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GASTROENTEROLOGY 2004;127:1592–1622

merican Gastroenterological Association Technical Review onhe Diagnosis and Treatment of Gastroparesis

his literature review and the recommendations herein were prepared for the American Gastroenterological Association Clinicalractice Committee. The paper was approved by the Committee on May 16, 2004, and by the AGA Governing Board on September
3, 2004.
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ormal gastric emptying reflects a coordinated effortbetween different regions of the stomach and the

uodenum as well as extrinsic modulation by centralervous system (CNS) and distal gut factors. Importantvents related to normal gastric emptying include fundicelaxation to accommodate food, antral contractions forrituration of large food particles, pyloric relaxation tollow food to exit the stomach, and antropyloroduodenaloordination of motor events. Gastric dysmotility in-ludes delayed gastric emptying (gastroparesis), rapidastric emptying (as seen in dumping syndrome), andther motor dysfunctions such as impaired fundic dis-ention most commonly found in functional dyspepsia.he importance of gastric dysrhythmias has not beenlearly defined. Disorders of gastric motility may presentith a spectrum of symptoms of variable severity. This

echnical review systematically assesses the clinical re-earch literature and formulates recommendations for theiagnosis and management of patients with gastropare-is. The published peer-reviewed literature on gastropa-esis was searched on PubMed using the key wordsastroparesis, gastric motility, and gastric dysmotility.eferenced articles from published manuscripts, book

hapters, and recent abstracts from national and interna-ional meetings were included in this review.

Symptoms and ClinicalPresentation of Gastroparesis

Gastroparesis is a symptomatic chronic disorder ofhe stomach characterized by delayed gastric emptying inhe absence of mechanical obstruction. Symptoms ofastroparesis are variable and include early satiety, nau-ea, vomiting, bloating, and upper abdominal discom-ort. In 146 patients with gastroparesis, nausea wasresent in 92%, vomiting in 84%, abdominal bloatingn 75%, and early satiety in 60%.1 Complications ofastroparesis may contribute to patient morbidity andnclude esophagitis, Mallory–Weiss tear, and vegetable-aden bezoars.2,3

Symptoms of gastroparesis are nonspecific and may
imic structural disorders such as ulcer disease, partial
astric or small bowel obstruction, gastric cancer, andancreaticobiliary disorders.2 There also is an overlapetween the symptoms of gastroparesis and functionalyspepsia. Functional dyspepsia is characterized byhronic or recurrent upper abdominal discomfort; how-ver, many individuals report symptoms of dysmotility,ncluding nausea, vomiting, and early satiety, and sub-ets of patients with functional dyspepsia exhibit delaysn gastric emptying.4,5 Indeed, idiopathic gastroparesisan be considered one of the causes of functional dyspep-ia. Recently, a quantitative instrument for gastroparesis-elated symptoms has been validated.6

Symptom correlation with delayed gastric emptying isariable for diabetic gastropathy, idiopathic gastropare-is, and functional dyspepsia.7–9 In recent studies, earlyatiety, postprandial fullness, and vomiting have beeneported to predict delayed emptying in patients withunctional dyspepsia.4,5 In patients with diabetes, ab-ominal fullness and bloating were found to predictelayed gastric emptying.10 In some drug trials of pro-inetic agents, the correlation between symptom im-rovement and acceleration of gastric emptying has beenoor. In contrast, cisapride was reported to reduce epi-astric pressure and bloating in association with im-roved emptying.11 In individuals with symptoms ofastroparesis who have normal rates of gastric emptying,ther motor, myoelectric, or sensory abnormalities maylicit symptoms.

Abdominal discomfort or pain is present in 46%–9% of patients with gastroparesis but is usually not theredominant symptom, in contrast to its prominence inunctional dyspepsia.1,12 Abdominal pain in gastroparesisesponds poorly to treatment of gastroparesis.12 Patientsith functional dyspepsia exhibit heightened sensitivity

o gastric distention suggestive of afferent neural dys-

Abbreviations used in this paper: CMV, cytomegalovirus; CNS, cen-ral nervous system; EGG, electrogastrography; FDA, Food and Drugdministration; GERD, gastroesophageal reflux disease; MMC, migrat-

ng motor complex.© 2004 by the American Gastroenterological Association

0016-5085/04/$30.00
doi:10.1053/j.gastro.2004.09.055

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November 2004 AMERICAN GASTROENTEROLOGICAL ASSOCIATION 1593

unction as a contributor to symptom pathogenesis.13

imilarly, in diabetic patients with dyspeptic symptoms,astric distention elicits exaggerated nausea, bloating,nd abdominal discomfort, suggesting that sensory nerveysfunction may participate in symptom genesis in someatients with gastroparesis.14

The majority of patients with gastroparesis areomen. In one large investigation, 82% of gastropareticatients were female.1 Women tend to exhibit slowermptying rates than men, especially during the laterortion of the menstrual cycle (the luteal phase).15,16 It iselieved that gastric muscle contractility is reduced byrogesterone.The prevalence and socioeconomic impact of gastro-

aresis are difficult to estimate due to the incompleteorrelation of symptoms with gastric emptying and thepparently higher prevalence of the disorder in academicedical centers than in the community. Most popula-

ion-based studies in patient subsets at risk for develop-ent of gastroparesis have focused on symptoms rather

han gastric scintigraphy findings. In such investiga-ions, 11%–18% of individuals with diabetes reportymptoms consistent with upper gastrointestinal dysmo-ility such as nausea and vomiting.17,18 However, therevalence of gastroparesis, as assessed by gastric empty-ng studies, in randomly selected patients in a diabeteslinic at an academic medical center was 48%.10 Usingalidated questionnaires, investigators have reported thatymptoms of gastroparesis are associated with reduceduality of life both in diabetic patients and in commu-ity populations.19,20

Health care expenditures for care of gastroparesis areignificant. In an analysis of the 1998 North Carolinaospital Discharge database, there were 45 admissionsith a primary diagnosis of diabetic gastroparesis and an

dditional 1431 admissions for diabetic patients inhich gastroparesis was a contributing factor to the need

or hospitalization.21 The average hospital stay in thistudy was 5 days. In an unpublished study of patientsith severe gastroparesis, health care costs from gastro-aresis were estimated to average $6972 per patient peronth.22 Most expenditures in this study were attrib-

ted to requirements for hospitalization and temporaryr long-term use of intravenous hyperalimentation. Di-gnostic testing in patients with presumed gastroparesiss associated with significant costs, especially from per-ormance of endoscopy and gastric emptying scintigra-hy. For some less well-established diagnostic modalitieserformed in referral centers (eg, antroduodenal manom-try, electrogastrography [EGG]), reimbursement fromhird-party payers may be difficult to obtain despite the
ecent granting of procedure codes.23 Similarly, novel w
reatments for patients with refractory gastroparesis (eg,yloric injection of botulinum toxin, gastric electricaltimulation) have been considered experimental by somensurers and reimbursement has been denied.

Evaluation of Patients WithSuspected Gastroparesis

Overview of Diagnostic Approach

Gastroparesis is diagnosed by demonstrating de-ayed gastric emptying in a symptomatic individual afterxclusion of other potential etiologies of symptoms (Ta-le 1). Gastroparesis is often suspected in patient sub-roups with specific profiles. Typical symptoms in anndividual with long-standing type 1 diabetes mellitusuggest diabetic gastroparesis, whereas similar symptomsn a young woman are consistent with idiopathic gastro-aresis. A diagnosis of functional dyspepsia may be en-ertained if pain is the dominant symptom, whereasoexistent defecation abnormalities suggest the possibil-ty of irritable bowel syndrome. Delayed gastric empty-ng may develop after abdominal surgery, especially ifhe vagus nerve has been damaged. Vomiting associated

able 1. Evaluation of Patients Suspected to HaveGastroparesis

. Initial investigationA. History and physical examinationB. Blood tests

Complete blood countComplete metabolic profile, including glucose, potassium,

creatinine, total protein, albumin, calciumAmylase, if abdominal pain is significant symptomPregnancy test, if appropriate

C. Abdominal obstruction series, if vomiting or pain is acute orsevere

. Evaluate for organic disordersA. Upper endoscopy to evaluate for mechanical obstruction or

mucosal lesions (alternative: barium upper gastrointestinalseries, often with small bowel follow-through)

B. Biliary ultrasonography if abdominal pain is a significantsymptom

. Evaluate for delayed gastric emptyingA. Solid-phase gastric emptying testB. Screen for secondary causes of gastroparesis

Thyroid function tests (thyroid-stimulating hormone)Rheumatologic serologies (eg, antinuclear antibody,

scleroderma antibody [Scl70])Glycosylated hemoglobin (HbA1C)

