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Experimental Studies |
1 Mallinckrodt Institute of Radiology, Washington University School of Medicine, Barnes-Jewish Hospital, 216 S Kingshighway Blvd, St Louis, MO 63110.
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Abstract |
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 TOP Abstract IntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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MATERIALS AND METHODS: In vitro attenuation measurements of multiple dilutions of gadodiamide and ioversol were compared. In three pigs, 50-mL boluses of undiluted gadodiamide were injected intravenously at 2 mL/sec, and repeated single-level scans were obtained through the lung bases, liver, and kidneys. The doses of 0.8–1.0 mmol of gadolinium per kilogram of body weight were approximately three times the highest doses currently used in patients. Enhancement was determined from attenuation measurements in the aorta, pulmonary arteries, liver, and kidneys.
RESULTS: In vitro, the attenuation of undiluted gadodiamide (3,069 HU) was equivalent to that of ioversol diluted to 106 mg of iodine per milliliter and at equimolar concentrations was 50% greater than that of ioversol. The magnitude of and time to peak enhancement were 141 HU and 27 seconds (n = 3) for the aorta; 168 HU and 21 seconds (n = 3) for the pulmonary arteries; 23 HU and 65 seconds (n = 2) for the liver; and 63 HU and 32 seconds (n = 1) for the kidneys. Time-attenuation curves revealed a useful duration of enhancement of 20–30 seconds for the aorta and pulmonary arteries.
CONCLUSION: Gadolinium produces good vascular enhancement, adequate renal enhancement, and suboptimal hepatic enhancement. Further study is needed to determine the safety of the gadolinium dose required to produce similar enhancement in patients.
Index terms: Computed tomography (CT), contrast enhancement, 60.12112, 60.12116, 761.12112, 761.12116, 81.12112, 81.12116 • Computed tomography (CT), contrast media, 60.12112, 60.12116, 761.12112, 761.12116, 81.12112, 81.12116 • Contrast media, experimental studies • Gadolinium
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Introduction |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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MATERIALS AND METHODS |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Animal Studies
Dynamic gadolinium-enhanced CT examinations were performed on three anesthetized pigs receiving mechanical ventilation and weighing 23, 24, and 31 kg (mean, 26 kg ± 3 [SD]). The CT scans were obtained by using 5-mm collimation, 250 mA, 120 kV, 25- or 30-cm field of view, and a 1-second scanning time. Contrast enhancement was assessed at three separate scanning levels: the lower lobe pulmonary arteries, the right lobe of the liver just below the portal vein, and the interpolar region of the kidneys. At each level, a 50-mL bolus of gadodiamide (0.8–1.0 mmol per kilogram of body weight, approximately three times the highest dose currently used in patients) was injected into a peripheral vein in the hind limb by using a Microprocessor CT Injector System (Medrad, Pittsburgh, Pa) at 1 or 2 mL/sec in the first pig and at 2 mL/sec in the second and third pigs. The volume and rate of injection were chosen so that they would be equivalent on a per kilogram basis to a volume of 100-150 mL and an injection rate of 4 mL/sec in a person of average size. Repeat images were obtained for 120 seconds at 5-second intervals (4-second interscan delay) in the first pig and at 3-second intervals (2-second delay) in the other two pigs. Respirator tidal volume was reduced while oxygen was administered during scanning to decrease motion artifacts. After 20 minutes of equilibration of contrast agent between the vascular and tissue compartments, contrast agent injection and scanning were performed at the next chosen level. All animal care and procedures performed in this study were approved by the Washington University Institutional Animal Studies Committee, St Louis, Mo.
To determine the degree of enhancement, we obtained region-of-interest attenuation measurements before and after contrast agent administration. A circular region of interest approximately 30 mm2 (6-mm diameter) was sampled within the aorta on each scan at each scanning level. At the level of the lower lobe pulmonary arteries, a circular region of interest approximately 15 mm2 (4-mm diameter) was sampled in the largest right lower lobe pulmonary artery branch and another was sampled in the largest left lower lobe pulmonary artery branch. At the level of the liver, circular regions of identical size to that used in the aorta were sampled at two locations in the right lobe of the liver, separate from any visibly enhancing vessels. At the level of the kidneys, one circular region of interest of identical size to that used in the aorta was sampled in the parenchyma of the right kidney and one in the left kidney. Time-enhancement curves were generated for the aorta at the level of the kidneys and for the mean of the two measurements in the pulmonary arteries, liver, and kidneys. Enhancement was expressed in Hounsfield units as the absolute attenuation above the baseline attenuation at the beginning of each injection.
