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Scintigraphic evaluation of gastric emptying
Scintigraphic Evaluation of Gastric Emptying Leon S. Malmud, Robert S. Fisher, Linda C. Knight, and Elizabeth Rock There has been recent, r e n e w e d interest in studies of gastric emptying due in part to the introduction of new therapies for peptic ulcer disease and attempts to b e t t e r understand gastric physiology. Of the methods available for studying gastric emptying patterns, nuclear medicine techniques are optimal due to their noninvasive character, reproducibility and q u a n t i t a t i v e ability. The modulation of gastric emptying is multifactorial, and includes motor control, electrical activity, hormonal influences, and the composition of the meal itself: liquid vs solid; protein, carbohydrate and fat content; fiber or particle size; osmolality; pH; and pharmacologic agents. Because of the ease of performing gastric emptying studies
using radiolabled physiologic meals, these tests are being employed w i t h increasing frequency in the evaluation of patients w i t h disorders such as diabetic gastroparesis, postgastrectomy gastroparesis or dumping syndrome, and in the study of normal gastric physiology in man. Present data suggests that combined liquid-solid, dual radionuclide studies afford t h e greatest information regarding simultaneous gastric emptying patterns of liquid and solid components of a meal, and t h a t single radionuclide, solid tests of gastric emptying are the m o r e sensitive technique for determining subtle abnormalities of gastric emptying, w h e n only a single tracer is employed.
U R I N G the previous century and a half, a number of techniques for measuring gastric emptying had been introduced, ranging from observations through a gastric fistula, I to a variety of intubation tests, 2~ radiographic procedures, 7-8 radionuclide tests, 9 15 and even a ferromagnetic technique. ~6 Recently there has been renewed interest in gastric emptying studies as a result of several stimuli, including an attempt to relate gastric emptying abnormalities to the etiology of peptic ulcer disease, ~7 and the development of reproducible, quantitative radionuclide methods for characterizing the pattern of gastric emptying. Abnormalities of gastric emptying occur in a variety of disorders other than in peptic ulcer disease, including diabetes, TM gastric cancer, 19 following medical therapy, such as, anticholinergic or cholinergic drugs, and following ulcer surgery. Several of the recently introduced intubation techniques 4'5'2~may prove useful as standards for comparison as the use of five lumens and infusions permits quantitation of both gastric emptying and gastric secretion. However, the invasive character of endogastric intubation suggests that the method will not meet with widespread acceptance by either patients or physicians.
PHYSIOLOGY OF GASTRIC EMPTYING 21'22
D
From the Department of Nuclear Medicine, Temple University Hospital and School of Medicine, Philadelphia, Pa. Address reprint requests to Leon S. Malmud, M.D., Department of Nuclear Medicine, Temple University Hospital and School of Medicine, Philadelphia, Pa. 19140. 9 1982 by Grune & Stratton, Inc. 0001-2998/82/1202~002502.00/0
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After food passes through the esophagus and lower esophageal sphincter, it is received and stored by the stomach, where it is mixed with gastric secretions, and delivered into the duodenum in an orderly fashion. In terms of its motor function, the stomach consists of two parts: a proximal receptacle, which includes the fundus and body; and the distal portion, the antrum and pylorus. 23 Regular, slow contractions in the fundus and peristaltic waves in the body, propel food towards the antrum where weaker waves fade, but stronger ones result in contractions of the antrum and coordinated duodenal muscular activity] 4 The pylorus represents the major component of the duodenogastric resistance and may serve as the anti reflux control device in man. 25 In general, the fundus controls the emptying rates of liquids, and the antrum controls solids, although antral contractions triggered by solids may play a role in the emptying of liquids. 23 26 Gastric emptying of liquids is also dependent upon the gastroduodenal pressure gradient. However, because the fundus of the stomach is able to relax in response to an increased volume, there is not a direct relationship between increased gastric volume and the rate of gastric emptying, although an indirect relationship has been demonstrated. 27 Other factors which control gastric emptying include electrical activity and the characteristics of the meal itself. 28'29The electrical activity appears to be mediated by both autonomic and higher neural activity 3~as well as by hormones such as enterogastrone, gastrin and
Seminars in Nuclear Medicine, Vol. Xll, No. 2 (April), 1982
GASTRIC EMPTYING SCINTIGRAPHY Table 1. Factors Which Affect Gastric Emptying
Accelerate Emptying Liquids or small particles Increased intragastric pressure Distention Delay Emptying Solids Osmolality of carbohydrates or amino acids Chain length of fatty acids Energy density of food Acidity Hormone release Gastrin Cholecystokinin Secretin Cigarette smoking Adapted from Rock E., Malmud, L. S., Fisher, R. S. Motor Disorders of the Stomach. Med Clin N Amer 65:1269-1289, 1981
secretin, the latter two which delay gastric emptying, although gastrin increases antral activity, while secretin decreases it. The anatomy of the stomach is also of functional significance. There are longitudinal and circular muscles with an additional thin oblique inner layer of muscle present in the fundus and in continuity with the lower esophageal sphincter. These oblique muscles are important in receptive relaxation of the fundus. In the antrum, there is a progressively thicker circular muscle layer which generates strong antral contractions capable of grinding solids. The pylorus itself is composed of thick circular muscles with a resting high pressure sphincter zone. 31 Gastrointestinal hormones as noted above may effect gastric motility on either a physiological or pharmacological basis. Secretin, cholecystokinin (CCK), and gastrin reduce gastric emptying, although by different mechanisms. CCK and gastrin increase antral motility and delay gastric emptying, while secretin decreases antral activity while increasing pyloric pressure. Glucagon is able to inhibit gastric motility, but only as pharmacological doses (Table 1). The pylorus serves to prevent reflux of duodenal contents and restrict the rate of gastric emptying of solids and particulate matter. 32'33 Thus, food eaten as solids, leaves the stomach more slowly than the liquid portion of a meal. Water ingested with a solid such as an egg, has little effect on the rate of emptying of the solid in the normal stomach 34 (Table 2). While antral
117
Table 2. Stimuli That Affect Pyloric Pressure Increase
Duodenal Stimuli O. 1 N hydrochloric acid Fat - - olive oil, sodium oleate Hypertonic amino acids Hypertonic glucose Exogenous Hormones Cholecystokinin Secretin Glucagon Insulin Motilin Pharmacologic Agents Epinephrine Isoproterenol + Phenylephrine Metoclopramide
Decrease
Alcohol
Gastrin Somatostatin
Nicotine Alcohol Beta Adrenergic Antagonist Salicylates (?)
Adapted from Rock E, Malmud L S, Fisher R S. Motor Disorders of the Stomach. Med Clin N Amer (in press).
activity propels the solid food to the pylorus, the pyloro~luodenal contractions retropulse solids back to the fundus, presumably because the pylorus is closed, or nearly so, permitting the passage only of liquids or very small particulate matter. This coordination of antral and pyloric function probably limits postprandial emptying of solid food to very small particles, but allows passage of larger inert substances during the interdigestive phase. Blending of the solid and liquid phases of a meal equalizes emptying of solids and liquids. The only demonstrable physiological accelerator of gastric emptying is distention of the stomach. The neurohumoral inhibitors of gastric emptying are small intestinal receptors for acid, hyperosmolarity, hypoosmolarity, fat, and tryptophan. In patients with pancreatic insufficiency, fat is without an inhibitory effect, suggesting that it is the products of fat digestion, rather than triglycerides, that are important. 35 Surgery and vagotomy also greatly alter the rate of gastric emptying. In dogs, gastric or truncal vagotomy inhibits emptying of solid, 0.7 cm plastic spheres and speeds emptying of water. Proximal gastric vagotomy speeds emptying of liquids, but liquids of different composition are still emptied at different rates. Truncalvagotomy and pyloroplasty slow the emptying of solid food in some patients and speed it in others. 36
1 18
MALMUD ET AL.
