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Published online before print June 11, 2007, 10.1148/radiol.2441060354
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(Radiology 2007;244:457-463.)
© RSNA, 2007

Experimental Studies

Effectiveness and Renal Tolerance of Multidetector Helical CT with Gadobutrol: Results of a Comparative Porcine Study1

Marc Kalinowski, MD, Kai Goldmann, MD, Martin Gotthardt, MD, PhD, Marion Rössler, MD, Andreas Pfestroff, MD, Klaus Jochen Klose, MD, PhD, and Hans-Joachim Wagner, MD, PhD

1 From the Departments of Diagnostic Radiology (M.K., K.J.K., H.J.W.), Anesthesiology and Intensive Care (K.G.), Nuclear Medicine (M.G., A.P.), and Pathology (M.R.), Philipps-University Hospital, Baldingerstrasse, 35033 Marburg, Germany. Received February 24, 2006; revision requested April 25; revision received May 17; accepted June 7; final version accepted November 1. Address correspondence to M.K. (e-mail: kalinows{at}med.uni-marburg.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To prospectively evaluate the safety and effectiveness of high doses of 1 mol/L gadobutrol as a contrast agent for computed tomography (CT).

Materials and Methods: Experiments were performed according to guidelines for care of laboratory animals. The local animal care committee approved the study protocol. Unenhanced and contrast material–enhanced CT images of the chest and abdomen were obtained randomly in nine domestic pigs. Gadobutrol was injected (1, 2, or 3 mL per kilogram of body weight; three pigs for each dose). Attenuation was measured in different vascular and parenchymal structures. Changes in blood chemistry and hematologic parameters were monitored before and 1, 2, 3, and 7 days after gadobutrol administration. Urine samples were evaluated before and 7 days after gadobutrol administration. Technetium 99m mertiatide renal scintigraphy was performed before and 7 days after contrast medium injection. Animals were sacrificed 7 days after contrast medium administration, and one kidney was removed from each animal for examination with light microscopy. No serious adverse events occurred. A mixed-model nested analysis of variance was used for statistical evaluation.

Results: Mean attenuations for the 1, 2, and 3 mL/kg gadobutrol doses, respectively, were 148 HU ± 20 (standard deviation), 282 HU ± 18, and 289 HU ± 20 in the thoracic aorta; 99 HU ± 11, 166 HU ± 9, and 153 HU ± 18 in the kidneys; and 106 HU ± 7, 186 HU ± 18, and 224 HU ± 24 in the inferior vena cava. No clinically relevant changes in hematologic, blood chemistry, or urine analysis results were detected. Markers for glomerular filtration and tubular function were unaffected in all groups. Scintigraphy revealed no differences between unenhanced and contrast-enhanced results. No morphologic changes of the renal parenchyma were found at histologic analysis.

Conclusion: Contrast-enhanced CT with a 2 or 3 mmol/kg dose of 1 mol/L gadobutrol resulted in excellent vascular and parenchymal enhancement. A gadobutrol dose of up to 3 mL/kg did not affect renal function.

© RSNA, 2007


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Intravascular iodinated contrast agents are currently the standard contrast agents used for computed tomography (CT). The development of nonionic monomer and dimer iodinated contrast agents has made the use of these agents safe, with only minimal adverse effects (1). While use of these agents is safe in most patients, it could be associated with a substantial incidence of serious adverse events, particularly in high-risk patients. Concerns include contrast material–induced nephropathy, induction of hyperthyroidism, and allergic reactions. In previous studies, researchers have found a rate of contrast material–induced nephropathy of up to 7% in an unselected patient population (2). The incidence of contrast material–induced nephropathy increases to 33% in a population with renal insufficiency and diabetes mellitus and represents the third leading cause of new acute renal failure in hospitalized patients (3–4).

