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Published online before print September 24, 2001, 10.1148/radiol.2212010154
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(Radiology. 2001;221:404-410.)
© RSNA, 2001

Nuclear Medicine

Normal Values for Sincalide Cholescintigraphy: Comparison of Two Methods1

Harvey A. Ziessman, MD, Larry R. Muenz, PhD, Anup K. Agarwal, CNMT and Ahmed A. M. ZaZa, MD

1 From the Division of Nuclear Medicine, Georgetown University Hospital, 3800 Reservoir Rd NW, Washington, DC 20007 (H.A.Z., A.K.A., A.A.M.Z.); and Larry R. Muenz and Associates, Gaithersburg, Md (L.R.M.). Received December 14, 2000; revision requested January 26, 2001; revision received April 25; accepted May 21. Address correspondence to H.A.Z. (e-mail: ziessmah@gunet.georgetown.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To establish normal gallbladder ejection fraction (GBEF) values for two sincalide (cholecystokinin [CCK]) infusion dose rates, 0.01 µg per kilogram of body weight infused for 3 minutes and 0.01 µg/kg infused for 60 minutes.

MATERIALS AND METHODS: Twenty healthy subjects were examined. GBEFs were calculated for the 3-minute infusion and for each 15-minute interval for the 60-minute infusion. Normal values were determined by using the mean ± 2 SDs and a more rigorous statistical analysis.

RESULTS: With the 3-minute infusion, GBEFs were significantly more variable than with the 45- and 60-minute values for the 60-minute infusion (P < .01, .002). With intervals including 95% of the population, the GBEF lower normal range was 16.8% for the 3-minute infusion but 31% and 41% for the 45- and 60-minute values, respectively. GBEFs of less than 35% were noted in six (30%) of 20 healthy subjects with the 3-minute infusion but in only one with the 60-minute infusion. Hepatobiliary ultrasonography was performed in six of seven subjects with GBEF of 36% or less, and US findings in all six were normal.

CONCLUSION: A 3-minute infusion of sincalide, 0.01 µg/kg, produces too variable a GBEF response to establish a clinically useful normal range. With 0.01 µg/kg infused for 60 minutes, clinically useful normal values were established at 45 and 60 minutes.

Index terms: Cholecystitis, 762.285 • Gallbladder, function • Gallbladder, radionuclide studies, 762.1216 • Hormones


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Cholecystokinin (CCK) often is used to initiate gallbladder contraction, for example, prior to cholescintigraphy in patients who have been fasting for more than 24 hours or are receiving hyperalimentation and in patients who have undergone conventional cholescintigraphy to calculate a gallbladder ejection fraction (GBEF) to confirm the clinical diagnosis of chronic acalculous cholecystitis (CAC) (1–8).

Sincalide (Kinevac; E. R. Squibb Diagnostics, Princeton, NJ) is the only form of CCK commercially available in the United States. Investigators and clinicians have used very different infusion methods, such as total doses ranging from 0.005 to 0.04 µg per kilogram of body weight and infusion durations of 30 seconds to 60 minutes (1–8). The dose rate of 0.02 µg/kg infused for 3 minutes became widely adopted after publication of a retrospective clinical investigation by Fink-Bennett et al in 1991 in which findings supported the use of CCK cholescintigraphy to diagnose CAC (3). In that study, a GBEF less than 35% was defined as abnormal. However, a thorough review of the medical literature reveals that normal values have never been established for that infusion method.

In 1992, Ziessman et al (9) reported that this sincalide dose rate, 0.02 µg/kg for 3 minutes, results in a wide variability of GBEFs (0%–100%) in healthy subjects, which makes defining a clinically useful normal range impossible. However, with a 30-minute infusion of the same total dose, normal values (GBEF > 30%) could be established. With the 3-minute infusion, eight (35%) of 23 healthy subjects had a GBEF less than 35%, in contrast to only two (9%) of 23 with 0.02 µg/kg infused for 30 minutes (9). Finally, 1–3-minute infusions often produce abdominal cramps and nausea in healthy subjects, but adverse symptoms do not occur with infusions of 30 minutes or longer (9,10).

