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Pulmonary Embolism: Prospective Comparison of Iso-osmolar and Low-Osmolarity Nonionic Contrast Agents for Contrast Enhancement at CT Angiography¹

¹ From the Department of Radiology, Centre Hospitalier Universitaire de Sherbrooke (CHUS), 3001 12^e Ave Nord, Local 2525, Sherbrooke, Quebec, Canada J1H 5N4. Received November 10, 2003; revision requested February 3, 2004; revision received April 6; accepted May 24. Address correspondence to J.P.B. (e-mail: Raddiagn-Med@USherbrooke.ca).

	ABSTRACT

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PURPOSE: To prospectively evaluate contrast enhancement on pulmonary computed tomographic (CT) angiograms obtained by using an iso-osmolar versus a low-osmolarity contrast agent to exclude pulmonary embolism.

MATERIALS AND METHODS: Written patient consent was obtained on a form approved by the institutional review board, and the board approved the study. This prospective, randomized, double-blinded clinical trial included 47 patients referred for multi–detector row CT angiography to exclude pulmonary embolism over a 5-month period. Patients received either iohexol or iodixanol as an intravenous contrast agent. Three radiologists independently evaluated enhancement homogeneity and quality in designated pulmonary artery branches at four consecutive levels in the lower lobe of the left lung from lobar to subsegmental arteries. This evaluation was performed at a workstation separately for homogeneity and quality with two different three-level scales established with consensus. Percentages of each given score were compared with the ² test. The mean attenuation (expressed in Hounsfield units) for each contrast agent was compared with Student t test, and interobserver agreement ( value) was calculated.

RESULTS: The percentages of arteries graded as excellent or not diagnostic were not statistically different (P > .05), with comparison of the two contrast agents at all levels. The intensity of enhancement (quantitative evaluation of enhancement by using mean attenuation of vessel lumen) was similar (P > .05) in the two groups. The values varied from 0.35 to 0.56 among readers.

CONCLUSION: Use of an iso-osmolar contrast agent at multi–detector row CT angiography to exclude pulmonary embolism did not significantly improve enhancement quality when this feature was compared with that of a low-osmolarity contrast agent.

© RSNA, 2005

	INTRODUCTION

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Pulmonary embolism is a common disorder with substantial morbidity and mortality and is associated with an unreliable clinical manifestation (1,2). This is why great efforts have been made to develop more efficient diagnostic tools, particularly in imaging. Spiral and multi–detector row computed tomography (CT), which allow better visualization of subsegmental arteries, have been rapidly consolidated in their role in the investigation of pulmonary embolism (3–7).

The effect of the most recently developed contrast agents, the nonionic iso-osmolar agents, for exclusion of pulmonary embolism at CT has not been studied. These agents arenonionic dimers with an osmolarity equal to that of plasma, and the osmolarity of nonionic iso-osmolar agents is two to three times lower than that of the widely used low-osmolarity agents. This characteristic gives the iso-osmolar agents several theoretical and observed advantages, and these advantages influence the choice of contrast agent to be used, with consideration that they are approximately 50% more expensive than low-osmolarity agents. The rates of injection-related pain (8–10) and of secondary renal insufficiency in high-risk patients are markedly lower (11,12). Theoretically, contrast agent dilution in plasma should be decreased with iso-osmolar contrast agents as a result of their molecular properties. The purpose of our study, therefore, was to prospectively evaluate contrast enhancement on CT angiograms obtained by using an iso-osmolar versus a low-osmolarity contrast agent to exclude pulmonary embolism.

	MATERIALS AND METHODS

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Patient Population
Between February and June 2003, 51 consecutive patients were included in this study. They were referred to our university hospital for pulmonary CT angiography because they were suspected of having an acute pulmonary embolism. Written consent was obtained on a form approved by the institutional review board, and the board also approved our study. Two patients were excluded because of technical problems with their examination. Two additional patients with emboli in both lower lobes were excluded, since the assessment of pulmonary artery enhancement was made in the normal arterial system of the lower lobe of either the left lung or the right lung.

Assuming any type of statistical data distribution, we calculated the power of the study to be at least 80% with a sample size of 50 patients. Because there was no similar study published in the literature, data distribution could not be estimated, and a complete power analysis was not performed.

