Advancing Gastric Emptying Studies: Standardization and New Parameters to Assess Gastric Motility and Function

Advancing Gastric Emptying Studies: Standardization and New Parameters to Assess Gastric Motility and Function Alan H. Maurer, MD For many years, gastric emptying (GE) studies were performed using various local protocols and different radiolabeled meals. This lack of standardization and normal values made the test results unreliable and difficult to compare from one site to another. A recent consensus has been published that now provides guidance and standardization on how to perform a radiolabeled solid-meal GE study. It is widely recognized, however, that simple measurement of total GE of a solid meal often does not provide an answer to the etiology of symptoms for a large number of patients who present with functional dyspepsia. Advances in our understanding of the different roles of the fundus and antrum and their complex interaction with the proximal small bowel and central nervous system have led to the development of new methods to study gastric motility. This review describes how a more comprehensive approach to studying GE is needed and how this will lead to better diagnosis and treatment for patients referred for GE studies. Semin Nucl Med 42:101-112 © 2012 Elsevier Inc. All rights reserved.

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astric emptying (GE) studies are typically ordered to confirm or exclude the presence of gastroparesis as a cause of a patient’s symptoms. Gastroparesis is a condition of abnormal gastric motility, which presents with symptoms suggesting delayed GE in the absence of an anatomic obstruction. The true prevalence of gastroparesis is unknown, but it may be present in as many as 65% of diabetic patients and 25%-40% of patients with upper gastrointestinal dyspepsia.1 Dyspepsia can be defined as pain or discomfort in the upper abdomen. The term functional dyspepsia (FD) is generally applied to symptoms thought to originate in the gastroduodenal region. Patients presenting with chronic upper abdominal symptoms are diagnosed with FD when there is failure to find a pathophysiologic explanation for their symptoms. GE scintigraphy (GES) continues to be the gold standard for evaluating patients with FD when the question is whether there is abnormal GE as a cause of symptoms. As currently performed in most imaging centers, GES is limited to evaluation of a potential delay or acceleration in GE of a solid radiolabeled meal.2

Department of Radiology, Nuclear Medicine, Temple University Hospital and School of Medicine, Philadelphia, PA. Address reprint requests to Alan H. Maurer, MD, Department of Radiology, Nuclear Medicine 1st Floor Parkinson Pavillion, Temple University Hospital 3401 N Broad St, Philadelphia, PA 19140. E-mail: [email protected]

0001-2998/12/$-see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1053/j.semnuclmed.2011.10.001

Gastroparesis may be caused by a variety of mechanisms, including infections, endocrine and neuromuscular disorders, autoimmune and connective tissue diseases, cancer and chemotherapy, upper gastrointestinal (GI) surgery with injury to the vagus nerve, as well as idiopathic causes. Diabetic gastroparesis usually develops when patients have associated retinopathy, neuropathy, and nephropathy.3 It has remained difficult to characterize gastroparesis in patients with FD based on etiology or symptoms.4 Complicating the workup of patients with FD are the multiple potential pathophysiologic mechanisms that currently are thought to possibly contribute to patients’ symptoms. Factors implicated include not only delayed or rapid GE but also hypersensitivity to gastric distention, lack of normal fundal accommodation, and abnormal duodenojejunal or antroduodenal dysmotility (Fig. 1). Central nervous system dysfunction, Helicobacter pylori infection, and acid reflux may also contribute to patients’ symptoms.5 Much of the latest research and many recent advances made in studying gastric motility are being directed at attempting to gain a broader understanding of the pathophysiology of FD and the role that more comprehensive GE studies can play in diagnosing and treating patients with this disorder. To appreciate these recent developments in GE studies, an understanding of the diverse symptoms, normal physiology, and pathophysiology of FD is needed. It has long been rec101

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Figure 1 Multiple factors are now considered important to explain how a patient’s symptoms may relate to abnormal GE. Rapid or delayed GE, impaired fundal accommodation, and visceral hypersensitivity are the 3 major factors under recent study. Lack of coordination of the antrum and pylorus and the role of duodenal-gastric feedback mechanisms are also considered important but not as well studied.

