THE EFFECT OF INTRAVENOUS DIAZEPAM ON SOLID PHASE GASTRIC EMPTYING IN NORMAL CATS
PHILLIP F. STEYN, BVSc, MRCVS, MS,l DAVIDTWEDT, DVM,2 WANDATOOMBS, CVT'
Intravenous diazepam has been advocated as an appetite stimulant in anorexic cats. Diazepam has also been used to stimulate the intake of radiographic contrast medium-food mixture to determine the gastric emptying time of a solid meal. Diazepam has been suspected to delay gastric emptying in cats. One study found diazepam combined with Valium to have little effect on gastric transit times in cats while diazepam alone accelerates gastric emptying in humans. The purpose of this study was to determine if diazepam influences gastric emptying times in normal cats. The gastric emptying half-time of solid food in normal, non-diazepam treated cats has been previously determined using a scintigraphic technique using ""'Tc-sulfur colloid to radiolabel solid dry food. The median gastric emptying half-time was 2.3 hours and the mean meal size was 16.1 grams. Gastric emptying half-times were determined in this study using diazepam as an appetite stimulant. The median gastric emptying half-times of diazepam treatment groups given both a 16.1 gram meal and a large meal were both significantly longer than the normal non-treated group (P c 0.05). Solid phase gastric emptying is therefore significantly delayed when diazepam is used as an appetite stimulant, irrespective of the volume of the meal. Veterinary Radiology C? Ultrasound, Vol. 38, No. 6, 1997, p p 469-473. Key words: cat, diazepam, solid phase gastric emptying, scintigraphy, 9 9 m Tsulfur ~ colloid.
Introduction
Intravenous diazepam given at a low dose in cats acts as a central nervous system mediated appetite stimulant." Diazepam was used to stimulate oral intake of radiographic HE RATE AT which the gastric contents are emptied is determined by various factors, including meal size, contrast medium mixed with food for the purpose of meafood consistency and caloric density. Gastric emptying is suring solid phase gastric emptying time which averaged further influenced by the metabolic state of the patient, con11.6 hours (ranging from 7 to 17 hours).' In this study current disease, stress factors and drug a d m i n i ~ t r a t i o n . ~ ~ ~diazepam ~' was a possible confounding factor influencing Solid food empties from the stomach under different control gastric function. The effect of diazepam in conjunction with mechanisms and takes considerably longer to empty than ketamine on feline gastric motility has been regarded as liquid.8 minimal, and the effect Bf diazepam on gastric function in Routine radiographic evaluations of gastric emptying frehumans is also considered minimal or s t i m ~ l a t o r y . ~ ~ ' ' ~ ~ ~ quently incorporate liquid barium sulphate suspension. The It has been shown that a poor correlation exists between gastric emptying time in normal cats using liquid barium meal size and gastric emptying half-time, but it was consulphate suspension ranges from 15 to 60 minutes.' Liquid cluded that this could have been the result of either the small contrast-medium studies, however may not detect abnorrange of meal sizes ingested by the cats, or by the relatively malities in gastric emptying of solid food. Arnbjerg invessmall number of cats ~ t u d i e d . ' ~ tigated the effect of solid food on gastric emptying and The purpose of this study was to determine the effect of reported a range of gastric emptying time of 4 to 14 hours intravenous diazepam given as an appetite stimulant on the in 3 groups of normal cats fed various diets." gastric emptying time of solid food in normal cats using a scintigraphic technique labeling solid food with 9 9 m T ~ 'Department of Radiological Health Sciences, 'Department of Clinical sulfur c01loid.l~ Sciences, College of Veterinary Medicine and Biological Sciences ColoSince the diazepam treated cats ate approximately 3.5 rado State University, 300 W Drake, Fort Collins, CO 80523. Address correspondence and reprint requests to Dr Phillip F. Steyn, times larger meals than in the control non-treated study, and Department of Radiological Health Sciences, Colorado State University, meal size has been shown to influence gastric emptying, a 300 W Drake, Fort Collins, CO 80523. second identical study was performed giving the same meal Funding for this project was provided by the Ralston Purina Company. Received July 19, 1994; accepted for publication November 26, 1996. size as the control group.
