became crystal clear (Fig. 2 (a)). The agarose gel solution was then kept in the conical flask (Fig. 2(b)).
(a)
(b)
FIGURE 2 a) Agarose solution heated in a microware oven and b) the 0.6% agarose gel after being heated in the microware (right) and after mixing with 0.3 mMol/dm3 NiCl2 (left) The agarose gel and NiCl2 were then mixed in a bikar and boiled up. The mixture was then stirred using a magnetic stirrer. The mixture was then separated into the 8 conical flasks accordingly to contain the eight (8) various volumes of GBCA using pipettes and was continuously stirred. Table 1 shows the volumes of the GBCA that were prepared. An amount of 50 ml of the mixture in the 8 conical flasks were poured into eight 50-ml centrifuge tubes each with diameter of 20 mm.
A blank centrifuge tube as a non-contrast phantom was also prepared for comparisons. The prepared phantoms were then partially immersed in water inside a plastic rectangular container containing water (Fig. 3(a)).
The whole set-up was finally placed in the middle of a birdcage radio frequency (RF) coil (Fig. 3(b)).
The MRI scans using a 1.5-T system (Magnetom Ara, Siemens Healthcare, Erlangen, Germany) were conducted in Hospital Selayang while the scans using a 3.0-T system (Magnetom Verio, Siemesn Healthcare, Erlangen, Germany) were conducted in the Institut Kanser Negara (IKN). This study was approved by the UiTM ethics committee, Clinical Research Centre (CRC) and Medical Research Ethics (MREC) from both IKN and Hospital Selayang for the utilization of their MRI scanners.
MRI SCANS
The MRI scans were performed on the phantom using the T1-MPRAGE sequence and single echo spin-echo (SE) sequence to obtain T1 and T2 relaxation images as shown in Fig. 4.
(a)
(b)
FIGURE 3 (a) The phantom was immersed in the water inside a plastic container and (b) placed in the middle of the RF birdcage coil for the scanning
TABLE 1 The phantoms under study
Phantom GBCA/% Phantom volume/ml GBCA A/ml GBCA B/ml 12
34 56 78
10075 5025 10075
5025
5050 5050 5050 5050
0.00500 0.00350 0.00250 0.00125
-- --
-- -- 0.0100 0.0075 0.0050 0.0025 GBCA A = Volume of gadobutrol (0.1 mmol/kg)
GBCA B = Volume of gadoterate Meglumine (0.05 mmol/kg)
(b)
FIGURE 4 Examples of MR images obtained from the phantom at 3T using (a) spin-echo sequence for T2 relaxation measurement and (b) T1-MPRAGE sequence for T1 relaxation measurement
(a)
For T2 relaxation measurements, the phantoms were scanned using a single echo spin-echo sequence for both 1.5 T and 3.0 T systems; TR = 2000 ms, TE = 12 ms, acquisition matrix = 128 × 102 and total scan time = 3 minutes 30 s per image. For T1 relaxation measurements, the images were obtained from 1-mm axial T1-MPRAGE isotropic 3D GRE sequence using 1.5 T system and 16-channel dedicated head coil. The parameters were TR = 2200 ms, TE = 2.79 ms, TI = 900 ms, FOV = 200 × 200 matrix, matrix size = 246 × 256, slice thickness = 1.0 mm, number of slices = 192, pixel bandwidth = 150 Hz/pix, number of averages = 1 and acquisition time = 4.59 s. For the 3.0 T system, the 1-mm axial T1-MPRAGE isotropic 3D GRE sequence with 16-channel dedicated head coil was used. The parameters were TR = 2300 ms, TE = 2.2 ms, TI = 900 ms, FOV = 200 × 200 matrix, matrix size = 320 × 320 pixel, slice thickness = 1.0 mm, number of slices = 128, pixel bandwidth = 200 Hz/pix, number of averages = 1 and acquisition time = 4.40 s. The remaining parameters were kept constant for both systems.
