GASTRIC EMPTYING AND INTESTINAL TRANSIT TIMES OF RADIOPAQUE MARKERS IN CATS FED A HIGH-FIBER DIET WITH AND WITHOUT LOW-DOSE INTRAVENOUS DIAZEPAM MARJORIE L. CHANDLER, MS, DVM, W. GRANT GUILFORD, BVSC, PHD, CHARLES R.O. LAWOKO, MA, MS, PHD,DIC, TEDWHITTEM, BVSc, PHD
Reference ranges for gastric emptying time (GET), small intestinal transit time (SITT), and colonic transit time of 1.5-mm and 5-mm radiopaque markers in healthy cats fed a high-fiber meal were determined, and the influence of low-dose diazepam intravenous injection on the gastrointestinal transit of the markers was examined. The mean GETs and SITTs, and the mean residence times (MRTs) and geometric centers (GCs) of markers in the colon were determined. The effect of intravenous diazepam injection and marker size on these parameters was examined. Diazepam injection had no significant influence on gastrointestinal transit. The GETs of the 1.5-mm markers were significantly more rapid than those of the 5.0-mm markers. There were no significant differences between the SITTs or GCs of the 1.5-mm and 5.0-mm markers. Reference values were developed for GET, SITT, and colonic transit of radiopaque markers for cats fed a high-fiber meal. Diazepam injection had no effect on these parameters. Veterinary Radiology & Ultrasound, Vol. 40, No. 1, 1999, p p 3-8 Key Words: gastric emptying, colonic transit, radiopaque markers, intestinal transit, cats, feline, diazepam, dietary fiber.
ti~n,'~*'~ and irritable bowel syndrome.16-" Separate evaluation of the proximal and distal segments of the colon is advantageous because of differences between the proximal and distal colon in function, motility, and response to drugs in humans18 and Colorectal transit can be evaluated by scintigraphy or radiopaque marker studies. Scintigraphy has been used for quantifying transit in the colonic segments of humans and Radiopaque marker studies have been used in humans and dogs to assess the effects of fiber on gastrointestinal transit time.2'5*8-'1*23In addition, radiopaque markers have been used in humans to determine if constipation is caused by generalized or segmental large bowel motility dysfunction'2 and to study colonic transit in inflammatory bowel syndrome.24 Recently, radiopaque marker studies have been used in healthy, fasted cats to evaluate segmental and over-all colonic transit time.25 Gastrointestinal transit studies are difficult to perform in cats that refuse to eat their test diets. Diazepam, administered intravenously at 0.5 mg (0.1 ml) per cat is known to stimulate appetite,26but its effect on gastrointestinal motility has not been closely examined. The principal objective of this study was to develop reference values for the gastric emptying, small intestinal transit, and segmental (proximal [ascending and transverse] and descending) colonic transit times of radiopaque markers in
Introduction E HAVE PREVIOUSLY reported the use of radiopaque markers to determine the gastric emptying rate (GET) and small intestinal transit time (SITT) of cats fed a lowfiber diet.' We extended these observations to cats fed a high-fiber diet, because we had limited evidence that highfiber diets increased the likelihood of detecting delays in gastrointestinal transit caused by subtle partial obstructions of the bowel. Fiber type and content is known to influence gastric emptying and orocolic transit rate in dogs24 and hurnans.j-' Therefore, it seemed likely that a different reference range would be required to evaluate gastrointestinal transit for radiopaque markers when using high-fiber diets. We also considered it likely that evaluation of colonic transit time with radiopaque markers would be facilitated by the increased volume of colonic contents resulting from a high-fiber diet. Evaluation of colonorectal transit is of value in such conditions as idiopathic megacolon, constipa-
'
From The Department of Veterinary Clinical Sciences and the Department of Statistics, Massey University, Palmerston North, New Zealand. Address for correspondence and reprint requests to M.L. Chandler, DVM, Small Animal Hospital, Department of Veterinary Clinical Science, University of Liverpool, Liverpool, UK, L7 7EX. Received May 13, 1997; accepted for publication February 17, 1998. Funded in part by Chemstock Animal Health Ltd., Christchurch, New Zealand.
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CHANDLER ET AL
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healthy cats fed a meal with a high insoluble fiber content. In addition, we aimed to determine the influence of an intravenous injection of diazepam, administered at a dose reported to stimulate appetite in cats, on gastric emptying and intestinal transit times of radiopaque markers.
