Assessment of Gastric Emptying Using a Low Fat Meal: Establishment of International Control Values

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1 THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 95, No. 6, by Am. Coll. of Gastroenterology ISSN /00/$20.00 Published by Elsevier Science Inc. PII S (00) Assessment of Gastric Emptying Using a Low Fat Meal: Establishment of International Control Values Gervais Tougas, M.D., C.M., Ervin Y. Eaker, M.D., F.A.C.P., Thomas L. Abell, M.D., Hasse Abrahamsson, M.D., Ph.D., Michel Boivin, M.D., F.R.C.P.C., Jiande Chen, Ph.D., Michael P. Hocking, M.D., Eamonn M. M. Quigley, M.D., F.R.C.P., F.A.C.P., F.A.C.G., Kenneth L. Koch, M.D., Aaron Zev Tokayer, M.D., M.H.S., Vincenzo Stanghellini, M.D., Ying Chen, M.Sc., Jan D. Huizinga, Ph.D., Johan Rydén, M.Sc., Ivan Bourgeois, M.B.A., and Richard W. McCallum, M.D., F.A.C.P., F.R.A.C.P., F.A.C.G. Intestinal Disease Research Program, McMaster University, Hamilton, Ontario, Canada; Division of Gastroenterology/Hepatology, University of Kansas Medical Center, Kansas City, Kansas; Department of Medicine, University of Tennessee, Memphis, Tennessee; Institute of Internal Medicine, University of Göteborg, Göteborg, Sweden; Division of Gastroenterology, University of Montréal, Montréal, Québec, Canada; Lynn Institute for Healthcare Research, Oklahoma City, Oklahoma; Department of Surgery, University of Florida, Gainesville, Florida; Section of Gastroenterology/Hepatology, University of Nebraska Medical Center, Omaha, Nebraska; GI Division, Hershey Medical Center, Hershey, Pennsylvania; Albert Einstein College of Medicine, Bronx, New York; Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy; and Bakken Research Center, Maastricht, The Netherlands OBJECTIVE: The diagnosis of gastroparesis implies delayed gastric emptying. The diagnostic gold standard is scintigraphy, but techniques and measured endpoints vary widely among institutions. In this study, a simplified scintigraphic measurement of gastric emptying was compared to conventional gastric scintigraphic techniques and normal gastric emptying values defined in healthy subjects. METHODS: In 123 volunteers (aged yr, 60 women and 63 men) from 11 centers, scintigraphy was used to assess gastric emptying of a 99 Tc-labeled low fat meal (egg substitute) and percent intragastric residual contents 60, 120, and 240 min after completion of the meal. In 42 subjects, additional measurements were taken every 10 min for 1 h. In 20 subjects, gastric emptying of a 99 Tc-labeled liver meal was compared with that of the 99 Tc-labeled low fat meal. RESULTS: Median values (95th percentile) for percent gastric retention at 60, 120, and 240 min were 69% (90%), 24% (60%) and 1.2% (10%) respectively. A power exponential model yielded similar emptying curves and estimated T 50 when using images only taken at 1, 2 and 4 h, or with imaging taken every 10 min. Gastric emptying was initially more rapid in men but was comparable in men and women at 4 h; it was faster in older subjects (p 0.05) but was independent of body mass index. CONCLUSIONS: This multicenter study provides gastric emptying values in healthy subjects based on data obtained using a large sample size and consistent meal and methodology. Gastric retention of 10%at4hisindicative of delayed emptying, a value comparable to those provided by more intensive scanning approaches. Gastric emptying of a low fat meal is initially faster in men but is comparable in women at 4 h; it is also faster in older individuals but is independent of body mass. (Am J Gastroenterol 2000;95: by Am. Coll. of Gastroenterology) INTRODUCTION Gastroparesis, conventionally defined as delayed gastric emptying in the absence of mechanical obstruction, is frequently associated with nonspecific symptoms such as nausea and vomiting (1). However in many patients with symptoms suggestive of gastroparesis, these symptoms may be present in the absence of definable delays in gastric emptying as measured by the current modalities. This may relate to a lack of sensitivity of the scintigraphic techniques used to determine gastric emptying and to identify delayed gastric emptying, or because other mechanisms besides gastroparesis are responsible for the symptoms. An objective, sensitive, and reliable measurement of gastric emptying would represent a useful clinical tool. Identification of significant delays in gastric emptying is therapeutically important, as prokinetic drugs may improve symptoms in patients with gastroparesis but are unlikely to be effective in those with normal gastric emptying, for whom other treatments may be more appropriate (2). Standardized methodology and comparable normal values would also be very important for multicenter studies. The diagnosis of delayed gastric emptying can be diffi-

