The gastric emptying of chyme is arguably the most important

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7: CLINICAL IMAGING Gastric Emptying LAWRENCE A. SZARKA and MICHAEL CAMILLERI Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), College of Medicine, Mayo Clinic, Rochester, Minnesota This article has an accompanying continuing medical education activity on page 810. Learning Objectives At the end of this activity the learner should be familiar with various modalities used to diagnose delayed gastric emptying and how they can be applied to patients. See CME exam on page 810. The gastric emptying of chyme is arguably the most important function of the stomach, just as the ejection of blood is the most important function of the heart. There is a rich history involving the assessment of gastric emptying, including the direct observation of gastric contents across a fistula, 1 use of intubation and aspiration methods, electrical impedance tomography, telemetric ph measuring devices, drug absorption assays, and stable isotope breath tests. However, imaging techniques have been most widely applied to measure gastric emptying because of the capacity to directly measure what is happening to the meal in the stomach in a noninvasive manner. One of the oldest methods, originally pioneered by Walter B. Cannon in the late nineteenth century in animal studies, involved administration of radiopaque contrast agent and use of fluoroscopy to assess gastric function after a meal. This is not a practical approach because of the substantial radiation exposure and the nonphysiological nature of the inert contrast meal. 2 Serial abdominal x-rays of barium pellets incorporated into a solid meal have also been used to determine gastric emptying, but the size and nature of the pellets indicate that the emptying occurs with the return of the interdigestive migrating motor complex rather than with the emptying of digestible food. 3 In contemporary times, gastric emptying scintigraphy (GES) has emerged as the most widely used test for the assessment of gastric emptying. New applications of magnetic resonance imaging (MRI) and ultrasonography (US) are also in development for measurement of gastric emptying. In this paper we will review the background, methodology, strengths, and limitations of gastric emptying scintigraphy, MRI, and US. Gastric Emptying Scintigraphy First described in 1966, 4 GES is widely regarded as the gold standard test to determine stomach emptying. 5,6 Early studies utilized dual-isotope labeling of solid and liquid phases of the meal. However, liquid emptying is physiologically different from stomach emptying of solids, because liquids require no trituration. Because liquid emptying does not become abnormal until gastroparesis is very severe, the emptying of liquids is not commonly tested in clinical practice. 7 If a single radiotracer is used to label the meal to measure stomach and small bowel transit, a second radiotracer has been used to assess colonic transit. 8 To obtain maximum information on gastric emptying from a single radiotracer, the optimal test meal labels the solid phase, and the composition must be standardized with regard to volume, density, and caloric and nutrient content. The method used for image acquisition also must be standardized. For example, changing body position from sitting or standing to supine can significantly slow gastric emptying by more than 50% at 1 hour. 9 Technical Precautions It is important to ensure that the radiolabel remains bound to the solid food while in the stomach and does not dissociate from the solids to empty with the faster liquid phase, which consists of gastric secretions and any ingested liquid component of the test meal. Simply mixing the radiotracer with a food does not result in binding of the tracer to the component that one wishes to measure. The validation of a radiolabeled test meal requires simulation of binding under typical gastric conditions with the meal minced and suspended in 0.1 M hydrochloric acid containing pepsin agitated for at least 3 hours at 37 Celsius. After separation by filtration, scintigraphic activity of both phases is measured to ensure that the radiolabel remains 98% bound to the solid phase. The first meal to demonstrate true association of the radiolabel with food under simulated conditions of the gastric environment was the in vivo-labeled chicken liver preparation, which involved injecting a live chicken with 99m Tc-sulfur colloid ( 99m Tc- SC) for binding of 99m Tc intracellularly to Kupffer cells, sacrificing the animal, removing the liver, dicing it into cubes, and cooking. More convenient meals, prepared by mixing 99m Tc-SC with whole eggs (where it binds to protein) followed by cooking which fixes the label to the egg white, have been validated. 10 The current consensus meal for comparability across centers or in multicenter studies was established by Tougas et al and is prepared by mixing Egg Beaters (ConAgra Foods Inc, Omaha, NE pasteurized egg white) with 99m Tc-SC. The stability of radiolabel binding of this meal was validated in vitro under Abbreviations used in this paper: 2D, 2-dimensional; 3D, 3-dimensional; 99m Tc-SC, 99m Tc-sulfur colloid; GES, gastric emptying scintigraphy; MRI, magnetic resonance imaging; US, ultrasonography by the AGA Institute /09/$36.00 doi: /j.cgh

