Methods and materials

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1 The British Journal of Radiology, 84 (2011), Effect of varying contrast material iodine concentration and injection technique on the conspicuity of hepatocellular carcinoma during 64-section MDCT of patients with cirrhosis 1 A GUERRISI, MD, 1,2 DMARIN,MD, 2 RCNELSON,MD, 1 G DE FILIPPIS, MD, 1 MDIMARTINO,MD, 3 H BARNHART, PhD, 4 RMASCIANGELO,MA, 1 I GUERRISI, MD, 1 R PASSARIELLO, MD and 1 C CATALANO, MD 1 Department of Radiological Sciences, University of Rome Sapienza, Rome 00159, Italy, 2 Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA, 3 Department of Biostatistics and Bioinformatics, Duke Clinical Research Institute, Durham, NC 27715, USA, and 4 Department of Statistics, University of Rome Sapienza, Rome 00159, Italy Objectives: The aim of this study was to compare the intraindividual effects of contrast material with two different iodine concentrations on the conspicuity of hepatocellular carcinoma (HCC) and vascular and hepatic contrast enhancement during multiphasic, 64-section multidetector row CT (MDCT) in patients with cirrhosis using two contrast medium injection techniques. Methods: Patients were randomly assigned to one of two groups with an equal iodine dose but different contrast material injection techniques: scheme A, fixed injection duration (25 s), and scheme B, fixed injection flow rate (4 ml s 21 ). For each group, patients were randomised to receive both moderate-concentration contrast medium (MCCM) and high-concentration contrast medium (HCCM) during two CT examinations within 3 months. Enhancement of the aorta, liver and portal vein and the tumour-toliver contrast-to-noise ratio (CNR) were compared between MCCM and HCCM. Results: 30 patients (mean age 59 years; range years; 16 patients in scheme A and 14 in scheme B) with a total of 31 confirmed HCC nodules were prospectively enrolled. For scheme B, the mean contrast enhancement of the aorta and tumour-to-liver CNR were significantly higher with HCCM than with MCCM during the hepatic arterial phase ( HU vs HU, p50.001, and +7.5 HU vs +5.5 HU, p50.004). For both groups, there was no significant difference between MCCM and HCCM for all other comparisons. Conclusion: For a constant injection flow rate, HCCM significantly improves the conspicuity of HCC lesions and aortic enhancement during the hepatic arterial phase on 64-section MDCT in patients with cirrhosis. Received 21 November 2009 Revised 17 February 2010 Accepted 24 February 2010 DOI: /bjr/ The British Institute of Radiology Along with MRI, multidetector row CT (MDCT) is the modality of choice for the diagnosis and follow-up of patients with hepatocellular carcinoma (HCC), as well as for tumour burden assessment. With the advent of volume MDCT, enabling the acquisition of 64 or more sections during a single gantry rotation, it has become possible to scan the entire abdomen with submillimetre section widths within a short scan time (less than 5 s for 300 mm of coverage). Although this technique has shown several advantages over conventional CT, including better discrimination between different circulatory phases, the potential for scanning during peak organ enhancement throughout the entire imaging volume and true isotropic CT data sets, it has raised considerable challenges for the design of scanning and contrast material injection protocols that are optimised for the detection of hypervascular HCC lesions [1]. Recent investigations have emphasised the importance of using test bolus or bolus-tracking methods to synchronise CT data acquisition with the peak tumourto-liver contrast for hypervascular HCC lesions [2, 3]; Address correspondence to: Daniele Marin, MD, Università di Roma Sapienza, Department of Radiological Sciences, Viale Regina Elena 324, Roma 00159, Italy. danielemarin2@gmail.com however, the most effective contrast medium injection technique for maximising tumour enhancement during the narrow temporal acquisition of modern MDCT systems remains largely unexplored. Previous studies with early generation MDCT scanners reported conflicting results with varying volumes and concentrations of iodine, injection flow rates and durations of injection of contrast material on the conspicuity of hypervascular HCC tumours [4 8]. Owing to large differences in study design, the demographic characteristics of patients, the type and dose of contrast medium and contrast material injection protocols, these data cannot be compared with each other. The purpose of our study was to compare the intraindividual effects of contrast material with two different iodine concentrations on the conspicuity of HCCs and vascular and hepatic contrast enhancement during multiphasic, 64-section MDCT in patients with cirrhosis, by using two contrast medium injection techniques. Methods and materials This prospective single-centre, open-label randomised trial was approved by our institutional review board and followed the principles of the Declaration of 698 The British Journal of Radiology, August 2011

