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Original Research |
1 Department of Radiology, 407, Taichung Veterans General Hospital, No. 160,
Section 3, Taichung Harbor Rd., Taichung, Taiwan, ROC.
2 Faculty of Medicine, Medical College of Chung Shan Medical University, Taiwan,
ROC.
3 Department of Medicine, National Yang Ming University, Taiwan, ROC.
4 Institute of Clinical Medicine, National Yang Ming University, Taiwan,
ROC.
5 Department of Nephrology, Taichung Veterans General Hospital, Taichung,
Taiwan, ROC.
6 Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan,
ROC.
7 Department of Applied Foreign Languages, Overseas Chinese Institute of
Technology, Taiwan, ROC.
Received May 9, 2007;
accepted after revision June 30, 2007.
Supported by Taichung Veterans General Hospital (grant TCVGH-955502A),
Taiwan, ROC.
Abstract
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SUBJECTS AND METHODS. During a 4-month period, 72 patients referred for cardiac MDCT were consecutively enrolled and randomized into two groups: iohexol 350 and iodixanol 320. The injection and scanning protocols were the same for both groups. Enhancement of the right heart, left heart, coronary arteries, and left ventricular (LV) myocardium in both the arterial and delayed phases was compared using two-tailed independent Student's t test.
RESULTS. Enhancement in the right heart, left heart, coronary arteries, and LV myocardium in the arterial phase showed no statistical difference (p > 0.05) between the two groups, although the iohexol group showed slightly higher enhancement (average, 11.2 H) in all of the areas. Surprisingly, in the delayed phase, the iodixanol group displayed significantly higher (7.7 H) persistent enhancement (p < 0.05) in the LV myocardium.
CONCLUSION. Iodixanol 320 can provide vascular enhancement in cardiac MDCT that is similar to iohexol 350. In the delayed phase, iodixanol 320 shows significantly higher delayed enhancement (7.7 H) in the LV myocardium than iohexol 350.
Keywords: cardiac imaging • contrast media • coronary arteries • CT coronary angiography • heart disease • hemodynamics • MDCT • myocardium
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Recently, a growing number of studies have confirmed the benefit of reducing injection-related pain [7] and contrast-induced nephropathy using iodixanol [8-10]. In selected patients with pending renal failure, iodixanol is used instead of iohexol in our hospital. However, according to the vendor's data, because of the viscosity limit, the highest iodine concentration of iodixanol that can be provided on the market is only 320 mg I/mL. In considering the quality of CT arteriography, a question arises: Is the reduction of iodine concentration from 350 to 320 mg I/mL also reducing vascular enhancement, which may correlate with a reduction in diagnostic accuracy?
Reviewing the literature, several studies compared the enhancement of iodixanol with 30 mg I/mL higher-iodine-concentration iohexol [7, 11, 12]. In those studies, even with a lower iodine concentration than iohexol, iodixanol still could provide similar enhancement in the peripheral vessels. The assumed general concept is that iohexol has not only higher iodine concentration but also higher osmolarity, which will absorb water and have a subsequent dilution effect [12]. Iodixanol has a lower iodine concentration, but the isoosmolarity characteristic might prevent the contrast bolus from overdilution.
Cademartiri et al. [5] evaluated iodixanol 320 mg I/mL (iodixanol 320) versus iohexol 350 mg I/mL (iohexol 350) for coronary artery enhancement in 16-MDCT and found no significant difference (mean ± SD, 333 ± 51 H vs 320 ± 55 H, respectively). However, no study, to our knowledge, has been performed using scanners with more than 32 channels, which are recommended for clinical use because the breath-hold duration is decreased.
Recently, the clinical applications of cardiac MDCT have been widening [2, 3, 6, 13-15]. Besides the popular CT coronary angiography, myocardium assessment in both the arterial phase and delayed phase is also important for observing myocardial perfusion, regional wall motion, and myocardial viability [13-15]. To comprehensively evaluate the enhancement change if iodixanol 320 is used instead of iohexol 350, we designed the following prospective comparison.
Thus, our study was designed to answer the following question: If compared with 350 mg I/mL higher-iodine-concentration iohexol, can iodixanol 320 provide similar enhancement in cardiac MDCT, including CT coronary angiography, myocardial assessment, and delayed phase?
