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Intraindividual Crossover Comparison of Gadoxetic Acid Dose for Liver MRI in Normal Volunteers

Purpose: We performed a quantitative intraindividual comparison of the performance of 0.025- and 0.05-mmol / kg doses for gadoxetic acid-enhanced liver magnetic resonance (MR) imaging. Materials and Methods: Eleven healthy volunteers underwent liver MR imaging twice, once with a 0.025- and once with a 0.05-mmol / kg dose of gadoxetic acid. MR spectroscopy and 3-dimensional gradient-echo T 1 -weighted images (3D-GRE) were obtained before and 3, 10, and 20 min after injection of the contrast medium to measure T 1 and T 2 values and signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) performance. During the dynamic phase, highly time-resolved 3D-GRE was used to estimate the relative CNR (CNR rel ) of the hepatic artery and portal vein (PV) to the liver. We used paired t-tests to compare the results of different doses. Results: During the hepatobiliary phase, we observed shorter T 1 values and higher SNRs of the liver ( P < 0.001) and higher liver-to-PV and liver-to-muscle CNRs ( P < 0.002) using 0.05 mmol / kg compared to 0.025 mmol / kg. Increasing the dose to 0.05 mmol / kg yielded a greater T 1 -shortening effect at 10 min delay even compared with 0.025 mmol / kg at 20 min ( P < 0.001). During the dynamic phase, the peak CNR rel for the hepatic artery and portal vein were higher using 0.05 mmol / kg ( P = 0.007 to 0.035). Conclusion: Use of gadoxetic acid at a dose of 0.05 mmol / kg leads to signi ﬁ cantly higher SNR and CNR performance than with 0.025 mmol / kg. Quantitatively, a 10-min delay may be feasible for hepatobiliary-phase imaging when using 0.05 mmol / kg of gadoxetic acid.


Introduction
Gadoxetic acid is a gadolinium-based contrast agent used primarily for hepatobiliary imaging applications, and it is now widely accepted as a pri-mary contrast agent in magnetic resonance (MR) imaging of the liver. 1,2 Its pharmacokinetics is similar to that of extracellular contrast agents immediately after bolus injection; it is taken up rapidly into hepatocytes and subsequently excreted into bile. Recent studies have demonstrated important advantages of gadoxetic acid-enhanced MR imaging over other methods for imaging liver disease. [3][4][5][6] Typically, maximum liver-to-lesion contrast is obtained in the hepatobiliary phase, approximately 20 min after injection, and good liver-to-lesion contrast persists about 2 to 3 hours. 7 In the hepatobiliary phase, normal liver and bile appear hyperintense from the presence of gadolinium, whereas blood vessels and focal liver lesions appear hypointense. This contrast enables detection of even very small hepatic metastases or hepatocellular carcinoma as hypointense lesions in bright liver tissue. 2,[8][9][10][11][12] The use of hepatobiliary-phase images for the evaluation of hepatic function has also been suggested. 13,14 The approved package insert dose of gadoxetic acid, 0.025 mmol/kg, yields a quarter of the dose of gadolinium of traditional formulation agents, including gadopentetate dimeglumine, gadoteridol, gadodiamide, gadoversetamide, and gadobenate dimeglumine. 15 This dose was determined based on preclinical studies 16,17 that demonstrated comparable early enhancement of hypervascular tumors between MRI with a 0.025 mmol/kg dose showed comparable early enhancement of hypervascular tumors to gadopentetate dimeglumine 16 A dose of 0.025 mmol/kg was also found to be the minimum effective dose during the hepatobiliary phase for the detection and characterization of lesions. 17 However, the imaging sequences used in these studies (both published in 1996) are no longer routinely used in clinical MR imaging. In fact, many institutions have adopted the use of higher doses, such as a fixed dose of 10 mL rather than a dose based on patient weight, as a standard in clinical MR imaging. [18][19][20] For patients weighing 50 to 100 kg, this results in effective doses of 0.025 to 0.05 mmol/kg. Considering that a dose of 0.025 mmol/kg of gadolinium is only a quarter of the conventional MR contrast agent dose, the expected risk of toxicity from dose escalation is likely to be minimal.
