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Shamaila Waseem, Department of Pediatric Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, Florida 32610, United States Baharak Moshiree, Peter V Draganov, Department of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, Florida 32610, United States Author contributions: Waseem S, Moshiree B and Draganov PV designed the format; Waseem S performed the literature search and wrote the first draft of the paper; Moshiree B and Draganov PV contributed new articles to the literature search and reviewed the article. Correspondence to: Peter V Draganov, MD, Department of Gastroenterology, Hepatology and Nutrition, University of Florida, 1600 SW Archer Rd, Room HD 602, PO Box 100214 Gainesville, Florida 32610, United States. dragapv@medicine.ufl.edu Telephone: +1-352-3922877 Fax: +1-352-3923618 Received: August 5, 2008 Revised: November 25, 2008 Accepted: December 2, 2008 Published online: January 7, 2009
Abstract Gastroparesis refers to abnormal gastric motility characterized by delayed gastric emptying in the absence of mechanical obstruction. The most common etiologies include diabetes, post-surgical and idiopathic. The most common symptoms are nausea, vomiting and epigastric pain. Gastroparesis is estimated to affect 4% of the population and symptomatology may range from little effect on daily activity to severe disability and frequent hospitalizations. The gold standard of diagnosis is solid meal gastric scintigraphy. Treatment is multimodal and includes dietary modification, prokinetic and anti-emetic medications, and surgical interventions. New advances in drug therapy, and gastric electrical stimulation techniques have been introduced and might provide new hope to patients with refractory gastroparesis. In this comprehensive review, we discuss gastroparesis with emphasis on the latest developments; from the perspective of the practicing clinician.
© 2009 The WJG Press and Baishideng. All rights reserved.
Key words: Gastroparesis, Nausea; Vomiting; Prokinetic; Therapy
Peer reviewer: Andrew Ukleja, MD, Assistant Professor, Clinical Assistant Professor of Medicine, Director of Nutrition Support Team, Director of Esophageal Motility Laboratory, Cleveland Clinic Florida, Department of Gastroenterology, 2950 Cleveland Clinic Blvd., Weston, FL 33331, United States
Waseem S, Moshiree B, Draganov PV. Gastroparesis: Current diagnostic challenges and management considerations. World J Gastroenterol 2009; 15(1): 25-37 Available from: URL: http://www.wjgnet.com/1007-9327/15/25.asp DOI: http://dx.doi.org/10.3748/wjg.15.25
INTRODUCTION Gastroparesis is a condition of abnormal gastric motility characterized by delayed gastric emptying in the absence of mechanical outlet obstruction. The true prevalence of gastroparesis is unknown; however, it has been estimated that up to 4% of the adult population experiences symptomatic manifestations of this condition. A large study on long-term outcomes of gastroparetic adults revealed that 82% of patients were female[1]. Gastroparesis has a higher prevalence in the patient population of tertiary medical centers than in the community hospital setting. Moreover, a widely available diagnostic test that could be applied in a standard fashion is currently lacking in the primary care setting.
PATHOPHYSIOLOGY Gastric motility results from the integration of tonic contractions of the fundus, phasic contractions of the antrum, and inhibitory forces of pyloric and duodenal contractions[2]. These contractions require a complex interaction between gastric smooth muscle, the enteric nervous system and specialized pacemaker cells, the interstitial cells of Cajal (ICC)[3]. Motor dysfunction of the stomach may result from autonomic neuropathy, enteric neuropathy, abnormalities of ICCs, fluctuations in blood glucose and psychosomatic factors[4-6]. The etiology of gastroparesis is multifactorial (Table 1). The three most common etiologies are diabetes, idiopathic, and post-surgical, especially if the vagus nerve is damaged. Other causes include medication, Parkinson’s disease, collagen vascular disorders, thyroid dysfunction, liver disease, chronic renal insufficiency, intestinal pseudo-obstruction and miscellaneous[1,7]. Originating in the region of ICCs, electrical activity in the form of gastric slow waves sweeps across the stomach toward the pylorus. However, these slow waves do not directly result in contraction of the gastric smooth muscle, but instead cause a simultaneous release of neurotransmitters from the enteric nerve endings, leading to smooth muscle contraction. Although neurohumoral control of gastric emptying is incompletely understood, both motilin and ghrelin are peptides secreted by the gastrointestinal endocrine cells that have been shown to increase gastric motor function[8,9]. In general, several factors affect gastric motility. These include motor dysfunction i.e. hypomotility and pyloric spasm, sensory dysfunction (such as impaired fundic relaxation, accommodation and abnormal sensation), electrical dysfunction (such as gastric arrhythmias and abnormal propagation), CNS effects resulting in nausea and vomiting, and others such as bacterial overgrowth, visceral hyperalgesia and gastrointestinal hormones.
SYMPTOMS AND EVALUATION Gastroparesis is diagnosed by the presence of delayed gastric emptying in a symptomatic patient after other potential etiologies such as ulcer disease, mechanical obstruction, gastric cancer or other malignancies are excluded[10,11]. Symptoms of gastroparesis include nausea, vomiting, early satiety, bloating, post-prandial fullness, abdominal pain, weight loss and/or weight gain. These symptoms are non-specific and may mimic other disorders[10]. A simple severity grading scale has been proposed for stratification of symptoms[12] (Table 2). Also, a patient-based symptom instrument, the gastroparesis cardinal symptom index (GCSI) has been developed to assess severity of gastroparesis[13]. The GCSI total scores are based on three subscales of nausea/vomiting, post-prandial fullness/early satiety, and bloating. The GCSI scale is used to rate symptom change by either physicians or by the patient’s own self-evaluations. In 146 patients with gastroparesis, nausea was present in 92%, vomiting in 84%, abdominal bloating in 75%, and early satiety in 60%. Abdominal pain or discomfort was present in 46%-89% of patients but was not the predominant symptom[1]. Abdominal pain in gastroparesis responds poorly to treatment[14]. Constipation may also be associated with gastroparesis. Treatment of constipation with an osmotic laxative has shown to improve dyspeptic symptoms as well as gastric emptying delay[15]. Complications of gastroparesis include esophagitis, Mallory-Weiss tear from chronic nausea/vomiting, malnutrition, volume depletion with acute renal failure (secondarily), electrolyte disturbances and bezoar formation[16,17].
DIAGNOSTIC TESTS Radiographic tests Gastric scintigraphy: Gastric emptying scintigraphy of a radiolabeled solid meal is the gold standard for the diagnosis of gastroparesis. This test provides a physiological, non-invasive and quantitative measure of gastric emptying. Measurement of emptying of solids is more sensitive by scintigraphy. This is due to the fact that liquid emptying may remain normal despite advanced disease. A variety of foods including chicken, liver, eggs, egg whites, oatmeal, or pancakes are used as meals. The content of the meal is one of the most important variables in gastric emptying. Solids versus liquids, indigestible residue, fat content, calories and volume of the test meal, can all alter gastric emptying time. Consensus recommendations for a standardized gastric emptying procedure have recommended a universally acceptable 99-m technetium sulfur-colloid labeled low fat, egg-white meal[18]. Medications that alter gastric emptying may be discontinued 48-72 h in advance, blood glucose in diabetics should be < 275 mg/dL on the day of the test and scinti-scanning at a minimum of 1, 2 and 4 h after test meal ingestion is performed in the upright position. This periodic measurement of radiolabeled solid meal has a specificity of 62% and a sensitivity of 93% when compared to continuous scinti-scanning[19]. Emptying of solids exhibits a lag phase followed by a prolonged linear emptying phase. The results of this test can be reported in two ways. The simplest approach is to report percent retention at defined times (minimum 1, 2, and 4 h). Half-times (T½ values) may also be calculated but may potentially be less accurate, particularly in patients with very long emptying for whom extrapolation is needed to calculate the half-time if it was not actually reached during the test. Retention of over 10% of the solid meal after 4 h is abnormal. A grading of severity based on 4 h values might be used: grade 1 (mild), 11%-20% retention at 4 h; grade 2 (moderate), 21%-35% retention at 4 h; grade 3 (severe), 36%-50% retention at 4 h; and grade 4 (very severe), > 50% retention at 4 h[18]. Prokinetics may also be administered intravenously after the last measurement (i.e. 4 h) to evaluate if the patient is a “responder” or “non-responder” to the agent. Again, percent retained or extrapolated T½ times can be calculated to assess the response. The drawbacks of the test include lack of standardization in different academic institutions, despite the current consensus recommendations, and radiation exposure, which is equivalent to about 1/3 of the average annual radiation exposure in the US from natural sources.
Radiopaque markers: After ingestion of indigestible markers, i.e. 10 small pieces of nasogastric tubing, none of the markers should remain in the stomach on an X-ray taken 6 h after ingestion with a meal[20]. This simple test correlates with clinical gastroparesis and is readily available and inexpensive. The drawbacks of the test include lack of standardization of the meal and size of markers and difficultly of determining if the markers are located in the stomach or other regions that overlap with the stomach (e.g. proximal small bowel, transverse colon).
Ultrasonography: Transabdominal ultrasound has been used to measure emptying of a liquid meal by serially evaluating cross-sectional changes in the volume remaining in the gastric antrum over time[21-23]. Emptying is considered complete when the antral area/volume returns to the fasting baseline. Some studies have revealed gastric emptying measurements similar to those seen with scintigraphy[24]. Three-dimensional ultrasound is a newly-developed technique that has recently been reported to be useful in determining stomach function[25,26] and duplex sonography can quantify transpyloric flow of liquid gastric contents. These techniques may be preferred over scintigraphy in patients such as pregnant women or children, in order to minimize radiation exposure. Drawbacks of the test include the fact that it is somewhat operator dependent, has proven reliable only for measurements of liquid emptying rates[24], and is less reliable when the patient is obese or when excessive gastric air is present. Moreover, liquid emptying is rarely impaired in patients with severe gastroparesis.