. Treatment trial with prokinetic agent and/or antiemetic agent

. If no clinical response, consider further investigationA. EGGB. Antroduodenal manometryC. Small bowel evaluation with enteroclysis or small bowel follow-

throughD. Further laboratory tests, if indicated

ANNA, tissue transglutaminase antibody

ith gastroparesis must be differentiated from regurgi-

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1594 AMERICAN GASTROENTEROLOGICAL ASSOCIATION GASTROENTEROLOGY Vol. 127, No. 5

ation due to gastroesophageal reflux disease (GERD) orumination syndrome, episodic vomiting in cyclic vom-ting syndrome, self-induced vomiting with bulimia, andbdominal pain and vomiting in superior mesentericrtery syndrome. Patients with long-standing, severeymptoms of gastroparesis may appear dehydrated oralnourished. A succussion splash, detected by auscul-

ation over the epigastrium while moving the patientide to side or rapidly palpating the epigastrium, indi-ates excessive fluid in the stomach from gastroparesis orechanical gastric outlet obstruction.24

Most individuals suspected to have gastroparesis re-uire upper endoscopy or a radiographic upper gastroin-estinal series to exclude mechanical obstruction or ulcerisease. Mechanical gastric outlet obstruction can beaused by pyloric stenosis, neoplasia, or active ulcerisease in the duodenum, pyloric channel, or prepyloricntrum. The presence of retained food in the stomachfter overnight fasting without obstruction is suggestivef gastroparesis. Bezoars may develop in severe cases.ndoscopy is more sensitive for detection of mucosal

esions than barium radiography.24 Double-contrastechniques have increased the sensitivity of radiologictudies. Contrast radiography of the small intestine iserformed in those patients with refractory symptoms,hose with symptoms suggestive of a small bowel etiol-gy (eg, profound distention, steatorrhea, feculent eme-is), or those who exhibit dilated small bowel loops onlain radiography. When upper gastrointestinal radiog-aphy is ordered, a small bowel follow-through can bencluded to screen for small bowel lesions. The smallowel follow-through is accurate for detection of high-rade small bowel obstruction, usually provides an ade-uate assessment of the terminal ileum, and may rarelyuggest superior mesenteric artery syndrome. Enterocly-is (small bowel enema), obtained after placement of aasoduodenal or oroduodenal tube, provides double-con-rast images and is more accurate in detecting smallntestinal mucosal lesions, mild to intermediate grades ofbstruction, and small bowel neoplasia.25 Computed to-ographic scanning with oral and intravenous contrastay also be useful for detection and localization of

ntestinal obstruction.After exclusion of mechanical disease of the stomach

nd small bowel, determination of the rate of gastricmptying of solid foods is usually obtained using scin-igraphy. An abnormal gastric emptying test result sug-ests but does not prove that symptoms are caused byastroparesis. If gastric emptying is normal, other causesor symptoms should be considered. However, a disorderf gastric motor function cannot be dismissed in symp-
omatic patients with normal gastric emptying because p
egional dysfunctions of the stomach, including impairedundic relaxation or gastric myoelectric dysrhythmias,ay be associated with symptoms.26

Other testing to complement the finding of delayedastric emptying includes thyroid chemistries to rule outypothyroidism, glycosylated hemoglobin levels to assessong-term glycemic control in diabetic patients, andther blood tests to screen for rheumatologic disorders,euromuscular conditions, or paraneoplastic phenomena.diopathic gastroparesis is diagnosed after other causesre excluded.

Evaluation of Gastric Emptying, MotorFunction, and Myoelectric Activity

Several methods have been proposed for quantifi-ation of gastric emptying, motor function, and myo-lectric activity (Table 2).

Radiographic contrast techniques. The upperastrointestinal barium series is an insensitive methodor measuring gastric emptying because it is difficult touantitate the relative fraction of contrast delivered tohe intestine and because barium is not a “physiologic”est meal.27 Nevertheless, gastric retention may be sug-ested by poor emptying of barium from the stomach,astric dilation, and the presence of retained food or aastric bezoar. Little or no emptying of barium at 30inutes and retention of gastric barium at 6 hours are

uggestive of gastroparesis.28 The greatest value of bar-um radiography lies in the exclusion of mucosal lesionsnd mechanical outlet obstruction.

Gastric emptying scintigraphy. Gastric emptyingcintigraphy of a solid-phase meal is considered the goldtandard for the diagnosis of gastroparesis because thisest quantifies the emptying of a physiologic caloriceal. Measurement of gastric emptying of solids is more

ensitive for detection of gastroparesis because liquidmptying may remain normal even in patients withdvanced disease. Liquid-phase emptying scans are moreommonly performed after gastric surgery in patientsuspected of having dumping syndrome. The usefulnessf gastric scintigraphy in directing therapy and predict-ng response has been debated.11,29 Some clinicians haveroposed performance of dual solid- and liquid-emptyingcintigraphy in patients who have undergone gastricurgery to determine if symptoms might result fromelayed solid emptying or rapid liquid emptying.For solid-phase testing, most centers use a 99mTc sul-

ur colloid–labeled egg sandwich as a test meal.27 Moreecently, a meal using Eggbeaters egg whites (ConAgraoods, Inc, Downers, IL) with standard imaging at 0, 1,, and 4 hours postprandially has been proposed to
rovide a degree of standardization between different

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enters.30 This test meal has a very low fat content andheoretically might produce different results than con-entional meals. Whatever meal is used, the radiolabeleeds to be cooked into it to ensure radioisotope bindingo the solid phase. This prevents elution of the radio-racer into the liquid phase, which might produce anrroneous measurement of the faster liquid-phase gastricmptying.31 Scintigraphic assessment of emptyinghould be extended to at least 2 hours after meal inges-ion. Even with extension of the scintigraphic study tohis length, there may be significant day-to-day variabil-ty (up to 20%) in rates of gastric emptying.32 Forhorter durations, the test is less reliable due to largerariations of normal gastric emptying. Extending scin-igraphy to 4 hours has been advocated by some inves-igators to improve the accuracy in determining theresence of gastroparesis.33,34

Emptying of solids typically exhibits a lag phase fol-owed by a prolonged linear emptying phase. A variety ofarameters can be calculated from the emptying profilef a radiolabeled meal. The simplest approach for inter-reting a gastric emptying study is to report the percentetention at defined times after meal ingestion (usually 2nd 4 hours). The half emptying time also may bealculated; however, extrapolation of the emptying curve

able 2. Tests to Assess Gastric Motor and Myoelectrical Fu

Ad

ests assessing gastric emptyingUpper gastrointestinal barium radiographic

studyAssess for muco

Scintigraphy Gold standardNoninvasiveAble to assess s

Breath tests using 13C Noninvasive

Ultrasonography for serial changes inantral area

NoninvasivePhysiologic

Magnetic resonance imaging Noninvasive

ests assessing gastric contractile activityAntroduodenal manometry Assesses contrac

postprandial peGastric barostat Measures proxim

and contractionests assessing gastric myoelectrical activityEGG Noninvasive

ests assessing gastric accommodationGastric barostat Measures proxim

accommodatio

Satiety test Measures combinaccommodatio

dapted from Quigley et al24 and Hasler WL, Koch KL. Diabetic gastr

rom an individual who did not empty 50% of the c

ngested meal during the actual imaging time may pro-ide an inaccurate determination of the half emptyingime.35

Patients should discontinue medications that may af-ect gastric emptying for an adequate period before thisest based on drug half-life (Table 3). For most medica-ions, this will be 48–72 hours. Opiate analgesics andnticholinergic agents delay gastric emptying. Proki-etic agents that accelerate emptying may give a falselyormal gastric emptying result. Serotonin receptor an-agonists such as ondansetron, which have little effect onastric emptying, may be given for severe symptomsefore performance of gastric scintigraphy. Hyperglyce-ia (glucose level �270 mg/dL) delays gastric emptying

n diabetic patients.26 It is not unreasonable to deferastric emptying testing until relative euglycemia ischieved to obtain a reliable determination of emptyingarameters in the absence of acute metabolic derange-ent. Premenopausal women have slower gastric emp-

ying than men,15,16 so some advocate using separateeference values for premenopausal women.4

Breath testing for gastroparesis. Breath tests us-ng the nonradioactive isotope 13C bound to a digestibleubstance have been validated for measuring gastric emp-ying. Most commonly, 13C-labeled octanoate, a medium-

n

ges Disadvantages

sions NonphysiologicRadiation exposure (moderate)

nd liquid emptying

Radiation exposure (minimal)

Need normal small intestinal absorption,liver metabolism, pulmonary excretion

Requires expertise for imaging andinterpretation

Primarily measures liquid emptyingExpensive, time consumingNeed specialized centers and software

in fasting and InvasiveNeed expertise to perform and interpret

mach relaxation InvasiveResearch technique

Movement artifact may make recordingdifficult to interpret

machponse

InvasiveResearch techniqueBalloon may interfere with accommodation

ofsensitivity

SimpleNot well standardized or accepted

sis. AGA Postgraduate Course, May 19–20, 2001.

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uffin.36–38 Other studies have bound 13C to acetate oro proteinaceous algae (Spirulina).31 After ingestion andtomach emptying, 13C-octanoate is absorbed in themall intestine and metabolized to 13CO2, which is thenxpelled from the lungs during respiration. The rate-imiting step is the rate of solid gastric emptying. Thus,ctanoate breath testing provides a measure of solid-hase emptying. The octanoate breath test provides re-roducible results that correlate with findings on gastricmptying scintigraphy.36–38 13C breath tests do not useonizing radiation and can be used to test patients in theommunity or even at the bedside, where gamma cameraacilities are not readily available. Breath samples can bereserved and shipped to a laboratory for analysis. Mostctanoate breath testing is performed for clinical researchnd pharmaceutical studies. The penetrance of this diag-ostic modality into clinical practice has been limited.alidation of this test in patients with emphysema,

irrhosis, celiac sprue, and pancreatic insufficiency iseeded, because rates of octanoate metabolism may bempaired in these disorders.