The growing use of doses that exceed the package insert dose motivated a systematic re-evaluation of higher dosing of gadoxetic acid when used with state-of-the-art MR imaging sequences. Greater arterial and tumor enhancement in the early dynamic phase is expected using a higher dose of 0.05 mmol/kg than the 0.025 mmol/kg, and this may improve the detection and characterization of small enhancing liver lesions. Moreover, a recent study demonstrated improved clinical performance of gadoxetic acid at a dose of 0.05 mmol/kg compared to 0.025 mmol/kg for both dynamic-and hepatobiliary-phase imaging in patients with cirrhosis. 21 The purpose of this crossover study was to perform a systematic and objective comparison of doses of 0.025 mmol/kg and 0.05 mmol/kg of gadoxetic acid in healthy volunteers. We compared the doses in both the dynamic and hepatobiliary phases using state-of-the-art pulse sequences and included measurements of signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). Further, we used MR spectroscopy-based relaxometry to measure the fundamental relaxation parameters of the liver after the administration of the contrast medium to facilitate optimization of future acquisition strategies.

Subjects
This prospective crossover study complied with Health Insurance Portability and Accountability Act (HIPAA) requirements and was approved by our institutional review board (IRB). We recruited 11 healthy subjects (4 men, 7 women; aged 23 to 64 years, mean, 38 « 15 years; weight 54 to 91 kg, mean 70 « 13 kg) from a local IRB-approved database of healthy volunteers and obtained their written informed consent prior to scans. We screened all volunteers to confirm they had no liver or renal disease.
The SNR and CNR measurements performed for hepatobiliary-phase images at 20 min after injection of 0.025 mmol/kg of gadoxetic acid in this study (see below) have also been used in a separate unrelated study. 22 However, the comparison between 2 doses of gadoxetic acid has not been previously investigated in these subjects.

Study protocol and contrast agent
This crossover study comprised 2 visits separated by more than 4 weeks (28 to 76 days, mean 57 days). At the first visit, gadoxetic acid-enhanced liver MR imaging was performed using 0.025 mmol/kg (0.1 mL/kg) of gadoxetic acid (Eovist μ , Bayer Healthcare). At the second visit, the same imaging protocol was repeated using a dose of 0.05 mmol/kg (0.2 mL/kg). The 0.025 mmol/kg dose was diluted 1:1 with saline (0.9% NaCl) to ensure injection of the same volume as for the 0.05 mmol/kg dose (off-label use for the study). Injections were performed using a power injector (Spectris Solaris μ , MedRad μ , Inc., Warrendale, PA, USA) at 2 mL/s by means of a 20-gauge antecubital intravenous catheter followed by a 20-mL saline chaser at the same injection rate. The volume and injection rate for each protocol were the same to ensure accurate comparisons of the time to peak enhancement as well as enhancement during the dynamic phase. 23

MR spectroscopy-based relaxometry
MRS was performed before and 3, 10, and 20 min after the injection of gadoxetic acid to measure liver T 1 and T 2 values. A single-voxel stimulated echo acquisition mode (STEAM) MRS sequence was acquired in a single 21-s breath-hold. This STEAM sequence used varying repetition times (TRs; 150 to 1000 ms) to enable calculation of the T 1 value of the object. Multiple echo times (TEs; 10 to 110 ms) were also acquired to measure T 2 values of the object. These multiple acquisitions (multi TR and multi TE) were completed within a single breath-hold to enable independent measurement of the T 1 and T 2 of water and fat (if present). 24,25 The MRS voxel was 20 © 20 © 20 mm 3 and was placed in the right lobe (segments 6 or 7) of each subject, avoiding large blood vessels or bile ducts. Other acquisition parameters included: receiver bandwidth, « 2500 Hz; number of acquired points, 256; total number of spectra acquired, 32 (including 4 prepulse excitations to reach steady state).