T
469
470
STEYN ET AL
Materials and Methods
1997
A
The same ten normal adult cats that were used for the reported solid phase GET1,, study were used in this study.14 Each cat had normal abdominal radiographs, complete blood count, biochemical profile and negative fecal examinations. Their weight ranged from 3.2 kg to 6.8 kg, with a mean weight of 4.7 kg. All the cats were current on vaccinations, and had no recent history of vomiting or other gastrointestinal disorders. The cats were fed the diet 14 days before the control trial and were allowed three days to adapt to their new surroundings prior to testing. The diazepam study was performed within one week of the control study. Solid food was withheld for 24 hours but water was available ad lib. On the morning of the trial the cats were administered diazepam intravenously as a bolus at a dose of 0.18 mgkg, and offered the test meal for 30 minutes. The meal comprised of approximately 200 grams of a commercially available dry cat food* with 74 MBq (2 mCi) 99mTc-sulfur colloid that had been carefully applied to the food, using a technique previously d e s ~ r i b e d . ' ~ ~ 'Following ~1. removal of the test meal any food remaining was weighed to determine the amount ingested. Sixty second left lateral and ventral planar images were acquired at 30 minute intervals post prandial using a 20 inch by 14.5 inch rectangular field of view imaging system with a high resolution collimator.$ Images were acquired for up to eight hours post prandial, or until the stomach was determined to be empty (Fig. 1). Post processing of the images was performed using the NucLear Mac software program and a Macintosh TI FX computer system.ยง A second study was repeated one week later. Cats were given the identical meal size that each had eaten (average 16.1 g) in the previous non-diazepam study.'4
Data Processing A region of interest (ROI) was drawn around the stomach on each left lateral and ventral image. Care was taken not to include small bowel or colon into the stomach ROI. No counts were recorded when small or large bowel activity was superimposed over the stomach. The ROI's were analyzed and the total number of counts were determined and decay corrected for the decay of the isotope. Time activity curves were generated for the decay corrected counts from the geometric mean11 of the lateral and ventral counts. The gastric emptying half-time was determined by fitting the *Purina Cat Chow. Ralston Purina Company, St. Louis, MO. ?An-Sulfur Colloid, CIS-US, INC. Bedford MA 01730-2267. $Omega 500, Technicare Corporation, 29 100 Aurora Rd, Cleveland, Ohio 44139. PNucLear Mac, Scientific Imaging, 6032 South Brook Valley Way, Littleton, CO 80121. llgeometric mean = the square root of the product of the lateral and ventral counts.
FIG. 1. Ventral (A) and lateral (B) images of the abdomen. The radiolabelled meal can be seen in the stomach (arrows). Activity can also be visualized in the sinall bowel.
data to the equation f(t) = foe-xt,where F,, is the intercept, = the rate constant and t = time in hours. The mean, standard deviation, median and range of the gastric emptying half-times were calculated for each cat, having eaten a large meal and a small meal, (Table 1 ) . The gastric emptying half-times of the large meal and small meal were compared with non-diazepam treated values and with each other using the Kruskal Wallis One Way ANOVA test, and a P-value of less than 0.05 was considered significant.
VOL. 38, No. 6
47 1
DIAZEPAM AND GASTRIC EMPTYING IN CATS
TABLE1. The Mean, Standard Deviation (SD), Range and Median (In Hours) of Gastric Emptying Half-Times (Hours) in Normal Cats With Low Dose Intravenous Diazepam
Large meal, diazepam Small meal, diazepam Small meal, No diazepam14
Mean
SD
4.4 3.7 2.47
1.28 2.9-6.8 0.98 2.7-5.6 0.71 1.4-3.6
Range
Median
Mean meal size (grams)
4.5 3.3 2.37
56 16.1 16.1
ues. In the control study the mean (2.47 hours), standard deviation (0.71 hours), range (1.4-3.6 hours) and median (2.37 hours) gastric emptying half-time was determined using the geometric mean of the lateral and ventral counts. The mean meal size was 16.1 grams.14 The median gastric emptying half-times of the large meal (diazepam), the small meal (diazepam) and the normal control values (small meal, no diazepam) were all significantly different (P < 0.05, Kruskal Wallis One Way ANOVA test), (Fig. 2).