2 AJG June, cult, in part because of presently poorly defined criteria for what constitutes an abnormal gastric emptying, and in part because we lack a standardized approach to the measurement of gastric emptying among different institutions (3). Several methods are used to assess gastric emptying, with scintigraphy being the most widely available (4 8). More recently, the 13 C-labeled octanoic acid breath test has been proposed as a promising alternative to scintigraphy (9, 10), but its availability is currently limited to a few centers. This new technique seems, however, to be better suited to intraindividual comparisons of gastric emptying than to the identification of delayed gastric emptying per se in the clinical setting. The mathematical approach to the analysis of the data obtained by this latter technique also remains controversial. For these reasons, gastric scintigraphy remains the current gold standard for the assessment of gastric emptying. When gastric scintigraphy is used to determine gastric emptying, different hospitals use test meals that often differ markedly as to their composition, volume, and caloric content. The exact protocols, including the timing of the meal and the parameters subsequently analyzed, also vary widely (11). In many centers, the values used to define normality are based on very small control groups. For all of these reasons, comparisons between gastric emptying studies obtained in different institutions are difficult, and pooling of results from many centers are probably inappropriate in the context of clinical trials. Furthermore, current scintigraphic techniques are costly and labor-intensive, and require substantial time, personnel, and equipment (12). Similar limitations also apply to the use of the newer approaches based on the 13 C-labeled octanoic acid breath test. These issues limit the utility of these methods in an era of cost constraints. The aim of the present study was to establish international normal values for gastric emptying of a well tolerated standardized meal, using a simplified scintigraphic protocol in 11 centers located in four countries. MATERIALS AND METHODS Subjects A total of 123 healthy volunteers (60 women and 63 men; mean age 41 yr, range yr) without any history of GI illness or surgery and without any other ongoing medical condition participated in the study. The subjects were currently not taking any medication. Female subjects were either postmenopausal or had a negative pregnancy test (serum HCG). The majority of patients (n 102) were white. The remaining 21 identified themselves as Southeast Asian, African-American, or Hispanic. A total of 37 patients were from Canada (Hamilton, 27; Montréal, 10), 72 were from the US (Kansas City, 19; Oklahoma City and Omaha, 10 each; Gainesville, Hershey, and Memphis, nine each; New York City, six), and 14 were from Europe (Götenborg, 10; Bologna, four). Signed, informed consent was obtained from each participant, and the study was approved by the ethics review board of every institution. Test Meal, Composition, and Preparation In multicenter trials, it is essential that the meal composition be somewhat in keeping with the normal diet of the population tested. Furthermore, it must be easily prepared and inexpensive to administer. For these reasons, we chose a meal with relatively low fat content as many patients find it difficult to ingest meals with a high fat content in the morning. However, we also ensured that the caloric content of this new meal was nearly identical to that of other meals with higher fat content that were used in the past (13). The meal consists of a scrambled egg substitute (120 g EggBeater, 60 kcal, equivalent to the volume of two large eggs), two slices of bread (120 kcal), strawberry jam (30 g, 75 kcal), and water (120 ml). The meal has a caloric value of 255 kcal (nutritional composition: 72% carbohydrate, 24% protein, 2% fat and 2% fiber). First, 1 mci of 99 Tc-labeled sulfur colloid was mixed with the egg substitute; then this mixture was cooked in a microwave oven for 2 min, and stirred once during cooking (13). All studies were done in the morning, starting between 8 and 9 AM. The subjects fasted overnight. The meal was prepared just before the beginning of the study and consumed within 20 min. We assessed the stability of the 99 Tc labeling by collecting fresh gastric juice (100 ml) in healthy volunteers. After cooking a freshly prepared 99 Tc-labeled egg substitute, the scrambled preparation was incubated in gastric acid juice for 4 h at 37 C.The solution and egg were then sieved through gauze and the liquid and solid portions counted separately. In all experiments, 5% of the 99 Tc was found in the liquid, and 95% was found in the solid portion. Scintigraphy Anterior and posterior images were taken within 1 min of the completion of the meal (defined as time 0). Subsequent images were obtained at 60, 120, and 240 min in all patients. In 42 patients from three centers, additional images were also taken at 10-min intervals during the first 1 h and at 180 min. With the subject sitting upright, 1-min anterior and posterior images were taken in the 140 kev 99 Tc peak with a 20% window (140 kev 10%). Either two gamma scintillation cameras were used for simultaneous anterior and posterior projections, or a single camera was used with the patient turned for the posterior image. Between imaging periods, the subjects were allowed to sit in an adjacent waiting area, thereby freeing the scintigraphic camera counter for most of the study period. Analysis of Gastric Emptying Data were corrected for time decay. The region of interest was drawn around the image of the stomach for each time frame. For each time frame the geometric mean was calculated as the square root of the product of the counts mea-