MR imaging
A 3-dimensional (3D) T 1 -weighted MR sequence was used before and 3, 10, and 20 min after contrast injection using parameters: breath-hold T 1 -weighted 3D spoiled gradient-echo (SPGR) sequence with dual-echo chemical shift-encoded water-fat separation, 26 27 After the above-mentioned scans were performed using a fixed flip angle of 15°, the acquisition was repeated with flip angles from 10°to 50°at 5°increments to determine the optimal flip angle to maximize contrast between liver and muscle and between liver and the PV. To ensure that any observed signal differences were due to flip angle rather than slowly varying changes of the gadolinium concentration in the liver, we reversed the flip angle order in 6 of the 11 volunteers.
To determine the effects of dose on enhancement during the dynamic phase, we used a highly timeresolved T 1 -weighted 3D SPGR sequence. High spatial and temporal resolution were achieved using interleaved variable density (IVD) undersampling, 28 k-space corner-cutting, 29 and data-driven parallel imaging. 30 Autocalibration signal (ACS) lines were acquired at the center of the k-space only in the first time frame and then used for all 10 subsequent time frames acquired in the same breathhold. 31 Fat suppression was achieved using a dualecho chemical shift-encoded water-fat separation. 26 Imaging parameters for the dynamic IVD sequence included: TR, 3.9 ms; TE1, 1.2 ms; TE2, 2.3 ms; bandwidth, « 166.7 kHz; slab volume, 38 cm (R/L) © 34 cm (A/P) © 26 cm (S/I) matrix, 320 © 202 © 100, 15°flip angle; and partial k z (0.75) acquisition, R = 2 © 2 data-driven parallel imaging acceleration (autocalibrating reconstruction for Cartesian imaging [ARC], GE Healthcare), for true spatial resolution of 1.2 © 1.7 © 2.6 mm 3 (interpolated to 0.74 © 0.74 © 1.3 mm 3 through zero-filling). Scan time was 24 s for 11 time frames with a temporal resolution of ³2 s.
After obtaining the precontrast scan, dynamicphase imaging was performed with the same prescan values to facilitate relative CNR calculations. The scan delay was fixed at 13 s after the beginning of the gadoxetic acid injection.

Data processing and analysis
Quantification of the STEAM datasets was performed using a custom script developed in Matlab (The Mathworks, Inc., Natick, MA, USA). The processing script performed joint fitting of all 28 spectra acquired with different TRs and TEs by accounting for T 2 decay and T 1 recovery. Each spectrum was fitted using Voigt line shapes and assuming a single peak for water signals and 6 peaks for fat signals. 32 This processing resulted in estimates of water and fat T 1 and T 2 values as well as protondensity fat-fraction (PDFF) of the liver.
In addition, we calculated the estimated concentration of gadoxetic acid using: in which c (mM) is the estimated concentration of gadoxetic acid in the liver; T 1-Pre and T 1-Post are the measured T 1 values of the liver before and after contrast injection; and r 1 is the relaxivity of gadoxetic acid. The longitudinal relaxivity, r 1 , is dependent on field strength and tissue type. However, no available reports describe the r 1 of the human liver at 3T. Previous studies reported r 1 = 16.6 mM ¹1 0s ¹1 for rat liver at 0.47T, 33 and r 1 = 8.7 mM ¹1 0s ¹1 for plasma at 0.47T and 6.2 mM ¹1 0s ¹1 for plasma at 3T. 34 Considering all of these, we felt that the r 1 value for the liver at 0.47T, 16.6 mM ¹1 0s ¹1 , was most likely the closest to that of the human liver at 3T. We measured signals of MR images offline using open-source DICOM viewer software (OsiriX v. 5.8, Pixmeo, Geneva, Switzerland). A board-certified radiologist with fellowship training in abdominal MR imaging and 6 years of experience in diagnostic imaging drew regions of interest (ROI) in specific tissues of interest, copying the ROIs to identical positions in images obtained at different time points or with different flip angles. Slight manual corrections were made to ensure proper alignment with the relevant anatomy in the cases in which misregistration occurred from variability in breath-hold position. ROIs were placed in the liver (2 ROIs), muscle, and portal vein and in an artifactfree area outside the body. We used muscle as a surrogate for weakly enhancing liver lesions such as hypovascular metastasis. 