Krishnamurthy and Krishnamurthy (11,12) state that 0.02 µg/kg infused for 3 minutes is a nonphysiologic dose rate but assert that 0.01 µg/kg infused for 3 minutes is the optimal dose rate for sincalide and that this dose rate does not have the problems reported with 0.02 µg/kg for a 3-minute infusion, which makes a longer infusion unnecessary (11, 12). However, published data to support this assertion are limited.

Published data suggest that 0.01 µg/kg infused for 30 minutes produces a GBEF similar to that reported for 0.02 µg/kg infused for 30 minutes (9). Other data suggest that even longer infusions of 45–60 minutes may be superior to 30-minute infusions (4,10).

The purpose of this study was to establish normal values for both a 3- and 60-minute infusion of 0.01 µg/kg of sincalide.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Clinical Data
This investigational protocol was approved by the Georgetown University Institutional Review Board and Radiation Safety Committee. Signed informed consent was provided by 22 consecutively enrolled volunteers (20 women, two men) who met inclusion criteria. Female subjects were given preference, since gallbladder disease occurs predominantly in women, and much of the data on gallbladder contraction in the literature was obtained from male patients at veterans’ hospitals. All subjects were in good health. A detailed medical history was obtained by one author (H.A.Z.) to exclude any subject with symptoms of recurrent abdominal pain, postprandial nausea or postprandial vomiting, or a medical history of hepatobiliary disease.

Patients were excluded if they had chronic diseases (diabetes, sprue, achalasia, irritable bowel syndrome, truncal vagotomy, pancreatic insufficiency, sickle cell hemoglobinopathy, and hemolytic anemias), were pregnant, or were receiving medications (eg, morphine and morphine-related medications, atropine, calcium blockers, octreotide, progesterone, histamine 2 receptor stimulators, theophylline, glucagon, erythromycin, and indomethacin) known to alter gallbladder contraction. Subjects 2, 5, and 20 were receiving low-dose oral contraceptives (Table 1). The sister of subject 6 had gallstones. Subjects 9 and 13 received a past diagnosis of hypothyroidism; however, both were euthyroid and were receiving replacement thyroid hormone therapy.


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  		TABLE 1. Clinical Data and GBEFs Obtained with 3- and 60-Minute Sincalide Infusions in 20 Subjects

 
All subjects underwent two studies that were performed 1–10 days apart. All fasted for 4 hours prior to each study. After intravenous infusion of 175 MBq (5 mCi) of mebrofenin labeled with technetium 99m (Choletec; Bracco Diagnostics, Princeton, NJ), 60-minute conventional cholescintigraphy was performed in the anterior projection. Normal gallbladder filling occurred at 60 minutes in all but one subject. One subject had a large filling defect in the liver, which was later determined to be a benign cyst. Both subjects were disqualified and not included in the data analysis. Findings in the remaining 20 subjects (19 women, one man; age range, 21–52 years; mean age, 35 years ± 9.4 [SD]) are reported in this investigation (Table 1).

In the CCK study 1, sincalide, 0.01 µg/kg in a 10-mL volume, was slowly infused intravenously for 3 minutes by one technologist (A.K.A.). Computer acquisition (1 frame per minute) initiated at the beginning of the infusion was continued for 30 minutes. In study 2, the same total dose was administered (0.01 µg/kg) but was diluted in a 30-mL volume, infused for 60 minutes with a Harvard-type infusion pump (Sage Instruments, Orion Research, Cambridge, Mass), and computer-acquired (1 frame per minute) for the entire infusion period. Examination with the 60-minute infusion was performed as the first study in two subjects for scheduling reasons.