TECHNIQUES FOR DETERMINING GASTRIC EMPTYING There are three general categories of techniques for studying gastric emptying: (1) Intubation tests, (2) roentgenographic tests, and (3) radionuclide tests 37 (Table 3). A fourth method introduced recently, employs a ferro-magnetic tracer, and has not found widespread use as yetJ 6
Intubation Tests The oldest of the intubation techniques was the serial test meal, in which a nonabsorbable marker is added to liquid meals of known volume, and the entire gastric contents aspirated at different time intervals as the test is repeated on sequential days. The rate of gastric emptying and the volume of gastric secretions could then be calculated from the series of data points collected on those days. 2 The repetitive intubations and time requirements of that method made it impractical and gained for it poor patient acceptance. 37 In the double sampling technique of George, 38 the need for repetitive intubations was overcome by administering a liquid meal of known volume, and then introducing small volumes of nonabsorbable markers as the gastric aspirates are sampled. Since the concentration and volume of the marker in the original meal and subsequent administrations are known, the volume of the meal remaining in the stomach is able to be calculated. The limitations of this technique are that it requires intubation and can be used only with a liquid meal. A variant of this method, introduced in 1973, 39 requires that the duodenum first be perfused to a steady state, following which a test meal with a marker is Table 3. Methods for Measuring Gastric Emptying Intubation Methods Saline load Serial intubation and aspiration Multiple sampling Multilumen tube perfusion and aspiration Roentgenographic Methods Barium studies Liquid Barium Enteric Coated Granules Barium Burger Scintigraphic Methods Single isotope, single phase Dual isotope, solid-liquid phase
placed in the stomach. The duodenum is then aspirated sequentially and the rate of gastric emptying is calculated from the concentration of the marker in the duodenal aspirate which must be complete. Fordtran's group improved upon Meeroff's method 39 by employing solid, physiologic meals. ~7However, the method may alter the rate of gastric emptying, since it requires perfusing the stomach to an intragastric pH of 5.5 by repeated titration of NaHCO3, which is by no means a physiologic state.
Roentgenographic Techniques Three types of radiographic tests exist: barium liquid, barium enteric coated granules, and the barium burger. None is quantitative, and each has some limitation. Barium liquid is unphysiologic as the barium may precipitate out and irritate the gastric mucosa. 37 Barium enteric coated granules were developed to overcome the possible gastric irritation of the liquid, but they, as with the more recently introduced barium burger, rely upon complete gastric emptying, as neither can be accurately quantitated. 4~
Radionuclide Techniques When first introduced by Griffith ~4 in 1966, radionuclide tests of gastric emptying appeared to represent an optimal technique for noninvasively and quantitatively characterizing gastric emptying patterns. Griffith employed a Cr-51 label mixed with porridge and an external probe for quantitation. Subsequent investigators have used a variety of radionuclides and radiopharmaceuticals, and equipment ranging from the simple probe, to a rectilinear scanner, dual scanner, gamma camera, and most currently a dual window gamma camera on line to a digital computer for rapid data processing. Amongst the radionuclides employed, Cr-51sodium chromate was followed by 1-131, which had the advantages of being able to be imaged, as well as counted. However, 1-131 human serum albumin is broken down in the duodenum, the I-131 absorbed and then resecreted in the gastric juice. In addition, the 1-131 isotope is a beta emitter, which of necessity was administered in low doses in order to restrict the radiation burden to both the gastrointestinal tract and thyroid gland. Finally, the 1-131 label was replaced by more optimal gamma emitting radionuclides,
GASTRIC EMPTYING SCINTIGRAPHY
Table 4. Optimization of Radionuclide Technique for Gastric Emptying Studies 1. 2. 3. 4.
Gamma emitting labels only Label with affinity for foods employed Gamma camera imaging Computer Data Processing
including In-111, In-113m and Tc-99m. These radiolabels are optimal due to their relatively short half lives, suitable imaging characteristics for the gamma camera, high count rates, and acceptably low radiation burdens, suitable for repetitive studies (Table 4). However, the binding of the radionuclides to the meal was in each case eventually proven to be suboptimal, as some degree of dissociation between the radiolabel and the food was demonstrable. Thus, each of the radiolabeled meals overestimated the rate Of gastric emptying, as the tracer left the stomach in the liquid gastric secretions rather than with the food. The problem of tight bonding between the tracer and a solid food, appears to have been solved by Meyer, ~3 who administered Tc-99m sulfer colloid to live chickens and then harvested the chicken livers from the freshly slaughtered chickens (Table 5). This resulted: in a labeled solid food in which the tracer was incorporated in the chicken's Kupffer cells, so that when cooked and fed to patients, there is little dissociation of the label from the food. Alternate solid food labeling techniques introduced recently include Tc-99m sulfur colloid in whole eggs 36 or egg whites 34 and in vitro labeled chicken liver 37 (Table 6). Either of the Tc-99m labeled chicken liver or egg preparations appears to be quantitatively and qualitatively superior to the chelated products which have a greater degree of dissociation in gastric juice. The iodinated fiber (alpha methyl cellulose) solid tracer for gastric emptying, introduced by the Mayo Clinic group 4~ is another firmly bound solid food-isotopic marker. Table 5. Tc-99m Tagged Chicken Liver for Gastric Emptying Studies Advantages A. Solid Marker B. Tc-99m label incorporated into chicken liver Kopffer Cells C. Little dissociation in vivo (<10% at 2 br) D. Suitable for Imaging
119
Table 6. Gastric Emptying Agents (Solid) Tc-99m Chicken Liver (Sulfur Colloid) in vivo or in vitro labeling Tc-99m Egg (Sulfur Colloid) Tc-99m Egg Albumin (Electrolytic) I- 123 Fiber Others
However, the fact that it is not a Tc-99m labeled product suggests that its clinical acceptance will be limited in view of its cost and lesser availability. Present technology suggests that one of the following techniques is optimal for routine clinical gastric emptying studies. In each case, we recommend a large field of view gamma camera (ideally suited for dual isotope scintigraphy) and a computer for rapid, decay corrected data processing. A dual headed rectilinear scanner may be used with no loss of accuracy 9 in those departments still owning such instruments. 1. Combined liquid-solid (Chicken liver). 22 This technique permits simultaneous determination of the rate of liquid and solid gastric emptying, employing in vivo labeled chicken liver and In-111 DTPA in water. Preparation of Tc-99m labeled chicken liver. One mCi of sterile, pyrogen-free Tc-99m sulfur colloid is injected into the wing vein of a live, 6 to 9 pound chicken. Fifteen to thirty min later, the chicken is slaughtered, and the liver removed and placed in a water bath, where it is agitated gently for 5 min. The liver is then wrapped in aluminum foil and baked in a preheated broiler for 20 min at 350 ~. After cooking, the chicken liver is cut into 0.5 cm cubes and added to a preheated, 8 ounce can of chicken stew (Bounty Brand, Campbell Soup Co., Camden, New Jersey). The stew serves as the 'carrier' for the radioactive, and less palatable chicken liver. The patient is requested to complete the meal within 10 min. The In-111 liquid component of the meal is composed of 250 microcuries of In-I 11 DTPA added to 120 ml tap water. The patients are instructed to drink the liquid upon completion of the solid portion of the meal. 2. Alternate dual isotope meals. Although the in vivo radiolabeled chicken liver is the optimal solid meal from the standpoint of label stability, the requirement for live chickens in the hospital makes the method suboptimal for the
120
MALMUD ET AL.
Table 7 . S t a b i l i t y of Radiolabeled Foods i n G a s t r i c J u i c e
filtered % bound: initially % bound at 3 hr (mean of 33 samples)
Tc-OA Egg
Tc - S C Egg
Tc- MAA Egg
Tc - HSA Egg
In Vivo Liver
I njected Liver
Surface Liver
98
92
96
90
99
93
93
84 _+ 6
82 _+ 3
82-+ 9
74 +_ 9
98-+ 1
87_+ 8
84_+ 9
average nuclear medicine department. Alternative radiolabeled solid foods were recently evaluated for their in vitro stability, and then the best of the in vitro products were compared to in vivo labeled T c - 9 9 m chicken liver in normal volunteer subjects. The radiolabeled food tested in vitro included both radiolabeled chicken liver
DUAL ISOTOPE GASTRIC SCINTIGRAPHY (NORMAL SUBJECT) 99mTc-S.C.-Chicken Liver (SOLID)
1111n-DTPA in Water (LIQUID)
0min.