Magnetic resonance imaging: MRI using gadolinium has been found to accurately measure semi-solid gastric emptying and accommodation using sequential transaxial abdominal scans[27]. MRI provides excellent special resolution with a high sensitivity. It is also non-invasive and radiation free. Antral propagation waves can be observed and their velocity calculated. In gastroparesis, a significant reduction is seen in the velocity of these waves[28]. MRI can also differentiate gastric meal volume and total gastric volume, allowing gastric secretory rates to be calculated. New rapid techniques allow careful measurements of wall motion in both the proximal and distal stomach during emptying, and solid markers now permit measurement of solid meal emptying[29,30]. The drawback of this test is the expense and lack of availability.
Single-photon emission CT: This technique uses intravenously administered 99-Tc pertechnetate that accumulates within the gastric wall rather than the lumen and provides a three-dimensional outline of the stomach[31]. Measurement of regional gastric volumes in real-time to assess fundic accommodation and intragastric distribution can be made. The drawback of this test is the need of large radiation doses, and wide unavailability.
Stable isotope breath tests The non-invasive 13-C-labeled octanoate breath test is an indirect means of measuring gastric emptying. It is a medium chain triglyceride which is bound to a solid meal such as a muffin. After ingestion and stomach emptying, 13-C octanoate is rapidly absorbed in the small intestine and metabolized to 13 CO2 which is expelled from the lungs during expiration. The rate limiting step for the signal appearing in the breath is the rate of gastric emptying. Compared to detailed scintigraphy done over a period of 4 h, the breath test has a specificity of 80% and sensitivity of 86%[32]. The test assumes normal small bowel, pancreas, liver and pulmonary functions. Some studies have demonstrated a strong correlation between the carbon-labeled breath test and gastric scintigraphy[33,34]. The drawback of this test is the need for normal small intestinal absorption, liver metabolism, and pulmonary excretion to validate the test results.
Swallowed capsule telemetry The ingestible “SmartPill®” (VA Boston Healthcare System, MA, USA), or telemetry capsule, offers a promising new non-radioactive method for assessing gastric emptying. This capsule measures pH, pressure and temperature using miniaturized wireless sensor technology. This has been developed for ambulatory assessment of GI transit. The time taken for the pill to be expelled from the stomach into the duodenum is measured by monitoring the time point at which the acid readings of the stomach are replaced by the dramatic increase in pH as the capsule enters the duodenum. It has been shown that gastric transit time calculated using the SmartPill correlates well with gastric scintigraphy with good sensitivity (82%) and specificity (83%)[35]. The frequencies and amplitudes of antral contractions can be used to calculate motility indices. A current drawback is the cost of the pill and lack of widespread availability.
Antroduodenal manometry In antroduodenal manometry, a water-perfused or solid-state manometric catheter is passed from the nares or mouth and placed fluoroscopically into the stomach and small bowel to measure actual gastroduodenal contractile activity. The frequency and amplitude of fasting, interdigestive and post-prandial contractions can be recorded, and the response to prokinetic agents can be assessed. Distinct patterns characterize the fasting and fed phases. During the fasting period, three cyclical phases known as migrating motor complex (MMC) recur approximately every 2 h: Phase Ⅰ, Phase Ⅱ and Phase Ⅲ. Phase Ⅰ is a period of motor quiescence followed by Phase Ⅱ, a period of intermittent phasic contractions. Phase Ⅲ, considered the “intestinal housekeeper”, consists of an integrated peristaltic wave, initiated in the antrum, that sweeps indigestible solids from the stomach into the duodenum and beyond. Feeding disrupts the MMC and replaces it with a fed motor pattern of more regular antral contractions of variable amplitude that are either segmental or propulsive in character. Gastroparesis is characterized by loss of normal fasting MMC’s and reduced postprandial antral contractions and, in some cases pylorospasm[36]. Small intestinal motor dysfunction is detected in 17%-85% of patients with gastroparesis[37]. Manometry can also distinguish between myopathic and neuropathic small intestinal dysmotilities. However only in approximately 20%-25% of patients diagnosed with dysmotility syndromes by antroduodenal manometry, is clinical management influenced[38]. Antroduodenal manometry is usually reserved for the refractory gastroparesis patient evaluated at tertiary referral centers with the benefit of provocative testing to assess manometric response to treatment[39]. Drawbacks are that it is an invasive procedure, it needs motility expertise to perform and interpret the results, giving rise to problems with over interpretation in the unskilled hands.
Electrogastrography (EGG) EGG measures gastric slow-wave myoelectrical activity via serosal, mucosal or cutaneous electrodes. It is most conveniently recorded with cutaneous electrodes positioned along the long axis of the stomach. Initially a pre-prandial recording for 45-60 min is captured. Patients are given a 500 kcal cheese or turkey sandwich and an equivalent postprandial recording is captured. The recorded signals are amplified and filtered to exclude contamination by noise from cardiorespiratory activity and patient movement. Computer analysis converts raw EGG signals to a three-dimensional plot. In healthy persons, EGG recordings exhibit uniform waveforms of 3 cycles/min, which increase in amplitude after ingestion of a meal. Abnormality of EGG is defined by rhythm disruption of more than 30% of the recording time including tachygastria (frequency of > 4 cycles/min) and bradygastria (< 2 cycles/min) and a lack of signal amplitude with eating[40]. EGG abnormalities are present in 75% of patients with gastroparesis[40]. EGG is considered by some authors as more of an adjunct to gastric emptying measurement for a comprehensive evaluation of patients with refractory symptoms[40]. Drawbacks are the little documented utility of EGG in the management of patients with suspected gastric dysmotility and movement artifacts that make recordings difficult to interpret.
Other tests The gastric barostat test consists of a high compliance balloon device placed into the stomach to measure pressure-volume relationships and visceral sensation[41]. The drawback of this test is that it is invasive and is used therefore only as a research tool in a few tertiary centers. The satiety test involves ingestion of water or a liquid nutrient until the patient reports maximal fullness. This test is not frequently performed and its main drawback is that results are subjective. A common misconception is the use of barium upper gastrointestinal testing in the diagnosis of gastroparesis. Although this test can be used to evaluate anatomic abnormalities such as gastric outlet obstruction, it is not a functional study for the diagnosis of gastroparesis and other lesions such as malignancy may still be missed.
TREATMENT The general principles of 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[12,42]. In addition, patient education and explanation of the condition is an integral part of treatment. The disabling chronic symptoms of gastroparesis impact profoundly on the patient’s sense of wellbeing, mental state, behavior and social life. Sensitive caring from the clinical team and professional counseling might be necessary to help the patient cope with the disability. Patients should be informed that a number of drugs might be tried in an attempt to discover the optimal therapeutic regimen and that the aim of treatment is to control rather than cure the disorder[43]. The patient’s drug list should be reviewed to eliminate drugs that can cause gastric dysmotility. Management can be tailored to the severity of the gastroparesis. For grade 1 (mild) gastroparesis, dietary modifications should be tried. Low doses of antiemetic or prokinetic medications can be taken on an as-needed basis. Grade 2 (compensated) gastroparesis is treated by combination of antiemetic and prokinetic medications given at scheduled regular intervals. These agents relieve the more chronic symptoms of nausea, vomiting, early satiety and bloating. They frequently have no effect on abdominal pain. In grade 3 (severe) gastroparesis or gastric failure, more aggressive treatments including hospitalizations for i.v. hydration and medications, enteral or parenteral nutritional support and endoscopic or surgical therapy may be needed[12].
Dietary manipulation Dietary recommendations rely on measures that promote gastric emptying or, at least theoretically, do not retard gastric emptying. At the outset, it is advisable to introduce an experienced dietician who can discuss and explore the patient’s tolerance of solids, semi-solids and liquids, as well as dietary balance, meal size and timing of meals. Fats and fiber tend to retard emptying, thus their intake should be minimized. This should be stressed as many of these patients who often concomitantly also have constipation, have been told to take fiber supplementation for treatment of their constipation. Multiple small low fat meals about four or five times each day should be recommended. Carbonated liquids should be avoided to limit gastric distention. Patients are instructed to take fluids throughout the course of the meal and to sit or walk for 1-2 h after meals. If the above measures are ineffective, the patient may be advised to consume the bulk of their calories as liquid since liquid emptying is often preserved in patients with gastroparesis. Poor tolerance of a liquid diet is predictive of a future poor success[12].
Correction of glycemic control Patients with diabetes should be counseled to achieve optimal glycemic control. Hyperglycemia itself delays gastric emptying, even in the absence of neuropathy or myopathy, which is likely to be mediated by reduced phasic antral contractility and induction of pyloric pressure waves. Hyperglycemia can inhibit the accelerating effects of prokinetic agents[44]. Measures more likely to be effective include more aggressive glucose monitoring, with frequent dosing of short acting insulin preparations to prevent post-prandial hyperglycemia. Prevention of wide fluctuations of hyperglycemia may be more important than maintenance of a given steady-state blood glucose level[45]. Improvement of glucose control increases antral contractility, corrects gastric dysrhythmias and accelerates emptying.