ognized that the stomach is not a simple 1-component muscular organ. It is composed of the following 3 distinct muscular components: the fundus, antrum, and pylorus, each with different functions that contribute to overall GE.6 The fundus (proximal stomach) first must undergo accommoda-

tion or relaxation to receive the volume of the meal ingested. The fundus then acts as a reservoir that after receiving the meal generates a tonic pressure gradient that pushes solid and liquid contents into the distal stomach (antrum). The antrum then determines the rate of GE of solids by its grinding and trituration (breakdown) of large solids into smaller particles. The pylorus is a muscular high-pressure zone, which remains closed with antral contractions during the mixing and trituration phase of GE to prevent solids from entering the duodenum until the solid particles have been broken down into small particles of 2-3 mm size.7 Normal fundal accommodation and movement of solids into and out of the antrum should be visually apparent in a normal solidmeal GE study (Fig. 2). Liquids generally do not show preferential early fundal localization but rather distribute rapidly throughout the stomach. Liquids empty monoexponentially under predominant control by the fundal pressure gradient, whereas antral contractions mainly control the emptying rate of solids.8 Coordinated antropyloric contractions are needed to control the final emptying of solids and liquids. The muscular fundus and antrum are controlled by intrinsic and extrinsic nerves and hormones. The vagus nerve works to control both fundal relaxation and antral contractions. To further control GE, there are additional feedback mechanisms that help regulate the rate of GE of both solids and liquids. These include coordination of the antral contractions with pyloric relaxation as well as nutrient receptors in the duodenum, which help control the rate of nutrient flow

Figure 2 Normal solid-meal GE. Only anterior gastric images are shown. The graph shows the decay-corrected geometric mean of total raw gastric counts obtained from the manual regions of interest shown. Some commercial software packages now provide a power exponential curve fit to the raw data to calculate a T½ or 50% emptying time. Using the current consensus normative data, the total gastric retention at 2 hours (50%) and at 4 hours (1%) was normal. In addition to reporting the gastric retention values, one should visually look for a normal progression of the solids through the stomach. This should begin with visual confirmation of fundal accommodation and predominant localization of solids in the fundus (long arrows) immediately after meal ingestion. One should then confirm progressive movement of solids into the antrum (short arrows) followed by emptying of the antrum.

Advancing Gastric Emptying Studies into the proximal small bowel.9 Therefore, it is not surprising that more comprehensive GE testing, which can describe these multiple factors that control GE rather than a single measurement of total GE of a meal, may be needed to pinpoint a cause for a patient’s symptoms. It has been estimated that in up to 50% of patients evaluated by a gastroenterologist with a standard workup (which may include endoscopy, radiologic evaluation, and motility testing), a cause for the patient’s symptoms is not found.10 GE studies are indicated in patients with FD when anatomic or motility studies have failed to find a problem. Unfortunately, when the patient’s physician has a strong clinical suspicion of upper GI dysfunction as a cause of FD, a GE study that evaluates only total GE finds an abnormality in only up to 50% of patients.11 Many of the recent advances in the study of GE are motivated by the need to better define a pathophysiologic cause for a patient’s symptoms. Visceral hypersensitivity, lack of fundal accommodation, fundoantral and antroduodenal coordination, and abnormal intragastric distribution of the meal are only a few of the new GE variables under investigation.

Symptoms and Associated Pathophysiology of Abnormal GE The description of FD has undergone several revisions since the original 1988 Rome I meeting. Rome I classification specified 2 subgroups of ulcer-like and dysmotility-like dyspepsia.12 Rome II classification further subdivided subgroups with symptoms being either pain or discomfort.13 The most recent Rome III classification specifies the following 4 symptoms: postprandial fullness, early satiation, epigastric pain, and epigastric burning thought to originate from the gastroduodenal region.14 Multiple studies have shown that symptoms are induced by meal ingestion in the majority of patients with dyspepsia. However, there are dyspeptic patients in whom symptoms are not related to meal ingestion.15,16 Therefore, the Rome III committee proposed that there be a distinction between meal-induced and meal-unrelated symptoms. Both symptom types, however, are pathophysiologically and clinically relevant. FD is now subdivided into the following 2 diagnostic categories: (1) meal-induced dyspeptic symptoms (postprandial distress syndrome), characterized by postprandial fullness and early satiation, and (2) epigastric pain syndrome, characterized by epigastric pain and burning.10 There has been increased clinical interest in relating specific patients’ symptoms to abnormal gastric function. Delayed GE has been associated with postprandial fullness, nausea, and vomiting.17 Postprandial pain, belching, and weight loss have been associated with hypersensitivity to gastric distension.18 Impaired gastric accommodation has been associated with early satiety.19 More precise characterization of the intragastric distribution of a combined solid–liquid-phase meal has shown that early satiety was associated with early

