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Neuroradiology |
1 From the Dept of Clinical Radiology, Univ of Münster, Albert-Schweitzer-Strasse 33, D-48129 Münster, Germany (B.T., E.M.F.); Dept of Radiology/Nuclear Magnetic Resonance Center, Massachusetts General Hosp, Boston (T.B., A.G.S.); Dept of Radiology, Karlsruhe, Academic Teaching Hosp of Freiburg, Germany (P.R.); Dept of Radiology, Institute of Neuroradiology, Bezirksklinikum Regensburg, Germany (G.S.); and Schering, Berlin, Germany (V.G., T.W.). Received Dec 3, 2001; revision requested Jan 18, 2002; revision received May 20; accepted Jul 1. Supported in part by Schering, Berlin, Germany. A.G.S. supported in part by grant PHS RO1NS38477. Address correspondence to B.T. (e-mail: tombach@uni-muenster.de).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Forty-three healthy volunteers were enrolled in an intraindividually controlled, randomized crossover comparison study. Two gadobutrol formulations—0.5 and 1.0 mol/L— were randomly injected during two separate treatment periods. For intraindividual comparison of effectiveness parameters, single-section gradient-echo brain perfusion MR imaging was performed under identical conditions for both investigations. Quantitative and qualitative evaluations were performed. Differences between the two gadobutrol formulations were evaluated at analysis of covariance and tested for statistical significance (P < .05) with a t test.
RESULTS: Use of 1.0 mol/L gadobutrol resulted in a significantly smaller bolus width at half maximum signal intensity decrease, a smaller mean peak time, a higher contrast and contrast-to-noise ratio between gray and white matter, and significant increases in both maximum change in transverse relaxation rate (
R2max) and differences in peak enhancement in gray matter among all volunteers (P < .001). In white matter, increases in R2max (P = .262) and in differences in peak enhancement (P = .262) were smaller and not significant (P = .292). Parameter map analysis revealed improved quality and superior contrast in relative regional cerebral blood flow (P = .034) and mean transit time (P < .001). The lack of difference regarding relative regional cerebral blood volume maps was consistent with the use of the same dose of each gadobutrol formulation.
CONCLUSION: Brain perfusion images obtained with 1.0 mol/L gadobutrol were superior to those obtained with 0.5 mol/L gadobutrol in healthy volunteers examined with the described MR imaging protocol.
© RSNA, 2003
Index terms: Brain, MR, 10.121411, 10.121412, 10.12142, 10.12143, 10.12144 • Contrast media, comparative studies • Gadolinium • Magnetic resonance (MR), contrast media, 13.12143, 14.12143, 15.12143
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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The degree of signal intensity loss in a region of interest (ROI) (ie, microvasculature) is determined by using several determinants, such as T2* sensitivity of the sequence; contrast agent dose, injection rate, concentration, and magnetic properties; and physiologic aspects such as perfusion status, cardiac output, hematocrit concentration, oxygenation level, and size and architecture of the vascular compartment (7–9). The concentration of radiotracer in a voxel over time is the key determinant of the measured signal intensity change because it enables the measurement of cerebral hemodynamic characteristics (7,8,10). The results of theoretical and empirical studies have shown that the signal intensity changes seen on dynamic susceptibility-weighted MR images closely reflect the actual concentrations of the contrast agent in each voxel of the cerebral microvasculature (6,11–13). Therefore, a highly concentrated small bolus of contrast agent may be advantageous for MR brain perfusion imaging (5–7).