2 Effect of contrast material iodine concentrations during liver MDCT Helsinki and subsequent amendments [9]. All participants provided written informed consent before participating in the study. Study participants From May 2007 to December 2007, 260 consecutive patients with cirrhosis were referred to 1 of 2 centres in our hospital for the treatment of liver disease. Patients were referred for either routine 6 month surveillance (n5210) or follow-up diagnostic imaging after curative treatment for HCC (n550). Patients were eligible for enrolment if they (1) had histopathologically proven cirrhosis on liver biopsy within the 2 years before the study, (2) were suspected of having HCC on the basis of prior ultrasound, contrast-enhanced MDCT or MRI, with or without elevated a-fetoprotein levels (.200 ng ml 21 ), or (3) were referred clinically for multiphasic, contrastenhanced MDCT of the liver. Patients were excluded for any of the following reasons: (1) younger than 18 years; (2) pregnant or lactating woman; (3) left ventricular ejection fraction of 35% or less; (4) placement of a transjugular intrahepatic portosystemic stent; or (5) contraindication to iodinated contrast material, such as a history of anaphylactoid reaction or renal failure (serum creatinine level.2.0 mg dl 21 (177 mmol l 21 )measuredwithin 2 weeks before enrolment). Study design and randomisation The study was designed as an intraindividual cross-over comparison for the conspicuity of HCC lesions and enhancement of the abdominal aorta, liver and portal vein. Two contrast media with different iodine concentrations were compared. After being deemed eligible for the study, patients were randomly assigned to one of two groups with different monophasic intravenous injection schemes for the contrast material: scheme A, 560 mg I kg 21, with a fixed injection duration of 25 s and variable injection flow rates depending on the patient s total body weight, and scheme B, 560 mg I kg 21,usinga fixed injection flow rate of 4 ml s 21 and variable injection durations depending on the patient s total body weight. Current evidence suggests that a 25 s injection duration yields adequate peak enhancement in the abdominal aorta (>300 Hounsfield units (HU)) using a total iodine dose similar to that in our study [10]. For each injection scheme, patients were randomised to receive one of two contrast media with different iodine concentrations commonly used in our practice: a nonionic, iso-osmolar dimeric contrast medium with a moderate iodine concentration (320 mg I ml 21 ) (moderate-concentration contrast medium; MCCM) (iodixanol, Visipaque 320, GE Healthcare, Inc., Milwaukee, WI) and a non-ionic, low-osmolar monomeric contrast medium with a high iodine concentration (400 mg I ml 21 ) (high-concentration contrast medium; HCCM) (Iomeron 400, Bracco Diagnostic Imaging, Inc., Princeton, NJ). Patients received either MCCM (1.75 ml kg 21 )orhccm(1.4mlkg 21 )asthe first contrast agent during the initial CT examination, with crossover to the other contrast medium if a follow-up CT examination of the liver was performed within 3 months, as clinically indicated. Only patients who crossed over to the second contrast medium were included. Randomisation was performed on a 1:1 basis. The patient s total body weight was measured using a commercially available body scale (Seca 761, Hamburg, Germany) before each CT examination. Proof of tumour burden The diagnosis of HCC required one of the following criteria to be satisfied: (1) pathological proof of tumour burden based on the diagnostic criteria of the International Working Party s Terminology of Nodular Hepatocellular Lesions [11]; (2) evidence of conclusive criteria for the diagnosis of HCC at imaging [12]; or (3) demonstration of substantial lesion growth defined as an increase in the longest tumour diameter by greater than 5 mm at follow-up CT or MRI, or both. Patients with multiple nodules were considered to have multifocal HCC when the other lesions had the same imaging appearance as the biopsy-proven HCC nodule. Injection technique In all patients, contrast medium was administered by a dual-chamber mechanical power injector (Stellant D CT; Medrad, Indianola, PA) through an 18-gauge, 45 mm long intravenous angiocatheter (Becton, Dickinson and Co., Franklin Lakes, NJ) inserted into a right antecubital vein. Immediately before scanning, the patency of the angiocatheter was tested with a fast manual flush of saline with the patient s arm in the scanning position. The contrast bolus was followed by a flush of 40 ml saline (0.9% sodium chloride solution) using an injection flow rate of 4 ml s 21. This injection flow rate was selected based on our clinical experience (unpublished data) and was corroborated by the results of two recent studies on physiological flow phantoms that compared the time-enhancement curves for the thoracic aorta at different injection flow rates of a saline chaser [13, 14]. The volume of the saline chaser was selected based on the average volume of fluid (40 ml) in the peripheral venous compartment interposed between the injection site and the right atrium [13]. Both before and during injection, contrast material was warmed to approximately 37 u C, which resulted in a contrast material viscosity of 11.8 and 13.6 mpa s 1 for MCCM and HCCM, respectively. Normal saline as a chaser was administered at room temperature. At the conclusion of the CT examination, patients were questioned about any discomfort at the injection site, and the site was inspected by a nurse or technologist to identify any associated signs or symptoms of contrast material extravasation (e.g. swelling, blistering or decreased pulse rate). MDCT technique Multiphasic, contrast-enhanced MDCT was performed using a 64-section MDCT scanner (Somatom Sensation 64; Siemens Medical Systems, Erlangen, Germany) The British Journal of Radiology, August

3 A Guerrisi, D Marin, R C Nelson et al equipped with flying focal spot technology, which enables acquisition of double projection data for an identical position of the detector by rapid variation of the focal spot position on the anode [15] (Table 1). All patients were scanned in the head-first supine position. After acquisition of an anteroposterior digital scout radiograph, each patient was scanned craniocaudally from the dome of the liver to the iliac crest, before and after intravenous contrast medium administration during the hepatic arterial, hepatic venous and delayed phases. To determine the scanning delay for hepatic arterial phase imaging, the contrast medium transit time in the abdominal aorta was assessed by a low-dose (120 kvp, 50 mas) automatic bolus-tracking technique with automated scan-triggering software (Care Bolus CT; Siemens Medical Systems). Arterial phase scanning was started automatically 18 s after the trigger threshold (150 HU above the baseline ( HU in absolute value)) was reached at the level of the supracoeliac abdominal aorta (range s) [2]. The hepatic venous and delayed phases were started automatically 70 and 180 s, respectively, after the start of contrast medium injection. Quantitative image analysis Quantitative measurements were performed on a commercially available workstation (Leonardo; Siemens Medical Solutions) by an abdominal radiology fellow with 1 year s experience in gastrointestinal and hepatobiliary imaging. The reader was aware of the size and segmental localisation of all HCC nodules, but was blinded to the patient s injection Scheme Assignment. Mean CT numbers in HU of the aorta, liver and portal vein were obtained by manually placing circular or ovoid regions of interest (ROIs) at the level of the main portal vein during each acquisition phase: unenhanced, late hepatic arterial, hepatic venous and delayed. The attenuation of the aorta was recorded from a single ROI (mean pixel number, 200; range, pixels) drawn to encompass 90% or more of each aortic cross-sectional area. Calcifications and soft plaques of the aortic wall were carefully avoided. Liver parenchymal attenuation was recorded as the mean of four ROIs (mean pixel number, 450; range, pixels) placed in the anterior and posterior segments of the right hepatic lobe and the medial and lateral segments of the left hepatic lobe. Areas of focal changes in parenchymal density, large vessels and prominent artefacts, if any, were carefully avoided. The attenuation of the portal vein was recorded from a single ROI (mean pixel number, 100; range, pixels) drawn as large as the vessel lumen. To ensure consistency, all measurements were repeated three times at three consecutive levels, and average values were calculated. Finally, for each patient, the contrast enhancement (in HU) of the aorta, liver and portal vein was calculated as the absolute difference in the average attenuation of each organ between the pre-contrast scan and each of the postcontrast scans acquired during the hepatic