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Technical Developments |
1 From the Departments of Diagnostic and Interventional Radiology (G.A., H.K., T.C.L., E.H., T.B., S.C.G., J.F.D.), Nuclear Medicine (J.K., W.J., T.B.), and Pharmacy (H.S.), University Hospital Essen, Hufelandstrasse 55, D-45122 Essen, Germany. Received October 7, 2002; revision requested December 17; final revision received July 13, 2003; accepted August 18. Address correspondence to G.A. (e-mail: gerald.antoch@uni-essen.de).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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© RSNA, 2004
Index terms: Dual-modality imaging, PET/CT
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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To improve PET image quality and reduce examination times by as much as 30%, the CT data are used for the purpose of PET attenuation correction in combined PET/CT (3,4). Typical CT-based attenuation-correction algorithms are based on a two-step scaling method in which a threshold is set to separate soft tissue from bone. To obtain the corresponding attenuation map at 511 keV, CT values are scaled with a scaling factor for either soft tissue or bone (3). In comparison to the PET annihilation quanta of 511 keV, however, CT x-rays with energies of 70–140 keV are attenuated substantially more by structures that contain elements with high atomic numbers, such as iodine and barium (5). If these differences in attenuation are not accounted for, contrast agents may lead to biases in the estimated attenuation coefficients, which may translate into artifacts in the corrected PET images.
It has been shown that after administration of oral contrast agents at typical clinical concentrations, the increase in intraluminal attenuation may lead to overestimation of PET activity concentration after CT-based attenuation correction of up to 20% (6). While the qualitative effect of this overestimation on the PET data is negligible in most cases (7,8), local accumulation of oral contrast agents caused either by ingestion of highly concentrated iodine or barium or by a delay in the intestinal passage can introduce severe PET artifacts if CT-based PET attenuation correction is performed (9). These artifacts are areas of apparent focal tracer uptake in coregistration with a contrast material–enhanced stomach or bowel loop and may cause interpretation errors. Furthermore, as a result of the time interval (approximately 10 minutes) between performance of the CT and PET components of the combined scanning procedure, bowel loops may shift in the abdomen. After CT-based PET attenuation correction, apparently increased glucose metabolism may be seen in the area where the contrast material–enhanced bowel loop was originally located during the CT acquisition. Hence, an artifact-free oral contrast agent would be highly desirable for PET/CT. Because all positive oral contrast agents are implicitly associated with an increase in attenuation, only a negative oral contrast agent has the potential to completely avoid high-attenuation artifacts.
The purpose of our study was to qualitatively and quantitatively assess a solution containing 2.5% mannitol and 0.2% locust bean gum (LBG) (hereafter, mannitol-LBG) in comparison to barium or water for distention of the stomach and the small bowel while avoiding PET artifacts.
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Materials and Methods |
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TOPABSTRACTINTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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Oral Contrast Agents
In 20 patients, 800 mL of barium (Micropaque CT; Guerbet, Sulzbach, Germany), a positive contrast material, was administered orally at a concentration of 1.5 g per 100 mL. The patients were instructed to slowly and steadily ingest the barium over the course of 50 minutes beginning directly after the injection of radioactive tracer, and another 200 mL was ingested to distend the stomach immediately before the patient was transferred onto the PET/CT table.
In another 20 patients, 1.8 L of tap water, a negative contrast material, was administered orally without additives at a constant rate over the course of 1 hour after injection of the radioactive tracer, and another 200 mL was ingested to distend the stomach immediately before the patient was transferred onto the PET/CT table. The tap water was provided at room temperature for patient comfort.
Two liters of a solution containing 0.2% LBG and 2.5% mannitol dissolved in water, a negative contrast material, was given to another 20 patients. Analogous to the water protocol, 1.8 L of mannitol-LBG was administered at a constant rate over 60 minutes, and 200 mL was ingested to distend the stomach immediately before the patient was transferred onto the PET/CT table. The choice of concentration for mannitol-LBG was based on results of previous studies to evaluate the two components for small-bowel scanning with magnetic resonance imaging (10). LBG, which is extracted from seeds of the European carob tree, is widely used in the production of ice cream and canned products. Inherent osmotic properties cause bowel distention. The effect of mannitol-LBG is limited to the bowel lumen, where absorption is prevented by the chemical structure.
To assess potential unfavorable effects of the contrast agents, the patients were asked about a diuretic urge during PET/CT scanning and symptoms of diarrhea after the examination. Patients were interviewed by a radiologist (G.A.) at 1–4 hours after the scanning procedure.