SIGNAL INTENSITY AND SIGNAL-TO-NOISE RATIO (SNR) CALCULATION
The mean signal intensity and signal to noise ratio (SNR) were measured for each tube to assess the quantitative assessment of image quality. The signal intensity and SNR were measured by identifying the area of interest and circulating the designated area (ROI). Measurement of the signal intensity, SNR and noise were done three times for each dataset, at three different slices to obtain an average value for each set and to avoid any error or bias. The ROIs were 1.0–1.3 cm2 in size and were manually drawn and estimated by the researcher. The scanned images of all the phantoms containing the designated volumes are shown in Figs. 5 and 6.
(a)
(b)
(c)
FIGURE 5 (a – c) Three sagittal slices of the T1-MP-RAGE isotropic 3D GRE images with the same volumes labelled as CE1, CE2 and CE3 (from top to bottom) obtained from the 3T system. Each ROI was drawn in the middle of the image and on the background at the same location for each different slice. The image of the non-contrast phantom is shown at the top of the image
(a)
CONTRAST ENHANCEMENT EVALUATIONS Contrast enhancement images were analysed using a Picture Achieving and Communication System (PACS) (Infinit, Seoul Korea) using a monitor with a spatial resolution of 1600 x 1200. The 4-point score are 4 for excellent, 3 for moderate, 2 for adequate and 1 for poor (Colafati et al. 2018). Two radiologists with more than 8 years of experience in neuroradiology were given the images and were required to give the scoring based on the criteria provided. The observers were asked to score the contrast enhancement of the experiment images and compare with the control images. A short briefing regarding the scoring was given and they were not provided with the details of the parameters, condition
of the phantoms and the MRI system used for all the 16 phantom images. However, the control image is informed to the observers to make the comparison. The control images scanned with the 1.5 T system were labelled as
‘1’ for the image of the phantom containing gadobutrol and ‘5’ for the image of the phantom containing godeterate meglumine. The control image scanned with the 3.0 T system were labelled as ‘9’ for the image of the phantom containing gadobutrol and ‘13’ for the image of the phantom containing godeterate meglumine. The experimental phantoms scanned using the 1.5 T system were labelled as ‘2, 3, 4, 6, 7’ while the experimental phantoms scanned using the 3.0 T system were labelled as ‘10, 11, 12, 14, 15 and 16’.
STATISTICAL ANALYSIS
This study employed Shapiro-Wilk for the normality test. Kruskal-Wallis H test was performed to compare the signal intensity between the scanners and both contrast agents. The inter-rater agreement between observers was determine using the Cohen;s Kappa test .
RESULTS
SNR ASSESSMENT
Table 2 shows the SNR obtained from 1.5 T-images of phantoms containing gadobutrol and gadoterate meglumine (GBCA) at different GBCA volumes of 75%, 50% and 25%. The SNR decreases as the CBCA is increased. The Kruskal-Wallis H test showed that there was no significant different in SNR when the prepared volumes were compared with 100% GBCA for gadobutrol (X2(2) = 5.956, p = 0.051) with a mean rank contrast volume 7.33 for 75%, 5.62 for 50% and 2.0 for 25%. However, there was a significant different in SNR when the reduced volumes were compared with 100% GBCA for gadoterate meglumine (X2(2) = 7.2, p
= 0.027) with a mean rank contrast volume 8 for 75%, 5 for 50% and 2 for 35%. Hence, the SNR comparisons showed that the use of 75% volume of the gadoterate (c)
FIGURE 6 (a – c) Three sagittal slices of the T1-MP-RAGE isotropic 3D GRE images with the same volumes labelled as CE4, CE5, CE6 (top to bottom) obatained from the 3 T system. Each ROI was drawn in the middle of the image and on the background at the same location for eash different slice. The image of the non-contrast phantom is shown at the top of the image
(b)
TABLE 2 The SNR obtained from 1.5 T-images of phantoms containing gadobutrol and gadoterate meglumine at different volumes
GBCA Volume/%
SNR (Mean ± SD)
Gadobutrol Gadoterate meglumine 75%50%
25%
262.47 ± 0.50 240.30 ± 0.50 167.87 ± 3.59
294.6 ± 3.5 242.7 ±2.8 184.3 ±3.32
meglumine is acceptable at 1.5 T. Furthermore, the SNR results explained the lower signal intensity of 25%
GBCA on the phantom images.
