GASTROENTEROLOGY 2004;127:1592–1622 American Gastroenterological Association Technical Review on the Diagnosis and Treatment of Gastroparesis This literature review and the recommendations herein were prepared for the American Gastroenterological Association Clinical Practice Committee. The paper was approved by the Committee on May 16, 2004, and by the AGA Governing Board on September 23, 2004. ormal gastric emptying reflects a coordinated effort between different regions of the stomach and the duodenum as well as extrinsic modulation by central nervous system (CNS) and distal gut factors. Important events related to normal gastric emptying include fundic relaxation to accommodate food, antral contractions for trituration of large food particles, pyloric relaxation to allow food to exit the stomach, and antropyloroduodenal coordination of motor events. Gastric dysmotility includes delayed gastric emptying (gastroparesis), rapid gastric emptying (as seen in dumping syndrome), and other motor dysfunctions such as impaired fundic distention most commonly found in functional dyspepsia. The importance of gastric dysrhythmias has not been clearly defined. Disorders of gastric motility may present with a spectrum of symptoms of variable severity. This technical review systematically assesses the clinical research literature and formulates recommendations for the diagnosis and management of patients with gastroparesis. The published peer-reviewed literature on gastroparesis was searched on PubMed using the key words gastroparesis, gastric motility, and gastric dysmotility. Referenced articles from published manuscripts, book chapters, and recent abstracts from national and international meetings were included in this review. N Symptoms and Clinical Presentation of Gastroparesis Gastroparesis is a symptomatic chronic disorder of the stomach characterized by delayed gastric emptying in the absence of mechanical obstruction. Symptoms of gastroparesis are variable and include early satiety, nausea, vomiting, bloating, and upper abdominal discomfort. In 146 patients with gastroparesis, nausea was present in 92%, vomiting in 84%, abdominal bloating in 75%, and early satiety in 60%.1 Complications of gastroparesis may contribute to patient morbidity and include esophagitis, Mallory–Weiss tear, and vegetableladen bezoars.2,3 Symptoms of gastroparesis are nonspecific and may mimic structural disorders such as ulcer disease, partial gastric or small bowel obstruction, gastric cancer, and pancreaticobiliary disorders.2 There also is an overlap between the symptoms of gastroparesis and functional dyspepsia. Functional dyspepsia is characterized by chronic or recurrent upper abdominal discomfort; however, many individuals report symptoms of dysmotility, including nausea, vomiting, and early satiety, and subsets of patients with functional dyspepsia exhibit delays in gastric emptying.4,5 Indeed, idiopathic gastroparesis can be considered one of the causes of functional dyspepsia. Recently, a quantitative instrument for gastroparesisrelated symptoms has been validated.6 Symptom correlation with delayed gastric emptying is variable for diabetic gastropathy, idiopathic gastroparesis, and functional dyspepsia.7–9 In recent studies, early satiety, postprandial fullness, and vomiting have been reported to predict delayed emptying in patients with functional dyspepsia.4,5 In patients with diabetes, abdominal fullness and bloating were found to predict delayed gastric emptying.10 In some drug trials of prokinetic agents, the correlation between symptom improvement and acceleration of gastric emptying has been poor. In contrast, cisapride was reported to reduce epigastric pressure and bloating in association with improved emptying.11 In individuals with symptoms of gastroparesis who have normal rates of gastric emptying, other motor, myoelectric, or sensory abnormalities may elicit symptoms. Abdominal discomfort or pain is present in 46%– 89% of patients with gastroparesis but is usually not the predominant symptom, in contrast to its prominence in functional dyspepsia.1,12 Abdominal pain in gastroparesis responds poorly to treatment of gastroparesis.12 Patients with functional dyspepsia exhibit heightened sensitivity to gastric distention suggestive of afferent neural dysAbbreviations used in this paper: CMV, cytomegalovirus; CNS, central nervous system; EGG, electrogastrography; FDA, Food and Drug Administration; GERD, gastroesophageal reﬂux disease; MMC, migrating motor complex. © 2004 by the American Gastroenterological Association 0016-5085/04/$30.00 doi:10.1053/j.gastro.2004.09.055 November 2004 function as a contributor to symptom pathogenesis.13 Similarly, in diabetic patients with dyspeptic symptoms, gastric distention elicits exaggerated nausea, bloating, and abdominal discomfort, suggesting that sensory nerve dysfunction may participate in symptom genesis in some patients with gastroparesis.14 The majority of patients with gastroparesis are women. In one large investigation, 82% of gastroparetic patients were female.1 Women tend to exhibit slower emptying rates than men, especially during the later portion of the menstrual cycle (the luteal phase).15,16 It is believed that gastric muscle contractility is reduced by progesterone. The prevalence and socioeconomic impact of gastroparesis are difficult to estimate due to the incomplete correlation of symptoms with gastric emptying and the apparently higher prevalence of the disorder in academic medical centers than in the community. Most population-based studies in patient subsets at risk for development of gastroparesis have focused on symptoms rather than gastric scintigraphy findings. In such investigations, 11%–18% of individuals with diabetes report symptoms consistent with upper gastrointestinal dysmotility such as nausea and vomiting.17,18 However, the prevalence of gastroparesis, as assessed by gastric emptying studies, in randomly selected patients in a diabetes clinic at an academic medical center was 48%.10 Using validated questionnaires, investigators have reported that symptoms of gastroparesis are associated with reduced quality of life both in diabetic patients and in community populations.19,20 Health care expenditures for care of gastroparesis are significant. In an analysis of the 1998 North Carolina Hospital Discharge database, there were 45 admissions with a primary diagnosis of diabetic gastroparesis and an additional 1431 admissions for diabetic patients in which gastroparesis was a contributing factor to the need for hospitalization.21 The average hospital stay in this study was 5 days. In an unpublished study of patients with severe gastroparesis, health care costs from gastroparesis were estimated to average $6972 per patient per month.22 Most expenditures in this study were attributed to requirements for hospitalization and temporary or long-term use of intravenous hyperalimentation. Diagnostic testing in patients with presumed gastroparesis is associated with significant costs, especially from performance of endoscopy and gastric emptying scintigraphy. For some less well-established diagnostic modalities performed in referral centers (eg, antroduodenal manometry, electrogastrography [EGG]), reimbursement from third-party payers may be difficult to obtain despite the recent granting of procedure codes.23 Similarly, novel AMERICAN GASTROENTEROLOGICAL ASSOCIATION 1593 Table 1. Evaluation of Patients Suspected to Have Gastroparesis 1. Initial investigation A. History and physical examination B. Blood tests Complete blood count Complete metabolic profile, including glucose, potassium, creatinine, total protein, albumin, calcium Amylase, if abdominal pain is significant symptom Pregnancy test, if appropriate C. Abdominal obstruction series, if vomiting or pain is acute or severe 2. Evaluate for organic disorders A. Upper endoscopy to evaluate for mechanical obstruction or mucosal lesions (alternative: barium upper gastrointestinal series, often with small bowel follow-through) B. Biliary ultrasonography if abdominal pain is a significant symptom 3. Evaluate for delayed gastric emptying A. Solid-phase gastric emptying test B. Screen for secondary causes of gastroparesis Thyroid function tests (thyroid-stimulating hormone) Rheumatologic serologies (eg, antinuclear antibody, scleroderma antibody [Scl70]) Glycosylated hemoglobin (HbA1C) 4. Treatment trial with prokinetic agent and/or antiemetic agent 5. If no clinical response, consider further investigation A. EGG B. Antroduodenal manometry C. Small bowel evaluation with enteroclysis or small bowel followthrough D. Further laboratory tests, if indicated ANNA, tissue transglutaminase antibody treatments for patients with refractory gastroparesis (eg, pyloric injection of botulinum toxin, gastric electrical stimulation) have been considered experimental by some insurers and reimbursement has been denied. Evaluation of Patients With Suspected Gastroparesis Overview of Diagnostic Approach Gastroparesis is diagnosed by demonstrating delayed gastric emptying in a symptomatic individual after exclusion of other potential etiologies of symptoms (Table 1). Gastroparesis is often suspected in patient subgroups with specific profiles. Typical symptoms in an individual with long-standing type 1 diabetes mellitus suggest diabetic gastroparesis, whereas similar symptoms in a young woman are consistent with idiopathic gastroparesis. A diagnosis of functional dyspepsia may be entertained if pain is the dominant symptom, whereas coexistent defecation abnormalities suggest the possibility of irritable bowel syndrome. Delayed gastric emptying may develop after abdominal surgery, especially if the vagus nerve has been damaged. Vomiting associated with gastroparesis must be differentiated from regurgi- 1594 AMERICAN GASTROENTEROLOGICAL ASSOCIATION tation due to gastroesophageal reflux disease (GERD) or rumination syndrome, episodic vomiting in cyclic vomiting syndrome, self-induced vomiting with bulimia, and abdominal pain and vomiting in superior mesenteric artery syndrome. Patients with long-standing, severe symptoms of gastroparesis may appear dehydrated or malnourished. A succussion splash, detected by auscultation over the epigastrium while moving the patient side to side or rapidly palpating the epigastrium, indicates excessive fluid in the stomach from gastroparesis or mechanical gastric outlet obstruction.24 Most individuals suspected to have gastroparesis require upper endoscopy or a radiographic upper gastrointestinal series to exclude mechanical obstruction or ulcer disease. Mechanical gastric outlet obstruction can be caused by pyloric stenosis, neoplasia, or active ulcer disease in the duodenum, pyloric channel, or prepyloric antrum. The presence of retained food in the stomach after overnight fasting without obstruction is suggestive of gastroparesis. Bezoars may develop in severe cases. Endoscopy is more sensitive for detection of mucosal lesions than barium radiography.24 Double-contrast techniques have increased the sensitivity of radiologic studies. Contrast radiography of the small intestine is performed in those patients with refractory symptoms, those with symptoms suggestive of a small bowel etiology (eg, profound distention, steatorrhea, feculent emesis), or those who exhibit dilated small bowel loops on plain radiography. When upper gastrointestinal radiography is ordered, a small bowel follow-through can be included to screen for small bowel lesions. The small bowel follow-through is accurate for detection of highgrade small bowel obstruction, usually provides an adequate assessment of the terminal ileum, and may rarely suggest superior mesenteric artery syndrome. Enteroclysis (small bowel enema), obtained after placement of a nasoduodenal or oroduodenal tube, provides double-contrast images and is more accurate in detecting small intestinal mucosal lesions, mild to intermediate grades of obstruction, and small bowel neoplasia.25 Computed tomographic scanning with oral and intravenous contrast may also be useful for detection and localization of intestinal obstruction. After exclusion of mechanical disease of the stomach and small bowel, determination of the rate of gastric emptying of solid foods is usually obtained using scintigraphy. An abnormal gastric emptying test result suggests but does not prove that symptoms are caused by gastroparesis. If gastric emptying is normal, other causes for symptoms should be considered. However, a disorder of gastric motor function cannot be dismissed in symptomatic patients with normal gastric emptying because GASTROENTEROLOGY Vol. 127, No. 5 regional dysfunctions of the stomach, including impaired fundic relaxation or gastric myoelectric dysrhythmias, may be associated with symptoms.26 Other testing to complement the finding of delayed gastric emptying includes thyroid chemistries to rule out hypothyroidism, glycosylated hemoglobin levels to assess long-term glycemic control in diabetic patients, and other blood tests to screen for rheumatologic disorders, neuromuscular conditions, or paraneoplastic phenomena. Idiopathic gastroparesis is diagnosed after other causes are excluded. Evaluation of Gastric Emptying, Motor Function, and Myoelectric Activity Several methods have been proposed for quantification of gastric emptying, motor function, and myoelectric activity (Table 2). Radiographic contrast techniques. The upper gastrointestinal barium series is an insensitive method for measuring gastric emptying because it is difficult to quantitate the relative fraction of contrast delivered to the intestine and because barium is not a “physiologic” test meal.27 Nevertheless, gastric retention may be suggested by poor emptying of barium from the stomach, gastric dilation, and the presence of retained food or a gastric bezoar. Little or no emptying of barium at 30 minutes and retention of gastric barium at 6 hours are suggestive of gastroparesis.28 The greatest value of barium radiography lies in the exclusion of mucosal lesions and mechanical outlet obstruction. Gastric emptying scintigraphy. Gastric emptying scintigraphy of a solid-phase meal is considered the gold standard for the diagnosis of