PET/CT Scanning
PET/CT scanning was performed at 60 minutes after intravenous injection of 350 MBq of 18F FDG as a radioactive tracer. Before administration of 18F FDG, normal blood glucose levels were determined in capillary blood samples. In patients who ingested the mannitol-LBG solution, additional capillary blood samples were obtained immediately before the scanning procedure to demonstrate that blood glucose levels remained in the normal range. Scanning procedures were conducted with a dual-modality PET/CT scanner (Biograph; Siemens Medical Solutions, Hoffman Estates, Ill), which features one examination table that serves both the CT and PET components (2). The single-section spiral CT component (Somatom Emotion; Siemens Medical Solutions, Erlangen, Germany) provides a minimum gantry rotation time of 800 msec and a maximal scan time of 100 seconds.
CT parameters were set to 130 mAs, 130 kV, section thickness of 5 mm, and table feed of 8 mm per rotation. Whole-body CT scanning was performed in a craniocaudal direction. A dose of 140 mL of an intravenous contrast agent containing 300 mg of iodine per milliliter (Xenetix 300; Guerbet) was administered in all patients for vascular and parenchymal assessment. Immediately after the CT acquisition, PET data were collected in a caudocranial direction starting with the upper thigh and pelvis. The transverse scanning range was set from the upper thigh to the head. The PET component is based on an ECAT HR+ (Siemens Medical Solutions), which provides an in-plane spatial resolution of 4.6 mm and a transverse field of view of 15.5 cm for each bed position. The time to scan one bed position was set to 4 minutes. Depending on patient size, images were acquired in six to eight bed positions for whole-body coverage. Attenuation correction of the PET data was based on the CT transmission data (3), and iterative algorithms were performed for reconstruction.
Phantom Studies
Phantom measurements were performed for quantitative assessment of the effect of each contrast agent on the CT-based PET attenuation correction. The phantom was constructed as a main cylinder (20 cm in diameter) that contained two cylindric inserts (each 4.5 cm in diameter). The main cylinder was surrounded by a body-shaped compartment that contained radioactive water. The main cylinder was filled with radioactive (18F FDG) water (concentration, 16 KBq/mL), and the two cylindric inserts were filled with water (negative control) and the contrast agent being investigated. Mannitol-LBG was evaluated at 0-HU attenuation, while barium was evaluated at approximately 310-HU attenuation. To demonstrate similar effects of barium and iodine, the iodinated contrast material was also evaluated at 310-HU attenuation. Activity concentration was quantified by one radiologist (G.A.) by placing regions of interest with a minimum size of 800 pixels on the PET scans of the cylindric inserts. A ratio of the activity concentration in the presence of one of the contrast agents to that in the presence of water was determined for all substances being investigated on the basis of mean values plus or minus SDs of 10 measurements performed for each contrast agent.
Data Acquisition
CT images were evaluated separately by two radiologists (G.A., H.K.), who were blinded to each other’s image analysis, with a workstation that featured Syngo Fusion software (Siemens Medical Solutions). Images were randomized across groups for evaluation by the two radiologists. For quantitative assessment of stomach and small-bowel distention, the two radiologists measured five diameters each of the stomach, jejunum, and ileum. Thus, 30 measurements were obtained in every patient. The maximal diameter (in centimeters) of bowel loops was chosen for these measurements, with diameters in the stomach measured in the gastric fundus (two measurements), corpus (two measurements), and antrum (one measurement). Furthermore, attenuation measurements (in Hounsfield units) were performed in the same intestinal segments by placing regions of interest (minimum size, 20 pixels).
Standard uptake values were determined in all 60 patients by placing regions of interest (minimum size, 20 pixels) in five small-bowel loops that had been determined to show the highest 18F FDG uptake of all small-bowel loops at visual analysis. Standard uptake values were determined twice: once by a nuclear medicine physician (J.K.) and a second time by a radiologist (H.K.). Furthermore, PET/CT images were evaluated qualitatively by the physicians in consensus for areas of increased tracer uptake coregistered with either the small-bowel wall, lumen, or both. The following grading system was used: 1, no intestinal increase (homogeneous 18F FDG distribution); 2, mild increase (small-bowel loops can be delineated on the basis of PET images only); 3, moderate increase (tracer uptake in the bowel lumen comparable to that in liver parenchyma); 4, severe increase (focal or diffuse 18F FDG uptake values in the bowel exceed those in the liver). Qualitative evaluation of bowel tracer uptake, standard uptake values, and attenuation was determined only for the small bowel because the protocols being investigated were not designed to provide large-bowel distention.
Data and Statistical Analysis
Quantitative analysis of the ability of the contrast agent to distend intestinal structures was based on mean diameters plus or minus SDs determined for the stomach, jejunum, and ileum. Furthermore, mean attenuation values (in Hounsfield units) were determined from attenuation measurements in small-bowel loops in the presence of the three oral contrast agents being investigated.
