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Multi–Detector Row CT Angiography of Pulmonary Circulation with Gadolinium-based Contrast Agents: Prospective Evaluation in 60 Patients¹

¹ From the Departments of Radiology (M.R., J. Bahepar, J. Bruzzi, J.R.), Pulmonology (J.J.L.), and Nephrology (P.D.), Calmette Hospital, University Center of Lille, Boulevard Jules Leclerc, 59037 Lille, France; Schering SA, Lys-Lez-Lannoy, France (O.E.); and Department of Medical Statistics, University of Lille, Lille, France (V.D., A.D.). Received December 11, 2004; revision requested February 4, 2005; revision received April 1; accepted April 15; final version accepted May 26. Address correspondence to M.R. (e-mail: mremy-jardin{at}chru-lille.fr).

	ABSTRACT

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

 
Purpose: To prospectively evaluate gadolinium dose safety and effectiveness for 16-detector pulmonary computed tomographic (CT) angiography.

Materials and Methods: Ethics committee approval and informed consent were obtained. Sixty patients with contraindications to iodine underwent CT of the pulmonary circulation with 0.5 mmol/L gadolinium chelate given at either 0.3 (n = 29, group A) or 0.4 (n = 31, group B) mmol/kg; clinical and biologic tolerances were evaluated. Enhancement of central and segmental pulmonary arteries was measured (poor enhancement, <100 HU; good, 100–150 HU; excellent, >150 HU). Subsegmental artery enhancement was assessed as similar or inferior to that of segmental arteries. Confidence in analysis of the pulmonary arterial bed was graded according to arterial enhancement: Grades 1–3, diagnostic images; grade 4, nondiagnostic. The main effectiveness parameter for comparison between groups A and B was diagnostic value of CT angiograms. Nonparametric statistics were used to analyze results.

Results: The mean (± standard deviation) contrast material volume was 50.09 mL ± 8.45 (all patients: range, 30–64 mL; group A: 46.54 mL ± 8.59; group B: 53.42 mL ± 6.92). Diagnostic images were obtained in 55 (92%) patients, and confident analysis of pulmonary arteries to the subsegmental level was achieved in 26 (grade 1, 44%) and to the segmental level, in 21 (grade 2, 35%). Mean attenuation was higher in group B than in group A in central (180.61 HU ± 53.85 vs 148.14 HU ± 52.61; P = .04) and segmental (201.59 HU ± 54.70 vs 164.73 HU ± 59.26; P = .03) arteries. Number of diagnostic CT angiograms was higher (P = .02) in group B (n = 31 [100%]) than in group A (n = 24 [83%]). In both groups, mean enhancement of pulmonary arteries was significantly higher at 80 or 100 kV than at 120 kV. Renal function was impaired in two group A patients.

Conclusion: Gadolinium chelates may be used as an alternative CT contrast agent in patients who cannot receive iodine.

© RSNA, 2006

	INTRODUCTION

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In patients with a history of either renal insufficiency or severe allergic reaction to iodinated contrast media, imaging examinations with iodinated contrast agents are increasingly being replaced with gadolinium-enhanced magnetic resonance (MR) examinations. However, MR imaging may not have the same diagnostic effect as contrast media–enhanced computed tomography (CT). This is of particular clinical importance when one considers the evaluation of pulmonary circulation, which is more precisely investigated with CT than with MR imaging (1,2).

Despite technologic advances in MR imaging, the spatial resolution of CT remains superior to that of MR imaging; this is a key factor in the precise depiction of endo- and perivascular abnormalities, especially at the level of small pulmonary vessels. Moreover, pulmonary circulation cannot be evaluated without concurrent analysis of the surrounding anatomic structures—particularly the lung parenchyma—at the level at which the cause of respiratory impairment can be found, which cannot be evaluated with MR imaging (2). As recently emphasized by Ley et al (1), MR imaging of the lung parenchyma is hampered mainly by three factors: (a) low proton density, which results in a low signal-to-noise ratio; (b) signal loss due to physiologic motion (cardiac pulsation and respiration); and (c) the unique combination of air and soft tissue that constitutes an inflated lung, which results in substantial susceptibility artifacts. In addition, CT can also enable detailed analysis of the collateral systemic blood supply to the lung, which develops in numerous pulmonary vascular diseases.

Use of a gadolinium-based contrast agent in CT angiographic evaluation of pulmonary circulation should have been the ideal alternative in patients with contraindications to iodinated contrast agents, as it has been known since 1989 that gadolinium-based contrast agents produce vascular enhancement on CT images (3). However, this approach was unrealistic for CT angiographic evaluation of pulmonary circulation with sequential or single–detector row CT technology because of the relatively long acquisition times. The advent of multi–detector row CT technology has renewed interest in the use of gadolinium-based contrast agents in the examination of the chest, with successful detection of acute pulmonary embolism on gadolinium-enhanced spiral CT images, as reported by Coche et al (4).

A recent study of 37 patients showed that it is possible to obtain diagnostic multi–detector row CT angiograms of pulmonary circulation by using gadolinium-based contrast agents; this finding emphasizes the contributions of recently developed CT technology in obtaining high-quality images (5). Comparing the overall image quality in two subsets of patients examined with four– or 16–detector row CT equipment, these authors demonstrated the superiority of 16–detector row CT technology, which led them to obtain levels of enhancement comparable to those achieved with iodinated contrast agents. The purpose of our study, therefore, was to prospectively evaluate the safety and effectiveness of gadolinium-enhanced 16–detector row CT angiography of the pulmonary circulation according to the gadolinium dose administered.