gastroparesis because this test quantifies the emptying of a physiologic caloric meal. Measurement of gastric emptying of solids is more sensitive for detection of gastroparesis because liquid emptying may remain normal even in patients with advanced disease. Liquid-phase emptying scans are more commonly performed after gastric surgery in patients suspected of having dumping syndrome. The usefulness of gastric scintigraphy in directing therapy and predicting response has been debated.11,29 Some clinicians have proposed performance of dual solid- and liquid-emptying scintigraphy in patients who have undergone gastric surgery to determine if symptoms might result from delayed solid emptying or rapid liquid emptying. For solid-phase testing, most centers use a 99mTc sulfur colloid–labeled egg sandwich as a test meal.27 More recently, a meal using Eggbeaters egg whites (ConAgra Foods, Inc, Downers, IL) with standard imaging at 0, 1, 2, and 4 hours postprandially has been proposed to provide a degree of standardization between different November 2004 AMERICAN GASTROENTEROLOGICAL ASSOCIATION 1595 Table 2. Tests to Assess Gastric Motor and Myoelectrical Function Advantages Tests assessing gastric emptying Upper gastrointestinal barium radiographic study Scintigraphy Breath tests using 13 C Assess for mucosal lesions Gold standard Noninvasive Able to assess solid and liquid emptying Noninvasive Ultrasonography for serial changes in antral area Noninvasive Physiologic Magnetic resonance imaging Noninvasive Tests assessing gastric contractile activity Antroduodenal manometry Gastric barostat Tests assessing gastric myoelectrical activity EGG Tests assessing gastric accommodation Gastric barostat Satiety test Disadvantages Nonphysiologic Radiation exposure (moderate) Radiation exposure (minimal) Need normal small intestinal absorption, liver metabolism, pulmonary excretion Requires expertise for imaging and interpretation Primarily measures liquid emptying Expensive, time consuming Need specialized centers and software Assesses contractility in fasting and postprandial periods Measures proximal stomach relaxation and contraction Invasive Need expertise to perform and interpret Invasive Research technique Noninvasive Movement artifact may make recording difficult to interpret Measures proximal stomach accommodation response Invasive Research technique Balloon may interfere with accommodation Simple Not well standardized or accepted Measures combination of accommodation and sensitivity Adapted from Quigley et al24 and Hasler WL, Koch KL. Diabetic gastroparesis. AGA Postgraduate Course, May 19 –20, 2001. centers.30 This test meal has a very low fat content and theoretically might produce different results than conventional meals. Whatever meal is used, the radiolabel needs to be cooked into it to ensure radioisotope binding to the solid phase. This prevents elution of the radiotracer into the liquid phase, which might produce an erroneous measurement of the faster liquid-phase gastric emptying.31 Scintigraphic assessment of emptying should be extended to at least 2 hours after meal ingestion. Even with extension of the scintigraphic study to this length, there may be significant day-to-day variability (up to 20%) in rates of gastric emptying.32 For shorter durations, the test is less reliable due to larger variations of normal gastric emptying. Extending scintigraphy to 4 hours has been advocated by some investigators to improve the accuracy in determining the presence of gastroparesis.33,34 Emptying of solids typically exhibits a lag phase followed by a prolonged linear emptying phase. A variety of parameters can be calculated from the emptying profile of a radiolabeled meal. The simplest approach for interpreting a gastric emptying study is to report the percent retention at defined times after meal ingestion (usually 2 and 4 hours). The half emptying time also may be calculated; however, extrapolation of the emptying curve from an individual who did not empty 50% of the ingested meal during the actual imaging time may provide an inaccurate determination of the half emptying time.35 Patients should discontinue medications that may affect gastric emptying for an adequate period before this test based on drug half-life (Table 3). For most medications, this will be 48 –72 hours. Opiate analgesics and anticholinergic agents delay gastric emptying. Prokinetic agents that accelerate emptying may give a falsely normal gastric emptying result. Serotonin receptor antagonists such as ondansetron, which have little effect on gastric emptying, may be given for severe symptoms before performance of gastric scintigraphy. Hyperglycemia (glucose level ⬎270 mg/dL) delays gastric emptying in diabetic patients.26 It is not unreasonable to defer gastric emptying testing until relative euglycemia is achieved to obtain a reliable determination of emptying parameters in the absence of acute metabolic derangement. Premenopausal women have slower gastric emptying than men,15,16 so some advocate using separate reference values for premenopausal women.4 Breath testing for gastroparesis. Breath tests using the nonradioactive isotope 13C bound to a digestible substance have been validated for measuring gastric emptying. Most commonly, 13C-labeled octanoate, a mediumchain triglyceride, is bound into a solid meal such as a 1596 AMERICAN GASTROENTEROLOGICAL ASSOCIATION Table 3. Medications That Affect Gastric Emptying Delay gastric emptying Opioid analgesics Anticholinergic agents Tricyclic antidepressants Calcium channel blockers Progesterone Octreotide Proton pump inhibitors H2-receptor antagonists Interferon alfa L-dopa Fiber Sucralfate Aluminum hydroxide antacids ␤-adrenergic receptor agonists Glucagon Calcitonin Dexfenfluramine Diphenhydramine Alcohol Tobacco/nicotine Tetrahydrocannabinol Accelerate gastric emptying Prokinetic agents Metoclopramide Erythromycin/clarithromycin Cisapride Domperidone Tegaserod ␤-adrenergic receptor antagonists muffin.36 –38 Other studies have bound 13C to acetate or to proteinaceous algae (Spirulina).31 After ingestion and stomach emptying, 13C-octanoate is absorbed in the small intestine and metabolized to 13CO2, which is then expelled from the lungs during respiration. The ratelimiting step is the rate of solid gastric emptying. Thus, octanoate breath testing provides a measure of solidphase emptying. The octanoate breath test provides reproducible results that correlate with findings on gastric emptying scintigraphy.36 –38 13C breath tests do not use ionizing radiation and can be used to test patients in the community or even at the bedside, where gamma camera facilities are not readily available. Breath samples can be preserved and shipped to a laboratory for analysis. Most octanoate breath testing is performed for clinical research and pharmaceutical studies. The penetrance of this diagnostic modality into clinical practice has been limited. Validation of this test in patients with emphysema, cirrhosis, celiac sprue, and pancreatic insufficiency is needed, because rates of octanoate metabolism may be impaired in these disorders. EGG. EGG records gastric myoelectrical activity, known as the slow wave, using cutaneous electrodes affixed to the anterior abdomen overlying the stomach.39 The slow wave is responsible for controlling the maximal GASTROENTEROLOGY Vol. 127, No. 5 frequency and the controlled aboral propagation of distal gastric contractions. The normal gastric slow wave frequency is approximately 3 cpm. Meal ingestion increases the amplitude of the EGG signal, which is believed to result either from increased antral contractility or from mechanical distention of the stomach. EGG testing quantifies the dominant frequency and regularity of gastric myoelectrical activity, quantifies the percentage of time in which abnormal slow wave rhythms are present during fasting and postprandially, and assesses the increase in amplitude (or power) after a meal.35 In general, an abnormal EGG is defined when the percent time in dysrhythmias exceeds 30% of the recording time and/or when meal ingestion fails to elicit an increase in signal amplitude.40 Gastric dysrhythmias (tachygastria, bradygastria) and decreased EGG amplitude responses to meal ingestion have been characterized in patients with idiopathic and diabetic gastroparesis.41 Gastric myoelectric abnormalities also have been described in patients with unexplained nausea and vomiting, motion sickness, and nausea and vomiting of pregnancy.35 EGG abnormalities are present in 75% of patients with gastroparesis versus 25% of symptomatic patients with normal gastric emptying.40 Some investigators suggest that EGG abnormalities and delayed gastric emptying may define slightly different patient populations with dyspeptic symptoms.42 Symptomatic responses to antiemetic or prokinetic drug treatments have correlated better with resolution of gastric dysrhythmias than acceleration of delayed emptying in some patient subsets.8 Hyperglycemia may provoke dysrhythmias in diabetic patients.43 Clinically, EGG has been used to demonstrate gastric myoelectric abnormalities in patients with unexplained nausea and vomiting or functional dyspepsia. EGG is considered an adjunct to gastric emptying scintigraphy as part of a comprehensive evaluation of patients with refractory symptoms suggestive of an upper gastrointestinal motility disorder.35,40 However, to date, there has been little investigation to validate the utility of EGG in the management of patients with suspected gastric dysmotility. Antroduodenal manometry. Antroduodenal manometry provides information about gastric and duodenal motor function in both fasting and postprandial periods.35,44 Manometry may be performed in stationary settings over a 5- to 8-hour period or in ambulatory fashion over 24 hours using solid-state transducers. Ambulatory studies afford the advantage of correlating symptoms with abnormal motor patterns; however, catheter migration in these studies may limit interpretation of gastric motility. Rather, ambulatory manometry is November 2004 best reserved for characterization of duodenal motor function. The proposed indications for antroduodenal manometry include (1) characterization of motor dysfunction in patients with unexplained nausea and vomiting, (2) delineation of the cause of gastric or small bowel stasis (eg, visceral neuropathy or myopathy), and (3) support of a suspected diagnosis of chronic intestinal pseudo-obstruction.35 Distinct gastrointestinal motor patterns are present in the interdigestive (fasting) and digestive (fed) periods. The interdigestive (fasting) pattern consists of 3 cyclical phases known as the migrating motor complex (MMC) that recur at approximately 2-hour intervals unless interrupted by a meal. Phase I is a period of motor quiescence that is followed by a period of intermittent phasic contractions (phase II). The MMC culminates in a burst of regular rhythmic contractions that propagate from the antrum through the proximal small intestine (phase III, activity front). The intense propulsive contractions during phase III have been considered to be a physiologic “intestinal housekeeper” and are responsible for clearance of dietary fiber and indigestible solids from the upper gut. Feeding disrupts the MMC and replaces it with a fed motor pattern of more regular antral and duodenal contractions of variable amplitude that may be either segmental or propagative in character. In gastroparesis, antroduodenal manometry may exhibit a decreased frequency/force of antral contractions and origination of most phase III complexes in the duodenum. In some individuals, increased tonic and phasic activity of the pylorus (“pylorospasm”) or irregular bursts of small intestinal contractions may be observed.45 Furthermore, the prevalence of concomitant small intestinal motor dysfunction in patients with gastroparesis ranges from 17% to 85% in different studies.46,47 Antroduodenal manometry can help confirm or exclude an underlying dysmotility syndrome when results of gastric emptying testing are normal or borderline. With an accurate stationary recording, reductions in the postprandial distal antral motility index correlate with impaired gastric emptying of solids.48 Normal findings on manometry coupled with a normal transit test result strongly suggest that antral motor dysfunction is not the cause of symptoms.35 Antroduodenal manometry may differentiate between small intestinal neuropathic and myopathic disease and may suggest unsuspected small bowel obstruction or a rumination syndrome.35,49 Myopathic disorders, such as scleroderma or amyloidosis, produce contractile activity of abnormally low amplitude, whereas neuropathic conditions are characterized by contractions of normal amplitude with abnormal propagation, including loss of AMERICAN GASTROENTEROLOGICAL ASSOCIATION 1597 intestinal phase III, random bursts, and failure of conversion to the fed pattern after meal ingestion. Occult mechanical obstruction of the small intestine may be suggested by 2 patterns of small bowel motor abnormalities: (1) postprandial clustered contractions for ⬎30 minutes’ duration separated by quiescence or (2) simultaneous prolonged (⬎8 seconds) or summated contractions suggesting a common cavity phenomenon from a dilated segment of intestine.50 In some patients with rumination syndrome, antroduodenal manometry may demonstrate a characteristic pattern of simultaneous contractions in all recording sites (R waves) secondary to increases in intra-abdominal pressures from somatic muscle activity, especially during the postprandial period.51 In pediatric studies, the absence of MMCs predicts a poor response to prokinetic agents.52 Some investigators perform antroduodenal manometry with infusions of erythromycin and/or octreotide to predict the patient’s clinical response to long-term treatment with these agents.53 Other studies have suggested that findings of antroduodenal manometry may influence treatment decisions in small numbers of patients (⬃20%) with dysmotility syndromes.54 Validation of manometry as a critical diagnostic test for managing patients with suspected gastric or small intestinal dysmotility is incomplete. Other tests of