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MR Angiography with Superparamagnetic Iron Oxide: Feasibility Study¹

¹ From the Department of Radiology, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, 12 200 Berlin, Germany. Received April 29, 1998; revision requested July 6; final revision received January 4, 1999; accepted April 30. Address reprint requests to S.A.S. (e-mail: s.schmitz@medizin.fu-berlin.de).

	Abstract

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Magnetic resonance (MR) angiography with blood-pool superparamagnetic iron oxide (SPIO) particles was evaluated in the whole-body vascular system. In 12 adult patients, three-dimensional fast imaging with steady-state precession was performed in successive steps from the lungs to the calves before and after a standard dose for liver imaging (15 µmol of iron per kilogram of body weight) of AMI-25. On SPIO-enhanced MR angiograms, visualization of the pulmonary arterial, whole-body, and lower extremity venous systems was graded as good or sufficient in all patients, and femoral vein thrombosis was clearly demonstrated in one patient.

Index terms: Abdomen, MR, 95.12942, 95.12943 • Extremities, MR, 92.12942, 92.12943, 93.12942, 93.12943 • Iron • Magnetic resonance (MR), vascular studies, _**.12142² • Thorax, MR, 56.12142, 56.12143, 94.12942, 94.12943

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Fast three-dimensional gradient-echo sequences enhanced by means of rapid application of gadolinium-based contrast media have become a routine clinical tool at magnetic resonance (MR) imaging to evaluate the arterial system of the body (1,2). Short acquisition times allow image generation during a single breath hold. Owing to these technical advances, MR imaging has been suggested for evaluation of the pulmonary arterial and deep venous system within a single examination (3).

Acquisition of images of large regions (eg, thorax, abdomen, or pelvis) is feasible over a period of approximately 20 seconds each, but the patient has to be moved mechanically, with the region of study placed in the isocenter of the magnet, to produce high-quality images. With current clinical MR imaging equipment, the patient must be studied region by region from the lungs to the calves, which increases the overall examination time. A region-by-region examination would be too time-consuming, however, given the pharmacokinetic properties of gadolinium-based contrast media currently used for breath-hold MR angiography. These substances are not ideal for imaging of the venous system because they rapidly extravasate while in the capillary passage, which increases tissue contrast and decreases venous contrast.

So-called blood pool agents such as ultrasmall superparamagnetic iron oxide (SPIO) particles have been applied for imaging of the vascular system (4–7). Their pharmacokinetics are favorable for examinations of the venous system owing to their intravascular distribution and long blood half-life of 81 minutes in rats (8,9). They are particularly interesting for use in studies of the deep venous system, where slow flow or blood stasis limits the use of flow-sensitive MR angiographic techniques. In contrast material–enhanced MR angiography, in which slow blood exchange prevents the buildup of a sufficient intravascular concentration of extracellular contrast media, however, the concentration of blood-pool agents would be sufficient.

The potential for SPIO particles such as AMI-25 (Endorem; Guerbet, Roissy, France) to produce negative enhancement due to their T2 or T2_* relaxivity is well established and clinically applied in MR studies of the liver and spleen (10,11). As shown by Chambon et al (12), however, SPIO particles may also be used as a positive enhancer if low tissue concentrations of SPIO and short echo times are applied that sufficiently suppress T2 or T2_* effects and allow the strong T1 relaxivity of SPIO to contribute to the MR signal intensity (SI).

SPIO particles such as AMI-25 have a short blood half-life of 6 minutes in the rat (8) and are not considered a blood-pool agent. Unlike extravasating contrast media, however, SPIO particles have an intravascular distribution similar to that of ultrasmall SPIO particles and may have enough of a blood-pool effect to allow imaging in a patient from the lungs to the calves.

The purpose of this study was to determine the feasibility of pulmonary arterial and whole-body venous imaging with SPIO-enhanced MR angiography. Our primary study goal was to depict normal vasculature and not to apply this technique in patients suspected of having pulmonary embolism or deep venous thrombosis.

	Materials and Methods

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Contrast Media
AMI-25 was supplied as an opaque, dark brown solution with 89.6 mg of iron in 8-mL vials.

Patient Measurements
The ethics committee at our institution approved acquisition of additional sections of the vasculature in patients who received AMI-25 for an MR examination of the liver. Informed consent was obtained from 12 patients (eight men and four women; age range, 32–77 years; mean age, 61 years) with histologically proved primary malignant tumors and suspected or known focal liver lesions demonstrated with other imaging modalities. Eleven of the patients had liver disease. One patient, with femoral vein thrombosis proved at compression color-coded duplex ultrasonography (US), had a history of adverse reactions to iodinated contrast media, and MR imaging was performed instead of computed tomography or x-ray phlebography to rule out pelvic venous thrombosis.