Pharmacological therapy The pharmacotherapy of gastroparesis is stepwise, incremental and long term. The most commonly used drug classes include pro-motility and anti-emetic agents. There has been little in the way of randomized controlled investigations directly comparing the different agents. Consequently, a selection of drugs is used by trial and error.
Prokinetic agents: Prokinetic medications enhance the contractility of the GI tract, correct gastric dysrhythmias, and promote the movement of luminal contents in the antegrade direction. Prokinetics may improve predominantly symptoms of nausea, vomiting and bloating. They do not seem to relieve abdominal pain and early satiety associated with gastroparesis. They should be administered 30 min before meals to elicit maximal clinical effects. Bedtime doses are often added to facilitate nocturnal gastric emptying of indigestible solids. The response to treatment is usually judged clinically rather than with serial gastric emptying tests because symptom improvements correlate poorly with the acceleration of gastric emptying[46]. A meta-analysis assessing benefits of four different drugs in 514 patients in 36 clinical trials reported that the macrolide antibiotic erythromycin is the most potent stimulant of gastric emptying, while erythromycin and the dopamine receptor antagonist, domperidone, are best at reducing symptoms of gastroparesis[47]. Several factors must be considered when choosing a prokinetic drug for patients with gastroparesis, including efficacy, toxicity, regional availability and cost. (Ⅰ) Erythromycin. Erythromycin is a macrolide antibiotic that is also a motilin receptor agonist[48]. The intravenous form is the most potent stimulant of solid and liquid gastric emptying[49,50]. Motilin is a polypeptide hormone present in the distal stomach and duodenum that increases lower esophageal sphincter pressure and is responsible for initiating the MMC in the antrum of the stomach[51,52]. Erythromycin binds to motilin receptors and hence increases the amplitude of antral peristalsis, triggers premature MMC phase Ⅲ activity, and stimulates gastric emptying[53]. Interestingly, erythromycin has also been shown to accelerate emptying in post-vagotomy and antrectomy patients[54]. This may be due to its stimulatory effects on the fundus. Erythromycin should be started at a low dose (200 mg per 5 mL) and is most rapidly absorbed when administered as a suspension[55]. However, tachyphylaxis develops in patients on chronic erythromycin therapy, due to down-regulation of motilin receptors which can develop as early as a few days of initiating therapy[53]. If tachyphylaxis develops, erythromycin can be discontinued for 2 wk and then restarted again. Intravenous erythromycin is used occasionally for inpatients with severe refractory gastroparesis[55]. Common side effects include skin rashes, nausea, cramping and abdominal pain. A large cohort reported that erythromycin increases the risk of sudden cardiac arrest by 2.01 times when compared to control population[56]. The risk for death was further increased in those patients who also were on CYP3A (cytochrome P-450 3A) inhibitors such as selected antipsychotics, cardiac antiarrythmics, antifungals, calcium antagonists, antidepressants, and anti-emetics. Therefore, prior to initiating EES therapy for treatment of gastroparesis, all these factors need to be considered. Although this has not undergone formal testing, in our institution, a QTc of 450 ms in men and 460 ms in women has been used as the cut-off value over which EES is not administered due to risk of QT prolongation. (Ⅱ) Metoclopramide. Metoclopramide is a substituted benzamide with several prokinetic actions, which include combined serotonin 5-hydroxytryptamine (HT) 4 receptor agonism, dopamine D2 receptor antagonism, and direct stimulation of gut smooth muscle contraction. The drug also has anti-emetic effects via brainstem D2 receptor antagonism, vagal and brainstem 5-HT3 receptor antagonism. 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. Metoclopramide is administered orally in pill or liquid suspension form. Intravenous forms commonly are reserved for inpatients that cannot retain oral medications. Subcutaneous administration has also been reported to provide symptom control[57]. At least five controlled trails and four open label series have studied the efficacy of metoclopramide in gastroparesis[10]. In these nine trials, symptoms improved in seven studies, but improvement in gastric emptying was noted in only five. Patients may develop tolerance to the prokinetic action of metoclopramide over time; however, its antiemetic effects are sustained[58]. Metoclopramide is effective for the short-term treatment of gastroparesis for up to several weeks[59,60]. The long-term utility of metoclopramide has not been proven[61]. Side effects of metoclopramide occur in up to 30% of patients and result from antidopaminergic effects on the CNS. Acute dystonic reactions such as facial spasm, oculogyric crisis, trismus, and torticollis occur in 0.2%-6% of patients and are often observed in patients less than 30 years of age and within 48 h of initiating therapy[62]. Drowsiness, fatigue, and lassitude are reported by 10% of patients. Metoclopramide can worsen depression. Other side effects include restlessness, agitation, irritability, akathisia and hyperprolactinemic effects. Prolonged treatment with metoclopramide can produce extrapyramidal symptoms. These symptoms usually subside with 2-3 mo of discontinuation of the drug. Irreversible tardive dyskinesia is a catastrophic consequence that occurs in 1% to 10% of cases when metoclopramide is taken for more than 3 mo[62]. This condition is disabling and can develop without warning, therefore, it should be discussed in detail with the patients or their families with documentation of the discussion in their medical record. The current standard has been to sign an informed consent to document communicating the risks of metoclopramide. (Ⅲ) Domperidone. Domperidone, a benzimidazole derivative, is a peripheral dopamine D2 receptor antagonist with benefits similar to those of metoclopramide. Domperidone does not cross the blood-brain barrier and consequently it has fewer central side effects. Brainstem structures regulating vomiting are outside the blood-brain barrier, therefore, domperidone has potent central anti-emetic action. At least five controlled trials and four open case series have assessed domperidone in patients with gastroparesis and diabetic gastropathy[63]. Symptoms improved in all studies, but accelerated gastric emptying was not uniformly observed. Domperidone may show tachphylaxis on repeated administration[64]. Adverse reactions to domperidone are commonly related to hyperprolectinemia due to the porous blood-brain barrier in the anterior pituitary[65]. These include menstrual irregularities, breast engorgement, and galactorrhea. An intravenous formulation of domperidone was removed in 1980 due to generation of cardiac arrhythmias[66]. Domperidone is not approved by the FDA for prescription in the United States, although it can be obtained in Canada, Mexico, New Zealand, Europe, and Japan. It is available in the US with approval of local institutional review boards, through an FDA investigational new drug application (IND) to patients with gastroparesis refractory to other therapies. (Ⅳ) Tegaserod. This is a 5-HT4 receptor partial agonist used in the treatment of constipation predominant irritable bowel syndrome. In healthy volunteers, the drug stimulates small-intestinal motility and post-prandial antral and intestinal motility. Tegaserod has been shown to accelerate gastric emptying in some[67] but not all studies of healthy volunteers[68]. Tegaserod was completely withdrawn form the US market in April 2008 due to a reported increase in the risk of cardiovascular adverse effects. (Ⅴ) Cisapride. Cisapride is a 5-HT4 receptor agonist with weak 5-HT3 antagonist properties that once was widely used for gastroparesis. This drug was withdrawn from the market in the United States in 2000 because of numerous reports of sudden death from cardiac arrhythmias[69]. Although the drug is still available overseas in numerous countries and obtainable from overseas websites, a recent consensus document did not recommend its use in gastroparesis[12]. (Ⅵ) Bethanechol. Bethanechol is an approved smooth muscle muscarinic agonist that increases lower esophageal sphincter pressure and evokes fundoantral contractions but does not induce propulsive contractions or accelerate gastric emptying[70]. Rarely, the drug may be used as an adjunct with other prokinetic medications in patients refractory to standard treatment with prokinetics and anti-emetic drugs. Prominent adverse effects include abdominal cramps, skin flushing, diaphoresis, lacrimation, salivation, nausea, vomiting, bronchoconstriction, urinary urgency, and miosis. Dangerous cardiovascular effects include abrupt decreases in blood pressure in hypertensive patients and atrial fibrillation in patients with hyperthyroidism. (Ⅶ) Drugs in research. (1) Motilin receptor agonists. (a) Azithromycin is a macrolide antibiotic similar to erythromycin. It has been postulated that azithromycin is also a motilin receptor agonist. In preliminary studies, intravenous administration of azithromycin improves antroduodenal contractions as measured by manometry[71]. However, there are no data available revealing an improvement in gastric emptying rates or patient symptoms after the administration of i.v. or oral azithromycin. The potential benefit of azithromycin is the longer half-life (68 h) as compared to erythromycin (1.5-2 h) and thus the less frequent dosing may help improve compliance with the medication (once a day versus four times a day). Furthermore, azithromycin is not metabolized, and elimination is largely in the feces, following excretion into the bile, with less than 10% excreted in the urine. Thus, it does not utilize the P-450 pathway in the liver and has less adverse effects due to drug interactions. It also appears that azithromycin has lower pro-arrhythmic potential compare with erythromycin but nevertheless cardiac adverse events have been reported[72-74]. From that prospective, it seems prudent to check the length of the QTc interval prior to initiating azithromycin therapy as well. (b) Mitemcinal is also a macrolide derived motilin receptor agonist with prokinetic properties. It does not have any antimicrobial actions. It produced symptom benefit in patients with diabetic gastropathy who had a body mass index of < 35 kg/m2 and with hemoglobin A1C values < 10%[75]. In addition, tachyphylaxis was not observed during the study period. (c) Atilmotin is another motilin receptor agonist, which, when given i.v., has been shown to accelerate gastric emptying of liquids and solids in healthy subjects[76]. It is not known whether atilmotin has significant effects on symptoms in patients with gastroparesis. (d) Ghrelin is a neurohumoral transmitter secreted by the stomach and is believed to play a physiological role as a stimulant of food intake and is also structurally related to motilin. Ghrelin has prokinetic properties, and has been shown to accelerate gastric emptying of a test meal in diabetic patients with slow gastric emptying[77], as well as improve gastric emptying and decreased meal-related symptoms in patients with idiopathic gastroparesis[78]. (2) Dopamine antagonists and serotonin agonists. (a) Itopride is a new D2 antagonist with anti-acetylcholinesterase effects. This drug showed prokinetic properties in animal models as well as promising effects in functional dyspepsia[79]. However, in healthy subjects, itopride had no effect on gastric emptying[80]. (b) Sulpiride is a dopamine blocker used for psychiatric disorders. Initial studies have shown that oral levosulpiride is superior to placebo[81], and may be as effective as cisapride in relieving nausea and vomiting in patients with gastroparesis[82,83]. Although this drug is not new, further studies are of interest to see whether it deserves a more established position for these gastrointestinal indications. (c) Mosapride is a 5-HT4 receptor agonist that accelerates gastric emptying in healthy volunteers and patients with diabetic gastroparesis[84]. In contrast to cisapride, mosapride has little effect on potassium-channel activity and seems to exhibit a significantly lower cardiac dysrhythmogenic potential[85]. (d) Renzapride is a combined 5-HT4 receptor agonist and 5-HT3-receptor antagonist. Future studies are needed to determine if renzapride exhibits efficacy in gastroparesis[12]. (3) Miscellaneous. (a) Physiostigmine and neostigmine are muscarinic receptor activators that stimulate gut motor activity by increasing acetylcholine levels. These drugs increase gastric contractions but have limited action in accelerate gastric emptying. However, pyridostigmine has been recently noted to reduce symptoms in a patient with gastroparesis secondary to underlying autoimmune disease[86]. (b) Nizatidine is a H2-receptor antagonist which exhibits anticholinesterase activity and stimulates gastric emptying but its efficacy in long-term treatment of gastroparesis is unknown[87]. (c) Cholecystokinin receptor antagonists such as loxiglumide and dexloxiglumide accelerate gastric emptying in some studies. The utility of such agents in gastroparesis remains to be determined[88]. (d) Sildenafil is a phosphodiesterase 5 inhibitor which has been shown to restore gastric emptying of liquids in an animal model of diabetes[89]. Sildenafil also reduced the dysrhythmias of the stomach induced experimentally by hyperglycemia in humans[90]. On the other hand, a thorough study of the effects of sildenafil on human gastric sensimotor functions showed that the drug significantly increases postprandial gastric volume and slows liquid (though not solid) emptying rate[91]. Sildenafil has also been found to inhibit interdigestive motor activity of the antrum and duodenum[92]. Clinical trials are clearly needed before this medication can be considered for the treatment of gastroparesis.