In the past, gadolinium-based contrast agents have been used as an alternative to iodinated contrast agents for x-ray absorption in patients with relative or absolute contraindications to iodinated contrast media (5–14). When gadolinium-based contrast agents are used in doses approved for magnetic resonance (MR) imaging, the risk of adverse reactions and altered renal function seems lower. However, the concentrations of commercially available gadolinium chelates differ from those of currently used iodinated contrast agents.

The majority of gadolinium chelates marketed for contrast material–enhanced MR imaging are 0.5 mol/L solutions that contain 78.6 mg of gadolinium per milliliter. In comparison, standard iodinated contrast agents contain 300 mg of iodine per milliliter (iodine concentration, 0.79 or 2.4 mol/L). Consequently, administration of an equimolar amount of gadolinium would require the five fold volume of a 0.5 mol/L solution (eg, 500 mL of a 0.5 mol/L gadolinium chelate solution is equivalent to 100 mL of a 2.5 mol/L iodinated contrast agent solution). The upper dose limit for most of the currently available gadolinium chelates used for MR imaging is 0.3 mmol of gadolinium per kilogram of body weight (eg, a 45-mL volume for a 75-kg person).

Gadobutrol (Gadovist 1.0; Schering, Berlin, Germany) is a 1 mol/L concentrated agent that enables contrast enhancement similar to that with 240 mg/mL iodinated contrast agents to be achieved with CT (15–17). Gadobutrol doses of up to 0.3 mmol/kg have been approved for MR imaging of the central nervous system and MR angiography. However, use of gadolinium chelates for clinical CT would require administration of substantially higher doses, and to our knowledge, the safety of such doses has not been studied in patients. Therefore, the purpose of our investigation was to prospectively evaluate the safety and effectiveness of high doses of 1 mol/L gadobutrol as a contrast agent for CT.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Animals
The study group consisted of nine adult domestic pigs with a mean body weight of 52 kg ± 4 (standard deviation). All experiments were performed according to guidelines for the care of laboratory animals. The local animal care committee of the state government approved the study protocol. The pigs were acclimatized at the animal care facility for 4–6 days before investigation and had free access to food and water until 12 hours before the experiments; thereafter, they had free access to only water.

All experiments were performed with general anesthesia. The animals were premedicated with an intramuscular injection of azaperone (4 mg/kg), midazolam (0.2 mg/kg), s-ketamine (2 mg/kg), and atropine (0.02 mg/kg). When the pigs lost consciousness, an intravenous line was established by puncturing an auricular vein. Thereafter, general anesthesia and volume-controlled mechanical ventilation were administered via a laryngeal mask. During examination, the pigs were monitored continuously with electrocardiography and intraarterial blood pressure and transcutaneous oxygen saturation measurements (Fig 1).


Figure 1
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  		Figure 1: Flowchart shows study design. CM/kg BW = contrast material per kilogram of body weight, 99mTc-MAG3 = 99mTc mertiatide.

 
CT Examination
Imaging was performed with a four–detector row helical CT scanner (Somatom Volume Zoom; Siemens, Erlangen, Germany). The CT images were obtained with 2.5-mm collimation, 13.5-mm table feed, 3-mm reconstruction increment, 180-mAs tube current, 120-keV tube voltage, and 0.75-second tube rotation time. In all animals, continuous thoracic and abdominal helical CT scanning was performed in the craniocaudal orientation with a bolus-triggered examination protocol (CARE-Bolus; Siemens). Helical CT was performed if attenuation in a circular region of interest (ROI) placed in the thoracic aorta was 100 HU greater than the baseline value. CT scanning started 5 seconds after the bolus trigger. Total scanning time was approximately 25 seconds. In all animals, unenhanced CT images were obtained with the same examination protocol before contrast-enhanced CT images were obtained.

Contrast Material Injection
The applied volume (1, 2, or 3 mL/kg; three pigs for each dose) of 1 mol/L gadobutrol (gadolinium concentration, 157.2 mg/mL) was selected from a computer-generated random list. Contrast medium was injected at a flow rate of 3 mL/sec with a standard CT injector system (OP100; Medrad, Pittsburgh, Pa).