All studies were performed on a 1.5-T imager (Vision; Siemens Medical Systems, Erlangen, Germany) with a body array coil. The coil was first placed on the upper abdomen to study metastatic hepatic disease with use of a standard pulse sequence (three-dimensional fast imaging with steady-state precession [FISP]: repetition time msec/echo time msec = 5/2 with 25° flip angle) (step 1). The coil was then placed on the thorax for precontrast MR angiography (section orientation, coronal; slab thickness, 80 mm; 32 partitions; one signal acquired; 256 matrix; imaging time, 26 seconds) (step 2). These parameters were adapted to the patient's body size and ability to maintain a breath hold, which resulted in an acquisition time of 19–26 seconds. Thoracic imaging was performed with the patients' arms raised above their heads, if possible. AMI-125 was administered at the standard recommended dose for liver imaging of 15 µmol of iron per kilogram of body weight while the patient rested on the imager table. AMI-125 with the appropriate iron volume was added to 100 mL of 5% dextrose solution. This preparation was passed through the 5-µm filter of the application set during the 30-minute intravenous drip infusion. Postcontrast MR angiography was started from the thorax at 15 minutes after the beginning of the infusion, with the same parameters as were used in the precontrast study. Sagittal slabs on either side of the thorax were also obtained.

While the infusion was administered, the patient was removed from the magnet bore, and the coil was placed on the pelvis. The patient was then placed inside the magnet again for a coronal study with use of the same imaging sequence without a breath hold and with increased spatial resolution (slab thickness, 160 mm; 64 partitions; two signals acquired; 256 or 512 matrix; imaging time, 154 seconds) (step 3). Studies of the upper and lower legs and the abdomen were performed accordingly (steps 4–6). Before imaging of the lower legs, a tourniquet was placed above the knees to distend the calf veins. Imaging was performed with additional sequences and other section orientations to study the underlying disease in more detail if necessary.

Finally, the coil was placed on the abdomen (step 7) for coronal imaging during a breath hold with the same parameters as were used for imaging of the thorax. With the same coil position, images of the liver were acquired by using a standard technique. During the MR examination, patients were asked if they felt comfortable and if they wished to complete the study.

Image Analysis
Quantitative analysis was performed by one investigator (S.A.S.). He selected a section within the inner half of the slab volume and placed regions of interest at the following intravascular sites: a lobar pulmonary artery and vein, the portal vein, the abdominal aorta and inferior vena cava, a common or external iliac artery and vein, a femoral artery and vein, and a popliteal artery and vein. Regions of interest were also placed at extravascular sites: lung or muscle and extracorporeal background. The intravascular, pulmonary, and muscular SIs were divided by the SD of the background to normalize the SI to the noise of the particular image (signal-to-noise ratio). Enhancement (E) of the lung parenchyma and pulmonary arteries and veins was calculated as E = (SI_post - SI_pre)/SI_pre, where SI_pre and SI_post denote the values before and after administration of SPIO, respectively.

Qualitative image analysis was performed to assess the ability of a reader to visualize the vessels of interest: pulmonary arteries and veins; the vena cava; the common, external, and internal iliac veins; the femoral and popliteal veins, great saphenous vein, and peroneal veins; and the anterior and posterior tibial veins. Two radiologists (S.A.S., T.A.) independently graded a set of hard copies of the two-dimensional source MR images and the corresponding three-dimensional maximum intensity projection reconstruction images on the basis of a three-point scale: 0, insufficient (neither study fulfills the criteria of a sufficient study); 1, sufficient (the vessels of interest on the source images are homogeneously hyperintense and clearly delineated compared with the surrounding structures); 2, good (vascular contrast on the MR angiograms and the reconstruction images fulfills the criteria of a sufficient study).

So as not to overgrade, the lower of both quality judgments was considered the final grade if the two observers disagreed in their independent grading. In addition, both readers sought to determine a consensus decision and the reason why image quality had not been graded as good but as sufficient or insufficient.

Statistical Analysis
Normalized SI was expressed by means of descriptive statistical analysis. Pre- and postcontrast SI measurements in the lung parenchyma and pulmonary artery and vein were compared by means of the t test for paired samples. Differences with a P value less than .05 were considered statistically significant.