Anti-emetic medications: It is likely that a component of the clinical benefits observed with some of the available prokinetic drugs, such as metoclopramide and domperidone, stem from their anti-emetic actions on brain-stem nuclei. Nausea and vomiting are the most disabling symptom of gastroparesis and anti-emetic agents without stimulatory activity are often used alone or in concert with prokinetic drugs to treat gastroparesis. Antiemetic medications act on a broad range of distinct receptors subtypes in the peripheral and central nervous systems. Like prokinetics, the choice of antiemetic is empirical and it is reasonable to try the less expensive therapies initially.
(Ⅰ) Phenothiazines. These are the most commonly prescribed traditional antiemetics which include prochlorperazine and tiethyperazine. These drugs are both dopamine and cholinergic receptor antagonists acting on the area postrema (chemoreceptor trigger zone) in the brainstem. Prochlorperazine can be administered in the tablet form, liquid suspension, suppository and by injection. Side effects include sedation and extra-pyramidal effects such as drowsiness, dry mouth, constipation, skin rashes and Parkinsonian-like tardive dyskinesia.
(Ⅱ) Serotonin 5-HT3 receptor antagonist. These medications include ondansetron, granisetron, and dolasetron and are useful for prophylaxis of chemotherapy induced nausea and vomiting, as well as symptoms occurring post operatively or during radiation therapy. These drugs may act on the chemoreceptor trigger zone as well as on peripheral afferent nerve fibers within the vagus nerve[42]. Ondansetron has no effect on gastric emptying in healthy volunteers and patients with gastroparesis and moreover can cause constipation[93,94]. This class of drugs maybe helpful when all other drugs have failed to provide symptom relief and are best given on an as-needed basis.
(Ⅲ) Anti-histamines. Antihistamines acting on H1 receptors exhibit central antiemetic effects[42]. Commonly prescribed antiemetics include diphenhydramine, dimenhydrinate and meclizine. These agents are most useful to treat symptoms related to motion sickness. The mechanism of action is poorly understood but is likely to involve both labyrinthine and chemoreceptor trigger zones. Side effects include drowsiness, dry mouth, blurred vision, difficulty urinating, constipation, palpitations, dizziness, insomnia and tremor.
(Ⅳ) Low-dose tricyclic antidepressants. Tricyclic antidepressants (TCAs) impair gastrointestinal motility through their anticholinergic activity but have been shown to relieve nausea, vomiting and pain in functional dyspepsia[95,96]. In a recent publication, 88% of diabetic patients with nausea and vomiting reported benefits with TCAs[97], of which one third had delayed gastric emptying, suggesting that these agents may have utility in gastroparesis. However, formal prospective trials of these antidepressants for the treatment of gastroparesis have not been performed, thus their use is still considered off-label. Side effects of low-dose TCAs are uncommon, excessive sedation and dry mouth occasionally limits use.
(Ⅴ) Other antiemetics. (1) Cannabinoids. Cannabinoid drugs such as dronabinol have been studied for improvement of gastrointestinal symptoms from chemotherapy and appear to have potency similar to standard antidopaminergics. Their benefit for gastroparesis has not been evaluated and they may also delay gastric emptying. (2) Benzodiazepines. These are useful for anticipatory nausea and vomiting before chemotherapy, but their efficacy in gastroparesis is unknown. These drugs maybe useful for their sedating effects in those patients with associated anxiety. (3) Neurokinin NK1-receptor antagonists. These are new antiemetics which treat both acute and delayed chemotherapy-induced nausea and vomiting[98,99], but their actions on gastric motor activity and symptoms in gastroparesis are uninvestigated. (4) Corticosteriods. Corticosteriods are employed as antiemetics in the postoperative setting or in the prevention of chemotherapy-induced emesis. One individual with idiopathic myenteric ganglionitis exhibited improvement with corticosteroid therapy, confirming the inflammatory basis of some cases of upper gut dysmotility[100].
Complementary and alternative therapies: Ginger, a traditional Chinese antiemetic agent, has weak 5-HT3 receptor antagonist properties and has gastric slow wave antidysrhythmic effects in humans[101,102]. These therapies are often given for treatment of nausea and vomiting of diverse etiologies. Acupressure and electrical acustimulation on the P6 acupuncture point reduce nausea postoperatively, after chemotherapy, and during nausea of pregnancy. One group observed benefits with acupuncture in 35 diabetic gastroparesis patients[103].
Medications for control of symptoms other than nausea and vomiting: (1) Early satiety. Early satiety has been related to defects in fundic accommodation in patients with functional dyspepsia[104]. Nitrates, buspirone, sumitriptan, and selective serotonin reuptake inhibitors promote fundic relaxation in this condition[105,106]. The use of fundic relaxants in managing early satiety in gastroparesis has not been investigated; (2) Abdominal pain. Epigastric pain is disabling in some individuals with gastroparesis and can result in excessive utilization of healthcare resources. The pathogenesis of pain is poorly understood and treatments for this symptom are largely unsatisfactory. Pain in gastroparesis has been postulated to be due to sensory rather than motor dysfunction, and therapies to reduce afferent dysfunction may be more effective for this symptom[107]. However, this hypothesis has not been tested. Although, non-steroidal anti-inflammatory drugs (NSAID’s) have been shown to ameliorate gastric slow wave dysrhythmias in several healthy subjects[108], their adverse effects including renal dysfunction and ulcerogenic properties, limit their usage on a chronic basis. Antidepressant medications may help with gastroparesis associated neuropathic pain[109]. These include low dose tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRIs), selective noradrenaline reuptake inhibitors (SNRIs) and combined serotonin/noradrenaline reuptake inhibitors. Paroxetine, an SSRI, may selectively accelerate small intestinal transit[110,111]. Opiates, including milder agents such as tramadol, should be avoided because of their inhibitory effects on motility as well as risk of addiction. (3) Nutritional support, enteral and parenteral. Some patients with refractory gastroparesis benefit from enteral or parenteral nutrition intermittently for symptom flares or for permanent support. Patients with chronic symptoms of gastroparesis may develop dehydration, electrolyte abnormalities and/or extreme malnutrition. The choice of nutritional support and its administration route depends on the severity of disease. The indications for supplementation of enteral nutrition include unintentional loss of 10% or more of the usual body weight during a period of 3 to 6 mo, inability to achieve the recommended weight by the oral route, repeated hospitalizations for refractory symptoms, interference with delivery of nutrients and medications, need for nasogastric intubation to relieve symptoms, and nausea and vomiting resulting in poor quality of life[12]. Except in cases of profound malnutrition or electrolyte disturbance, enteral feeding are preferable to chronic parenteral nutrition because of the significant risks of infection and liver disease in the latter treatment. On the other hand, short-term total parenteral nutrition (TPN) can reverse rapid weight decline and ensure adequate fluid delivery. Home intravenous TPN may be needed for individuals who cannot tolerate enteral feeding. Several options for enteral access and feeding are available and no data exists favoring one approach over the other. However, nasogastric tubes and gastrostomy tubes are not encouraged due to the possibility of worsening gastroparesis and risk of pulmonary aspiration. Jejunostomy tubes are preferred in order to bypass the gastroparetic stomach except if the patient has small bowel dysmotility. Short-term nasojejunal feeding is often used to help determine if the patient will tolerate chronic small bowel feeding through a permanent enteral access. Formulas that are low in osmolarity (e.g. Peptamen, Isocal) and with a caloric density of 1.0-1.5 cal/mL are recommended. A dietician should be consulted early on. Initially, infusion rates should be low and then advanced every 4-12 h as tolerated to meet caloric needs. Eventually, infusions can be converted to nocturnal feedings to free up daytime h for optional oral intake and to participate in normal daily activities.