7,18 We used the following equations to calculate the SNR of the liver, portal vein, and muscle: in which SI tissue is the average of signal intensity in tissues of interest and SD air is the standard deviation of the signal of air measured in areas outside the body not compromised by artifacts. We used a correction factor of 0.7049 to account for differences in the behavior of the noise variance in the background region in magnitude images acquired with multi-channel coils. 35 We calculated the CNR to compare the contrast between the portal vein and muscle with the liver parenchyma (liver-to-portal vein and liver-to-muscle CNR). The CNR was calculated as the difference in SNR between the liver and the tissue of interest: We placed ROIs in the hepatic artery, portal vein, and liver (2 ROIs) to evaluate the performance of the time-resolved IVD scan during the dynamic phase, used the average signal of the 2 liver ROIs in all subjects to minimize the effect of signal variations, and placed all ROIs equidistant to the anterior and posterior coils to account for the higher coil sensitivity for tissue closer to the coils. We measured the performance of the relative CNR (CNR rel ) in the dynamic phase of gadoxetic acid to determine the impact of contrast dose during the dynamic phase using: in which SI vessels is the signal intensity of the portal vein and hepatic artery and SI liver is that of the liver during the dynamic phase. SI Precontrast liver is the signal intensity of the liver before contrast injection. Relative CNR was used to evaluate the performance of the time-resolved acquisition because accurate absolute SNR and CNR measurements are not possible when using parallel imaging. 27 Statistical analysis All data are presented as the mean with 95% confidence intervals (95%CI) in all plots. We used paired t-test with Bonferroni correction to compare post-contrast (3, 10, and 20 min) T 1 and T 2 values of the liver with those values prior to contrast administration and paired t-tests to compare T 1 values of the liver, estimated contrast agent concentration in the liver, and SNR, CNR, and CNR rel of 0.025and 0.05-mmol/kg doses at each time point. We also used paired t-test to compare measurements with a dose of a 0.05 mmol/kg at a 10-min delay to measurements with a dose of 0.025 mmol/kg at a 20-min delay to explore the potential advantage of a higher dose for shortening the total scan time. A 2-sided t-test with P value less than 0.05 was considered statistically significant. All statistical tests were performed using Microsoft Excel 2010.

Results
T 1 and T 2 value and signal alteration at 3-, 10-, and 20-min delays After injection of gadoxetic acid, the T 1 values decreased significantly (P < 0.001) from ³1000 ms before contrast administration to 284 ms with 0.025 mmol/kg and 220 ms with 0.05 mmol/kg. We observed significant changes in the T 1 value of the liver even 3 min after injection. The mean (95% CI) T 1 values were significantly lower for 0.05 mmol/kg than for 0.025 mmol/kg at all time points after injection of gadoxetic acid (all P < 0.001) (Fig. 1a). The mean (95% CI) T 1 values of the 0.05-mmol/kg dose compared to the 0.025-mmol/ kg dose were: 293 ms (263-323 ms) versus 376 ms (344 -408 ms) at 3 min; 248 ms (223-272 ms) versus 326 ms (297-356ms) at 10 min; and 220 ms (199-241 ms) versus 284 ms (258-311 ms) at 20 min. Figure 1b shows the corresponding estimated concentrations of gadoxetic acid in the liver.
The average of the precontrast T 1 values over all subjects was slightly lower, although not significantly, between the first and second scans (1063 « 171 ms versus 997 « 159 ms, P = 0.08). This initially suggested that a very small amount of contrast may have remained in the liver in some subjects. For this reason, we plotted the precontrast T 1 values in Fig. 2. As the figure shows, precontrast T 1 values were lower for the first scan in half (n = 5) of the subjects and for the second scan in the other half (n = 6). However, we observed a relatively large difference in 2 subjects with lower T 1 values at the second scan that led to an overall decrease in the average of the precontrast T 1 values between the 2 scans. The intervals of the 2 examinations in the 2 subjects were 28 and 69 days.