Thus, our study included 47 patients (age range, 22–89 years; mean age, 57.2 years), 27 of whom were women (age range, 22–89 years; mean age, 57.3 years) and 20 of whom were men (age range, 23–75 years; mean age, 57.0 years). Twenty-two patients were assigned to receive iohexol (Omnipaque 240; Amersham Health, Oakville, Canada), and 25 were assigned to receive iodixanol (Visipaque 270; Amersham Health) according to a table of random numbers. Patients in the iohexol group included 12 women and 10 men, and those in the iodixanol group, 15 women and 10 men. No significant difference was demonstrated between the two groups in regard to the demographic characteristics (P > .05). Respiratory rate, heart rate, and oxygen saturation were measured by a CT technician immediately before the examination to characterize each patient, as well as to evaluate the similarity of the two groups.

CT Scanning Techniques
CT angiography was performed with a four-section CT scanner (Aquilion; Toshiba Canada, Kirkland, Canada), according to a standard single-breath-hold protocol (200 mA, 100 mAs, 120 kV). Section thickness was 2 mm, with 3-mm reconstructions every 1.5 mm, a pitch of 1.25 at 0.5 second per gantry rotation, and a total scanning time of 12–15 seconds. The imaging field of view spanned from the pulmonary apex to the diaphragm, and scans were acquired in a craniocaudal direction (4). The volume of contrast agent injected was calculated to provide an equal quantity of iodine. One hundred milliliters of a low-osmolarity contrast agent, iohexol, or 90 mL of an iso-osmolar contrast agent, iodixanol, was injected, with a total of 24 or 24.3 g of iodine, respectively. With an automatic injector (EnvisionCT; Medrad, Indianola, Pa), we controlled the contrast agent injection at a rate of 3 mL/sec via an antecubital catheter of preferably at least 20 gauge. To ensure optimal enhancement independently of cardiac output parameters and location of the injection site, we used a bolus-tracking device (Sure-Start; Toshiba Canada).

Image Interpretation
The assigned radiologist read the CT angiograms, as usual, for care of the patient, apart from this study. A Digital Imaging and Communications in Medicine image file was archived on a CD-ROM without multiplanar reconstructions. The digital images were then independently interpreted by three designated radiologists, who were blinded to each other’s interpretation and to that of the assigned radiologist, which was not included in the results. These radiologists were two chest radiologists with 12 and 14 years of experience in chest CT and one angiographer with 3 years of experience in vascular imaging. They each evaluated the quality of vascular enhancement at four specific levels of the pulmonary arteries of the lower lobe of the left lung, namely the lobar artery, one segmental (posterobasal) artery, and two subdivisions of this segmental artery (posterior and mediobasal ramus), according to the Boyden nomenclature (13). If an embolus was identified in the lower lobe of the left lung, the equivalent arteries of the lower lobe of the right lung were used instead.

It was decided to evaluate the pulmonary arteries of the lower lobe, since the majority of pulmonary emboli are found in this location. After the main investigator (J.P.B.) reviewed 10 cases in which pulmonary CT angiography was used but which were not included in the study, it was noted that there was less anatomic variation in the pulmonary vascular tree in the lower lobe of the left lung than there was in the lower lobe of the right lung. This finding prompted the decision to evaluate the arteries in the lower lobe of the left lung rather than those in the lower lobe of the right lung.

For the first 28 patients, readers themselves had to choose the sections that contained the arteries in which vascular enhancement was to be graded. Prior to the first reading session, readers were shown how to correctly identify the arteries that were to be evaluated for the study in 10 cases in which CT angiography was used but which were not included in the study. For the 19 subsequent patients, the main investigator, blinded to the contrast agent used, identified the sections that showed the arteries to evaluate. This procedure was followed to alleviate the burden of the reading session and maintain a narrow interobserver difference.

Evaluation of vascular enhancement was performed with a 1200 x 1600 high-definition workstation (Barco, Kortrijk, Belgium) by using software (Merge eFilm, Milwaukee, Wis). The readers were encouraged to adjust window level and width. Global quality of enhancement was assessed at four levels of the pulmonary vascular tree as either good to excellent, limited but of diagnostic value, or not diagnostic. Good to excellent enhancement corresponded to a definitely optimal enhancement to allow confident diagnosis of the presence or absence of a clot, whereas limited but of diagnostic value enhancement was not optimal but correct enough to allow the diagnosis of the presence or absence of a clot. The enhancement was considered not diagnostic if it was inadequate to allow a diagnosis of the presence or absence of a clot (Fig 1). Homogeneity of vascular enhancement was graded on a scale from 1 to 3 by using a template obtained from CT angiographic examinations performed prior to the study. A score of 1 corresponded to an entirely homogeneous appearance of the vessel; a score of 2, to a dotted appearance, in which distinct dots were seen; and a score of 3, to a streaky appearance (Fig 2). Homogeneity and quality scales were based on defined criteria obtained with the consensus of the three readers, with the main objective of achieving representative criteria of clinical evaluation. The quality and homogeneity scales were established prior to the study and were illustrated on a template. Each score on the scale was linked to images from 10 CT angiographic examinations performed in patients who were not included in the study. Images on the template were also taken from those examinations. Readers had to review all selected examples for each level of the scale before every reading session to maintain calibration throughout the reading session.