3 1458 Tougas et al. AJG Vol. 95, No. 6, 2000 Table 1. Descriptive Statistics of Gastric Emptying in 123 Subjects Percent Retention Median First Quartile Third Quartile Skewness Probability of Normality 90th Percentile 95th Percentile 1 h h h T 50 * (min) Lag phase* (min) * Predicted by power exponential model of prop t { ( t) }. sured on the anterior and posterior images. The main parameters measured were percent gastric retention at 60, 120, and 240 min. In 42 subjects, six additional images were also taken at 10-min intervals for the first 1 h and at 180 min. Gastric retention curves were generated using a power exponential model defined as prop t { ( t) } where prop t is the proportion of retention at time t (14). All data are expressed as a percentage of the isotope remaining in the stomach. The lag phase was defined as the period before emptying of 5% of the gastric content at time 0 (immediately after the end of the meal). T 50 was defined as the time to emptying of 50% of the gastric content initially measured at time 0 (13). Using the 123 subjects in the data set, the predicted T 50 was 83 min and the lag phase 21 min (Table 1). These values are comparable to those obtained with frequent sampling in 42 subjects with p values of 0.3 for both (Fig. 2). Statistical Analysis As the data were not normally distributed, all results are reported as median, with 90th and 95th percentiles provided. Data were compared when appropriate using Kruskal-Wallis test, Wilcoxon rank-sum test, or repeated measures analysis of variance and Spearman s rank correlation test. Differences are considered significant if the p value was RESULTS Table 1 shows the median percent retention at 60, 120, and 240 min, as well as the first and third quartile values. The data are not normally distributed but instead are highly skewed, particularly at 4h(p ); consequently, the median and 90th or 95th percentile, rather than the mean and SD, were used to determine the normal range (Fig. 1A C). The 90th percentile values for percent gastric retention at 1, 2, and 4 h were 86%, 50%, and 6.3%, respectively, and the 95th percentile values were 90%, 60%, and 10% for the same periods. Overall, there were only small differences in percent gastric retention among the 11 centers at 4 h (Table 2). A power exponential model was used to create a gastric emptying curve. In the 42 patients with frequent measures, two different curves were created for each subject. The first curve was based on the samples obtained at 0, 60, 120, and 240 min, whereas the other curve was based on all available data points (Fig. 2). The overall estimated curves were generated using the median and calculated from the 42 individual subjects. The two curves, whether generated with only three (60, 120, and 240 min) or with more frequent sampling, were very similar. Figure 1. Distribution of percent gastric retention at 1, 2, and 4 h.

4 AJG June, Table 2. Percent Gastric Retention at 4 h in Individual Centers Center N Median Percent Retention Mean Percent Retention SD 95th Percentile % 1.5% 1.0% % 3.2% 3.3% % 1.0% 0.6% % 2.1% 3.5% % 1.3% 1.1% % 4.4% 6.2% 7 9 0% 5.4% 11.1% % 5.1% 3.7% % 1.7% 0.9% % 2.1% 1.6% % 2.9% 3.1% Overall % 2.9% 4.6% 10% Effects of Age, Gender, and Body Mass Index on Gastric Emptying Rates of a Low Fat Meal Gastric emptying increased consistently with increasing age (Fig. 3). Women had a greater percent residual than men at 60 and 120 min but a comparable percent residual at 240 min (Fig. 4). In premenopausal women, we did not control for the phase of the menstrual cycle. The present study did not have sufficient power to detect differences in gastric emptying with increasing age specifically in men or women, however, from the data, it seems that the age-related response is not gender-specific. There was no relationship between gastric emptying and body mass index (Fig. 5). Comparison With Gastric Emptying of a 99 Tc-Labeled Beef Liver In 20 age- and sex-matched subjects (mean age, yr), we compared the emptying of a 99 Tc-labeled beef liver meal given according to a previously validated method (13, 15) with the gastric emptying of a low fat meal. All subjects were from two centers (Hamilton and Montréal). The caloric content of the two meals was comparable (liver meal, 253 kcal; low fat meal, 255 kcal). The liver meal had a higher fat content and the two meals had a different nutritional composition (liver meal: 5% carbohydrate, 47% protein, 28% Figure 2. Percent residual gastric contents over 4 h generated using a power exponential model, either with frequent imaging (dashed line, median and median 1.72), or with imaging only at 0, 60, 120, and 240 min (dotted line, median and median 1.88) both in the same 42 subjects. The solid line represents the curve generated using imaging at 0, 60, 120, and 240 min with the entire data set of 123 subjects (median and median 1.86). The power exponential model is defined as prop t { ( t) }(see Materials and Methods). Figure 3. Box and whiskers plot of the percent residual gastric retention at 1, 2, and 4hindifferent age groups (19 30 yr, yr, and yr). The box represents the median and the first and third quartile; the whiskers indicating the 10th and 90th percentiles. There was a significant overall age effect (p 0.05, repeated measures analysis of variance based on rank of percent gastric retention), with greater percent retention in younger subjects at 1, 2,and4h(p 0.03, p 0.08, and p 0.04 respectively, Kruskal-Wallis test).