Compared with other commercially available low-molecular-weight extracellular MR contrast agents with a gadolinium concentration of 0.5 mol/L, highly concentrated (1.0 mol of gadolinium per liter) gadobutrol (gadolinium-DO3A-butriol, Gadovist 1.0; Schering, Berlin, Germany) injected in an intravenous bolus has the potential to facilitate a sharper bolus peak and an increased first-pass gadolinium concentration in blood because of the reduced injection volume (8,14–16). T2*-weighted brain perfusion studies in rats have revealed an increased sensitivity to perfusion alterations between ischemic and nonischemic brain tissue following the administration of 1.0 mol/L gadobutrol at doses of 0.3–0.4 mmol of gadolinium per kilogram of body weight (8). In an animal model, the gadolinium concentration in the common carotid artery was found to be approximately 30% higher following the fast bolus injection of 1.0 mol/L gadobutrol compared with that following the injection of 0.5 mol/L gadobutrol (both at a dose of 0.3 mmol/kg) (17). The results of a computer simulation study indicated that the benefit of increasing concentrations of a contrast agent is not that large due to increased bolus widening in humans compared with animals (18). To the best of our knowledge, investigations involving the use of variable concentrations of MR contrast agents in humans have not yet been reported.
The purpose of our study was to compare the potential advantages of using a 1.0 mol/L formulation of the gadolinium chelate gadobutrol with those of using a 0.5 mol/L formulation of this agent for MR brain perfusion imaging in healthy volunteers.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Volunteers
The study was approved by the institutional review boards and ethics committee of the Department of Clinical Radiology, University of Münster. Fully informed signed consent was obtained from each volunteer at least 24 hours prior to the study. A total of 45 healthy volunteers (27 men, 18 women) were initially enrolled. Twenty-eight (62%) of these 45 subjects were white (17 [61%] men; mean age, 33.0 years ± 6.1 [SD]; age range, 22–45 years; mean body weight, 78.8 kg ± 11.7; weight range, 61–108 kg), and 17 (38%) were Japanese (10 [59%] men; mean age, 32.3 years ± 5.6; age range 22–40 years; mean body weight, 60.9 kg ± 9.9; weight range, 47–85 kg). The Japanese volunteers were included to exclude racial differences.
Forty-three of the 45 volunteers received both gadobutrol injections (0.5 mol/L formulation: mean of 42.60 mL ± 8.03; 1.0 mol/L formulation: mean of 21.30 mL ± 4.06) and were eligible for the analyses. Two white male volunteers received only one dose of gadobutrol because of technical problems that occurred during image acquisition, and their participation in the study was prematurely discontinued.
Exclusion Criteria
The following exclusion criteria were used: age younger than 18 years or older than 45 years, systolic blood pressure of 140 mm Hg or higher, diastolic blood pressure of 90 mm Hg or higher, pulse lower than 50 bpm or higher than 100 bpm, medical history of drug or alcohol abuse, pregnancy or lactation, use of any investigational drug within 30 days before the study, history of severe adverse reaction to drugs or contrast agents, history of severe anaphylactoid allergy to any other allergen, and/or any contraindication to MR imaging.
MR Imaging
MR imaging was performed with a 1.5-T unit (Magnetom Vision; Siemens Medical Systems, Erlangen, Germany). To exclude any unknown intracerebral abnormality that might have interfered with the results of the study, a transverse T2-weighted spin-echo sequence (2,500/90 [repetition time msec/echo time msec], one signal acquired, 172 x 230-mm field of view, 192 x 256 matrix), a time-of-flight MR angiographic sequence (35/7.2, one signal acquired, 200 x 200-mm field of view, 200 x 512 matrix), and a diffusion-weighted sequence (5,100/103, one signal acquired, 240 x 240-mm field of view, 128 x 128 matrix, diffusion weighting factors of 0 and 1,000 sec/mm2, three acquisition directions to produce trace-weighted images) to encompass the entire brain were performed before contrast agent administration. Immediately prior to the second gadobutrol injection 20–25 hours later, another diffusion-weighted sequence was performed by using the same parameters as those used prior to the first administration of gadobutrol.