EGG. EGG records gastric myoelectrical activity,nown as the slow wave, using cutaneous electrodesffixed to the anterior abdomen overlying the stomach.39

able 3. Medications That Affect Gastric Emptying

Delay gastric emptyingOpioid analgesicsAnticholinergic agentsTricyclic antidepressantsCalcium channel blockersProgesteroneOctreotideProton pump inhibitorsH2-receptor antagonistsInterferon alfaL-dopaFiberSucralfateAluminum hydroxide antacids�-adrenergic receptor agonistsGlucagonCalcitoninDexfenfluramineDiphenhydramineAlcoholTobacco/nicotineTetrahydrocannabinol

Accelerate gastric emptyingProkinetic agents

MetoclopramideErythromycin/clarithromycinCisaprideDomperidoneTegaserod

�-adrenergic receptor antagonists

he slow wave is responsible for controlling the maximal o

requency and the controlled aboral propagation of distalastric contractions. The normal gastric slow wave fre-uency is approximately 3 cpm. Meal ingestion increaseshe amplitude of the EGG signal, which is believed toesult either from increased antral contractility or fromechanical distention of the stomach. EGG testing

uantifies the dominant frequency and regularity of gas-ric myoelectrical activity, quantifies the percentage ofime in which abnormal slow wave rhythms are presenturing fasting and postprandially, and assesses the in-rease in amplitude (or power) after a meal.35 In general,n abnormal EGG is defined when the percent time inysrhythmias exceeds 30% of the recording time and/orhen meal ingestion fails to elicit an increase in signal

mplitude.40

Gastric dysrhythmias (tachygastria, bradygastria) andecreased EGG amplitude responses to meal ingestionave been characterized in patients with idiopathic andiabetic gastroparesis.41 Gastric myoelectric abnormali-ies also have been described in patients with unex-lained nausea and vomiting, motion sickness, and nau-ea and vomiting of pregnancy.35 EGG abnormalities areresent in 75% of patients with gastroparesis versus 25%f symptomatic patients with normal gastric emptying.40

ome investigators suggest that EGG abnormalities andelayed gastric emptying may define slightly differentatient populations with dyspeptic symptoms.42 Symp-omatic responses to antiemetic or prokinetic drug treat-ents have correlated better with resolution of gastric

ysrhythmias than acceleration of delayed emptying inome patient subsets.8 Hyperglycemia may provoke dys-hythmias in diabetic patients.43

Clinically, EGG has been used to demonstrate gastricyoelectric abnormalities in patients with unexplained

ausea and vomiting or functional dyspepsia. EGG isonsidered an adjunct to gastric emptying scintigraphys part of a comprehensive evaluation of patients withefractory symptoms suggestive of an upper gastrointes-inal motility disorder.35,40 However, to date, there haseen little investigation to validate the utility of EGG inhe management of patients with suspected gastricysmotility.

Antroduodenal manometry. Antroduodenal ma-ometry provides information about gastric and duode-al motor function in both fasting and postprandialeriods.35,44 Manometry may be performed in stationaryettings over a 5- to 8-hour period or in ambulatoryashion over 24 hours using solid-state transducers. Am-ulatory studies afford the advantage of correlatingymptoms with abnormal motor patterns; however, cath-ter migration in these studies may limit interpretation
f gastric motility. Rather, ambulatory manometry is

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est reserved for characterization of duodenal motorunction. The proposed indications for antroduodenalanometry include (1) characterization of motor dys-

unction in patients with unexplained nausea and vom-ting, (2) delineation of the cause of gastric or smallowel stasis (eg, visceral neuropathy or myopathy), and3) support of a suspected diagnosis of chronic intestinalseudo-obstruction.35

Distinct gastrointestinal motor patterns are present inhe interdigestive (fasting) and digestive (fed) periods.he interdigestive (fasting) pattern consists of 3 cyclicalhases known as the migrating motor complex (MMC)hat recur at approximately 2-hour intervals unless in-errupted by a meal. Phase I is a period of motor quies-ence that is followed by a period of intermittent phasicontractions (phase II). The MMC culminates in a burstf regular rhythmic contractions that propagate from thentrum through the proximal small intestine (phase III,ctivity front). The intense propulsive contractions dur-ng phase III have been considered to be a physiologicintestinal housekeeper” and are responsible for clearancef dietary fiber and indigestible solids from the upperut. Feeding disrupts the MMC and replaces it with a fedotor pattern of more regular antral and duodenal con-

ractions of variable amplitude that may be either seg-ental or propagative in character.In gastroparesis, antroduodenal manometry may ex-

ibit a decreased frequency/force of antral contractionsnd origination of most phase III complexes in theuodenum. In some individuals, increased tonic andhasic activity of the pylorus (“pylorospasm”) or irregularursts of small intestinal contractions may be observed.45

urthermore, the prevalence of concomitant small intes-inal motor dysfunction in patients with gastroparesisanges from 17% to 85% in different studies.46,47

ntroduodenal manometry can help confirm or excluden underlying dysmotility syndrome when results ofastric emptying testing are normal or borderline. Withn accurate stationary recording, reductions in the post-randial distal antral motility index correlate with im-aired gastric emptying of solids.48 Normal findings onanometry coupled with a normal transit test result

trongly suggest that antral motor dysfunction is not theause of symptoms.35

Antroduodenal manometry may differentiate betweenmall intestinal neuropathic and myopathic disease anday suggest unsuspected small bowel obstruction or a

umination syndrome.35,49 Myopathic disorders, such ascleroderma or amyloidosis, produce contractile activityf abnormally low amplitude, whereas neuropathic con-itions are characterized by contractions of normal am-
litude with abnormal propagation, including loss of t
ntestinal phase III, random bursts, and failure of con-ersion to the fed pattern after meal ingestion. Occultechanical obstruction of the small intestine may be

uggested by 2 patterns of small bowel motor abnormal-ties: (1) postprandial clustered contractions for �30inutes’ duration separated by quiescence or (2) simul-

aneous prolonged (�8 seconds) or summated contrac-ions suggesting a common cavity phenomenon from ailated segment of intestine.50 In some patients withumination syndrome, antroduodenal manometry mayemonstrate a characteristic pattern of simultaneous con-ractions in all recording sites (R waves) secondary toncreases in intra-abdominal pressures from somatic mus-le activity, especially during the postprandial period.51

In pediatric studies, the absence of MMCs predicts aoor response to prokinetic agents.52 Some investigatorserform antroduodenal manometry with infusions ofrythromycin and/or octreotide to predict the patient’slinical response to long-term treatment with thesegents.53 Other studies have suggested that findings ofntroduodenal manometry may influence treatment de-isions in small numbers of patients (�20%) with dys-otility syndromes.54 Validation of manometry as a

ritical diagnostic test for managing patients with sus-ected gastric or small intestinal dysmotility isncomplete.

Other tests of gastric motor function. Severalther techniques for measuring gastric motor functionave been proposed.

Ultrasonography. Transabdominal ultrasonogra-hy measures several parameters of gastric motor func-ion. Serial changes in antral cross-sectional area canrovide an index of gastric emptying.55 Gastric empty-ng is considered complete when the antral area returnso the fasting baseline level. Duplex sonography canuantify transpyloric flow of liquid gastric contents.ltrasonography also has been used to measure accom-odation in the proximal stomach.31 Unfortunately, ul-

rasound determinations of gastric emptying are operatorependent and have proven reliable only for measure-ents of liquid emptying rates. Testing may be difficult

n obese individuals. As a consequence of these draw-acks, ultrasonography most commonly is used only inesearch settings.

Magnetic resonance imaging. Magnetic resonancemaging can measure gastric emptying and accommoda-ion using transaxial abdominal scans every 15 min-tes.31 Magnetic resonance imaging can differentiate be-ween gastric meal volume and total gastric volume,llowing determination of gastric secretory rates. Thisoninvasive, radiation-free test is appealing; however,
he specialized equipment, time needed for interpreta-

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ion, and expense have limited its use to clinical researchrimarily in European centers.

Single-photon emission computed tomography. Radio-uclide imaging of the gastric wall following the intra-enous injection of 99mTc pertechnetate, which localizesn the gastric mucosa, with subsequent single-photonmission computed tomography imaging has been useds a noninvasive measure of gastric accommodation.56 In2 patients with functional dyspepsia, single-photonmission computed tomography imaging after 99mTcertechnetate infusion suggested that impaired gastricccommodation (41%) may be detected more commonlyhan delayed emptying (9%) in dyspeptic patients re-erred to tertiary centers.57 The majority of dyspepticatients had normal emptying and accommodation.