	MATERIALS AND METHODS

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Investigated Protocol
This study was initiated as a randomized single-center clinical trial aimed at investigating the effectiveness and safety of gadolinium-enhanced multi–detector row spiral CT angiography of pulmonary circulation.

This study was supported by Schering (Berlin, Germany); this company provided us with gadopentetate dimeglumine (Magnevist). A power injector was provided by Medrad (Pittsburgh, Pa); this enabled us to inject gadopentetate dimeglumine followed by a saline flush. Authors who are not employees of Schering (M.R., J. Bahepar, J.J.L., P.D., J. Bruzzi, V.D., A.D., J.R.) had control of all data and information that might have represented a conflict of interest for the author (O.E.) who is a Schering employee.

Patients who (a) had an indication for spiral CT angiography of pulmonary circulation for a diagnostic or follow-up purpose and (b) had a contraindication to the administration of iodinated contrast agents were eligible for inclusion in the present investigation. Exclusion criteria included clinical instability, pregnancy, breast feeding, age younger than 18 years, examination with iodinated contrast media performed or planned within 24 hours of gadolinium-enhanced CT, gadolinium-enhanced examination performed within 24 hours of the gadolinium-enhanced CT protocol, impossibility of peripheral vein catheterization with an 18-gauge catheter necessary for high-flow administration of gadolinium–based contrast material, history of hemolytic anemia, and severely impaired renal function with no possibility of hemodialysis. Vital signs, various laboratory serum parameters, and general tolerance were monitored to assess safety and tolerance of the gadolinium doses administered in this protocol. This protocol was approved by our institutional review board and ethics committee. Informed consent was obtained from all patients before they were included in this trial.

Population Studied
Between April 2002 and June 2004, 60 consecutive patients who met our study criteria (19 men, 41 women) were referred to the Department of Radiology, Calmette Hospital, to undergo gadolinium-enhanced multi–detector row spiral CT angiography of pulmonary circulation with a 16–detector row CT scanner. Findings in the first 18 patients who were examined were presented in a previous report that was based on a similar study design, including randomization of the administered dose of gadolinium (5).

The mean (± standard deviation) age of patients in the study group was 63 years ± 14 (age range, 19–84 years). All patients had relative or absolute contraindications to iodine-containing contrast media, including (a) preexisting impaired renal function (n = 27); (b) known intolerance to iodinated contrast agents (n = 14); (c) diabetes mellitus (n = 9); (d) previous history of severe anaphylactic reactions after drug (ie, aspirin, penicillin) administration, which is associated with a substantial incidence of life-threatening adverse events after administration of iodinated contrast media (n = 6); and (e) recent history of acute renal failure, with a return to normal renal function, leading the clinicians to favor gadolinium-based contrast material instead of iodine-based contrast material for CT angiography (n = 4). Previous history of intolerance to iodinated contrast media included severe allergic skin reactions (n = 6), laryngeal edema (n = 6), and anaphylactic reactions (n = 2); these patients received specific premedication, which consisted of oral corticosteroids and histamine, 24 hours before gadolinium-enhanced CT angiography.

The 27 patients at risk for iodinated contrast agent–induced nephrotoxicity had chronically elevated serum creatinine levels (>1.5 mg/dL [133 µmol/L]) and decreased creatinine clearance values (<70 mL/min). In this study, the nephrologist (P.D., 35 years of experience) graded chronic renal failure as moderate in six of 27 patients (ie, creatinine clearance of 50–70 mL/min), marked in 11 patients (ie, creatinine clearance of 30–50 mL/min), and severe in 10 patients (ie, creatinine clearance of less than 30 mL/min). None of these patients required chronic renal dialysis treatment. The cause of renal insufficiency was diabetic nephropathy in eight patients, drug-related renal failure in seven patients (chemotherapy, n = 5; iodine, n = 2), renal vascular disease in four patients, sequelae of hemodynamically mediated acute renal failure in one patient, multiple myeloma in one patient, and ureteral obstruction in the context of pelvic carcinoma in one patient. The cause of renal insufficiency was unknown in five patients. Despite the absence of renal insufficiency in nine patients, presence of diabetes mellitus in these patients was considered a risk factor for radiocontrast nephrotoxicity (6,7).

According to a computer-generated randomization list, all patients were assigned to receive a dose of either 0.3 mmol or 0.4 mmol per kilogram of body weight of 0.5 mol/L gadopentetate dimeglumine). These doses were chosen to administer a volume of gadolinium-based contrast agent sufficient for CT angiography of pulmonary circulation, while remaining in the range of doses previously reported, without side effects. Patients who received a dose of 0.3 mmol/kg of body weight are referred to as group A patients. Patients who received a dose of 0.4 mmol/kg of body weight are referred to as group B patients.

The randomization list was established by using the SAS plan procedure SAS Institute (Cary, NC). To reduce the chances of imbalance in the size of groups, we used blocks of six subjects. Blinded envelopes were prepared by the department of biostatistics and sent to the study coordinator. Envelopes were labeled from 1 to N (where N refers to the total sample size) in the same order as the randomization list. Information pertaining to the dose to be administered (group A or group B) was enclosed in each envelope. The indications for multi–detector row spiral CT angiography included (a) suspicion of acute pulmonary embolism (n = 40) or (b) pretherapeutic evaluation or follow-up of tumoral disease in close contact with hilar vessels (n = 20). In this second group, no attempt was made to characterize the level of soft-tissue enhancement. Patients with a history of an allergic-like syndrome to iodinated contrast agents received the usual preventive antihistamine and corticosteroid chemotherapy 48 hours before the examination.