A large-field-of-view gamma camera was positioned in the left anterior oblique projection to minimize activity of overlap among the gallbladder, biliary ducts, and duodenum. An experienced technologist (A.K.A.) reviewed the images in cine format, looked for possible motion and overlap of radioactivity, and then drew a tight region of interest on the computer to encompass the maximum volume of the gallbladder and an adjacent semilunar 3–5-pixel region of interest for adjacent liver background. Time-activity curves were then generated. The resulting images and time-activity curves were reviewed by one physician (H.A.Z.) to ensure that there were no potential sources of error. In two cases, one with overlap of biliary clearance and gallbladder activity and another with motion, regions of interest were drawn for the initial and final images to assure accurate quantification. The maximum GBEF was calculated (maximum minus minimum gallbladder counts divided by maximum counts, all corrected for background and decay) for the 30-minute acquisition time of the 3-minute infusion and for each 15-minute interval for the 60-minute study.

All subjects were questioned after each study regarding adverse symptoms during sincalide infusion. Hepatobiliary sonography was performed, and scans were interpreted on a clinical basis in the Abdominal Imaging Division of the Department of Radiology at Georgetown University Hospital, Washington, DC, in six of seven subjects who had GBEFs of 36% or less with the 3-minute study to evaluate for evidence of gallbladder or hepatobiliary disease. One subject refused further evaluation.

Statistical Analysis
Lower and upper percentiles of the distribution of observations define a normal range; for data with a bell-shaped (Gaussian) distribution, a range is sometimes estimated by the mean plus or minus a multiple of the SD (Table 2). In our study, because of the nonnormal distribution of GBEF values, their cumulative distribution after the 3-minute infusion was estimated by using a robust "kernel" smoothing method (13) and percentiles taken from that smoothed estimate.


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  		TABLE 2. Means and SDs of GBEF Obtained with 3- and 60-Minute Sincalide Infusions with and without Inclusion of Outlier Subject 19

 
For the repeated measures study (60-minute infusion) with observations at 15, 30, 45, and 60 minutes, the method of Generalized Estimating Equations (14) was used to fit a regression model to the GBEFs after an arc-sine transformation to deal with the non-Gaussian distribution. Terms for time and time squared were included, but no term for patient’s age that did not predict GBEF was included. The variance of the model’s prediction at a time point plus the error variance was used to estimate the variance of a single new observation. Prediction intervals for times from 15 to 60 minutes were based on that variance. For both 3- and 60-minute infusion experiments, intervals including 80% and 90% of the population were defined by the 10th and 90th percentiles and by the 5th and 95th percentiles, respectively (Table 3). These percentiles were estimated by using all 20 subjects and also after eliminating a single subject with unusual data. Less than the 5th or more than the 95th percentile were chosen to represent the lower and upper limits of normal.


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  		TABLE 3. Estimated Percentiles of GBEFs Obtained with 3- and 60-Minute Sincalide Infusions with and without Inclusion of Outlier Subject 19

 
Contrasts within a Generalized Estimating Equations model with indicators for times after 3 minutes were used to compare the mean of the 3-minute infusion with repeated observations from the 60-minute infusion and also among the repeated observations. A variant of the F test, the Pitman-Morgan test (14) applied to ranks, was used to compare variances of the paired data. P values of .05 or less for two-sided tests were considered significant. Analyses were performed with statistical software (SAS, version 8.1; SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
With the 3-minute sincalide infusion, adverse symptoms were reported by one subject with nausea and two with abdominal cramps. No subject had adverse symptoms with the 60-minute infusion. The patient with a family history of gallstones had normal GBEFs (Table 1, subject 6).

Means and SDs (Table 2) and estimated percentiles (Table 3) were determined in all 20 subjects for the two infusion methods (0.01 µg/kg for 3 minutes and 0.01 µg/kg for 60 minutes) at the designated time intervals. There were five GBEF observations in each of 20 subjects, one for the 3-minute infusion and four for the 60-minute infusion, at 15, 30, 45, and 60 minutes. The GBEF values are listed in Table 1 and graphed in Figure 1. These show substantial variation for the 3-minute infusion. For the 60-minute infusion, the GBEF values increased but with less variation among subjects at each time measurement. Paired comparisons of GBEFs showed that the 3-minute GBEF values significantly exceeded the 15-minute values, that they did not differ from the 30-minute values, and that they were significantly less than the 45- and 60-minute values (P values of .007, .29, .010, and .006 by contrasts within the Generalized Estimating Equations model). At 45 minutes, GBEFs were significantly less than at 60 minutes (P < .001). This latter difference, combined with the shape of the lines in Figure 1, suggests that the GBEF might have continued to increase had the infusion lasted longer.