Materials and Methods The experimental protocol was approved by the Massey University Animal Ethics Committee. Ten healthy domestic cats with no history of gastrointestinal disease were used. Cats were caged separately. Seven were neutered males and three were neutered females, age ranged from 9 months to 7 years. Food was withheld for 24 hours prior to the study, but water was available at all times. Cats were randomly divided into one of two treatment groups: 1) fed a meal of 60 gm of a high-fiber canned cat food,* or 2) fed as in treatment 1 and administered diazepam? (0.5 mg intravenously) prior to eating the test meal. A randomized cross-over study design was used, with 1 week between treatments. The cats were fed commercial cat food during intervals between study periods. An excipient control for the diazepam injection was not used because our aim was to evaluate the combined effects of the stress of diazepam injection on transit time, not just the pharmacodynamic effect of diazepam. Thirty small (1.5 mm) and 9 large (5 mm) spherical barium-impregnated polyethylene markers$ were mixed into the food. Most cats ate the meal and markers readily, but several large markers often had to be administered per 0s after the cats had completed the meal. Immediately after the cats consumed the meal, left lateral and dorsoventral abdominal radiographs were made. Radiographs were then made every hour for 12 hours, then at 14, 16,24,30,36, and 48 hours or until at least 90% of all the markers were in the rectum or passed in the feces. The percentage of small markers that had left the stomach was determined at each time point and plotted against time to develop gastric emptying curves. The same procedure was used for large markers. Mean times for 50,75, and 90% GET were calculated by interpolation for both the large and small markers for each treatment. The 50, 75, and 90% GETs of the large and small markers were compared between the diazepam-treated and nondiazepam-treated groups by Wilcoxon signed rank test. Mean 50,75, and 90% GETs of the large markers were compared to those of the small markers for each treatment group using Wilcoxon signed rank test. For each treatment, the percentage of markers that were in the proximal (ascending and transverse) and distal (de*Prescription Diet Feline r/d, Hill's Pet Product, Topeka, Kansas. t Pamlin, Parnell Laboratories, 233 Porchester Road, Takanini, New Zealand. SBIPS, Chemstock Animal Health Ltd., Christchurch, New Zealand.
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scending) segments of the colon was determined. The ascending and transverse segments of the colon were combined as the proximal colon because of the functional similarity between these two segments. The percentages of markers in each segment were plotted against time. The total percentage of each size sphere that had entered the colon was also calculated and plotted against time to develop colonic filling curves. Mean SITT was determined by calculating the area between the mean gastric emptying and colonic filling curves.' Mean SITT of both the large and small markers was compared between the diazepam- and nondiazepamtreated groups using Wilcoxon signed rank test. Mean SITT of the large markers was compared to that of the small markers for each treatment group using Wilcoxon signed rank test analyses. The colonic data were analyzed by three methods. The 95% confidence intervals about the mean percentage of markers in the proximal, distal, and total colon (exclusive of the rectum) were determined for each time point. The resultant percentage versus time (hours) curves were developed for use as reference ranges for diagnosis of motility diseases and obstructions of the colon. Two methods, the mean residence time (MRT) and the geometric center (GC) were used to quantify colonic transit rate of the markers. For the MRT analysis, the proximal colon and distal colon were each defined as distinct kinetic spaces. Additionally, the entire colon was analyzed independently as a distinct kinetic space. For each kinetic space, the MRT of the markers within that space was calculated according to the general formula: MRT =
Jr
(F x t)dt/SI (F)dt 0
where F is the fraction of administered markers remaining in the kinetic space, and t is time measured in hours from the time of first entry of the markers into the proximal colon.27 The integral functions were estimated using the linear trapezoidal rule. The MRTs of the diazepam and nondiazepam groups were compared by Wilcoxon signed rank test for the large and small markers. The MRT of the combined treatment groups was also determined for both the large and small markers. The geometric center, which is used to generate a number that reflects the center of over-all progression of colonic contents, was determined for both treatment groups and both size markers using a method similar to that used for scintigraphy data.28 To determine the geometric center, each segment of the colon plus the rectum and feces was assigned a number. The regions and their respective numbers were: the cecum and ascending colon (l), the transverse colon (2), descending colon (3), and the rectum and feces (4). The number of markers in the rectum and feces were determined by subtracting the number orad from
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AND INTESTINAL TRANSIT TIMEIN CATS GASTRIC EMPTYING
VOL. 40, No. 1
TABLE 1. Median Gastric Emptying Times of 50, 75, and 90% of Small and Large Markers Gastric Emptying Time (h)
Diazepam No diazepam
50% 75% 90% 50% 75% 90%
Small Markers Median i Range
Large Markers Median f Range
4.86 & 2.89 5.31 f 2.15* 5.86 f 3.04* 5.36 & 3.62" 5.89 f 4.06* 6.54 r 3.68*
5.14 i 2.85 5.61 f 2.59t 6.26 f 2.657 6.31 f 2.30t 6.69 i 2.8717.00 i 2.20t
The gastric emptying times bearing different superscripts (* or f) within the same row are significantly different. The superscripts (* and t) should not be compared within columns of the table.