Satiety testing. Satiety testing with symptom-lim-ted consumption of a test liquid has been proposed as aoninvasive technique to evaluate accommodation. Inhe water load test, the patient drinks water until he orhe feels very full.58 Other investigators have used nu-rient-containing test meals that are consumed at a fixedlow rate until satiety is achieved.59,60 Results of satietyesting correlate with the degree of gastric accommoda-ion as measured by a barostat. Satiety tests offer theotential to noninvasively evaluate for abnormalities ofastric accommodation and perhaps visceral sensitivity.31

o date, most studies have quantified defects in satiety inatients with functional dyspepsia. Investigations char-cterizing responses to satiety testing have not beeneported in patients with gastroparesis.

Disorders With Delayed GastricEmptying (Gastroparesis)

Gastroparesis occurs in many clinical settings;diopathic, diabetic, and postsurgical etiologies comprisehe majority of cases in most series. In one series of 146atients, gastroparesis was idiopathic in 36%, diabetic in9%, and postsurgical in 13% of patients.1 Several gas-rointestinal and systemic diseases are associated withastroparesis (Table 4). Selected individual disorders fre-uently referred to gastroenterologists for evaluation andanagement are discussed in the following text.

Diabetic Gastroparesis

Gastroparesis is a recognized complication of di-betes mellitus and is classically considered to occur inhose individuals with long-standing type 1 diabetesellitus and other associated complications such as ret-

nopathy, nephropathy, and peripheral neuropathy.any affected patients have associated findings of dys-

utonomia, including postural hypotension. Longitudi- t

al studies suggest that delayed gastric emptying isresent in 25%–55% of patients with type 1 diabetesellitus and is not correlated with nongastrointestinal

omplications.61,62 Gastroparesis has also been describedn approximately 30% of patients with type 2 diabetesellitus.7 However, highly variable rates of gastric emp-

ying, including acceleration of transit, have been re-orted in type 1 diabetes mellitus and type 2 diabetesellitus, suggesting that development of gastroparesis is

ot universal or inevitable.62,63 Many individuals withapid emptying have diabetes of relatively short dura-ion. In those with accelerated emptying, impairment ofundic receptive relaxation to meal ingestion may beathogenic of the motor defect.64 Gastroparesis tradi-ionally has been considered to confer a poor prognosisor affected diabetic patients; however, recent investiga-ions suggest that this may be incorrect.61

Clinical consequences of diabetic gastroparesis includenduction of gastrointestinal symptoms, alteration inrug absorption, and destabilization of glycemic con-

able 4. Etiology of Gastroparesis (Nonobstructive DelayedGastric Emptying)

diopathiciabetes mellitusostsurgicalPartial gastric resection/vagotomyPostbariatric surgeryNissen fundoplicationTransplantation: lung, heart-lung

astrointestinal disorders associated with delayed gastric emptyingDiffuse gastrointestinal motor disorders (eg, chronic intestinal

pseudo-obstruction)GERDAchalasiaGastric ulcerAtrophic gastritisFunctional dyspepsiaHypertrophic pyloric stenosisCeliac disease

ongastrointestinal disorders associated with delayed gastricemptying

Eating disorders: anorexiaNeurologic disorders

CNS tumorsParkinson’s disease

Collagen vascular disordersSclerodermaSystemic lupus erythematosusAmyloidosis

Endocrine and metabolic disordersThyroid dysfunctionParathyroid dysfunctionChronic renal insufficiency

Gastric infectionChronic mesenteric ischemiaTumor associated (paraneoplastic)Medication associated

rol.61 Symptoms in affected diabetic patients include

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ausea, vomiting, early satiety, fullness, and abdominaliscomfort. The presence of abdominal bloating andullness particularly seems to be associated with theagnitude of emptying delay.10 Symptom severity, how-

ver, does not necessarily correlate well with the degreef gastric stasis.7,65 Some patients with severe symptomsay have near-normal to normal emptying patterns. In

hese individuals, other abnormalities, including im-aired fundic relaxation, gastric slow wave dysrhythmias,r visceral hypersensitivity, may be potentially responsi-le for dyspeptic symptoms.7 The term “diabetic gas-ropathy” is commonly used because symptoms may notredict delays in gastric emptying and responses to pro-inetic treatment may not be consequences of acceleratedmptying.

Changes in gastric emptying may affect postprandiallood glucose concentrations. Delayed gastric emptyingontributes to poor glycemic control because of unpre-ictable delivery of food into the duodenum.66 Impairedastric emptying with continued administration of ex-genous insulin may produce hypoglycemia. Conversely,cceleration of emptying has been reported to causeyperglycemia.63 Problems with blood glucose controlay be the first indication that a diabetic patient is

eveloping gastroparesis.66 In type 1 diabetic patientsith gastroparesis, prokinetic therapy may potentiallyenefit glycemic control although this has not beenniversally observed.67–69 Long-term oral administrationf the prokinetic agents levosulpiride and erythromycinave decreased plasma glucose and glycosylated hemo-lobin levels in diabetic patients.70,71 However, studiesith cisapride suggested that long-term improvement inastric emptying had no effect on overall glycemic con-rol in patients with type 1 diabetes mellitus.72,73

Diabetic gastroparesis is likely to result from impairedeural control of gastric motility, possibly at the level ofhe vagus nerve. In one investigation, morphologic ab-ormalities of the gastric myenteric plexus or vagus iniabetic patients were not identified by conventionalistology,74 although abnormal myenteric neurotrans-ission involving both inhibitory and excitatory path-ays has been described in animal models of diabetes.onversely, in an older autopsy study of diabetic pa-

ients, inflammatory changes were observed in some au-onomic ganglia and dropout of vagal myelinated fibersas noted.75 Other factors, including impairment of the

nhibitory nitric oxide–containing nerves,76 damage ofhe pacemaker interstitial cells of Cajal,77 and underlyingmooth muscle dysfunction, have been described in an-mal models and patients with diabetic gastropare-is.78–80 In one study, selective loss of pyloric NO syn-
hase was shown to contribute to gastroparesis in an w
nimal model and was reversible by administration ofnsulin or agents that restore NO activity.81

Hyperglycemia alone also may reversibly affect gastricotility and reduce the effectiveness of prokinetic

gents. Hyperglycemia decreases antral contractility, de-reases antral phase III of the MMC, increases pyloricontractions, causes gastric dysrhythmias (primarilyachygastria), delays gastric emptying, and even modu-ates fundic relaxation properties.43,66 Normalization oferum glucose levels in hyperglycemic patients has beenhown to stabilize gastric myoelectric activity, improveastric emptying, and restore antral phase III activity.82

yperglycemia appears to cause a reversible impairmentf vagal efferent function.83 Glucose-responsive neuronsave been identified in the CNS that may modify vagalfferent activity.84 Prostaglandins may also be involved,ecause indomethacin can reverse abnormal gastric elec-rical rhythms that occur during hyperglycemia inealthy volunteers.85

Patients with type 1 diabetes mellitus also exhibitncreased perception of gastric distention, with exagger-ted nausea, fullness, and epigastric pain for a givenistending stimulus.14 In addition to its effects on motorunction, hyperglycemia increases nausea and fullnessuring proximal gastric distention.66,86 Increased sensi-ivity of the proximal stomach may be responsible forostprandial dyspeptic symptoms when the stomach isistended by a meal.14,86

Postsurgical Gastroparesis

Gastroparesis may occur as a complication of aumber of different surgical procedures. Historically,ost cases have resulted from performance of vagotomy

n concert with gastric drainage for medically refractoryeptic ulcer disease. More recently, with the advent ofaparoscopic techniques to treat GERD, more individualsre presenting with gastroparesis as a complication ofundoplication.

Postvagotomy gastroparesis. Postsurgical gastro-aresis is most often a consequence of peptic ulcer surgery,sually with concurrent performance of vagotomy.87 Theagus nerves regulate both meal-evoked fundic relaxationsnd phasic antral contractions. The effects of complete vagalenervation are to accelerate gastric emptying of liquids ando retard emptying of solids. To avert the gastropareticffects of vagotomy, most surgeons perform a gastric drain-ge procedure such as a pyloroplasty or gastroenterostomy.n most patients, the net result is that vagotomy combinedith a drainage procedure produces little alteration in gas-

ric emptying.Approximately 5% of patients undergoing vagotomy

ith antral resection and gastrojejunostomy develop se-

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ere postsurgical gastroparesis.87 In these individuals,he antrum is not present to triturate solids and theroximal stomach is unable to generate sufficient pres-ure to empty solid food residue.