	Results

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The MR examination was terminated early without images of the knee-calf region in two of the 12 patients (one experienced pain from spinal metastases, and one felt uncomfortable in the small bore of the magnet). The liver studies were completed in both patients. No adverse reactions were observed. Time from the beginning of infusion to acquisition of the last postcontrast MR angiogram was 51 minutes ± 8 (mean ± SD). Given the 15-minute delay from the beginning of infusion to acquisition of the first postcontrast MR angiogram, the time to acquire all postcontrast MR angiograms from the lungs to the calf was 36 minutes.

Figures 1–4 are sample MR angiograms obtained during or after SPIO infusion. In a comparison of postcontrast and precontrast images in a lobar pulmonary artery and vein, intravascular SI was significantly increased (normalized SI, from 10 arbitrary units ± 6 to 36 arbitrary units ± 13 and from 8 arbitrary units ± 5 to 22 arbitrary units ± 9, respectively) as was intravascular enhancement (3.6 arbitrary units ± 1.9 and 2.1 arbitrary units ± 1.2, respectively). In a comparison of postcontrast and precontrast images in lung parenchyma, however, there were no significant differences in SI (precontrast difference in the mean, 4 arbitrary units ± 1). The normalized SI values in the other anatomic regions are listed in the Table.

View larger version (182K): [in this window] [in a new window]   Figure 1. Maximum intensity projection reconstruction image from coronal breath-hold FISP data (5/2 with 25° flip angle, 256 matrix) during infusion of AMI-25. Since the patient's arms were raised above his head, the subclavian and axillary arteries and veins are elevated (large arrow = subclavian vein). The right interlobar pulmonary artery (small arrow) and right inferior pulmonary vein (arrowhead) are clearly visible. The left hilar veins are obscured by the left ventricle. The left hilar pulmonary artery is partly obscured by the main pulmonary artery (small ). Large = ascending aorta.

View larger version (107K): [in this window] [in a new window]   Figure 2. Maximum intensity projection reconstruction image from coronal breath-hold SPIO-enhanced FISP data (5/2 with 25° flip angle, 256 matrix) depicts abdominal and pelvic vasculature. The abdominal aorta () is clearly visible. The inferior vena cava (arrow) and proximal common iliac veins (arrowheads) are not fully depicted.

View larger version (173K): [in this window] [in a new window]   Figure 3a. Thrombosis of the left superficial femoral vein. (a) Axial FISP image (5/2 with 25° flip angle; 256 matrix; imaging time, 31 seconds). (b) Oblique maximum intensity projection reconstruction image from the data in a. The filling defect is indicated by an arrow. The common iliac veins (arrowheads) are depicted with high SI, indicating their patency. Image quality is reduced owing to the high SI of bowel contents ().

View larger version (177K): [in this window] [in a new window]   Figure 3b. Thrombosis of the left superficial femoral vein. (a) Axial FISP image (5/2 with 25° flip angle; 256 matrix; imaging time, 31 seconds). (b) Oblique maximum intensity projection reconstruction image from the data in a. The filling defect is indicated by an arrow. The common iliac veins (arrowheads) are depicted with high SI, indicating their patency. Image quality is reduced owing to the high SI of bowel contents ().

View larger version (165K): [in this window] [in a new window]   Figure 4a. Coronal FISP images (5/2 with 25° flip angle; 512 matrix; imaging time, 154 seconds) in a tall patient necessitated use of three coil placements to image the legs entirely. (a) Single-section and (b) three-dimensional MR angiographic reconstruction images depict the popliteal artery (small straight arrow) and vein (large straight arrow). Owing to stronger tourniquet compression, the venous system on the left is more distended and more clearly visible than that on the right as exemplified by the great saphenous veins (arrowheads in b). A small perforating vein (curved arrow in b) is depicted on the left.

View larger version (133K): [in this window] [in a new window]   Figure 4b. Coronal FISP images (5/2 with 25° flip angle; 512 matrix; imaging time, 154 seconds) in a tall patient necessitated use of three coil placements to image the legs entirely. (a) Single-section and (b) three-dimensional MR angiographic reconstruction images depict the popliteal artery (small straight arrow) and vein (large straight arrow). Owing to stronger tourniquet compression, the venous system on the left is more distended and more clearly visible than that on the right as exemplified by the great saphenous veins (arrowheads in b). A small perforating vein (curved arrow in b) is depicted on the left.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

 
The data from our preliminary study show that pulmonary MR angiography and whole-body venography can be performed during and after slow infusion of a standard dose of SPIO. On the basis of the subjective impression of two readers, image quality was good or sufficient in all patients. Clear demonstration of a filling defect consistent with findings at color-coded US in one patient indicates that this technique might be useful in the assessment of deep venous thrombosis or, possibly, pulmonary embolism.