value of p < .05 was considered significant for all comparisons.
x
YI
Results
time (hours)
FIG.1. Gastric emptying of small markers in healthy cats given diazepam and healthy cats not given diazepam.
the rectum from the total number administered. The geometric center was calculated by multiplying the percentage of markers in each region by the region number and then adding these products, represented by the formula:
C = Region' x markers'hotal markers where Region' represents the region number and markers' represents the number of markers in that region. The GCs of the two treatment groups and the large versus the small markers were compared by Wilcoxon signed rank test. Normal distribution of the data was verified, and Wilcoxon signed rank test was used because of small sample size. A 125
The mean 50, 75, and 90% GETs of the small markers were not significantly different between the cats given diazepam and those not given diazepam (Figs. 1, 2, Table 1). The effect of diazepam on emptying of large markers from the stomach was nearly significant (0.053 6 p G .06). The 50, 75, and 90% GETs of the small markers were significantly (p < .05) more rapid than the large markers in the cats not given diazepam. In the cats given diazepam, the 75 and 90%, but not the 50% GETs, of the small markers were significantly more rapid than that of the large markers (Table 1). The SITT was not significantly different between the treatment groups or for large versus small markers (Table 2). The MRTs of the small and the large markers for the proximal, descending, and total colon were not significantly different between cats given diazepam and those not given diazepam (Table 3). When data from both treatment groups were combined, the MRT of the small markers was significantly longer than for large markers in the proximal colon, but significantly shorter in the descending and total colon (Table 3). There was no significant difference in the geometric center between treatment groups or between large and small markers (Fig. 3).
Discussion The radiopaque marker gastric emptying curves of cats fed a high-fiber diet (Figs. 1,2) are similar in shape to those of our previous study,' in which cats were fed a low-fiber TABLE 2. Median Small Intestinal Transit Times of Small and Large Markers -A,
- - 0- - Didzepam, means +/- SE
I,
I
I
1
0
In
-c
In
N
c
-
I
Small Intestinal Transit Time (h)
I
0
time (hours)
FIG.2. Gastric emptying of large markers in healthy cats given diazepam and healthy cats not given diazepam.
Small markers Large markers
Diazepam Median rt Range
No Diazepam Median f Range
2.49 i 2.98 2.37 i 1.96
2.48 f 2.14 2.29 i 2.20
CHANDLER ET
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TABLE 3. Mean Residence Times of Large and Small Markers in Proximal, Descending, and Total Colon of 10 Healthy Cats Proximal Colon
Small markers Large markers Small markers combined data* Large markers, combined data*
Diazepam Mean 2 SD
No Diazepam Mean k SD
7.15 & 5.02 5.11 4.16
9.40 k 10.94 1.73 f 10.66
*
8.58 k 7.13* 6.15 k7.11*
Descending Colon
Small markers Large markers Small markers, combined data* Large markers, combined data*
Diazepam Mean f SD
No Diazepam Mean f SD
11.89 f 6.38 16.63 8.25
15.14 k 8.43 18.47 f 10.51 13.51
6.14"
11.55 k 7.64*
Total Colon
Small markers Large markers Small markers, combined data* Large markers, combined data*
Diazepam Mean ? SD
No Diazepam Mean k SD
20.59 2 10.94 22.14 k 11.39
25.20 k 10.85 28.44 & 13.14 22.89 r 1.79* 25.59 f 8.66*
*Combined data from diazepam-treated cats and cats not given diazepam; combined data from small markers is significantly different from large markers for each colonic segment.
diet.ยง However, the mean time for 90% of the small markers to empty from the stomach of the nondiazepam-treated cats fed the high-fiber diet (6.6 2 1.3 hr) was considerably shorter than that of nonsedated cats fed the low-fiber prescription diet in our previous study (9.1 f 4.0 hrs). The faster gastric emptying rate of markers in cats fed a high insoluble fiber diet is consistent with the effect of cellulose on gastric-emptying rate in humans,29330 the effect of wheat bran on oro-cecal transit time in dogs,3' and the effect of cellulose on gastrointestinal transit time in dogs.3 However, the diets used in our present and previous study of feline gastric emptying differ in other such respects as fat content. Therefore, the different gastric-emptying rate recorded in these two studies cannot be definitely attributed to fiber content. Similarly, comparison between gastric-emptying rate of cats in the present study with those determined by other investigators is compromised by use of different diets, varying quantities of food, and different methods to assess the gastric e m p t ~ i n g . ~ For ~ -these ~ ~ reasons, the mean time for complete gastric emptying of food in cats in previous studies have varied from 4.7 to 12.5 $Prescription Diet did, Hill's Pet Products, Topeka, KS.