gastric motor function. Several other techniques for measuring gastric motor function have been proposed. Ultrasonography. Transabdominal ultrasonography measures several parameters of gastric motor function. Serial changes in antral cross-sectional area can provide an index of gastric emptying.55 Gastric emptying is considered complete when the antral area returns to the fasting baseline level. Duplex sonography can quantify transpyloric flow of liquid gastric contents. Ultrasonography also has been used to measure accommodation in the proximal stomach.31 Unfortunately, ultrasound determinations of gastric emptying are operator dependent and have proven reliable only for measurements of liquid emptying rates. Testing may be difficult in obese individuals. As a consequence of these drawbacks, ultrasonography most commonly is used only in research settings. Magnetic resonance imaging. Magnetic resonance imaging can measure gastric emptying and accommodation using transaxial abdominal scans every 15 minutes.31 Magnetic resonance imaging can differentiate between gastric meal volume and total gastric volume, allowing determination of gastric secretory rates. This noninvasive, radiation-free test is appealing; however, the specialized equipment, time needed for interpreta- 1598 AMERICAN GASTROENTEROLOGICAL ASSOCIATION GASTROENTEROLOGY Vol. 127, No. 5 tion, and expense have limited its use to clinical research primarily in European centers. Single-photon emission computed tomography. Radionuclide imaging of the gastric wall following the intravenous injection of 99mTc pertechnetate, which localizes in the gastric mucosa, with subsequent single-photon emission computed tomography imaging has been used as a noninvasive measure of gastric accommodation.56 In 32 patients with functional dyspepsia, single-photon emission computed tomography imaging after 99mTc pertechnetate infusion suggested that impaired gastric accommodation (41%) may be detected more commonly than delayed emptying (9%) in dyspeptic patients referred to tertiary centers.57 The majority of dyspeptic patients had normal emptying and accommodation. Satiety testing. Satiety testing with symptom-limited consumption of a test liquid has been proposed as a noninvasive technique to evaluate accommodation. In the water load test, the patient drinks water until he or she feels very full.58 Other investigators have used nutrient-containing test meals that are consumed at a fixed slow rate until satiety is achieved.59,60 Results of satiety testing correlate with the degree of gastric accommodation as measured by a barostat. Satiety tests offer the potential to noninvasively evaluate for abnormalities of gastric accommodation and perhaps visceral sensitivity.31 To date, most studies have quantified defects in satiety in patients with functional dyspepsia. Investigations characterizing responses to satiety testing have not been reported in patients with gastroparesis. Table 4. Etiology of Gastroparesis (Nonobstructive Delayed Gastric Emptying) Disorders With Delayed Gastric Emptying (Gastroparesis) nal studies suggest that delayed gastric emptying is present in 25%–55% of patients with type 1 diabetes mellitus and is not correlated with nongastrointestinal complications.61,62 Gastroparesis has also been described in approximately 30% of patients with type 2 diabetes mellitus.7 However, highly variable rates of gastric emptying, including acceleration of transit, have been reported in type 1 diabetes mellitus and type 2 diabetes mellitus, suggesting that development of gastroparesis is not universal or inevitable.62,63 Many individuals with rapid emptying have diabetes of relatively short duration. In those with accelerated emptying, impairment of fundic receptive relaxation to meal ingestion may be pathogenic of the motor defect.64 Gastroparesis traditionally has been considered to confer a poor prognosis for affected diabetic patients; however, recent investigations suggest that this may be incorrect.61 Clinical consequences of diabetic gastroparesis include induction of gastrointestinal symptoms, alteration in drug absorption, and destabilization of glycemic control.61 Symptoms in affected diabetic patients include Gastroparesis occurs in many clinical settings; idiopathic, diabetic, and postsurgical etiologies comprise the majority of cases in most series. In one series of 146 patients, gastroparesis was idiopathic in 36%, diabetic in 29%, and postsurgical in 13% of patients.1 Several gastrointestinal and systemic diseases are associated with gastroparesis (Table 4). Selected individual disorders frequently referred to gastroenterologists for evaluation and management are discussed in the following text. Diabetic Gastroparesis Gastroparesis is a recognized complication of diabetes mellitus and is classically considered to occur in those individuals with long-standing type 1 diabetes mellitus and other associated complications such as retinopathy, nephropathy, and peripheral neuropathy. Many affected patients have associated findings of dysautonomia, including postural hypotension. Longitudi- Idiopathic Diabetes mellitus Postsurgical Partial gastric resection/vagotomy Postbariatric surgery Nissen fundoplication Transplantation: lung, heart-lung Gastrointestinal disorders associated with delayed gastric emptying Diffuse gastrointestinal motor disorders (eg, chronic intestinal pseudo-obstruction) GERD Achalasia Gastric ulcer Atrophic gastritis Functional dyspepsia Hypertrophic pyloric stenosis Celiac disease Nongastrointestinal disorders associated with delayed gastric emptying Eating disorders: anorexia Neurologic disorders CNS tumors Parkinson’s disease Collagen vascular disorders Scleroderma Systemic lupus erythematosus Amyloidosis Endocrine and metabolic disorders Thyroid dysfunction Parathyroid dysfunction Chronic renal insufficiency Gastric infection Chronic mesenteric ischemia Tumor associated (paraneoplastic) Medication associated November 2004 nausea, vomiting, early satiety, fullness, and abdominal discomfort. The presence of abdominal bloating and fullness particularly seems to be associated with the magnitude of emptying delay.10 Symptom severity, however, does not necessarily correlate well with the degree of gastric stasis.7,65 Some patients with severe symptoms may have near-normal to normal emptying patterns. In these individuals, other abnormalities, including impaired fundic relaxation, gastric slow wave dysrhythmias, or visceral hypersensitivity, may be potentially responsible for dyspeptic symptoms.7 The term “diabetic gastropathy” is commonly used because symptoms may not predict delays in gastric emptying and responses to prokinetic treatment may not be consequences of accelerated emptying. Changes in gastric emptying may affect postprandial blood glucose concentrations. Delayed gastric emptying contributes to poor glycemic control because of unpredictable delivery of food into the duodenum.66 Impaired gastric emptying with continued administration of exogenous insulin may produce hypoglycemia. Conversely, acceleration of emptying has been reported to cause hyperglycemia.63 Problems with blood glucose control may be the first indication that a diabetic patient is developing gastroparesis.66 In type 1 diabetic patients with gastroparesis, prokinetic therapy may potentially benefit glycemic control although this has not been universally observed.67– 69 Long-term oral administration of the prokinetic agents levosulpiride and erythromycin have decreased plasma glucose and glycosylated hemoglobin levels in diabetic patients.70,71 However, studies with cisapride suggested that long-term improvement in gastric emptying had no effect on overall glycemic control in patients with type 1 diabetes mellitus.72,73 Diabetic gastroparesis is likely to result from impaired neural control of gastric motility, possibly at the level of the vagus nerve. In one investigation, morphologic abnormalities of the gastric myenteric plexus or vagus in diabetic patients were not identified by conventional histology,74 although abnormal myenteric neurotransmission involving both inhibitory and excitatory pathways has been described in animal models of diabetes. Conversely, in an older autopsy study of diabetic patients, inflammatory changes were observed in some autonomic ganglia and dropout of vagal myelinated fibers was noted.75 Other factors, including impairment of the inhibitory nitric oxide– containing nerves,76 damage of the pacemaker interstitial cells of Cajal,77 and underlying smooth muscle dysfunction, have been described in animal models and patients with diabetic gastroparesis.78 – 80 In one study, selective loss of pyloric NO synthase was shown to contribute to gastroparesis in an AMERICAN GASTROENTEROLOGICAL ASSOCIATION 1599 animal model and was reversible by administration of insulin or agents that restore NO activity.81 Hyperglycemia alone also may reversibly affect gastric motility and reduce the effectiveness of prokinetic agents. Hyperglycemia decreases antral contractility, decreases antral phase III of the MMC, increases pyloric contractions, causes gastric dysrhythmias (primarily tachygastria), delays gastric emptying, and even modulates fundic relaxation properties.43,66 Normalization of serum glucose levels in hyperglycemic patients has been shown to stabilize gastric myoelectric activity, improve gastric emptying, and restore antral phase III activity.82 Hyperglycemia appears to cause a reversible impairment of vagal efferent function.83 Glucose-responsive neurons have been identified in the CNS that may modify vagal efferent activity.84 Prostaglandins may also be involved, because indomethacin can reverse abnormal gastric electrical rhythms that occur during hyperglycemia in healthy volunteers.85 Patients with type 1 diabetes mellitus also exhibit increased perception of gastric distention, with exaggerated nausea, fullness, and epigastric pain for a given distending stimulus.14 In addition to its effects on motor function, hyperglycemia increases nausea and fullness during proximal gastric distention.66,86 Increased sensitivity of the proximal stomach may be responsible for postprandial dyspeptic symptoms when the stomach is distended by a meal.14,86 Postsurgical Gastroparesis Gastroparesis may occur as a complication of a number of different surgical procedures. Historically, most cases have resulted from performance of vagotomy in concert with gastric drainage for medically refractory peptic ulcer disease. More recently, with the advent of laparoscopic techniques to treat GERD, more individuals are presenting with gastroparesis as a complication of fundoplication. Postvagotomy gastroparesis. Postsurgical gastroparesis is most often a consequence of peptic ulcer surgery, usually with concurrent performance of vagotomy.87 The vagus nerves regulate both meal-evoked fundic relaxations and phasic antral contractions. The effects of complete vagal denervation are to accelerate gastric emptying of liquids and to retard emptying of solids. To avert the gastroparetic effects of vagotomy, most surgeons perform a gastric drainage procedure such as a pyloroplasty or gastroenterostomy. In most patients, the net result is that vagotomy combined with a drainage procedure produces little alteration in gastric emptying. Approximately 5% of patients undergoing vagotomy with antral resection and gastrojejunostomy develop se- 1600 AMERICAN GASTROENTEROLOGICAL ASSOCIATION vere postsurgical gastroparesis.87 In these individuals, the antrum is not present to triturate solids and the proximal stomach is unable to generate sufficient pressure to empty solid food residue. The Roux-en-Y stasis syndrome is characterized by postprandial abdominal pain, bloating, nausea, and vomiting.87 The combination of vagotomy, distal gastric resection, and Roux-en-Y gastrojejunostomy predisposes to severe gastric stasis as a result of both slow emptying from the gastric remnant and delayed small bowel transit in the denervated Roux efferent limb.87 Ectopic jejunal pacemakers may develop in the transected and reattached jejunal segment. Furthermore, myoelectric and motor activity in the Roux limb may be retrograde, causing reverse peristalsis toward the stomach and allowing the Roux limb to cause a functional obstruction.88 Postfundoplication gastric motor dysfunction. Mild acceleration of gastric emptying has been reported to occur after Nissen fundoplication and has been attributed to increased intragastric pressure due to prevention of fundic receptive relaxation from the mechanical effects of the wrap.89,90 This is supported by regional scintigraphic studies showing rapid proximal gastric emptying after fundoplication. These effects of fundoplication may promote development of early satiety.90 In some patients with reflux who have preexisting delayed gastric emptying, fundoplication may normalize emptying.90 In other patients, early satiety, postprandial fullness, nausea, and vomiting develop after fundoplication as a consequence of postprandial antral hypomotility or delayed gastric emptying.91–93 The delay in emptying may have preceded the surgery but was unrecognized at the time of operation. The development of postoperative gastroparesis after an open Nissen fundoplication is uncommon but at times may result in significant morbidity.93 Vagal nerve injury occurs in 4%– 40% of patients undergoing laparoscopic fundoplication.94,95 The gasbloat syndrome refers to postoperative gaseous symptoms, including inability to belch, pain, and bloating. Gas bloat postoperatively occurs more often in patients with preoperative delayed gastric emptying.96 Thus, preexistent gastroparesis has been considered a relative contraindication to performance of fundoplication for GERD. Postbariatric surgery. Surgical therapy for morbid obesity has become popular over the past 5 years. Most operations are designed to restrict the size of the stomach.97 The most commonly performed surgical procedure is the Roux-en-Y gastric bypass, in which the stomach is partitioned into a small proximal fundic pouch and a bypassed distal stomach. A loop gastrojejunostomy through a small gastroenterostomy drains the GASTROENTEROLOGY Vol. 127, No. 