CT Examination
Scanning protocol.—The limited maximum amount of gadolinium that could be administered, as well as the unpredictable contrast material travel time for each patient, required the investigators to reduce the z-axis coverage to the middle third of the thorax and to scan this region in the shortest period of time. The region examined extended from the level of the aortic arch to the level of the inferior pulmonary veins.

Gadolinium-enhanced CT angiography was systematically preceded by unenhanced CT scanning of the entire thorax; thus, a complete CT examination of the chest was performed. CT examinations were performed with a 16–detector row CT scanner (Sensation 16; Siemens, Forchheim, Germany) with the following parameters: 80–120 kV, 70–120 mAs, 0.5-second rotation time, 16.0 x 1.5-mm collimation, pitch of 1.5, and reconstruction of 2-mm-thick contiguous images. Because the attenuation of gadolinium increases with decreasing tube voltage (8), care was taken to select the lowest tube voltage setting available on the CT unit at the time of the examination; otherwise, tube voltage was adapted to the patient's body morphotype. Tube voltage was set at 100 kV (subsequently set at 80 kV) when the patient's weight was less than or equal to 70 kg (n = 19; four patients were scanned at 100 kV, and 15 were scanned at 80 kV) and at 120 kV when the patient's weight was greater than 70 kg (n = 41) with subsequent adaptation of the tube current. This modification of the CT protocol was directly linked to improvements in CT technology during this 27-month investigation (April 2002 to June 2004).

Because the availability of 100-kV tube voltage preceded that of 80-kV tube voltage on the previously mentioned CT equipment, the first four patients scanned with a "low kilovoltage setting" were scanned at 100 kV, while the remaining 15 patients were scanned at 80 kV. No dose reduction system was used for gadolinium-enhanced spiral CT examinations. Both unenhanced and gadolinium-enhanced spiral CT images were acquired in the craniocaudal direction. Contiguous mediastinal and lung images were systematically reconstructed with low- and high-spatial-frequency algorithms, respectively. All CT images were photographed at two window settings appropriate for viewing the lung parenchyma (window width, 1600 HU; window level, –600 HU) and mediastinum (window width, 350 HU; window level, 30 HU).

Administration of gadolinium.—Each patient received a gadolinium dose of either 0.3 or 0.4 mmol/kg. The corresponding volume of contrast material was administered with a power injector (Spectris; Medrad) at a flow rate of 6 mL/sec. The choice of this flow rate was reported previously in our preliminary experience with gadolinium-enhanced spiral CT of the pulmonary circulation (5). Gadolinium concentration of 0.5 mmol/mL shows approximately the same CT attenuation as that shown with iodinated contrast material with a concentration of 150 mg/mL (9). In a preliminary experience with single–detector row CT angiography of the pulmonary circulation, the administration of an iodinated contrast agent with a concentration of 120 mg/mL at a rate of 6 mL/sec enabled Remy-Jardin et al (10) to achieve good to excellent quality of pulmonary artery enhancement in the majority of cases. No attempt was made to modulate the flow rate according to the volume of contrast material administered in the absence of knowledge on the influence of this parameter on the level of arterial enhancement after administration of gadolinium. The injection of gadolinium-based contrast material was followed by a saline flush in all patients (15 mL of saline serum administered at 3 mL/sec). The use of the automatic bolus-triggering software program available on the CT unit (Care Bolus software; Siemens) was systematically applied, with a circular region of interest positioned at the level of the pulmonary artery trunk. The threshold for triggering data acquisition was preset at 50–70 HU. The length of time from reaching the bolus-triggering threshold to the start of scanning was 4 seconds.

Evaluation of Safety and Effectiveness of Gadolinium-enhanced Spiral CT
Safety.—Because adverse reactions have been reported after administration of gadolinium-based contrast agents (11), we systematically evaluated the patients' clinical and biologic tolerance of gadolinium. The occurrence of any adverse clinical event—such as sensation of warmth at the injection site, local pain (in case of gadolinium extravasation), or mild to severe allergic reactions that included nausea, vomiting, headaches, flush, allergic skin reaction, severe anaphylactic reaction, or convulsive attack—was recorded 24 hours after administration of gadolinium-based contrast material.

Biologic tolerance of gadolinium was assessed with blood samples obtained within 24 hours before (baseline) and 24 hours after administration of gadolinium-based contrast material. The latter time was chosen from various intervals reported in the literature to define contrast-induced nephropathy (12), in agreement with the nephrologist (P.D.) involved in the present investigation. Levels of creatinine, electrolytes, iron, and haptoglobin—as well as blood cell count and number of reticulocytes—were monitored in the serum.

To evaluate renal tolerance of gadolinium, the primary variable was the change in serum creatinine level after contrast material injection in patients with normal renal function and the change in creatinine clearance after contrast material injection in patients with preexisting renal impairment. In patients with normal renal function before CT angiography, an acute contrast material–induced reduction in renal function was defined as an increase in the serum creatinine concentration by at least 0.5 mg/dL (44.2 µmol/L) 24 hours after administration of the contrast agent. For patients with preexisting renal failure, a decrease of 10% or more in the serum creatinine clearance value within 24 hours after the examination defined an acute contrast material–induced reduction in renal function. The creatinine clearance was estimated with the Cocroft formula, as follows: [(140 – A) x W]/[7.2 x SCC], where A is patient age, W is patient weight, and SCC is serum creatinine concentration. In female patients, the result was multiplied by 0.85. In each patient, the volume of gadolinium administered was recorded systematically.

