Contrast material enhanced computed tomography (CT) is the most commonly used imaging modality for the detection and characterization of liver metasta

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1 Note: This copy is for your personal, non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at Hiroshi Kondo, MD Masayuki Kanematsu, MD Satoshi Goshima, MD Yuhei Tomita, RT Myeong-Jin Kim, MD Noriyuki Moriyama, MD Minoru Onozuka, PhD Yoshimune Shiratori, MD Kyongtae T. Bae, MD, PhD Body Size Indexes for Optimizing Iodine Dose for Aortic and Hepatic Enhancement at Multidetector CT: Comparison of Total Body Weight, Lean Body Weight, and Blood Volume 1 Purpose: Materials and Methods: To evaluate and compare total body weight (TBW), lean body weight (LBW), and estimated blood volume (BV) for the adjustment of the iodine dose required for contrast material enhanced multidetector computed tomography (CT) of the aorta and liver. Institutional review committee approval and written informed consent were obtained. One hundred twenty patients (54 men, 66 women; mean age, 64.1 years; range, years) who underwent multidetector CT of the upper abdomen were randomized into three groups of 40 patients each: (a) TBW group (0.6 g of iodine per kilogram of TBW), (b) LBW group (0.821 g of iodine per kilogram of LBW), and (c) BV group (men, 8.6 g of iodine per liter of BV; women, 9.9 g of iodine per liter of BV). Change in CT number between unenhanced and contrastenhanced images per gram of iodine and maximum hepatic enhancement (MHE) adjusted for iodine dose were examined for correlation with TBW, LBW, and BV by using linear regression analysis. ORIGINAL RESEARCH n GASTROINTESTINAL IMAGING 1 From the Departments of Radiology (H.K., M.K., S.G.), Radiology Services (M.K.), and Medical Informatics (Y.S.), Gifu University Hospital, 1-1 Yanagido, Gifu, Japan; Research Center of Brain and Oral Science (M.K., M.O.) and Department of Physiology and Neuroscience (M.O.), Kanagawa Dental College, Yokosuka, Japan; Department of Radiology, Kizawa Memorial Hospital, Minokamo, Japan (Y.T.); Department of Diagnostic Radiology, Yonsei University College of Medicine, Seoul, Korea (M.J.K.); Research Center for Cancer Prevention and Screening, National Cancer Center Hospital, Tsukiji, Japan (N.M.); and Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (K.T.B.). Received February ; revision requested April 1; revision received June 16; accepted July 8; fi nal version accepted July 28. Supported by the Grant for Scientifi c Research Expenses for Health Labour and Welfare Programs, Foundation for the Promotion of Cancer Research, and Research on Cancer Prevention and Health Services. Address correspondence to H.K. Results: Conclusion: In the portal venous phase, correlation coefficients for the correlation of change in CT number per gram of iodine with TBW for the aorta and liver were and , respectively, in the TBW group; and , respectively, in the LBW group; and and , respectively, in the BV group. In the liver, they were marginally higher in the LBW group than in the BV group ( P =.03). Adjusted MHE remained constant at 77.9 HU (standard deviation) in the LBW group with respect to TBW, but it increased in the TBW ( r = 0.80, P,.001) and BV ( r = 0.70, P,.001) groups as TBW increased. When LBW, rather than TBW or BV, is used, the iodine dose required to achieve consistent hepatic enhancement may be estimated more precisely and with reduced patient-to-patient variability. q RSNA, 2009 q RSNA, 2009 Radiology: Volume 254: Number 1 January 2010 n radiology.rsna.org 163

2 Contrast material enhanced computed tomography (CT) is the most commonly used imaging modality for the detection and characterization of liver metastases ( 1 ). For this application, it is crucial to achieve maximum hepatic enhancement (MHE) to improve tumor-to-liver contrast on images. Enhancement of the liver on CT images is affected by multiple factors (eg, contrast material dose [ 2 ], concentration [ 3 ], injection rate [ 4,5 ], and injection duration [ 6 ]; scan delay used after contrast material injection [ 7 ]; and patient-related factors such as body weight [ 2,8 ], lean body weight [LBW] [ 9 ], and cardiac output [ 10 ]). Ho et al ( 9 ) reported that calculation of contrast material dose on the basis of LBW leads to increased patient-to-patient uniformity of hepatic parenchymal and vascular enhancement. In particular, a patient s body weight and the amount of contrast material are closely related to the degree of contrast enhancement ( 8,11 18 ). For a given contrast material dose, the magnitude of contrast enhancement is reduced proportionally to the patient s weight. When reproducible contrast enhancement is desired for a number of different patients, the amount of iodinated contrast material administered should be adjusted according to each patient s body