15min.
30 min.
and radiolabeled e g g . 42 The specific preparations tested and the method of preparation are listed below: 1. In vivo chicken liver. Prepared as above. 2. Surface in vitro chicken liver. Raw liver was cut into 1 cm cubes. T c - 9 9 m - s u l f u r colloid was squirted onto the surface of the cubes. The cubes of liver were wrapped in foil and cooked as for the in vivo label. 3. Injected in vitro chicken liver. Same as surface label, except that the T c - 9 9 m - s u l f u r colloid was injected into each cube of liver before cooking. 4. Sulfer colloid egg. T c - 9 9 m - s u l f u r colloid was injected into a beaten raw egg. The egg was then cooked until firm in consistency. 5. M A A egg. T c - 9 9 m - m a c r o a g g r e g a t e d albumin was mixed with a beaten raw egg and cooked as above. 6. H S A egg. T c - 9 9 m - h u m a n serum albumin was mixed with a beaten raw egg and cooked as above. 7. Ovalbumin egg. T c - 9 9 m - o v a l b u m i n was prepared by labeling purified ovalbumin with T c - 9 9 m in an electrolytic method similar to a kit GASTRIC EMPTYINGOF SOLIDS AND LIQUIDS (NORMAL SUBJECTS; MEAN • S E.M.)
I00 90
,!"
4r
41-
-iP
41-
-ii
120
135
150
~ eo
~ TO ~ 60 m 50 o
~ 40
60 min.
c~ 3 0
I[/""i//'U/~
20 Io
15
120 min.
Fig. 1. Gastric emptying curves of components mixed solid-liquid meals in normal subjects.
of
30
45
60
T5 90 105 TIME (MINUTES)
Fig. 2. Composite results of dual isotope gastric emptying studies in 10 normal subjects. Each point represents the mean _+ SEM in 10 subjects, w h o received a liquid meal (above). then a combined liquid-solid meal. Note that the presence of a solid meal ( T c - 9 9 m in v i v o chicken liver) delayed t h e emptying of t h e liquid component, which was significantly more rapid (*) w h e n given alone.
GASTRIC EMPTYING SClNTIGRAPHY
for T c - 9 9 m - H S A (New England Nuclear) based on the method of Dworkin and Gutkowski. 43 The labeled ovalbumin was mixed with a beaten raw egg and cooked as above. The stability of the radiolabeled-food binding was tested by chopping the liver or egg preparation into particles of 3mm to simulate chewing, then dropping the particles into warm (37 ~) human gastric juice to simulate gastric activity. The stability of the radiolabeled products in gastric juice after 3 hr is summarized in Table 7. The best solid food, therefore, is in vivo chicken liver. However, either electrolytically labeled Tc-99m-ovalbumin egg, Tc-99m-sulfur colloidDUAL ISOTOPE GASTRIC SCINTIGRAPHY (DELAYED EMPTYING OF LIQUID AND SOLID) 99 mTc-S.C.-Chicken Liver (SOLID)
1111n-DTPAinWater (LIQUtD)
121
egg or in vitro injected chicken liver are almost as satisfactory. Gastric emptying curves of components of mixed solid liquid meals in normal subjects are illustrated in Fig. 1. Note that, despite the differences in label binding measured in vitro, that the curve for Tc-99m sulfur colloid is almost indistinguishable from the emptying pattern of T c 99m in vivo chicken liver. 3. Single labeled meal. If a single label is to be employed in gastric emptying studies, then it should be attached to a solid food and not a liquid. A liquid meal is less sensitive than a solid meal for detecting subtle abnormalities in gastric emptying 44 but if employed should contain fiber, protein, or fat, which leave the stomach more slowly than water or carbohydrate alone. While the iodinated fiber may serve as a research technique, the ready availability of T c - 9 9 m
GASTRIC EMPTYING OF LIQUIDS
Omin.
9 MEAN +_ I SD, N O R M A L S U B J E C T S [3 SINGLE PATIENT
I00 90
~ 7o 7~ 6o
15min.
w o_
50
m
N 3o 20
1 15
i 50
; 45
T 60
1 75
T 90
I 105
t 120
1 135
1 150
I 135
I 150
TIME (MINUTES)
30rain.
GASTRIC EMPTYING OF SOLIDS 9 o
I00
MEAN _+ I S D , N O R M A L SUBJECTS SINGLE PATIENT
90 80 70
6Omin.
GO 50 40 :50 2.0
120min.
15
i 50
i 45
I 60
i 75
I 90
i 105
I 120
TIME (MINUTES)
Fig. 3. Serial gastric emptying dual scintigraphy in a patient with marked diabetic neuropathy and gastroparesis. Note delayed emptying of both solid (left column) and liquid (right column) components.
Fig. 4. Delayed gastric emptying curves for liquid (In111 DTPA in water) above, and solid (Tc-99m-Sulfur Colloid Chicken Liver) below, in the patient whose serial scintigraphy is shown in Figure 3. Although delayed, the liquid curve retains an exponential-like shape, while the solid approximates a zero order equation.
122
MALMUD ET AL.
makes either the Tc-99m-sulfur colloid eggs or Tc-99m sulfur colloid chicken liver preparations more practical. The recent study by Knight 42 indicates in vivo labeled liver is best, but that in vitro (injected) chicken liver is as satisfactory a marker in patient studies.
DUAL ISOTOPE GASTRIC SCINTIGRAPHY (DELAYED EMPTYING OF SOLID) 99mTc- S.C.-Chicken Liver (SOLID)
1111n-DTPAin Water (LIQUID)
0 min.
15 min.
30 min.
60 min.
20rain.
Fig. 5. Serial gastric emptying dual scintigraphy in a patient with delayed emptying of the solid component of the meal (left column) but normal emptying of the liquid (right column). Images were obtained immediately, then at 15, 30, 60 and 120 minutes after ingestion of T c - 9 9 m labeled chicken liver and In-111 DTPA in water. Note persistent gastric activity at 60 min and 120 min in the Tc-99m w i n d o w (solid food label), while the I n - l l I window (liquid component) has emptied. This patient had a partial obstruction which allowed only liquid and small particles to pass through the pylorus. The abnormality was not detected by the saline load test, but was confirmed and relieved at surgery.