103 distal redistribution of the liquid phase of the meal, and fullness was associated with late proximal retention.15 Several studies have shown a weak correlation between patients’ symptoms of dyspepsia and the results of GE. One meta-analysis including 17 studies of 868 patients found only a 40% incidence of delayed GE in symptomatic patients.2 Other reports also demonstrate a similar weak correlation between symptoms and delayed GE in only 30%-40% patients.16,20 Because of this weak correlation, more recent studies have tried to determine a relationship between specific symptoms and a delay in either solid or liquid GE. One study (using breath testing to measure GE) reported vomiting and postprandial fullness to be associated with delayed solid emptying, whereas severe early satiety and postprandial fullness were associated with delayed liquid emptying.21 In another study using GES, symptoms of gastroparesis (nausea, vomiting, loss of appetite, early satiety, and feeling excessively full after meals) were correlated with delayed solid emptying, whereas liquids were associated only with early satiety and loss of appetite.22 In one study of 4 large patient groups preparing to undergo therapeutic trials for dyspepsia, a solid-meal GE study was not found useful to stratify patients symptomatically.23 Postprandial fullness was independently associated with delayed GE, but the association was weak. The authors concluded that although quality of life in patients with dyspepsia was significantly impaired, this could not be explained by delayed GE. In an accompanying commentary to this publication, it was stressed that this conclusion could be questioned because the analysis was based on a retrospective analysis and not a prospective design. In addition, it stressed the importance of the need to look for multiple causative factors associated with abnormal GE rather than just rapid or delayed emptying.24 The commentary further cited a review by Tack,11 which showed that 40%-50% of patients with FD had impaired gastric accommodation, 34%-66% had gastric hypersensitivity, and 23%-59% had delayed GE. Although a delay in GE does not necessarily correlate with a cause for the patient’s symptoms, solid-meal GES, however, remains a first-line study for evaluation of patients with FD. One large meta-analysis of 17 studies with 868 patients and 397 controls found a significant delay of solid GE in approximately 40% of cases.2 However, such previous studies have often lacked standardization of the method for measuring GE and had small patient sizes. A recent single-institution study, which used the current consensus recommended meal and methodology, included 560 patients. The patients completed a standardized Patient Assessment of GI Symptoms questionnaire for 2 weeks before GES and during the GE study. This study found symptoms of stomach fullness, bloating, and abdominal pain were higher in patients during GES with delayed GE than in patients with normal GE. In addition, the symptoms recorded during the GES correlated with those recorded in the previous 2 weeks during daily life activities.25 As further evidence of the need to improve our understanding of gastroparesis was the establishment of a National Institutes of Health–funded National Institute of Diabetes

104 and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium Registry in 2004. The original announcement called for a “network of clinical centers and one datacoordinating center, which will work cooperatively to conduct clinical research to elucidate the pathophysiology and develop better treatments for this condition.” This multi-institution consortium has already advanced our understanding of the role of GE studies especially as it relates to patient symptoms. This consortium recently completed a study of 243 patients with idiopathic gastroparesis correlating data on medical histories, symptom questionnaires, and 4-hour GES studies.26 Severe delay in GE (⬎35% retention at 4 h) was found in 28% of patients. Predominant symptoms included nausea (34%), vomiting (19%), and abdominal pain (23%). Women had more severe nausea, satiety, and constipation. Patients with an acute-onset idiopathic gastroparesis had worse nausea than those with gradual onset. Overweight patients had more bloating and gastric retention at 2 hours but less loss of appetite. Patients with severely delayed GE had worse vomiting and more loss of appetite and overall symptoms. Severe anxiety and depression were present in 36% and 18%, respectively. Because of the high incidence of psychological distress in patients with gastroparesis, a second study evaluated patients referred for GE studies who had anxiety and depression. They found higher levels of depression and anxiety were associated with greater bloating and postprandial fullness. Nausea and vomiting scores were higher in those with greater depression. The study, however, showed no correlation between psychological dysfunction parameters and gastric retention, and the authors could not determine whether the psychological problems were the cause or result of the patients’ symptoms.27

Current Consensus Recommendations for Solid-Meal GES—Need for 4-Hour Imaging Before discussing the recent advances toward a more multifactorial assessment of GE, it is important to review the recent standards established for solid-meal GES. It has been more than 15 years since an editorial in the Seminars of Nuclear Medicine raised concern about the loss of GES as a “gold standard” because of lack of standardization of the method and the advances from other competing modalities.28 In 2007, a consensus recommendation was finally achieved and published jointly by the Gastrointestinal Council of the Society of Nuclear Medicine (SNM) and the American Neurogastroenterology and Motility Society.29 These consensus recommendations on GES have also been adopted in a joint American College of Radiology (ACR)/Society for Pediatric Radiology (SPR) and SNM practice guideline, ACR-SNM-SPR Practice Guideline for the Performance of Gastrointestinal Scintigraphy (http://www.acr.org/ SecondaryMainMenuCategories/quality_safety/guidelines/nuc_ med/gi_scintigraphy.aspx). This consensus was the result of a series of meetings that included the participation of nuclear medicine imagers, gas-