arterial, hepatic venous and delayed phases. The mean CT numbers of HCC nodules were assessed by manually placing circular or ovoid ROIs, which were drawn to encompass as much of the lesion as possible (mean pixel number, 170; range, pixels). The tumour-to-liver contrast-to-noise ratio (CNR) was calculated with the following formula: CNR~ ROI tumour{roi liver SD noise where ROI tumour is the mean attenuation of the tumour, ROI liver is the mean attenuation of the non-tumorous liver parenchyma and SD noise is the image noise, defined by the standard deviation of the pixel values from a circular or ovoid ROI (mean pixel number, 300; range, pixels) drawn in a homogeneous region of the subcutaneous fat of the anterior abdominal wall. Quantitative analysis was not performed on HCC nodules that either were treated during the interval between the two CT examinations (e.g. percutaneous tumour ablation or partial liver resection) or had a transverse maximum diameter #5 mm, which would lead to inaccurate ROI measurements caused by partial volume averaging. HCC lesions were categorised as hypervascular or hypovascular if their lesion-to-liver CNR during the hepatic arterial phase was greater or less than 0, respectively. To maximise the consistency of our quantitative assessment, for each patient, the two serial CT examinations Table 1. Multidetector row CT scanning parameters, reconstruction algorithm and radiation dose CT parameters Pre-contrast phase Post-contrast phases Detector configuration (mm) 64 (32 6 2) (32 6 2) Peak kilovoltage (kvp) Tube current time product (mas) Gantry revolution time (s) Beam pitch Scanning direction Craniocaudal Craniocaudal Scan length (cm) Scan time (s) Reconstructed section thickness (mm) Section overlap (mm) Reconstruction kernel Soft-tissue Soft-tissue Volumetric CT dose index (mgy) Dose length product (mgy 6 cm) The British Journal of Radiology, August 2011

4 Effect of contrast material iodine concentrations during liver MDCT performed using either MCCM or HCCM were displayed side by side in a random order. This approach allowed the reader to select the same anatomical level and to keep the size and shape of the ROIs constant between the two examinations by applying a copy and paste function on the workstation. Manual adjustments of the location of the ROI were occasionally necessary to correct for subtle changes in the position of target organs or HCC lesions during different breath-holds. Statistical analysis Differences between scheme A and B in terms of demographic and clinical characteristics, as well as the number, size and vascular appearance of HCC lesions, were tested using the x 2 test and t-test for categorical and continuous variables, respectively. For scheme A and B, the tumour-to-liver CNR and contrast enhancement values for the abdominal aorta, liver and portal vein were compared between MCCM and HCCM for the same patients using a two-tailed paired t-test. The Pearson product-moment correlation coefficient (r) was used to investigate the relationships between patient weight and aortic contrast enhancement during the hepatic arterial phase, and patient weight and liver or portal vein contrast enhancement during the hepatic venous phase. All statistical analyses were performed with a statistical software package (SAS v.9.0; SAS Software, Cary, NC). A two-sided p-value of,0.05 was considered to indicate statistical significance. Results Study participants 87 (33%) out of 260 patients with cirrhosis and suspected of having HCC met our inclusion criteria and were prospectively enrolled in the study, including 44 patients assigned to scheme A (fixed injection duration, 25 s) and 43 to scheme B (fixed injection flow rate, 4mls 21 ) (Figure 1). Of these 87 patients, 57 (66%) (28 in scheme A and 29 in scheme B) were excluded for the following reasons: lost to follow-up or underwent follow-up CT imaging later than 3 months after the first CT examination (n540), underwent transarterial chemoembolisation (n59) or liver transplantation (n55) during the interval between the serial CT examinations, contrast material extravasation (n52) and withdrawal of consent (n51). The remaining 30 patients (mean age, 59 years; range, years), including 16 patients in scheme A (9 men and 7 women; mean age, 57 years; range, years; mean body weight, 71 kg; range, kg) and 14 patients in scheme B (8 men and 6 women; mean age, 62 years; range, years; mean body weight, 69 kg; range, kg), who underwent 2 consecutive CT examinations of the liver within 3 months (mean interval, 64 days; range, days), constituted our final study cohort (Table 2). The mean ( standard deviation) change in each patient s total body weight between the two serial CT examinations was +0.3 ( 0.2) kg and 20.3 ( 0.3) kg for groups A and B, respectively. Proof of tumour burden 24 of the 30 evaluated patients had 50 confirmed HCC nodules (Table 3). 