Effectiveness.—The CT parameters evaluated in the present investigation included measurement of the attenuation within (a) central pulmonary arteries, with a circular region of interest positioned successively in three central pulmonary arteries (the main pulmonary artery and the right and left interlobar pulmonary arteries [average size of the region of interest, 1.5 cm²]) (the mean value of the three measurements defined the level of enhancement within the central pulmonary arteries) and (b) segmental pulmonary arteries, with a circular region of interest positioned successively in the anterior segmental artery of the right and left upper lung lobes and in the posterobasal segmental artery of the right and left lower lung lobes (average size of the region of interest, 0.15 cm²). The mean value of these four measurements defined the attenuation within segmental pulmonary arteries. These arteries were chosen because of their horizontal and vertical orientations to the planes of reconstruction, a priori excluding partial volume effects on these vascular sections and erroneous measurements of attenuation.

On the basis of our preliminary experience with a 16–detector row CT scanner demonstrating the absence of any gradient of pulmonary artery enhancement from top to bottom of the volume scanned, we assumed that the previously mentioned measurements would provide information on the level of enhancement within the segmental pulmonary arterial bed. Care was taken to verify this assumption in each CT examination prior to the measurement of attenuation. Measurements at the level of the subsegmental divisions of the segmental arteries of interest were not performed because of the small size of the vascular sections and the risk of erroneous attenuation measurements. Attenuation at the subsegmental level was therefore categorized as similar to or inferior to that observed at the segmental level, as described previously. A radiologist (M.R., 15 years of experience in chest CT) measured the region of interest, with no image magnification, obtained in all gadolinium-enhanced CT examinations. These measurements were obtained after data acquisition from each CT angiogram during the clinical care of each patient. The interval between these measurements and rating of CT angiograms ranged from several weeks to 2 years.

The attenuation within central and segmental pulmonary arteries was separately graded as excellent when greater than 150 HU; good when between 100 and 150 HU; or poor when less than 100 HU. According to the attenuation observed within the central, segmental, or subsegmental pulmonary arteries, readers rated the level of confidence in analyzing the pulmonary arterial bed. Namely, readers rated the ability to confidently depict endoluminal abnormalities, perivascular abnormalities, or both with a four-point scale, as follows: (a) grade 1, confident analysis of pulmonary arteries was possible to the subsegmental level because of good or excellent attenuation within central, segmental, or subsegmental pulmonary arteries; (b) grade 2, confident analysis of pulmonary arteries was possible to the segmental level because of good or excellent attenuation within central or segmental pulmonary arteries, with poor opacification of subsegmental arteries; (c) grade 3, confident analysis was limited to the main and lobar pulmonary arteries because of good attenuation within central pulmonary arteries and poor opacification beyond this anatomic level; and (d) grade 4, poor level of opacification within central and segmental pulmonary arteries, precluding depiction of endoluminal abnormalities, perivascular abnormalities, or both. Grade 1, 2, or 3 images were considered sufficient for diagnostic purposes, whereas grade 4 images were considered insufficient. The main effectiveness parameter for the comparison of image quality between groups A and B was the diagnostic value of the CT angiograms (ie, the number of diagnostic CT angiograms). For each examination, we systematically recorded the z-axis coverage and duration of data acquisition.

Conditions of evaluation of clinical, biologic, and CT parameters.—During this investigation, clinical and biologic tolerance of gadolinium-enhanced multi–detector row spiral CT angiography was first investigated by the radiologist in charge of the examination and subsequently investigated by the referring physician. Each patient's clinical and biologic results were systematically recorded on a case report form by the principal investigator (M.R.). To assess immediate general clinical tolerance of gadolinium-enhanced multi–detector row spiral CT angiography, patients were closely observed during the examination and were nonsuggestively questioned about their health at the end of the CT examination and approximately 30 minutes after injection. Patients were blinded to the dose of gadolinium administered. CT findings were prospectively interpreted during the course of clinical work-up by the principal investigator as part of patient care.

In the present study, gadolinium-enhanced CT findings were reinterpreted by two radiologists (M.R., a faculty radiologist with 15 years experience with chest CT angiography; J.Bahepar, a fellow with 5 years experience with CT) working in consensus. These readers were not blinded to the differences in CT scanning protocols (tube current and tube voltage settings). They were, however, blinded to the gadolinium dose administered and to clinical data, particularly the presence of renal dysfunction at the time of CT angiography. The rating of CT angiograms by these readers was assessed in consensus by using reference images depicting the four image grades defined in our protocol. Prospective analysis of the biologic tolerance of gadolinium was performed by a nephrologist (P.D.) who was blinded to the injected dose of gadolinium.

Statistical Analysis
In this pilot study, there were no data available to estimate the differences between groups A and B with regard to the safety and effectiveness of gadolinium-enhanced spiral CT; subsequently, a reliable sample size could not be defined a priori. We chose to include 60 patients (ie, two groups of 30 patients); we considered this a compromise between the cost of recruitment and the power of the study.

