Ultrasound Evaluation of Gallbladder Dyskinesia: Comparison of Scintigraphy and Dynamic 3D and 4D Ultrasound Techniques

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1 Gastrointestinal Imaging Original Research Irshad et al. Ultrasound of Gallbladder Dyskinesia Gastrointestinal Imaging Original Research bid Irshad 1 Susan J. ckerman 1 Kenneth Spicer 1 Nathanial aker 2 my Campbell 1 Munazza nis 1 Mehwish Shazly 1 Irshad, ckerman SJ, Spicer K, et al. Keywords: biliary dyskinesia, cholecystitis, gallbladder emptying, sonography DOI:1.2214/JR Received July 27, 21; accepted after revision pril 25, Department of Radiology, Medical University of South Carolina, 169 shley ve, Charleston, SC ddress correspondence to. Irshad (irshada@musc.edu). 2 Department of iostatistics and Epidemiology, Medical University of South Carolina, Charleston SC. JR 211; 197: X/11/ merican Roentgen Ray Society Ultrasound Evaluation of Gallbladder Dyskinesia: Comparison of Scintigraphy and Dynamic 3D and 4D Ultrasound Techniques OJECTIVE. The purpose of this study was to determine the efficacy of 3D and 4D ultrasound in correlation with hepatoiminodiacetic acid (HID) scanning for calculating gallbladder ejection fraction (EF). SUJECTS ND METHODS. prospective study was conducted with 4 adult patients with suspected gallbladder dyskinesia. Cholecystokinin-provoked 99m Tc-HID scintigraphy was performed, and concurrent 3D and 4D ultrasound images of the gallbladder were obtained before cholecystokinin infusion and 2, 3, and 4 minutes after infusion. The EF values calculated from the ultrasound images and HID scan were compared. RESULTS. The gallbladder EF values (mean ± standard error of the mean) calculated 2 minutes after cholecystokinin infusion from HID scans and 3D and 4D ultrasound images were 54.1% ± 5.%, 58.9% ± 6.3%, and 62.8% ± 5.5%. Thirty minutes after infusion the EF values were 56.3% ± 4.7%, 56.9% ± 5.7%, and 59.1% ± 4.6%. The numbers of patients with an EF less than 5% were 14, 12, and 13, and the numbers with an EF less than 35% were 1, seven, and eight. For the patients with an EF less than 5%, the kappa agreement between HID scanning and 3D ultrasound was.89 (95% CI,.73 1.), between HID scanning and 4D ultrasound was.83 (95% CI,.65 1.), and between 3D and 4D ultrasound was.83 (95% CI,.64 1.). CONCLUSION. oth 3D and 4D ultrasound techniques correlate well with HID scanning for calculating gallbladder EF in patients with suspected biliary dyskinesia. P atients with gallbladder (biliary) dyskinesia frequently have right upper quadrant pain. lthough ultrasound is considered the modality of choice for evaluating gallstones [1], it currently has a limited application in evaluating functional biliary disease, such as gallbladder dyskinesia. Gallbladder dyskinesia has traditionally been evaluated by assessment of gallbladder contractility in terms of ejection fraction (EF) calculated from a hepatoiminodiacetic acid (HID) scan [2 6]. Patients with symptoms and a low gallbladder EF are frequently treated with cholecystectomy [6 9]. HID scanning (cholescintigraphy, biliary scintigraphy, cholecystokininprovoked HID scanning) is the imaging modality most commonly used to evaluate gallbladder EF, but there have been controversies regarding the lack of standardization of HID scanning technique [1, 11]. Various centers have been using different rates of cholecystokinin infusion and different cutoff values of EF to differentiate a normal from an abnormal EF [12 14]. The Society of Nuclear Medicine has been trying to establish a protocol, but discrepancy in current clinical practice exists among institutions. The role of ultrasound in calculating gallbladder EF has yet to be established and standardized because not many studies have been conducted in this field [15 24]. In clinical practice, ultrasound has an established role in evaluation of the gallbladder and is generally used as the first imaging modality for evaluating gallbladder disease. ecause ultrasound imaging does not involve ionizing radiation and is more readily available than HID scanning, one may intuitively think that if increased accuracy and consistency can be achieved in the measurement of gallbladder volume (hence EF) with ultrasound, ultrasound may be a relatively easy and accurate alternative method of assessing gallbladder contractility and EF. In this study, we tried to determine whether gallbladder EF calculated with ultrasound correlates with EF calculated with HID scanning. In addition to the conventional 3D volume JR:197, November