2 824 SZARKA AND CAMILLERI CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 8 gastric conditions, and also compared in human subjects with the in vivo-labeled chicken liver meal. 11 Indications The typical indications for performing GES or any other measure of gastric emptying are: (1) unexplained nausea, vomiting, and dyspeptic symptoms; (2) assessment of gastric motility prior to fundoplication for gastroesophageal reflux disease; (3) assessment of gastric motility prior to small bowel transplantation or colectomy for colonic inertia; and (4) to screen for gastroparesis in diabetic patients who are being considered for treatment with medications that may further retard gastric emptying (eg, pramlintide [Amylin, Amylin Pharmaceuticals, Inc, San Diego, CA] and exenatide [Byetta, Amylin Pharmaceuticals, Inc]). Procedure The principles of the consensus method are: discontinuation of all motility altering medications for 48 hours prior to the test; ensuring blood glucose control of 275 mg/dl on the day of the test; a 255 kcal low fat test meal composed of Egg Beaters (120 g) labeled with 0.5 mci 99m Tc-SC radioisotope (cooked either in a nonstick frying pan or microwaved), 2 slices of bread, strawberry jam (30 g), and water (120 ml). The subject ingests the Egg Beaters sandwich meal within 10 minutes. Technical factors may complicate interpretation of results of the gastric emptying test: use of a nonstandard test meal, lack of well-validated normal ranges, and imaging over 90 or 120 minutes with mathematical extrapolation of the T 1/2. Scanning of the gastric area with an external gamma camera is performed immediately after meal ingestion (t- 0), and at 1, 2 and 4 hours (Figure 1), and anterior and posterior images are obtained in standing position. In between imaging sessions, subjects are permitted to sit and to walk to and from the imaging room and bathroom, avoiding strenuous activity. Anterior and posterior images can be obtained simultaneously with a dualhead camera or sequentially with a single-headed camera to correct for tissue attenuation, as counts can increase or decrease according to the distance of gastric contents from the detector. Quantification of gastric emptying is performed by drawing regions of interest (ROI) on the anterior and posterior digital images of the entire stomach for all acquisition times (Figure 1), with attention to avoid small bowel loops in proximity to the stomach. This is typically not a problem with GES of solids, but it can be a real challenge when GES of radiolabeled liquids is evaluated. The counts measured from the stomach at each time point are directly proportional to the amount of the meal remaining in the stomach, and they are corrected for depth or distance between the camera and the intragastric radioactivity, as the plane of the stomach differs for the proximal and distal regions, and it may also differ with degree of obesity [(anterior counts posterior counts) 1/2 ]. Similarly, corrections are needed for 99m Tc decay, using standard tables. The final results are expressed as percent remaining in the stomach at each time point, normalized to 100% for time t 0 (first image set immediately after meal ingestion). The normal values are: at 1 hour (37% 90%), 2 hours (30% 60%), and 4 hours (0% 10%). Limitations and Pitfalls The major limitations to widespread use of GES was lack of standardization of meal composition, patient positioning, timing of image acquisition, and lack of appropriate normal values with some meals. A consensus statement, published from the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine, described in detail a standardized protocol for Egg Beaters meal 11 labeling and image acquisition intended for uniform adoption. 12 Because there is significant intraindividual variation in gastric emptying rates (up to 15%, even in healthy individuals 13 ), and the relationship of gastric emptying rates with symptoms remains controversial, 14 results of GES should be interpreted judiciously in clinical practice. Thus, it is not clear that patient s symptoms are actually caused by the impaired gastric emptying. In laboratory-based studies that induced dyspepsia by altering of gastric emptying, and in patients with dyspepsia, the rate of gastric emptying accounted for 50% of the variance in symptoms. 15,16 Similarly, the degree of delay on the scintigraphy study should not be used alone to grade the severity of gastroparesis. Severity of gastroparesis is better assessed by clinical parameters including frequency of vomiting, hydration, ability to tolerate oral feeding, and nutritional status, as well as gastric residual at 4 hours. 17 Radiation exposure is an important consideration; radiation dose absorbed for the total body in healthy subjects from exposure to 0.5mCi 99m Tc-SC in eggs is 10 mrad. 18 This compares to approximately 12 mrad radiation exposure from a chest x-ray and yearly exposure to 300 mrad from background radiation. 