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After enrollment, patients were randomized into two groups. In group 1, iohexol with 350 mg I/mL (Omnipaque 350) was used, whereas in group 2, iodixanol with 320 mg I/mL (Visipaque 320) was used. In each group, patient age, sex, body height, weight, initial heart rate, and systolic and diastolic blood pressures were recorded.
Cardiac CT Protocol
The calcium score was obtained using the factory default value with
prospective ECG triggering at a 70% R-R interval, tube voltage of 120 kV,
effective tube current of 140 mA, rotation time of 0.42 second, and
collimation of 16 x 2.5 mm in the sequential scan mode to cover the
heart during 1 breath-hold.
All patients with an initial heart rate of > 60 beats per minute (bpm) were given 40 mg of oral propranolol 1 hour before MDCT examination (Cardilol, Veteran's Pharmaceutical Factory). No additional IV β-blocker was administered. CT coronary angiographic studies were performed using a 40-MDCT unit (Brilliance 40, Philips Medical Systems). The parameters were a tube voltage of 120 kV, effective tube current of 700 mAs per section, pitch of 0.2, collimation of 40 x 0.625 mm, and rotation time of 0.42 second with ECG gating from 1 cm below the carina to the lower border of the heart in a craniocaudal direction. Online ECG-based dose modulation (DoseRight Cardiac, Brilliance 40, Philips) was not applied because of the possibility of impairment of image quality during the systolic phase.
A 20-gauge IV catheter was placed in the right antecubital vein, and 100 mL of contrast medium (group 1, Omnipaque 350; group 2, Visipaque 320) was injected at a flow rate of 4 mL/s. This injection was followed with a 30-mL saline bolus given at the same flow rate. Both iohexol 350 and iodixanol 320 were prewarmed to 37°C using a constant temperature heater. At that temperature, iohexol 350 has a viscosity of 10.6 mPa x s; and iodixanol 320, 11.4 mPa x s. To synchronize imaging with the injection of contrast agent, we used a bolus-tracking technique with a threshold of 150 H and a region of interest (ROI) placed in the ascending aorta. Once the threshold in the ascending aorta had been met, scanning started after a 7-second delay, which included table movement and automated breath-hold instruction.
After 6 minutes, delayed phase imaging was performed on the same scan range with an 80-kV tube voltage, 320-mAs slice tube current, pitch of 0.2, rotation time of 0.5 second, and 32 x 1.25 mm collimation with online ECG-based dose modulation (DoseRight Cardiac). DoseRight Cardiac is a dose-reduction technique that varies the tube current the full nominal value (100%) around the time of the desired phase (in our study, 70% of the interval between two R waves of the ECG tracing [R-R interval]) and 20% the tube current from the full nominal value around the phases other than desired.
A senior CT technologist with more than 10 years of experience with CT obtained all of the scans. In determining calcium scores, the images were reconstructed with a slice thickness of 2.5 mm without overlapping. In CT coronary angiography, images were reconstructed from 0% to 90% R-R interval with a 10% interval and were reviewed to choose the most quiescent phase for interpretation. Another set was reconstructed using the 70% R-R interval with the slice thickness and interval set at 5 mm for bolus geometry analysis. For the delayed phase, images were reconstructed with a slice thickness of 1.4 mm and an interval of 0.7 mm.
The average and SD values of heart rate, time to threshold after injection, and scanning time were recorded.
Clinical Interpretation
A senior cardiothoracic radiologist with 3 years of cardiac CT experience
first interpreted the scans using a dedicated MDCT workstation (Extended
Brilliance Workspace, Philips). The interpretation included calcium score, CT
coronary angiography, arterial phase myocardium assessment, left ventricular
(LV) wall motion, and delayed phase myocardium assessment. Because our study
also focused on the myocardium and recent studies in the literature had
suggested that significant coronary artery stenosis might result in decreased
myocardial attenuation on arterial and delayed phase images
[13-15],
cases were excluded if there was significant stenosis (> 50% luminal
stenosis) in the coronary arteries, heavy calcification that made lumen
assessment impossible, abnormal myocardium enhancement, an enhancement defect
in the arterial or delayed phase, abnormal myocardium thickness in diastole
(> 12 or < 5 mm of short axis), or abnormal LV wall motion. In addition,
the included cases had to be radiographically negative on cardiac CT
reports.