weight. Advances in Knowledge n Change in CT number per gram of iodine for the abdominal aorta and liver correlated more strongly with total body weight (TBW) when lean body weight (LBW) rather than TBW or blood volume (BV) was used to calculate the iodine dose. n The dose of iodine required to achieve a specified change in hepatic CT number may be calculated by using the following equation: I = LBW ( D HU/77.9), where I is iodine dose in grams, LBW is in kilograms, and D HU is the desired change in CT number. A heavier patient needs to be given more iodine than does a lighter patient to achieve the same magnitude of enhancement. It has been reported ( 8 ) that approximately 0.5 g of iodine per kilogram of total body weight (TBW) is required to achieve a 50-HU increase in contrast enhancement in the liver. This relationship can be described by the following equation: I = TBW( D HU/96), where I is the required amount of iodine in grams, TBW is given in kilograms, and D HU is the desired increase in contrast enhancement in Hounsfield units ( 8 ). TBW, however, may not be an optimal body size index for adjusting iodine dose. For example, blood volume (BV) and liver weight are not directly proportional to TBW ( 19 ). In particular, obese patients may have abundant body fat, which has a small vascular and interstitial space in the tissue and thus contributes little to dispersing or diluting the contrast material in the blood. In these patients, adjusting the iodine dose proportionally to TBW may lead to an overestimation of the amount of contrast material needed. We postulate that body size indexes other than TBW may be more appropriate for adjusting the required iodine dose. Thus, the purpose of our study was to evaluate and compare the patient s TBW, LBW, and estimated BV for the calculation of the iodine dose required for contrast-enhanced multidetector CT of the aorta and liver. Materials and Methods Patients This study was approved by the Kizawa Memorial Hospital institutional review committee, and patients gave written informed consent. During an 11-month period (November 2006 to October 2007), 159 patients suspected of hav- Implication for Patient Care n When adjusting iodine dose for patient body size in a CT protocol of the abdomen, it is preferable to factor in LBW instead of TBW or estimated BV. ing abdominal disease at previous ultrasonography (55%, 87 of 159) or laboratory evaluation (100%, 159 of 159) underwent unenhanced and dual-phase (portal venous and equilibrium phases) contrast-enhanced CT of the upper abdomen because previous examinations were not sufficient for diagnosis. Patients with cirrhosis of the liver were excluded prior to enrollment because such a functional disorder has a potential influence on hepatic blood flow. We excluded 39 patients for the following reasons: severe fatty liver (liver attenuation, 40 HU) ( n = 11), numerous liver metastases ( n = 10), previous total splenectomy ( n = 8), partial hepatectomy ( n = 8), and technical failure related to contrast material injection or mechanical problems during the CT examination ( n = 2). The remaining 120 patients (mean age, 64.1 years; range, years), including 54 men (mean age, 63.6 years; range, years) and 66 women (mean age, 64.5 years; range, years), constituted the study population. In these 120 patients, the clinical diagnoses were colorectal cancer ( n = 32), gastric cancer ( n = 26), lung cancer ( n = 12), abdominal pain ( n = 10), uterine cancer ( n = 9), malignant lymphoma ( n = 6), esophageal cancer ( n = 6), ovarian cancer ( n = 3), breast Published online before print /radiol Radiology 2010; 254: Abbreviations: BV = blood volume CI = confi dence interval LBW = lean body weight MHE = maximum hepatic enhancement TBW = total body weight Author contributions: Guarantors of integrity of entire study, H.K., M.K.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of fi nal version of submitted manuscript, all authors; literature research, H.K., M.K., S.G., N.M., M.O., K.T.B.; clinical studies, H.K., M.K., Y.T., Y.S.; statistical analysis, H.K., M.K., S.G., Y.T., M.O.; and manuscript editing, H.K., M.K., S.G., M.J.K., N.M., M.O., K.T.B. Authors stated no fi nancial relationship to disclose. 164 radiology.rsna.org n Radiology: Volume 254: Number 1 January 2010