View larger version (49K): [in this window] [in a new window] [Download PPT slide]   Figure 1a. Images show template of the quality scale used in the evaluation of pulmonary arteries. (a) Artery with good to excellent enhancement (arrow). (b) Artery with enhancement that was limited but of diagnostic value (arrow). (c) Artery with enhancement that was not diagnostic (arrow).

View larger version (137K): [in this window] [in a new window] [Download PPT slide]   Figure 1b. Images show template of the quality scale used in the evaluation of pulmonary arteries. (a) Artery with good to excellent enhancement (arrow). (b) Artery with enhancement that was limited but of diagnostic value (arrow). (c) Artery with enhancement that was not diagnostic (arrow).

View larger version (104K): [in this window] [in a new window] [Download PPT slide]   Figure 1c. Images show template of the quality scale used in the evaluation of pulmonary arteries. (a) Artery with good to excellent enhancement (arrow). (b) Artery with enhancement that was limited but of diagnostic value (arrow). (c) Artery with enhancement that was not diagnostic (arrow).

View larger version (82K): [in this window] [in a new window] [Download PPT slide]   Figure 2a. Images show template of the homogeneity scale used in the evaluation of pulmonary arteries. (a) Artery assigned score 1, entirely homogeneous appearance of the vessel lumen (arrow). (b) Artery assigned score 2, dotted appearance (arrow). (c) Artery assigned score 3, streaky appearance (arrow).

View larger version (127K): [in this window] [in a new window] [Download PPT slide]   Figure 2b. Images show template of the homogeneity scale used in the evaluation of pulmonary arteries. (a) Artery assigned score 1, entirely homogeneous appearance of the vessel lumen (arrow). (b) Artery assigned score 2, dotted appearance (arrow). (c) Artery assigned score 3, streaky appearance (arrow).

View larger version (204K): [in this window] [in a new window] [Download PPT slide]   Figure 2c. Images show template of the homogeneity scale used in the evaluation of pulmonary arteries. (a) Artery assigned score 1, entirely homogeneous appearance of the vessel lumen (arrow). (b) Artery assigned score 2, dotted appearance (arrow). (c) Artery assigned score 3, streaky appearance (arrow).

Statistical Analysis
Statistical analysis for this study was performed with statistical software (SPSS, version 10.0.0; SPSS, Chicago, Ill). The two groups of patients were compared in regard to demographic and clinical characteristics. Qualitative variables, such as sex and use of oxygen supplementation during the examination, were compared with the ² test, and quantitative variables, such as age, oxygen saturation, and respiratory and heart rates, were compared with the Student t test by using 95% confidence intervals.

At every level of the pulmonary arteries examined, we compared the distribution of scores of homogeneity and quality of contrast enhancement between the two contrast agents by using a ² test. This comparison was performed with data from the three readers and also with mode data, which correspond to the scores most frequently given by the readers for each artery evaluated. By using mode data, we excluded data from all arteries that were assigned three different scores by the three readers. Mode data are a better reflection of general agreement among readers (14).

A comparison of the mean vascular lumen attenuation (in Hounsfield units) between the two contrast agents was performed by using the Student t test. A P value less than .05 was considered significant in all statistical analyses in this study. The interobserver agreement for the attribution of the different scores was calculated with the Cohen statistic.

	RESULTS

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A total of 188 pulmonary arterial branches were examined in the 47 patients included in the study. Among those, in only one patient was evaluation of the vessels of the lower lobe of the right lung required, secondary to emboli of the lower lobe of the left lung. The group of patients who received iohexol and the group of patients who received iodixanol were statistically similar with regard to demographic characteristics and clinical parameters, including heart rate, respiratory rate, and oxygen saturation (P > .05). There was, however, a statistically significant difference (P = .03) in the number of patients who received oxygen at the time of the examination in the two groups (Table 1).

The interobserver variability for the attribution of qualitative scores in the evaluation of enhancement homogeneity and quality was calculated. This value was between 0.34 and 0.56 for the 47 patients, which corresponds to a fair to moderate degree of interobserver agreement (15). The value was also calculated for the 28 patients included in the first reading session separately from the 19 subsequently included in the second reading session. The values were similar: 0.30–0.59 for the first session and 0.34–0.49 for the second session.