A.H. Maurer troenterologists, and a patient advocacy group represented by the Gastroparesis and Dysmotilites Association (http:// www.digestivedistress.com). Not only was there agreement between the physicians for the need of a more standardized test, but also there was a plea from frustrated patients who could not get GE results performed or interpreted in a standard manner. As stated in the consensus report, there has been “a lack of standardization of the test, including differences in meals used, patient positioning, frequency, and duration of imaging. There are differences in the quantitative data reported, eg, half-time of emptying, rate of emptying (percent per minute), or the percent retention or emptying at different time points during the study. Normal values often have not been established for some of the protocols used, and the performance characteristics of the test with the specified meal may not have been established or published. Lack of standardization limits the clinical utility of the test and presents problems for patients and their physicians as the latter try to interpret study results from other institutions.”1 To address these issues, the consensus group developed recommendations on how to perform a solid-meal GE test for routine clinical use “using readily available technology and normative data, which can provide clinicians with standardized results.” The report addressed “those aspects that the multidisciplinary group considers were in the greatest need of immediate standardization—the meal, the frequency of imaging, the duration of the test, and the normative data.” The consensus group recommended use of a low-fat, liquid egg-white sandwich meal, with images acquired at 0, 1, 2, and 4 hours after meal ingestion based on normative data from a large multicenter study.4 The consensus recommended that GES should be performed up to 4 hours because previous studies have shown a greater sensitivity for the detection of abnormal GE if GES is continued for 4 hours.30,31 Some patients with severe gastroparesis will show delayed GE throughout the study. If a study shows abnormal retention at 2 hours and one is simply testing for the presence of gastroparesis (delayed emptying), the study could be terminated at 2 hours as GE is obviously delayed. One group of investigators has published suggested criteria for early termination at 2 hours.32 However, few laboratories actually perform “real-time” GE calculations and usually dismiss the patient at the end of a predefined protocol. Because of the complex individual roles of the fundus and antrum, some patients may have abnormal findings at 2 hours and normal ones at 4 hours, whereas others may have normal findings at 2 hours and abnormal ones at 4 hours. This is not unexpected because the early phase (0-2 h) of a solid GE study reflects more fundal function (pushing solids toward the antrum for trituration) and the later phase (2-4 h) reflects more antral trituration and propulsion of the meal into the duodenum. Therapies in the future may reflect targeting differently the fundus and antrum, and a 4-hour GE study will be needed to characterize both early- or late-emptying abnormalities (refer case examples which follow). In a series of appendices, the consensus report includes additional recommendations on patient preparation, meal preparation, image acquisition and analysis, reporting, and pa-

Advancing Gastric Emptying Studies tient instructions, as well as a sample patient questionnaire used to acquire clinical information important to those interpreting and receiving the results of a GE study. Additional sample patient information and instructional forms are also provided. The reader is referred to the complete consensus report for full details. However, an overview and summary of this consensus includes the following. Patients are instructed to report for meal ingestion and imaging after an overnight fast. Patients are told to stop any medications that might affect GE for 3 days before the test. Prokinetic drugs that can accelerate GE, such as metoclopramide (Reglan), tegaserod (Zelnorm), erythromycin, and domperidone (Motilium), are stopped at least 2 days before the test. Drugs that can delay GE such as opiates, including Demerol (meperidine), codeine, morphine, OxyContin (oxycodone), and anticholinergic antispasmodic agents, such as Bentyl (dicyclomine), Donnatal (beladonna and phenobarbital), Levsin (hyoscyamine), and Robinul (glycopyrrolate), are also stopped for 2 days before the test. Patients may take their other medications with a small quantity of water the morning of the test. Smoking is prohibited starting the morning of the test and for the 4 hours of imaging. The importance of glucose control in diabetic patients is emphasized. Diabetic patients should check their fasting glucose before starting the test. If glucose is ⬎275 mg/dL, a small dose of short-acting insulin may be administered before meal ingestion, and the patient is monitored until the glucose is below 275 mg/dL. Typically diabetic patients are instructed to bring their insulin with them, and if glucose is under 275 mg/dL, they are told to take approximately half of their standard daily dose of insulin with the test meal ingestion because no additional eating will take place during the next 4 hours. GES is performed after ingestion of a 99mTc-sulfur colloid– radiolabeled, low-fat, liquid egg-white sandwich with jam and water. The meal consists of 4 oz. (120 g, equal to 2 large eggs) liquid egg white (Eggbeaters; ConAgra Foods, Inc, Omaha, NE, USA, or a generic equivalent) mixed with 99mTcsulfur colloid and thoroughly cooked, 2 slices of white bread (120 kcal), strawberry jam (30 g, 74 kcal), and water (120 mL). The total caloric value of the meal is 255 kcal (72% carbohydrate, 24% protein, 2% fat, and 2% fiber). A recent study has shown that the low-fat, liquid egg-white sandwich meal can be cooked using either a skillet or in a microwave, provided it is cooked to a firm rubbery consistency.33 GES images are obtained at 0, 60, 120, 180, and 240 minutes after ingestion of the radiolabeled meal. Images are processed using standard nuclear medicine software with a manually drawn, single region of interest placed around the total stomach. The geometric mean of decaycorrected anterior and posterior counts is calculated for each time point (Fig. 2). GE is reported as the percentage of radioactivity retained in the stomach for each time point. GE for solids is considered delayed if gastric retention is ⬎60% at 2 hours and ⬎10% at 4 hours. As the symptoms of rapid GE can mimic those of delayed GE, the consensus provides values for measurement of rapid GE. With the consensus recommended meal, rapid GE is present if there