Endoscopic treatment Therapeutic endoscopy with pyloric injection of botulinum toxin A may provide benefit in some patient with gastroparesis. Botulinum toxin A is a bacterial toxin that inhibits acetylcholine release, causing muscle paralysis. Manometric studies in patients with diabetic gastroparesis have shown evidence of prolonged pylorospasm producing a functional outlet obstruction[36]. Several uncontrolled case series have reported reduced symptoms and acceleration of gastric emptying after botulinum toxin treatment[112-114]. The largest series reported 63 highly selected patients with primary idiopathic gastroparesis, 43% of whom responded symptomatically with mean response duration of 5 mo[115]. A double-blind controlled trial found no efficacy of botulinum toxin over placebo[116]. However, this report was underpowered to detect the effect of the drug. Another recent double-blind placebo-controlled trial revealed that intrapyloric injection of botulinum toxin improved gastric emptying in patients with gastroparesis, although this benefit was not superior to placebo at one month. Also, in comparison to placebo, symptoms did not improve significantly after 1 mo of injection[117]. The use of botulinum toxin for gastroparesis is considered off-label and should be considered when other accepted therapies have failed or produced unacceptable side effects. To date, few adverse effects have been reported with botulinum toxin therapy.
Surgical treatment Surgical intervention is increasingly used to treat medically refractory/severe gastroparesis. Limited data are available concerning surgical treatment of gastroparesis[118]. The most common procedure is gastric electrical stimulation (GES). Other procedures offered include venting/feeding gastrostomy and jejunostomy tubes, surgical pyloroplasy, gastrectomy and surgical drainage procedures and pancreatic transplantation in diabetic patients. Apart from GES and feeding tubes, other surgical procedures are performed as a last resort in carefully evaluated patients with profound gastric stasis.
GES: Over the past decade, GES has been used for treatment of medically refractory gastroparesis[10,12,119]. Paced GES using an implantable stimulator (Enterra therapy, by Medtronic Inc.) has been approved by the FDA through a humanitarian device exemption. Electrical stimulation is delivered by two electrodes usually placed laproscopically on to the serosal surface of the stomach overlying the pacemaker area in the body of the stomach. Leads from the electrodes connect to a pulse generator that resembles a cardiac pacemaker that is implanted in a subcutaneous pocket of the anterior abdominal wall. The pulse generator delivers low energy 0.1-s trains of pulses at a frequency of 12 cycles/min. Within each pulse train, individual pulses oscillate at a frequency of 14 cycles/s[12]. Although the exact mechanism of action of the GES is unknown, the clinical effect is believed to be mediated by local neurostimulation. The stimulation impulses used are able to excite nerves but are too weak to excite gastric smooth muscles. Furthermore, poor correlation is observed between patients’ symptoms and gastric emptying rates[119,120]. It has been hypothesized that the mechanism may stem from a vagal and cerebral pathway[121]; however, GES has been shown to work well even in patients with vagotomy[122]. Multiple uncontrolled studies in diabetic, idiopathic and post-surgical gastroparesis have shown efficacy of GES. In one uncontrolled multicenter trial, 35 of 38 patients experienced > 80% reductions in nausea and vomiting which persisted for 2.9-15.6 mo, with an associated 5.5% increase in weight and reduced requirement of supplemental nutrition[123]. Other studies reported similar long-term symptom benefits, which may persist for at least 10 years with improvements in body mass index, serum albumin and glycemic control[124,125]. In the only controlled trial of GES, 33 patients with idiopathic or diabetic gastroparesis completed a 2-mo double-blind, crossover, sham stimulation-controlled phase followed by 12 mo uncontrolled observation, with the device activated[119]. During the blinded phase, frequency of weekly vomiting in all patients was 6.8 times when the device was ON as opposed to 13.5 times when it was OFF. Although there was not a significant reduction in the total symptom score (TSS) in the ON vs OFF state, 21 patients preferred the stimulation ON, whereas seven preferred OFF and five had no preference. Symptom reductions were more impressive during the unblinded phase where median vomiting frequency decreased by > 80% for 50% of all patients. TSS was also significantly improved in all patients from a score of 16.8 at baseline to 11.1 and 11.4 at 6 and 12 mo, respectively. The major adverse effect of GES is infection resulting in removal of the device in approximately 10% of patients[119,123]. The frequency of such infections seems to be decreasing during recent years. This may be explained by more careful surgical technique and the increasing use of laparoscopy instead of open surgery. The second concern is of the non-responder issue. In the earlier mentioned randomized trial[119] 13% of the patients were non-responders with < 25% symptom reduction. There seems to be a higher non-responder rate in idiopathic gastroparesis[125,126]. Abell and colleagues have applied temporary mucosal GES with endoscopically placed electrodes and used the effects on symptoms after ≥ 3 d as a measure of response[127].
Other surgical options: 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. Pyloroplasty may be considered as another option but limited data are available on the efficacy of this procedure. There are limited controlled data concerning gastrectomy in gastroparesis[118]. A study of patients with near-total gastrectomy revealed long-term symptom relief in 43% patients with postsurgical gastroparesis[128]. The literature is sparse concerning correction of diabetic gastroparesis status post-pancreas and pancreas-kidney transplant in patients with type 1 diabetes[129,130].
REFERENCES 1 Soykan I, Sivri B, Sarosiek I, Kiernan B, McCallum RW. Demography, clinical characteristics, psychological and abuse profiles, treatment, and long-term follow-up of patients with gastroparesis. Dig Dis Sci 1998; 43: 2398-2404 PubMed DOI 2 Park MI, Camilleri M. Gastroparesis: clinical update. Am J Gastroenterol 2006; 101: 1129-1139 PubMed DOI 3 Huizinga JD. Neural injury, repair, and adaptation in the GI tract. IV. Pathophysiology of GI motility related to interstitial cells of Cajal. Am J Physiol 1998; 275: G381-G386 PubMed 4 Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care 2003; 26: 1553-1579 5 Ziegler D, Schadewaldt P, Pour Mirza A, Piolot R, Schommartz B, Reinhardt M, Vosberg H, Brosicke H, Gries FA. [13C] octanoic acid breath test for non-invasive assessment of gastric emptying in diabetic patients: validation and relationship to gastric symptoms and cardiovascular autonomic function. Diabetologia 1996; 39: 823-830 PubMed DOI 6 Ordog T, Takayama I, Cheung WK, Ward SM, Sanders KM. Remodeling of networks of interstitial cells of Cajal in a murine model of diabetic gastroparesis. Diabetes 2000; 49: 1731-1739 PubMed DOI 7 Ali T, Hasan M, Hamadani M, Harty RF. Gastroparesis. South Med J 2007; 100: 281-286 PubMed 8 Peeters TL. New motilin agonists: a long and winding road. Neurogastroenterol Motil 2006; 18: 1-5 PubMed DOI 9 Murray CD, Martin NM, Patterson M, Taylor SA, Ghatei MA, Kamm MA, Johnston C, Bloom SR, Emmanuel AV. Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study. Gut 2005; 54: 10 Parkman HP, Hasler WL, Fisher RS. American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology 2004; 127: 1592-1622 PubMed DOI 11 Parkman HP, Schwartz SS. Esophagitis and gastroduodenal disorders associated with diabetic gastroparesis. Arch Intern Med 1987; 147: 1477-1480 PubMed DOI 12 Abell TL, Bernstein RK, Cutts T, Farrugia G, Forster J, Hasler WL, McCallum RW, Olden KW, Parkman HP, Parrish CR, Pasricha PJ, Prather CM, Soffer EE, Twillman R, Vinik AI. Treatment of gastroparesis: a multidisciplinary clinical review. Neurogastroenterol Motil 2006; 18: 263-283 PubMed DOI 13 Revicki DA, Rentz AM, Dubois D, Kahrilas P, Stanghellini V, Talley NJ, Tack J. Gastroparesis Cardinal Symptom Index (GCSI): development and validation of a patient reported assessment of severity of gastroparesis symptoms. Qual Life Res 2004; 13: 833-844 PubMed DOI 14 Hoogerwerf WA, Pasricha PJ, Kalloo AN, Schuster MM. Pain: the overlooked symptom in gastroparesis. Am J Gastroenterol 1999; 94: 1029-1033 PubMed DOI 15 Boccia G, Buonavolonta R, Coccorullo P, Manguso F, Fuiano L, Staiano A. Dyspeptic symptoms in children: the result of a constipation-induced cologastric brake? Clin Gastroenterol Hepatol 2008; 6: 556-560 PubMed DOI 16 Parkman HP, Schwartz SS. Esophagitis and gastroduodenal disorders associated with diabetic gastroparesis. Arch Intern Med 1987; 147: 1477-1480 PubMed DOI 17 Blam ME, Lichtenstein GR. A new endoscopic technique for the removal of gastric phytobezoars. Gastrointest Endosc 18 Abell TL, Camilleri M, Donohoe K, Hasler WL, Lin HC, Maurer AH, McCallum RW, Nowak T, Nusynowitz ML, Parkman HP, Shreve P, Szarka LA, Snape WJ Jr, Ziessman HA. Consensus recommendations for gastric emptying scintigraphy: a joint report of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. Am J Gastroenterol 2008; 103: 753-763 PubMed DOI 19 Camilleri M, Zinsmeister AR, Greydanus MP, Brown ML, Proano M. Towards a less costly but accurate test of gastric emptying and small bowel transit. Dig Dis Sci 1991; 36: 609-615 PubMed DOI 20 Feldman M, Smith HJ, Simon TR. Gastric emptying of solid radiopaque markers: studies in healthy subjects and diabetic patients. Gastroenterology 1984; 87: 895-902 PubMed 21 Bateman DN, Whittingham TA. Measurement of gastric emptying by real-time ultrasound. Gut 1982; 23: 524-527 22 Bolondi L, Bortolotti M, Santi V, Calletti T, Gaiani S, Labo G. Measurement of gastric emptying time by real-time ultrasonography. Gastroenterology 1985; 89: 752-759 PubMed 23 Holt S, Cervantes J, Wilkinson AA, Wallace JH. Measurement of gastric emptying rate in humans by real-time ultrasound. Gastroenterology 1986; 90: 918-923 PubMed 24 Gentilcore D, Hausken T, Horowitz M, Jones KL. Measurements of gastric emptying of low- and high-nutrient liquids using 3D ultrasonography and scintigraphy in healthy subjects. Neurogastroenterol Motil 2006; 18: 1062-1068 25 Gilja OH, Detmer PR, Jong JM, Leotta DF, Li XN, Beach KW, Martin R, Strandness DE Jr. Intragastric distribution and gastric emptying assessed by three-dimensional ultrasonography. Gastroenterology 1997; 113: 38-49 PubMed DOI 26 Gilja OH. Ultrasound of the stomach--the EUROSON lecture 2006. Ultraschall Med 2007; 28: 32-39 PubMed DOI 27 Kim DY, Myung SJ, Camilleri M. Novel testing of human gastric motor and sensory functions: rationale, methods, and potential applications in clinical practice. Am J Gastroenterol 2000; 95: 3365-3373 PubMed DOI 28 Ajaj W, Goehde SC, Papanikolaou N, Holtmann G, Ruehm SG, Debatin JF, Lauenstein TC. Real time high resolution magnetic resonance imaging for the assessment of gastric motility disorders. Gut 2004; 53: 1256-1261 PubMed DOI 29 Kunz P, Feinle C, Schwizer W, Fried M, Boesiger P. Assessment of gastric motor function during the emptying of solid and liquid meals in humans by MRI. J Magn Reson Imaging 1999; 9: 75-80 PubMed DOI 30 Feinle C, Kunz P, Boesiger P, Fried M, Schwizer W. Scintigraphic validation of a magnetic resonance imaging method to study gastric emptying of a solid meal in humans. Gut 1999; 44: 106-111 PubMed 31 Kuiken SD, Samsom M, Camilleri M, Mullan BP, Burton DD, Kost LJ, Hardyman TJ, Brinkmann BH, O'Connor MK. Development of a test to measure gastric accommodation in humans. Am J Physiol 1999; 277: G1217-G1221 PubMed 32 Viramontes BE, Kim DY, Camilleri M, Lee JS, Stephens D, Burton DD, Thomforde GM, Klein PD, Zinsmeister AR. Validation of a stable isotope gastric emptying test for normal, accelerated or delayed gastric emptying. Neurogastroenterol Motil 2001; 13: 567-574 PubMed DOI 33 Ghoos YF, Maes BD, Geypens BJ, Mys G, Hiele MI, Rutgeerts PJ, Vantrappen G. Measurement of gastric emptying rate of solids by means of a carbon-labeled octanoic acid breath test. Gastroenterology 1993; 104: 1640-1647 PubMed 34 Braden B, Adams S, Duan LP, Orth KH, Maul FD, Lembcke B, Hor G, Caspary WF. The [13C]acetate breath test accurately reflects gastric emptying of liquids in both liquid and semisolid test meals. Gastroenterology 1995; 108: 1048- 35 Kuo B, McCallum RW, Koch KL, Sitrin MD, Wo JM, Chey WD, Hasler WL, Lackner JM, Katz LA, Semler JR, Wilding GE, Parkman HP. Comparison of gastric emptying of a nondigestible capsule to a radio-labelled meal in healthy and gastroparetic subjects. Aliment Pharmacol Ther 2008; 27: 186-196 PubMed 36 Mearin F, Camilleri M, Malagelada JR. Pyloric dysfunction in diabetics with recurrent nausea and vomiting. Gastroenterology 1986; 90: 1919-1925 PubMed 37 Camilleri M, Malagelada JR. Abnormal intestinal motility in diabetics with the gastroparesis syndrome. Eur J Clin Invest 38 Soffer E, Thongsawat S. Clinical value of duodenojejunal manometry. Its usefulness in diagnosis and management of patients with gastrointestinal symptoms. Dig Dis Sci 1996; 41: 859-863 PubMed DOI 39 Camilleri M, Hasler WL, Parkman HP, Quigley EM, Soffer E. Measurement of gastrointestinal motility in the GI laboratory. Gastroenterology 1998; 115: 747-762 PubMed DOI 40 Parkman HP, Hasler WL, Barnett JL, Eaker EY. Electrogastrography: a document prepared by the gastric section of the American Motility Society Clinical GI Motility Testing Task Force. Neurogastroenterol Motil 2003; 15: 89-102 PubMed DOI 41 Azpiroz F, Malagelada JR. Gastric tone measured by an electronic barostat in health and postsurgical gastroparesis. Gastroenterology 1987; 92: 934-943 PubMed 42 Quigley EM, Hasler WL, Parkman HP. AGA technical review on nausea and vomiting. Gastroenterology 2001; 120: 263- 286 PubMed 43 Patrick A, Epstein O. Review article: gastroparesis. Aliment Pharmacol Ther 2008; 27: 724-740 PubMed 44 Petrakis IE, Vrachassotakis N, Sciacca V, Vassilakis SI, Chalkiadakis G. Hyperglycaemia attenuates erythromycin- induced acceleration of solid-phase gastric emptying in idiopathic and diabetic gastroparesis. Scand J Gastroenterol 45 Gentilcore D, O'Donovan D, Jones KL, Horowitz M. Nutrition therapy for diabetic gastroparesis. Curr Diab Rep 2003; 3: 46 Talley NJ. Diabetic gastropathy and prokinetics. Am J Gastroenterol 2003; 98: 264-271 PubMed DOI 47 Sturm A, Holtmann G, Goebell H, Gerken G. Prokinetics in patients with gastroparesis: a systematic analysis. Digestion 48 Farrugia G, Macielag MJ, Peeters TL, Sarr MG, Galdes A, Szurszewski JH. Motilin and OHM-11526 activate a calcium current in human and canine jejunal circular smooth muscle. Am J Physiol 1997; 273: G404-G412 PubMed 49 DiBaise JK, Quigley EM. Efficacy of prolonged administration of intravenous erythromycin in an ambulatory setting as treatment of severe gastroparesis: one center's experience. J Clin Gastroenterol 1999; 28: 131-134 PubMed DOI 50 Kendall BJ, Chakravarti A, Kendall E, Soykan I, McCallum RW. The effect of intravenous erythromycin on solid meal gastric emptying in patients with chronic symptomatic post-vagotomy-antrectomy gastroparesis. Aliment Pharmacol Ther 51 Peeters TL. Agonist effect of erythromycin and its analogues on motilin receptors. A new family of prokinetics? Clinical interest. Acta Gastroenterol Belg 1993; 56: 257-260 PubMed 52 Parkman HP, Pagano AP, Vozzelli MA, Ryan JP. Gastrokinetic effects of erythromycin: myogenic and neurogenic mechanisms of action in rabbit stomach. Am J Physiol 1995; 269: G418-G426 PubMed 53 Richards RD, Davenport K, McCallum RW. The treatment of idiopathic and diabetic gastroparesis with acute intravenous and chronic oral erythromycin. Am J Gastroenterol 1993; 88: 203-207 PubMed 54 Ramirez B, Eaker EY, Drane WE, Hocking MP, Sninsky CA. Erythromycin enhances gastric emptying in patients with gastroparesis after vagotomy and