The examination outlined in the following text was performed with each of the two gadobutrol injections (ie, 0.5 and 1.0 mol/L). After obtaining the appropriate scout views, we performed a single-section, dynamic susceptibility-weighted gradient-echo sequence (31.74/22, 225 x 300-mm field of view, 48 x 128 acquisition matrix, 128 x 128 image matrix, 6-mm section thickness) in a paraxial position to image the middle cerebral artery, putamen, cortex, and white matter (Fig 1, A–C). Exactly 10 seconds after the start of the acquisition of a total of 45 images with a temporal resolution of 1.5 seconds, gadobutrol (0.3 mmol/kg of both formulations) was injected by means of intravenous bolus by using an MR-compatible injector (Spectris SMR 200; Medrad, Pittsburgh, Pa) at a rate of 5 mL/sec. The gadobutrol injection was followed by a 30-mL saline flush (0.9% NaCl) through an intravenous 18-gauge cannula inserted into an antecubital vein.
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Effectiveness Variables
Two independent investigators performed automated quantitative analysis (T.B.) and visual interpretation of image quality (A.G.S.). These investigators were not involved in the MR data acquisitions and were blinded with regard to all information on the volunteers, the formulations of gadobutrol administered, and the treatment period. We labeled the images by using a randomized numerical code system. All qualitatively and quantitatively analyzed parameters of the perfusion images and calculated maps are summarized in Table 2.
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The maximum change in transverse relaxation rate (R2max) in the putamen, cortex, and white matter was used as the primary effectiveness variable. Peak enhancement, contrast between gray and white matter, and contrast-to-noise ratio between gray and white matter were calculated as secondary effectiveness variables (Table 3). The contrast and the contrast-to-noise ratio between the gray and white matter were calculated for both the putamen and the cortex on a representative precontrast MR image, the peak postcontrast MR image, and the subtraction MR image. The contrast between the cortex and the white matter was also calculated on the rrCBV, rrCBF, and mean transit time maps. Peak time was defined as the interval between the start of the contrast material injection and the time of acquisition of the image showing the maximum signal intensity decrease. Bolus width, defined as the full width of the signal intensity–time curve at half maximum, was determined in the middle cerebral artery, cortex, putamen, and white matter.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Quantitative analysis among all the volunteers revealed a significant increase in R2max and in differences in peak enhancement in the gray matter (ie, putamen and cortex) (P < .001) after the administration of 1.0 mol/L gadobutrol as compared with these parameters after the administration of 0.5 mol/L gadobutrol. In the white matter, increases in R2max (P = .262) and in differences in peak enhancement (P = .292) were smaller and not statistically significant (Tables 4 and 5). The contrast and the contrast-to-noise ratio on the MR images obtained before administering either gadobutrol formulation were comparable and thus a valid basis for comparison of the postcontrast data.
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The bolus width at a half-maximum signal intensity decrease was significantly smaller following the injection of 1.0 mol/L gadobutrol in all investigated regions (Table 6). The extent of the reduction in bolus width was similar in the middle cerebral artery, cortex, and putamen, as indicated by the mean of the intraindividual differences in bolus width between the two gadobutrol formulations: 2.5, 2.6, and 2.6 seconds, respectively. The reduction in bolus width in the white matter was somewhat smaller; the mean of the intraindividual differences was 2.1 seconds with both gadobutrol formulations (Table 6).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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In addition, approximately more than 20% of an injected 0.5 mol/L extracellular concentration of gadolinium-based contrast agent already enters the extravascular space during the first pass through the lungs (10). Ideally, a narrow bolus of contrast agent would be administered; however, this is not realistic in clinical practice. Approaches to increase the maximum signal intensity decrease at brain perfusion imaging in humans are therefore based on the optimization of sequence-related susceptibility changes or the modification of bolus geometry achieved by increasing the contrast agent dose or injection rate or using different contrast materials (8,10,22,23).