5 1460 Tougas et al. AJG Vol. 95, No. 6, 2000 Figure 4. Box and whiskers plot of the percent residual gastric retention at 1, 2, and 4 h in 63 male subjects (left) and 60 female subjects (right). The box represents the median and the first and third quartile; the whiskers indicating the 10th and 90th percentiles. There was a clear (p , repeated measures analysis of variance, based on rank of percent gastric retention) overall gender effect, and a significantly greater percent retention in female subjects at 1 and 2h(p and , respectively, Wilcoxon rank-sum test). However at 4 h, there were no differences between the percent gastric retention in the two groups. fat, and 2% fiber; low fat meal: 72% carbohydrate, 24% protein, 2% fat, and 2% fiber). As shown in Figure 6, there were no differences in the measured gastric residuals at 1 and 2 h. However, there was a small (albeit significant) difference in the percent gastric residuals obtained using the two different meals at 3h(p 0.007). Most subjects preferred the synthetic egg to the liver meal in terms of palatability, odor, and appearance. DISCUSSION Gastroparesis is defined as delayed gastric emptying in the absence of mechanical obstruction. Its diagnosis implies the demonstration of a prolonged gastric emptying, yet defining what is abnormal remains an elusive goal. Institutions presently use various techniques and meals, and define normal gastric emptying with widely different values (3). These factors make it very difficult to conduct multicenter trials in gastroparesis, as pooling of data is impossible. Camilleri et al. have previously proposed, using the gastric retention at 2 and 4 h, to identify rapid and delayed gastric emptying, respectively (12, 16). The same group has also suggested that a similar approach could be useful in the clinical assessment of GI motility (17) To our knowledge, the present study is the first to provide much-needed normative data from multiple centers in several countries using a simple and standardized approach. The method is primarily intended to identify patients with prolonged gastric emptying. Therefore, the normal period required for nearly complete evacuation of a standardized meal from the stomach must first be determined. Figure 5. Scattergram of the relationship between body mass index (BMI) and percent gastric retention at 60, 120, and 240 min in all subjects. There was no significant correlation between increased BMI and percent residual gastric retention (correlation coefficient between BMI and percent residuals being 0.07 at 60 min, 0.15 at 120 min, and 0.09 at 4 h, with p 0.5, 0.2 and 0.4, respectively). Many of the presently available scintigraphic measures of gastric emptying are labor intensive, requiring repeated images (usually every 10 min for 2 4 h), thereby monopolizing a gamma camera for the entire period, which is inconvenient, costly, and limits the accessibility of the test for diagnostic purposes. The analysis of gastric emptying data may also involve sophisticated computerized analysis and mathematical modeling to provide useful physiological data. The present method, intended as a screening test for delayed emptying, measures the percent residual of the meal

6 AJG June, Figure 6. Comparison of percent gastric retention of a radiolabeled liver meal (beef liver) and of a low fat meal. There was no significant overall difference between the two meals (p 0.2, repeated measures analysis of variance based on rank of percent retention), and no significant differences at 1 and 2h(p 1.0 and 0.1, respectively, Wilcoxon rank-sum test). There was a small but significant difference at 3 h with a significantly greater percent retention of the liver meal (p 0.007, Wilcoxon rank-sum test). remaining at 4 h to differentiate delayed from normal emptying. A gastric retention of 10% of the meal at 4his diagnostic of a significantly delayed gastric emptying, based on the present normative data. The meal used in the present study is palatable and easy to prepare, in contrast to liverbased meals, to which both healthy controls and patients often object. The test meal is low in fat and avoids the inherent gastric emptying delays induced by fat (18). Its low caloric content could make it easier to consume by gastroparetic patients. As it contains no animal protein, it can also be used in vegetarian individuals. Because the distribution of the data obtained at 1, 2, and 4 h are highly skewed, expected ranges in healthy controls should not be based on the assumption of a normal distribution (mean 2 SD). Instead, one should rely on the median and a conventionally accepted range such as the 95th percentile. Using these criteria, gastric retention of 10% at 4 h indicates a significant deviation from the normal range of gastric emptying seen in healthy