105 is ⬍70% retained at 30 minutes or ⬍30% retained at 1 hour. The final report should include an estimate of the total amount of the meal ingested. If only a small portion of the meal is ingested, this should be noted, as the study cannot be considered diagnostic because GE is more rapid for a smaller meal. Premeal fasting glucose in diabetic patients should be reported. The report should also describe any incidental abnormal findings if observed, including esophageal retention or reflux of the meal, hiatal hernia, fundal wrap, and lack of fundal accommodation (Figs. 2-6). Finally, the consensus recognizes the complexity of GE and limitations of the final consensus recommendations. It acknowledges the limitations of the report and includes a list of items that require further clarification, including additional optimization of image timing, need for normative data on other meals, glycemic control in diabetic patients, the value of monitoring symptoms during the study, a scale to assess the severity of delayed GE, the need for different postoperative reference data, the clinical role of analyzing fundal and antral gastric function, and other methods of quantitation (curve fitting, lag phase, total abdominal counts). The need for commercial nuclear medicine camera/computer companies to develop software to support the consensus recommendations was addressed, but this has been resolved as most vendors now provide appropriate software.

Rapid vs Delayed GE As the symptoms of rapid GE may be the same as delayed GE, there remains continued interest in detecting rapid GE.34 The cyclic vomiting syndrome (CVS) in adults is characterized by recurrent episodes of severe nausea, vomiting, and abdominal pain. These episodes are distinctly separated by symptom-free periods. This syndrome has recently been associated with rapid GE. In a study of 92 adults who met diagnostic clinical criteria for CVS, 59% had rapid GE, 27% had normal GE, and 14% had delayed GE. The subset with delayed GE had a high incidence of other drug use that could slow GE.35 In a large study of 545 patients referred for a GE study, 48 (9%) had rapid GE. A wide spectrum of final clinical diagnoses was found, with 35% having CVS, 25% FD, with the remaining diabetic, postsurgical, or with irritable bowel syndrome.36 The incidence of rapid GE found in this study was similar to that previously reported (11%) by Singh et al.34 Autonomic dysfunction is common in diabetes; however, it may be idiopathic. It can be associated with a range of gastrointestinal symptoms. Tests for autonomic dysfunction include sudomotor axon reflex testing, thermoregulatory sweat testing, cardiovagal heart rate response to deep breathing and Valsalva maneuver, and vasomotor blood pressure response to Valsalva maneuver during tilt-table testing. Using these screening tests to define a group of patients with autonomic dysfunction, rapid GE was found to be more common than delayed GE.37

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Figure 3 Lack of normal fundal accommodation and rapid GE. Images and analysis same as given in Fig 2. Visual inspection of the gastric images shows clear lack of normal fundal accommodation immediately after meal ingestion (large arrows). The solids were seen to localize early in the distal stomach (small arrows). With lack of normal accommodation, there may be associated rapid GE as in this case where only 21% of the meal was present at 1 hour (rapid emptying by consensus standard is ⬍30% retained at 1 h).

Should We Perform Solid GE, Liquid GE, or Both? Liquid emptying from the stomach is faster than solids. Liquids disperse rapidly throughout the stomach and

empty more quickly than solids with no lag phase because there is no need for trituration of solids. Non-nutrient liquids empty monoexponentially. There is slowing of liquid emptying with increasing nutrient and caloric content of the meal.38

Figure 4 Primary fundal dysmotility. Images and analysis same as given in Fig 2. This patient demonstrates a lack of normal fundal to antral movement, with persistent retention of solids in the fundus (large arrows). Although there is a borderline 2-hour retention (62%), 4-hour retention (28%) is abnormal, with significant fundal retention and little activity in the antrum (small arrows) at 3 and 4 hours.

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Figure 5 Fundal retention and gastroesophageal reflux. Images and analysis same as given in Fig 2. In addition to persistent retention in the fundus, an episode of gastroesophageal reflux is noted (small arrow at 30 min). The significant fundal retention may be contributory to the gastroesophageal reflux. Note that the total GE was normal at 2 hours (50%) but abnormal at 4 hours (35%).