5 proximal pouch. With gastric bypass, induction of early satiety by the small gastric pouch precludes ingestion of large meals. Solid gastric emptying is slower and liquid emptying is more rapid after gastric bypass surgery.98 The gastrojejunostomy configuration also can produce a relative malabsorptive state and promotes dumping syndrome if a high-carbohydrate liquid meal is ingested. Less commonly performed surgeries are gastric restrictive procedures such as vertical-banded gastroplasty and adjustable gastric banding. Vomiting has been reported to occur in 21% of patients after vertical-banded gastroplasty.99 Another study observed normal emptying from the proximal pouch.100 Gastroparesis after lung and heart-lung transplantation. Gastroparesis has been reported after heart and lung transplantation.101–103 This may have serious consequences in the patient receiving a lung transplant, because gastroparesis predisposes to development of gastroesophageal reflux with microaspiration and subsequent pulmonary infection. Symptomatic delays in gastric emptying have been reported in 25% of patients after single lung transplantation and 50% of patients after combined heart-lung transplantation.101 Another study reported delayed gastric emptying in 8 of 10 patients after combined heart-lung transplantation.102 Explanations include vagal nerve dysfunction or injury during surgery, opportunistic viral infection secondary to immunosuppressive medications, and motor-inhibitory effects of the immunosuppressive drugs themselves. Vagal nerve dysfunction from thermal or ischemic injury and/or dissection of the posterior mediastinum during surgery has been suggested as the most likely culprit.101–103 Idiopathic Gastroparesis Idiopathic gastroparesis refers to symptomatic disease in patients with no primary underlying abnormality. This may represent the most common form of gastroparesis.1 As with other causes of gastroparesis, symptoms may fluctuate, with episodes of pronounced symptoms interspersed with relatively symptom-free intervals. Most patients with idiopathic gastroparesis are women; typically the condition presents in young or middle-aged individuals.4 Symptoms of idiopathic gastroparesis overlap with those of functional dyspepsia; in some individuals, it may be difficult to provide a definitive distinction between the two. Abdominal pain/discomfort typically is the predominant symptom in functional dyspepsia, whereas nausea, vomiting, early satiety, and bloating predominate in idiopathic gastroparesis. The histologic basis of idiopathic gastroparesis is poorly understood. In one case, myenteric hypogangli- November 2004 onosis and reductions in numbers of interstitial cells of Cajal were observed.104 A subset of patients with idiopathic gastroparesis report sudden onset of symptoms after a viral prodrome, suggesting a potential viral etiology for their symptoms. In one series, a postviral etiology was suspected in 23% of cases based on histories of viral prodromes rather than any microbiologic confirmation.105 In this patient subset, previously healthy subjects develop the sudden onset of nausea, vomiting, diarrhea, fever, and cramps suggestive of a systemic viremic response. However, instead of experiencing resolution of symptoms, these individuals note persistent nausea, vomiting, and early satiety for more than 3 months and exhibit delays in gastric emptying on scintigraphy. Viruses that have been implicated in rare cases include cytomegalovirus, Epstein–Barr virus, and varicella zoster. However, the responsible organism remains elusive in most patients with postviral gastroparesis. These patients appear to have slow resolution of their symptoms over several years.105,106 In contrast, individuals with idiopathic gastroparesis without a viral trigger tend to show less improvement over time.105 Other Disorders Associated With Delayed Gastric Emptying Other gastrointestinal and nongastrointestinal disorders can be associated with gastroparesis. Some conditions produce similar symptoms but do not always delay emptying. Gastrointestinal disorders with associated delayed gastric emptying. Gastroparesis associated with GERD. Delayed gastric emptying has been detected in subsets of patients with GERD. Some investigators have reported gastroparesis prevalence rates of 40% in patients with GERD,107 whereas others have observed a much lower prevalence (10%).108 The role of delayed gastric emptying in the pathophysiology of GERD remains controversial. Gastric stasis with distention may promote transient lower esophageal sphincter relaxations with subsequent gastroesophageal reflux of acid.109 Recent studies suggest that slow emptying from the proximal stomach, but not from the overall stomach, may correlate with esophageal acid exposure.110 Even though a causative role is unproved, it is not unreasonable to perform gastric scintigraphy in patients with GERD symptoms refractory to acid-suppressive therapy. Such testing also should be considered in those individuals considered for procedures to increase the barrier function of the gastroesophageal junction, including fundoplication to reduce the likelihood of postoperative complications as described previously.96 AMERICAN GASTROENTEROLOGICAL ASSOCIATION 1601 Hypertrophic pyloric stenosis. Infantile hypertrophic pyloric stenosis presents in up to 0.3% of newborns. In typical cases, nonbilious vomiting develops in the first 4 weeks of life secondary to hypertrophy of the inner circular muscle of the pylorus with impaired sphincteric relaxation. There is a lack of inhibitory nerves in the pylorus, primarily those containing NO, and loss of the interstitial cells of Cajal.111,112 An enlarged pylorus (pyloric olive) can be palpated or detected radiologically. Treatment with surgical pyloromyotomy is effective, and patients usually remain symptom-free after surgery with resolution of the smooth muscle hypertrophy. Defects in interstitial cell numbers and NO transmission partially reverse after pyloromyotomy; however, pyloric tone may remain elevated with less frequent phasic pyloric pressure waves.113,114 Medical treatment with atropine has been proposed by some European groups. The condition also has been correlated with use of erythromycin for pertussis prophylaxis in neonates.115–117 Hypertrophic pyloric stenosis in adults, not secondary to peptic ulcer disease or neoplasm, is exceedingly rare.118 Endoscopic dilation and laparoscopic pyloroplasty have occasionally been used as treatment.118,119 Generalized disorders of gastrointestinal motility. Gastroparesis may occur as a component of a definable generalized gut dysmotility syndrome. Chronic intestinal pseudo-obstruction is a syndrome with recurrent symptoms suggestive of intestinal obstruction in the absence of mechanical blockage. Radiologic findings of chronic intestinal pseudo-obstruction include luminal dilation with air-fluid levels throughout the small intestine. The term “diffuse gastrointestinal motility disorder” has been proposed if several gut regions exhibit delayed transit but have no luminal dilation or air-fluid levels on radiographic examination.27 Chronic intestinal pseudo-obstruction can be caused by a variety of systemic diseases, including scleroderma, amyloidosis, myxedema, longstanding diabetes mellitus, and paraneoplastic complications most commonly seen with small cell lung carcinoma. However, many cases are idiopathic in nature. The 2 main forms of chronic intestinal pseudo-obstruction are myopathic and neuropathic. Small bowel manometry may assist in differentiating these 2 forms. In intestinal myopathy, low-amplitude contractions that propagate normally are seen. In intestinal neuropathy, contractions are normal in amplitude but disorganized in morphology, including disruption of phase III activity, bursts of nonpropagating activity during fasting, and failure to convert from the fasting to the postprandial fed motor pattern. Delayed gastric emptying is not uncommonly observed in patients with constipation. In one study, 19% 1602 AMERICAN GASTROENTEROLOGICAL ASSOCIATION of patients with primary constipation were found to have delayed gastric emptying.120 A second investigation of patients with irritable bowel syndrome observed delayed emptying of solids in 64% of patients, especially in those with constipation predominance.121 This has important implications for treatment because patients with chronic severe constipation with proximal gut dysmotility exhibit unsatisfactory responses to subtotal colectomy. Volitional suppression of defecation can also retard gastric emptying.122 Furthermore, colonic distention inhibits gastric motor function suggestive of a neurally mediated cologastric reflex. Nongastrointestinal disorders associated with delayed gastric emptying. Ischemic gastroparesis. Gastric ischemia may occur as a consequence of chronic atherosclerotic disease. In many cases, gastric ischemia is insidious and difficult to recognize. Ischemic gastropathy secondary to atherosclerosis may present as gastritis, ulceration, or gastroparesis.123,124 Typically, the diagnosis is made angiographically. Surgical revascularization may improve gastric emptying and correct gastric dysrhythmias in affected patients.124 Malignancy-associated gastroparesis. Malignancy-associated gastroparesis has been described with esophageal, gastric, pancreatic, breast, and lung carcinoma. The pathophysiology is unknown but frequently is attributed to paraneoplastic effects, neural invasion by the tumor, or side effects of chemotherapy. In nonobstructing gastric cancers, tumor infiltration into the stomach wall may disrupt coordinated smooth muscle or neural function. Delayed gastric emptying is reported in 40%– 60% of patients with pancreatic adenocarcinoma. Usually gastroparesis secondary to pancreatic cancer is asymptomatic, but it may contribute to nausea, vomiting, abdominal pain, and pain radiating to the back in selected individuals.125 Gastroduodenal obstruction from the tumor, retroperitoneal nerve invasion from the tumor, or a paraneoplastic syndrome may all cause delayed gastric emptying in these patients. Intestinal pseudo-obstruction with delayed gastric emptying may be a paraneoplastic complication of malignancy, most commonly small cell lung carcinoma.126 Intestinal dysmotility is postulated to result from autoimmune destruction of myenteric neurons, because histologic studies have shown degeneration of the myenteric plexus with plasma cell and lymphocyte infiltration.127 The onset of gut motor dysfunction may precede detection of the cancer.126 Antroduodenal manometry may show a typical neuropathic pattern of uncoordinated contractions of normal amplitude. A variety of autoimmune serologies may be detectable with paraneoplastic GASTROENTEROLOGY Vol. 127, No. 5 pseudo-obstruction, including the type 1 antineuronal nuclear antibody (ANNA-1 or anti-Hu antibody).126 Delayed gastric emptying with nausea and vomiting can occur during treatment of malignancies. Gastroparesis can occur after abdominal radiation therapy,128 during treatment with chemotherapeutic agents,129 after bone marrow transplantation,130 and after celiac plexus blockade for chronic pain from pancreatic cancer.131 Chronic pancreatitis. In a retrospective series, 44% of patients with small-duct chronic pancreatitis had delayed gastric emptying.132 Some of the abdominal pain, nausea, and vomiting seen in patients with presumed or documented chronic pancreatitis may be due to gastroparesis. A recent study showed impaired gastric myoelectrical activity in chronic pancreatitis133; this abnormality was restored toward normal with replacement of pancreatic enzymes. Gastric emptying is variable in cystic fibrosis; it may be rapid early in the disease but delayed later in the disease.134 Renal failure. Patients on hemodialysis commonly report nausea, vomiting, anorexia, and early satiety. In one investigation, the degree of gastric emptying delay correlated with the magnitude of dyspeptic symptoms.135 A second study reported that the delay in solid gastric emptying is associated with changes in biochemical indicators of nutritional status.136 Infectious causes of gastroparesis. Delayed gastric emptying may occur with acute viral infection with varicella zoster, Epstein–Barr virus, cytomegalovirus, rotavirus, and parvovirus-like agents such as the Norwalk and Hawaii viruses.137,138 In most cases, the delay in gastric emptying is transient and resolves over time with recovery from the viral infection.106 Although reports largely are anecdotal, a small number of individuals develop chronic symptoms and comprise a subset of idiopathic gastroparesis.139,140 Gastric cytomegalovirus (CMV) infection most commonly presents in immunosuppressed individuals, particularly in those who have undergone organ transplantation.141 CMV infection of the upper gut is reported to occur in one third of patients after liver transplantation and produces typical symptoms of gastroparesis, including nausea and abdominal fullness. Endoscopy may show large antral folds, gastric inflammation including acute superficial gastritis, and duodenal erosions and ulcerations. Viral cultures of gastric biopsy specimens and histologic demonstration of CMV inclusions in the gastric mucosa may provide the diagnosis.141 Gastrointestinal infection with CMV is unusual in immunocompetent individuals.139 Gastric emptying is delayed in one third of individuals seropositive for human immunodeficiency virus, partic- November 2004 ularly in those with advanced disease evidenced by low CD4 counts, marked weight loss, and enteric infections.142,143 In many of these immunocompromised patients, the acute stage of gastritis and gastroparesis from viruses and other infectious agents, especially CMV and mycobacterium avium-intracellulare, may persist for prolonged periods. Some investigators have observed delayed emptying of solids with diminished postprandial antral motility and with coexistent rapid emptying of the liquids suggestive of an autonomic neuropathy secondary to human immunodeficiency virus.144 The effects of Helicobacter pylori on gastric motor function have been the subject of controversy. Although a handful of studies