Table 2 shows the SNR obtained from 3.0 T-images of phantoms containing gadobutrol and gadoterate meglumine (GBCA) at different GBCA volumes of 75%, 50% and 25%. Similar to the previous results, the SNR decreases as the CBCA is increased. The highest mean difference in SNR is between the 25% volume and 100% volume for gadobutrol. The Kruskal-Wallis H test showed that there was no significant different in SNR when the prepared volumes were compared with 100% GBCA for gadobutrol (H = 3103, df = 3, p = 0.376) with a mean rank contrast volume 6.33 for 75%, 5.33 for 50% and 3.33 for 25%. Insignificant results (H = 6.897, df = 3, p = 0.075) were also obtained for gadoterate meglumine when the prepared volumes were compared with 100% GBCA with a mean rank contrast volume contrast volume 8.0 for 75%, 6.0 for 50% and 2.33 for 25%.
The signal intensity on the images of both 75% GBCA volume obtained using the 1.5 T and 3.0 T system was rated as “acceptable”. The signal intensity on the images of both 50% GBCA volume obtained using the 1.5 and 3.0 T systems was rated “moderate”. As expected, the image appearance and the contrast agent enhancement were dramatically rated as “worse” for images of 25%
GBCA volume obtained using the 3.0 T system and even
“worse” and almost “zero” signal intensity when using the 1.5 T. The 25% volume of both GBCA at 1.5 T and 3.0 T is “not acceptable” and should be avoided at all cause based on the radiologists’ preferences and liking.
Cohen’s Kappa was chosen to determine the agreement between observer 1 and observer 2 regarding the signal intensity of the images for both GBCA volumes of 75%
measured using the 1.5 T system. There was a very weak agreement between both observers, which was not statistically significant k = -0.067 (95% CI), p > 0.05. The same test was conducted to identify the agreement on the signal intensity of the images obtained using the 3.0 T system, whether the signal intensities from both GBCAs were excellent, moderate, poor or worse. It was found that both observers have a moderate agreement regarding the signal intensity of the images from both GBCA with 75%
volume at 3T, k = 0.704 (95% CI), p < 0.001.
DISCUSSSION
The aim of this experimental study was to evaluate the effects of gadobutrol (0.1 mmol/kg) and gadoterate meglumine (0.05 mmol/kg) volume reduction on image quality at 1.5 T and 3 T using agarose gel phantoms. In this study, various volumes reduction of contrast agents was applied on NiCl2 doped agarose gel phantom. This study found a significant different in SNR when the reduced volumes were compared with 100% GBCA for gadoterate meglumine. This showed that the volume reduction of GBCAs is applicable when scanned with 3T. It is known that the signal intensity will increase linearly with magnetic field strength (Krautmacher et al.
2015). Past studies found that, a higher GBCAs dose is required for low magnetic field strengths, such as 0.2T (Brekenfeld et al. 2001)Bracco-Byk Gulden. A recent study comparing between half volume of GBCAs at 3T and full volume of GBCAs at 1.5T showed better lesion enhancement at 3.0T as compared to full volume of GBCAs at 1.5T. According to Noebauer-Huhmann
& P.Szomolanyi (2015), who studied the comparison between 3T and 7T , the lesion enhancement was higher at 7T with a half volume of GBCAs (gadobenate dimeglumie) than a full volume of GBCAs in patients with brain tumours at 3T. With the current trends for utilizing higher MR strength in clinical centers, administering lower volume at 75% especially for 3T TABLE 3 The SNR obtained from 3.0 T-images of phantoms
containing gadobutrol and gadoterate meglumine at different volumes
GBCA Volume/%
SNR (Mean ± SD) Gadobutrol Gadoterate
meglumine 75%50%
25%
153.5 ± 41.0 144.8 ± 41.0 114.1 ± 32.0
185.8 ± 28.0 162.0 ± 25.0 133.0 ± 20.0 From the results obtained, this study shows that different volumes of GBCA provide different signal intensity when measured using the 1.5-T and 3.0-T systems. The present study also found that by reducing the volume of both GBCA to 50%, the measured intensity using the 3.0 T-system was almost equal to the intensity for 100% volume of GBCA measured using the 1.5-T system.