Statistical analysis was performed with commercially available software. Data were expressed as means ± standard deviations for continuous variables and as frequencies or percentages for categorical variables. Percentages were compared with the ² or Fisher exact test. Stratified analysis was performed with the Cochran-Mantel-Haenszel test. For numerical variables, comparisons between groups A and B were performed as follows: The assumption of normality was first assessed with the Shapiro-Wilk test. When this assumption was accepted, an unpaired Student t test was used; when this assumption was rejected, an unpaired Wilcoxon rank sum test was used. All other comparisons were performed with either the unpaired Wilcoxon rank sum test or the Kruskal-Wallis test. A P value of less than .05 was considered to indicate a significant difference.

	RESULTS

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Effectiveness of Gadolinium-enhanced Spiral CT
Effectiveness in the overall population studied.—In the overall study group, (a) the mean volume of gadolinium-based contrast material administered was 50.09 mL ± 8.45 (range, 30–64 mL), (b) the mean z-axis coverage was 133.01 mm ± 48.19 (range, 50–278 mm), and (c) the mean duration of data acquisition was 1.79 seconds ± 0.56 (range, 0.69–3.86 seconds). The mean attenuation within central pulmonary arteries was 164.92 HU ± 55.28 (range, 51.93–294.33 HU). The mean attenuation within segmental pulmonary arteries was 183.48 HU ± 59.45 (range, 33.10–331.00). The pulmonary arterial bed was confidently analyzed to the subsegmental level in 26 patients (grade 1, 44%) and to the segmental level in 21 patients (grade 2, 35%). Confident interpretation was limited to central pulmonary arteries in eight patients (grade 3, 13%), and five studies were nondiagnostic (grade 4, 8%). A total of 55 CT angiograms (92%) were classified as diagnostic (ie, grade 1, 2, or 3 images), whereas five (8%) were classified as nondiagnostic (ie, grade 4 images). A significant difference (P < .001) was found between the mean attenuation within the central pulmonary artery and the mean attenuation within the segmental pulmonary artery when comparing grade 1 CT angiograms with grade 3 CT angiograms (Table 1) (Kruskal-Wallis test).

View larger version (125K): [in this window] [in a new window] [Download PPT slide]   Figure 1: Transverse gadolinium-enhanced CT angiogram at level of right middle lobe bronchus in a 72-year-old man with a history of anaphylactic reaction to penicillin (weight, 70 kg; height, 168 cm) to follow-up right-sided mesothelioma (80 kV; 80 mAs; gadolinium dose, 0.3 mmol/kg; volume administered, 42 mL). Image shows excellent opacification of pulmonary arteries (right lower lobe pulmonary artery [large arrow], 265 HU; left lower lobe segmental pulmonary arteries [small arrows], 237 HU), which enables precise delineation of the right hilar tumoral extent. Note excellent degree of opacification of aorta, pulmonary veins, and left atrium, as well as additional presence of right lung retraction and abnormal right pleural thickening ().

View larger version (125K): [in this window] [in a new window] [Download PPT slide]   Figure 2a: Transverse gadolinium-enhanced multi–detector row CT angiograms obtained in a 75-year-old man (weight, 57 kg; height, 172 cm) for follow-up of right upper lobe carcinoma in the context of chemotherapy-related renal failure (80 kV; 80 mAs; gadolinium dose, 0.4 mmol/kg; volume administered, 46 mL). Scans obtained at the levels of the (a) carina and (b) right bronchus intermedius show excellent opacification of central () (273 HU) and peripheral (segmental [large arrow] and subsegmental [small arrows]) (277 HU) pulmonary arteries despite the presence of large pericardial and bilateral pleural effusions.

View larger version (124K): [in this window] [in a new window] [Download PPT slide]   Figure 2b: Transverse gadolinium-enhanced multi–detector row CT angiograms obtained in a 75-year-old man (weight, 57 kg; height, 172 cm) for follow-up of right upper lobe carcinoma in the context of chemotherapy-related renal failure (80 kV; 80 mAs; gadolinium dose, 0.4 mmol/kg; volume administered, 46 mL). Scans obtained at the levels of the (a) carina and (b) right bronchus intermedius show excellent opacification of central () (273 HU) and peripheral (segmental [large arrow] and subsegmental [small arrows]) (277 HU) pulmonary arteries despite the presence of large pericardial and bilateral pleural effusions.

View larger version (125K): [in this window] [in a new window] [Download PPT slide]   Figure 3a: Transverse gadolinium-enhanced multi–detector row CT angiograms obtained in a 64-year-old man (weight, 88 kg; height, 175 cm) suspected of having acute pulmonary embolism in the context of lung carcinoma and chemotherapy-related renal failure (120 kV; 100 mAs; gadolinium dose, 0.3 mmol/kg; volume administered, 53 mL). Scans obtained at the levels of the (a) tracheal bifurcation, (b) right bronchus intermedius, and (c) lower lobes show the overall good level of enhancement within pulmonary arteries (pulmonary trunk, 124 HU), which enables depiction of numerous filling defects (arrows) (72 HU) surrounded by contrast-enhanced blood (142–162 HU).