All imaging procedures were technically successful. Contrast medium injection was performed successfully and was uneventful. During all procedures, none of the animals showed signs of respiratory, cardiac, or other serious adverse reactions to contrast medium administration. No allergic reactions were noted.

Attenuation Measurement
All images were viewed on a workstation (Leonardo; Siemens). To determine the degree of enhancement, we measured ROI attenuation before and after contrast agent injection (M.K., 8 years of experience in abdominal CT). Manually drawn circular ROIs were placed centrally in vascular regions and parenchymal organs. At the level of the common carotid arteries, an approximately 0.1-cm2 circular ROI was used. ROIs of approximately 0.6 cm2 were placed in the aortic arch, the descending thoracic aorta at two levels (the tracheal bifurcation and the level of the diaphragm), and the abdominal aorta. In the liver, a 1.5-cm2 circular ROI that did not cover any of the large vessels was placed in the parenchyma. At the level of the kidneys, one ROI was placed in the renal cortex of the left kidney and another was placed in the inferior vena cava (both 0.4 cm2). Enhancement was measured in Hounsfield units and calculated as the increase in attenuation compared with baseline attenuation at different ROIs. Attenuation was measured with identical window settings in all animals. The magnitude of enhancement in the different regions of each animal was defined as the mean value of three measurements.

Technetium 99m Mertiatide Renal Scintigraphy
Scintigraphy was performed immediately before and 7 days after contrast medium injection. Animals were placed in the prone position and examined with a standard dual-head gamma camera (DIACAM; Siemens). After injection of 200 MBq of technetium 99m (99mTc) mertiatide, data were stored (5-second frame rate for 60 frames initially and 15-second frame rate for 60 frames thereafter). ROIs were drawn manually for each kidney; this procedure was followed by automatic fitting of the process of the ROIs to the renal cortex contour. A background ROI was drawn laterally to the kidney, and a vascular ROI was placed over the infrarenal abdominal aorta manually (M.G.). Real-time activity curves with subtracted background activity were generated for both kidneys. Tubular extraction rate and time to peak renal parenchymal activity were calculated for the individual kidney.

Blood and Urine Sampling
Blood sampling was performed immediately before and 1, 2, 3, and 7 days after contrast material was administered. The following parameters were measured: blood cell count (leukocytes, erythrocytes, hemoglobin, hemtaocrit, and platelets), creatinine and urea levels as markers for glomerular filtration, and cystatin C and ß2-microglobulin levels as markers for excretory renal function.

Urine samples were obtained immediately before and 7 days after contrast medium injection by puncturing the bladder during anesthesia. In these samples, creatinine, urea, and albumin levels served as markers for glomerular function, and the {alpha}1-microglobulin level served as a marker for tubular function.

Histopathologic Verification
At the end of the study, animals were sacrificed with intravenous injection of a lethal dose of potassium chloride while they were in a state of deep anesthesia. Immediately thereafter, one kidney was removed according to a computer-generated random list and placed in a formalin solution. Histopathologic examination was performed (M.R.) after hematoxylin-eosin staining of representative regions of the kidney, including cortical and medullary regions and parts of the urine collecting system.