A previously postulated basic tenet was that liquid GE added little to the evaluation of patients with dyspepsia.1,39 It was believed that as liquids require no trituration, liquid GE was preserved until the late stages of gastroparesis and was

less sensitive than solids for detecting gastroparesis. An early investigation found delayed liquid but normal solid emptying in 24% of diabetic patients.40 Liquid GE studies have been used clinically because rapid emptying of nutrient-con-

Figure 6 Primary antral dysmotility. Images and analysis same as given in Fig 2. Visually, there is normal early fundal accommodation (large arrows) followed by progressive movement into the antrum (small arrows). In this case, GE is delayed because of failure of solids to empty from the antrum. Both the 2-hour (80%) and 4-hour (40%) retention values were abnormal.

108 taining liquids may be associated with early satiety, nausea, and/or vomiting as in the “dumping syndrome.”39 A study using breath testing showed an association between delayed GE of liquids and symptoms of postprandial fullness.21 However, more recent studies using combined dual-isotope solid- and liquid-phase meals have demonstrated that liquids can demonstrate abnormal GE when solid GE is normal. For these studies, a mixed physiologic meal using 99mTclabeled egg and In-111 diethyltriaminopentacetic acid (DTPA) in water is usually administered. One large study, which included 476 patients, found only a 5% incidence of delayed liquid GE when solid GE was normal.41 This included a broad spectrum of cases: nonulcer dyspepsia (n ⫽ 180), gastroesophageal reflux (n ⫽ 123), post antireflux dyspepsias (n ⫽ 29), diabetes (n ⫽ 96), and cystic fibrosis (n ⫽ 48). A second study, which included 449 patients being evaluated for dyspepsia, found 60 patients (57 nondiabetic) had normal solid GE but delayed liquid GE. This was 26% of 228 patients with normal solid GE.42 This study included a correlative study of patients’ predominant symptoms. GE of solids was mildly correlated with nausea, vomiting, loss of appetite, early satiety, and feeling excessively full after meals. Liquid GE was associated with early satiety and loss of appetite. Another recent study showed a better association of delayed GE of solids and liquids with symptoms of postprandial fullness, nausea, and vomiting.21 Although this study used a breath testing method for measuring GE, the severity of 8 dyspeptic symptoms was scored. GE of solids and liquids was delayed in 23% and 35% of the patients, respectively. Multivariate analysis showed that postprandial fullness was associated with delayed liquid GE. Delayed GE of solids was associated with postprandial fullness and vomiting. Delayed emptying for liquids was also associated with postprandial fullness and severe early satiety. Ziessman et al43 reported on a combined retrospective review of 21 patients and prospective study of an additional 40 patients who were studied with a non-nutrient water GE study performed on a separate day from a solid meal. The liquid meal consisted of 500 mL of tap water mixed with 1 mCi 99mTc sulfur colloid. The solid and liquid GE studies were performed on 2 separate days in the retrospective study and then sequentially in the prospective study (liquid meal for 30 minutes followed by solid meal for 4 h). In the retrospective study, 17 of 21 patients had normal solid GE. Of these, 13 (76%) had delayed liquid GE. In the prospective study, 10 (33%) patients with normal solid GE had delayed liquid GE. In a second larger study of 101 patients who underwent both solid and non-nutrient liquid meal GE on the same day with the same protocol, delayed GE was found in 36% of liquid and 16% of solid studies. Of patients with normal solid emptying, 32% had delayed liquid emptying.44 Based on these results, these authors have suggested that a non-nutrient water–liquid GE study may be better to detect a problem with fundal gastric motility and that use of liquid GE studies may help to improve the detection rate of gastric dysmotility in patients with FD. The physiologic effects of a non-nutrient water meal have not been well studied particularly in patients with FD. A

A.H. Maurer water load given after a nutrient meal has been shown to inhibit antral motility and increase cholecystokinin (CCK) release in healthy subjects. It is theorized that the increase of CCK is a response to inflow of fatty chyme into the duodenum, with resultant feedback causing slowing of entry of the meal into the duodenum. This duodenogastric interaction has been termed the “duodenal break.”45 Further study of the physiology and clinical significance of use of a non-nutrient water–liquid meal is needed.