View larger version (129K): [in this window] [in a new window] [Download PPT slide]   Figure 3b: Transverse gadolinium-enhanced multi–detector row CT angiograms obtained in a 64-year-old man (weight, 88 kg; height, 175 cm) suspected of having acute pulmonary embolism in the context of lung carcinoma and chemotherapy-related renal failure (120 kV; 100 mAs; gadolinium dose, 0.3 mmol/kg; volume administered, 53 mL). Scans obtained at the levels of the (a) tracheal bifurcation, (b) right bronchus intermedius, and (c) lower lobes show the overall good level of enhancement within pulmonary arteries (pulmonary trunk, 124 HU), which enables depiction of numerous filling defects (arrows) (72 HU) surrounded by contrast-enhanced blood (142–162 HU).

View larger version (145K): [in this window] [in a new window] [Download PPT slide]   Figure 3c: Transverse gadolinium-enhanced multi–detector row CT angiograms obtained in a 64-year-old man (weight, 88 kg; height, 175 cm) suspected of having acute pulmonary embolism in the context of lung carcinoma and chemotherapy-related renal failure (120 kV; 100 mAs; gadolinium dose, 0.3 mmol/kg; volume administered, 53 mL). Scans obtained at the levels of the (a) tracheal bifurcation, (b) right bronchus intermedius, and (c) lower lobes show the overall good level of enhancement within pulmonary arteries (pulmonary trunk, 124 HU), which enables depiction of numerous filling defects (arrows) (72 HU) surrounded by contrast-enhanced blood (142–162 HU).

View larger version (99K): [in this window] [in a new window] [Download PPT slide]   Figure 4a: Transverse gadolinium-enhanced multi–detector row CT angiograms obtained in a 51-year-old woman (weight, 57 kg; height, 160 cm) suspected of having acute pulmonary embolism in the context of previous laryngeal edema after administration of iodinated contrast material (80 kV; 80 mAs; gadolinium dose, 0.3 mmol/kg; volume administered, 34 mL). Scans obtained at the levels of the (a) right bronchus intermedius, (b) right middle lobe bronchus, and (c) lower lung lobes depict almost complete filling defects at the level of the right pulmonary arterial bed (arrow). Note the presence of pseudo–filling defects within left-sided pulmonary arteries, which are most likely to be linked to image noise and dilution of gadolinium from unenhanced blood owing to the limited amount of gadolinium-based contrast material administered.

View larger version (99K): [in this window] [in a new window] [Download PPT slide]   Figure 4b: Transverse gadolinium-enhanced multi–detector row CT angiograms obtained in a 51-year-old woman (weight, 57 kg; height, 160 cm) suspected of having acute pulmonary embolism in the context of previous laryngeal edema after administration of iodinated contrast material (80 kV; 80 mAs; gadolinium dose, 0.3 mmol/kg; volume administered, 34 mL). Scans obtained at the levels of the (a) right bronchus intermedius, (b) right middle lobe bronchus, and (c) lower lung lobes depict almost complete filling defects at the level of the right pulmonary arterial bed (arrow). Note the presence of pseudo–filling defects within left-sided pulmonary arteries, which are most likely to be linked to image noise and dilution of gadolinium from unenhanced blood owing to the limited amount of gadolinium-based contrast material administered.

View larger version (98K): [in this window] [in a new window] [Download PPT slide]   Figure 4c: Transverse gadolinium-enhanced multi–detector row CT angiograms obtained in a 51-year-old woman (weight, 57 kg; height, 160 cm) suspected of having acute pulmonary embolism in the context of previous laryngeal edema after administration of iodinated contrast material (80 kV; 80 mAs; gadolinium dose, 0.3 mmol/kg; volume administered, 34 mL). Scans obtained at the levels of the (a) right bronchus intermedius, (b) right middle lobe bronchus, and (c) lower lung lobes depict almost complete filling defects at the level of the right pulmonary arterial bed (arrow). Note the presence of pseudo–filling defects within left-sided pulmonary arteries, which are most likely to be linked to image noise and dilution of gadolinium from unenhanced blood owing to the limited amount of gadolinium-based contrast material administered.

Tables 7 and 8 show renal tolerance of the gadolinium dose administered. In group A, 15 patients had normal renal function before gadolinium-enhanced CT angiography and 14 had preexisting renal insufficiency. In Group B, 18 patients had normal renal function before gadolinium-enhanced CT angiography and 13 had preexisting renal insufficiency.

No variations in hematologic results or clinical chemistry values were found in the studied population during the observation period, with the exception of one patient. This patient had severe renal failure, and laboratory tests performed in the months before CT angiography revealed a chronic borderline kalemia value of 4.9 mEq/L (4.9 mmol/L) (upper limit of normal value, 5 mEq/L [5 mmol/L]). He experienced transient increase in the kalemia value 24 hours after administration of gadolinium (5.3 mEq/L [5.3 mmol/L]).

	DISCUSSION

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

 
On the basis of the results of our investigation involving 60 patients examined with a 16–detector row CT scanner, we conclude that gadolinium-based contrast agents should be considered as alternative contrast material for CT angiography of pulmonary circulation in patients with contraindications to traditional iodinated contrast agents. Fifty-five (92%) of the 60 CT angiographic examinations performed with gadolinium-based contrast agents yielded good or excellent vascular enhancement and enabled radiologists to provide clinicians with diagnostic information in this population. These results confirm the findings of a preliminary study, in which the authors showed that gadolinium-based contrast agents could provide a quality of vascular enhancement of pulmonary circulation similar to that provided by iodinated contrast agents, thus yielding satisfactory diagnostic studies with a 16–detector row CT system (5).