GASTRIC EMPTYING IMAGING AND QUANTITATION STUDIES
Immediately after ingestion of the labeled meal, the patient is positioned supine under a large field of view gamma camera fitted with a parallel hole collimator. The Tc-99m window is set at 140 ___ 10 Kev and if a dual isotope study, the In-111 window set at 171 _+ 10 Kev. There is approximately 8% scatter from the Tc-99m into the In-111 window, and 23% Compton scatter from the In-111 window into the Tc-99m window, although these figures should be reconfirmed employing phantom studies on the individual gamma camera and specific settings employed .45 Images are obtained for 60 sec at 15 min intervals for up to 3 hr. The patients are encouraged to sit upright or walk ad lib during the 14 min intervals between images. Each radionuclide's activity is imaged and quantitated separately as the liquid and solid components empty. In normal subjects, the liquid component of the mixed meal empties more rapidly from the stomach than does the solid. In addition, the liquid emptying curve approximates a mono-exponential curve, while solids empty in a zero order fashion. Illustrated in Fig. 2 are the emptying curves for serial scintigraphy of a liquid-solid meal in a normal subject (Fig. 2), compared to the same liquid meal administered above. Delayed gastric emptying of both liquids and solids is seen in the patient study in Figure 3. Note the visual evidence of delayed emptying at 60 min and 120 min. The quantitative results are shown in Fig. 4. An example of a patient with a selective delay in emptying of solids only is illustrated in Figures 5 and 6. This last example was in a patient eventually proven to have a partial gastric outlet obstruction due to tumor, but whose complaint of vomiting solid, undigested food several hours after eating, was not confirmed by either the saline load test, nor the liquid scintigraphic method. Data can most conveniently be reported on arithmetic graphs superimposed on normal ranges for both liquids and solids in the laboratory employing one of the standardized test meals described above, or its own standard meal. However, it must be stressed that normal values
GASTRIC
EMPTYING
123
SCINTIGRAPHY
Table 8. Causes of Delayed Gastric Emptying
GASTRIC EMPTYING OF LIQUIDS i MEAN _+ I SD, NORMAL SUBJECTS E} SINGLE PATIENT
I00 90
~ ao ~
70
~ 6o w 50 ~_ 4o c~ 30 BO
/ ,5'
3'0
o~
so'
~' ~'o ,05 ' T,ME ~M,NUTESl
,02'
,5~'
,50 '
BASTR,C EMPTY,NG OP SOUOS 9 MEAN _+ I SD, NORMAL SUBJECTS ~5 SINGLE PATIENT
I00 90
~ ao
~ ~o ~ eb
Mechanical Obstruction Duodenal ulcer Pyloric channel ulcer Cancer of the stomach Hypertrophic pyloric stenosis Functional Obstruction Vagotomy Diabetic Gastroparesis Idiopathic intestinal pseudo-obstruction Progressive systemic sclerosis Hypothyroidism Tachygastria Bulbar poliomyelitis Brain tumor Gastric ulcer Gastroesophageal reflux disease Intra-abdominal inflammation Electrolyte imbalance Trauma Anticholinergic agents Opiates
m 50 ~ 4o ~ 30 2o
0
15
30
45
60
75 90 105 TIME (MINUTES)
120
t35
150
Fig. 6. Normal gastric emptying curve for liquid component of a meal (above) in the patient whose serial scintigraphs are shown in Figure 5. Note the normal range (grey hatched area) +1 SD. Below, delayed gastric emptying of the solid component of the meal in the same patient, with the normal range _+1 SD for the solid component of the meal represented by the grey hatched area,
for gastric emptying depend greatly upon the composition of the specific test meal employed. DISORDERS OF GASTRIC EMPTYING 21
A number of clinical disorders may disrupt normal gastric emptying resulting in either delayed or accelerated rates, z5 Delayed gastric emptying is designated as either mechanical or functional obstructive. Mechanical obstruction results from narrowing or occlusion of the lumen with resultant increased resistance to normal aboral flow, while functional obstruction results from an abnormality of gastric motility, associated with either an inability to reduce solids into small particulate matter necessary for emptying or an inability to generate a gastroduodenal pressure gradient of sufficient magni-
tude to push chyme out of the stomach, across the pylorus and into the small bowel. The clinical causes of delayed gastric emptying are listed in Table 8. Rapid gastric emptying occurs less frequently, and is usually iatrogenic, although duodenal ulcer, Zollinger-Ellison Syndrome and hyperthyroidism may also induce rapid gastric transit (Table 9). In conclusion, radionuclide techniques appear to be the current method of choice for determining the rate and pattern of gastric emptying. Isotopic methods are quantitative, do not require intubation, may be used with solid meals for greater sensitivity, give a low radiation burden to the patient in comparison to fluoroscopy, and are suitable and acceptable to the patient for repetitive studies. By comparison, other methods are either invasive or nonquantitative. Of the radionuclide methods currently available, the solid meals, either liver or egg, are best, and dual
Table 9. Causes of Rapid Gastric Emptying Postsurgical Pyloroplasty Hemigastrectomy Duodenal ulcer Gastrinoma (Zollinger-Ellison Syndrome) Hyperthyroidism
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MALMUD ET AL.
l i q u i d - s o l i d s t u d i e s offer a d d i t i o n a l p h y s i o l o g i c
ing w i t h d i e t , m e d i c a t i o n a n d s u r g e r y r e q u i r e s
data. Gastric emptying abnormalities may result f r o m c o m m o n d i s o r d e r s s u c h as d i a b e t e s m e l l i tus, u l c e r d i s e a s e , a n d m e d i c a t i o n or g a s t r i c s u r g e r y , as well as f r o m m o r e o b s c u r e d i s o r d e r s s u c h as Z o l l i n g e r - E l l i s o n S y n d r o m e . T h e p h y s i c i a n ' s a b i l i t y to t r e a t d i s o r d e r s o f g a s t r i c e m p t y -
t h a t w e b e a b l e to q u a n t i t a t i v e l y d e t e r m i n e b a s e line g a s t r i c e m p t y i n g r a t e s as well as posttherapy rates. At the same time, our understanding o f g a s t r i c p h y s i o l o g y in m a n c a n n o w b e better understood using nuclear medicine techniques.
REFERENCES
I. Beaumont W: Experiments and observations on the gastric juice and the physiology of digestion. Plattsburgh, Allen, 1833 2. Hunt JN, Spurrell WR: The pattern of emptying of the human stomach. J Physiol (London) 113:157-168, 1951 3. George JD: New clinical method for measuring the rate of gastric emptying: The double sampling test method. Gut 9:237-242, 1968 4. Malagelada JR, Longstreth GF, Summerskill WHJ, et al: Measurement of gastric functions during digestion of ordinary solid meals in man. Gastroenterology 70:203-210, 1976 5. Malagelada JR: Quantification of gastric solid-liquid discrimination during digestion of ordinary meals. Gastroenterology 72:1265-1267, 1977 6. Fordtran JS and Walsh JH: Gastric acid secretion rate and buffer content of the stomach after eating: Results in normal subjects and in patients with duodenal ulcer. J Clin Invest 62:645-657, 1973 7. Horton RE, Ross FGM, Darling GH: Determination of the emptying time of the stomach by use of enteric coated barium granules. Br Med J 1:1537 1539, 1965 8. Pendergrass EP, Ravdin IS, Johnston CG, et al: Studies of the small intestine, II The effect of food and various pathologic states on gastric emptying and the small intestinal pattern. Radiology 26:651-662, 1936 9. Heading RC, Tothill P, McLoughlin GP, et al: Gastric emptying rate measurement in man: A double isotope scanning technique for simultaneous study of liquid and solid components of a meal. Gastroenterology 71:45-50, 1976 10. Harvey RF, Brown NJG, Mackie DB, et al: Measurement of gastric emptying time with a gamma camera. Lancet 1:16-18, 1970 11. Jones T, Clark JC, Kocak N, et al: Measurement of gastric emptying using the scintillation camera and Cs-129. Br J Radiology 43:537-541, 1970 12. Calderon M, Sonnemaker RE, Hersh T, et al: Tc-99m human albumin microspheres (HAM) for measuring the rate of gastric emptying. Radiology 101:371-374, 1971 13. Meyer JH, MacGregor MB, Gueller R, et al: Tc-99m tagged chicken liver as a marker of solid food in the human stomach. Dig Dis 21:296-304, 1976 14. Griflith GH, Owen GM, Kirkman S, et al: Measurement of rate of gastric emptying using Chromium-51. Lancet 1:1244-1245, 1966 15. Heading RC, Tothill P, Lardlow AJ et al: Gastric emptying rate measurement in man: A double isotope scanning technique for simultaneous study of liquid and solid components of a meal. Gastroenterology 71:45-50, 1976