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  		Figure 1. Line graph shows GBEF percentage for 3- and 60-minute infusion, with 15-minute intervals at 15, 30, 45, and 60 minutes. The raw data in 20 subjects plus mean and 1 SD error bar are shown at each measurement.

 
There is one outlier with the 60-minute infusion (subject 19), whose GBEF was 25% after the 3-minute infusion but did not exceed 15% for the 60-minute infusion. Table 2 displays means and SDs at each time point, with and without this subject. Exclusion of this subject had little impact on variation with the 3-minute infusion or at 15 or 30 minutes with the 60-minute infusion, but there was a decrease in the SDs by 24% and 35% at 45 and 60 minutes, respectively.

The hypothesis was tested that intersubject variability of GBEF was less for the 60-minute infusion than it was for the 3-minute infusion. There were two significant differences in the SD, both of which were noted after the removal of outlier subject 19: With the 3-minute infusion method, the GBEF was significantly more variable than GBEFs at 45 or 60 minutes with the 60-minute infusion (P values, .013 and .022; Pitman-Morgan test on ranks). There were no other significant differences in variability.

Estimated percentiles from the distribution at each time point appear in Table 3. For the 45- and 60-minute time points, the data are also presented with and without the outlier. Distributions with the 3- and 60-minute data are displayed in Figure 2.



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  		Figure 2a. Line graphs show data with (a) 3- and (b) 60-minute infusion. (a) Three-minute infusion: empirical percentiles ({blacklozenge}) and kernel density-based percentiles (smoothed line) for GBEF percentage. (b) Sixty-minute infusion: empirical percentiles for GBEF percentage with outlier removed.

 


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  		Figure 2b. Line graphs show data with (a) 3- and (b) 60-minute infusion. (a) Three-minute infusion: empirical percentiles ({blacklozenge}) and kernel density-based percentiles (smoothed line) for GBEF percentage. (b) Sixty-minute infusion: empirical percentiles for GBEF percentage with outlier removed.

 
With the 3-minute infusion, intervals of GBEF values that were estimated to include 80% and 90% of the population were 21.0% and 67.0% and those that were estimated to include 5% and 95% of the population were 16.8% and 70.2%, respectively (Table 3). At the end of the 60-minute infusion, excluding the outlier, these intervals decreased in width to (53.7%, 86.1%) for the 80% interval and (48.5%, 89.5%) for the 90% interval. The 60-minute intervals are more than 23% narrower than the 3-minute intervals. Inclusion of the outlier had little impact on the upper end of the interval, but the lower end was decreased by 5%–10%, which, had this subject’s data been retained, would have decreased the tendency of the longer infusion period to produce a narrower normal range. For both the 3- and 60-minute infusions, Figure 3 shows the estimated 80th and 90th percentiles by elapsed time since the infusion began.



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  		Figure 3. Line graph shows GBEF estimated percentiles of study population for the 3- and 60-minute infusion methods. Lower 90% = {lozenge}, lower 80% = x, upper 80% = *, upper 90% = {triangleup}.

 
With the infusion of 0.01 µg/kg for 3 minutes, six (30%) of 20 normal subjects had a GBEF of less than 35%. With the infusion of 0.01 µg/kg for 60 minutes, the following numbers of subjects had GBEFs of less than 35%: 17 of 20 at 15 minutes, seven of 20 at 30 minutes, and one of 20 at 45 minutes (subject 19) or 60 minutes (subject 19). Six of seven subjects with GBEFs (3-minute infusion) less than 36% underwent hepatobiliary ultrasonography. One subject refused further evaluation. Findings of all ultrasonography studies were interpreted as normal (including those in subject 19), without evidence of cholelithiasis, gallbladder distention, wall thickening, sludge, or biliary dilation. Subject 19 remained asymptomatic for 1 year of follow-up.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
REFERENCES
 