19 of the 50 HCC nodules in 12 patients were not quantitatively assessed because they were treated with percutaneous tumour ablation or partial liver resection during the interval between the 2 CT examinations. This resulted in a total of 31 HCC nodules, all of which were hypervascular (17 in scheme A (mean size, 14.9 mm; range, 7 19 mm) and 14 in scheme B (mean size, 12.9 mm; range, 6 18 mm)), in 22 patients that were included in the quantitative analysis. No significant differences between groups A and B were observed in the baseline demographic or clinical characteristics, nor in the number, size and vascular appearance of the HCC lesions. Injection technique In scheme A, the injection flow rate was higher for MCCM than for HCCM (mean injection flow rate, 5mls 21 (range, ml s 21 ) vs 4mls 21 (range, ml s 21 )), although the iodine delivery rate remained constant (22.4 mg I kg 21 s 21 ) using either contrast medium. In scheme B, the use of MCCM yielded a longer duration of contrast material injection and a slower iodine delivery rate than HCCM (mean injection duration, 30 s (range, s) vs 24 s (range, s); mean iodine delivery rate, 18.6 mg I kg 21 s 21 (range, mg I kg 21 s 21 ) vs 23.3 mg I kg 21 s 21 (range, mg I kg 21 s 21 ), respectively). Quantitative image analysis During the hepatic arterial phase, the mean contrast enhancement of the aorta was significantly higher for HCCM than for MCCM in scheme B ( HU vs HU, p50.001), with a trend towards higher contrast enhancement, which was not statistically significant, in scheme A ( HU vs HU, p50.081) (Table 4). For both injection schemes, there was no significant difference between MCCM and HCCM for the mean contrast enhancement of the aorta during the hepatic venous and delayed phases and for the mean contrast enhancement of the liver and portal vein during all vascular phases. The mean tumour-to-liver CNR of HCC during the hepatic arterial phase was significantly higher for HCCM than for MCCM in scheme B ( HU vs HU, p50.004) (Figures 2 and 3). No significant difference was noted in the mean tumour-to-liver CNR of HCC between MCCM and HCCM during the hepatic arterial phase in scheme A and during the hepatic venous and delayed phases in both groups (Figure 2). Regardless of the iodine concentration in the contrast medium, there was a strongly negative correlation between the patient s body weight and the contrast enhancement of the abdominal aorta during the hepatic The British Journal of Radiology, August

5 A Guerrisi, D Marin, R C Nelson et al Figure 1. Flowchart of the study enrolment population and randomisation. MDCT, multidetector CT; TACE, transarterial chemoembolisation; OLT, orthotopic liver transplantation; HCC, hepatocellular carcinoma. arterial phase in scheme B (r50.89 for MCCM, p,0.0001; r50.84 for HCCM, p50.008); this trend was not observed in scheme A (Figure 4). Regardless of the iodine concentration in the contrast medium, there was a weakly positive association between the patient s body weight and the contrast enhancement of the liver and Table 2. Demographic and clinical findings of the study patients (n530) Scheme A Scheme B Age (years), mean (range) 57 (45 77) 62 (49 80) Sex, no. (%) Male 9 (56) 8 (57) Female 7 (44) 6 (43) Weight (kg), mean (range) 71 (54 85) 69 (52 90) Body mass index (kg m 22 ), mean (range) 23 (20 27) 22 (19 27) Race or ethnic group, no. (%) White 15 (94) 12 (86) Black 0 1 (7) Other 1 (6) 1 (7) Aetiology of cirrhosis, no. (%) Viral hepatitis B 2 (13) 1 (7) Viral hepatitis C 7 (44) 5 (36) Alcohol abuse 4 (25) 5 (36) Non-alcoholic steatohepatitis 1 (6) 2 (14) Other 2 (13) 1 (7) Child Pugh class, no. (%) Class A 9 (56) 6 (43) Class B 6 (38) 7 (50) Class C 1 (6) 1 (7) Time interval between serial CT examinations (days) Mean (SD) 62 ( 21) 66 ( 14) Range Note that percentages may not total 100 because of rounding. SD, standard deviation. n516 n The British Journal of Radiology, August 2011