controls. Further studies involving patients assessed using different methods will be required to determine whether the 95th percentile offers optimal diagnostic sensitivity and specificity. The large interpatient variance that has previously been reported is likely to account partly for the substantial standard variation observed relative to the mean (19 21). However, with its large sample size, the present study has lower relative variance than previous reports. Body mass index had no influence on the gastric emptying of a low fat meal, a finding in keeping with a previous report (22). However, in the present study we find that women show greater initial retention, a finding also reported by others (19, 23). Older patients exhibit more rapid gastric emptying, an observation that is different from that of Madsen (24) who found that age had no effect, and from the study of Kao et al., which reported slower emptying in elderly patients (25). However, the number of subjects in these two studies was much smaller. In addition, the study of Kao et al. involved an Asian population, whereas the present study is conducted primarily in whites. When the gastric emptying of an egg substitute meal is compared to the emptying of a beef liver meal, the gastric emptying of the beef liver meal is slower, with a greater percent gastric retention at 3 h. This is likely due to the higher fat content of the liver meal (26, 27). There are no data to indicate that using a meal incorporating an egg or an egg substitute is superior to using a meal incorporating liver as a screening test for delayed gastric emptying. It has been suggested the radiolabeled liver, which is solid and less likely than radiolabeled eggs to disintegrate, may provide a more sensitive instrument to diagnose delayed emptying (29). However, the study of Poitras et al. (15) and the present study show that the two methods provide comparable gastric emptying values in healthy volunteers at 1 and 2 h. However, at 3 h, gastric emptying of a liver meal is less complete than the emptying of a low-fat egg meal. In another study that we have recently completed in 69 healthy Canadian volunteers, we have found a similar difference in the respective gastric retention of solid meals using liver or an egg substitute at 2 and 3 h (13). Although the present approach provides a good screening test, it has no predictive utility in the determination of the possible physiological mechanism (or mechanisms) responsible for the altered gastric emptying. Generally, delayed emptying will be found to be associated with either a marked prolongation of the lag phase or a decreased slope of the emptying curve something that cannot be estimated with the present technique but requires a more precise assessment of the early phases of emptying (28, 30). The present method, developed in a multicenter setting under standardized conditions, provides a large gastric emptying data base and a simple and economical test to identify patients with delayed gastric emptying, and thus represents a useful approach to identify patients with gastroparesis. In addition to providing a useful clinical tool to identify patients with gastroparesis it also has important implications for the conduct of multicenter trials in patients with symptoms compatible with gastroparesis. This is particularly relevant to therapeutic trials, either of drugs or of nonpharmacological approaches to the treatment of symptoms compatible with gastroparesis. Although further studies will determine the applicability and clinical utility of the method, we believe that the establishment of an international database of normative values constitutes an important first step. ACKNOWLEDGMENT This work was supported through an unrestricted grant from Medtronic, Minneapolis, MN.

7 1462 Tougas et al. AJG Vol. 95, No. 6, 2000 Additional Contributors The following people also participated in this study: Dr. Geoffrey Coates, Dr. William E. Waterfall, Mrs. Usha Chauhan, Mr. Michael Stösser, Mr. Benoit Marchand, Dr. Mark Mellow, Ms. Beatrice Salvioli, Ms. Rosanna Cogliandro, Dr. Roberto Corinaldesi, Dr. Irene Sarosiek, Ms. Faye Park, and Dr. Bernt Everts. Reprint requests and correspondence: Gervais Tougas, M.D., C.M., F.R.C.P.C., Division of Gastroenterology, Digestive Disease Research Unit, Room 3N5D, McMaster University Medical Centre, 1200 Main Street West, Hamilton, ON, Canada L8N 3Z5. Received Nov. 11, 1999; accepted Feb. 25, REFERENCES 1. Moore JG. Gastroparesis. Pathogenesis and evaluation. In: Champion MC, Orr WC, eds. Evolving concepts in gastrointestinal motility. Oxford: Blackwell Science, 1996: Jian R, Ducrot F, Ruskone A, et al. Symptomatic, radionuclide, and therapeutic assessment of chronic idiopathic dyspepsia. 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