19 Due to radiation exposure and absence of normal values, GES is not recommended in pregnant women and, when performed in children, there should be due consideration of the benefit to risk ratio. Magnetic Resonance Imaging Magnetic resonance imaging (MRI) for measurement of gastrointestinal functions was first described by Stehling et al in Schwizer et al investigated emptying of a liquid enteral nutrient test meal labeled with gadolinium tetra-azacyclododecane tetra-acetic acid (Gd-DOTA) as an MRI marker. They obtained good contrast between stomach content and surrounding tissue and validated this method by comparison with scintigraphy in 5 healthy subjects and 5 patients with delayed gastric emptying. 21 The method has also been used to study effect of prokinetic medication on gastric contractility and emptying However, the stability of gadolinium tetra-azacyclododecane tetra-acetic acid labeling to the liquid phase of the meal has not been completely validated. Because clinically relevant information is usually based on gastric emptying of a solid meal, 25 an MRI method was developed using a 523 kcal pancake meal composed of egg, potato, bacon, butter, and water. This solid meal gave sufficient contrast without addition of a contrast agent, and subjects were examined in supine position over 120 minutes with separate scans performed every 15 minutes to determine gastric volume, secretion, and motility. Gastric emptying and secretion are measured by defined areas of interest on each slice and then by determining the total volume of gastric contents by addition of the individual slice volumes. 26 Net gastric meal volumes, corrected for gastric secretion, are then fitted to a power exponential to obtain T 1/2. The gastric emptying rates of equivalent macronutrient content, homogenized liquids, and solids, measured by MRI were similar in healthy subjects. This contrasts with findings on

3 August 2009 SCINTIGRAPHY, MAGNETIC RESONANCE, ULTRASONOGRAPHY 825 scintigraphy, which show solid emptying slower than homogenized liquids, as emptying of solids is associated with a well defined lag period to allow for trituration, which is not required by nutrient liquids. In subsequent MRI studies of test meals of different composition, nutrient content was a more important factor in delaying gastric emptying than meal viscosity 27 and, in a separate study, body position did not affect gastric emptying rates for nonnutritive liquids. 28 This is consistent with the extremely rapid, exponential emptying of noncaloric liquids. Additional Advantages of MRI of Gastric Emptying With sufficient contrast between the gastric wall and intraluminal content obtained with MRI and use of coronal scans to estimate diameters of proximal and distal stomach, the motor function of the stomach can be measured, providing visual and quantitative assessment of gastric emptying and motility including the frequency, amplitude, speed, and direction of propagated antral contractions. 29 A small study of 10 patients and 10 controls suggests that a gastric motility index (amplitude of antral contractions multiplied by the frequency) measured by MRI can distinguish normal patients from those with gastroparesis. 30 Limitations One drawback of gastric emptying assessment by MRI is that it does not provide a direct assessment of the meal emptying from the stomach, because the volume of gastric contents measured has to be corrected for the gastric secretions which dilute the meal. Therefore, an estimate must be made of the amount of the gastric secretion based upon the relative signal intensity obtained by ex vivo imaging of the test meal at various dilutions by the addition of 0.01 M hydrochloric acid to the container. 24 MRI has not been validated to the same degree as scintigraphy; there are few studies in disease states or in response to different perturbations other than the effects of different nutrients or drugs. MRI is also comparatively expensive (equipment, imaging time, and expertise). Current protocols require frequent imaging sequences, and subject cooperation is also necessary, such as holding breath in expiration to reduce motion artifacts during scans. Unlike GES, MRI can simultaneously assess other extragastric organs, excluding anatomical, inflammatory, or neoplastic processes in the upper abdomen, and it can evaluate relevant secretory and motility functions of the stomach, gallbladder, 31 pancreas, 32 and intestines. 33 It may also become possible to simultaneously study gut functions during brain assessment by functional MRI for a comprehensive one-stop assessment. 34 Summary Further refinements and validation are needed before MRI is ready for application in clinical practice or research; however, the ability to resolve wall motion and assess extragastric organs and absence of radiation are additional attributes of the MRI test. Figure 1. Scintigraphic gastric emptying demonstrating accelerated or delayed gastric emptying. Scintiscans show the radiolabeled meal in the stomach, identified by the variable region of interest. The gamma camera quantitates the amount of radioactivity in the stomach, allowing for an estimation of the percentage of the meal emptied from the stomach at each time point.