6 Effect of contrast material iodine concentrations during liver MDCT Table 3. Characteristics of hepatocellular carcinoma (HCC) lesions and proof of tumour burden (n531) Scheme A Scheme B No. of HCCs per patient Mean (SD) 1.5 ( 1) 1.3 ( 0.7) Range HCC vascular pattern, no. (%) Hypervascular 17 (100) 14 (100) Hypovascular 0 (0) 0 (0) Baseline HCC size (mm) Mean (SD) 14.9 ( 4.3) 12.9 ( 4) Range Interval increase at follow-up CT (mm) Mean (SD) 1.3 ( 1) 1.2 ( 0.9) Range Proof of tumour burden, no. (%) Liver transplantation/partial resection 4 (24) 2 (14) Percutaneous liver biopsy 6 (35) 8 (57) Characteristic imaging findings 1 (6) 0 Extended imaging follow-up 6 (35) 4 (29) Note that percentages may not total 100 because of rounding. SD, standard deviation. n517 n514 portal vein during the hepatic venous phase in both groups (Figure 4). Discussion Our results demonstrate that, if the injection flow rate remains constant, the use of a higher iodine concentration in the contrast medium significantly improves the conspicuity of HCC lesions and aortic enhancement during the hepatic arterial phase on 64-section MDCT in patients with cirrhosis. In our study, using a fixed injection flow rate of 4 ml s 21 and a total iodine dose of 560 mg I kg 21 of the patient s body weight, HCCM yielded an increase of 55.1% (95% confidence interval (CI), %) for the tumour-to-liver CNR of HCCs and 17.5% (95% CI, %) for the enhancement of the abdominal aorta during the hepatic arterial phase, compared with MCCM in the same patient (p and 0.001, respectively). These findings, which corroborate the results of previous reports either in the same [6] or in different [5, 16] patient groups, are probably caused by two concurrent factors. First, when the injection flow rate remains constant, an increase in the iodine concentration in the contrast medium yields proportionally higher amounts of iodine administered per unit of time. There is compelling evidence that, during early arterial contrast medium dynamics, increasing the iodine delivery rate using either faster injection flow rates or a higher iodine concentration contrast medium, or both has a profound influence on the magnitude of enhancement of the arterial system [5, 16, 17] of wellperfused organs, such as the renal cortex, pancreas and spleen [17, 18], and of hypervascular liver tumours [5 8]. The second factor for the differences we found in tumour conspicuity and arterial enhancement between MCCM and HCCM during the hepatic arterial phase is the discrepancy in the duration of the contrast material injection (on average, 30 s vs 24 s, respectively, for scheme B) using a fixed injection flow rate. Although our bolus-tracking technique compares favourably with that proposed by two recent investigations on the optimal timing for the acquisition of the hepatic arterial phase using fast MDCT systems [2, 3], it should be noted that our protocol did not adjust the post-triggering delay according to the contrast material injection duration. The small disparity in the average injection duration (approximately 6 s) between MCCM and HCCM could have resulted in suboptimal synchronisation of CT data acquisition with contrast medium enhancement [19, 20]. This effect could have been further compounded by the extremely narrow temporal window for CT data acquisition (less than 5 s for the entire abdomen) with our 64- section MDCT system. Another important finding of the present study is that, when the iodine delivery rate was kept constant (i.e. using a fixed injection duration and total iodine dose per kilogram of the patient s body weight), we observed no impact of contrast medium iodine concentration on both tumour conspicuity and arterial enhancement during the hepatic arterial phase. Although our clinical data are in accordance with those reported by Itoh et al [16], they seem to contradict the results of Awai et al [4], who showed increased conspicuity for hypervascular HCCs and higher enhancement of the abdominal aorta during the hepatic arterial phase using a lower as compared with a higher iodine concentration of contrast medium. While many factors could partly explain the differences between our results and those of Awai et al, including dissimilarities in study design (intraindividual vs interindividual), patients body sizes and shapes (mean body weight 71 kg in our study vs 59 kg in Awai s), tumour characteristics (e.g. size, histological grade, vascularity) and type and iodine concentration of contrast agents, we presume this discrepancy is most likely caused by our use of a saline chaser. Previous studies demonstrated that fast injection of a bolus of saline (5% dextrose solution) immediately after the intravenous administration of contrast material increases the efficiency of contrast medium use by avoiding dispersion of contrast material within the peripheral venous The British Journal of Radiology, August