The findings of gadolinium-enhanced CT angiography of pulmonary circulation contradict previous statements that administration of gadolinium-based contrast media in approved intravenous doses (up to 0.3 mmol/kg) will not yield radiologic information sufficient for diagnosis in most cases (13). Twenty-four (83%) CT angiograms in group A and 31 (100%) CT angiograms in group B were rated as diagnostic. Because the overall quality of vascular enhancement influences the diagnostic value of CT angiograms, we stratified the level of confidence in depicting endovascular abnormalities, perivascular abnormalities, or both on CT images into four categories.

It is noteworthy that there was confident analysis of pulmonary circulation to the segmental level in 21 patients (grade 2 CT images, 30%) and to the subsegmental level in 26 patients (grade 1 CT images, 43%), with levels of arterial opacification comparable to those of iodinated contrast-enhanced CT angiograms. The practical implication is that gadolinium-enhanced CT angiography—with a diagnostic performance that is comparable to that of iodine-enhanced CT angiography—should be considered an alternative to iodine-enhanced CT angiography in the diagnostic work-up of acute pulmonary embolism in high-risk patients (14–16).

In the studied population, 40 patients (67%) were referred for evaluation because they were suspected of having acute pulmonary embolism. In these patients, five studies were considered suboptimal; 35 were considered diagnostic and enabled identification of endoluminal clots within central and segmental pulmonary arteries in two patients and exclusion of acute pulmonary embolism in 33 patients. Among the 33 patients with negative CT angiograms, confident interpretation of findings in both central and peripheral pulmonary arteries was possible in 26 (79%), whereas confident interpretation was limited to central arteries in seven (21%). It is notable that all CT angiograms obtained to evaluate tumoral disease in close contact with pulmonary vessels were rated as diagnostic, with confident analysis of the pulmonary arterial bed to the subsegmental level in 13 patients (65%) and to the segmental level in six (30%). The role of gadolinium-enhanced CT angiography in the pretherapeutic or follow-up evaluation of patients with thoracic tumoral disease and contraindications to iodinated contrast agents has yet to be established.

The overall image quality and the diagnostic value of gadolinium-enhanced CT angiograms were influenced by two parameters: the dose of gadolinium administered to the patient and the tube voltage used for image acquisition. Because the gadolinium dose that provides the best image quality at CT angiography of pulmonary circulation has not been established, we compared the highest approved doses for MR imaging (0.3 mmol/kg and 0.4 mmol/kg), both of which had already been administered and did not cause any side effects (17–20). The decision to administer higher doses of gadolinium than those usually used for contrast-enhanced MR imaging (which range between 0.1 and 0.2 mmol/kg) (13) was dictated by the technical requirements of CT angiography. CT angiography cannot be performed with excessively small amounts of contrast material.

Luboldt et al (21) emphasized the need for careful coordination between the injection and examination times. We observed that the mean attenuation within central and segmental pulmonary arteries was significantly higher in group B than in group A, with a significantly higher rate of diagnostic examinations. Although individual parameters may also account for overall image quality, it is likely that the greater dose of gadolinium and the significantly higher volume of gadolinium-based contrast material administered in group B compared with that administered in group A (53 vs 46 mL, P = .001) has favorably influenced overall image quality in group B.

Despite the lack of a statistically significant difference in the weight of patients in groups A and B, the limited number of patients included in the present study requires a more nuanced interpretation of mean patient weight in both groups. Our results suggest a trend for the mean weight of group A patients to be greater than that of group B patients; this did not negatively influence the magnitude of differences in attenuation between the groups. Comparing the attenuation within central and segmental pulmonary arteries in group A patients with that in group B patients, we observed that the values in patients scanned at 80 or 100 kVp were significantly higher than those in patients scanned at 120 kVp. It was possible to examine patients with a low tube voltage setting in only the last 6 months of this investigation, starting with the availability of the 100-kV setting and followed by the availability of an 80-kV setting. This accounts for the limited number (19 of 60 examinations) of examinations performed at 80 or 100 kVp.

Schmitz et al (8) demonstrated that the attenuation of both iodine and gadolinium decreased with increasing tube voltage when measured from 80 to 137 kV and that this decrease was more pronounced for iodine. The higher attenuation of gadolinium is caused mainly by photoelectric interaction of higher energetic photons and has been described in the literature (3,22–24). In the present investigation, the higher attenuation observed on CT images obtained with low tube voltage was independent from the weight of patients in group A. However, it should be mentioned that the superior attenuation observed in group B patients examined with a low tube voltage might have been influenced by patient weight, as these patients received a significantly higher volume of gadolinium per kilogram of body weight compared with group B patients scanned at 120 kV. Although the contrast between gadolinium-enhanced pulmonary vessels and their surrounding structures is increased with the use of a lower tube voltage, one should mention the associated increase in image noise, which might alter lesion conspicuity as a result of the lowering of the overall contrast-to-noise ratio. This aspect was not specifically investigated in this study and requires further investigation before definitive conclusions regarding the diagnostic value of gadolinium-enhanced CT angiograms of pulmonary circulation are drawn.