The potential of SPIO particles to act as a positive enhancer has been evaluated in more detail by Chambon et al (12). They found positive enhancement by SPIO particles in vitro and in vivo with use of low concentrations of SPIO and echo times as short as 20 msec in spin-echo imaging and 15 msec in gradient-echo imaging. Under these circumstances, T2 or T2_* effects are reduced, and the strong T1 relaxivity of SPIO can dominate the SI. Reimer et al (13) performed SPIO-enhanced MR angiography with a two-dimensional time-of-flight sequence (31/10) during clinical testing of another SPIO preparation (SH U 555A, Resovist; Schering, Berlin, Germany). They found improved visualization of the portal venous system owing to a significant loss in SI in the surrounding liver but could not demonstrate a significant difference in intravascular SI after SPIO administration. Although we used a gradient-echo sequence, which is known to be very sensitive to T2_* effects that lower the SI (14), significant enhancement in the major pulmonary arteries and veins and high intravascular SI were seen on the images obtained in our patients after a standard dose of AMI-25. We speculate that this is a result of the short echo time of 2 msec used in our study.

The pharmacokinetics of AMI-25 are complex owing to the wide spectrum of particle sizes and the size-dependent clearance rates. The blood half-life of AMI-25 in the rat was studied by two groups using radiolabeled iron 59 AMI-25 with a 40- or 50-µmol dose. Although Weissleder et al (8) fit their blood half-life data to a monophasic elimination model and found a blood half-life of 6 minutes, Majumdar et al (15) chose a biphasic elimination model and found that each fraction was approximately 50% of the injected dose with a half-life of 10 minutes of the first and 92 minutes of the second fraction. Irrespective of these discrepancies, the short half-life of SPIO is critical for a 30-minute MR examination. Therefore, we hoped to counterbalance the rapid elimination by starting the MR angiographic experiments during the infusion. To our surprise, intravascular SI remained high in nine of 12 patients when we studied their legs at the end of the MR examination.

In our study, the mean time for examination from the lungs to the calves was 51 minutes. This period included 15 minutes during which the patient remained on the MR imager table without imaging being performed to receive the first half of the infusion. The period required for imaging was only 36 minutes. Addition to the 51 minutes of 5 minutes for positioning the patient and 5 minutes for helping the patient off the table would, however, result in a hypothetical overall imaging time of approximately 60 minutes. The true imaging time, however, was approximately 7 minutes. The most time-consuming part of the investigation was placement of the body region so that it was covered by the body array coil. In our study, five separate regions were imaged, for which the patient had to move cephalad and caudad on the table. Use of other coils (eg, body coils or larger array coils) would help the study of larger patient sections, but such coils were not available. Image calculations and sequence preparations also extended the overall examination time.

If instead of liver imaging the clinical indication for the imaging study had been deep venous thrombosis or pulmonary embolism, the examination would have been performed from the lungs to the calves, because less patient movement would be required. For image analysis, single sections may be more useful than three-dimensional reconstruction images, since superimposition of arterial and venous structures may obscure relevant imaging findings.

Given that the price per patient dose of AMI-25 is US $210 (price in Germany), the cost of the SPIO-enhanced MR angiographic examination may be prohibitively high compared with the cost of color-coded US and lung scintigraphy, which are used to assess deep venous thrombosis and pulmonary embolism in many hospitals. The cost may be competitive, however, in patients with complicated diagnoses if inpatient treatment and catheter angiography can be avoided.

In conclusion, the data acquired in this study show that SPIO-enhanced MR angiography allows display of arteries and veins in human subjects. Pulmonary arterial imaging and whole-body and lowerextremity venous imaging can be performed during a single MR angiographic session. We suggest further studies with this technique in comparison with standard imaging tests to determine if it is useful for the assessment of deep venous thrombosis or pulmonary embolism.

	Footnotes

 
_**. Multiple body systems

Abbreviations: FISP = fast imaging with steady-state precession SI = signal intensity SPIO = superparamagnetic iron oxide

Author contributions: Guarantor of integrity of entire study, S.A.S.; study concepts and design, S.A.S.; definition of intellectual content, S.A.S.; literature research, S.A.S.; clinical studies, S.A.S.; data acquisition, S.A.S.; data analysis, T.A., S.A.S.; statistical analysis, S.A.S.; manuscript preparation and editing, S.A.S.; manuscript review, S.A.S., T.A., K.J.W.

	References

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