Statistical Analysis
All data are expressed as means ± standard deviations. A variance model (F test) for repeated measurements was used to determine if there were differences between the groups. Statistical significance was evaluated with the Wilcoxon rank sum test. A P value less than .05 indicated statistical significance. P values were calculated with statistical software (SPSS for Windows, version 11; SPSS, Chicago, Ill) and were not adjusted for multiplicity. The measured attenuation at the aortic ROI was analyzed with a mixed-model nested analysis of variance that reflected the hierarchical data structure, with the highest level (ie, dose of contrast agent, ordinal) being of model type 1 (fixed treatment effects) and the subordinate classifications (animals then ROIs) being modeled as nested variance components (random effects). Correspondingly, these data were analyzed with a mixed-model nested analysis of variance that took into account the fact that data at the subordinate levels might be dependent and clustered.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Enhancement in Different Vascular Structures and Organs
In all animals, differentiation of vascular and parenchymal structures was facilitated after gadobutrol injection (Fig 2). The mean magnitudes of enhancement for 1, 2, and 3 mL/kg gadobutrol doses, respectively, were 148 HU ± 20, 282 HU ± 18, and 289 HU ± 20 in the thoracic aorta (Fig 3); 99 HU ± 11, 166 HU ± 9, and 153 HU ± 18 in the kidneys; and 106 HU ± 7, 186 HU ± 18, and 224 HU ± 24 in the inferior vena cava (Fig 4). Because CT was performed during the arterial phase of contrast medium administration, no significant (P = .6) differences in enhancement of the liver parenchyma were found with use of 1, 2, or 3 mL/kg gadobutrol doses when compared with the enhancement seen on the native CT images (Fig 2).


Figure 2
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  		Figure 2: Graph shows magnitude of enhancement after injection of a 1, 2, or 3 mL/kg dose of gadobutrol in different regions of the body. AA = ascending aorta, AbA = abdominal aorta, CA = carotid artery, DA-1 = descending aorta 1 (thoracic level), DA-2 = descending aorta 2 (diaphragmatic level), and IVC = inferior vena cava. * = no significant difference.

 

Figure 3A
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  		Figure 3a: Transverse CT scans at the level of the descending aorta after injection of a (a) 1, (b) 2, or (c) 3 mL/kg gadobutrol dose. Excellent differentiation of vascular structures is seen in b and c.

 

Figure 3B
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  		Figure 3b: Transverse CT scans at the level of the descending aorta after injection of a (a) 1, (b) 2, or (c) 3 mL/kg gadobutrol dose. Excellent differentiation of vascular structures is seen in b and c.

 

Figure 3C
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  		Figure 3c: Transverse CT scans at the level of the descending aorta after injection of a (a) 1, (b) 2, or (c) 3 mL/kg gadobutrol dose. Excellent differentiation of vascular structures is seen in b and c.

 

Figure 4A
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  		Figure 4a: Transverse CT scans at the level of the kidneys after injection of a (a) 1, (b) 2, or (c) 3 mL/kg gadobutrol dose. Excellent differentiation of vascular structures is seen in b and c.

 

Figure 4B
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  		Figure 4b: Transverse CT scans at the level of the kidneys after injection of a (a) 1, (b) 2, or (c) 3 mL/kg gadobutrol dose. Excellent differentiation of vascular structures is seen in b and c.

 

Figure 4C
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  		Figure 4c: Transverse CT scans at the level of the kidneys after injection of a (a) 1, (b) 2, or (c) 3 mL/kg gadobutrol dose. Excellent differentiation of vascular structures is seen in b and c.

 
For the mixed-model nested analysis of variance, the following mean squares were calculated with the aortic ROI data: among treatment groups, 72 414.4 (df = 2); among pigs within the same group, 3677.1 (df = 6); and within pigs, 670.4 (df = 36). The resulting F statistic indicated significant differential effects of treatment (F = 19.69, P < .003) and proved that pigs introduce a significant variance component (F = 5.485, P < .001). As treatment led to significant differences between groups, a priori planned pairwise comparisons (1 vs 2 mL/kg, 2 vs 3 mL/kg) were performed with standard analysis of variance by using a mean square of 3677.1 as the error term (df = 6). This analysis revealed a significant difference between 1 and 2 mL/kg gadobutrol doses (F = 23.21, P = .003) but no remarkable difference between 2 and 3 mL/kg gadobutrol doses (F = 1.16, P = .324).