The Roux-en-Y stasis syndrome is characterized byostprandial abdominal pain, bloating, nausea, and vom-ting.87 The combination of vagotomy, distal gastricesection, and Roux-en-Y gastrojejunostomy predisposeso severe gastric stasis as a result of both slow emptyingrom the gastric remnant and delayed small bowel transitn the denervated Roux efferent limb.87 Ectopic jejunalacemakers may develop in the transected and reattachedejunal segment. Furthermore, myoelectric and motorctivity in the Roux limb may be retrograde, causingeverse peristalsis toward the stomach and allowing theoux limb to cause a functional obstruction.88

Postfundoplication gastric motor dysfunction.ild acceleration of gastric emptying has been reported

o occur after Nissen fundoplication and has been attrib-ted to increased intragastric pressure due to preventionf fundic receptive relaxation from the mechanical effectsf the wrap.89,90 This is supported by regional scinti-raphic studies showing rapid proximal gastric emptyingfter fundoplication. These effects of fundoplication mayromote development of early satiety.90 In some patientsith reflux who have preexisting delayed gastric empty-

ng, fundoplication may normalize emptying.90

In other patients, early satiety, postprandial fullness,ausea, and vomiting develop after fundoplication as aonsequence of postprandial antral hypomotility or de-ayed gastric emptying.91–93 The delay in emptying mayave preceded the surgery but was unrecognized at theime of operation. The development of postoperativeastroparesis after an open Nissen fundoplication is un-ommon but at times may result in significant morbid-ty.93 Vagal nerve injury occurs in 4%–40% of patientsndergoing laparoscopic fundoplication.94,95 The gas-loat syndrome refers to postoperative gaseous symp-oms, including inability to belch, pain, and bloating.as bloat postoperatively occurs more often in patientsith preoperative delayed gastric emptying.96 Thus, pre-

xistent gastroparesis has been considered a relative con-raindication to performance of fundoplication forERD.

Postbariatric surgery. Surgical therapy for mor-id obesity has become popular over the past 5 years.ost operations are designed to restrict the size of the

tomach.97 The most commonly performed surgical pro-edure is the Roux-en-Y gastric bypass, in which thetomach is partitioned into a small proximal fundicouch and a bypassed distal stomach. A loop gastrojeju-
ostomy through a small gastroenterostomy drains the p
roximal pouch. With gastric bypass, induction of earlyatiety by the small gastric pouch precludes ingestion ofarge meals. Solid gastric emptying is slower and liquidmptying is more rapid after gastric bypass surgery.98

he gastrojejunostomy configuration also can produce aelative malabsorptive state and promotes dumping syn-rome if a high-carbohydrate liquid meal is ingested.ess commonly performed surgeries are gastric restrictiverocedures such as vertical-banded gastroplasty and ad-ustable gastric banding. Vomiting has been reported toccur in 21% of patients after vertical-banded gastro-lasty.99 Another study observed normal emptying fromhe proximal pouch.100

Gastroparesis after lung and heart-lung trans-lantation. Gastroparesis has been reported after heartnd lung transplantation.101–103 This may have seriousonsequences in the patient receiving a lung transplant,ecause gastroparesis predisposes to development of gas-roesophageal reflux with microaspiration and subse-uent pulmonary infection. Symptomatic delays in gas-ric emptying have been reported in 25% of patientsfter single lung transplantation and 50% of patientsfter combined heart-lung transplantation.101 Anothertudy reported delayed gastric emptying in 8 of 10atients after combined heart-lung transplantation.102

xplanations include vagal nerve dysfunction or injuryuring surgery, opportunistic viral infection secondary tommunosuppressive medications, and motor-inhibitoryffects of the immunosuppressive drugs themselves. Va-al nerve dysfunction from thermal or ischemic injurynd/or dissection of the posterior mediastinum duringurgery has been suggested as the most likelyulprit.101–103

Idiopathic Gastroparesis

Idiopathic gastroparesis refers to symptomaticisease in patients with no primary underlying abnor-ality. This may represent the most common form of

astroparesis.1 As with other causes of gastroparesis,ymptoms may fluctuate, with episodes of pronouncedymptoms interspersed with relatively symptom-free in-ervals. Most patients with idiopathic gastroparesis areomen; typically the condition presents in young oriddle-aged individuals.4 Symptoms of idiopathic gas-

roparesis overlap with those of functional dyspepsia; inome individuals, it may be difficult to provide a defin-tive distinction between the two. Abdominal pain/dis-omfort typically is the predominant symptom in func-ional dyspepsia, whereas nausea, vomiting, early satiety,nd bloating predominate in idiopathic gastroparesis.

The histologic basis of idiopathic gastroparesis is
oorly understood. In one case, myenteric hypogangli-

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nosis and reductions in numbers of interstitial cells ofajal were observed.104 A subset of patients with idio-athic gastroparesis report sudden onset of symptomsfter a viral prodrome, suggesting a potential viral eti-logy for their symptoms. In one series, a postviraltiology was suspected in 23% of cases based on historiesf viral prodromes rather than any microbiologic confir-ation.105 In this patient subset, previously healthy sub-

ects develop the sudden onset of nausea, vomiting,iarrhea, fever, and cramps suggestive of a systemiciremic response. However, instead of experiencing res-lution of symptoms, these individuals note persistentausea, vomiting, and early satiety for more than 3onths and exhibit delays in gastric emptying on scin-

igraphy. Viruses that have been implicated in rare casesnclude cytomegalovirus, Epstein–Barr virus, and vari-ella zoster. However, the responsible organism remainslusive in most patients with postviral gastroparesis.hese patients appear to have slow resolution of their

ymptoms over several years.105,106 In contrast, individ-als with idiopathic gastroparesis without a viral triggerend to show less improvement over time.105

Other Disorders Associated With DelayedGastric Emptying

Other gastrointestinal and nongastrointestinalisorders can be associated with gastroparesis. Some con-itions produce similar symptoms but do not alwayselay emptying.

Gastrointestinal disorders with associated de-ayed gastric emptying. Gastroparesis associated with

ERD. Delayed gastric emptying has been detected inubsets of patients with GERD. Some investigators haveeported gastroparesis prevalence rates of 40% in patientsith GERD,107 whereas others have observed a much

ower prevalence (10%).108 The role of delayed gastricmptying in the pathophysiology of GERD remainsontroversial. Gastric stasis with distention may promoteransient lower esophageal sphincter relaxations withubsequent gastroesophageal reflux of acid.109 Recenttudies suggest that slow emptying from the proximaltomach, but not from the overall stomach, may correlateith esophageal acid exposure.110 Even though a caus-

tive role is unproved, it is not unreasonable to performastric scintigraphy in patients with GERD symptomsefractory to acid-suppressive therapy. Such testing alsohould be considered in those individuals considered forrocedures to increase the barrier function of the gastro-sophageal junction, including fundoplication to reducehe likelihood of postoperative complications as de-
cribed previously.96 s
Hypertrophic pyloric stenosis. Infantile hypertrophicyloric stenosis presents in up to 0.3% of newborns. Inypical cases, nonbilious vomiting develops in the first 4eeks of life secondary to hypertrophy of the inner

ircular muscle of the pylorus with impaired sphinctericelaxation. There is a lack of inhibitory nerves in theylorus, primarily those containing NO, and loss of thenterstitial cells of Cajal.111,112 An enlarged pylorus (py-oric olive) can be palpated or detected radiologically.reatment with surgical pyloromyotomy is effective, andatients usually remain symptom-free after surgery withesolution of the smooth muscle hypertrophy. Defects innterstitial cell numbers and NO transmission partiallyeverse after pyloromyotomy; however, pyloric tone mayemain elevated with less frequent phasic pyloric pressureaves.113,114 Medical treatment with atropine has beenroposed by some European groups. The condition alsoas been correlated with use of erythromycin for pertussisrophylaxis in neonates.115–117 Hypertrophic pyloric ste-osis in adults, not secondary to peptic ulcer disease oreoplasm, is exceedingly rare.118 Endoscopic dilation andaparoscopic pyloroplasty have occasionally been used asreatment.118,119

Generalized disorders of gastrointestinal motility. Gas-roparesis may occur as a component of a definable gen-ralized gut dysmotility syndrome. Chronic intestinalseudo-obstruction is a syndrome with recurrent symp-oms suggestive of intestinal obstruction in the absencef mechanical blockage. Radiologic findings of chronicntestinal pseudo-obstruction include luminal dilationith air-fluid levels throughout the small intestine. The

erm “diffuse gastrointestinal motility disorder” has beenroposed if several gut regions exhibit delayed transitut have no luminal dilation or air-fluid levels on radio-raphic examination.27 Chronic intestinal pseudo-ob-truction can be caused by a variety of systemic diseases,ncluding scleroderma, amyloidosis, myxedema, long-tanding diabetes mellitus, and paraneoplastic complica-ions most commonly seen with small cell lung carci-oma. However, many cases are idiopathic in nature. Themain forms of chronic intestinal pseudo-obstruction areyopathic and neuropathic. Small bowel manometryay assist in differentiating these 2 forms. In intestinalyopathy, low-amplitude contractions that propagate

ormally are seen. In intestinal neuropathy, contractionsre normal in amplitude but disorganized in morphol-gy, including disruption of phase III activity, bursts ofonpropagating activity during fasting, and failure toonvert from the fasting to the postprandial fed motorattern.Delayed gastric emptying is not uncommonly ob-

erved in patients with constipation. In one study, 19%

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f patients with primary constipation were found to haveelayed gastric emptying.120 A second investigation ofatients with irritable bowel syndrome observed delayedmptying of solids in 64% of patients, especially in thoseith constipation predominance.121 This has important

mplications for treatment because patients with chronicevere constipation with proximal gut dysmotility ex-ibit unsatisfactory responses to subtotal colectomy. Vo-itional suppression of defecation can also retard gastricmptying.122 Furthermore, colonic distention inhibitsastric motor function suggestive of a neurally mediatedologastric reflex.