1999
AL
The suggestion of more rapid gastric emptying of large markers in cats treated with diazepam may be attributable to decreased anxiety in treated cats. In our previous study, we found that acetylpromazine increased the speed of gastric emptying of both small and large markers in cats, and this difference was attributed to a decrease in anxiety.' Another explanation for the suggestion of a faster rate of gastric emptying of large markers in diazepam-treated cats may be an effect of the diazepam on the pyloric sphincter. Diazepam, a GABA agonist, decreases the tone of the lower esophageal sphincter,38and may have a similar effect on the pylorus. The large markers, in particular, would pass through the pylorus more easily if the tone of the pyloric sphincter was decreased. It is unlikely that the minor stress of the intravenous injection of the diazepam was responsible for this trend, because stress would be expected to slow rather than speed gastric emptying.39,40 The GETS of the small markers were faster than those of the large markers in both treatment groups. This is consistent with the findings in our previous study of cats.' The reason for the slower gastric emptying of the large markers in cats is likely attributable to retention of large markers by the pylorus until near the end of the gastric-emptying period. This phenomenon has also been reported in dog^.^"^' The small intestinal transit times were not significantly different between the two treatment groups or between the two sizes of markers (over-all mean 2.5 h). The SITTs were also similar to those reported for cats fed a low-fiber diet in our previous study (over-all mean 2.6 h), supporting the idea that the majority of control of oro-colic transit time is exercised by the stomach, not the small intestine. The similar SITTs in our previous and present study also suggest the different dietary compositions of the diets used in the two studies had little influence on small intestinal transit. Insoluble fiber has been reported to decrease intestinal transit time,5'6 an effect not noticed in the present study.
time (hrs)
FIG.3. Geometric centers of small and large markers in healthy cats not given diazepam.
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GASTRIC EMPTYING AND INTESTINAL TRANSIT TIMEIN CATS
In comparison of proximal and distal colon filling curves there is a more rapid filling and emptying in the proximal colon than the distal colon. However, it is noteworthy that, although more markers were leaving the proximal colon than were entering it by 12 hours after eating, the proximal colon still retained markers for 48 hours or more. The protracted retention of markers in the proximal colon is consistent with the predominant motility pattern of antiperistalsis in this segment of large intestine and with previous suggestions that, in the cat, the transverse segment of the proximal colon has a storage function, as well as mixing and dehydration f~nctions.4~ The more prolonged retention of markers in the distal colon than the proximal colon is consistent with the storage role of this part of the gastrointestinal tract. Two mathematical methods were used to quantify transit through the colon: mean residence time and geometric center. The GC method is frequently used in scintigraphic studies of colonic transit;13,1X,19.21.22,28,43whereas, MRT is applied to pharmacologic studies evaluating drug concentrations in kinetic compartment^.^^ In the present study, we used both methods. No difference between large and small markers in large bowel transit was detected with the GC technique, but with MRT, a difference was found. Thus, either MRT is a more sensitive technique or, alternatively, differences identified with the MRT are not physiologically important. It is noteworthy that scintigraphic geometric center data have been reported to be less sensitive for identifying differences in feline segmental colon transit than area under the time curve analyses2' The lack of a significant difference in the colonic MRTs
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and GCs between cats treated with diazepam and those not treated is likely attributable to the elimination of most of the drug by the time the markers reached the colon, or possibly caused by a lack of effect of the injection of diazepam on colonic motility. The shorter proximal colon MRTs of large markers is consistent with studies in humans where faster transit of 6-mm particles as compared to 1-mm particles through the right colon was found,42 and there was a faster passage through the ascending colon of a single 2.5 x 0.9 cm capsule than of 1-mm pellets. The reason for faster passage of large markers through the proximal colon in previous and present studies is unclear, particularly when we consider that in the present study, the speed of transit of large markers became slower than for small markers in the distal colon, Given that an important function of the proximal colon is to dehydrate feces, we can speculate that it may selectively retain smaller diameter particles because of their greater contribution to fecal osmolality than larger indigestible particles. In conclusion, this study provides reference values for the gastric emptying, small intestinal transit, segmental colonic transit, and total colonic transit rates of large and small radiopaque markers in healthy cats fed a meal with a high insoluble fiber content. These reference ranges may be of value to clinicians investigating diseases affecting colonic motility in the cat. Injection of diazepam, used at low doses to stimulate appetite, had no significant effect on the gastric emptying, small intestinal transit, or colonic transit times in cats. Finally, the gastric emptying of a diet with a high insoluble fiber content seemed to be more rapid than that of a diet with low-fiber content in cats.
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