2 Irshad et al. calculation method used by some investigators, we used a 4D calculation method and compared the gallbladder EF measured with ultrasound with that measured with HID scanning. We also calculated in vitro the volume of water-filled balloon phantoms (simulating the gallbladder shape) to assess the accuracy of 3D and 4D ultrasound for this purpose. Fig year-old woman with chronic right upper quadrant pain. Three-dimensional ultrasound image acquisition from two static images., Ultrasound image shows transducer placed along long axis of gallbladder for measurement of maximum length and anteroposterior dimension (height) (calipers 1 and 2)., Ultrasound image obtained after 9 rotation of transducer (transverse image of gallbladder) shows maximum transverse gallbladder diameter (width) (calipers). Fig year-old woman with chronic postprandial pain. Four-dimensional ultrasound image acquisition., Ultrasound images obtained before cholecystokinin (CCK) administration for 4D volume cine clip through gallbladder (G) show last projection (sixth rotation [ROT 6]). Gallbladder perimeter (contour) is manually traced to include asymmetric gallbladder neck (top left). t completion of last tracing, volume is automatically calculated, and surface-rendered view of gallbladder appears showing result of calculation (bottom right)., Four-dimensional ultrasound image generated from surface-rendered volume overlays before and after cholecystokinin administration is used for visual assessment of gallbladder contractility. Subjects and Methods Subjects This prospective study was conducted in compliance with HIP regulations after institutional review board approval was obtained. Forty patients who met the inclusion criteria consecutively enrolled in the study from ugust 28 to July 29. Clinicians had referred the patients to our nuclear medicine department for HID scanning. ll of the patients had undergone initial evaluation by the referring clinicians, and gallbladder dyskinesia was clinically suspected on the basis of the symptoms (e.g., postprandial abdominal pain, chronic right upper quadrant pain, epigastric pain). The study model included concurrent use of ultrasound for evaluating gallbladder contraction 114 JR:197, November 211

3 Ultrasound of Gallbladder Dyskinesia Gallblader Volume (ml) Time Since CCK (min) (EF) in addition to the routine HID scan. Informed consent was obtained from all patients according to our institutional review board protocol. ll adult patients (men and women older than 18 years) with an adequately visualized gallbladder on a screening ultrasound scan were included in the study. The exclusion criteria were presence of gallstones or poor visibility of the gallbladder on a screening ultrasound scan, unstable medical condition, and critical illness. Ultrasound Imaging The same ultrasound system (Logiq 9, GE Healthcare) was used for all ultrasound imaging. ll ultrasound measurements were obtained by one of two sonographers trained ( 1-hour training session) to scan and obtain 3D and 4D ultrasound measurements of the gallbladder. efore HID scanning, screening ultrasound was performed in all cases to rule out gallstones and to assess adequate visibility of the gallbladder. fter inclusion in the study, patients lay supine on the nuclear medicine scanning table to proceed with HID scanning according to department protocol. During acquisition of the HID scan (while the patient was supine on the table), 3D and 4D ultrasound images were obtained before administration of cholecystokinin and 2, 3, and 4 minutes after the start of cholecystokinin infusion. Gallbladder volumes were calculated during postprocessing from 3D and 4D ultrasound images obtained at these four time points. The gallbladder EF at various time TLE 1: Mean Gallbladder Volume (ml) Over Time 4D 3D Fig. 3 Graph shows results of comparative analysis of