antrectomy. Dig Dis Sci 1994; 39: 2295-2300 PubMed DOI 55 Ehrenpreis ED, Zaitman D, Nellans H. Which form of erythromycin should be used to treat gastroparesis? A pharmacokinetic analysis. Aliment Pharmacol Ther 1998; 12: 373-376 PubMed DOI 56 Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med 2004; 351: 1089-1096 PubMed DOI 57 McCallum RW, Valenzuela G, Polepalle S, Spyker D. Subcutaneous metoclopramide in the treatment of symptomatic gastroparesis: clinical efficacy and pharmacokinetics. J Pharmacol Exp Ther 1991; 258: 136-142 PubMed 58 Malagelada JR, Rees WD, Mazzotta LJ, Go VL. Gastric motor abnormalities in diabetic and postvagotomy gastroparesis: effect of metoclopramide and bethanechol. Gastroenterology 1980; 78: 286-293 PubMed 59 Perkel MS, Moore C, Hersh T, Davidson ED. Metoclopramide therapy in patients with delayed gastric emptying: a randomized, double-blind study. Dig Dis Sci 1979; 24: 662-666 PubMed DOI 60 Snape WJ Jr, Battle WM, Schwartz SS, Braunstein SN, Goldstein HA, Alavi A. Metoclopramide to treat gastroparesis due to diabetes mellitus: a double-blind, controlled trial. Ann Intern Med 1982; 96: 444-446 PubMed 61 Lata PF, Pigarelli DL. Chronic metoclopramide therapy for diabetic gastroparesis. Ann Pharmacother 2003; 37: 122- 62 Ganzini L, Casey DE, Hoffman WF, McCall AL. The prevalence of metoclopramide-induced tardive dyskinesia and acute extrapyramidal movement disorders. Arch Intern Med 1993; 153: 1469-1475 PubMed DOI 63 Soykan I, Sarosiek I, McCallum RW. The effect of chronic oral domperidone therapy on gastrointestinal symptoms, gastric emptying, and quality of life in patients with gastroparesis. Am J Gastroenterol 1997; 92: 976-980 PubMed 64 Horowitz M, Harding PE, Chatterton BE, Collins PJ, Shearman DJ. Acute and chronic effects of domperidone on gastric emptying in diabetic autonomic neuropathy. Dig Dis Sci 1985; 30: 1-9 PubMed DOI 65 Brogden RN, Carmine AA, Heel RC, Speight TM, Avery GS. Domperidone. A review of its pharmacological activity, pharmacokinetics and therapeutic efficacy in the symptomatic treatment of chronic dyspepsia and as an antiemetic. Drugs 1982; 24: 360-400 PubMed DOI 66 Bruera E, Villamayor R, Roca E, Barugel M, Tronge J, Chacon R. Q-T interval prolongation and ventricular fibrillation with i.v. domperidone. Cancer Treat Rep 1986; 70: 545-546 PubMed 67 Degen L, Matzinger D, Merz M, Appel-Dingemanse S, Osborne S, Luchinger S, Bertold R, Maecke H, Beglinger C. Tegaserod, a 5-HT4 receptor partial agonist, accelerates gastric emptying and gastrointestinal transit in healthy male subjects. Aliment Pharmacol Ther 2001; 15: 1745-1751 PubMed DOI 68 Prather CM, Camilleri M, Zinsmeister AR, McKinzie S, Thomforde G. Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome. Gastroenterology 2000; 118: 463-468 PubMed DOI 69 Griffin JP. Prepulsid withdrawn from UK & US markets. Adverse Drug React Toxicol Rev 2000; 19: 177 PubMed 70 McCallum RW, Fink SM, Lerner E, Berkowitz DM. Effects of metoclopramide and bethanechol on delayed gastric emptying present in gastroesophageal reflux patients. Gastroenterology 1983; 84: 1573-1577 PubMed 71 Moshiree B, Gupta V, Verne GN, Toskes PP. Azithromycin: a new therapy for gastroparesis. Gastroenterology 2005; 128: A547 (Abstract) 72 Huang BH, Wu CH, Hsia CP, Yin Chen C. Azithromycin-induced torsade de pointes. Pacing Clin Electrophysiol 2007; 30: 1579-1582 PubMed 73 Kezerashvili A, Khattak H, Barsky A, Nazari R, Fisher JD. Azithromycin as a cause of QT-interval prolongation and torsade de pointes in the absence of other known precipitating factors. J Interv Card Electrophysiol 2007; 18: 243-246 74 Milberg P, Eckardt L, Bruns HJ, Biertz J, Ramtin S, Reinsch N, Fleischer D, Kirchhof P, Fabritz L, Breithardt G, Haverkamp W. Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes. J Pharmacol Exp Ther 2002; 303: 218-225 PubMed DOI 75 McCallum RW, Cynshi O. Clinical trial: effect of mitemcinal (a motilin agonist) on gastric emptying in patients with gastroparesis - a randomized, multicentre, placebo-controlled study. Aliment Pharmacol Ther 2007; 26: 1121-1130 76 Park MI, Ferber I, Camilleri M, Allenby K, Trillo R, Burton D, Zinsmeister AR. Effect of atilmotin on gastrointestinal transit in healthy subjects: a randomized, placebo-controlled study. Neurogastroenterol Motil 2006; 18: 28-36 PubMed DOI 77 Murray CD, Martin NM, Patterson M, Taylor SA, Ghatei MA, Kamm MA, Johnston C, Bloom SR, Emmanuel AV. Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study. Gut 2005; 54: 78 Tack J, Depoortere I, Bisschops R, Verbeke K, Janssens J, Peeters T. Influence of ghrelin on gastric emptying and meal- related symptoms in idiopathic gastroparesis. Aliment Pharmacol Ther 2005; 22: 847-853 PubMed DOI 79 Holtmann G, Talley NJ, Liebregts T, Adam B, Parow C. A placebo-controlled trial of itopride in functional dyspepsia. N Engl J Med 2006; 354: 832-840 PubMed DOI 80 Choung RS, Talley NJ, Peterson J, Camilleri M, Burton D, Harmsen WS, Zinsmeister AR. A double-blind, randomized, placebo-controlled trial of itopride (100 and 200 mg three times daily) on gastric motor and sensory function in healthy volunteers. Neurogastroenterol Motil 2007; 19: 180-187 PubMed DOI 81 Mansi C, Savarino V, Vigneri S, Sciaba L, Perilli D, Mele MR, Celle G. Effect of D2-dopamine receptor antagonist levosulpiride on diabetic cholecystoparesis: a double-blind crossover study. Aliment Pharmacol Ther 1995; 9: 185-189 82 Mansi C, Borro P, Giacomini M, Biagini R, Mele MR, Pandolfo N, Savarino V. Comparative effects of levosulpiride and cisapride on gastric emptying and symptoms in patients with functional dyspepsia and gastroparesis. Aliment Pharmacol Ther 2000; 14: 561-569 PubMed DOI 83 Mearin F, Rodrigo L, Perez-Mota A, Balboa A, Jimenez I, Sebastian JJ, Patan C. Levosulpiride and cisapride in the treatment of dysmotility-like functional dyspepsia: a randomized, double-masked trial. Clin Gastroenterol Hepatol 2004; 84 Kanaizumi T, Nakano H, Matsui Y, Ishikawa H, Shimizu R, Park S, Kuriya N. Prokinetic effect of AS-4370 on gastric emptying in healthy adults. Eur J Clin Pharmacol 1991; 41: 335-337 PubMed DOI 85 Potet F, Bouyssou T, Escande D, Baro I. Gastrointestinal prokinetic drugs have different affinity for the human cardiac human ether-a-gogo K(+) channel. J Pharmacol Exp Ther 2001; 299: 1007-1012 PubMed 86 Pasha SF, Lunsford TN, Lennon VA. Autoimmune gastrointestinal dysmotility treated successfully with pyridostigmine. Gastroenterology 2006; 131: 1592-1596 PubMed DOI 87 Ueki S, Seiki M, Yoneta T, Aita H, Chaki K, Hori Y, Morita H, Tagashira E, Itoh Z. Gastroprokinetic activity of nizatidine, a new H2-receptor antagonist, and its possible mechanism of action in dogs and rats. J Pharmacol Exp Ther 1993; 264: 152-157 PubMed 88 Scarpignato C, Kisfalvi I, D'Amato M, Varga G. Effect of dexloxiglumide and spiroglumide, two new CCK-receptor antagonists, on gastric emptying and secretion in the rat: evaluation of their receptor selectivity in vivo. Aliment Pharmacol Ther 1996; 10: 411-419 PubMed DOI 89 Watkins CC, Sawa A, Jaffrey S, Blackshaw S, Barrow RK, Snyder SH, Ferris CD. Insulin restores neuronal nitric oxide synthase expression and function that is lost in diabetic gastropathy. J Clin Invest 2000; 106: 373-384 PubMed DOI 90 Coleski R, Gonlachanvit S, Owyang C, Hasler WL. Selective reversal of hyperglycemia-evoked gastric myoelectric dysrhythmias by nitrergic stimulation in healthy humans. J Pharmacol Exp Ther 2005; 312: 103-111 PubMed DOI 91 Sarnelli G, Sifrim D, Janssens J, Tack J. Influence of sildenafil on gastric sensorimotor function in humans. Am J Physiol Gastrointest Liver Physiol 2004; 287: G988-G992 PubMed DOI 92 Bortolotti M, Mari C, Lopilato C, La Rovere L, Miglioli M. Sildenafil inhibits gastroduodenal motility. Aliment Pharmacol Ther 2001; 15: 157-161 PubMed DOI 93 Netzer P, Gaia C, Lourens ST, Reber P, Wildi S, Noelpp U, Ritter EP, Ledermann H, Luscher D, Varga L, Kinser JA, Buchler MW, Scheurer U. Does intravenous ondansetron affect gastric emptying of a solid meal, gastric electrical activity or blood