Interestingly, the T 1 measured in enhanced liver tissue using 0.05 mmol/kg of gadoxetic acid at 10 min was significantly shorter than that for 0.025 mmol/kg at 20 min (P < 0.001). The estimated concentration of gadoxetic acid in the liver was also significantly higher at 10 min using the 0.05mmol/kg dose than at 20 min using the 0.025mmol/kg (P = 0.008, Fig. 1a).
T 2 values of the liver also decreased significantly, though just slightly (P < 0.001), after injection of gadoxetic acid from ³27 ms before contrast administration to ³25 with the 0.025-mmol/kg dose and ³23 ms with the 0.05-mmol/kg dose. Significant, though small, changes in the T 2 values of liver were seen even at 3 min after injection. T 2 values did not differ significantly at any time point between the 2 doses of gadoxetic acid (P = 0.112 to 0.183) (Fig. 1a).

SNR performance in the hepatobiliary phase
The SNR of the liver during the hepatobiliary phase was significantly higher using 0.05 mmol/kg compared to 0.025 mmol/kg at all time points (P < 0.001; Figs. 3,4). The SNR in the portal vein was also significantly higher using a 0.05-mmol/kg dose at 3 and 10 min (P < 0.001) and at 20 min (P = 0.006). There was no significant difference between the 2 doses for the SNR of muscle (P = 0.581 to 0.761). The CNR of the liver relative to the portal vein was significantly higher using 0.05 mmol/kg than 0.025 mmol/kg (P = 0.002 at 3 min; P < 0.001 at 10 and 20 min), and the CNR of the liver relative to muscle was significantly higher for 0.05 mmol/kg than 0.025 mmol/kg at all time points (all P < 0.001).
As observed with the T 1 measurements, the SNR of the liver (P = 0.002, Fig. 4) and CNR of the liver relative to muscle (P = 0.006, Fig. 4b) were also significantly higher at 10 min using 0.05 mmol/kg than at 20 min using 0.025 mmol/kg, whereas no significant difference was observed in the CNR of T 2 values measured from magnetic resonance (MR) spectroscopy were slightly, though significantly (P < 0.001), shorter after than before contrast administration for both doses. After contrast administration, T 1 values were significantly shorter with 0.05 mmol/kg than 0.025 mmol/kg at all time points (3, 10, and 20 min, P < 0.01), but T 2 values were not (P = 0.112 to 0.183). Estimated concentrations of the contrast agent in the liver were also significantly higher using 0.05 mmol/kg at all time points. The estimated concentration of the contrast agent was calculated using the measured T 1 values of the liver and known r 1 value in the liver of rats at 0.47T (16.6 mM ¹1 0s ¹1 ). The graphs show mean values with 95% confidence intervals.  2. (a) We observed a small but insignificant difference between the average of precontrast T 1 values (1063 « 171 ms versus 997 « 159 ms, P = 0.08) between the first and second scans despite a relatively long washout period between scans (28 to 76 days, average 57 days). This initially suggested that a very small amount of contrast medium may have remained in the liver of some subjects. (b) However, the change between precontrast T 1 values in the subjects was highly variable and not related to the number of days between 2 scans. The relatively larger apparent change in T 1 values of 2 subjects may have skewed the average. Fig. 3. Representative 3-dimensional (3D) gradient-echo T 1 -weighted images of the liver in a 32-year-old woman obtained 3, 10, and 20 min after injection of gadoxetic acid at 0.05 mmol/kg (bottom) and 0.025 mmol/kg (top). All images are shown with the same window width and window level. Images with a dose of 0.05 mmol/kg show higher signal-to-noise (SNR) and contrast-to-noise (CNR) ratios than those with 0.025 mmol/kg at every time point. Note: The CNR at 10 min using 0.05 mmol/kg was higher than that at 20 min with 0.025 mmol/kg. The CNR of the liver to portal vein (Liver-PV) and liver to muscle (Liver-muscle) are shown in the right bottom of each image. the liver relative to the portal vein (P = 0.751, Fig. 4a).