Accommodation Response—Fundal and Antral Distribution of the Meal Early satiety is the predominant symptom associated with low gastric capacity and poor accommodation response. Studies continue to show a correlation between dyspeptic symptoms and hypersensitivity to fundal distension and impaired fundal accommodation.46,47 A gastric barostat test measures the volume to which a gastric balloon can inflate at a given pressure and measures fundal compliance. Patients with visceral hypersensitivity will experience symptoms at low levels of distention. Although barostat testing is relatively invasive, it is the best direct measurement of fundal accommodation.48 A less invasive water load test has also been used to demonstrate the correlation between impaired fundal accommodation and dyspeptic symptoms. Both water loading and nutrient liquid meals have been shown to provide abnormal results and to produce symptoms in approximately 50% of patients with FD.49 Further evidence of the importance of visceral hypersensitivity and association of symptoms of dyspepsia associated with fundal accommodation is the use of positron emission tomography imaging of the brain demonstrating specific neuroactivation pathways linked to fundal distention.50 Because of the association between impaired fundal accommodation and symptoms, there has been continued interest in using 99mTc pertechnetate imaging of the gastric mucosa to generate single-photon emission computed tomography (SPECT) 3D volume measurements of the gastric accommodation response. In a recent study, gastric compliance was measured directly using the volume response to 2-mm Hg increments of an intrabag press at 30-second intervals up to 12 mm Hg above the baseline pressure or until the patient perceived abdominal pain. This was correlated with “gastric sensitivity” using an aggregate individual reported score for nausea, fullness, and discomfort. Direct comparison of gastric volumes, postprandial/fasting volume ratios, and postdistention volume ratios between an in vivo balloon barostat and SPECT have shown SPECT to be an accurate measurement in healthy and postfundoplication patients.51 SPECT volume measurements can be performed simultaneously with a solid-meal GE study.52 Abnormal accommodation can lead to disturbed intragastric distribution of the meal, especially early postprandially when early satiety symptoms are more likely present. Specific

Advancing Gastric Emptying Studies intragastric distribution patterns have been associated with symptoms of dyspepsia. In one study using 3D SPECT, early proximal GE was lower and the T½ of the proximal stomach was longer when SPECT gastric accommodation was impaired.53 In another study, early satiety was associated with early distal redistribution of the meal, and fullness was associated with later proximal retention.15 The added clinical utility of noninvasive SPECT measurements of accommodation response was demonstrated in a review of a large number of patients with dyspepsia studied during a 3-year period at the Mayo Clinic, Rochester. Of 214 patients, gastric accommodation was impaired in 47% of patients with dyspepsia, and 25% of patients with normal GE had impaired accommodation.54 Abnormal fundal accommodation can be observed in routine planar GE images (Figs. 3 and 4). A recent study comparing a water drink load test with SPECT gastric volumes found that fasting gastric volumes were significantly higher in patients with FD compared with controls. The patients with FD ingested significantly less water and had an impaired filling of the distal stomach after the water load test. However, symptoms of bloating, pain, and fullness were determined more by the proximal rather than distal stomach volume.55 Impaired gastric accommodation from surgical fundoplication, gastric banding, and balloon placement promotes displacement of solids into the distal stomach and more rapid GE. Pharmacologically induced increases in fundic tone and decreased gastric accommodation also increase GE rates. In one study of patients with FD and low gastric volume accommodation, 13% of patients were found to have rapid GE and 28% had normal GE.56 In contrast, Camilleri57 et al found that proximal stomach emptying was reduced in patients with low postprandial accommodation but that overall GE in these patients was normal. They theorized that compensatory mechanisms accelerate overall GE despite delayed proximal GE. These authors further concluded that interventions like use of drugs or fundoplication that impair gastric accommodation are not appropriate models to study the effects of impaired accommodation in patients.

Dynamic Antral Contraction Studies (DACS) Gastric motility is known to be directly related to myoelectric activity of the stomach. Electrogastrography (EGG) is a noninvasive method for recording the gastric myoelectrical activity using simple cutaneous electrodes. It has been the most attractive method for studying the electrophysiology of the stomach and is in more widespread use for studying gastric dysrhythmias than DACS.58 Although EGG abnormalities and gastric dysrhythmias can be documented in a high percentage of patients with symptoms of FD, the association of abnormal EGG parameters with symptoms and delayed GE has been variable.59,60 Dynamic antral contraction scintigraphy was reviewed in a previous edition of the Seminars in Nuclear Medicine as early

109 as 1995. At that time, the method was thought to be “the most significant development in gastric emptying over the past 5 years.”61 Although the methodology has not gained widespread use, the technique has remained a potentially powerful, noninvasive method for studying normal physiology of antral contractions as related to overall GE.62 As opposed to the EGG, which measures only an electrical signal strength, DACS can provide both a measure of antral contraction frequency and a measure of the amplitude of the individual antral contractions. A more recent study comparing separate DACS for solid and liquids in healthy individuals demonstrated a higher frequency and amplitude of antral contractions for solids compared with liquids as a normal physiologic finding.63 Another recent study used DACS to investigate how gastric antral contractions correlated with GE in patients with gastroesophageal reflux disease (GERD).64 These authors found that they could measure an increase in antral contractions in patients with reflux and delayed GE and that this might be a compensatory defense mechanism to help reduce reflux. Troncon et al65 demonstrated that increased antral contractions as measured by DACS correlated with the symptom of postprandial nausea in patients with FD. Although there have been recent investigations of DACS, the technique has not gained any widespread clinical application. Much of this is likely related to the increased time for acquisition and processing without additional financial reimbursement.