Because the administered doses were not formally approved, it was necessary to evaluate clinical and biologic tolerance. With regard to clinical tolerance, no side effect was reported either immediately after the examination or at subsequent follow-up. We encountered no allergic reactions in the 14 patients with a known history of allergic reaction to iodine. Renal tolerance of the gadolinium dose administered was the second major issue. The literature suggests that a gadolinium dose of 0.3–0.4 mmol/kg has been safely administered—both intravenously and intrarterially—for CT, angiography, and interventional procedures (25). To our knowledge, however, there is no documented experience with systematic evaluation of renal tolerance of unapproved doses of gadolinium administered for non–MR imaging applications. We encountered no change in renal function in the 33 patients with normal renal function, whether they received a gadolinium dose of 0.3 mmol/kg or 0.4 mmol/kg. These results confirm the excellent patient tolerance of these gadolinium doses when renal function is normal (17,26,27).

A total of 27 patients were referred for gadolinium-enhanced CT angiography because of chronic renal insufficiency and were considered at risk for iodinated contrast material–induced nephrotoxicity. Among them, two patients showed a significant decrease in creatinine clearance 24 hours after administration of gadolinium. Both patients were classified as having marked preexisting renal insufficiency and had received a gadolinium dose of 0.3 mmol/kg. In one patient, gadolinium-based contrast material–induced renal failure was observed with a transient decrease in the creatinine clearance that returned to baseline renal function within 2 days. In the other patient, gadolinium-induced nephrotoxicity was observed in the context of a fulminant hepatic carcinoma; this patient died of multiorgan failure within 24 hours. These preliminary results in a small group of patients confirm previous findings in the literature.

In patients with renal insufficiency, intravenous administration of gadopentetate dimeglumine at doses of up to 0.4 mmol/kg for MR imaging was not found to induce nephrotoxicity (4,18,28). Moreover, in four patients with renal insufficiency, a gadoversetamide dose of 0.5 mmol/kg resulted in no adverse effect on renal function (19). The limited numbers of patients in our experience and in the literature preclude us from drawing any definitive conclusion on the safety of these higher doses. In addition, one should note the potential underestimation of gadolinium-induced renal dysfunction in our study group that was due to the criterion selected for assessment of contrast material–induced insufficiency (ie, 24 hours after CT).

Further research should take into account recent developments in multi–detector row CT technology and the introduction of concentrated (1.0 mol/L) gadolinium chelates, which have been reported to be well tolerated, even in patients with severely reduced renal function (29). However, cautious management of chronic renal insufficiency aimed at avoiding contrast material–induced renal damage should not mean that other ways of minimizing the side effects of iodinated contrast agent administration in patients with altered renal function should be overlooked. In this specific subset of patients, special treatment—such as prehydratation and administration of mannitol and furosemide—has been reported to ameliorate contrast material–induced reductions in renal function (30).

Tepel et al (31) reported that prophylactic administration of the antioxidant acetylcysteine and hydration prevented the reduction in renal function induced by a nonionic low-osmolality iodinated contrast agent in patients with renal insufficiency. The debate has recently been enlarged because of the findings of a prospective randomized multicenter study, in which the likelihood of contrast material–induced nephropathy in high-risk patients was significantly reduced when an iso-osmolar iodinated contrast medium was used instead of a low-osmolar nonionic iodinated contrast medium (32). Thus, there is a need to evaluate such different approaches to define the optimal means of preventing renal damage caused by the administration of iodinated or gadolinium-based contrast agents in patients with chronic renal insufficiency.

Several limitations of the present investigation should be emphasized. First, our results are derived from analysis of findings in a limited number of patients, and they need to be confirmed in a larger series of patients. Second, CT angiography was not used to scan the entire chest; thus, the apices and lung bases—namely, the anatomic regions where small clots can be found in patients suspected of having acute pulmonary embolism—were not scanned. Moreover, we did not have a reference standard for the diagnosis of pulmonary embolism; thus, we could not determine the accuracy of gadolinium-enhanced CT angiography in the detection of pulmonary embolism, especially at the subsegmental level. Third, alteration of renal function after administration of gadolinium-based contrast material was evaluated 24 hours after injection of the contrast agent, so we may have underestimated the nephrotoxic effect of gadolinium. However, careful follow-up data of renal function were systematically obtained in all patients with renal insufficiency in the context of clinical follow-up by nephrologists.

We conclude that gadolinium may be used as an alternative CT contrast agent in patients who cannot receive iodinated contrast agents and in whom contrast-enhanced CT is the examination of choice; we recommend that a gadolinium dose of 0.4 mmol/kg be administered to ensure the best image quality. While the cost of gadolinium-based contrast agents might prohibit their routine use, this cost might be justified in selected clinical studies. Moreover, the subgroup of patients who cannot receive iodinated contrast agents and who have contraindications to MR imaging—such as the presence of cardiac pacemakers, defibrillators, or other implantable devices—could also benefit from gadolinium-enhanced CT scanning.

	ADVANCES IN KNOWLEDGE

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

 

• Gadolinium-enhanced CT angiography of the pulmonary circulation with a 16–detector row system yields diagnostic radiologic information.
  
• Gadolinium may be used as an alternative CT contrast agent in patients who cannot receive iodinated contrast agents and in whom contrast-enhanced CT is the examination of choice.
  
• A dose of 0.4 mmol gadolinium per kilogram of body weight ensures the best image quality.
  

	FOOTNOTES

 
See Materials and Methods for pertinent disclosures.

Author contributions: Guarantors of integrity of entire study, M.R., J. Bruzzi, J.R.; 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.R., J. Bruzzi, J.R.; clinical studies, M.R., J. Bahepar, J.J.L., P.D., O.E.; statistical analysis, V.D., A.D.; and manuscript editing, M.R., J. Bruzzi, J.R.

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

 

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