7 704 The British Journal of Radiology, August 2011 Table 4. Contrast enhancement for the aorta, liver and portal vein for moderate-concentration contrast medium (MCCM) and high-concentration contrast medium (HCCM) in schemes A and B Scheme A (n516) Enhancement values (HU) MCCM HCCM Absolute difference p-value MCCM HCCM Absolute difference p-value Hepatic arterial phase Aorta ( 46.1) ( 58.5) 33.6 (24 to 71) ( 41) ( 22.9) 49.4 (23 to 75) [ ] [ ] [ ] [ ] Liver 16.8 ( 8.8) 17.6 ( 8.8) 0.8 (25 to 7) ( 5.9) 20.7 ( 6.8) 1.9 (23 to 6) [6 41] [3 31] [9 34] [7 35] Portal vein 92.1 ( 25.9) ( 54.8) 19.3 (211 to 50) ( 38.1) ( 47.7) 16.7 (216 to 50) [44 157] [27 235] [16 128] [27 159] Hepatic venous phase Aorta ( 16.6) ( 28.7) 8.4 (28 to 25) ( 12.2) ( 28) 6.5 (210 to 23) [92 144] [73 180] [97 142] [82 177] Liver 54 ( 11) 58 ( 20.1) 4.0 (27 to 15) ( 14.5) 60.2 ( 15.4) 7.3 (24 to 18) [37 75] [26 99] [33 73] [39 90] Portal vein ( 24.1) ( 52.6) 4.3 (225 to 33) ( 21.5) ( 42.7) 13.2 (213 to 39) [ ] [49 277] [97 168] [87 214] Delayed phase Aorta 73.3 ( 13) 79.2 ( 17.5) 5.9 (25 to 17) ( 15.8) 79.4 ( 11.1) 6.9 (23 to 17) [59 102] [54 123] [52 102] [58 98] Liver 39.9 ( 7.8) 43.4 ( 13.7) 3.5 (24 to 11) ( 6.9) 44.5 ( 8.1) 3.7 (22 to 9) [27 53] [24 81] [32 57] [33 56] Portal vein 76.2 ( 11.7) 83 ( 22) 6.8 (25 to 19) ( 14.6) 86.7 ( 11.8) 7.8 (22 to 18) [61 98] [45 136] [56 103] [70 111] Note that, for MCCM and HCCM, data are mean values with standard deviation in parentheses and ranges in square brackets. For the absolute difference, data are mean values with 95% confidence intervals in parentheses. HU, hounsfield units. Scheme B (n514) A Guerrisi, D Marin, R C Nelson et al

8 Effect of contrast material iodine concentrations during liver MDCT (a) (b) (c) Figure 2. Box plots of the tumour-to-liver contrast-to-noise ratio (CNR) of hepatocellular carcinoma (HCC) for moderateconcentration contrast medium (MCCM) (320 mg I ml 21 ) and high-concentration contrast medium (HCCM) (400 mg I ml 21 ) for groups A and B during (a) the hepatic arterial, (b) the hepatic venous and (c) the delayed phases. The solid line within each box corresponds to the median. The upper and lower bars of each box correspond to the first and third quartiles, respectively. The two vertical lines (whiskers) outside each box extend to the minimum and maximum values of the analysis variable (i.e. CNR variation across patients). The asterisk indicates statistical significance. compartment interposed between the injection site and the right atrium (approximately 40 ml in a normal-sized adult) [21]. The effect of a saline bolus is particularly beneficial when injecting lower volumes of a high iodine concentration contrast medium compared with larger volumes of a medium-concentration contrast medium, because a proportionally larger amount of iodine is dispersed in the peripheral venous compartment [4, 22]. Our study did not demonstrate an effect of the iodine concentration in the contrast medium on the conspicuity of HCC lesions and the degree of enhancement of the aorta, liver and portal vein during the hepatic venous and delayed phases. Our data are in accordance with those of previous investigations in patients with or without cirrhosis [23 25] and support the notion that the total amount of iodine, and not the iodine delivery rate, is a major determinant of vascular and parenchymal enhancement during the hepatic parenchymal phase [26]. In our study, although the contrast medium dose was tailored to the patient s body weight to achieve consistent enhancement among different patients [27], when the injection flow rate was kept constant, we found a strongly negative correlation between body weight and aortic enhancement during the hepatic arterial phase. This finding, which is in agreement with the results of another study by Awai et al [10], is probably related to the longer duration of injection of contrast material in heavier patients. It has been suggested that lengthening the injection duration for a fixed total iodine dose of contrast medium results in a linear decrease in arterial enhancement owing to progressive diffusion of contrast from the central blood compartment to the extravascular, The British Journal of Radiology, August

9 A Guerrisi, D Marin, R C Nelson et al (a) (b) Figure 3. Images obtained in a 57-year-old man (70 kg) with hepatitis C (Child Pugh A) and pathologically proven hepatocellular carcinoma (HCC) in scheme B (fixed injection rate, 4 ml s 21 ). (a) Transverse contrast-enhanced CT image obtained during the hepatic arterial phase with moderate-concentration contrast medium (MCCM) (injection duration, 30.6 s; iodine delivery rate, 18.3 mg I kg 21 s 21 ) reveals a 0.9 cm hypervascular lesion (black arrow) in the right liver lobe, which is barely visible against the background liver (contrast-to-noise ratio (CNR)51.6). (b) At follow-up CT imaging after 65 days, the corresponding image obtained during the