To quantitatively assess glucose utilization in the bowel in the presence of the contrast agents, mean standard uptake values plus or minus SDs were determined and compared between the three groups.
Before the study, no hypothesis for di-rectional outcome could be made because of the lack of previous studies or data; therefore, differences between the contrast agents were evaluated with the unpaired Student t test to establish difference versus no difference. Bonferroni correction was applied to account for multiple comparisons (three oral contrast agents). In cases in which a significant two-tailed difference was detected, a one-sided Student t test was used to test for directionality after the mean values for the respective groups were compared with each other. A P value of less than .05 was considered to indicate a statistically significant difference. Correlation of measurements by the two observers was determined with the Pearson correlation coefficient.
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Results |
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TOPABSTRACTINTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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Distention of the stomach and small bowel with mannitol-LBG proved to be superior to that with water or barium (Fig 1). After administration of mannitol-LBG, the mean diameter of the stomach was 6.4 cm ± 1.8, of the jejunum was 2.1 cm ± 0.3, and of the ileum was 2.0 cm ± 0.3. Differences in stomach and small-bowel diameters between mannitol-LBG and the other contrast agents were statistically significant (P < .05 to P < .001) (Table 1). The ingestion of water alone resulted in poor small-bowel distention in comparison to that with mannitol-LBG or barium. Correlation coefficientsfor intestinal diameters determined by the two readers were 0.92 for the stomach, 0.76 for the ileum, and 0.71 for the jejunum; the correlation coefficient for the standard uptake value was 0.87.
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Results of quantitative analysis of glucose uptake in the small bowel revealed standard uptake values of 1.8 ± 0.5 for mannitol-LBG, 1.7 ± 0.5 for water, and 2.5 ± 0.6 for barium. Differences in small-bowel glucose uptake between mannitol-LBG and barium, as well as between water and barium, were significant (P < .001) (Table 1).
Qualitative evaluation of 18F FDG uptake in the bowel by the two observers included "mild" and "moderate" uptake in more patients who had ingested barium than in those who had ingested water or mannitol-LBG (Table 2). At qualitative evaluation, the smallest number of patients with intestinal 18F FDG uptake was found with mannitol-LBG (Fig 2). Glucose utilization occurred primarily in the bowel wall with mannitol-LBG or water, while 18F FDG uptake mainly coregistered with the bowel lumen with barium (Fig 3).
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Discussion |
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TOPABSTRACTINTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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Superior bowel distention with mannitol-LBG is based on two components: The osmotic quality of mannitol enhances secretion of water into the bowel, while the thickening property of LBG prevents intestinal water absorption. The combination of the two additives thus overcomes the main limitation of water as an oral contrast agent: intestinal absorption (11,12). Differences in intestinal diameters were also significant between mannitol-LBG and barium. This result is to be expected because only 1,000 mL of barium was ingested in comparison to 2,000 mL of mannitol-LBG. The dose of 1,000 mL of barium was chosen on the basis of typical amounts of barium used clinically for CT studies at our institution.
More relevant for PET/CT scanning, tracer quantification revealed significantly higher standard uptake values with barium than with mannitol-LBG or water. This finding is likely a result of the higher attenuation values with barium (mean, 310 HU) on CT images in comparison to those with water (7 HU) or mannitol-LBG (7 HU). With the bilinear scaling and segmentation approach for CT-based attenuation correction in our PET/CT system (3), the higher attenuation values translate into an overestimation of the attenuation coefficients at 511 keV and, in turn, to overestimation of the calculated emission activity (6). Thus, tracer activity concentration is apparently increased when quantified with standard uptake values. Similar results were reported by Carney et al (6) for iodine-based contrast agents. This observation is further supported by phantom measurements in the current study, which revealed apparently higher tracer concentration in the cylindric inserts that contained barium or iodinated contrast material in comparison to those with mannitol-LBG or water.
Accurate quantification of tracer activity concentration is, however, crucial for differentiating benign from malignant lesions or for the determination of treatment response (13–15). A potential solution to overestimation of CT-based PET attenuation may be accurate image segmentation in the area of contrast- enhanced bowel loops. CT-based attenuation measurements could then be converted into the accurate values for linear attenuation at 511 keV. This approach, however, is not feasible with currently available PET/CT scanners; CT-based attenuation correction algorithms are typically based on thresholds in the histograms of the CT attenuation values, followed by scaling of the segmented classes of pixel values (3). Therefore, the use of a negative oral contrast agent may be beneficial with the currently implemented attenuation-correction techniques in PET/CT scanners because they avoid contrast material–induced artifacts, while at the same time offering excellent intestinal distention for optimum CT diagnosis.