Results Cats were given 0.18 mgkg diazepam intravenously and ate an average of 56.0 grams (ranging from 30-85 grams) of the ad lib test meal in the 30 minutes. The mean (4.4 hours), standard deviation (1.28 hours), range (2.9-6.8 hours) and median (4.5 hours) gastric emptying half-time were determined using the decay corrected geometric mean of the lateral and ventral counts. In the second phase of the trial the cats were given diazepam, but were limited in the amount of food ingested. They were offered the same amount of food that they had eaten in the non-diazepam study which averaged 16.1 grams and ranged from 10-20 grams.14 Each cat ate the entire meal. The mean (3.7 hours), standard deviation (0.98 hours), range (2.7-5.6 hours) and median (3.3 hours) gastric emptying half-time were determined using the decay corrected geometric mean of the lateral and ventral counts. Data from the earlier study in which the solid phase gastric emptying half-times of the same cats were determined without intravenous diazepam served as normal control val-
Discussion Scintigraphic evaluation of gastric function has been used in humans, dogs and cat^."^^-'^ These nuclear medicine techniques offer several advantages over positive contrastmedium radiographic procedures for evaluating gastric emptying. Barium studies are poorly quantified and require large radiation exposures. Scintigraphic techniques are simple, non-invasive, reproducible, accurate, more palatable, are met with less patient non-compliance, and are easily This study was designed to evaluate the effect of diazepam used as an appetite stimulant on gastric emptying times determined scintigraphically. The physiology of gastric emptying is complex, and many different factors play a role. Liquids have been shown to leave the stomach faster and by a different mechanism than solids in humans, dogs and ~ a t s . ~ The ~ ~ meal , ' ~ size , ~ ~ as well as caloric density will also influence the rate of gastric emptying. Numerous drugs such as diazepam are also thought to influence the rate of gastric emptying.
Gastric Emptying
Small Meal, Diazepam Large Meal, Diazepam
I .c
Small Mcal, No Diazepam (Control)
FIG.2. Example of a time-activity curve of percentage of total counts to time (hours post prandial). The gastric emptying half-time was determined by fitting the data to the equation f(t) = foe-', where F, is the intercept, = the rate constant and t = time in hours. The gastric emptying half-time of the three curves were all significantly different from each other.
472
STEYN ET
Cats are considered to be picky eaters, however they eat relatively constant volumes of dry matter (approximately 2-3% of body mass) irrespective of the caloric content. Cats prefer meat or fat flavors and often require 3 to 4 days to adjust to a new diet." In spite of adjustment periods some cats will have variable dietary intake due to the effects of disease, or the stresses associated with a clinical or research environment. The lateral hypothalamus normally excretes endogenous opiates which stimulate eating. The release of these endogenous opiates is inhibited by serotonin and cholecystokinin release, thus inhibiting eating. GABA stimulates eating by reducing the activity of serotonin containing neurons. Benzodiazepines enhance the inhibitory effect of GABA on the serotonin containing neurons, thereby stimulating eating. Diazepam has been used clinically as an appetite stimulant to induce eating in anorectic cats." In one clinical study diazepam administered intravenously at a rate of 0.18 mg/ kg in anorectic cats found them to start eating within 29 seconds and to consume 24 grams in approximately 19 minutes. Diazepam has also been used to stimulate cats to eat a relatively unpalatable barium-food mixture. Long gastric emptying times of 9.5-13.7 hours (95% confidence interval) were suggested and diazepam was reported to be a confounding factor in this study.' The effect of drugs on gastric motility rate is important clinically because the absorption of orally administered drugs may be affected, delayed emptying of food may also increase the risk of aspiration during anesthesia and incorrect radiographic diagnosis of gastric motility problems may be made.
'
AL
1997
In humans, opioid analgesic drugs delay gastric emptying and the absorption of medications taken orally.23 However diazepam given intramuscularly at a dose of 0.165 mg/kg had no effect on human gastric emptying, l 2 but significantly accelerated gastric emptying when given orally at 0.25 mg/ kg.13 The fact that diazepam is better absorbed in the stomach than after intramuscular injection is offered as an explanation for the apparent contradiction.24325Gastric transit time of liquid barium in normal cats was not significantly changed following the administration of a ketamine (6 mg/ lb) and diazepam (0.2mg/lb) c~mbination.~ This study was designed to investigate the effect of diazepam on solid phase gastric emptying in felines. Our results indicate that intravenous diazepam given at 0.18 mg/ kg has a marked effect on the amount of food ingested by cats; cats in this trial ate approximately 3 times more than the control group. The significantly longer (P < 0.05) gastric emptying half-time could have been the result of either the diazepam, or the larger meal size. When a smaller meal (identical to the control group meal) was evaluated with diazepam therapy the gastric emptying half-times were significantly different (P < 0.05) from non-diazepam values as well as diazepam (large volume meal) gastric emptying half-times. Larger meals have longer gastric emptying halftimes in cats that have received intravenous diazepam suggesting that either the increased volume ingested or the effect of diazepam prolongs solid phase gastric emptying in cats. ACKNOWLEDGEMENTS The authors acknowledge Dr M D Salman's assistance with the statistical evaluation of the results.