same contrast-enhanced phase with high-concentration contrast medium (HCCM) (24.5 s, 22.8 mg I kg 21 s 21 ) demonstrates markedly increased conspicuity of this lesion (black arrow) (CNR57.1). (a) (b) (c) Figure 4. Scatterplots show the relationship between the patient s body weight and the contrast enhancement of (a) the aorta (during the hepatic arterial phase) and (b,c) the liver and portal vein (during the hepatic venous phase) for both injection schemes. In scheme B, aortic contrast enhancement demonstrated a strongly negative correlation with patients total body weight (r50.89 for moderate-concentration contrast medium (MCCM), p,0.0001; r50.84 for high-concentration contrast medium (HCCM), p50.008). For both contrast media, there was no significant correlation between aortic contrast enhancement and the patient s body weight in scheme A, and contrast enhancement of the liver and portal vein and the patient s body weight in both injection groups. 706 The British Journal of Radiology, August 2011

10 Effect of contrast material iodine concentrations during liver MDCT extracellular space of well-perfused organs [26]. This suggestion is supported by the lack of correlation we found between body weight and aortic enhancement using a fixed duration injection protocol. Our data also indicated a weakly positive association between the patient s body weight and contrast enhancement of the liver and portal vein during the hepatic venous phase for both contrast media and both injection schemes. This trend is in agreement with the results of a recent study [28] and supports the concept that a body weight-tailored approach for determining contrast medium dose may result in inconsistent enhancement among different patients. Such an approach could lead to (1) excessively high doses of contrast material in heavier patients, thus increasing the risk of renal toxicity and material cost, or (2) inappropriately low doses in smaller patients, thus compromising the diagnostic quality of the CT examination. Other more accurate descriptors of a patient s body composition, such as lean body weight, body surface area and blood volume, appear promising and are currently under investigation for reducing interpatient variability of contrast medium enhancement on abdominal MDCT [28 30]. Some potential limitations of our study merit consideration. First, the number of patients in each group of contrast material injection (groups A and B) is small. It must be emphasised, however, that our cross-over study design minimised the influence of many confounding variables such as body weight, cardiac output, and type and severity of cirrhosis by using each patient as his or her own control. Second, pathological confirmation of HCC was obtained in only 20 (65%) of 31 nodules. However, the presence of other proven HCC tumours, the small size of many nodules and the patient s clinical history frequently made biopsy of individual lesions unnecessary or impractical from an ethical standpoint. Third, despite our attempts to reduce possible confounding by restricting the time interval allowed between the two serial CT examinations to 3 months and by randomising the order in which individual contrast agents were assigned, a potential bias secondary to subtle changes over time in HCC characteristics cannot be entirely excluded. Fourth, although the tumour-toliver CNR has been validated as an objective metric for tumour conspicuity, particularly in the assessment of liver lesions, the clinical effect or relevance of our quantitative data on the sensitivity and specificity for the diagnosis of HCC remains to be determined. Finally, we compared two contrast materials with different molecular structures (monomeric vs dimeric). Although this could have partly affected our results, recent data in an animal model showed only a negligible effect of the contrast material molecular structure on the contrast enhancement of the thoracic aorta [31]. Conclusion Our study demonstrates that, for a fixed injection flow rate protocol, a higher concentration of iodine in the contrast medium significantly improves the conspicuity of HCC lesions and aortic enhancement during the hepatic arterial phase on 64-section MDCT in patients with cirrhosis. Increasing the iodine concentration of the contrast medium has little or no effect on either tumour conspicuity or the magnitude of vascular and hepatic enhancement if the duration of injection of the contrast material is kept constant (i.e. a constant iodine delivery rate) or if CT scanning is performed during the hepatic venous or the delayed phase. References 1. 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