have suggested an association with gastroparesis,145 most investigations observe no relationship between active H pylori infection and delayed gastric emptying or functional dyspepsia.146 Medication-induced gastroparesis. Nausea and vomiting are frequent side effects of medications and usually present early in their use. Thus, medications are considered to cause acute rather than chronic nausea and vomiting.24 Many medications, including anticholinergics, narcotics, tricyclic antidepressants, and calcium channel blockers, are known to delay gastric emptying (Table 3). Curiously, many acid-suppressive medications delay gastric emptying, although this effect is not likely to be of clinical relevance in most cases.147 Conversely, the histamine receptor antagonist nizatidine has been reported to exhibit weak prokinetic properties.148 Gastric emptying of solids is delayed in patients receiving total parenteral nutrition (TPN).149 As a result, some have advocated that the TPN formulation should be converted to intravenous saline during diagnostic evaluation of gastric emptying and antral motility.35 TPN-associated gastroparesis has been postulated to result from induction of hyperglycemia by the intravenous nutrient infusion. Intravenous infusion of fat emulsions also delays gastric emptying and may contribute to this phenomenon.149,150 Eating disorders. Anorexia nervosa is a psychiatric disorder occurring primarily in adolescent and young adult women that is characterized by distorted body image and fear of obesity with compulsive dieting and self-imposed starvation to maintain a profoundly low body weight. Gastrointestinal symptoms are prevalent in anorexia nervosa and include lack of appetite, early satiety, epigastric fullness, abdominal bloating, nausea, and vomiting.151,152 Patients with anorexia nervosa often exhibit delayed gastric emptying primarily for solids.152 Realimentation and restoration of normal body weight improve gastric emptying and symptoms.151,153 These observations suggest that the delay in gastric emptying is AMERICAN GASTROENTEROLOGICAL ASSOCIATION 1603 secondary to the effects of pronounced weight loss with malnutrition or to the psychiatric issues that affect these women.151,153 Prokinetic drug therapy may improve gastric emptying and facilitate refeeding,152 although other studies have shown no effect on weight gain.154 Bulimia nervosa is characterized by recurrent episodes of binge eating, with a feeling of lack of control over the eating behavior during the binges, often followed by self-induced vomiting, the use of laxatives or diuretics, strict dieting or fasting, or vigorous exercise to prevent weight gain.155 Self-induced vomiting allows bulimic patients to continue eating or terminate the binge. In contrast to anorexia nervosa, concern about weight and body size does not lead to a decrease in weight below normal values. Most cases present in young women, with a peak age at onset of 18 years. Symptoms of postprandial fullness, early satiety, bloating, nausea, and epigastric pain may occur and may relate to the degree of associated depression.156 Gastric emptying studies in bulimia have shown conflicting results as to the presence of gastroparesis.157,158 Therapy consists of cognitive-behavior therapy and pharmacotherapy to interrupt the binge-purge cycles. Nongastrointestinal disorders that mimic gastroparesis. Rumination syndrome. Rumination syndrome re- fers to the effortless regurgitation of recently ingested food into the mouth with subsequent remastication and reswallowing or expectoration of food. Initially described in children and mentally retarded institutionalized individuals, there is an increasing awareness of this disorder in adults of normal intelligence. Rumination can become a habit, often initiated by a belch, a swallow, or stimulation of the palate with the tongue. Abdominal muscle contraction with relaxation of the lower esophageal sphincter in the early postprandial period is responsible for regurgitation.159 Typically, the effortless repetitive regurgitation occurs within 15 minutes of beginning to eat, in contrast to vomiting in gastroparesis, which commonly occurs later in the postprandial period.51 The difficulty in diagnosing rumination syndrome results from a lack of awareness of the disorder and the challenge in differentiating rumination from vomiting due to gastroparesis or regurgitation due to GERD. Results of gastric emptying studies and esophageal pH monitoring tests usually are normal. Gastroduodenal manometry may show characteristic transient simultaneous increases in gastric and small bowel pressure (“R waves”) in all abdominal recording ports during the postprandial period. These reflect the effects of abdominal wall contraction. Treatment relies on behavioral modification and biofeedback therapy administered in a formal eating regulation program.160 1604 AMERICAN GASTROENTEROLOGICAL ASSOCIATION Cyclic vomiting syndrome. Cyclic vomiting syndrome is characterized by recurrent episodes of relentless nausea and vomiting lasting hours to days separated by symptom-free periods of variable lengths. The vomiting begins abruptly in most cases, although some individuals experience a prodrome of nausea and abdominal pain. The vomiting reaches its highest intensity during the first hours, diminishes thereafter, and ends rapidly. The duration of vomiting averages 1– 4 days and can result in marked dehydration. This disorder is much more prevalent in children, with a mean age at onset of 5– 8 years, but recently has been described in adults.161,162 In adults, the vomiting episodes are longer (3–5 days) and less frequent (every 3– 4 months) and triggering events are less evident.162 In most patients, findings of gastric scintigraphy, antroduodenal manometry, and EGG are normal, suggesting that symptoms do not result from gastrointestinal dysmotility.163 Precipitating events, identified in a minority of patients, include onset of menstrual periods and stress. Cyclic vomiting syndrome is associated with migraine headaches.162 The underlying causes of cyclic vomiting syndrome are poorly understood. Other proposed etiologies include derangements of the hypothalamic-pituitary axis, inappropriate activation of the vomiting reflex, and mitochondrial disorders.161,164 There are no uniformly effective therapies for cyclic vomiting syndrome. Sleep, a quiet environment, and the use of benzodiazepines such as lorazepam may be effective in some milder cases.162 Tricyclic antidepressants and ␤-blockers may serve a prophylactic role, similar to their use in migraine therapy.162 Antiemetics such as the 5-HT3 receptor antagonist ondansetron and prokinetic agents such as metoclopramide or erythromycin can provide temporary relief during vomiting episodes. Antimigraine therapies such as the 5-HT1D receptor agonist sumatriptan may reduce the severity of attacks. Use of nonsteroidal anti-inflammatory drugs such as indomethacin or intramuscular ketorolac have been reported to reduce the intensity of attacks, perhaps via their prostaglandin-inhibitory effects and their ability to reverse some gastric slow wave dysrhythmias.161 Functional vomiting. A number of patients present with nausea and vomiting of uncertain etiology and exhibit normal findings on both structural and functional testing. The Rome II committee devised diagnostic criteria for functional vomiting, a condition that may share pathogenic features with other functional disorders, including functional dyspepsia and irritable bowel syndrome.165 GASTROENTEROLOGY Vol. 127, No. 5 Treatment of Symptomatic Gastroparesis The general principles for treatment of symptomatic gastroparesis are to (1) correct fluid, electrolyte, and nutritional deficiencies; (2) identify and rectify the underlying cause of gastroparesis if possible; and (3) reduce symptoms.24 The patient’s medication list should be reviewed to eliminate drugs that might exacerbate the underlying dysmotility disorder or prevent the beneficial actions of a prokinetic agent. Diabetic patients should strive for optimal glycemic control to minimize any inhibitory effects of hyperglycemia on gastric emptying. For relatively mild disease, dietary modifications and a low-dose antiemetic or prokinetic agent might provide satisfactory control of symptoms. Patients with more severe manifestations of gastroparesis, such as refractory vomiting, pronounced dehydration, or chaotic glucose control, might require hospitalization, intravenous hydration, nasogastric suction to decompress the stomach, insulin for blood glucose control, and/or intravenous administration of antiemetic and prokinetic agents. As with the diagnostic approach to gastroparesis, most recommendations regarding its treatment are based on the cumulative experience and opinions of clinicians who specialize in the care of these patients. There is little in the way of controlled investigation to validate any therapeutic algorithm for the management of this challenging condition. Dietary Recommendations Dietary recommendations for the patient with gastroparesis rely on measures that promote gastric emptying, although few studies have been performed to validate this concept. Increasing the liquid nutrient component of the ingested meal should be emphasized because liquid emptying often is preserved in patients with gastroparesis who have delayed solid emptying. Fats and fiber tend to retard emptying; thus, their intake should be minimized. Indigestible fiber and roughage may predispose to bezoar formation. Meal size should be restricted because the stomach may only empty a given number of calories in a fixed period of time.166 To compensate for small meal size, patients may need to eat 4 or 5 times daily. Carbonated beverages release carbon dioxide, which can aggravate gastric distention. High doses of alcohol can decrease antral contractility and impair gastric emptying.167 This also is true of tobacco smoking.168 Commercial or self-prepared liquid nutrient meals may be tolerated in small quantities. Larger volumes needed to cover daily caloric needs may exacerbate symp- November 2004 toms of gastroparesis. Enteral alimentation delivered into the small intestine may be helpful in patients with dysmotility restricted to the stomach. In some severe cases, TPN may be needed. Metabolic Control Diabetic patients with gastroparesis frequently exhibit labile blood glucose concentrations with prolonged periods of significant hyperglycemia. Hyperglycemia itself delays gastric emptying even in the absence of fixed gastric motor deficits, which is likely mediated by reduced phasic antral contractility and induction of pyloric pressure waves.66,82 Hyperglycemia can inhibit the accelerating effects of prokinetic agents on gastric emptying.169 Improvement of glucose control increases antral contractility, corrects gastric dysrhythmias, and accelerates emptying. To date, there have been no longterm studies confirming the beneficial effects of maintenance of near euglycemia on gastroparetic symptoms. Nevertheless, the consistent findings of physiologic studies in healthy volunteers and diabetic patients provide a compelling argument to strive for near-normal blood glucose levels in affected diabetic patients. Antiemetic Agents Medications that act on peripheral and central neural structures as antiemetic agents provide the backbone for the treatment of many conditions with nausea and vomiting.24 Antiemetic drugs may serve as primary therapy for some patients with gastric dysmotility or as adjuncts to medications that promote gastric emptying. Phenothiazines are commonly prescribed antiemetic agents. These dopamine receptor antagonists act at the level of the area postrema of the medulla oblongata, a region termed the chemoreceptor trigger zone.24 Commonly used antiemetic agents include prochlorperazine, trimethobenzamide, and promethazine. Phenothiazines may be administered as tablets, capsules, liquid suspensions, or suppositories or by injection. For patients with severe symptoms, suppositories or injectable forms may be more efficacious. Side effects from phenothiazines are common and include sedation and extrapyramidal effects. Serotonin (5-HT3) receptor antagonists, including ondansetron, granisetron, and dolasetron, are useful for prophylaxis of chemotherapy-induced nausea and vomiting as well as symptoms occurring postoperatively or during radiation therapy. 