3 Quantitative Image Analysis Mean CT numbers in Hounsfield units for the aorta and liver were measured (H.K., with 11 years experience in body CT) in all patients with a CT console monitor by placing a circular region-ofcancer ( n = 2), laryngeal cancer ( n = l), acute cholecystitis ( n = 5), cholelithiasis ( n = 3), nausea and vomiting ( n = 1), urinary stone ( n = 1), and fever of an unknown cause ( n = 3). Contrast Material Injection and CT Protocols Imaging was performed by using a multidetector CT scanner (LightSpeed QX/i; GE Healthcare, Milwaukee, Wis) with four sections at 2.5-mm detector collimation, a table feed speed of 15 mm per rotation, and a pitch of 1.5. The images were displayed as 40 5-mmthick sections with no intersection gap for each phase set. Gantry rotation time was 0.7 seconds, and acquisition time was 8.9 seconds. All patients were administered nonionic iodinated contrast material (iohexol, Omnipaque 300; Daiichi Sankyo, Tokyo, Japan) containing 300 mg of iodine per milliliter at body temperature. It was injected through a 21-gauge plastic intravenous catheter placed in an antecubital (96%, 115 of 120) or radial (4%, five of 120) vein over a fixed period of 30 seconds by using a power injector (Dual Shot GX; Nemoto Kyorindo, Tokyo, Japan). By using a random-number table, patients were prospectively randomized into three protocol groups of 40 patients each: (a) TBW group (mean age, 60.5 years; range, years), in which patients received 0.6 g of iodine per kilogram of TBW; (b) LBW group (mean age, 67.3 years; range, years), in which patients received g of iodine per kilogram of LBW; and (c) BV group (mean age, 64.3 years; range, years), in which men received 8.6 g of iodine per liter of estimated BV and women received 9.9 g of iodine per liter of estimated BV. LBW was determined by using the following equation ( 9 ): TBW(1 2 BFP/100), where BFP is body fat percentage as measured by using a commercially available body fat monitor (HBF-306; Omron, Kyoto, Japan) and TBW is given in kilograms. Estimated BV was calculated by using the following equations ( 18 ): [( H /2.54) ] [(TBW/0.4536) ] for men and 34.85[( H /2.54) ][(TBW/0.4536) ] for women, where H is height in centimeters. The amount of iodine administered per kilogram of LBW was determined on the basis of our previous results ( 20 ), in which 821 mg of iodine was prescribed in an adult patient with 23% body fat percentage to achieve a 60-HU hepatic enhancement increase in the portal venous phase. The amount of iodine administered per liter of BV was determined under the assumption that an adult Japanese patient of average height and weight (men: mean height of 171 cm, mean weight of 64 kg, mean BV of 4463 ml; women: mean height of 155 cm, mean weight of 52 kg, mean BV of 3148 ml) should be prescribed 600 mg of iodine per kilogram of TBW. A bolus-tracking software program (SmartPrep; GE Healthcare) was used to determine the time of initiation of diagnostic scanning following contrast material injection. This enabled realtime monitoring and the automatic calculation of CT numbers in a region of interest, as well as manual initiation of diagnostic scanning after the CT number in the aorta reached a threshold level increase of 100 HU. The region-ofinterest cursor for bolus tracking was placed in the aorta at a level just above the diaphragmatic dome; this level was also used as a starting position for diagnostic scans. Real-time low-dose (120 kvp, 50 ma) serial monitoring scans were initiated 5 seconds after the start of the contrast material injection. During this 5-second interval, patients were carefully monitored by a radiologist for extravasation or acute adverse events associated with contrast material injection. The unenhanced and dual-phase scans were initiated 45 seconds after reaching the bolus-tracking threshold level for the portal venous phase and 160 seconds afterwards for the equilibrium phase. interest cursor, which ranged in diameter from 10 to 30 mm on unenhanced and portal venous phase images. CT numbers in hepatic parenchyma were measured in eight areas according to the Couinaud segmental classification, and the numbers were averaged. Focal hepatic lesions, blood vessels, bile ducts, calcifications, and artifacts were carefully excluded from regions of interest. The degree of contrast enhancement was expressed as the change in CT number ( D HU), which was calculated by subtracting CT numbers on unenhanced images from those on contrast-enhanced images. Enhancement parameters obtained for the aorta and liver were change in CT number, change in CT number per gram of iodine, and adjusted MHE. The adjusted MHE was calculated on the basis of the method proposed by Heiken et al ( 8 ): D HU/( I /BW), where BW is either TBW (TBW and BV groups) or LBW (LBW group) in kilograms. Statistical Analysis Statistical analysis was performed by using statistical software (JMP, version 5; SAS Institute, Cary, NC). Analysis of variance and multiple comparisons with the Scheffé criterion ( 21 ) were used to evaluate the following factors in the three groups: patient age, TBW, body fat percentage, contrast material injection rate, and change in CT number of the abdominal aorta and liver. Linear regressions between change in CT number per gram of iodine and TBW, LBW, and BV were evaluated for aortic and hepatic enhancement. Adjusted MHE was also assessed for correlations with TBW, LBW, and BV. We calculated 95% confidence intervals (CIs) for variables. Correlation coefficients were compared among the three groups by using the Fisher Z transformation with a Bonferroni adjustment. P values of less than.017 were considered to indicate significant differences. Results No significant differences were found between the three groups in terms of patient age, TBW, body fat percentage, Radiology: Volume 254: Number 1 January 2010 n radiology.rsna.org 165