16. Benmair Y, Dreyfuss F, Fischel, B, et al: Study of gastric emptying using a ferro-magnetic tracer. Gastroenterology 73:1041-1045, 1977 17. Fordtran JS: Acid secretion inpeptic ulcer. In Gastrointestinal Disease. MH Sleisenger, JS Fordtran (eds), Philadelphia, Saunders, 1973, pp 174-188 18. Scarpello JHB, Barber DC, Hague RV, et al: Gastric emptying of solid meals in diabetes. Br Med J 2:671-673, 1976 19. Griffith GH, Owen GM, Campbell H, et al: Gastric emptying in health and in gastroduodenal disease. Gastroenterology 54:1-7, 1968 20. Malagelada JR, Longstreth GF, Deering TB, et al: Gastric secretion and emptying after ordinary meals in duodenal ulcer. Gastroenterology 73:989-994, 1977 21. Rock E, Malmud LS, Fisher RS: Motor disorders of the stomach. Med Clin N A m e r 65:1269-1289, 1981 22. Malmud LS, Long WB: Radionuclide studies of gastric emptying. In Abdominal Imaging: The Role of Computerized Tomography, Ultrasound and Nuclear Medicine Techniques, Alavi A and Arger P (eds), New York NY, Grune and Stratton, 1980, pp 87-96 23. Cohen S, Long WB, Snape W J: Gastrointestinal motility. In International Review of Physiology, Gastrointestinal Physiology III Vol 19, RK Crane (ed), Baltimore, University Park, 107-149, 1979 24. Sarna SK, Daniel EE, Kingma JE: Stimulation of electrical control activity of the stomach by an array of relaxation oscillators. Am J Dig Dis 17:122, 1972 24. Sarna SK, Daniel EE, Kingma JE: Stimulation of electrical control activity of the stomach by an array of relaxation oscillators. Am J Dig Dis 17:122, 1972 25. Code CF, Marlett JA: The interdigestive myoelectric complex of the stomach and small bowel of dogs. J Physiol (London) 246:289, 1975 26. Christensen J, Torres El: Three layers of the opossum stomach: responses to nerve stimulation. Gastroenterology 69:641, 1975 27. Fisher R, Cohen S: Physiological characteristics of the human pyloric sphincter. Gastroenterology, 64:67, 1973 28. Burnstock G: Purinergic nerves. Pharmacol Rev 24:509, 1972 29. Jahnberg T: Gastric adaptive relaxation effects of vagal activation and vagotomy--An experimental study in dogs and in man. Scand J Gastroenterol 12:(Suppl 46)1, 1977 30. Anuras S, Cooke AR, Christensen J: An inhibitory i n n e r v a t i o n at the g a s t r o d u o d e n a l j u n c t i o n . J Clin Invest 54:529, 1974
GASTRIC EMPTYING SCINTIGRAPHY
31. Debas HT, Farooq O, Grossman MI: Inhibition of gastric emptying is a physiological action of cholecystokinin. Gastroenterology 68:1211, 1975 32. Fisher RS, Lipshutz W, Cohen S: The hormonal regulation of pyloric sphincter function. J Clin Invest 52:1289, 1973 33. Hinder RA, Kelly KA: Canine gastric emptying of solids and liquids. Am J Physiol 233:E335, 1977 34. Kroop HS, Long WB, Hansell JR, et al: Effect of water and fat on gastric emptying of solid meals in man. Gastroenterology (in press) 35. Long WB, Weiss JB: Rapid gastric emptying of fatty meals in pancreatic insufficiency. Gastroenterology 67:920, 1974 36. MacGregor IL, Martin P, Meyer JH: Gastric emptying of solid food in normal man and after subtotal gastrectomy and trunctal vagotomy with pyloroplasty. Gastroenterology 7:206, 1977 37. Sheiner H J: Progress Report: Gastric emptying tests in man. Gut 16:235 247, 1975 38. George JD: Gastric acidity and motility. Am J Dig Dis 13:376-383, 1968
125
39. Meeroff JC, Go VLM, Phillips SF: Gastric emptying of liquids in man: quantification by duodenal recovery marker. Mayo Clinic Proc 48:728-732, 1973 40. Sun DCH, Shay H, Woloshin H J: Effect of tricyclamol on gastric emptying and intestinal transit. Am J Dig Dis 4:282-288, 1959 41. Carlson GL: Radiolabeled fiber. A physiologic marker for gastric emptying and intestinal transit of solids. Dig Dis Sci 25:81-87, 1980 42. Knight LC, Malmud LS: Tc-99m-ovalbumin labeled eggs: Comparison with other solid food markers in vitro. J Nucl Med 22:28, 1981 43. Dworkin JH, Gutkowski RF: Rapid closed system production of Tc-99m-albumin using electrolysis. J Nucl Med 12:562-565, 1971 44. Bandini P, Malmud LS, Applegate G, et al: Dual radionuclide studies of gastric emptying using a physiologic meal. J Nucl Med 21:66, 1980 45. Fisher RS, Malmud LS: Functional scintigraphy: Diagnostic applications in gastroenterology. In: Developments in Digestive Disease 3, JE Berk (ed), Philadelphia, Lea and Febiger, 139-164, 1980
using radiolabled physiologic meals, these tests are being employed w i t h increasing frequency in the evaluation of patients w i t h disorders such as diabetic gastroparesis, postgastrectomy gastroparesis or dumping syndrome, and in the study of normal gastric physiology in man. Present data suggests that combined liquid-solid, dual radionuclide studies afford t h e greatest information regarding simultaneous gastric emptying patterns of liquid and solid components of a meal, and t h a t single radionuclide, solid tests of gastric emptying are the m o r e sensitive technique for determining subtle abnormalities of gastric emptying, w h e n only a single tracer is employed.
U R I N G the previous century and a half, a number of techniques for measuring gastric emptying had been introduced, ranging from observations through a gastric fistula, I to a variety of intubation tests, 2~ radiographic procedures, 7-8 radionuclide tests, 9 15 and even a ferromagnetic technique. ~6 Recently there has been renewed interest in gastric emptying studies as a result of several stimuli, including an attempt to relate gastric emptying abnormalities to the etiology of peptic ulcer disease, ~7 and the development of reproducible, quantitative radionuclide methods for characterizing the pattern of gastric emptying. Abnormalities of gastric emptying occur in a variety of disorders other than in peptic ulcer disease, including diabetes, TM gastric cancer, 19 following medical therapy, such as, anticholinergic or cholinergic drugs, and following ulcer surgery. Several of the recently introduced intubation techniques 4'5'2~may prove useful as standards for comparison as the use of five lumens and infusions permits quantitation of both gastric emptying and gastric secretion. However, the invasive character of endogastric intubation suggests that the method will not meet with widespread acceptance by either patients or physicians.
PHYSIOLOGY OF GASTRIC EMPTYING 21'22
D
From the Department of Nuclear Medicine, Temple University Hospital and School of Medicine, Philadelphia, Pa. Address reprint requests to Leon S. Malmud, M.D., Department of Nuclear Medicine, Temple University Hospital and School of Medicine, Philadelphia, Pa. 19140. 9 1982 by Grune & Stratton, Inc. 0001-2998/82/1202~002502.00/0
116
After food passes through the esophagus and lower esophageal sphincter, it is received and stored by the stomach, where it is mixed with gastric secretions, and delivered into the duodenum in an orderly fashion. In terms of its motor function, the stomach consists of two parts: a proximal receptacle, which includes the fundus and body; and the distal portion, the antrum and pylorus. 23 Regular, slow contractions in the fundus and peristaltic waves in the body, propel food towards the antrum where weaker waves fade, but stronger ones result in contractions of the antrum and coordinated duodenal muscular activity] 4 The pylorus represents the major component of the duodenogastric resistance and may serve as the anti reflux control device in man. 25 In general, the fundus controls the emptying rates of liquids, and the antrum controls solids, although antral contractions triggered by solids may play a role in the emptying of liquids. 23 26 Gastric emptying of liquids is also dependent upon the gastroduodenal pressure gradient. However, because the fundus of the stomach is able to relax in response to an increased volume, there is not a direct relationship between increased gastric volume and the rate of gastric emptying, although an indirect relationship has been demonstrated. 27 Other factors which control gastric emptying include electrical activity and the characteristics of the meal itself. 28'29The electrical activity appears to be mediated by both autonomic and higher neural activity 3~as well as by hormones such as enterogastrone, gastrin and
Seminars in Nuclear Medicine, Vol. Xll, No. 2 (April), 1982
GASTRIC EMPTYING SCINTIGRAPHY Table 1. Factors Which Affect Gastric Emptying
Accelerate Emptying Liquids or small particles Increased intragastric pressure Distention Delay Emptying Solids Osmolality of carbohydrates or amino acids Chain length of fatty acids Energy density of food Acidity Hormone release Gastrin Cholecystokinin Secretin Cigarette smoking Adapted from Rock E., Malmud, L. S., Fisher, R. S. Motor Disorders of the Stomach. Med Clin N Amer 65:1269-1289, 1981
secretin, the latter two which delay gastric emptying, although gastrin increases antral activity, while secretin decreases it. The anatomy of the stomach is also of functional significance. There are longitudinal and circular muscles with an additional thin oblique inner layer of muscle present in the fundus and in continuity with the lower esophageal sphincter. These oblique muscles are important in receptive relaxation of the fundus. In the antrum, there is a progressively thicker circular muscle layer which generates strong antral contractions capable of grinding solids. The pylorus itself is composed of thick circular muscles with a resting high pressure sphincter zone. 31 Gastrointestinal hormones as noted above may effect gastric motility on either a physiological or pharmacological basis. Secretin, cholecystokinin (CCK), and gastrin reduce gastric emptying, although by different mechanisms. CCK and gastrin increase antral motility and delay gastric emptying, while secretin decreases antral activity while increasing pyloric pressure. Glucagon is able to inhibit gastric motility, but only as pharmacological doses (Table 1). The pylorus serves to prevent reflux of duodenal contents and restrict the rate of gastric emptying of solids and particulate matter. 32'33 Thus, food eaten as solids, leaves the stomach more slowly than the liquid portion of a meal. Water ingested with a solid such as an egg, has little effect on the rate of emptying of the solid in the normal stomach 34 (Table 2). While antral
117
Table 2. Stimuli That Affect Pyloric Pressure Increase
Duodenal Stimuli O. 1 N hydrochloric acid Fat - - olive oil, sodium oleate Hypertonic amino acids Hypertonic glucose Exogenous Hormones Cholecystokinin Secretin Glucagon Insulin Motilin Pharmacologic Agents Epinephrine Isoproterenol + Phenylephrine Metoclopramide
Decrease
Alcohol
Gastrin Somatostatin
Nicotine Alcohol Beta Adrenergic Antagonist Salicylates (?)