	DISCUSSION

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Many studies (3–7) have shown the efficiency of pulmonary CT angiography in the diagnosis of pulmonary embolism. With the addition of multi–detector row CT, CT angiography has even surpassed conventional angiography, particularly at the subsegmental level, as demonstrated by a few groups of researchers (3,16,17).

The quality of enhancement relies mainly on a few parameters: the injection rate, the amount of contrast agent used, and the delay between injection and scanning. Once these parameters are optimized, the effect of the choice of contrast agent on enhancement quality can be evaluated. Iso-osmolar contrast agents are expected to allow a decrease in contrast agent dilution while they improve vascular enhancement. The effect of their use has been studied in coronary angiography, CT angiography of the abdominal aorta, and conventional arteriography of the lower limbs and cerebral vessels, and there has not been any significant improvement (9,18–20). To our knowledge, no study about the evaluation of the effect of iso-osmolar agents on pulmonary CT angiography for pulmonary embolism has been published. Only an abstract was published (21), and in it the authors reported results that agree with those of our study.

We estimated that having a radiologist judge the global enhancement quality of a CT angiogram as good to excellent, diagnostic but of limited value, or not diagnostic would be the best method to evaluate enhancement quality, since it reflects clinical situations. However, this qualitative assessment of enhancement implies subjectivity. Two precautions were taken to minimize that limitation and make this evaluation as objective and reproducible as possible. First, the research team in consensus established homogeneity and quality scales with the three readers, and these scales were illustrated on a template prior to the study. Readers had to review all selected examples for each level of the scale before every reading session. The setup for analysis of enhancement was also created to represent the clinical setting (evaluation on a monitor and adjustment of windowing by readers). Second, we used attenuation measurement (expressed in Hounsfield units) of the vessels as an alternative method to objectively compare enhancement.

We are aware that the use of score 3, corresponding to a streaky aspect on our homogeneity scale, is a limitation in the comparative evaluation of enhancement. This aspect is related to CT artifacts (beam artifacts) rather than to the contrast agent used. Independent values for the first ( = 0.30–0.59) and second ( = 0.34–0.49) reading sessions were similar. Section location of arterial branches to evaluate was specified for the second reading session to reduce the reader’s burden, but this added specification did not change the interobserver variability.

In our relatively small sample of 47 patients, a total of 188 arteries were examined. We did not demonstrate any significant differences between the two contrast agents for either homogeneity or global quality of enhancement by using qualitative criteria and objective measures. These results agree with those in studies in which iso-osmolar and low-osmolarity contrast agents were compared for arterial enhancement (9,18,19). However, renal parenchymal enhancement at abdominal CT has proved to be significantly greater with iso-osmolar agents (18). At intravenous pyelography, iso-osmolar contrast agents demonstrated a greater level of filling and attenuation of the renal calices and the renal pelvis (8,22). Since arterial enhancement studies require a shorter lag time between the injection and imaging, dilution effect related to osmolarity of contrast agents may not be as apparent. This may explain why the use of iso-osmolar agents, when compared with low-osmolarity agents, does not significantly improve the quality of enhancement in arterial studies.

It has been well demonstrated that iso-osmolar contrast agents have established advantages, namely reduced pain related to injection and reduction in likelihood of contrast medium–induced nephropathy in high-risk patients. Despite the theoretical advantages of iodixanol over low-osmolarity contrast agents in terms of enhancement, no significant difference was shown in arterial enhancement quality at CT angiography in patients who were suspected of having pulmonary embolism, according to subjective and objective criteria. Therefore, we believe enhancement quality alone should not be considered an indication for the preference of iso-osmolar over low-osmolarity agents in that specific clinical setting.

	FOOTNOTES

 
The Department of Radiology and the research team (J.P.B., C.B., Y.G.P.) had an agreement with Amersham Health in Canada for financial support. Amersham Health contributed to the fees related to clerical assistance, secretarial work, and reading sessions made by three radiologists. The financial support was given independently of the study’s outcomes. The data and results are the property of the researchers.

Author contributions: Guarantor of integrity of entire study, J.P.B.; study concepts and design, J.P.B., C.B.; literature research, J.P.B.; clinical studies, J.P.B., C.B.; data acquisition, J.P.B., C.B.; data analysis/interpretation, J.P.B., C.B., Y.G.P.; statistical analysis, J.P.B., E.M.; manuscript preparation and definition of intellectual content, J.P.B.; manuscript editing, J.P.B., C.B., Y.G.P.; manuscript revision/review and final version approval, all authors

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This Article Abstract Figures Only Full Text (PDF) All Versions of this Article: 2343031811v1 234/3/929    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bédard, J. P. Articles by Monga, E. Search for Related Content PubMed PubMed Citation Articles by Bédard, J. P. Articles by Monga, E.