Patients in the current study ingested barium as a positive contrast agent, but iodinated contrast material was not explicitly evaluated in vivo. Barium and iodine are known to have similar atomic numbers (barium, 56; iodine, 53), which causes very similar linear attenuation for each substance density (5). Barium and iodine are, therefore, expected to have analogous effects on CT-based PET attenuation correction. This assumption is supported by results in our phantom study.
Results of qualitative evaluation of intestinal tracer uptake further support the results of quantitative analysis by demonstrating significantly more patients with apparently increased tracer uptake in the small intestine with barium than with mannitol-LBG or water. This finding calls into question the results reported by Dizendorf et al (8) that did not indicate differences in small-bowel uptake between a group of patients who had ingested iodinated oral contrast material and a second group who had not ingested any oral contrast agent. They reported a statistically significant increase in 18F FDG uptake in only in the ascending colon. This effect is likely a result of the timing of administration of the oral contrast material in their protocol. They administered 1,000 mL of iodinated contrast material before injection of the radioactive tracer, which increased the interval between contrast material ingestion and PET/CT scanning. This led to high attenuation in the ascending colon, while the amount of con-trast material in the small bowel decreased. Since contrast material–induced artifacts in PET/CT scanning are known to be dependant on the intraluminal attenuation (5,9,16), it may be presumed that apparently increased 18F FDG uptake in the small bowel would have been present if PET/CT scanning had been performed earlier.
In the current study, the site of intestinal tracer uptake was mainly coregistered with the bowel wall in patients who had ingested negative oral contrast material (mannitol-LBG or water). In patients who had ingested barium, apparently increased tracer uptake was mainly found in coregistration with the contrast-enhanced bowel lumen. The latter reflects increased attenuation in the bowel lumen, which results in apparently increased tracer uptake. The uptake of 18F FDG in the small-bowel wall in patients who ingested water or mannitol-LBG may reflect increased glucose utilization of the bowel wall as a result of increased fluid absorption (water) or secretion (mannitol-LBG). The uptake of 18F FDG into mucosal structures provoked by enhanced absorption or secretion has been described before (17).
A rapidly arising diuretic urge complicated the examination of patients who ingested 2 L of water. Induced by extensive water resorption during the 30-minute whole-body PET/CT examination, the diuretic urge required the interruption of one examination. In addition, several patients felt uncomfortable. Water resorption is prevented by the osmotic property of mannitol and the thickening property of LBG, which avoids an early diuretic urge. Mannitol alone, however, is known to induce watery diarrhea. LBG provides mitigating action based on its thickening properties (10). While mannitol alone has been associated with diarrhea in up to 83% of patients (10,18,19), only two of 20 patients examined with mannitol-LBG in the current study had watery diarrhea following the examination. In addition to favorable PET/CT scanning characteristics, excellent bowel distention, and minimal effect on patient comfort, the mannitol-LBG solution is not expensive. The cost for 1 L of the pharmacy-compounded solution is $3, which is lower than the price of $3.50 for a 500-mL bottle of the barium contrast material. Thus, the administration of mannitol-LBG as an oral contrast agent does not increase the cost of a PET/CT examination over that with barium.
While findings in this study are promising for use of mannitol-LBG as a negative oral contrast agent in combined PET/CT scanning, further questions need to be addressed in the future. It will be important to assess if use of a negative oral contrast agent improves the overall accuracy of the combined scanning approach over that with nonenhanced scanning. Furthermore, potential differences in diagnostic accuracy of PET/CT with negative and positive oral contrast agents need to be evaluated.
Mannitol-LBG is a feasible oral contrast material in combined PET/CT scanning with substantial benefit over barium or water. As an oral contrast agent, it permits delineation of intestinal structures while preventing PET artifacts because of its water-based nature. Mannitol-LBG may, therefore, be used to provide contrast in dual-modality PET/CT scanning.
In conclusion, a solution containing 0.2% LBG and 2.5% mannitol can be used as an oral contrast agent in PET/CT scanning because it provides excellent bowel distention while avoiding contrast material–induced PET artifacts.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Author contributions: Guarantor of integrity of entire study, G.A.; study concepts and design, G.A., H.K., J.F.D., T.B., H.S., T.C.L.; literature research, G.A., H.K.; clinical and experimental studies, G.A., J.K., E.H.; data acquisition, G.A., J.K., T.B., W.J., E.H.; data analysis/interpretation, G.A., J.K., H.K., S.C.G., W.J.; statistical analysis, G.A., S.G.; manuscript preparation, G.A.; manuscript definition of intellectual content, G.A., T.B.; manuscript editing, G.A.; manuscript revision/review and final version approval, all authors
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TOPABSTRACTINTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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