REFERENCES
I . Abell TL, Malagelada J. Delayed gastric emptying Medical Grand Rounds 1984;3:26-34. 2. Steyn PF, Twedt DC. Gastric emptying in the normal cat; a radiographic study. J Am Anim Hosp Assoc 1994;30:78-80. 3. Hunt JN, Stubbs DF. The volume and energy content of meals as determinants of gastric emptying. J Physiol 1975;245:209-225. 4. Minami H, McCallum RW. The physiology and pathophysiology of gastric emptying in humans. Gastroenterology 1984;86:1592-1610. 5. Hinder RA, Kelly KA. Canine gastric emptying of solids and liquids. Am J Physiol 1977;233:E335-E340. 6. Burrows CF, Bright RM, Spencer CP. Influence of dietary composition on gastric emptying and motility in dogs: potential involvement in acute gastric dilatation. Am J Vet Res 1985;46:2609-2612. 7. Hogan PM, Aronson E. Effect of sedation on transit time of feline gastrointestinal contrast studies. Vet Rad 1988;29:85-88. 8. Chaudhuri TK, Fink S. Gastric emptying in human disease states. Am J Gastroenterology 1991;86:533-537. 9. Morgan JP. The upper gastrointestinal examination in the cat: normal radiographic appearance using positive contrast medium. Vet Rad 1981 ;22: 159-169. 10. Arnbjerg J. Gastric emptying time in the dog and cat. J Am Anim Hosp Assoc 1992;28:77-81. 11. Macy DW, Gasper PW. Diazepam-induced eating in anorexic cats. J Am An Hosp Assoc 1985;21:17-20.
12. Todd JG, Nimmo WS. Effect of premedication on drug absorption and gastric emptying. ''Br J Anaesth 1983;55: I1 89-1 193. 13. Schurizek B$ Kraglund K, Andreasen F, Jensen LV, Juhl B. Gastrointestinal motility and gastric pH and emptying following ingestion of' diazepam. Br J Anaesth 1988;61:712-719. 14. Steyn PF, Twedt DC, Toombs WK. The scintigraphic evaluation of solid phase gastric emptying in normal cats. Vet Rad and Ultrasound 1994; in print. 15. Hornof WJ, Koblik PD, Strombeck DR, Morgan JP. Scintigraphic evaluation of solid-phase gastric emptying in the dog. Vet Rad 1989;30: 242-248. 16. Gue M, Fioramonti J, Bueno L. A simple double radiolabeled technique to evaluate gastric emptying of canned food meal in dogs. Application to pharmacological tests. Gastroenterologie Clinique et Biologique 1988;12:425430. 17. Horowitz M, Collins PJ, Shearman DJ. Disorders of gastric emptying in humans and the use of radionuclide techniques. Arch Intern Med 1985;145: 1467-1472. 18. Chaudhuri TK, Fink S. Update: pharmaceuticals and gastric emptying. Am J Gastroenterology I 990;85:223-230. 19. Gould RJ, Fioravanti C, Solomon HF. A model of gastric emptying in cats shows solid emptying is promoted by MK-329: a CCK antagonist. J Nucl Med 1990;31:1494-1449.
VOL. 38, No. 6
DIAZEPAM AND GASTRIC EMPTYING IN CATS
20. Hall JA, Burrows CF, Twedt DC. Gastric motility in dogs. Part I. Normal gastric function. Comp Sm Anim 1988;10:1282-1291. 21. Macy DW, Ralston SL. Cause and control of decreased appetite. In: Kirk, ed. Current Veterinary Therapy X, Small Animal Practice. Philadelphia: WB Saunders Co, 1989:18-24. 22. Squires RF, Braestrup C. Benzodiazepine receptors in rat brain. Nature 1977;266:732-734. 23. Nimmo WS, Heading RC, Wilson J, Precott L. Reversal of narcotic
413
induced delay in gastric emptying and paracetamol absorption by naloxone. Br Med J 1979;2:1189. 24. Assaf RAE, Dundee JW, Gamble JAS. The influence of the route of administration on clinical action of diazepam. Anaesthesia 1975;30: 152158. 25. Gamble JAS, Dundee JW, Assaf RAE. Plasma diazepam levels after single dose oral and intramuscular administration. Anaesthesia 1975;30: 164-1 69.