The magnitude of and time to peak enhancement in the aorta for each pig were determined as the mean value of the measurements at the three scanned levels. For the kidneys, liver, and lower lobe pulmonary arteries, the magnitude of and time to peak enhancement in each pig were determined as the mean of the two measurements obtained. The aorta and pulmonary arteries were studied by using an injection rate of 2 mL/sec in all three pigs, the liver was studied by using an injection rate of 1 mL/sec in pig 1 and 2 mL/sec in pigs 2 and 3, and the kidneys were studied by using an injection rate of 1 mL/sec in pig 1 and 2 mL/sec in pig 3. In pig 2, renal enhancement data could not be used because an unknown amount of contrast agent leaked during the injection.
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RESULTS |
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DISCUSSION |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Despite the lower in vitro attenuation of undiluted gadodiamide compared with that of ioversol, gadodiamide produced substantial vascular and tissue enhancement with an injection volume and rate analogous to that used with iodinated contrast agents in humans. The peak vascular enhancement of 141 HU for the aorta was visually prominent, although less than the enhancement of 216–271 HU obtained with similar injection volumes and rates of iodinated contrast agents in pigs (11) and less than the 180 HU obtained in humans (12). Likewise, the peak hepatic enhancement of 23 HU is less than the peak of 48–51 HU obtained in pigs (11), less than the 48–75 HU found by using various iodine concentrations and injection rates in humans (12–15), and below the desirable level of at least 50-HU enhancement (12–14). We are unaware of reports of renal enhancement levels obtained with iodinated contrast agents in humans or pigs to compare with the peak enhancement of 63 HU obtained by using gadolinium in our study.
One study (1) in a human volunteer found no change in hepatic attenuation and a 9–11-HU increase in renal attenuation after injection of 0.5 mol/L gadopentetate dimeglumine, but the injection volume and rate were not specified and measurements were made only at 30 seconds and 2, 3, and 9 minutes. In another study (10), performed by injecting 1 mL per kilogram of body weight of 0.5 mol/L gadopentetate dimeglumine in dogs, a smaller volume than that used in our study, the peak aortic and hepatic enhancement levels were similar to those obtained in our study; the injection rate was not specified.
The shape of the aortic and hepatic time-attenuation curves in our study is similar to that in other studies with iodinated contrast agents in pigs (11) and in humans (12,16) and is consistent with the similar biodistribution and excretion of gadolinium-based contrast agents and iodinated contrast agents. The time to peak enhancement is a function of injection duration (11,17) and cardiac output (18), and it therefore differed from that in studies (12,16) in which iodinated contrast agents were used in humans and from that in one animal study (10) in which gadolinium was used but for which injection parameters were not specified; the time to peak enhancement was nearly identical to that seen with similar volumes and injection rates of iodinated contrast agents in pigs of similar size (11).
The duration of contrast enhancement above a specific level indicates the available window in which scanning should be performed. Obtaining scans through the area of interest before sufficient contrast enhancement has occurred or after the contrast agent has substantially equilibrated between vascular and tissue compartments will compromise the diagnostic value of the study. A standard method of quantifying the duration of diagnostically useful enhancement has not been defined; one approach defines a contrast enhancement index as the area under the time-attenuation curve above a specified enhancement threshold (19). Although this may be useful, its relevance to our study of animals smaller than adult human patients is uncertain, and we did not apply this or other quantitative measures. However, by visual inspection of the time-attenuation curves, we estimate that there was at least 20–30 seconds of useful contrast enhancement for the aorta and pulmonary arteries, an adequate imaging window for the chest or abdomen at spiral CT. As has been found with iodinated contrast agents (12), vascular enhancement with use of gadolinium would be expected to last longer in human subjects with larger volumes of contrast agent and longer injection times.
On the basis of our results, it appears that at currently manufactured concentrations, gadolinium-based contrast agents would have the greatest potential value for CT studies of the aorta or pulmonary arteries or in chest CT examinations when mediastinal vascular enhancement is important. The quantitative and visual enhancement observed and the duration of enhancement were more than adequate for diagnostic examination of these vessels with current spiral CT technology. In addition, the higher k edge of gadolinium results in decreased low-energy filtration and less beam-hardening artifact than does the k edge of iodine (20), which potentially reduces mediastinal vascular artifacts related to the concentrated bolus of contrast agent in the superior vena cava. Although an arteriographic corticomedullary phase was not observed, the degree of renal enhancement should be adequate for distinguishing a cyst from a solid mass and for detecting less enhanced lesions. Enhancement of the hepatic parenchyma was suboptimal, with distinction between parenchymal and vascular enhancement seen in only one of the three pigs. Animal or patient studies of lesion detection could better define the diagnostic usefulness of these levels of enhancement.