Flip angle optimization in the hepatobiliary phase
The SNRs in the portal vein and muscle were highest with the lowest flip angle (10°) for both doses, whereas the SNR in the liver was highest at 15°for the 0.025-mmol/kg dose and at 20°for the 0.05-mmol/kg dose (Figs. 5, 6). The CNR of the liver to the portal vein was highest at a flip angle of 20°for both doses, 0.025 mmol/kg (mean [SD], 168 32 ) and 0.05 mmol/kg (232 31 ). The CNR of the liver to muscle was also the highest at 20°for both doses, 0.025 mmol/kg (174 25 ) and 0.05 mmol/kg (262 52 ) (Fig. 6).
Comparing the 2 doses, the CNRs of both the liver to the portal vein and the liver to muscle were significantly higher using the 0.05-mmol/kg dose Fig. 4. Absolute signal-to-noise ratio (SNR) and contrast-to-noise (CNR) performance for delayed T 1 -weighted imaging for 0.025-and 0.05-mmol/kg doses of gadoxetic acid. SNRs of the liver were significantly higher using 0.05 mmol/kg than 0.025 mmol/kg at every time point (P < 0.001). SNRs of the portal vein were also higher with 0.05 mmol/kg (left, P < 0.006) but not for muscle (right, P = 0.581 to 0.761). Both liver-to-portal vein and liver-to-muscle CNRs were significantly higher with 0.05 mmol/kg than 0.025 mmol/kg at every time point (P < 0.002). The graph plots are mean value with 95% confidence interval. SNR values of the liver are shown in both graphs as solid bars.  Fig. 3. Liver-to-portal vein (L-PV) and liver-tomuscle (L-muscle) CNR are shown in the right bottom of each image. compared to 0.025 mmol/kg for all flip angles (all P < 0.013) except for CNR of liver to portal vein at the lowest flip angle of 10°(P = 0.161) (Fig. 6).

Contrast enhancement of the vessels in the dynamic phase
During the dynamic phase, the CNR rel of the hepatic artery to the liver was significantly higher using 0.05 mmol/kg compared to 0.025 mmol/kg at a 17-to 25-s delay, whereas the CNR rel of the portal vein to the liver was highest at a 27-to 35-s delay (Fig. 7). These data show the significant increase of peak enhancement in both the hepatic artery and portal vein with 0.05 mmol/kg (P < 0.035) (Fig. 8).

Discussion
In this work, we have performed a systematic and objective comparison of 0.025-mmol/kg and 0.05-mmol/kg doses of gadoxetic acid as part of an intraindividual crossover study. Specifically, we performed MR relaxometry to measure both T 1 and T 2 values in the liver after the injection of the different doses of gadoxetic acid. Further, we quantified a significant improvement in SNR and CNR performance during both the dynamic and hepatobiliary phases by increasing the dose from 0.025 mmol/kg to 0.05 mmol/kg. We also performed flip angle optimization to determine the T 1 weighting that maximizes SNR and CNR performance in the hepatobiliary phase for both contrast doses.
Our results indicate that increasing the dose of gadoxetic acid significantly reduces the T 1 value of the liver and increases the SNR of the liver and CNR of the liver relative to the portal vein and muscle during the hepatobiliary phase. During the dynamic phase, enhancement was significantly higher in both the hepatic artery and portal vein with the 0.05-mmol/kg dose than with 0.025 mmol/kg. Further, we determined 20°as the optimal flip angle to maximize the CNR of the liver versus the portal vein/muscle for either dose protocol.