The ejection fraction in every patient was also measured. We loaded the 10-phase thin-section images into the analysis software (Cardiac Review, Extended Brilliance Workspace, Philips) and created 14 cuts of 5-mm short-axis images from the apex to the LV base. Then, the short-axis images of the 10 phases were loaded into another software program (LV/RV Analysis, Extended Brilliance Workspace, Philips) to automatically define the LV cavity area excluding the papillary muscle. The ejection fraction was then reported and recorded.
Measurements
Concerning measurements, we compared the following enhancement parameters
between the two groups [4,
16]: first, the enhancement at
every second in the right heart and left heart, which has been called
"bolus geometry" in previous studies
[16]; second, the enhancement
in the proximal coronary arteries, including the left main, proximal left
anterior descending, proximal circumflex, and proximal right coronary
arteries; third, the enhancement in the LV cavity and myocardium at the
arterial phase; and, fourth, the enhancement in the LV cavity and myocardium
at the delayed phase. The same interpreting radiologist performed and
collected all the measurements at a workstation.
Bolus geometry in the right heart and left heart (Figs. 1A, 1B, 1C, 1D, 2A, 2B, 2C, 2D and 3)—The 70% R-R interval reconstructed images with a slice thickness and interval of 5 mm were loaded into the program (Viewer, Extended Brilliance Workspace, Philips). Using a window level and width of 150 and 600 H, respectively, the ROIs were obtained using an ROI size of approximately half the target diameter to avoid partial volume effects from the adjacent vessel wall, trabeculae, or myocardium. Enhancement on the route from the superior vena cava to the right atrium and right ventricle was measured every second to represent the bolus geometry in the right heart (Figs. 1A, 1B, 1C, 1D and 3). Enhancement on the route of the ascending aorta, aortic root, LV outflow tract, and LV was also recorded every second to represent the left heart bolus geometry (Figs. 2A, 2B, 2C, 2D and 3).
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The varying sizes and morphologic features of the heart and great vessels in the individual subjects resulted in different scanning times and in different lengths of ROIs along the z-axis. To achieve consistent results [16], only time-related contrast measurements for each respective vessel that were available in all patients were included in this study.
Coronary artery enhancement measurements (Fig.4A, 4B)—After reviewing all 10 phases of reconstructed thin-section images, the most quiescent phase was selected for coronary artery enhancement measurements. The selected phase images were loaded into the program (Cardiac Viewer, Extended Brilliance Workspace, Philips). Because of the small size of the coronary arteries, maximal-intensity-projection rendered axial images with a 3-mm thickness were used to avoid partial volume effect. Using a window level and width of 150 and 600 H, respectively, the ROIs were drawn in the center of the left main, proximal left anterior descending, proximal circumflex, and proximal right coronary arteries, with the size of each ROI approximately half that of the vessel diameter.
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The right heart enhancement of both groups was compared at every second from the start of scanning. Average enhancement of the right heart was also compared. The left heart average enhancement and enhancement in every second were also compared. Then, the left main, left anterior descending, left circumflex, right coronary artery, and average coronary artery enhancement were also compared. Finally, the LV cavity and LV myocardium measured at the arterial phase and delayed phase were also compared.
Differences between the groups were assessed with the two-tailed independent Student's t test. The sex distribution was compared using a chisquare test. A p value of < 0.05 was considered to indicate a statistically significant difference.
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The patients' characteristics were compared before the following enhancement comparisons. The results are shown in Table 1. All the patient characteristics, including ejection fraction, showed no significant difference between the two groups.
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Comparison of right heart enhancement showed that both the average enhancement and enhancements at every second starting from the top of the area scanned were all statistically the same (Fig. 6). The left heart showed the same results (Fig. 7). Furthermore, the enhancement values for the two patient groups showed no significant difference, regardless of individual or average coronary artery enhancement (Table 2).
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In the arterial phase, both the LV cavity and LV myocardium had similar enhancement in both groups; no significant difference could be found (Table 2). Notably, all measurements obtained during the arterial phase showed no statistical difference between the two patient groups.