Nongastrointestinal disorders associated with de-ayed gastric emptying. Ischemic gastroparesis. Gastricschemia may occur as a consequence of chronic athero-clerotic disease. In many cases, gastric ischemia is in-idious and difficult to recognize. Ischemic gastropathyecondary to atherosclerosis may present as gastritis,lceration, or gastroparesis.123,124 Typically, the diagno-is is made angiographically. Surgical revascularizationay improve gastric emptying and correct gastric dys-

hythmias in affected patients.124

Malignancy-associated gastroparesis. Malignancy-as-ociated gastroparesis has been described with esopha-eal, gastric, pancreatic, breast, and lung carcinoma. Theathophysiology is unknown but frequently is attributedo paraneoplastic effects, neural invasion by the tumor, oride effects of chemotherapy. In nonobstructing gastricancers, tumor infiltration into the stomach wall mayisrupt coordinated smooth muscle or neural function.elayed gastric emptying is reported in 40%–60% ofatients with pancreatic adenocarcinoma. Usually gastro-aresis secondary to pancreatic cancer is asymptomatic,ut it may contribute to nausea, vomiting, abdominalain, and pain radiating to the back in selected individ-als.125 Gastroduodenal obstruction from the tumor, ret-operitoneal nerve invasion from the tumor, or a para-eoplastic syndrome may all cause delayed gastricmptying in these patients.

Intestinal pseudo-obstruction with delayed gastricmptying may be a paraneoplastic complication of ma-ignancy, most commonly small cell lung carcinoma.126

ntestinal dysmotility is postulated to result from auto-mmune destruction of myenteric neurons, because his-ologic studies have shown degeneration of the myentericlexus with plasma cell and lymphocyte infiltration.127

he onset of gut motor dysfunction may precede detec-ion of the cancer.126 Antroduodenal manometry mayhow a typical neuropathic pattern of uncoordinatedontractions of normal amplitude. A variety of autoim-
une serologies may be detectable with paraneoplastic s
seudo-obstruction, including the type 1 antineuronaluclear antibody (ANNA-1 or anti-Hu antibody).126

Delayed gastric emptying with nausea and vomitingan occur during treatment of malignancies. Gastropa-esis can occur after abdominal radiation therapy,128 dur-ng treatment with chemotherapeutic agents,129 afterone marrow transplantation,130 and after celiac plexuslockade for chronic pain from pancreatic cancer.131

Chronic pancreatitis. In a retrospective series, 44%f patients with small-duct chronic pancreatitis had de-ayed gastric emptying.132 Some of the abdominal pain,ausea, and vomiting seen in patients with presumed orocumented chronic pancreatitis may be due to gastro-aresis. A recent study showed impaired gastric myoelec-rical activity in chronic pancreatitis133; this abnormalityas restored toward normal with replacement of pancre-

tic enzymes. Gastric emptying is variable in cysticbrosis; it may be rapid early in the disease but delayedater in the disease.134

Renal failure. Patients on hemodialysis commonlyeport nausea, vomiting, anorexia, and early satiety. Inne investigation, the degree of gastric emptying delayorrelated with the magnitude of dyspeptic symp-oms.135 A second study reported that the delay in solidastric emptying is associated with changes in biochem-cal indicators of nutritional status.136

Infectious causes of gastroparesis. Delayed gastricmptying may occur with acute viral infection witharicella zoster, Epstein–Barr virus, cytomegalovirus, ro-avirus, and parvovirus-like agents such as the Norwalknd Hawaii viruses.137,138 In most cases, the delay inastric emptying is transient and resolves over time withecovery from the viral infection.106 Although reportsargely are anecdotal, a small number of individualsevelop chronic symptoms and comprise a subset ofdiopathic gastroparesis.139,140

Gastric cytomegalovirus (CMV) infection most com-only presents in immunosuppressed individuals, par-

icularly in those who have undergone organ transplan-ation.141 CMV infection of the upper gut is reported toccur in one third of patients after liver transplantationnd produces typical symptoms of gastroparesis, includ-ng nausea and abdominal fullness. Endoscopy may showarge antral folds, gastric inflammation including acuteuperficial gastritis, and duodenal erosions and ulcer-tions. Viral cultures of gastric biopsy specimens andistologic demonstration of CMV inclusions in the gas-ric mucosa may provide the diagnosis.141 Gastrointesti-al infection with CMV is unusual in immunocompetentndividuals.139

Gastric emptying is delayed in one third of individuals
eropositive for human immunodeficiency virus, partic-

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larly in those with advanced disease evidenced by lowD4 counts, marked weight loss, and enteric infec-

ions.142,143 In many of these immunocompromised pa-ients, the acute stage of gastritis and gastroparesis fromiruses and other infectious agents, especially CMV andycobacterium avium-intracellulare, may persist for

rolonged periods. Some investigators have observed de-ayed emptying of solids with diminished postprandialntral motility and with coexistent rapid emptying of theiquids suggestive of an autonomic neuropathy secondaryo human immunodeficiency virus.144

The effects of Helicobacter pylori on gastric motor func-ion have been the subject of controversy. Although aandful of studies have suggested an association withastroparesis,145 most investigations observe no relation-hip between active H pylori infection and delayed gastricmptying or functional dyspepsia.146

Medication-induced gastroparesis. Nausea and vom-ting are frequent side effects of medications and usuallyresent early in their use. Thus, medications are consid-red to cause acute rather than chronic nausea and vom-ting.24 Many medications, including anticholinergics,arcotics, tricyclic antidepressants, and calcium channellockers, are known to delay gastric emptying (Table 3).uriously, many acid-suppressive medications delay gas-

ric emptying, although this effect is not likely to be oflinical relevance in most cases.147 Conversely, the his-amine receptor antagonist nizatidine has been reportedo exhibit weak prokinetic properties.148

Gastric emptying of solids is delayed in patients re-eiving total parenteral nutrition (TPN).149 As a result,ome have advocated that the TPN formulation shoulde converted to intravenous saline during diagnosticvaluation of gastric emptying and antral motility.35

PN-associated gastroparesis has been postulated to re-ult from induction of hyperglycemia by the intravenousutrient infusion. Intravenous infusion of fat emulsionslso delays gastric emptying and may contribute to thishenomenon.149,150

Eating disorders. Anorexia nervosa is a psychiatricisorder occurring primarily in adolescent and youngdult women that is characterized by distorted bodymage and fear of obesity with compulsive dieting andelf-imposed starvation to maintain a profoundly lowody weight. Gastrointestinal symptoms are prevalent innorexia nervosa and include lack of appetite, early sati-ty, epigastric fullness, abdominal bloating, nausea, andomiting.151,152 Patients with anorexia nervosa often ex-ibit delayed gastric emptying primarily for solids.152

ealimentation and restoration of normal body weightmprove gastric emptying and symptoms.151,153 These
bservations suggest that the delay in gastric emptying is r
econdary to the effects of pronounced weight loss withalnutrition or to the psychiatric issues that affect theseomen.151,153 Prokinetic drug therapy may improve gas-

ric emptying and facilitate refeeding,152 although othertudies have shown no effect on weight gain.154

Bulimia nervosa is characterized by recurrent episodesf binge eating, with a feeling of lack of control over theating behavior during the binges, often followed byelf-induced vomiting, the use of laxatives or diuretics,trict dieting or fasting, or vigorous exercise to preventeight gain.155 Self-induced vomiting allows bulimicatients to continue eating or terminate the binge. Inontrast to anorexia nervosa, concern about weight andody size does not lead to a decrease in weight belowormal values. Most cases present in young women, withpeak age at onset of 18 years. Symptoms of postprandial

ullness, early satiety, bloating, nausea, and epigastricain may occur and may relate to the degree of associatedepression.156 Gastric emptying studies in bulimia havehown conflicting results as to the presence of gastropa-esis.157,158 Therapy consists of cognitive-behavior ther-py and pharmacotherapy to interrupt the binge-purgeycles.