Intragastric Distribution and GERD In some cases, GES is ordered in patients with known GERD to determine whether some component of gastric stasis may contribute to GERD. Studies in both humans and animals have shown that gastric distention may induce GER by triggering lower esphageal sphincter (LES) relaxation.66 The role that abnormal GE may play in contributing to GERD has not been well established. Studies on the role that abnormal GE may play in reflux have been contradicting. Kastelik et al67 have shown that GE was not delayed in patients with GERDrelated chronic cough. However, the results of this study may be called into question, as the investigators used a microwave to cook and radiolabel whole egg. This labeling method has recently been evaluated, and it has been shown that falsenegative studies for delayed GE can result from incomplete binding of the 99mTc sulfur colloid to the egg white; therefore, GE may appear more rapid because the radiopharmaceutical is not fully incorporated into the solid meal.33 Some studies have shown delayed GE may be associated with GERD, and some have suggested that abnormal GE may produce reflux episodes68,69 (Fig. 5). Herculano et al70 have shown that decreased retention of gastric contents in the proximal stomach after a liquid meal may contribute to acid reflux and symptoms of dyspepsia. They theorized that overdistension of the antrum caused by rapid transfer of food from the proximal stomach might increase the rate of tran-

A.H. Maurer

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Table 1 Association of Specific Symptoms of Dyspepsia with Presumed Pathophysiology and Potential Targeted Therapies5,72 Pathophysiology

Symptom(s) Associated

Delayed gastric emptying Impaired accommodation

Nausea, vomiting, fullness Early satiety, weight loss

Hypersensitivity gastric distention

Pain, belching, weight loss

Duodenal hypersensitivity Gastric dysrhythmias Acid secretion

Nausea Nausea Pain, nausea

Treatment(s) Prokinetics (metoclopramide, cisapride, erythromycin) Serotonergic, 5-HT antagonists, CCK-1, kappa-opioid agonists, octreotide, nitrergic drugs Tachykinin receptor antagonists, opioid and NMDA agonists, capsaicin, antidepressants (tricylics, SSRIs, desipramine) No current treatment No current treatment Proton pump inhibitors, H2-receptor antagonists

CCK-1, dexloxiglumide; 5-HT, Sumatriptan, alosetron, tegaserod; NMDA agonists, dextromethorphan.

sient lower esophageal relaxation and acid reflux into the esophagus. Decreased retention of food in the proximal stomach has been ascribed to decreased fundal accommodation. As noted previously, impaired proximal accommodation has consistently been associated with symptoms of FD. In their study of antral contractility, Troncon et al65 were not able to show any relationship between delayed GE and any intragastric maldistribution of food and specific postprandial symptoms.

Abnormal Intragastric and Accommodation GE Case Examples Although there are no current accepted standards for measuring abnormal intragastric (fundal vs antral) distribution of solid or liquids or impaired gastric accommodation, such abnormalities may be observed in routine images acquired as a part of GES. Because of the growing recognition of their potential clinical significance, it is important that we begin to include specific fundal and antral abnormal findings in our interpretation of GE studies. In the future, therapy may be directed specifically to these problems (Table 1).71 A simple visual approach is to look first for normal proximal fundal accommodation in the images (Fig. 2). With a lack of normal fundal accommodation, solids appear to move rapidly into the antrum. This may be associated with rapid GE (Fig. 3). With a delay in GE because of primary fundal dysfunction, the solids will remain persistently in the fundus during the course of the 4-hour study. Delayed GE primarily caused by an antral motility problem will show localized retention of solids in the antrum at the end of the 4-hour study (Fig. 4). If fundal retention is contributing to symptoms of reflux, this may be observed in the images (Fig. 5). Finally, a diffuse disorder involving the fundus and antrum as in diabetic gastroparesis will show both fundal and antral retention during the course of the study (Fig. 6).

No Advances in Reimbursement Although recent research suggests that there is value in increasing the complexity and analysis of GES studies, there are no outcome studies that have yet demonstrated clinical value

in doing so. In addition, there is little incentive to do this when reimbursement for such time and effort is not available. Currently in the United States, a GE study is reimbursed at the same dollar amount if 60 minutes or 240 minutes of imaging is performed. No additional payment is provided for combined solid–liquid meals or the addition of analysis of fundal accommodation or separate fundoantral function. If no efforts are made to change the low level of reimbursement for more time-consuming and complex analysis, they will not likely obtain any widespread clinical acceptance. Application to the American Medical Association (AMA) Current Procedural Terminology (CPT) Editorial Panel for new CPT codes requires that the clinical efficacy of any new procedure be well established and documented in US peer-reviewed literature. Only if more centers begin to use these procedures and demonstrate clinical value can an application to the AMA CPT coding committee be successful. It is hoped that based on the information in this review, more centers will begin to investigate these techniques so that such evidence-based clinical data can be developed. Eventually this should lead to better diagnosis and treatment of patients with functional bowel disease.

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