Finally and surprisingly, comparison of the delayed phase values showed similar enhancement in the LV cavity, but the LV myocardium showed higher attenuation values using iodixanol 320 with statistical significance, even though the total iodine in the iodixanol group was 9.3% less than that in the iohexol group (Table 2 and Fig. 8).
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This unique finding has not, to our knowledge, been reported in the literature before now. A supposed reason for similar enhancement in the arterial phase has also been proposed in previous articles in the literature dealing with other examination protocols [5, 11, 12]. Although iohexol 350 has a greater iodine concentration, because its osmolarity (780 mOsm/kg H2O2) is still much higher than that of blood (290 mOsm/kg H2O2), it will absorb water, causing a dilution effect that decreases its enhancement. The dilution effect causes its 9.3% higher concentration of iodine in the original package to decrease to no significant difference in the heart when compared with iodixanol 320. Furthermore, the higher viscosity of iodixanol 320 at 37°C (11.4 vs 10.6 mPa x s of iohexol 350) might also result in a more concentrative flow pattern intravascularly, which also contributes to the similar intracardiac iodine concentration.
Regarding the delayed phase change, we think the reason for the change is related to the large dimeric molecular structure of iodixanol. Contrast medium enters the myocardium via the coronary arteries in the arterial phase, but in the subsequent delayed period, it is gradually washed out by normal blood [13, 14]. Possibly because of its large dimeric molecular structure, iodixanol stays in the myocardium for a longer time. However, the clinical implication of the phenomenon is unclear. Because we selected only patients without myocardial infarction, we do not know whether this persistent high enhancement also appears in infarcted myocardium and would subsequently provide better conspicuity for nonviable parts. Further animal studies may be required to answer this question.
To our knowledge, there are no articles in the literature comprehensively studying the differences in bolus geometry and myocardial enhancement between iodixanol 320 and iohexol 350 in cardiac MDCT. Pannu et al. [12], in a study similar to ours, performed a precisely controlled animal study to compare enhancement in the descending aorta between these two contrast agents. They found that even though iodixanol 320 has a lower iodine concentration, enhancement in the descending aorta showed no statistically significant difference in comparison with iohexol 350.
Clinically, the meaning of our study results is as follows: In hospitals in which the clinical routine of performing cardiac CT is to use iohexol 350 for diagnosis, iodixanol 320 may be used instead in patients with renal insufficiency because iodixanol 320 results in the same high enhancement as iohexol 350, regardless of chamber or coronary artery, during the arterial phase. Thus, the fear of decreasing enhancement, or even decreasing diagnostic accuracy of CT coronary angiography, is no longer established. This finding has been reported once in the literature using 16-MDCT [5], and our study further confirms it using faster 40-MDCT. Furthermore, we also incidentally found that compared with iohexol 350, iodixanol 320, even with its lower iodine concentration, has persistently higher enhancement in the LV myocardium in the delayed phase, possibly because of its large dimeric molecular structure.
Our study has some limitations. First, a better study design would have been to evaluate healthy volunteers and to inject different contrast media over several weeks to exclude patient bias. However, because of ethical concerns, subjecting patients to double the radiation and contrast material dose to eliminate selection bias is not practical. Second, we did not compare iodixanol 320 with other monomeric low-osmolar contrast media with even higher concentrations of iodine, such as 370 or 400 mg I/mL. This is because the high diagnostic accuracy (97.9%) of iohexol 350 at our institution had already been confirmed [6]. Thus, our study could assume that iodixanol 320 would share the good results of iohexol 350 when used for cardiac CT. Finally, even though the authors of many studies have reported the advantages of iodixanol [7-10], some studies still question whether iodixanol is superior to other low-osmolality contrast media [17]. The debate over renal safety of iodixanol is another ongoing issue.
In conclusion, to reduce injection-related pain [7] or to decrease osmotoxicity [8-10] in cardiac CT, using iodixanol 320 to replace iohexol 350 will result in similar vascular, chamber, and myocardial enhancement during the arterial phase. However, in delayed phase imaging, the LV myocardium has a significantly higher (7.7 H) persistent enhancement with iodixanol 320 than with iohexol 350, although the clinical significance is unclear and needs to be studied in the future.
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