VISUAL AND REGION OF INTEREST BASED INTER RATER AGREEMENT OF SIGNAL
INTENSITY ASSESSMENT
The evaluation of contrast enhancement at 75%, 50% and 25% volume of gadobutrol and gadoterate meglumine was done manually by two radiologists using the scoring sheet. From the scoring sheet, the results show that each radiologist has a preference of image contrast enhancement. This could be due to their working experiences at reporting images and the types of monitor used during the scoring process. The signal intensity on the images of both 100% GBCA volume obtained using the 1.5 and 3.0 T systems was rated “excellent”.
would be beneficial for cost effectiveness and reducing gadolinium toxicity to patients.
The contrast enhancement effect of GBCA in different magnetic field is influenced by T1 relaxation rate of the tissue and relaxivity (R1) of the GBCAs (Noebauer-Huhmann & P.Szomolanyi 2015). The T1- shortening effect of a GBCA will be greater with longer T1 relaxation times in higher magnetic field strength.
The appearance of GBCA is related to signal intensity that can be determining factors for image quality and the diagnostic accuracy. The image appearance of the phantom injected with the contrast agents at 75% were considered acceptable at 3T by the observers’ agreement.
The introduction of GBCA will increase the sensitivity and specificity in detecting signal changes between tissues. The T1-shortening effect of a GBCA depends on the baseline T1 relaxation time of local tissue. The T1-shortening effect of a GBCA will be greater with longer baseline T1 relaxation times in higher magnetic field strength. Thus, the signal intensity changes caused by GBCA should be stronger in 3 T compared to 1.5 T (Krautmacher et al. 2015). This gives an advantage to 3T as use at 1/2 half GBCA volume can still produce good SNR compared to 1.5T. Based on the finding from the current study’s, the gadobutrol and gadobenate dimeglumin shown to have a higher SNR at 3T as compared to 1.5T at 100% volume. Furthermore, the present study postulated that by reducing to 3/4 volume of gadobutrol(0.1 mmol/kg) is sufficient to provide acceptable signal intensity and acceptable image appearance at 1.5 T and much better for 3T. We can reduce the volume of GBCA up to 50% for scanning using 3T however not advisable for 1.5T scanner. This is due to the magnetic strength of 3T and its linear relationship with the signal intensity.
CONCLUSION
There were several limitations of this study; firstly, the results of the study were not verified in clinical settings as this is an exploratory study using phantom. The researcher was only able to evaluate the signal intensity and observer agreement for the image brightness.
Nonetheless, it is indeed possible to administer less volume from recommended volume when scanning using 3.0T because of the machine sensitivity in detecting signal intensity and shortening of the relaxation time in high magnetic field strength. The use of 50% (half) volume of gadobutrol or gadoterate meglumine at 3.0T is possible and acceptable for the image quality (SNR) without degrading anatomical appearance and GBCAS enhancement when compared to the 100% volume at
1.5.T. It is suggested for future study to explore the image quality in terms of the image contrast enhancement embedded with lesions, tumours and in dynamic study.
Future investigation may also consider exploring the effects of other GBCA concentration, viscosity, and its relations to the contrast-noise (CNR) ratio, SNR and scanning protocols such as repetition time (TR). Even so, this study recommended that reduction of gadobutrol (0.1mmol/kg) to half of the volume could be consider clinically for 3T scanner.
ACKNOWLEDGMENT
The authors would like to express their gratitude to Mr.
Radzi Ikhsan Ahmad for preparing the agarose phantoms.
Special thanks to Diagnostic Imaging Department, Hospital Selayang, Selangor and Department of Radiology, Institut Kanser Negara, Putrajaya for the permission to use their MRI scanners.
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