5-HT3 antagonists may act both on the area postrema as well as on peripheral afferent nerve fibers within the vagus.24 Although often used, there are no studies documenting their efficacy in AMERICAN GASTROENTEROLOGICAL ASSOCIATION 1605 gastroparesis. If drugs in this class are considered, they are best given on an as-needed basis. Antihistamines acting on H1 receptors exhibit central antiemetic effects.24 Commonly prescribed antihistamines include diphenhydramine, dimenhydrinate, and meclizine. There is little evidence that antihistamines serve important roles in symptom control in gastroparesis. These agents are most useful for treatment of motion sickness via their actions on H1 receptors in the vestibular apparatus. In experimental motion sickness in healthy volunteers, dimenhydrinate reduced tachygastria, decreased symptoms, and evoked drowsiness, suggesting that symptom improvement may result from stabilization of gastric myoelectric rhythm or from depression of CNS activity.170 Transdermal hyoscine (scopolamine patch) is occasionally used for nausea and vomiting, primarily from motion sickness and recovery from anesthesia and surgery. This anticholinergic agent may delay gastric emptying. Benzodiazepines such as lorazepam and diazepam are most commonly used for the prevention of anticipatory nausea and vomiting before administration of chemotherapy.24 Cannabinoid drugs such as tetrahydrocannabinol have been studied for symptoms from chemotherapy and appear to have potency similar to standard antidopaminergics. A clear role in management of the patient with gastroparesis has not been established for either drug class. Prokinetic Agents Prokinetic medications enhance gut contractility and promote the aboral movement of luminal contents (Table 5). In the stomach, prokinetic agents increase antral contractility, correct gastric dysrhythmias, and improve antroduodenal coordination. Some prokinetics, including metoclopramide and domperidone, also exhibit antiemetic properties. Most commonly, motor stimulatory medications are administered 30 minutes before meals to elicit maximal clinical effects. Bedtime doses often are added to facilitate nocturnal gastric emptying of indigestible solids. Because symptom improvements correlate poorly with acceleration of gastric emptying, the response to treatment is usually judged clinically rather than following up with serial gastric emptying tests.171 Delayed gastric emptying is present in 20%– 40% of patients with functional dyspepsia. Prokinetic medications, including metoclopramide, cisapride, and domperidone, have demonstrated utility in treating functional dyspepsia in placebo-controlled trials and in metaanalyses.172–175 A recent meta-analysis suggested that favorable trials are selectively published, raising ques- 1606 AMERICAN GASTROENTEROLOGICAL ASSOCIATION GASTROENTEROLOGY Vol. 127, No. 5 Table 5. Prokinetic Agents for Gastroparesis Agent Metoclopramide Erythromycin Cisapride Mechanism of action Dopamine receptor antagonist central/peripheral Also 5-HT3 antagonist Also 5-HT4 agonist Motilin receptor agonist Tegaserod 5-HT4 receptor agonist facilitates acetylcholine release Also 5-HT3 antagonist Dopamine receptor antagonist peripheral 5-HT4 partial agonist Bethanechol Muscarinic receptor agonist Domperidone Comments FDA approved for gastroparesis CNS side effects in 20–30% Prokinetic and antiemetic properties Gastrointestinal side effects in many: nausea/vomiting/abdominal pain Tachyphylaxis with long-term oral administration Taken off market in March 2000 for prolonging QT interval Was only approved for nocturnal heartburn Currently not available as prescription in United States Prokinetic and antiemetic properties Available in Europe/Canada/Mexico/New Zealand but not in United States FDA approved for irritable bowel syndrome, constipation predominant in women Improves gastric emptying, no data on symptoms Increases amplitude of contractions, not peristalsis Not a true prokinetic agent FDA, Food and Drug Administration. tions about the true utility of prokinetics in functional dyspepsia.176 Metoclopramide. Metoclopramide, a substituted benzamide structurally related to procainamide, has been used for 35 years to treat gastroparesis. It exhibits both prokinetic and antiemetic actions.177 The drug releases acetylcholine from intrinsic myenteric cholinergic neurons via activation of 5-HT4 receptors and serves as a dopamine receptor antagonist in the stomach. It also exhibits weak 5-HT3 receptor antagonism.178 The prokinetic properties of metoclopramide are limited to the proximal gut. Metoclopramide increases esophageal, fundic, and antral contractile amplitudes, elevates lower esophageal sphincter pressure, and improves antropyloroduodenal coordination. Antidopaminergic actions in the area postrema explain the additional antiemetic actions. Metoclopramide is approved for use in diabetic gastroparesis and for prevention of postoperative and chemotherapy-induced nausea and vomiting. Controlled trials report that metoclopramide provides symptomatic relief while accelerating gastric emptying of solids and liquids in patients with idiopathic, diabetic, and postvagotomy gastroparesis and in patients with GERD (Table 6).179 –187 Metoclopramide is effective for the short-term treatment of gastroparesis for up to several weeks.181,182 Symptomatic improvement does not necessarily accompany improvement in gastric emptying. Indeed, some investigations have reported extended symptom benefits of metoclopramide without prolonged prokinetic action.188 The long-term utility of metoclopramide has not been proven.188 In diabetic patients with gastroparesis, gastric emptying is accelerated by short-term adminis- tration of metoclopramide but not by long-term dosing for more than 1 month.189 The usual starting dose of metoclopramide in adults is 10 mg 30 minutes before meals and at bedtime. Dosing can be increased to 20 mg if the response to 10 mg is inadequate. For patients hospitalized for symptom exacerbations in gastroparesis, metoclopramide may be administered intravenously. The drug also can be taken in a liquid form. It has also been reported to be effective subcutaneously, by suppository, or even intraperitoneally in patients on peritoneal dialysis.190 The side effects from metoclopramide result from antidopaminergic actions in the CNS and may restrict its use in up to 30% of patients. Acute dystonic reactions such as facial spasm, oculogyric crisis, trismus, and torticollis occur in 0.2%– 6% of patients; when this occurs, it is often observed within 48 hours of initiating therapy.191 Drowsiness, fatigue, and lassitude are reported by 10% of patients. Metoclopramide can aggravate underlying depression. Other side effects may include restlessness, agitation, irritability, and akathisia. Increased prolactin release may result in breast engorgement, lactation, and menstrual irregularity. Prolonged treatment with metoclopramide can produce Parkinsonian-like symptoms.191 Parkinsonian symptoms usually subside within 2–3 months following discontinuation of metoclopramide. Because of this effect, patients with Parkinson’s disease should be given metoclopramide cautiously, if at all. Tardive dyskinesia, characterized by involuntary movements of the face, tongue, or extremities, may occur with prolonged use and may not reverse after stopping the medication. The prevalence of tardive dyskinesia ranges from 1% to 15% when taking metoclopramide for at least 3 months, and the complication has been reported to November 2004 AMERICAN GASTROENTEROLOGICAL ASSOCIATION 1607 Table 6. Systematic Review of Studies on Oral Metoclopramide for Treatment of Gastroparesis Author/year/ reference Brownlee and Kroopf, 1974179 Longstreth et al, 1977180 Perkel et al, 1979181 Study design No. of subjects Types of patients Dosage of metoclopramide Length of study Open label, crossover 1 Diabetic gastroparesis 10 mg QID 5 mo Improved symptoms Improved gastric emptying Open label 1 Diabetic gastroparesis 15 mg QID 6 mo Improved symptoms Improved gastric emptying Improved symptoms by 29% Randomized, double-blind, parallel group placebo controlled Randomized, double-blind, crossover placebo controlled 28 Diabetic gastroparesis (5) Postsurgical gastroparesis (4) Idiopathic gastroparesis (19) 10 mg QID 3 wk 10 Diabetic gastroparesis 10 mg QID 3 wk McCallum et al, 1983183 Multicenter, placebo controlled 18 Diabetic gastroparesis 10 mg QID 3 wk Loo et al, 1984184 Open label 8 Diabetic gastropathy 10 mg QID 6 mo Ricci et al, 1985185 Randomized 7 Diabetic gastroparesis 10 mg QID 3 wk Erbas et al, 1993186 Randomized, single-blind, crossover 13 Diabetic gastroparesis 10 mg TID 3 wk Patterson et al, 1999187 Randomized, double-blind, multicenter 45 Diabetic gastropathy 10 mg QID 4 wk Snape et al, 1982182 Outcome results Improved symptoms in 7 of 10 by 56% Improved gastric emptying by 31% Poor correlation between gastric emptying and symptoms Improved symptom score by 25% Improved gastric emptying by 25% Improved symptoms in only 3 of 8 patients Side effects precluded treatment in many Improved symptoms in 52% Gastric emptying improved but did not correlate with symptom improvement Symptoms improved in 10 of 11 subjects by 62% Gastric emptying improved by 24% Symptoms improved by 39% QID, 4 times a day; TID, 3 times a day. occur with short-term use.191 Metoclopramide-evoked tardive dyskinesia is 3-fold more common in women than men.192 Erythromycin and motilides. The macrolide antibiotic erythromycin exerts prokinetic effects via action on gastroduodenal receptors for motilin, an endogenous peptide responsible for initiation of the MMC in the upper gut.193,194 When administered exogenously, motilin stimulates antral contractility and elicits premature antroduodenal phase III activity. Erythromycin binds to motilin receptors on smooth muscle and on cholinergic neurons, the latter of which appear to be important for actions.193,195 Erythromycin produces effects on gastroduodenal motility similar to motilin. Clinically, erythromycin has been shown to stimulate gastric emptying in diabetic gastroparesis, idiopathic gastroparesis, and postvagotomy gastroparesis (Table 7).196 –204 Indeed, the effects of erythromycin on gastric emptying are greater than observed with other prokinetic drugs. Interestingly, erythromycin accelerates emptying in postsurgical patients in whom the antrum, the primary site of its motor effect, has been resected.202 In these individuals, erythromycin may exert stimulatory effects on the fundus. Erythromycin may be most potent when used intravenously.205 In one investigation, treatment with intravenous erythromycin lactobionate (200 mg) markedly accelerated emptying of solids in patients with diabetic gastroparesis.196 In these same patients, 4 weeks of treatment with oral erythromycin ethylsuccinate (250 mg 30 minutes before meals) elicited much less potent stimulatory effects. Other studies performed over longer observation periods have reported reductions 1608 AMERICAN GASTROENTEROLOGICAL ASSOCIATION GASTROENTEROLOGY Vol. 127, No. 5 Table 7. Systematic Review of Studies on Oral Erythromycin and Motilides for Treatment of Gastroparesis Author/year/reference Study design No. of subjects Length of study Types of patients Intervention Diabetic gastroparesis Erythromycin 250 mg TID Erythromycin 200 mg TID Erythromycin 250 mg QID Erythromycin 200 mg QID Erythromycin 250 mg TID 4 wk Improved symptoms and gastric emptying 9 mo Improved symptoms and gastric emptying 2 wk Improved symptoms Improved gastric emptying 6 mo Improved symptoms and gastric emptying 3 wk Symptoms improved in 11 of 13 patients by 75% Gastric emptying improved by 26% Symptoms improved in 7 of 10 patients by 20% Gastric emptying improved by 43% Symptoms improved in 3 of 9 patients by 15% Gastric emptying improved by 40% No overall improvement in symptoms (15% decrease, not significant) No overall improvement in symptoms Janssens et al, 1990196 Open label 10 Dull et al, 1990197 Open label 1 Scleroderma gastroparesis Mozwecz et al, 1990198 Open label 1 Postvagotomy gastroparesis Klutman and Eisenach, 1992199 Open label 2 Idiopathic gastroparesis Erbas et al, 1993200 Single-blind, randomized, crossover 13 Diabetic gastroparesis Richards et al, 1993201 Open label 10 Diabetic gastroparesis (2) Erythromycin Idiopathic gastroparesis (8) 250 mg QID 4 wk Ramirez et al, 1994202 Open label 9 Postsurgical (total vagotomy and antrectomy) Erythromycin 150 mg TID 2 wk Samson et al, 1997203 Double-blind, placebo controlled, crossover 12 Diabetic gastroparesis Erythromycin 250 mg TID 2 wk Talley et al, 2001204 Randomized, double blind, placebo controlled, parallel group 270 Diabetic gastropathy ABT-229 4 wk Outcome results TID, 3 times a day; QID, 4 times a day. of benefit over time with oral administration. Limited data exist concerning the clinical efficacy of erythromycin in reducing symptoms of gastroparesis (Table 7). In a systematic review of studies on oral erythromycin with symptom assessment as a clinical end point, improvement was noted in 43% of patients.206 One study comparing erythromycin and metoclopramide in an openlabel, crossover fashion in diabetic gastroparesis found similar efficacy.206 Oral administration of erythromycin should be initiated at low doses (eg, 125–250 mg 3 or 4 times daily). Many physicians prefer using erythromycin liquid suspension because it is rapidly absorbed and facilitates dosage modifications.207 Intravenous erythromycin (100 mg every 8 hours) is used for inpatients hospitalized for severe refractory gastroparesis.208 Side effects of erythromycin at higher doses include nausea, vomiting, and abdominal pain. Because these symptoms may mimic those of gastroparesis, erythromycin may have a narrow therapeutic window in some patients. Hyperglycemia attenuates the stimulation of antral contractility and gastric emptying by erythromycin.169 Investigators have searched for macrolide compounds that activate motilin receptors but do not exhibit the antimicrobial effects of erythromycin. One such motilide compound, ABT-229, was not effective for relief of postprandial dyspeptic symptoms in diabetic gastroparesis or functional dyspepsia.204,209 Others are now being tested. Domperidone. Domperidone is a benzimidazole derivative and is a specific dopamine (D2) receptor antagonist. The effects of domperidone on the upper gut are similar to those of metoclopramide, including stimulation of antral contractions and promotion of antroduodenal coordination (Table 8).8,210 –218 Domperidone does not readily cross the blood-brain barrier; therefore, it is much less likely to cause extrapyramidal side effects than metoclopramide.217 In addition to prokinetic actions in the stomach, domperidone exhibits antiemetic properties via action on the area postrema, a brainstem region with a porous blood-brain barrier. Domperidone has been studied primarily in patients with diabetic gastroparesis, in whom it increases both solid and liquid emptying.212 Symptomatic improvement with domperidone does not clearly relate to its November 2004 AMERICAN GASTROENTEROLOGICAL ASSOCIATION 1609 Table 8. Systematic Review of Studies on Oral Domperidone for Treatment of Gastroparesis Author/year/reference Nagler and Miskovitz, 1981210 Watts et al, 1985211 Study design Randomized, placebo controlled Open label No. of subjects Dosage of Length of domperidone study Type of patients Outcome results 3 Diabetic gastroparesis 10 mg QID 4 wk Symptoms improved in 2 of 3 patients 3 Diabetic gastroparesis 10 mg QID 6 mo Symptoms improved Gastric emptying improved Symptoms improved in 11 of 12 patients No change in gastric emptying of solids, decrease in gastric emptying of liquids Improved symptoms Improved gastric emptying by 37% Horowitz et al, 1985212 Open label 12 Diabetic gastropathy 20 mg TID 1–2 mo Champion et al, 1987213 Double-blind, placebo controlled, parallel group Double-blind, randomized, placebocontrolled Open label 19 Diabetic gastroparesis 20 mg QID 4 wk 9 Idiopathic