We also demonstrated that using the 0.05-mmol/ kg dose of gadoxetic acid, the T 1 value of the liver at 10 min was shorter than that using 0.025 mmol/ kg at 20 min. The CNR between the liver and muscle using 0.05 mmol/kg at 10 min was also higher than that using 0.025 mmol/kg at 20 min. Interestingly, the T 2 values of the liver during the hepatobiliary phase were only minimally (albeit statistically significantly) affected by gadoxetic acid in general and not affected by increasing the gadolinium dose. Several researchers have suggested that T 2 -weighted imaging can be performed after gadoxetic acid injection, before the 20-min hepatobiliary as a means to shorten the overall protocol time. [36][37][38][39] Our T 2 measurements confirm that T 2weighted imaging after the injection of gadoxetic acid at either 0.025 or 0.05 mmol/kg should have minimal impact on T 2 contrast and can be used to shorten the overall protocol time. Enhancement of the vessels during the dynamic phase typically depends upon the concentration of the contrast agent in the vessels, which is affected by both dose and injection speed. 40,41 The recommended dose of gadoxetic acid, 0.025 mmol/kg, and injection speed,¯2 mL/s, 42 would result in lower intravascular gadolinium concentration dur-ing the dynamic phase than that obtained with conventional gadolinium-based contrast agents, which are typically administered with a dose of 0.1 mmol/ kg at ³2 mL/s. 43 Even considering the higher r 1 value effect with gadoxetic acid, the contrast effect is less with 0.025 mmol/kg of gadoxetic acid than that obtained with conventional gadolinium-based  contrast agents. 34 Emerging evidence also demonstrates that 0.025 mmol/kg may be an insufficient dose for dynamic-phase imaging. 18,44 -46 Therefore, some radiologists prefer to use an undiluted fixed dose of 10 mL of gadoxetic acid independent of the patient's weight and thereby often exceed the recommended package insert dose. 47 As expected, we observed significantly greater arterial and portal enhancement in the early dynamic phase using a higher dose, which may support the use of doses exceeding 0.025 mmol/kg in clinical practice.
During the hepatobiliary phase, however, the impact of higher doses for liver-to-vessel and liverto-lesion contrast have been controversial. 17 A recent intraindividual comparison of 0.025 and 0.05 mmol/kg in patients with cirrhosis suggested significant improvement of liver-to-lesion (hepatocellular carcinoma) contrast in patients with decreased hepatic function (Child-Pugh class B disease) but not in patients with preserved hepatic function (Child-Pugh class A disease). 21 A study performed in the early stages of gadoxetic acid development also showed that liver-to-lesion contrast during the hepatobiliary phase was not necessarily higher using 0.05 compared with 0.025 mmol/kg, although the degree of enhancement compared to precontrast images was consistently higher using 0.05 mmol/kg. 16 Our estimates of gadoxetic acid concentration in the liver during the hepatobiliary phase (Fig. 1b) demonstrated that using 0.05 mmol/kg significantly increased but did not double the intrahepatic concentration. This can be explained by the ability of the hepatocytes to take up gadoxetic acid; according to Michaelis-Menten kinetics, a higher concentration of contrast agents results in their slower uptake ratio due to the limitation of receptor ability. 48 This speculation is complicated by the increased renal excretion that would be expected with higher contrast doses, but it is supported by the higher SNR of the portal vein with a higher dose. Additionally, we have demonstrated that the use of greater flip angles can improve SNR and CNR performance. It is possible that the previous study could not demonstrate a difference in lesion-to-liver CNRs between 0.025-and 0.05-mmol/kg doses because we used a suboptimal flip angle (12°). 21 Further, the difference in results between the previous and current studies can be explained by the homogeneity of the study subjects; in this study, we assessed volunteers and not patients with cirrhosis and muscle rather than liver lesions as the object.