The clinically approved low-molecular-weight gadolinium chelates for imaging the central nervous system are prepared in a 0.5 mol/L formulation and can be injected at a dose of 0.1 mmol/kg, and some are approved for injection at doses of up to 0.3 mmol/kg (10,24,25). None of these agents has been approved for the specific indication of cerebral perfusion imaging; however, all gadolinium-based contrast agents are useful for this purpose. In several animal and human brain perfusion studies (8,18,26–28), increasing doses of gadolinium chelates have resulted in a more marked signal intensity decrease during bolus passage. For a 0.3 mmol/kg dose of a 0.5 mol/L gadolinium chelate, large injection volumes of 36–60 mL in patients with a body weight of 60–100 kg require the use of power injectors at a high flow rate, in the order of 5 mL/sec, to yield a reduced injection time of 7–12 seconds. However, the increase in injection rate is limited by the diameter of the intravenous catheter and the viscosity of the contrast agent (29). To our knowledge, intraindividual MR brain perfusion comparison studies involving the use of variable injection rates have not yet been performed in patients. Claussen et al (29) observed a 15% increase in peak enhancement height at computed tomography when the injection rate was increased from 4 to 8 mL/sec (volume, 50 mL). On the basis of experimental and clinical experiences in brain perfusion imaging, we used a high injection rate of 5 mL/sec (6,7,10,30,31).
Another approach to increasing the maximum signal intensity decrease is to use more highly concentrated gadolinium chelates, which to our knowledge have not yet been investigated in humans in an intraindividual comparison study. Compared with 0.5 mol/L contrast material formulations, the 1.0 mol/L formulation of the gadolinium chelate gadobutrol, which is approved for imaging the central nervous system in Europe, Australia, Canada, and New Zealand at doses of up to 0.3 mmol/kg, enables one to decrease the injection volume to 50% and narrow the bolus profile at comparable doses. Therefore, this agent appears to be particularly suited for perfusion imaging, because the susceptibility effects should be more pronounced as a result of the higher gadolinium concentration.
The results of initial perfusion-weighted MR imaging studies in a rat stroke model following the bolus injection of both 0.5 mol/L gadobutrol and 1.0 mol/L gadobutrol showed an increased sensitivity to perfusion alterations at the higher dose and higher gadolinium concentration. The contrast between ischemic and nonischemic regions increased at a dose range of 0.1–0.4 mmol/kg, and the differentiation between ischemic and nonischemic regions was superior with the 1.0 mol/L formulation (8). An animal study to investigate the influence of 0.5 mol/L versus 1.0 mol/L gadobutrol on the concentration of gadolinium in the common carotid artery revealed an approximately 30% higher concentration with the more concentrated formulation (17). The results of a computer simulation study (18) indicated that there is a smaller benefit of higher contrast agent concentrations in humans compared with the benefit in animals because of greater bolus widening. A double-blinded randomized study of cerebral perfusion dose finding involving the use of 1.0 mol/L gadobutrol was performed in patients with unilateral carotid artery stenosis or unilateral cerebral infarction (32). With use of a T2*-weighted fast low-angle shot sequence at 1.0 T, a 0.3 mmol/kg dose of gadobutrol was shown to be diagnostically adequate for the clinical applications of brain perfusion imaging. The analysis was based on quantitative effectiveness and qualitative assessments, including quality of differentiation between gray and white matter and quality of rrCBV maps (32).
In our study, we investigated the hypothesis that the use of 1.0 mol/L gadobutrol, as compared with the use of 0.5 mol/L gadobutrol, may be advantageous for brain perfusion imaging, and designed the study as an intraindividually controlled, randomized two-period crossover comparison in healthy volunteers. On the basis of the results of a previous study (32) with gradient-echo MR imaging sequences, we chose a dose of 0.3 mmol/kg for both gadobutrol formulations. The results of blinded reader analysis of the qualitative and quantitative parameters in our study confirmed the animal study data regarding both gadobutrol formulations (17). Use of the more concentrated gadobutrol formulation resulted in a mean increase of 15%–20% of the maximal signal intensity decrease at doses of 0.3–0.4 mmol/kg in nonischemic brain tissue in the rat study (8), as compared with mean increases of 26% in the putamen, 21% in the cortex, and 5% in the white matter in our study with humans. Heiland et al (8) did not discriminate between gray and white matter, probably because of the low spatial resolution in the rat brain.