gastroparesis 20 mg QID 6 wk Symptoms improved in 7 of 9 patients by 36% No change in gastric emptying 6 Diabetic gastroparesis 20 mg QID 6 mo Idiopathic gastroparesis (12) Diabetic gastroparesis (3) Postsurgical gastroparesis (2) Diabetic gastropathy 20 mg QID 2y Symptoms improved in 5 of 6 patients Gastric emptying improved in 4 of 6, not significant Symptom score improved by 68% Gastric emptying improved by 34% 20 mg QID 4 wk Davis et al, 1988214 Koch et al, 19898 Soykan et al, 1997215 Open label 17 Silvers et al, 1998216 Single-blind 287 Patterson et al, 1999217 Multicenter, randomized, double blind 48 Diabetic gastropathy 20 mg QID 4 wk Dumitrascu and Weinbeck, 2000218 Double-blind 10 Diabetic gastroparesis 10 mg TID N/A Symptoms improved in 208/269 patients by 63% Symptom score improved by 41% (similar efficacy to metoclopramide but less side effects) Symptoms improved Gastric emptying improved by 27% (better than metoclopramide) QID, 4 times a day; TID, 3 times a day. motor stimulatory actions; rather, its efficacy may stem from its antiemetic effects.8,217 In controlled clinical trials, domperidone provided relief of symptoms and improvement in quality of life to greater degrees than placebo in patients with diabetic gastropathy; symptom improvement was similar to that observed for metoclopramide and cisapride but with fewer CNS side effects.217 Furthermore, symptomatic diabetic patients with normal gastric emptying reported beneficial effects with domperidone therapy.214 The prokinetic actions of domperidone may be transitory in nature. At 6 weeks, the effect of domperidone on solid-phase gastric emptying was lost, while that on liquid emptying was maintained.212 Another investigation reported persistent reductions in nausea and vomiting after 6 weeks of treatment with no acceleration of solid gastric emptying.214 Other studies report that improvements in gastric emptying and symptoms were still present after 1 year of treatment.215 Domperidone has been advocated for ther- apy of nausea and vomiting in patients with Parkinson’s disease, in whom symptoms may be secondary to gastroparesis or to dopaminergic drugs used to treat the disease (eg, L-dopa).215 Dosing of domperidone typically begins at 10 mg before meals and at bedtime and can be increased as tolerated to achieve symptom control. In many patients, the dose of domperidone can be more easily increased to improve symptom control because of the near lack of neuropsychiatric and extrapyramidal side effects. The most common side effects of domperidone relate to induction of hyperprolactinemia, with induction of menstrual irregularities, breast engorgement, and galactorrhea. An intravenous formulation of domperidone was removed in the 1980s due to generation of cardiac arrhythmias. Domperidone is not approved by the Food and Drug Administration (FDA) for prescription in the United States, although it can be obtained in Canada, Mexico, New Zealand, Europe, and Japan. In the United 1610 AMERICAN GASTROENTEROLOGICAL ASSOCIATION States, the drug had been prepared in capsules by compounding pharmacies.219 Recently, an investigational new drug (IND) application can now be opened by physicians through the FDA to provide domperidone to patients with gastroparesis refractory to other therapies. Tegaserod. Tegaserod, an aminoguanidine indole compound, is a partial 5-HT4 receptor agonist approved for the treatment of constipation-predominant irritable bowel syndrome. In healthy volunteers, tegaserod stimulates interdigestive small intestinal motility and postprandial antral and intestinal motility.220 Tegaserod has been shown to accelerate gastric emptying in some221 but not all studies of healthy volunteers.222 In unpublished studies, tegaserod was shown to accelerate solid-phase gastric emptying in patients with gastroparesis in dose-dependent fashion, with 6 mg 3 times daily and 12 mg twice daily showing greater effect than the standard dose for constipation (6 mg twice daily).223 Effects of tegaserod on symptoms have not been reported in patients with gastroparesis. However, tegaserod has a marginal effect on symptoms in functional dyspepsia with some improvement in early satiety and postprandial fullness.224 Other prokinetic agents. Bethanechol is a nonspecific cholinergic muscarinic receptor agonist. It enhances amplitude of contractions throughout the gastrointestinal tract. Unfortunately, bethanechol does not elicit coordinated contractions and acceleration of gastric emptying and small bowel transit is not reliably demonstrated. As a consequence, bethanechol is not a true prokinetic agent.225 Rarely, the drug may be helpful as an adjunct with other prokinetic medications in patients refractory to standard treatment with prokinetic and antiemetic drugs. The typical dose is 25 mg orally 4 times daily. Side effects of bethanechol are prominent and include increased salivation, blurred vision, abdominal cramps, and bladder spasm. Acetylcholinesterase inhibitors, such as physostigmine and neostigmine, stimulate gut motor activity by increasing acetylcholine levels with subsequent muscarinic receptor activation. As with bethanechol, anticholinesterase agents do not improve antroduodenal coordination and have inconsistent effects on gastric emptying.226 In animal studies, gut transit is accelerated at lower doses but inhibited at higher doses.227 This dual effect may be related to activation of different muscarinic receptor subtypes. Their utility in gastroparesis has not been studied. Cisapride is a 5-HT4 receptor agonist that facilitates release of acetylcholine from myenteric cholinergic nerves throughout the gut.24 Cisapride stimulates antral GASTROENTEROLOGY Vol. 127, No. 5 and duodenal contractions, improves antroduodenal coordination, and accelerates gastric emptying.44,72 Cisapride accelerates gastric emptying and decreases symptoms in patients with gastroparesis, an effect that may last for 1 year. Cisapride was approved by the FDA for nocturnal heartburn in patients with GERD. However, postmarketing surveillance identified a number of cases of cardiac arrhythmias and sudden death.24,225 These effects were not due to the 5-HT4 agonist properties of cisapride but rather were a direct action of cisapride on cardiac potassium channels, which prolonged the QT interval and predisposed patients to development of ventricular arrhythmias, including torsades de pointes. As a consequence, cisapride was withdrawn from the US market in 2000. It is only available under compassionateuse/limited-access programs with strict patient monitoring through Janssen Pharmaceutica.219 Its use is strongly discouraged in individuals with underlying cardiac disease, especially of the conduction system, and in patients on medications known to affect the QT interval. Management of Refractory Gastroparesis There is no consensus regarding management of patients with gastroparesis who do not respond to simple antiemetic or prokinetic therapy or who develop severe medication-induced side effects. In one investigation of 110 patients with “refractory” gastroparesis, 74% responded to use of another prokinetic agent while only 26% were refractory to all prokinetic agents.1 Patients with gastroparesis who did not respond to prokinetic therapy were usually postgastrectomy patients, those with myopathic connective tissue disorders, those with type 1 diabetes mellitus with profoundly delayed gastric emptying, and those with idiopathic gastroparesis with abdominal pain. Managing the patient with refractory gastroparesis includes ensuring that gastroparesis is responsible for symptoms, optimizing current therapy, and changing prokinetic agents if maximal doses of the current treatment program are inadequate.225 It is unclear why some patients respond to one prokinetic agent and not another. Refractory patients often require treatment with both prokinetic and antiemetic agents. For patients who are truly refractory to all attempts at pharmacotherapy of gastroparesis, placement of a feeding jejunostomy and/or venting gastrostomy can be considered. Use of TPN should be temporary if possible due to the risk of complications. Newer therapies being evaluated are pyloric injection of botulinum toxin and gastric electric stimulation. Gastric resection usually is of limited value for most etiologies of gastroparesis. November 2004 Combination prokinetic therapy. Prokinetic agents act via different mechanisms to enhance gastric emptying (Table 5). Theoretically, addition of a second prokinetic agent may augment the response of the first drug if the 2 agents act on different receptor subtypes. Dual prokinetic therapy with domperidone and cisapride has been reported to accelerate emptying and reduce symptoms in some patients with refractory gastroparesis.228 Combinations of available prokinetic agents in the United States, such as metoclopramide and erythromycin, have not been specifically studied. Psychotropic medications. Tricyclic antidepressants may have significant benefits in suppressing symptoms in some patients with nausea and vomiting as well as patients with abdominal pain.229 In one retrospective analysis, tricyclic antidepressants reduced symptoms in patients with functional vomiting.230 In 2 recent studies in functional dyspepsia and one in diabetic gastropathy, low-dose tricyclic antidepressants decreased dyspeptic symptoms and abdominal pain.231,232 In an unpublished retrospective evaluation of diabetic patients with nausea and vomiting, tricyclic antidepressants provided better symptom reduction than prior trials of antiemetic and prokinetic drugs.233 In this study, nearly one third of patients exhibited delayed gastric emptying, suggesting that the presence of impaired motor function is not necessarily a contraindication to use of this drug class. Doses of tricyclic antidepressants used are lower than used to treat depression. A reasonable starting dose for a tricyclic drug is 10 –25 mg at bedtime. If benefit is not observed in several weeks, doses are increased by 10- to 25-mg increments up to 50 –100 mg. Side effects are common with use of tricyclic antidepressants and can interfere with management and lead to a change in medication in 25% of patients.229 The secondary amines, nortriptyline and desipramine, may have fewer side effects. There are limited data on the use of selective serotonin reuptake inhibitors in gastroparesis or functional dyspepsia. Pyloric botulinum toxin injection. Gastric emptying is a highly regulated process reflecting the integration of the propulsive forces of proximal fundic tone and distal antral contractions with the functional resistance provided by the pylorus. Manometric studies of patients with diabetic gastroparesis show prolonged periods of increased pyloric tone and phasic contractions, a phenomenon termed pylorospasm.45 One unpublished investigation has reported symptom benefits with surgical pyloromyotomy in patients with diabetic gastroparesis.234 Botulinum toxin is a potent inhibitor of neuromuscular transmission and has been used to treat spastic somatic muscle disorders as well as achalasia.235 Several AMERICAN GASTROENTEROLOGICAL ASSOCIATION 1611 studies have tested the effects of pyloric injection of botulinum toxin in patients with diabetic and idiopathic gastroparesis (Table 9).236 –242 These studies have all been unblinded in small numbers of patients from single centers and have observed mild improvements in gastric emptying and modest reductions in symptoms for several months. Double-blind controlled studies are needed to support the efficacy of this treatment. Gastric electric stimulation. Gastric electric stimulation is an emerging treatment for refractory gastroparesis (Table 10).243–249 There are several techniques for stimulating the stomach. Electrical stimulation at a frequency 10% higher than that of the intrinsic slow wave entrains and paces gastric myoelectric activity with high-energy, long-duration pulses. This technique has been reported to accelerate gastric emptying and improve dyspeptic symptoms in a small uncontrolled series.244 More recently, an implantable neurostimulator that delivers a high-frequency (12 cpm), low-energy signal with short pulses has been studied in patients with idiopathic and diabetic gastroparesis. The higher-frequency stimulus does not entrain slow waves or reverse underlying slow wave dysrhythmias. With this device, stimulating wires are sutured into the gastric muscle along the greater curvature during laparoscopy or laparotomy. These leads are attached to the electric stimulator, which is positioned in a subcutaneous abdominal pouch. An initial study showed effectiveness in 20 of 26 patients, with decreases in nausea and vomiting at 3 and 6 months.248 In this investigation, gastric neurostimulation promoted gastric emptying of liquids but not solids. In long-term follow-up, 3 patients underwent total gastrectomy due to unsatisfactory results and 3 required device removal secondary to erosion or infection. A second study of 33 patients with chronic gastroparesis consisted of an initial double-blind sham stimulation-controlled trial for 2 months followed by an open phase in which the device was activated for 1 year.249 During the blinded phase of the investigation, patients felt better when the stimulator was turned on with a small but significant reduction in vomiting frequency. The improvement was seen primarily in patients with diabetic rather than idiopathic gastroparesis. Long-term follow-up over 1 year showed a decrease in the mean vomiting frequency from 25 to 6 times per week with an associated improvement in quality of life. Subsequent studies have reported improvements in nutritional parameters and decreased requirements for supplemental feedings.250 Some open-label studies have not shown benefit.251 The main complication of the implantable neurostimulator has been infection, which has necessitated device removal in approximately 5%–10% of cases. 