4 826 SZARKA AND CAMILLERI CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 8 Functional Ultrasonography Functional ultrasonography is a relatively inexpensive, safe, noninvasive method to gastric function. Gastric emptying of liquids using 2-dimensional (2D) ultrasonography was first described in the early 1980s. 35 2D ultrasonography indirectly determines gastric emptying by the changes in the antral area over time. This has been validated by comparison with GES in healthy subjects, 36,37 patients with type 1 diabetes mellitus, 38 and functional dyspepsia. 39 Duplex Doppler techniques have been applied to study transpyloric flow of liquid meals, 40,41 with episodes of gastric emptying defined with a mean velocity of 10 cm/sec, lasting for 1 sec. 42 Using this method, timing of postprandial dyspeptic symptoms and transpyloric passage of gastric contents can be studied with great temporal and spatial resolution, 43 including assessment of the effect of pharmacological intervention. 44 Hausken et al developed a noninvasive method to evaluate transpyloric flow and duodenogastric reflux stroke volumes using a 3-dimensional (3D) guided digital color Doppler imaging model. 45 This offers greater accuracy and less variability than 2D ultrasonography. Healthy subjects were studied during ingestion of a liquid meal and 10 minutes postprandially. The 3D position and orientation data were acquired using a magnetic sensing system. There were high intra- and inter-individual variations of the stroke volumes of transpyloric flow episodes during the initial gastric emptying. The duodenogastric reflux episodes lasted on average 2.4 sec with an average volume of 8.3 ml. 3D ultrasonography has been validated against scintigraphy in a small number of healthy volunteers. 46 3D ultrasonography allows measurement of proximal stomach accommodation after a meal in adults 47 and adolescents, 48 and this is impaired in dyspepsia. 47 The advantages of US techniques are widely available equipment, modest running costs, and no radiation exposure. Ultrasonography shows reasonably good interobserver agreement in the evaluation of the gastric emptying of a liquid meal. 49 Limitations of ultrasonography are that it is best suited for assessing gastric emptying of liquids, which is of limited clinical utility. With 3D ultrasonography, very few studies have utilized a solid meal and simultaneous scintigraphy. 50,51 Disadvantages are the need for a skilled operator, and suboptimal imaging in people who are not lean, and when there is air in the stomach. Ultrasonography is generally impractical for prolonged observations. Conclusion MRI has the advantage of providing comprehensive information, but it has significant costs and requires further validation. Functional ultrasonography is being developed to expand current capabilities and 3D US could conceivably become the most cost-effective gastric emptying and accommodation test. However, validation is needed. Thus, GES, improved by recent consensus procedural recommendations, remains the current gold standard. References 1. Beaumont W. Experiments and observations on the gastric juice and the physiology of digestion. Plattsburgh: FF Allen, Cannon WB. The movements of the stomach studied by Rontgen rays. 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J Ultrasound Med 2003;22: Reprint requests Address requests for reprints to: Michael Camilleri, MD, Mayo Clinic, Charlton 8-110, 200 First Street Southwest, Rochester, Minnesota camilleri.michael@mayo.edu; fax: (507) Conflicts of interest The authors disclose no conflicts.