The smaller difference between the R2max and peak enhancement in the white matter and those in the gray matter (ie, putamen or cortex) with both gadobutrol formulations was likely due to the lower vascularity of white matter relative to gray matter. The lack of a distinct improvement in rrCBV maps with the more concentrated formulation in both the rat study (8) and our study is consistent with the fact that rrCBV maps are based on the integrated signal intensities of all images obtained following gadobutrol injection and are therefore dependent on the dose rather than the transitory concentration of the contrast agent during the first pass through a given ROI. The observed improvement in rrCBF map quality but not in rrCBV map quality represents important, and, in our opinion, novel evidence that the cerebral blood flow calculation approach used in this study is appropriate: It yielded maps with flow-related contrast rather than maps that were influenced by cerebral blood volume only or contrast agent arrival time only (as some investigators have feared). The improved quality of and superior contrast on the rrCBF maps at a constant contrast-to-noise ratio were due to improved profiles of the arterial input function for the more concentrated gadobutrol formulation.
Analyses of the racial subgroups revealed some differences in effectiveness variables. With the exception of the contrast between the cortex and the white matter on the rrCBF maps, all secondary effectiveness variables were improved with use of the higher molar gadolinium concentration in the subgroup of white volunteers. In the Japanese volunteers, the gadolinium concentration–related differences among the variables tended to be smaller than those in the white volunteers and were probably related to the substantially smaller mean body weight in this subgroup. However, we observed a noticeable improvement in the secondary effectiveness variables—specifically, the peak enhancement in the putamen, the contrast between the putamen and the white matter on the images showing peak enhancement, the contrast between the cortex and the white matter on the mean transit time maps, and the contrast-to-noise ratio between the putamen and the white matter on the images showing peak enhancement.
There were limitations in our study. The applicability of our study results to studies with other pulse sequences or other contrast agent doses must be handled with care. Also, more pronounced effects (eg, between ischemic and nonischemic tissue) are expected in patients with cerebrovascular disorders. The gradient-echo sequence used in our study was chosen for comparison and consistency with the MR sequences used in previous studies (17,32). Additional studies of spin-echo– and gradient-echo–based echo-planar sequences performed in patients with cerebrovascular disorders should be performed.
We conclude that in healthy volunteers, 1.0 mol/L gadobutrol administered at a dose of 0.3 mmol/kg in a gradient-echo sequence yields MR brain perfusion images that are superior to those obtained with the 0.5 mol/L formulation of this agent.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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R2max = maximum change in transverse relaxation rate,
ROI = region of interest,
rrCBF = relative regional cerebral blood flow,
rrCBV = relative regional cerebral blood volume Author contributions: Guarantors of integrity of entire study, B.T., P.R., G.S., T.B., A.G.S.; study concepts and design, all authors; literature research, B.T., T.B., T.W.; clinical studies, B.T., E.M.F., P.R.; data acquisition, B.T., E.M.F., P.R.; data analysis/interpretation, all authors; statistical analysis, B.T., T.W., V.G.; manuscript preparation and definition of intellectual content, all authors; manuscript editing, B.T., P.R., T.B.; manuscript revision/review and final version approval, all authors.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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This article has been cited by other articles:
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  M Fenchel, A Franow, P Martirosian, M Engels, U Kramer, N I Stauder, U Helber, H Vogler, C D Claussen, and S Miller 1 M Gd-chelate (gadobutrol) for multislice first-pass magnetic resonance myocardial perfusion imaging Br. J. Radiol., November 1, 2007; 80(959): 884 - 892. [Abstract] [Full Text] [PDF]
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C W Ryu, D H Lee, H S Kim, J H Lee, C G Choi, S J Kim, and D C Suh Acquisition of MR perfusion images and contrast-enhanced MR angiography in acute ischaemic stroke patients: which procedure should be done first? Br. J. Radiol., December 1, 2006; 79(948): 962 - 967. [Abstract] [Full Text] [PDF]
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