Blood and Urine Samples
The creatinine, urea, and ß2-microglobulin measurements obtained over 7 days were not significantly different between groups (P = .45, P = .6, and P = .75, respectively; Figs 5–7). Cystatin C was also unaffected in all groups. The same results were found in urine samples, with no significant differences in creatinine, urea, albumin, or {alpha}1-microglobulin levels (data not shown).


Figure 5
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  		Figure 5: Graph shows serum creatinine levels at different times, as measured with a 1, 2, or 3 mL/kg gadobutrol dose. There was no significant increase compared with baseline values. In one animal that received a 2 mL/kg dose, signs of interstitial nephritis were detected, but there were no sequelae in blood parameters. BW = body weight.

 

Figure 6
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  		Figure 6: Graph shows serum urea levels at different times, as measured with a 1, 2, or 3 mL/kg gadobutrol dose. There was no significant increase compared with baseline values. In one animal that received a 2 mL/kg dose, signs of interstitial nephritis were detected, but there were no sequelae in blood parameters. BW = body weight.

 

Figure 7
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  		Figure 7: Graph shows ß2-microglobulin levels at different times, as measured with a 1, 2, or 3 mL/kg gadobutrol dose. There was no significant increase compared with baseline values. In one animal that received a 2 mL/kg dose, signs of interstitial nephritis were detected, but there were no sequelae in blood parameters. BW = body weight.

 
99mTc Mertiatide Renal Scintigraphy and Histopathologic Analysis
Impairment of renal function was not detected in any animal (Table). Over a 7-day observation period, no change in tubular extraction rate was seen, even with gadobutrol doses of 3 mL/kg.


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  		Tubular Extraction Rates Determined with 99mTc Mertiatide Renal Scintigraphy

 
There were no signs of contrast material–induced renal damage (eg, vacuolization of proximal tubular cells at histopathologic examination). In an animal that received a 2-mL/kg gadobutrol dose, histopathologic signs of interstitial nephritis were seen and interpreted as signs of anesthesia-induced toxic inflammation.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
Our results show that contrast enhancement similar to that of iodinated contrast-enhanced CT can be achieved with conventional CT and CT angiography if a high dose (2 or 3 mL/kg) of gadobutrol is used. Furthermore, we found no negative effect on renal function in a porcine model with use of these high doses of a 1 mol/L gadobutrol solution.

Although gadolinium is used primarily for its paramagnetic properties, it can serve as a radiographic contrast agent. It has a higher atomic number (Z = 64) than iodine (Z = 53), and its higher k edge (50 keV, compared with 33 keV for iodine) is better matched to the peak intensity of the postfiltration energy spectrum produced during CT scanning. Thus, gadolinium absorbs a greater fraction of the energy spectrum and is a better attenuator of x-rays produced during clinical CT scanning (18).

Since 1989, when Bloem and Wondergreen (14) published their findings on the use of gadolinium chelates with CT, there has been an increasing number of studies in which gadolinium chelates have been used for contrast-enhanced CT. In several experimental and clinical studies, researchers have evaluated the image quality and patient tolerance of gadolinium-based agents for CT angiography. No adverse event has been reported, and sufficient enhancement for diagnostic purposes has been achieved (15–18). Gadobutrol has been evaluated previously for use as a CT contrast agent. Schmitz et al (16) studied rabbits to evaluate contrast enhancement with different gadobutrol concentrations (0.7, 1.0, and 1.5 mmol/kg; 1 mol/L solution) and to compare gadobutrol-induced enhancement with iodinated contrast material enhancement in helical CT examinations. Schmitz et al demonstrated that gadobutrol was as effective as iodinated contrast media for CT. A gadobutrol dose of up to 1.5 mmol/kg resulted in CT enhancement similar to that observed with clinical doses of iopromide. For a gadobutrol dose of 1.0 mmol/kg, they found a mean aortic enhancement of 313 HU; this is similar to our results, which were obtained in a larger animal model and more closely resemble the results obtained with clinical use of iodinated contrast media. We did not perform additional CT examinations in the portal or delayed venous phases in this setting. However, in previous studies we have shown that the attenuation curves of gadolinium chelates and iodinated contrast media are quite similar; thus, adequate parenchymal enhancement with higher doses of gadobutrol in delayed scanning phases could be expected (19).