hormone levels in healthy volunteers? Aliment Pharmacol Ther 2002; 16: 119-127 PubMed DOI 94 Nielsen OH, Hvid-Jacobsen K, Lund P, Langoholz E. Gastric emptying and subjective symptoms of nausea: lack of effects of a 5-hydroxytryptamine-3 antagonist ondansetron on gastric emptying in patients with gastric stasis syndrome. Digestion 1990; 46: 89-96 PubMed 95 Loldrup D, Langemark M, Hansen HJ, Olesen J, Bech P. Clomipramine and mianserin in chronic idiopathic pain syndrome. A placebo controlled study. Psychopharmacology (Berl) 1989; 99: 1-7 PubMed DOI 96 Mertz H, Fass R, Kodner A, Yan-Go F, Fullerton S, Mayer EA. Effect of amitriptyline on symptoms, sleep, and visceral perception in patients with functional dyspepsia. Am J Gastroenterol 1998; 93: 160-165 PubMed DOI 97 Sawhney MS, Prakash C, Lustman PJ, Clouse RE. Tricyclic antidepressants for chronic vomiting in diabetic patients. Dig Dis Sci 2007; 52: 418-424 PubMed DOI 98 Dando TM, Perry CM. Aprepitant: a review of its use in the prevention of chemotherapy-induced nausea and vomiting. Drugs 2004; 64: 777-794 PubMed DOI 99 Diemunsch P, Schoeffler P, Bryssine B, Cheli-Muller LE, Lees J, McQuade BA, Spraggs CF. Antiemetic activity of the NK1 receptor antagonist GR205171 in the treatment of established postoperative nausea and vomiting after major gynaecological surgery. Br J Anaesth 1999; 82: 274-276 PubMed 100 De Giorgio R, Barbara G, Stanghellini V, Cogliandro RF, Arrigoni A, Santini D, Ceccarelli C, Salvioli B, Rossini FP, Corinaldesi R. Idiopathic myenteric ganglionitis underlying intractable vomiting in a young adult. Eur J Gastroenterol Hepatol 2000; 12: 613-616 PubMed 101 Gupta YK, Sharma M. Reversal of pyrogallol-induced delay in gastric emptying in rats by ginger (Zingiber officinale). Methods Find Exp Clin Pharmacol 2001; 23: 501-503 PubMed DOI 102 Gonlachanvit S, Chen YH, Hasler WL, Sun WM, Owyang C. Ginger reduces hyperglycemia-evoked gastric dysrhythmias in healthy humans: possible role of endogenous prostaglandins. J Pharmacol Exp Ther 2003; 307: 1098-1103 103 Wang L. Clinical observation on acupuncture treatment in 35 cases of diabetic gastroparesis. J Tradit Chin Med 2004; 24: 163-165 PubMed 104 Tack J, Piessevaux H, Coulie B, Caenepeel P, Janssens J. Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology 1998; 115: 1346-1352 PubMed DOI 105 Tack J, Broekaert D, Coulie B, Fischler B, Janssens J. Influence of the selective serotonin re-uptake inhibitor, paroxetine, on gastric sensorimotor function in humans. Aliment Pharmacol Ther 2003; 17: 603-608 PubMed DOI 106 Coulie B, Tack J, Sifrim D, Andrioli A, Janssens J. Role of nitric oxide in fasting gastric fundus tone and in 5-HT1 receptor-mediated relaxation of gastric fundus. Am J Physiol 1999; 276: G373-G377 PubMed 107 Hasler WL. Gastroparesis: symptoms, evaluation, and treatment. Gastroenterol Clin North Am 2007; 36: 619-647, ix 108 Hasler WL, Soudah HC, Dulai G, Owyang C. Mediation of hyperglycemia-evoked gastric slow-wave dysrhythmias by endogenous prostaglandins. Gastroenterology 1995; 108: 727-736 PubMed DOI 109 Gorelick AB, Koshy SS, Hooper FG, Bennett TC, Chey WD, Hasler WL. Differential effects of amitriptyline on perception of somatic and visceral stimulation in healthy humans. Am J Physiol 1998; 275: G460-G466 PubMed 110 Chial HJ, Camilleri M, Ferber I, Delgado-Aros S, Burton D, McKinzie S, Zinsmeister AR. Effects of venlafaxine, buspirone, and placebo on colonic sensorimotor functions in healthy humans. Clin Gastroenterol Hepatol 2003; 1: 211-218 111 Gorard DA, Libby GW, Farthing MJ. 5-Hydroxytryptamine and human small intestinal motility: effect of inhibiting 5- hydroxytryptamine reuptake. Gut 1994; 35: 496-500 PubMed DOI 112 Lacy BE, Crowell MD, Schettler-Duncan A, Mathis C, Pasricha PJ. The treatment of diabetic gastroparesis with botulinum toxin injection of the pylorus. Diabetes Care 2004; 27: 2341-2347 PubMed DOI 113 Arts J, van Gool S, Caenepeel P, Verbeke K, Janssens J, Tack J. Influence of intrapyloric botulinum toxin injection on gastric emptying and meal-related symptoms in gastroparesis patients. Aliment Pharmacol Ther 2006; 24: 661-667 114 Gupta P, Rao SS. Attenuation of isolated pyloric pressure waves in gastroparesis in response to botulinum toxin injection: a case report. Gastrointest Endosc 2002; 56: 770-772 PubMed DOI 115 Bromer MQ, Friedenberg F, Miller LS, Fisher RS, Swartz K, Parkman HP. Endoscopic pyloric injection of botulinum toxin A for the treatment of refractory gastroparesis. Gastrointest Endosc 2005; 61: 833-839 PubMed DOI 116 Arts J, Holvoet L, Caenepeel P, Bisschops R, Sifrim D, Verbeke K, Janssens J, Tack J. Clinical trial: a randomized- controlled crossover study of intrapyloric injection of botulinum toxin in gastroparesis. Aliment Pharmacol Ther 2007; 26: 1251-1258 PubMed 117 Friedenberg FK, Palit A, Parkman HP, Hanlon A, Nelson DB. Botulinum toxin A for the treatment of delayed gastric emptying. Am J Gastroenterol 2008; 103: 416-423 PubMed DOI 118 Jones MP, Maganti K. A systematic review of surgical therapy for gastroparesis. Am J Gastroenterol 2003; 98: 2122- 119 Abell T, McCallum R, Hocking M, Koch K, Abrahamsson H, Leblanc I, Lindberg G, Konturek J, Nowak T, Quigley EM, Tougas G, Starkebaum W. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 2003; 120 Lin Z, Forster J, Sarosiek I, McCallum RW. Treatment of diabetic gastroparesis by high-frequency gastric electrical stimulation. Diabetes Care 2004; 27: 1071-1076 PubMed DOI 121 McCallum RW, Dusing RW, Sarosiek I, Cocjin J, Forster J, Lin Z. Mechanisms of high-frequency electrical stimulation of the stomach in gastroparetic patients. Conf Proc IEEE Eng Med Biol Soc 2006; 1: 5400-5403 PubMed DOI 122 McCallum R, Lin Z, Wetzel P, Sarosiek I, Forster J. Clinical response to gastric electrical stimulation in patients with postsurgical gastroparesis. Clin Gastroenterol Hepatol 2005; 3: 49-54 PubMed DOI 123 Abell TL, Van Cutsem E, Abrahamsson H, Huizinga JD, Konturek JW, Galmiche JP, VoelIer G, Filez L, Everts B, Waterfall WE, Domschke W, Bruley des Varannes S, Familoni BO, Bourgeois IM, Janssens J, Tougas G. Gastric electrical stimulation in intractable symptomatic gastroparesis. Digestion 2002; 66: 204-212 PubMed DOI 124 Abell T, Lou J, Tabbaa M, Batista O, Malinowski S, Al-Juburi A. Gastric electrical stimulation for gastroparesis improves nutritional parameters at short, intermediate, and long-term follow-up. JPEN J Parenter Enteral Nutr 2003; 27: 277-281 125 Lin Z, Sarosiek I, Forster J, McCallum RW. Symptom responses, long-term outcomes and adverse events beyond 3 years of high-frequency gastric electrical stimulation for gastroparesis. Neurogastroenterol Motil 2006; 18: 18-27 PubMed DOI 126 Maranki JL, Lytes V, Meilahn JE, Harbison S, Friedenberg FK, Fisher RS, Parkman HP. Predictive factors for clinical improvement with Enterra gastric electric stimulation treatment for refractory gastroparesis. Dig Dis Sci 2008; 53: 2072- 2078 PubMed 127 Ayinala S, Batista O, Goyal A, Al-Juburi A, Abidi N, Familoni B, Abell T. Temporary gastric electrical stimulation with orally or PEG-placed electrodes in patients with drug refractory gastroparesis. Gastrointest Endosc 2005; 61: 455-461 128 Forstner-Barthell AW, Murr MM, Nitecki S, Camilleri M, Prather CM, Kelly KA, Sarr MG. Near-total completion gastrectomy for severe postvagotomy gastric stasis: analysis of early and long-term results in 62 patients. J Gastrointest Surg 1999; 3: 15-21, discussion 21-23 PubMed DOI 129 Murat A, Pouliquen B, Cantarovich D, Lucas B, Bizais Y, Vecchierini MF, Charbonnel B, Galmiche JP, Soulillou JP. Gastric emptying improvement after simultaneous segmental pancreas and kidney transplantation. Transplant Proc 1992; 24: 855 PubMed 130 Hathaway DK, Abell T, Cardoso S, Hartwig MS, el Gebely S, Gaber AO. Improvement in autonomic and gastric function following pancreas-kidney versus kidney-alone transplantation and the correlation with quality of life. Transplantation
S- Editor Cheng JX L- Editor Stewart GJ E- Editor Yin DH
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