The physiology of gallbladder contraction has been well described (15). CCK is released endogenously by duodenal mucosa in response to a fatty meal. The serum CCK rises and peaks during 20–30 minutes and remains elevated until there is no longer a stimulus for secretion, that is, after the meal has passed through the upper small bowel. The serum CCK then promptly returns to baseline due to its rapid metabolism (2.5-minute serum half-life) (16). Gallbladder contraction is initiated when the serum CCK reaches a threshold that is considerably lower than the peak CCK (16). Simultaneously, CCK relaxes the sphincter of Oddi, allowing bile to empty into the small bowel where it facilitates fat absorption.

The physiologically active portion of CCK is its C-terminal octapeptide. Sincalide, a synthetic analogue of CCK, is the C-terminal octapeptide. The pharmacokinetics of sincalide and the physiology of gallbladder contraction vary depending on the method of CCK infusion. It has been known from the days of oral cholecystography use that when CCK is administered as an intravenous bolus, poor contraction often results because of spasm of the neck of the gallbladder (17). This was likely the rationale for the Food and Drug Administration package insert recommendation that sincalide should be infused for 30–60 seconds.

Published investigations of sincalide use in cholescintigraphy for the diagnosis of CAC from 1980 to 1991 often used different values to define an abnormal GBEF, for example, less than 35% to less than 65% (1–8,18). Where these values came from is often not certain. Prior to 1992, very limited data were published regarding normal sincalide GBEF values. Not only were few healthy subjects studied but also different methods of infusion and dose rates were used. Total sincalide doses varied from 0.005 to 0.04 µg/kg, and infusion times varied from 30 seconds to 60 minutes (1–10,18,22–28).

Some investigators reporting on the clinical utility of sincalide cholescintigraphy (5–8), Krishnamurthy and Krishnamurthy (11, 12), and Fink-Bennett (19, 20) state, without equivocation, that an abnormal GBEF is less than 35% with 1–3-minute infusions of 0.01–0.02 µg/kg; sometimes these authors cite specific references (21–23) to this information. Scrutiny of these articles reveals that in one study a fatty meal was used as a stimulus (23), while in the others, few subjects were included and mixed dose rates were used (21,22). These limited data and other data from the medical literature (24–27), all reported by one investigational group, show a wide range of GBEFs for 3-minute infusions with group means and SDs that do not support the assertion that less than 35% is abnormal (Table 3). In fact, the data suggest that the lower range of normal is 0%–14%, and this range of normal values is not clinically useful.

In the 1991 retrospective clinical investigation of sincalide cholescintigraphy to diagnose CAC, Fink-Bennett et al (3) incidentally reported on 27 healthy volunteers. Sixteen (59%) healthy subjects had GBEFs less than 35%. Not surprisingly, they did not serve as the healthy control subjects for this investigation that defined an abnormal GBEF as less than 35%.

In 1990, Drane and Johnson studied 31 healthy subjects with 0.02 µg/kg infused for 1–2 minutes (27). They found a wide variability of GBEF response (range, 7%–85%). However, the data in these subjects are not detailed, and normal values were not calculated. Thirteen (41%) of 31 subjects had GBEFs less than 35%.

In 1982, Krishnamurthy et al (28) studied various doses (0.005, 0.01, 0.02, and 0.04 µg/kg) of sincalide infused for 3 minutes each. The 0.01 µg/kg dose had the highest mean GBEF (Table 4). This is the basis for the assertion that 0.01 µg/kg infused for 3 minutes is the optimal dose rate for sincalide infusion and that a GBEF less than 35% is abnormal (11,12). However, only seven subjects received this dose rate, far too few to establish reliable normal values.