mean gallbladder volume calculated with 3D and 4D ultrasound techniques over time after cholecystokinin (CCK) infusion in 4 patients. points was calculated with the following equation: EF = [(volume before cholecystokinin infusion volume after cholecystokinin infusion) / volume before cholecystokinin infusion] 1. The peak (maximum) EF was considered the highest EF obtained on any of the three scans obtained after cholecystokinin administration. Three-Dimensional Ultrasound Method ll 3D ultrasound images were obtained with a standard convex-array 2- to 5-MHz transducer. During real-time scanning, the transducer was placed over the gallbladder area, and the long axis was aligned with the longest gallbladder dimension. The first static ultrasound image was obtained along the longest dimension of the gallbladder (longitudinal image of the gallbladder). The maximum gallbladder length (L) and anteroposterior dimension (height [H]) were measured on this image (Fig. 1). The transducer was then rotated in a right-angle plane for viewing of the cross-section of the gallbladder, and the maximum transverse diameter was found. second static image was obtained in this plane, and the greatest transverse gallbladder diameter (width [W]) was measured (Fig. 1). ll measurements were obtained from inner wall to inner wall. The 3D image acquisition, which generally lasted 1 2 minutes, was followed by 4D gallbladder volume acquisition, which also lasted 1 2 minutes. The gallbladder volume obtained with the 3D method was mathematically calculated at a later stage with the following equation for a prolate ellipsoid: Time Since Cholecystokinin Infusion (min) 3D Ultrasound 4D Ultrasound Difference ml % volume = (L H W).523. The gallbladder wall thickness was measured in each case. Four-Dimensional Ultrasound Method The 4D ultrasound images of the gallbladder were acquired with a square transducer (4D3-CL, GE Healthcare). The 4D transducer was placed over the gallbladder and positioned adequately. With the transducer stationary in its position, a 6-second volume sweep in the form of a cine clip was performed from the gallbladder neck to the fundus to complete the 4D image acquisition. t postprocessing, six projections (called rotations) of the gallbladder were isolated from the volume data, and the gallbladder perimeter was manually traced at the inner gallbladder walls in each projection (Fig. 2). The actual volumes were automatically calculated with the virtual organ calculation software, which also generated a surface-rendered view for visual assessment (Fig. 2). In Vitro alloon Volume To assess and compare the accuracy of volume calculation with the 3D and 4D ultrasound methods, we conducted an experiment using 3 balloons filled with varying amounts of water to simulate the shape of the gallbladder. Into each of these balloons we injected a predetermined amount of water varying from 5 to 11 ml and tied the balloon at its neck. These balloons were placed in a phantom (turkey breast filled with ultrasound gel), and the volumes were calculated with the 3D and 4D ultrasound techniques. The sonographers were blinded to the actual injected volume. The calculated balloon volume in each case was compared with the actual injected volume. Interoperator Variability In an assessment of interoperator variability, 2 healthy volunteers underwent scanning by two sono graphers who measured gallbladder volumes with 3D and 4D ultrasound. oth operators independently scanned and measured the gallbladder volumes in each volunteer while blinded to the other operator s findings. The scan interval between operators was less than 5 minutes in each efore 24.6 ± ± ± ± ± ± ± ± Note Values are mean ± standard error. a djustment with Tukey honestly significant difference. t p a JR:197, November