Adapted from Rock E, Malmud L S, Fisher R S. Motor Disorders of the Stomach. Med Clin N Amer (in press).
activity propels the solid food to the pylorus, the pyloro~luodenal contractions retropulse solids back to the fundus, presumably because the pylorus is closed, or nearly so, permitting the passage only of liquids or very small particulate matter. This coordination of antral and pyloric function probably limits postprandial emptying of solid food to very small particles, but allows passage of larger inert substances during the interdigestive phase. Blending of the solid and liquid phases of a meal equalizes emptying of solids and liquids. The only demonstrable physiological accelerator of gastric emptying is distention of the stomach. The neurohumoral inhibitors of gastric emptying are small intestinal receptors for acid, hyperosmolarity, hypoosmolarity, fat, and tryptophan. In patients with pancreatic insufficiency, fat is without an inhibitory effect, suggesting that it is the products of fat digestion, rather than triglycerides, that are important. 35 Surgery and vagotomy also greatly alter the rate of gastric emptying. In dogs, gastric or truncal vagotomy inhibits emptying of solid, 0.7 cm plastic spheres and speeds emptying of water. Proximal gastric vagotomy speeds emptying of liquids, but liquids of different composition are still emptied at different rates. Truncalvagotomy and pyloroplasty slow the emptying of solid food in some patients and speed it in others. 36
1 18
MALMUD ET AL.
TECHNIQUES FOR DETERMINING GASTRIC EMPTYING There are three general categories of techniques for studying gastric emptying: (1) Intubation tests, (2) roentgenographic tests, and (3) radionuclide tests 37 (Table 3). A fourth method introduced recently, employs a ferro-magnetic tracer, and has not found widespread use as yetJ 6
Intubation Tests The oldest of the intubation techniques was the serial test meal, in which a nonabsorbable marker is added to liquid meals of known volume, and the entire gastric contents aspirated at different time intervals as the test is repeated on sequential days. The rate of gastric emptying and the volume of gastric secretions could then be calculated from the series of data points collected on those days. 2 The repetitive intubations and time requirements of that method made it impractical and gained for it poor patient acceptance. 37 In the double sampling technique of George, 38 the need for repetitive intubations was overcome by administering a liquid meal of known volume, and then introducing small volumes of nonabsorbable markers as the gastric aspirates are sampled. Since the concentration and volume of the marker in the original meal and subsequent administrations are known, the volume of the meal remaining in the stomach is able to be calculated. The limitations of this technique are that it requires intubation and can be used only with a liquid meal. A variant of this method, introduced in 1973, 39 requires that the duodenum first be perfused to a steady state, following which a test meal with a marker is Table 3. Methods for Measuring Gastric Emptying Intubation Methods Saline load Serial intubation and aspiration Multiple sampling Multilumen tube perfusion and aspiration Roentgenographic Methods Barium studies Liquid Barium Enteric Coated Granules Barium Burger Scintigraphic Methods Single isotope, single phase Dual isotope, solid-liquid phase
placed in the stomach. The duodenum is then aspirated sequentially and the rate of gastric emptying is calculated from the concentration of the marker in the duodenal aspirate which must be complete. Fordtran's group improved upon Meeroff's method 39 by employing solid, physiologic meals. ~7However, the method may alter the rate of gastric emptying, since it requires perfusing the stomach to an intragastric pH of 5.5 by repeated titration of NaHCO3, which is by no means a physiologic state.
Roentgenographic Techniques Three types of radiographic tests exist: barium liquid, barium enteric coated granules, and the barium burger. None is quantitative, and each has some limitation. Barium liquid is unphysiologic as the barium may precipitate out and irritate the gastric mucosa. 37 Barium enteric coated granules were developed to overcome the possible gastric irritation of the liquid, but they, as with the more recently introduced barium burger, rely upon complete gastric emptying, as neither can be accurately quantitated. 4~
Radionuclide Techniques When first introduced by Griffith ~4 in 1966, radionuclide tests of gastric emptying appeared to represent an optimal technique for noninvasively and quantitatively characterizing gastric emptying patterns. Griffith employed a Cr-51 label mixed with porridge and an external probe for quantitation. Subsequent investigators have used a variety of radionuclides and radiopharmaceuticals, and equipment ranging from the simple probe, to a rectilinear scanner, dual scanner, gamma camera, and most currently a dual window gamma camera on line to a digital computer for rapid data processing. Amongst the radionuclides employed, Cr-51sodium chromate was followed by 1-131, which had the advantages of being able to be imaged, as well as counted. However, 1-131 human serum albumin is broken down in the duodenum, the I-131 absorbed and then resecreted in the gastric juice. In addition, the 1-131 isotope is a beta emitter, which of necessity was administered in low doses in order to restrict the radiation burden to both the gastrointestinal tract and thyroid gland. Finally, the 1-131 label was replaced by more optimal gamma emitting radionuclides,
GASTRIC EMPTYING SCINTIGRAPHY
Table 4. Optimization of Radionuclide Technique for Gastric Emptying Studies 1. 2. 3. 4.