The volume of gadodiamide per kilogram of animal weight resulting in the level of enhancement seen in our study was equivalent to that used with iodinated contrast agents in patient body CT examinations, but 0.8–1.0 mmol of gadodiamide per kilogram was eight to 10 times higher than the manufacturer's recommended dose of 0.1 mmol per kilogram for MR imaging in humans. To our knowledge, the safety of such a dose in humans has not been tested. Hemodynamic effects related to osmolality may be similar to those of nonionic iodinated contrast agents, because the osmolal load of the gadodiamide used in this study (789 mOsm/kg H2O) is similar to that of 320 mg of iodine per milliliter of ioversol (702 mOsm/kg H2O), approximately 2.8 times the osmolality of plasma, and just over half the osmolality of ionic iodinated contrast agents.
Three times the recommended dose is commonly used in MR angiographic studies (21–23), and the incidence and nature of adverse reactions with such a dose are no different than those with the standard 0.1 mmol/kg dose (24). In addition, the minimum lethal dose of gadodiamide in mice (reported in the manufacturer's package insert) is more than 20 mol/kg, which is more than 20 times the doses used in our study; this compares favorably with the dose of ioversol fatal to 50% of test mice (also reported in the manufacturer's package insert), which is 17 g of iodine per kilogram, or more than 20 times the typical dose of 0.6 g of iodine per kilogram administered to the average-size adult. However, clinical testing is needed to determine the lowest dose providing acceptable enhancement while minimizing adverse effects.
We conclude that gadolinium may be an alternative CT contrast agent for patients who cannot receive iodinated contrast agents and in whom contrast-enhanced CT is the examination of choice. While the current high cost of gadolinium-based contrast agents might prohibit their routine use, the cost might be justifiable in various infrequent clinical situations, particularly for vascular studies. For example, CT assessment for aortic dissection could be performed with gadolinium in a patient who had a severe allergy to iodinated contrast agents and who was too unstable for MR or had a pacemaker or other contraindication to MR. The lack of exacerbation of renal insufficiency with gadolinium-based contrast agents (5,6) is an additional advantage. As the CT assessment of suspected pulmonary embolism further improves and is performed more often, a gadolinium-based contrast agent could be an option in patients with multiorgan failure who need intensive care and for whom iodine might exacerbate renal insufficiency. Experience with specific lesions is necessary to determine the value of gadolinium-based contrast agents in evaluating the kidneys and liver; in most cases, other imaging methods such as MR or ultrasonography can provide the desired information. However, studying the safety and efficacy of dynamic gadolinium-enhanced CT in patients could lead to the availability of an alternate contrast agent in selected circumstances.Practical application: Vascular and tissue enhancement similar to that seen in this porcine model should be obtainable in patients at CT examinations with use of gadolinium-based contrast agents at the injection volumes and rates typically used with iodinated contrast agents. The degree of enhancement seen in this study indicates considerable potential utility of gadolinium as an alternative to iodine in CT studies of the aorta, pulmonary arteries, and mediastinum in patients with contraindications to iodinated contrast agents and MR imaging. Gadolinium at commercially manufactured concentrations likely would be inadequate in the assessment of the liver but may prove useful in the characterization of renal lesions. Clinical applications will require determining the safety and efficacy of the necessary higher gadolinium doses in humans.
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Acknowledgments |
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Footnotes |
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Address reprint requests to D.S.G.
Author contributions: Guarantor of integrity of entire study, D.S.G.; study concepts and design, D.S.G., K.T.B.; definition of intellectual content, D.S.G., K.T.B.; literature research, D.S.G., K.T.B.; experimental studies, D.S.G., K.T.B.; data acquisition and analysis, D.S.G., K.T.B.; statistical analysis, D.S.G., K.T.B.; manuscript preparation, D.S.G.; manuscript editing and review, D.S.G., K.T.B.
Received January 6, 1998;
revision requested March 31, 1998; revision received August 24, 1998;
accepted October 7, 1998.
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References |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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