4 Irshad et al. TLE 2: Mean Ejection Fraction (%) Over Time Time Since Cholecystokinin Infusion (min) Scintigraphy case. The volume calculations were performed later at postprocessing, and the difference in calculated volumes in each case was noted. Mean observerdetermined volumes were compared between observers by paired Student t test for correlated data. Interobserver agreement was assessed with the concordance correlation coefficient. Hepatoiminodiacetic cid Scanning ccording to routine protocol in our department, scintigraphy was performed with one of two gamma scanners (Vertex V 6 or Skylight dual head detector, Philips Healthcare). The radiotracer (6 8 mci 99m Tc) and cholecystokinin (.2 µg/kg body weight) were infused IV over 2 minutes to induce gallbladder contraction. HID scanning was begun after the baseline screening ultrasound scan. Scintigraphic images ( ) of the gallbladder were acquired at 3-second intervals until the gallbladder was adequately visualized. fter optimal visualization, cholecystokinin infusion was started and continued for 2 minutes. Scintigraphic imaging was continued for 3 6 minutes after the start of cholecystokinin infusion until the peak (maximum) EF was identified. The gallbladder EF calculated with HID scanning was compared with the EF calculated with 3D and 4D ultrasound in each case. For analyzing and comparing our results, we used two arbitrary cutoff EF values (35% and 5%) to differentiate normal from abnormal EF. Ultrasound 3D Ultrasound vs Scintigraphy Statistical nalysis Descriptive statistics were mean and standard error of the mean [SEM] for continuous variables and percentage for categoric variables. Data were analyzed by paired Student t test, oneway analysis of variance, and repeated-measures analysis of variance. The Tukey honestly significant difference test was used for all pairwise comparisons [25]. One-way analysis of variance was used to determine differences in peak EF with the three measurement methods. The repeatedmeasures analysis of variance model was used to test differences in longitudinal measurement methods, linear and quadratic time trends, and possible time by measurement interactions for the gallbladder volume estimates. Effects of both time and measurement method were modeled within subject. Cohen kappa statistics [26] were used as a measure of agreement in classification of normal and abnormal EF for the three methods of measurement. Natural logarithms of the volume measurements were used in the analysis to correct for the lack of normality in the residuals. In analysis of balloon simulation data, generalized linear model analysis was used to assess differences between the 3D and 4D methods. Percentage error was calculated as a secondary measure of precision, and the Lin concordance correlation coefficient [27] was used as a measure of reproducibility between the 3D or 4D ultrasound measurement and the p 4D Ultrasound vs Scintigraphy 3D 4D Unadjusted Tukey HSD Unadjusted Tukey HSD ± ± ± ± ± ± N 35.1 ± ± 5.2 Peak 58.3 ± ± ± Note Values are mean ±standard error. HSD = honestly significant difference, N = not applicable. Ejection Fraction (%) D US 3D US NM S Measurement Technique Fig. 4 Graph shows results of comparative analysis of peak ejection fraction calculated with 4D and 3D ultrasound (US) and biliary scintigraphy in 4 patients. Pairwise comparisons are as follows: 4D versus 3D, p =.284; 4D versus scintigraphy, p =.2; 3D versus scintigraphy, p =.73. actual volume. Statistical analysis was performed with SS software (version 9.2, SS Institute). dditional plots and analysis were performed with the R program (version 2.7., R Project). Patient Outcome The patients underwent follow-up for 1 year after imaging to determine surgical outcome. For patients who underwent cholecystectomy within this period, the pathologic results on the cholecystectomy specimens were reviewed for signs of inflammation. The pathologic findings were compared with the gallbladder EF calculated with the various imaging techniques. The cholecystectomy patients underwent follow-up for 3 months after surgery for evaluation of relief of symptoms. Results The mean age of the 4 patients was 43.2 ± 2.3 years ([SEM] range, 2 72 years), and five of the subjects (12.5%) were men. The gallbladder volume obtained with 3D ultrasound before cholecystokinin administration (mean, 24.6 ± 2.8 [SEM] ml; range ml) was lower than the volume obtained with 4D ultrasound (31.4 ± 3.9 ml; range, ml) (t 14 = 4.4; p =.2). The overall gallbladder volumes after cholecystokinin administration differed significantly between the 3D and 4D methods (F 1,246 = 1.2; p =.2). The 3D method of volume measurement yielded consistently lower values than the 4D method (F 1,246 = 1.2; p =.2). significant (positive) quadratic time effect also was observed in the data (F 1,251 = ; p <.1), indicating recovery in gallbladder volume within the 4 minutes after cholecystokinin infusion (Fig. 3). fter administration of cholecystokinin, the 4D gallbladder measurement was significantly greater than the 3D measurement at all time points (p <.5) (Table 1). The mean EF at each time point for each measurement method and the peak EF for each are shown in Table 2 and Fig- 116 JR:197, November 211