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  		TABLE 4. Literature Review prior to 1992: GBEF Normal Values for 3-Minute Sincalide Infusion

 
In 1988, Raymond et al (29) published data on a 15-minute infusion of 0.02 µg/kg of sincalide. In the study, GBEFs (mean, 57% ± 28) in patients with chronic cholecystitis were compared with GBEFs (76% ± 22) in 15 healthy subjects. They concluded that gallbladder disease could be diagnosed with confidence when the GBEF was 35% or less. However, data on these healthy subjects are quite limited. Findings in this study may be part of the reason for the misconception regarding what is a normal GBEF, that is, 15-minute data were applied to 3-minute infusion protocols. Furthermore, other data (9), including those in this investigation, do not support the use of a 15-minute infusion.

In 1991, Yap et al (4) studied 40 healthy subjects by using a dose rate of 0.02 µg/kg/h infused for 45 minutes. The mean GBEF was 75% ± 12. No subject had a GBEF less than 40% (mean ± 3 SDs). These subjects served as healthy control subjects for their investigation of patients with clinically suspected CAC. Patients with a low GBEF were randomly assigned to undergo surgery or medical follow-up. With cholecystectomy, greater than 90% had relief of symptoms and evidence of chronic cholecystitis pathologically. Those followed up medically remained symptomatic. This was a rigorous randomized prospective investigation of CCK cholescintigraphy to diagnose CAC. Most other investigations have been retrospective and not randomized.

In 1985, Sarva et al directly compared the effect of different durations of infusion on the GBEF (10). In 22 subjects, 0.02 µg/kg of sincalide was infused for 1 minute and 45 minutes in two groups. The mean GBEF (52% vs 77%) was lower and the range (12%–92% vs 65%–96%) was much wider with the 1-minute compared with the 45-minute infusion. These important data are limited by the fact that subjects were not true healthy subjects, but rather symptomatic patients with nonbiliary diseases; all were men with a disease that occurs mostly in women; few subjects received both dose rates; and 1-minute rather than 3-minute infusions were used. Interestingly, in one of three subjects who received both dose rates, a major discrepancy manifested, that is, the subject had a GBEF of 12% (1-minute infusion) versus 75% (45-minute infusion).

In 1992, Ziessman et al (9) compared two dose rates, 0.02 µg/kg infused for both 3 minutes and 30 minutes in the same 23 healthy subjects (10 men, 13 women). Mean GBEFs were significantly higher for the 30-minute infusion than for the 3-minute infusion (70% vs 52%, respectively). With the 3-minute infusion, there was an extremely variable response and a wide range of GBEFs (range, 0%–100%; mean, 52% ± 26), and clinically useful normal values could not be established. A GBEF of less than 35% was found in eight (35%) of 23 subjects, the often quoted lower limit for normal (3,11). With the 30-minute infusion, the range of GBEFs was much narrower, and normal values could be established (>=30%). Only two subjects had a GBEF of less than 35% (Table 5). Adverse symptoms of nausea and abdominal cramping occurred in 49% of subjects with the 3-minute infusion, but they occurred in no one with the 30-minute infusion. Thirteen subjects also received 0.01 µg/kg infused for 30 minutes, with results similar to results with the dose rate of 0.02 µg/kg infused for 30 minutes.


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  		TABLE 5. Published GBEF Normal Values Obtained with 3- and 30- to 60-Minute Sincalide Infusions and Percentage of Healthy Subjects with GBEFs Less than 35%

 
Data in this investigation show that 0.01 µg/kg infused for 3 minutes also results in a wide variation of GBEFs (range, 12%–74%; mean, 46% ± 20) in healthy subjects. GBEFs were less than 35% in 30% of healthy subjects (Table 4). The lower range of normal would be greater than 6%, determined by using 2 SDs from the mean, or greater than 16.8%, determined with our more sophisticated statistical analysis. Neither is a clinically useful normal range. The data from this study and from the prior study of Ziessman et al (9) show that neither 0.01 µg/kg nor 0.02 µg/kg should be administered as a 3-minute infusion, since the response is too variable, and, thus, clinically normal values cannot be established.