Acquisition of reliable hepatobiliary-phase images by gadoxetic acid-enhanced MR imaging requires a delay of approximately 20 min after the administration of the contrast medium. To shorten the total protocol time, some researchers have suggested the equivalent diagnostic ability for the detection of liver lesions of hepatobiliary-phase images obtained after 10 min. 49,50 Despite the comparable results of visual assessment, quantitative results have shown lower contrast between the liver and lesion at 10 than 20 min. 51 Our results suggest that the use of 0.05 mmol/kg resulted in higher SNR and CNR at 10 min than did 0.025 mmol/kg at 20 min. Considering these results, the use of a 10min delay with an increased dose of gadoxetic acid can be justified both quantitatively and qualitatively. Shortening the overall protocol time may at least partially mitigate the increased cost of using a higher contrast dose.
This study had several limitations. First, our subjects were all healthy volunteers without liver disease. Because the pharmacokinetics of gadoxetic acid could be different in patients, especially those with cirrhosis, 52 the clinical utility of 0.05 mmol/kg compared to 0.025 mmol/kg should be further evaluated in patients with focal liver lesions and/or diffuse liver disease. However, before studying patients with disease, it is important to optimize acquisition parameters and measure the range of normal relaxometry values in normal subjects.
An additional limitation is that we used the signal intensity of muscle as a surrogate for that of hypovascular intrahepatic lesions like metastases from colorectal carcinoma. According to this assumption, the advantage of a 0.05-mmol/kg over 0.025-mmol/kg dose was quantitatively obvious. However, we cannot conclude a definitive advantage of the 0.05-mmol/kg dose of gadoxetic acid until the diagnostic ability of the 2 doses is compared in patients with focal liver lesions.
Further, during the dynamic phase, we employed high temporal resolution (2 s) to show the time-tointensity curve of each vessel. This sequence was well validated in previous studies. 31 However, the view-sharing technique used in this sequence can introduce temporal blurring that can affect signal measurement. Nevertheless, we believe that the relative signal intensity among the phases within a single scan offers a reasonable comparison.
Estimation of the concentration in the liver has important limitations. The longitudinal relaxivity (r 1 ) of a contrast agent may vary between different field strengths, solvents, or tissues. The resulting concentration estimates in our study were calculated assuming the known r 1 in the liver of rats at 0.47T, which may lead to inaccurate estimates of concentration in the human liver at 3T. In any case, the relative estimates of concentration remain meaningful because the r 1 value is a simple scaling co-efficient.
Finally, the order of injection of the 2 different doses of gadoxetic acid was the same in all subjects, 0.025 mmol/kg followed by 0.05 mmol/kg a month or more later. Although precontrast T 1 values did not differ significantly between the 2 doses of gadoxetic acid, that of the second scan (0.05 mmol/kg) was slightly lower than that of the first (Fig. 1). If we assume that the precontrast liver at the first scan had 0 mM of gadoxetic acid, the estimated residual concentration of gadoxetic acid in the liver at the second scan would be approximately 0.004 « 0.007 mM, assuming r 1 = 16.6 mM ¹1 s ¹1 . Considering the estimated concentration of gadoxetic acid in the liver between the 2 doses at 3 min (0.025 and 0.05 mmol/kg, 0.10 and 0.14 mM), 10 min (0.13 and 0.19 mM), and 20 min (0.16 and 0.22 mM), the effect of the precontrast T 1 value is probably not very important. Furthermore, previous research suggests that residual gadoxetic acid in the liver 7 days after administration was ³0.17% of the total dose for rats and 0.28 to 0.52% of the total dose for monkeys. 33 Those findings indicate that the effect of residual contrast in the liver at 4 weeks should be minimal compared to the further T 1 shortening effect achieved by doubling (200%) the dose.
In conclusion, our study has demonstrated that 0.05 mmol/kg of gadoxetic acid for hepatobiliaryphase MR imaging yields shorter T 1 values, higher SNR of the liver, and higher CNR of the liver relative to the portal vein and muscle than those with 0.025 mmol/kg. The higher dose also results in higher arterial and portal venous enhancement during the dynamic phase. These quantitative results also support the use of gadoxetic acid-enhanced hepatobiliary-phase images at 10 min instead of 20 min when using a 0.05-mmol/kg dose. Further work is needed to confirm these results in patients with diffuse liver disease and focal liver lesions.