5 Ultrasound of Gallbladder Dyskinesia Ejection Fraction (%) Calculated With 3D Ultrasound Ejection Fraction (%) Calculated With Scintigraphy ure 4. nalysis of peak EF showed a significant main effect of the measurement method (F 2,39 = 5.66; p =.7). The peak EF measured with the 4D ultrasound method (65.9% ± 4.9%) was significantly greater than the peak found with the standard HID scintigraphic technique (58.3% ± 4.7%) (t 39 = 3.28; p =.2). The peak EF calculated with the 3D ultrasound method (63.7% ± 5.7%) was only marginally greater than that calculated with HID scintigraphy (58.3% ± 4.7%) (t 39 = 1.84; p =.73). The peak EF was not significantly different between the 3D (63.7% ± 5.7%) and 4D (65.9% ± 4.9%) ultrasound methods of measurement (t 39 = 1.9; p =.284). Figure 5 shows the relation between peak EF measured with the 3D and 4D ultrasound methods compared with peak EF calculated with HID scanning. In the assessment of normal EF categoric cutoffs of 5% and greater and 35% and greater, the numbers of patients with an EF less than 5% according to HID scintigraphic and 3D and 4D ultrasound results were 14, 12, and 13; the numbers with an EF less than 35% were 1, seven, and eight (Table 3). Twelve of the 14 patients (85.7%) who had less than 5% EF with HID scintigraphy also had less than Ejection Fraction (%) Calculated With 4D Ultrasound Ejection Fraction (%) Calculated With Scintigraphy 5% EF with both 3D and 4D ultrasound. Seven of the 1 patients (7%) who had less than 35% EF with HID scintigraphy also had less than 35% EF with 3D and 4D ultrasound. The kappa values for agreement between HID scintigraphy and 3D and 4D ultrasound for the cutoff values of 35% and 5% for abnormal EF are shown in Table 3. mong the 27 patients who had greater than 5% EF calculated from HID scans, 26 (96.3%) also had greater than 5% EF with the 4D ultrasound method; all 27 (1%) had greater than 5% EF with the 3D ultrasound method. In all cases, the kappa value was adequate to determine that the measures were concordant in determining whether the EF of a gallbladder was healthy [28]. The gallbladder wall thickness in all 4 patients measured less than 4 mm. Interoperator Variability Results in 2 Volunteers The mean 3D ultrasound measured volume did not differ significantly between observer 1 and observer 2 (12.5 [SD, 5.5] ml versus 12.1 [SD, 5.3] ml; p =.4); 18 of the 2 measurements (9%) by observer 2 were within 2% of the volume estimates of observer 1. Similarly, the mean volume between observers for the Fig. 5 Lin concordance correlation coefficient and regression plots., Graph shows relation between peak ejection fraction calculated with 3D ultrasound and that calculated with scintigraphy (concordance correlation coefficient,.831; 95% CI, ). Dashed line indicates line of perfect agreement., Graph shows relation between peak ejection fraction calculated with 4D ultrasound and that calculated with scintigraphy (concordance correlation coefficient,.856; 95% CI, ). Dashed line indicates line of perfect agreement. TLE 3: Number of Patients With Less Than Normal Peak Ejection Fraction and Measurement greement Measurement Method No. of Patients with EF < 35% a No. of Patients with EF < 5% a greement (k) b EF < 35% EF < 5% 3D Ultrasound 4D Ultrasound 3D Ultrasound 4D Ultrasound Scintigraphy 1 (25.) 14 (35.).78 (.54 1.).71 (.45.97).89 (.73 1.).83 (.65 1.) 3D ultrasound 7 (17.5) 12 (3.).92 (.76 1.).83 (.64 1.) 4D ultrasound 8 (2.) 13 (32.5) Note EF = ejection fraction. a Values in parentheses are percentages. b Values in parentheses are ranges. 