Nongastrointestinal disorders that mimic gastro-aresis. Rumination syndrome. Rumination syndrome re-ers to the effortless regurgitation of recently ingestedood into the mouth with subsequent remastication andeswallowing or expectoration of food. Initially describedn children and mentally retarded institutionalized indi-iduals, there is an increasing awareness of this disordern adults of normal intelligence. Rumination can becomehabit, often initiated by a belch, a swallow, or stimu-

ation of the palate with the tongue. Abdominal muscleontraction with relaxation of the lower esophagealphincter in the early postprandial period is responsibleor regurgitation.159 Typically, the effortless repetitiveegurgitation occurs within 15 minutes of beginning toat, in contrast to vomiting in gastroparesis, which com-only occurs later in the postprandial period.51 The

ifficulty in diagnosing rumination syndrome resultsrom a lack of awareness of the disorder and the challengen differentiating rumination from vomiting due to gas-roparesis or regurgitation due to GERD. Results ofastric emptying studies and esophageal pH monitoringests usually are normal. Gastroduodenal manometryay show characteristic transient simultaneous increases

n gastric and small bowel pressure (“R waves”) in allbdominal recording ports during the postprandial pe-iod. These reflect the effects of abdominal wall contrac-ion. Treatment relies on behavioral modification andiofeedback therapy administered in a formal eating
egulation program.160

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Cyclic vomiting syndrome. Cyclic vomiting syn-rome is characterized by recurrent episodes of relent-ess nausea and vomiting lasting hours to days sepa-ated by symptom-free periods of variable lengths.he vomiting begins abruptly in most cases, although

ome individuals experience a prodrome of nausea andbdominal pain. The vomiting reaches its highestntensity during the first hours, diminishes thereafter,nd ends rapidly. The duration of vomiting averages– 4 days and can result in marked dehydration. Thisisorder is much more prevalent in children, with aean age at onset of 5– 8 years, but recently has been

escribed in adults.161,162 In adults, the vomiting ep-sodes are longer (3–5 days) and less frequent (every– 4 months) and triggering events are less evident.162

n most patients, findings of gastric scintigraphy,ntroduodenal manometry, and EGG are normal, sug-esting that symptoms do not result from gastroin-estinal dysmotility.163 Precipitating events, identi-ed in a minority of patients, include onset ofenstrual periods and stress. Cyclic vomiting syn-

rome is associated with migraine headaches.162 Thenderlying causes of cyclic vomiting syndrome areoorly understood. Other proposed etiologies includeerangements of the hypothalamic-pituitary axis, in-ppropriate activation of the vomiting reflex, and mi-ochondrial disorders.161,164 There are no uniformlyffective therapies for cyclic vomiting syndrome.leep, a quiet environment, and the use of benzodiaz-pines such as lorazepam may be effective in someilder cases.162 Tricyclic antidepressants and �-block-

rs may serve a prophylactic role, similar to their usen migraine therapy.162 Antiemetics such as the 5-HT3

eceptor antagonist ondansetron and prokinetic agentsuch as metoclopramide or erythromycin can provideemporary relief during vomiting episodes. Antimi-raine therapies such as the 5-HT1D receptor agonistumatriptan may reduce the severity of attacks. Use ofonsteroidal anti-inflammatory drugs such as indo-ethacin or intramuscular ketorolac have been re-

orted to reduce the intensity of attacks, perhaps viaheir prostaglandin-inhibitory effects and their abilityo reverse some gastric slow wave dysrhythmias.161

Functional vomiting. A number of patients presentith nausea and vomiting of uncertain etiology and

xhibit normal findings on both structural and functionalesting. The Rome II committee devised diagnostic cri-eria for functional vomiting, a condition that may shareathogenic features with other functional disorders, in-luding functional dyspepsia and irritable bowel
yndrome.165 n
Treatment of SymptomaticGastroparesis

The general principles for treatment of symptom-tic gastroparesis are to (1) correct fluid, electrolyte, andutritional deficiencies; (2) identify and rectify the un-erlying cause of gastroparesis if possible; and (3) reduceymptoms.24 The patient’s medication list should beeviewed to eliminate drugs that might exacerbate thenderlying dysmotility disorder or prevent the beneficialctions of a prokinetic agent. Diabetic patients shouldtrive for optimal glycemic control to minimize anynhibitory effects of hyperglycemia on gastric emptying.or relatively mild disease, dietary modifications and aow-dose antiemetic or prokinetic agent might provideatisfactory control of symptoms. Patients with moreevere manifestations of gastroparesis, such as refractoryomiting, pronounced dehydration, or chaotic glucoseontrol, might require hospitalization, intravenous hy-ration, nasogastric suction to decompress the stomach,nsulin for blood glucose control, and/or intravenousdministration of antiemetic and prokinetic agents. Asith the diagnostic approach to gastroparesis, most rec-mmendations regarding its treatment are based on theumulative experience and opinions of clinicians whopecialize in the care of these patients. There is little inhe way of controlled investigation to validate any ther-peutic algorithm for the management of this challeng-ng condition.

Dietary Recommendations

Dietary recommendations for the patient withastroparesis rely on measures that promote gastric emp-ying, although few studies have been performed toalidate this concept. Increasing the liquid nutrient com-onent of the ingested meal should be emphasized be-ause liquid emptying often is preserved in patients withastroparesis who have delayed solid emptying. Fats andber tend to retard emptying; thus, their intake shoulde minimized. Indigestible fiber and roughage may pre-ispose to bezoar formation. Meal size should be re-tricted because the stomach may only empty a givenumber of calories in a fixed period of time.166 Toompensate for small meal size, patients may need to eator 5 times daily. Carbonated beverages release carbon

ioxide, which can aggravate gastric distention. Highoses of alcohol can decrease antral contractility andmpair gastric emptying.167 This also is true of tobaccomoking.168

Commercial or self-prepared liquid nutrient mealsay be tolerated in small quantities. Larger volumes

eeded to cover daily caloric needs may exacerbate symp-

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oms of gastroparesis. Enteral alimentation delivered intohe small intestine may be helpful in patients withysmotility restricted to the stomach. In some severeases, TPN may be needed.

Metabolic Control

Diabetic patients with gastroparesis frequentlyxhibit labile blood glucose concentrations with pro-onged periods of significant hyperglycemia. Hypergly-emia itself delays gastric emptying even in the absencef fixed gastric motor deficits, which is likely mediatedy reduced phasic antral contractility and induction ofyloric pressure waves.66,82 Hyperglycemia can inhibithe accelerating effects of prokinetic agents on gastricmptying.169 Improvement of glucose control increasesntral contractility, corrects gastric dysrhythmias, andccelerates emptying. To date, there have been no long-erm studies confirming the beneficial effects of mainte-ance of near euglycemia on gastroparetic symptoms.evertheless, the consistent findings of physiologic stud-

es in healthy volunteers and diabetic patients provide aompelling argument to strive for near-normal bloodlucose levels in affected diabetic patients.

Antiemetic Agents

Medications that act on peripheral and centraleural structures as antiemetic agents provide the back-one for the treatment of many conditions with nauseand vomiting.24 Antiemetic drugs may serve as primaryherapy for some patients with gastric dysmotility or asdjuncts to medications that promote gastric emptying.

Phenothiazines are commonly prescribed antiemeticgents. These dopamine receptor antagonists act at theevel of the area postrema of the medulla oblongata, aegion termed the chemoreceptor trigger zone.24 Com-only used antiemetic agents include prochlorperazine,

rimethobenzamide, and promethazine. Phenothiazinesay be administered as tablets, capsules, liquid suspen-

ions, or suppositories or by injection. For patients withevere symptoms, suppositories or injectable forms maye more efficacious. Side effects from phenothiazines areommon and include sedation and extrapyramidal ef-ects.

Serotonin (5-HT3) receptor antagonists, including on-ansetron, granisetron, and dolasetron, are useful forrophylaxis of chemotherapy-induced nausea and vomit-ng as well as symptoms occurring postoperatively oruring radiation therapy. 5-HT3 antagonists may actoth on the area postrema as well as on peripheralfferent nerve fibers within the vagus.24 Although often
sed, there are no studies documenting their efficacy in f
astroparesis. If drugs in this class are considered, theyre best given on an as-needed basis.

Antihistamines acting on H1 receptors exhibit centralntiemetic effects.24 Commonly prescribed antihista-ines include diphenhydramine, dimenhydrinate, andeclizine. There is little evidence that antihistamines

erve important roles in symptom control in gastropare-is. These agents are most useful for treatment of motionickness via their actions on H1 receptors in the vestib-lar apparatus. In experimental motion sickness inealthy volunteers, dimenhydrinate reduced tachy-astria, decreased symptoms, and evoked drowsiness,uggesting that symptom improvement may result fromtabilization of gastric myoelectric rhythm or from de-ression of CNS activity.170 Transdermal hyoscine (sco-olamine patch) is occasionally used for nausea and vom-ting, primarily from motion sickness and recovery fromnesthesia and surgery. This anticholinergic agent mayelay gastric emptying.Benzodiazepines such as lorazepam and diazepam areost commonly used for the prevention of anticipatory

ausea and vomiting before administration of chemo-herapy.24 Cannabinoid drugs such as tetrahydrocannab-nol have been studied for symptoms from chemotherapynd appear to have potency similar to standard antido-aminergics. A clear role in management of the patientith gastroparesis has not been established for eitherrug class.