When 0.01 µg/kg of sincalide is infused for 45 or 60 minutes, the results are far superior. Normal values were determined to be 31% or greater and 44% or greater, respectively, for the 45- and 60-minute infusions including the outlier and 38% or greater and 49% or greater, respectively, excluding the one outlier. Only one subject had a GBEF less than 35%. These results compare well with those in the study of Yap et al (4), with a 0.02 µg/kg/h infusion for 45 minutes (computer-acquired and calculated at 60 minutes), in which none of the 40 subjects had a GBEF less than 40%. The previously reported results of Ziessman et al (9), with 0.02 µg/kg infused for 30 minutes, are only slightly poorer, with a normal range of greater than 30% and with GBEFs less than 30% in only two of 23 subjects. We recommend one of these three methods (Table 5).

In this study, 19 of 20 subjects were female. This was a deliberate bias, since the vast majority of patients with chronic cholecystitis are female by a factor of at least 2:1 (30). Researchers in two investigations have reported a higher mean GBEF for male compared with female subjects, but that reached only borderline statistical significance (P < .04, <.05) (4,9), while a similar tendency was seen in a third study in which the difference in male and female GBEF did not reach statistical significance (P < .03) (31). In the study of Yap et al (4), with 21 female and 19 male patients, by using the mean ± 3 SDs to establish a normal range, the normal values were greater than 42% for male patients and greater than 40% for female patients. Thus, although our data were predominantly in female subjects, use of our normal values for male subjects seems clinically valid.

The different results obtained with 1–3-minute infusions and 30–60-minute infusions of the same total dose can be explained physiologically. Hopman et al (32) showed that when CCK is infused for 60 minutes, the serum CCK level slowly increases and decreases in a pattern similar to that seen with ingestion of a fatty meal, which was described previously. The gallbladder contracts until the infusion is discontinued. However, with a 1-minute infusion of the same dose, the serum CCK increases very rapidly, peaks at supraphysiologic levels, and then promptly returns to baseline. Maximal gallbladder contraction occurs at 15–20 minutes. The nonphysiologic 1–3-minute infusions (0.01–0.02 µg/kg infused for 1–3 min) often produce a gallbladder response similar to that which occurs with a bolus infusion. There is evidence that the cystic duct, fundus, and gallbladder have different contraction thresholds in response to CCK (33). With physiologic dose rates of CCK, the gallbladder, but not the fundus or cystic duct, contracts. With supraphysiologic dose rates, the fundus and cystic duct may contract simultaneously with the gallbladder, which results in obstruction to flow (33).

In conclusion, 3-minute sincalide infusions of 0.01 or 0.02 µg/kg should not be used because of the wide variability of gallbladder response and the lack of clinically useful normal values; infusions of 30–60 minutes are required.


   FOOTNOTES
 
Abbreviations: CAC = chronic acalculous cholecystitis, CCK = cholecystokinin, GBEF = gallbladder ejection fraction

Author contributions: Guarantor of integrity of entire study, H.A.Z.; study concepts and design, H.A.Z.; literature research, H.A.Z.; experimental studies, A.A.M.Z., H.A.Z., A.K.A.; data acquisition, A.K.A., A.A.M.Z.; data analysis/interpretation, L.R.M., H.A.Z., A.K.A.; statistical analysis, L.R.M.; manuscript preparation, H.A.Z.; manuscript definition of intellectual content, L.R.M., H.A.Z.; manuscript editing, H.A.Z.; manuscript revision/review, H.A.Z., L.R.M.; manuscript final version approval, all authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 

  1. Topper TE, Tyerson TW, Nora PF. Quantitative gallbladder imaging following cholecyostokinin. J Nucl Med 1980; 2121:694-696.
  2. Pickelman J, Peiss R, Henkin R, et al. The role of sincalide cholescintigraphy in the evaluation of patients with acalculous gallbladder disease. Arch Surg 1985; 120:693-697.
  3. Fink-Bennett D, DeRidder P, Kolozsi WZ, et al. Cholecystokinin cholescintigraphy: detection of abnormal gallbladder motor function in patients with chronic acalculous gallbladder disease. J Nucl Med 1991; 32:1695-1699.
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