4D measurements did not differ significantly (11.1 [SD, 5.] ml versus 1.3 [SD, 4.] ml; p =.8); 17 of the 2 (85%) measurements by observer 2 were within 2% of those of observer 1. Strong agreement also was found between the two observers for the 3D and 4D measurements of gallbladder volume (3D concordance correlation coefficient,.92 [95% CI,.8.97]; 4D concordance correlation coefficient,.9 [95% CI,.78.95]). alloon Volume mong the 3D volume measurements in 3 balloons, 83.3% (25/3) of the estimated volumes were within 2% of the actual volume; 1% of the 4D measurements were within 2%. When the error cutoff was reduced to 5%, only four of the 3D measurements (13.3%) were less than 5% different from the actual volume, but with the 4D method, 2 measurements (66.7%) were less than 5% different (Figs. 6 and 7 and Table 4). The results with the model show a significant difference in measurement by method (F 2,3 = 4.79; p =.16); use of the 3D ultrasound method resulted in consistent underestimates of the true volume. The resulting concordance correlation coefficient between the JR:197, November

6 Irshad et al. Volume Measured With 3D Ultrasound (ml) Volume Measured With 4D Ultrasound (ml) ctual Volume (ml) ctual Volume (ml) 3D ultrasound volume estimate and the actual volume was.963 (95% CI, ) (Fig. 6). For the 4D ultrasound method, the coefficient was.993 (95% CI, ) (Fig. 7). oth results indicated a strong level of reproducibility between the 3D and 4D ultrasound volume estimates and the true values. However, the 4D ultrasound estimate more closely matched the true volume than did the 3D ultrasound estimate (p <.5). Patient Outcome Follow-up information was available for 36 of 4 patients; 11 patients underwent cholecystectomy. Chronic cholecystitis was present in 9 of 11 specimens; the findings in the other two specimens were normal. ll cholecystectomy patients who had an EF less than 5% with the HID, 3D, and 4D methods scans had pathologic evidence of chronic cholecystitis. Six of 14 patients who had a less than 5% EF with the HID method underwent cholecystectomy, and all had chronic cholecystitis. Five of Difference etween 3D Measured and ctual Volume (ml) Difference etween 4D Measured and ctual Volume (ml) ctual Volume Measured (ml) ctual Volume Measured (ml) these six patients experienced relief of symptoms after surgery. mong the 12 patients who had a less than 5% EF with the 3D ultrasound method, five underwent cholecystectomy. ll of these patients had evidence of chronic cholecystitis and experienced symptomatic relief after surgery. Five of the 13 patients who had a less than 5% EF with the 4D ultrasound method underwent cholecystectomy, and all five had evidence of chronic cholecystitis and symptomatic relief within 3 months of surgery. Evaluation for symptomatic improvement within 3 months of surgery showed one patient was lost to follow-up and one patient had biloma as a complication. One of the other nine patients had persistent pain, and eight patients had symptomatic relief. Discussion Oral cholecystography was the first imaging modality used to assess gallbladder dyskinesia, and persistence of contrast enhancement more than 24 hours after administration Fig. 6 alloon volume calculated with 3D ultrasound versus actual injected volume., Graph shows Lin concordance correlation coefficient and regression plot (concordance correlation coefficient,.963; 95% CI, ). Solid line indicates regression axis; dashed line, perfect concordance., Graph shows Lin concordance correlation and land-ltman plot. Solid line indicates mean difference; dashed line, mean difference ± 2 SD. Fig. 7 alloon volume calculated with 4D ultrasound versus actual injected volume., Graph shows Lin concordance correlation and regression plot (concordance correlation coefficient,.993; 95% CI, ). Solid line indicates regression axis; dashed line, perfect concordance., Graph shows Lin concordance correlation and land-ltman plot. Solid line indicates mean difference; dashed line, mean difference ± 2 SD. was considered to indicate the presence of gallbladder disease [29, 3]. The symptoms of gallbladder dyskinesia (resulting in low EF) are considered secondary to underlying chronic cholecystitis in these