Use of gadolinium-enhanced contrast material as an alternative contrast agent for CT requires administration of gadolinium doses that are higher than those usually recommended for MR imaging. Currently, the dose limitation for most gadolinum chelates is 0.3 mmol/kg. For gadobutrol, this restricts the total volume per examination to 22.5 mL of a 1.0 mol/L solution in a 75-kg person. Compared with the volume of iodinated contrast media used for CT, this amount would not suffice. Application of 0.5 mmol/kg gadobutrol did not lead to adverse events in healthy volunteers (20,21). Based on the currently used doses, it seems that gadolinium-based contrast agents are less nephrotoxic than iodinated contrast agents, even in patients with renal insufficiency (22–27). It must be recognized that this is only true when equivalent equivolume doses of gadolinium chelates are compared with iodinated contrast agents. However, the concentration of gadolinium in gadolinium-based contrast agents that contain one gadolinium atom per molecule is only one-fifth that of iodine in standard solutions that contain 300 mg of iodine per milliliter. Only on an equimolar basis do gadolinium-based contrast agents produce greater attenuation and greater contrast in vivo than do iodine-based contrast agents; however, there is a substantial increase in nephrotoxic effects with gadolinium-based contrast agents (28). The assumption that contrast media must be compared exclusively in an equimolar fashion is reasonable from a stochiometric viewpoint but not from a clinical viewpoint. The purpose of clinical CT examinations is to achieve a certain dose of enhancement of vascular structures. As shown in this trial, use of a 1 mol/L gadobutrol solution achieves this goal as well as use of a standard 300 mg/mL iodine solution.

It is difficult to determine the exact volume of contrast media that will result in nephrotoxicity due to the multifactorial nature of this complication, and no one really knows how much contrast media can be administered safely in patients with renal insufficiency.

To our knowledge, there are no available published data that prove gadobutrol doses of up to 3.0 mL/kg are safe (corresponding to 3.0 mmol/kg); however, none of the animals used in this study showed signs of clinically relevant changes in hematologic, blood chemistry, or urine analysis results during the observation period. Markers for glomerular filtration and tubular function were not affected in any group. No morphologic changes in the renal parenchyma were found at histologic analysis. A limitation of our study was the small sample size and a potential lack of power to detect safety-related changes. Another limitation was that the animals did not suffer from renal insufficiency. Their kidney function was physiologically normal. It is difficult to create an animal model of renal insufficiency. This remains a drawback for any study on the evaluation of potential nephrotoxicity of contrast agents. Elmstahl et al (29) used complete temporary ischemia of a single kidney in a porcine model to simulate renal insufficiency. In their model, gadolinium chelates were more nephrotoxic than iohexol with an iodine concentration of 190 mg/mL (29).

In conclusion, our findings provide some preliminary answers to important clinical questions. However, prior to the routine use of gadobutrol in humans, further prospective clinical trials are needed to determine if use of larger gadobutrol volumes will be safe and will not be nephrotoxic.

Practical application: Intravenous administration of high doses of gadobutrol did not affect renal function in these animals. The results of the present investigation provide preliminary answers to important clinical questions regarding alternative contrast agents for CT.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   FOOTNOTES
 

Abbreviations: ROI = region of interest

Authors stated no financial relationship to disclose.

Author contributions: Guarantor of integrity of entire study, M.K.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, M.K., H.J.W.; experimental studies, M.K., K.G., M.G., M.R., A.P.; statistical analysis, M.K., M.G.; and manuscript editing, M.K., M.G., K.J.K., H.J.W.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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