4 injection rate, or volume of contrast material ( Table 1 ). No significant differences were found in the aorta or liver for the mean change in CT number among the three groups ( Table 2 ). When assessing the change in CT number per gram of iodine for the aorta during the portal venous phase in comparison to TBW, we found strong inverse correlations in the TBW ( r = ; 95% CI: , ; P,.001) and LBW ( r = ; 95% CI: , ; P,.001) groups and moderate correlation in the BV group ( r = ; 95% CI: , ; P,.001) ( Fig 1 a ). There were no significant differences among the three groups ( P =.25.8). When assessing the change in CT number per gram of iodine for the liver during the portal venous phase in comparison to TBW, we found strong inverse correlations in the TBW ( r = ; 95% CI: , ; P,.001) and LBW ( r = ; 95% CI: , ; P,.001) groups and moderate correlation in the BV group ( r = ; 95% CI: , ; P,.001) ( Fig 1b ). Correlations were higher with LBW than with BV ( P =.03). Change in CT number per gram of iodine in the aorta and liver correlated with TBW most strongly in the LBW group, although there were no significant differences in the correlation coefficient among the three groups ( P =.03.34). Adjusted MHE had strong direct correlation with TBW in the TBW and BV groups ( r = 0.80 and 0.70, respectively; both P,.001) ( Fig 2 ). However, the adjusted MHE is constant in the LBW group ( r = , P =.49). Mean adjusted MHE in the TBW, LBW, and BV groups was HU , 77.9 HU , and HU , respectively. Discussion Compared with extensive published studies ( 2,8,12 ) evaluating the effect of various patient and contrast material administration parameters (eg, contrast material dose, injection rate, scan delay) on hepatic enhancement, the effect of body weight has been infrequently addressed. Despite the well-established association between hepatic CT enhancement and body weight ( 12 ), a fixed dose of iodinated contrast material, which is based on the assumption of a standard patient size, is commonly used. This approach is inappropriate, particularly when a patient is quite heavy or quite light. In heavier patients, contrast enhancement achieved with the standard iodine dose is too low and may not provide adequate tumor-to-liver contrast on images for detection and characterization of tumors. In lighter patients, an excessive amount of contrast material is undesirable because it may be associated with a decrease in renal function. The use of unneeded contrast material may also incur unnecessary costs. In our study, we sought to identify the optimal body size index for determining the iodine dose required for abdominal CT. During contrast-enhanced CT of the liver, because the dose of iodine administered is directly related to MHE, MHE could be inversely related to TBW when a fixed iodine dose is used ( 8,12 ). Similarly in our study, change in CT number per gram of iodine in the abdominal aorta and liver correlated inversely with TBW strongly so during the portal venous phase. In our study, change in CT number per gram of iodine in the abdominal aorta and liver correlated more strongly with TBW in the LBW group than in the TBW and BV groups, which suggests that LBW may better serve for adjusting the iodine dose for patient size. Table 1 Patient Data in the Three Groups Factor TBW Group ( n = 40) LBW Group ( n = 40) BV Group ( n = 40) P Value Age (y) ( ) ( ) ( ).12 TBW (kg) ( ) ( ) ( ).76 Body fat (%) ( ) ( ) ( ).89 Contrast material Injection rate (ml/sec) ( ) ( ) ( ).73 Volume (ml) ( ) ( ) ( ).73 Note. Data are ranges, with means 6 standard deviations in parentheses. Table 2 Change in Contrast Enhancement in the Three Groups Location TBW Group ( n = 40) LBW Group ( n = 40) BV Group ( n = 40) Abdominal aorta ( ) ( ) ( ) Liver ( ) ( ) ( ) Note. Data are ranges, with means 6 standard deviations in parentheses, expressed in Hounsfi eld units. There were no signifi cant differences among the three groups for any factor ( P =.07.9). 166 radiology.rsna.org n Radiology: Volume 254: Number 1 January 2010