patients, and clinical improvement after cholecystectomy has been found in many studies [7 9]. Gallbladder imaging with provocative testing with cholecystokinin or fatty meals has been tried with oral cholecystography [15, 16], dynamic ultrasound [15 24], and HID scintigraphy [2 6]; however, lack of standardization of technique has been a problem with all of these methods. The duration of cholecystokinin infusion has varied from 3 to 6 minutes depending on experience [12 14]. iliary scintigraphy has been used for a long time, but the technique continues to face issues of standardization. Cutoff EF values ranging from 35% to 65% have been used in different studies [1]. Consequently, it has been a problem to use any particular cutoff value to determine which patients may benefit from cholecystectomy. 118 JR:197, November 211

7 Ultrasound of Gallbladder Dyskinesia TLE 4: alloon Data: Percentage Error in Measurement Estimate Compared With ctual Value Measurement Method Percentage Error Difference From ctual Volume (ml) Mean ± Standard Error Median Interquartile Range 2% 5% 3D ultrasound 14. ± (83.3) 4 (13.3) 4D ultrasound 1.3 ± (1.) 2 (66.7) Note Values in parentheses are percentages. Studies have shown a 7 9% incidence of chronic cholecystitis associated with an abnormal HID scan findings [31 35]. Previous researchers who used ultrasound to evaluate gallbladder EF used 3D technique, and most of them measured gallbladder volume using the equation for a prolate ellipsoid [18 2, 36, 37]. arr et al. [18], in a comparative study of cholecystokininprovoked scintigraphy and sonography performed with 2 healthy volunteers, found a consistently lower EF with scintigraphy (49%) than with ultrasound (66.3%). The results of our study supported those findings and showed lower EF with the scintigraphic (58.3%) than with either the 3D (63.7%) or the 4D (65.9%) ultrasound method. Siegel et al. [21], in a study with 17 patients, found a discrepancy between gallbladder EFs calculated with sonography and scintigraphy and assumed that the discrepancy was due to the variability of gallbladder shapes on ultrasound images. We believe the discrepancy might have occurred because those authors performed only one ultrasound scan after the cholecystokinin infusion, and that scan might not have captured the peak EF. To our knowledge, our study is the most extensive comparative study in which patients with symptoms of gallbladder disease underwent both ultrasound and HID scintigraphy. In addition, the patients underwent all imaging in the same position, eliminating movement as a variable. We incorporated an additional 4D ultrasound technique that to our knowledge has never been used for this purpose. Scanning at four time points helped us to assess the consistency of our results and to better capture peak EF. The reason EF measured with HID scans was persistently lower than that measured with ultrasound in our study (and in the study by arr et al. [18]) may be that both techniques entail conceptually different ways of calculating EF. With ultrasound, a change in gallbladder structural volume over time is measured, but with HID scintigraphy, a change in radioactivity in the gallbladder region is calculated over time. One can speculate that gallbladder radioactivity at HID scintigraphy may be overestimated owing to difficulty in excluding the superimposed activity in the cystic duct, bile duct, or duodenal bulb from the area of interest. This overestimate may lead to falsely high counts and result in underestimation of EF. On the other hand, the lower volume measurement with 3D than with 4D ultrasound may be attributed to the fact that use of the standard equation for a prolate ellipse for 3D ultrasound possibly oversimplifies the shape of the gallbladder (which is not an exact prolate ellipse), possibly discounting the tapered gallbladder neck area. These asymmetric areas are included in 4D ultrasound by manual tracing of the gallbladder contour, increasing the accuracy of 4D ultrasound for volume measurement (as found in our in vitro project). lthough 4D acquisition always followed 3D acquisition, it is unlikely that the observed difference between the 3D and 4D volumes was due to an