Gamma emitting labels only Label with affinity for foods employed Gamma camera imaging Computer Data Processing
including In-111, In-113m and Tc-99m. These radiolabels are optimal due to their relatively short half lives, suitable imaging characteristics for the gamma camera, high count rates, and acceptably low radiation burdens, suitable for repetitive studies (Table 4). However, the binding of the radionuclides to the meal was in each case eventually proven to be suboptimal, as some degree of dissociation between the radiolabel and the food was demonstrable. Thus, each of the radiolabeled meals overestimated the rate Of gastric emptying, as the tracer left the stomach in the liquid gastric secretions rather than with the food. The problem of tight bonding between the tracer and a solid food, appears to have been solved by Meyer, ~3 who administered Tc-99m sulfer colloid to live chickens and then harvested the chicken livers from the freshly slaughtered chickens (Table 5). This resulted: in a labeled solid food in which the tracer was incorporated in the chicken's Kupffer cells, so that when cooked and fed to patients, there is little dissociation of the label from the food. Alternate solid food labeling techniques introduced recently include Tc-99m sulfur colloid in whole eggs 36 or egg whites 34 and in vitro labeled chicken liver 37 (Table 6). Either of the Tc-99m labeled chicken liver or egg preparations appears to be quantitatively and qualitatively superior to the chelated products which have a greater degree of dissociation in gastric juice. The iodinated fiber (alpha methyl cellulose) solid tracer for gastric emptying, introduced by the Mayo Clinic group 4~ is another firmly bound solid food-isotopic marker. Table 5. Tc-99m Tagged Chicken Liver for Gastric Emptying Studies Advantages A. Solid Marker B. Tc-99m label incorporated into chicken liver Kopffer Cells C. Little dissociation in vivo (<10% at 2 br) D. Suitable for Imaging
119
Table 6. Gastric Emptying Agents (Solid) Tc-99m Chicken Liver (Sulfur Colloid) in vivo or in vitro labeling Tc-99m Egg (Sulfur Colloid) Tc-99m Egg Albumin (Electrolytic) I- 123 Fiber Others
However, the fact that it is not a Tc-99m labeled product suggests that its clinical acceptance will be limited in view of its cost and lesser availability. Present technology suggests that one of the following techniques is optimal for routine clinical gastric emptying studies. In each case, we recommend a large field of view gamma camera (ideally suited for dual isotope scintigraphy) and a computer for rapid, decay corrected data processing. A dual headed rectilinear scanner may be used with no loss of accuracy 9 in those departments still owning such instruments. 1. Combined liquid-solid (Chicken liver). 22 This technique permits simultaneous determination of the rate of liquid and solid gastric emptying, employing in vivo labeled chicken liver and In-111 DTPA in water. Preparation of Tc-99m labeled chicken liver. One mCi of sterile, pyrogen-free Tc-99m sulfur colloid is injected into the wing vein of a live, 6 to 9 pound chicken. Fifteen to thirty min later, the chicken is slaughtered, and the liver removed and placed in a water bath, where it is agitated gently for 5 min. The liver is then wrapped in aluminum foil and baked in a preheated broiler for 20 min at 350 ~. After cooking, the chicken liver is cut into 0.5 cm cubes and added to a preheated, 8 ounce can of chicken stew (Bounty Brand, Campbell Soup Co., Camden, New Jersey). The stew serves as the 'carrier' for the radioactive, and less palatable chicken liver. The patient is requested to complete the meal within 10 min. The In-111 liquid component of the meal is composed of 250 microcuries of In-I 11 DTPA added to 120 ml tap water. The patients are instructed to drink the liquid upon completion of the solid portion of the meal. 2. Alternate dual isotope meals. Although the in vivo radiolabeled chicken liver is the optimal solid meal from the standpoint of label stability, the requirement for live chickens in the hospital makes the method suboptimal for the
120
MALMUD ET AL.
Table 7 . S t a b i l i t y of Radiolabeled Foods i n G a s t r i c J u i c e
filtered % bound: initially % bound at 3 hr (mean of 33 samples)
Tc-OA Egg
Tc - S C Egg
Tc- MAA Egg
Tc - HSA Egg
In Vivo Liver
I njected Liver
Surface Liver
98
92
96
90
99
93
93
84 _+ 6
82 _+ 3
82-+ 9
74 +_ 9
98-+ 1
87_+ 8
84_+ 9
average nuclear medicine department. Alternative radiolabeled solid foods were recently evaluated for their in vitro stability, and then the best of the in vitro products were compared to in vivo labeled T c - 9 9 m chicken liver in normal volunteer subjects. The radiolabeled food tested in vitro included both radiolabeled chicken liver
DUAL ISOTOPE GASTRIC SCINTIGRAPHY (NORMAL SUBJECT) 99mTc-S.C.-Chicken Liver (SOLID)
1111n-DTPA in Water (LIQUID)
0min.
15min.
30 min.
and radiolabeled e g g . 42 The specific preparations tested and the method of preparation are listed below: 1. In vivo chicken liver. Prepared as above. 2. Surface in vitro chicken liver. Raw liver was cut into 1 cm cubes. T c - 9 9 m - s u l f u r colloid was squirted onto the surface of the cubes. The cubes of liver were wrapped in foil and cooked as for the in vivo label. 3. Injected in vitro chicken liver. Same as surface label, except that the T c - 9 9 m - s u l f u r colloid was injected into each cube of liver before cooking. 4. Sulfer colloid egg. T c - 9 9 m - s u l f u r colloid was injected into a beaten raw egg. The egg was then cooked until firm in consistency. 5. M A A egg. T c - 9 9 m - m a c r o a g g r e g a t e d albumin was mixed with a beaten raw egg and cooked as above. 6. H S A egg. T c - 9 9 m - h u m a n serum albumin was mixed with a beaten raw egg and cooked as above. 7. Ovalbumin egg. T c - 9 9 m - o v a l b u m i n was prepared by labeling purified ovalbumin with T c - 9 9 m in an electrolytic method similar to a kit GASTRIC EMPTYINGOF SOLIDS AND LIQUIDS (NORMAL SUBJECTS; MEAN • S E.M.)
I00 90
,!"
4r
41-
-iP
41-
-ii
120
135
150
~ eo
~ TO ~ 60 m 50 o
~ 40
60 min.
c~ 3 0
I[/""i//'U/~
20 Io
15
120 min.
Fig. 1. Gastric emptying curves of components mixed solid-liquid meals in normal subjects.
of
30
45
60
T5 90 105 TIME (MINUTES)
Fig. 2. Composite results of dual isotope gastric emptying studies in 10 normal subjects. Each point represents the mean _+ SEM in 10 subjects, w h o received a liquid meal (above). then a combined liquid-solid meal. Note that the presence of a solid meal ( T c - 9 9 m in v i v o chicken liver) delayed t h e emptying of t h e liquid component, which was significantly more rapid (*) w h e n given alone.
GASTRIC EMPTYING SClNTIGRAPHY
for T c - 9 9 m - H S A (New England Nuclear) based on the method of Dworkin and Gutkowski. 43 The labeled ovalbumin was mixed with a beaten raw egg and cooked as above. The stability of the radiolabeled-food binding was tested by chopping the liver or egg preparation into particles of 3mm to simulate chewing, then dropping the particles into warm (37 ~) human gastric juice to simulate gastric activity. The stability of the radiolabeled products in gastric juice after 3 hr is summarized in Table 7. The best solid food, therefore, is in vivo chicken liver. However, either electrolytically labeled Tc-99m-ovalbumin egg, Tc-99m-sulfur colloidDUAL ISOTOPE GASTRIC SCINTIGRAPHY (DELAYED EMPTYING OF LIQUID AND SOLID) 99 mTc-S.C.-Chicken Liver (SOLID)
1111n-DTPAinWater (LIQUtD)
121
egg or in vitro injected chicken liver are almost as satisfactory. Gastric emptying curves of components of mixed solid liquid meals in normal subjects are illustrated in Fig. 1. Note that, despite the differences in label binding measured in vitro, that the curve for Tc-99m sulfur colloid is almost indistinguishable from the emptying pattern of T c 99m in vivo chicken liver. 3. Single labeled meal. If a single label is to be employed in gastric emptying studies, then it should be attached to a solid food and not a liquid. A liquid meal is less sensitive than a solid meal for detecting subtle abnormalities in gastric emptying 44 but if employed should contain fiber, protein, or fat, which leave the stomach more slowly than water or carbohydrate alone. While the iodinated fiber may serve as a research technique, the ready availability of T c - 9 9 m
GASTRIC EMPTYING OF LIQUIDS
Omin.
9 MEAN +_ I SD, N O R M A L S U B J E C T S [3 SINGLE PATIENT
I00 90
~ 7o 7~ 6o
15min.
w o_
50
m
N 3o 20
1 15
i 50
; 45
T 60
1 75
T 90
I 105
t 120
1 135
1 150
I 135
I 150
TIME (MINUTES)
30rain.
GASTRIC EMPTYING OF SOLIDS 9 o
I00
MEAN _+ I S D , N O R M A L SUBJECTS SINGLE PATIENT
90 80 70
6Omin.