1612 AMERICAN GASTROENTEROLOGICAL ASSOCIATION GASTROENTEROLOGY Vol. 127, No. 5 Table 9. Systematic Review of Studies on Botulinum Toxin Injection Into the Pyloric Sphincter for Treatment of Gastroparesis Author/year/ reference Dose of botulinum toxin Length of study Study design No. of subjects Sharma et al, 1998236 Open label 1 Diabetic gastroparesis 80 U 4 mo Lacy et al, 2000237 Muddasani and Ismail-Beigi, 2001238 Ezzeddine et al 2002239 Open label Open label 3 1 Diabetic gastroparesis Diabetic gastroparesis 200 U 200 U 4–10 wk 4.5 mo Open label 6 Diabetic gastroparesis 100 U 6 wk Lacy et al, 2002240 Open label 8 Diabetic gastroparesis 200 U 12 wk Miller et al, 2002241 Open label 10 Idiopathic gastroparesis 80–100 U 4 wk Arts et al, 2003242 Open label 20 Diabetic gastroparesis (3) Idiopathic gastroparesis (17) 100 U 1 mo Types of patients Because of potential benefits, the gastric electric neurostimulator was granted humanitarian approval from the FDA for the treatment of chronic, refractory nausea and vomiting secondary to idiopathic or diabetic gastroparesis. Presently, reimbursement for implantation of this device is obtained by petitioning third-party payers on an individual basis. Further investigation is needed to confirm the effectiveness of gastric stimulation in longterm blinded fashion, which patients are likely to respond, the optimal electrode position, and the optimal stimulation parameters, none of which have been rigorously evaluated to date. Future improvements may include devices that sequentially stimulate the stomach in a peristaltic sequence to promote gastric emptying.252 Gastrostomy and jejunostomy placement. In refractory patients with severe nausea and vomiting, placement of a gastrostomy tube for intermittent decompression by venting or suctioning may provide symptom relief, especially of interdigestive fullness and bloating secondary to retained intragastric gas and liquids. This approach also has been suggested for patients with refractory vomiting that responds to nasogastric decompression.253 Venting gastrostomies may be placed endo- Outcome results Symptoms improved Gastric emptying improved by 33% Symptoms improved Symptoms improved Gastric emptying improved by 43% Symptoms decrease by 55% at 2 and 6 weeks Gastric emptying improved by 43% at 2 and 6 weeks Symptoms improved by 58% One half of patients had improvement in gastric emptying Symptoms improved by 38% at 1 month Gastric emptying improved by 48% at 1 month Many required subsequent treatments over 6month follow-up Symptoms improved by 29% at 1 month Gastric emptying of solids improved by 35% at 1 month scopically, surgically, or by interventional radiology. In one series, symptoms were reduced, patients gained weight, and 6 of 8 patients were able to return to full-time work or school.254 For patients with gastroparesis who are unable to maintain nutrition with oral intake, placement of a feeding jejunostomy may decrease symptoms and reduce hospitalizations.255 Jejunostomy tubes are effective for providing nutrition, fluids, and medications if there is normal small intestinal motor function.255,256 Except in cases of profound malnutrition or electrolyte disturbance, enteral feedings are preferable to chronic parenteral nutrition because of the significant risks of infection and liver disease with the latter treatment, especially in diabetic patients. In contrast, home intravenous hyperalimentation may be needed for individuals with generalized dysmotility unresponsive to dietary and medication management. The therapeutic response to jejunostomy infusion may be predicted by a trial of nasojejunal feedings,253 which should precede placement of a permanent jejunostomy tube if small bowel dysmotility is suspected. Jejunostomy tubes usually are surgically placed during laparoscopy or laparotomy, although a few centers November 2004 AMERICAN GASTROENTEROLOGICAL ASSOCIATION 1613 Table 10. Systematic Review of Studies on Gastric Electric Stimulation for Treatment of Gastroparesis Author/year/ reference Study design No. of subjects Types of patients Familoni et Open label al, 1997243 1 Diabetic gastroparesis McCallum et Open label al, 1998244 9 Diabetic gastroparesis (5) Idiopathic gastroparesis (3) Postsurgical gastroparesis (1) Forster et al, 2001245 Intervention Gastric electric stimulation (high frequency, low amplitude) Gastric pacing (low frequency, high amplitude) Length of study 1y 1 mo Open label 25 Diabetic gastroparesis (19) Gastric electric stimulation Idiopathic gastroparesis (3) (high frequency, low Postsurgical gastroparesis (3) amplitude) 12 mo Sobrino et al, Open label 2002246 15 7.3 mo Skole et al, 2002247 Open label 11 Diabetic gastroparesis (9) Idiopathic gastroparesis (5) Postvagotomy gastroparesis (1) Diabetic gastroparesis (7) Idiopathic gastroparesis (4) Abell et al, 2002248 Open label, multicenter 38 Abell et al, 2003249 Double-blind, multicenter 33 Gastric electric stimulation (high frequency, low amplitude) Gastric electric stimulation (high frequency, low amplitude) Idiopathic gastroparesis (24) Gastric electric stimulation Diabetic gastroparesis (9) (high frequency, low Postsurgical gastroparesis (5) amplitude) Diabetic gastroparesis (17) Gastric electric stimulation Idiopathic gastroparesis (16) (high frequency, low amplitude) place these endoscopically.257 Nutrient feedings are started at low infusion rates of 20 mL/h with diluted nutrient meals and advanced slowly (increase of 10 mL/h every 12 hours) until the goal of daily nutritional intake is obtained with iso-osmolar infusions. Glucose levels should be checked frequently in diabetic patients, with provision for supplemental insulin as necessary. Carefully regulated enteral nutrient infusion may improve glycemic control in diabetic patients with refractory vomiting.256 Nocturnal feedings only may permit daytime working and functioning. Complications include infection, tube dysfunction, and tube dislodgment.253,255 Surgical treatment of gastroparesis. There are limited controlled data concerning surgical treatment of diabetic or idiopathic gastroparesis.253 In general, most uncontrolled studies report disappointing responses to operative resection in these patients.24 Surgery is performed only as a last resort in carefully evaluated patients with profound gastric stasis.253 The procedure usually used is a partial gastrectomy with Roux-en-Y gastrojejunostomy. Subtotal gastrectomy (70%) with resection of antrum and pylorus, closure of the duodenum, and restoration of gastrointestinal continuity with a 60-cm Roux-en-Y jejunal loop has been reported to be of benefit in 2 small studies of 4 and 7 patients with type 1 Outcome results Symptoms improved Gastric emptying improved Symptoms decreased by 46% Gastric emptying improved by 26% Improved symptoms by 34% Gastric emptying improved in 14 of 21, not significant Symptoms improved in 14 of 15 patients 6 mo Symptoms improved in 6 of 11 patients 2–4 wk 11 mo Symptoms improved in 33 of 38 patients Improved symptoms Double blind: symptoms decreased by 15% Open label: symptoms decreased by 39% Gastric emptying improved by 19% 1 mo 12 mo diabetes mellitus who had gastroparesis and intractable vomiting, although 3 of the 7 patients in the second series developed renal failure and 2 died within 5 months of surgery.79,258 Gastric resection may be a more viable therapy for selected patients with postsurgical gastroparesis who are unresponsive to treatment with prokinetic or antiemetic drugs or in whom complications such as malnutrition or aspiration develop. These patients may require this radical surgery to eliminate stasis in an atonic stomach and creation or revision of a Roux limb to prevent enterogastric reflux. Most commonly, the remainder of the stomach is resected (completion gastrectomy), leaving only a small rim (⬍1 cm) of proximal stomach for construction of an anastomosis.259,260 A Roux limb of at least 45 cm to the rim of the stomach is constructed. Studies have suggested that this extensive surgery leads to improvement in 43%– 67% of patients.259,261,262 The combination of nausea, the need for TPN, and the presence of retained food at endoscopy predicted a poor outcome. Reports of completion gastrectomy for postsurgical gastroparesis are uncontrolled case series or retrospective reviews; prospective investigation is warranted to confirm the benefits of this operation.253 1614 AMERICAN GASTROENTEROLOGICAL ASSOCIATION Pancreas transplants and simultaneous kidney-pancreas transplants are being increasingly performed for patients with type 1 diabetes mellitus. With successful pancreatic transplantation, postprandial hyperglycemia resolves and treatment with insulin can be discontinued.263 Simultaneous kidney-pancreas transplantation may correct both uremia and hyperglycemia. Pancreatic transplantation has been shown to halt progression and slightly improve diabetic peripheral polyneuropathy.264 The literature is sparse concerning effects on gastric emptying. One study reported improvement in gastric emptying of liquids in 6 of 8 patients with previously delayed emptying but no improvement in emptying of solids 6 months after transplantation.263 Another study observed improved emptying in 8 of 23 patients 1 year after kidneypancreas transplantation.265 Some investigators reported improved symptoms and improved gastric dysrhythmias in diabetic patients after transplantation despite minimal acceleration of emptying.263,265 New Directions in the Treatment of Gastric Dysmotility Syndromes Novel prokinetic agents. New prokinetic agents being tested for gastroparesis include 5-HT4 receptor agonists (tegaserod and mosapride), dopamine receptor antagonists (levosulpiride), cholecystokinin receptor antagonists (dexloxiglumide), and motilin receptor agonists (mitemcinal [GM-611]). Levosulpiride, with both antiemetic and prokinetic effects, may relieve symptoms and accelerate gastric emptying in diabetic patients with gastroparesis.266 Loxiglumide, a cholecystokinin-A receptor antagonist, increases antral contractility and accelerates gastric emptying in healthy subjects, suggesting possible utility in gastroparesis.267 Fundic relaxing agents. Agents that relax the fundus and improve accommodation may be helpful in some patients with gastroparesis and functional dyspepsia, especially when early satiety is prominent. 5-HT1 receptor agonists (sumatriptan, buspirone),268 ␣-adrenergic receptor agonists (clonidine), and NO donors (nitroglycerin) have been evaluated in physiologic studies.269 Clonidine reduces proximal gastric tone and pain perception with gastric distention in healthy subjects.269 In dyspeptic patients, clonidine reduces symptoms by improving gastric accommodation.269 Clonidine has been reported to decrease symptoms and accelerate gastric emptying in diabetic patients with gastroparesis, although others have observed slowing of emptying with the drug.270,271 The 5-HT1 agonists evoke fundic relaxation through an NO-mediated pathway.268 Sumatriptan GASTROENTEROLOGY Vol. 127, No. 5 allows accommodation of larger volumes before perception or discomfort is reached and improves meal-induced satiety in patients with functional dyspepsia.268 Buspirone, another oral 5-HT1 agonist, has anxiolytic properties in addition to its fundic relaxant capabilities. Unpublished observations suggest that sildenafil augments gastric accommodation by enhancing the effects of NO.272 In an animal study, sildenafil promoted pyloric relaxation and accelerated gastric emptying.81 However, a subsequent investigation in rats reported that sildenafil delayed liquid gastric emptying and small bowel transit and an unpublished study in humans also observed delay of gastric emptying.273 Gastric slow wave antidysrhythmics. Many prokinetic drugs (metoclopramide, domperidone, cisapride) also stabilize dysrhythmic slow wave activity in patients with gastroparesis.8,274 In some studies, resolution of slow wave rhythm disturbances correlates better with symptomatic improvement than does acceleration of gastric emptying.8 Prostaglandin inhibitors have been shown to resolve tachygastrias during hyperglycemia.85 In some patients, indomethacin has reduced symptoms and reversed gastric myoelectrical abnormalities.275 Unfortunately, indomethacin is also ulcerogenic. Alternative and unconventional medical therapies. Complementary therapies and alternative medi- cines are used frequently by patients with gastroparesis and functional dyspepsia. Ginger, a traditional Chinese herbal remedy, reduces nausea and associated tachygastria caused by experimental motion sickness. Ginger also reduces hyperglycemia-induced gastric dysrhythmias and nausea.276 Psychodynamic interpersonal psychotherapy and hypnotherapy have been reported to be helpful in functional dyspepsia.277,278 Biofeedback and hypnotic techniques to accelerate gastric emptying in gastroparetic patients are being explored.279 Stimulation of the PC6 point on the wrist with acupuncture, electroacupuncture, electrical stimulation, or acupressure may control postoperative nausea, chemotherapyinduced nausea, and nausea during the first trimester of pregnancy.280 –283 The Zusanli point (ST36) located below the patella is another site of acupuncture stimulation with effects on gastric motility.284 Animal studies suggest that electroacupuncture accelerates gastric emptying by stimulation of vagal pathways.283 Electroacupuncture is postulated to modulate serotonin, substance P, and endogenous opioid pathways in the CNS.285 Naloxone, an opioid receptor antagonist, blocks the analgesic effect of acupuncture and worsens symptoms of motion sickness.285 November 2004 Conclusion This report has reviewed the diagnosis and treatment of gastroparesis. 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Electrical stimulation of acupuncture points enhances gastric myoelectrical activity in humans. Am J Gastroenterol 1997;92:1527– 1530. NIH Consensus Development Panel on Acupuncture. Acupuncture. JAMA 1998;280:1518 –1524. Address requests for reprints to: Chair, Clinical Practice Committee, AGA National Ofﬁce, c/o Membership Department, 4930 Del Ray Avenue, Bethesda, Maryland 20814. Fax: (301) 654-5920. The Clinical Practice Committee acknowledges the following individuals whose critiques of this review paper provided valuable guidance to the authors: Jeffrey A. Barnett, MD, Manoop S. Bhutani, MD, Jay Pascricha, MD, and John C. Rabine, MD.
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