interval change in gallbladder size. First, the time difference was very short (1 2 minutes), and second, a similar pattern of difference in measured balloon volumes also was also found with the two techniques. Most of our patients (3D, 39; 4D, 38) had their peak EF within 3 minutes after cholecystokinin infusion in both of the ultrasound methods. With the 3D method only one patient and with the 4D method only two patients had their peak EF 4 minutes after infusion, and even in these patients, the EF was only slightly (< 1%) higher than in the earlier intervals. ecause more than 95% of patients had their peak EF within 3 minutes, we believe scanning 4 minutes after cholecystokinin administration may not be necessary in clinical practice. Riyad et al. [9] in a study of cholescintigraphy found good correlation between less than 4% EF and chronic cholecystitis. Our study had similar findings because all of the cholecystectomy patients who had less than 5% EF with the HID scintigraphic and 3D and 4D ultrasound methods had evidence of cholecystitis at pathologic examination. The two patients who had a normal gallbladder at cholecystectomy had a greater than 5% EF with all techniques. Most patients (seven of nine) had symptomatic relief after cholecystectomy; ironically, two of the seven were those who had a normal gallbladder at pathologic examination. The advantage of HID scintigraphy over ultrasound is that scanning is continuous and can capture irregular contractions or a very early peak contraction of the gallbladder. Liver excretion and the patency of the common bile duct can be evaluated in the same study. In addition, gastric reflux of the radiotracer can be seen in some patients and may be attributed to the symptoms in some cases. The use of ionizing radiation, limited availability, and greater cost are the major disadvantages of scintigraphy. The advantage of ultrasound in addition to wide availability, low cost, and ease of use is that the liver, bile ducts, pancreas, and gallbladder can be evaluated in the same right upper quadrant examination. For patients who have clinical evidence of gallbladder disease, a protocol can be established to evaluate gallbladder EF during the same visit by adding cholecystokinin infusion and additional scanning 2 and 3 minutes after the start of the infusion. ecause our study specifically showed greater accuracy of 4D ultrasound for volume calculation in our in vitro experiment, this method also may prove to have greater consistency and accuracy in vivo in future studies. The limitations of our study were lack of a better reference standard for comparing the accuracy of our results. Our results may also have limitations due to a relatively small sample size. ecause our first scan was obtained 2 minutes after cholecystokinin infusion, we might have missed a few cases in which peak EF had occurred earlier than that. In addition, the patient outcome in many cases of low EF was unknown because less than half of these patients underwent cholecystectomy. In summary, even though measurements of EF with ultrasound methods are slightly higher than those with HID scintigraphy, there appears to be good correlation between JR:197, November

8 Irshad et al. both 3D and 4D ultrasound and HID scintigraphic results for calculating gallbladder EF for routine clinical purposes. The use of 4D ultrasound must be further explored because of its higher accuracy in volume calculation. Interest in 4D imaging has increased owing to its increased availability and improvements in 4D volume acquisition techniques, such as automatic tracing and color coding of the area of interest. These developments should increase the accuracy and efficiency of 4D ultrasound technique for determining gallbladder volume. cknowledgments We thank J. P. Moreland, Gina Sanders, Michelle arnett, and Michael Swaney for help and contributions in completing this study. References 1. Cooperberg PL, urhenne HJ. Real-time ultrasonography: diagnostic technique of choice in calculous gallbladder disease. N Engl J Med 198; 32: Wistow W, Subramanian G, Heertum RL, et al. n evaluation of 99m Tc-labeled hepatobiliary agents. 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