GO 50 40 :50 2.0
120min.
15
i 50
i 45
I 60
i 75
I 90
i 105
I 120
TIME (MINUTES)
Fig. 3. Serial gastric emptying dual scintigraphy in a patient with marked diabetic neuropathy and gastroparesis. Note delayed emptying of both solid (left column) and liquid (right column) components.
Fig. 4. Delayed gastric emptying curves for liquid (In111 DTPA in water) above, and solid (Tc-99m-Sulfur Colloid Chicken Liver) below, in the patient whose serial scintigraphy is shown in Figure 3. Although delayed, the liquid curve retains an exponential-like shape, while the solid approximates a zero order equation.
122
MALMUD ET AL.
makes either the Tc-99m-sulfur colloid eggs or Tc-99m sulfur colloid chicken liver preparations more practical. The recent study by Knight 42 indicates in vivo labeled liver is best, but that in vitro (injected) chicken liver is as satisfactory a marker in patient studies.
DUAL ISOTOPE GASTRIC SCINTIGRAPHY (DELAYED EMPTYING OF SOLID) 99mTc- S.C.-Chicken Liver (SOLID)
1111n-DTPAin Water (LIQUID)
0 min.
15 min.
30 min.
60 min.
20rain.
Fig. 5. Serial gastric emptying dual scintigraphy in a patient with delayed emptying of the solid component of the meal (left column) but normal emptying of the liquid (right column). Images were obtained immediately, then at 15, 30, 60 and 120 minutes after ingestion of T c - 9 9 m labeled chicken liver and In-111 DTPA in water. Note persistent gastric activity at 60 min and 120 min in the Tc-99m w i n d o w (solid food label), while the I n - l l I window (liquid component) has emptied. This patient had a partial obstruction which allowed only liquid and small particles to pass through the pylorus. The abnormality was not detected by the saline load test, but was confirmed and relieved at surgery.
GASTRIC EMPTYING IMAGING AND QUANTITATION STUDIES
Immediately after ingestion of the labeled meal, the patient is positioned supine under a large field of view gamma camera fitted with a parallel hole collimator. The Tc-99m window is set at 140 ___ 10 Kev and if a dual isotope study, the In-111 window set at 171 _+ 10 Kev. There is approximately 8% scatter from the Tc-99m into the In-111 window, and 23% Compton scatter from the In-111 window into the Tc-99m window, although these figures should be reconfirmed employing phantom studies on the individual gamma camera and specific settings employed .45 Images are obtained for 60 sec at 15 min intervals for up to 3 hr. The patients are encouraged to sit upright or walk ad lib during the 14 min intervals between images. Each radionuclide's activity is imaged and quantitated separately as the liquid and solid components empty. In normal subjects, the liquid component of the mixed meal empties more rapidly from the stomach than does the solid. In addition, the liquid emptying curve approximates a mono-exponential curve, while solids empty in a zero order fashion. Illustrated in Fig. 2 are the emptying curves for serial scintigraphy of a liquid-solid meal in a normal subject (Fig. 2), compared to the same liquid meal administered above. Delayed gastric emptying of both liquids and solids is seen in the patient study in Figure 3. Note the visual evidence of delayed emptying at 60 min and 120 min. The quantitative results are shown in Fig. 4. An example of a patient with a selective delay in emptying of solids only is illustrated in Figures 5 and 6. This last example was in a patient eventually proven to have a partial gastric outlet obstruction due to tumor, but whose complaint of vomiting solid, undigested food several hours after eating, was not confirmed by either the saline load test, nor the liquid scintigraphic method. Data can most conveniently be reported on arithmetic graphs superimposed on normal ranges for both liquids and solids in the laboratory employing one of the standardized test meals described above, or its own standard meal. However, it must be stressed that normal values
GASTRIC
EMPTYING
123
SCINTIGRAPHY
Table 8. Causes of Delayed Gastric Emptying
GASTRIC EMPTYING OF LIQUIDS i MEAN _+ I SD, NORMAL SUBJECTS E} SINGLE PATIENT
I00 90
~ ao ~
70
~ 6o w 50 ~_ 4o c~ 30 BO
/ ,5'
3'0
o~
so'
~' ~'o ,05 ' T,ME ~M,NUTESl
,02'
,5~'
,50 '
BASTR,C EMPTY,NG OP SOUOS 9 MEAN _+ I SD, NORMAL SUBJECTS ~5 SINGLE PATIENT
I00 90
~ ao
~ ~o ~ eb
Mechanical Obstruction Duodenal ulcer Pyloric channel ulcer Cancer of the stomach Hypertrophic pyloric stenosis Functional Obstruction Vagotomy Diabetic Gastroparesis Idiopathic intestinal pseudo-obstruction Progressive systemic sclerosis Hypothyroidism Tachygastria Bulbar poliomyelitis Brain tumor Gastric ulcer Gastroesophageal reflux disease Intra-abdominal inflammation Electrolyte imbalance Trauma Anticholinergic agents Opiates
m 50 ~ 4o ~ 30 2o
0
15
30
45
60
75 90 105 TIME (MINUTES)
120
t35
150
Fig. 6. Normal gastric emptying curve for liquid component of a meal (above) in the patient whose serial scintigraphs are shown in Figure 5. Note the normal range (grey hatched area) +1 SD. Below, delayed gastric emptying of the solid component of the meal in the same patient, with the normal range _+1 SD for the solid component of the meal represented by the grey hatched area,
for gastric emptying depend greatly upon the composition of the specific test meal employed. DISORDERS OF GASTRIC EMPTYING 21
A number of clinical disorders may disrupt normal gastric emptying resulting in either delayed or accelerated rates, z5 Delayed gastric emptying is designated as either mechanical or functional obstructive. Mechanical obstruction results from narrowing or occlusion of the lumen with resultant increased resistance to normal aboral flow, while functional obstruction results from an abnormality of gastric motility, associated with either an inability to reduce solids into small particulate matter necessary for emptying or an inability to generate a gastroduodenal pressure gradient of sufficient magni-
tude to push chyme out of the stomach, across the pylorus and into the small bowel. The clinical causes of delayed gastric emptying are listed in Table 8. Rapid gastric emptying occurs less frequently, and is usually iatrogenic, although duodenal ulcer, Zollinger-Ellison Syndrome and hyperthyroidism may also induce rapid gastric transit (Table 9). In conclusion, radionuclide techniques appear to be the current method of choice for determining the rate and pattern of gastric emptying. Isotopic methods are quantitative, do not require intubation, may be used with solid meals for greater sensitivity, give a low radiation burden to the patient in comparison to fluoroscopy, and are suitable and acceptable to the patient for repetitive studies. By comparison, other methods are either invasive or nonquantitative. Of the radionuclide methods currently available, the solid meals, either liver or egg, are best, and dual
Table 9. Causes of Rapid Gastric Emptying Postsurgical Pyloroplasty Hemigastrectomy Duodenal ulcer Gastrinoma (Zollinger-Ellison Syndrome) Hyperthyroidism
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MALMUD ET AL.
l i q u i d - s o l i d s t u d i e s offer a d d i t i o n a l p h y s i o l o g i c
ing w i t h d i e t , m e d i c a t i o n a n d s u r g e r y r e q u i r e s
data. Gastric emptying abnormalities may result f r o m c o m m o n d i s o r d e r s s u c h as d i a b e t e s m e l l i tus, u l c e r d i s e a s e , a n d m e d i c a t i o n or g a s t r i c s u r g e r y , as well as f r o m m o r e o b s c u r e d i s o r d e r s s u c h as Z o l l i n g e r - E l l i s o n S y n d r o m e . T h e p h y s i c i a n ' s a b i l i t y to t r e a t d i s o r d e r s o f g a s t r i c e m p t y -
t h a t w e b e a b l e to q u a n t i t a t i v e l y d e t e r m i n e b a s e line g a s t r i c e m p t y i n g r a t e s as well as posttherapy rates. At the same time, our understanding o f g a s t r i c p h y s i o l o g y in m a n c a n n o w b e better understood using nuclear medicine techniques.
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