5 Figure 1 Figure 1: Scatterplots show relationship between change in CT number per gram of iodine ( DHU/g) in (a) aorta and (b) liver during portal venous phase and TBW. (a) In aorta, with linear regression analysis, strong inverse correlations existed in TBW ( r =20.71, P,.001) and LBW ( r = 20.80, P,.001) groups, and moderate correlation existed in BV group ( r = 20.68, P,.001). (b) In liver, with linear regression analysis, strong inverse correlations existed in TBW ( r = 20.79, P,.001) and LBW ( r = 20.86, P,.001) groups, and moderate correlation existed in BV group ( r = 20.66, P,.001). Figure 2 Figure 2: Scatterplots show relationship between adjusted MHE (amhe) during portal venous phase (in CT number per gram of iodine per kilogram of TBW ) and TBW. Adjusted MHE had strong direct correlation with TBW in TBW and BV groups ( r = 0.80 and 0.70, respectively; both P,.001). However, adjusted MHE was constant in LBW group ( r = 20.11, P =.49). Adjusted MHE was calculated by using TBW in TBW and BV groups and by using LBW in LBW group. Heiken et al ( 8 ) also advocate the use of a formula incorporating MHE adjusted for total iodine dose and TBW. Using this formula, one can calculate the total iodine dose needed to achieve a desired level of hepatic enhancement in a pa- tient of known TBW. The formula used was as follows: MHE = D HU/( I /TBW), where MHE is reported as a constant Radiology: Volume 254: Number 1 January 2010 n radiology.rsna.org 167

6 3. Awai K, Takada K, Onishi H, Hori S. Aortic and hepatic enhancement and tumor-tovalue of 96 HU. For example, the iodine dose required for a change of 50 HU would be g of iodine per kilogram of TBW. However, in our study, adjusted MHE was not constant and showed strong direct correlations with TBW in the TBW and BV groups. On the other hand, adjusted MHE remained virtually constant as LBW varied, with a mean of 77.9 HU. We infer that if iodine load is determined by using LBW, the patient-to-patient enhancement variability caused by different amounts of body fat could be minimized. According to our results, the dose of iodine required for a hepatic enhancement change of 50 HU would be g of iodine per kilogram of LBW. When the amount of iodine required is estimated by using LBW, the amount is higher for lean patients and lower for obese patients than when it is estimated by using TBW. For example, the iodine dose required to achieve a 50- HU change in hepatic enhancement in a patient with TBW of 80 kg is estimated to be 41.7 g by using the TBW protocol. When a standard body fat percentage of 23% is assumed, the iodine dose is estimated to be 39.5 g by using the LBW protocol. If body fat percentage is assumed to be 40%, the iodine dose is estimated to be 30.8 g. This example illustrates that the iodine dose calculated on the basis of TBW may be an overestimate for obese patients. Ho et al ( 9 ) reported that calculations of contrast material dose on the basis of measured LBW marginally increased patient-to-patient uniformity with respect to hepatic parenchymal and vascular enhancements. Our result supports this observation. Furthermore, we were able to derive an equation for iodine dose estimation that would be clinically useful for the adjustment of iodine dose not only for body weight but also for body fat percentage. The equation is as follows: I = LBW( D HU/77.9). Bae et al ( 22 ) reported that aortic enhancement reflected the accumulation of contrast material in the central BV by using pharmacokinetic analysis and an experimental porcine model. However, there has been no study that investigated the direct relationship be- tween aortic or hepatic contrast enhancement and BV. The correlation of BV with aortic contrast enhancement is probably higher during the arterial phase than during the portal venous phase. In our study, CT images were not acquired during the arterial phase. Some limitations of our study should be mentioned. First, as patient TBW or body fat percentage increases, contrast-to-noise ratios decrease owing to the beam-hardening effect, which suggests that iodine dose may not be effectively reduced in obese patients unless x-ray tube current is increased to compensate for this factor. However, we did not take this factor into account. Second, the TBWs of the subjects in our study are lower than those reported in the European and American populations. Further study may be necessary to test and confirm our findings in a patient population with larger TBWs. Third, we did not evaluate tumorto-liver contrast on images, vascular enhancement, and subjective image quality; additional study is required to determine the optimal iodine doses that are based on LBW and are required for efficient tumor detection and vascular enhancement. In conclusion, when LBW, rather than TBW or BV, is used, the dose of iodine required to achieve a consistent change in hepatic CT number may be more precisely estimated, with reduced patient-to-patient variability. The dose of iodine required to achieve a specified change in hepatic enhancement may be calculated by using the following equation: I = LBW( D HU/77.9). References 1. Haider MA, Amitai MM, Rappaport DC, et al. 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