Prokinetic Agents

Prokinetic medications enhance gut contractilitynd promote the aboral movement of luminal contentsTable 5). In the stomach, prokinetic agents increasentral contractility, correct gastric dysrhythmias, andmprove antroduodenal coordination. Some prokinetics,ncluding metoclopramide and domperidone, also ex-ibit antiemetic properties. Most commonly, motortimulatory medications are administered 30 minutesefore meals to elicit maximal clinical effects. Bedtimeoses often are added to facilitate nocturnal gastric emp-ying of indigestible solids. Because symptom improve-ents correlate poorly with acceleration of gastric emp-

ying, the response to treatment is usually judgedlinically rather than following up with serial gastricmptying tests.171

Delayed gastric emptying is present in 20%–40% ofatients with functional dyspepsia. Prokinetic medica-ions, including metoclopramide, cisapride, and dom-eridone, have demonstrated utility in treating func-ional dyspepsia in placebo-controlled trials and in meta-nalyses.172–175 A recent meta-analysis suggested that
avorable trials are selectively published, raising ques-

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ions about the true utility of prokinetics in functionalyspepsia.176

Metoclopramide. Metoclopramide, a substitutedenzamide structurally related to procainamide, has beensed for 35 years to treat gastroparesis. It exhibits bothrokinetic and antiemetic actions.177 The drug releasescetylcholine from intrinsic myenteric cholinergic neu-ons via activation of 5-HT4 receptors and serves as aopamine receptor antagonist in the stomach. It alsoxhibits weak 5-HT3 receptor antagonism.178 The pro-inetic properties of metoclopramide are limited to theroximal gut. Metoclopramide increases esophageal, fun-ic, and antral contractile amplitudes, elevates lowersophageal sphincter pressure, and improves antropylo-oduodenal coordination. Antidopaminergic actions inhe area postrema explain the additional antiemeticctions.

Metoclopramide is approved for use in diabetic gas-roparesis and for prevention of postoperative and che-otherapy-induced nausea and vomiting. Controlled tri-

ls report that metoclopramide provides symptomaticelief while accelerating gastric emptying of solids andiquids in patients with idiopathic, diabetic, and postva-otomy gastroparesis and in patients with GERD (Table).179–187 Metoclopramide is effective for the short-termreatment of gastroparesis for up to several weeks.181,182

ymptomatic improvement does not necessarily accom-any improvement in gastric emptying. Indeed, somenvestigations have reported extended symptom benefitsf metoclopramide without prolonged prokinetic ac-ion.188 The long-term utility of metoclopramide has noteen proven.188 In diabetic patients with gastroparesis,

able 5. Prokinetic Agents for Gastroparesis

Agent Mechanism of action

etoclopramide Dopamine receptor antagonistcentral/peripheral

Also 5-HT3 antagonistAlso 5-HT4 agonist

FDCNPr

rythromycin Motilin receptor agonist GaTa

isapride 5-HT4 receptor agonistfacilitates acetylcholinerelease

Also 5-HT3 antagonist

TaWCu

omperidone Dopamine receptor antagonistperipheral

PrAv

egaserod 5-HT4 partial agonist FD

Imethanechol Muscarinic receptor agonist Inc

No

DA, Food and Drug Administration.

astric emptying is accelerated by short-term adminis- l

ration of metoclopramide but not by long-term dosingor more than 1 month.189

The usual starting dose of metoclopramide in adults is0 mg 30 minutes before meals and at bedtime. Dosingan be increased to 20 mg if the response to 10 mg isnadequate. For patients hospitalized for symptom exac-rbations in gastroparesis, metoclopramide may be ad-inistered intravenously. The drug also can be taken inliquid form. It has also been reported to be effective

ubcutaneously, by suppository, or even intraperitoneallyn patients on peritoneal dialysis.190

The side effects from metoclopramide result from anti-opaminergic actions in the CNS and may restrict its use inp to 30% of patients. Acute dystonic reactions such asacial spasm, oculogyric crisis, trismus, and torticollis occurn 0.2%–6% of patients; when this occurs, it is oftenbserved within 48 hours of initiating therapy.191 Drowsi-ess, fatigue, and lassitude are reported by 10% of patients.etoclopramide can aggravate underlying depression.ther side effects may include restlessness, agitation, irri-

ability, and akathisia. Increased prolactin release may resultn breast engorgement, lactation, and menstrual irregular-ty. Prolonged treatment with metoclopramide can producearkinsonian-like symptoms.191 Parkinsonian symptomssually subside within 2–3 months following discontinua-ion of metoclopramide. Because of this effect, patients witharkinson’s disease should be given metoclopramide cau-iously, if at all. Tardive dyskinesia, characterized by invol-ntary movements of the face, tongue, or extremities, mayccur with prolonged use and may not reverse after stop-ing the medication. The prevalence of tardive dyskinesiaanges from 1% to 15% when taking metoclopramide for at

Comments

proved for gastroparesise effects in 20–30%tic and antiemetic properties

ntestinal side effects in many: nausea/vomiting/abdominal painylaxis with long-term oral administrationff market in March 2000 for prolonging QT intervally approved for nocturnal heartburnly not available as prescription in United States

tic and antiemetic propertiesle in Europe/Canada/Mexico/New Zealand but not in United Statesproved for irritable bowel syndrome, constipation predominant inns gastric emptying, no data on symptomses amplitude of contractions, not peristalsisue prokinetic agent

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ccur with short-term use.191 Metoclopramide-evoked tar-ive dyskinesia is 3-fold more common in women thanen.192

Erythromycin and motilides. The macrolide anti-iotic erythromycin exerts prokinetic effects via actionn gastroduodenal receptors for motilin, an endogenouseptide responsible for initiation of the MMC in thepper gut.193,194 When administered exogenously, mo-ilin stimulates antral contractility and elicits prematurentroduodenal phase III activity. Erythromycin binds tootilin receptors on smooth muscle and on cholinergic

eurons, the latter of which appear to be important forctions.193,195 Erythromycin produces effects on gas-roduodenal motility similar to motilin.

Clinically, erythromycin has been shown to stimulate

able 6. Systematic Review of Studies on Oral Metoclopram

Author/year/reference Study design

No. ofsubjects Types of pat

rownlee andKroopf,1974179

Open label,crossover

1 Diabetic gastropare

ongstreth etal, 1977180

Open label 1 Diabetic gastropare

erkel et al,1979181

Randomized,double-blind,parallel groupplacebocontrolled

28 Diabetic gastroparePostsurgical gastroIdiopathic gastropa

nape et al,1982182

Randomized,double-blind,crossoverplacebocontrolled


cCallum et al,1983183

Multicenter,placebocontrolled


oo et al,1984184

Open label 8 Diabetic gastropath

icci et al,1985185

Randomized 7 Diabetic gastropare

rbas et al,1993186

Randomized,single-blind,crossover


atterson et al,1999187

Randomized,double-blind,multicenter

45 Diabetic gastropath

ID, 4 times a day; TID, 3 times a day.

astric emptying in diabetic gastroparesis, idiopathic o

astroparesis, and postvagotomy gastroparesis (Table).196–204 Indeed, the effects of erythromycin on gastricmptying are greater than observed with other prokineticrugs. Interestingly, erythromycin accelerates emptyingn postsurgical patients in whom the antrum, the pri-ary site of its motor effect, has been resected.202 In

hese individuals, erythromycin may exert stimulatoryffects on the fundus. Erythromycin may be most potenthen used intravenously.205 In one investigation, treat-ent with intravenous erythromycin lactobionate (200g) markedly accelerated emptying of solids in patientsith diabetic gastroparesis.196 In these same patients, 4eeks of treatment with oral erythromycin ethylsucci-ate (250 mg 30 minutes before meals) elicited muchess potent stimulatory effects. Other studies performed

r Treatment of Gastroparesis

Dosage ofmetoclopramide

Length ofstudy Outcome results

10 mg QID 5 mo Improved symptomsImproved gastric emptying

15 mg QID 6 mo Improved symptomsImproved gastric emptying

5)is (4)(19)

10 mg QID 3 wk Improved symptoms by29%

10 mg QID 3 wk Improved symptoms in 7of 10 by 56%

Improved gastric emptyingby 31%

Poor correlation betweengastric emptying andsymptoms

10 mg QID 3 wk Improved symptom scoreby 25%

Improved gastric emptyingby 25%

10 mg QID 6 mo Improved symptoms inonly 3 of 8 patients

Side effects precludedtreatment in many

10 mg QID 3 wk Improved symptoms in52%

Gastric emptyingimproved but did notcorrelate with symptomimprovement

10 mg TID 3 wk Symptoms improved in 10of 11 subjects by 62%

Gastric emptyingimproved by 24%

10 mg QID 4 wk Symptoms improved by39%

ide fo

ients

sis

sis

sis (paresresis

sis

sis

y

sis

sis

y

ver longer observation periods have reported reductions

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f benefit over time with oral administration. Limitedata exist concerning the clinical efficacy of erythromycinn reducing symptoms of gastroparesis (Table 7). In aystematic review of studies on oral erythromycin withymptom assessment as a clinical end point, improve-ent was noted in 43% of patients.206 One study com-

aring erythromycin and metoclopramide in an open-abel, crossover fashion in diabetic gastroparesis foundimilar efficacy.206

Oral administration of erythromycin should be initi-ted at low doses (eg, 125–250 mg 3 or 4 times daily).any physicians prefer using erythromycin liquid sus-

ension because it is rapidly absorbed and facilitatesosage modifications.207 Intravenous erythromycin (100g every 8 hours) is used for inpatients hospitalized for

evere refractory gastroparesis.208 Side effects of erythro-ycin at higher doses include nausea, vomiting, and

bdominal pain. Because these symptoms may mimichose of gastroparesis, erythromycin may have a narrowherapeutic window in some patients. Hyperglycemiattenuates the stimulation of antral contractility and

able 7. Systematic Review of Studies on Oral Erythromycin

Author/year/reference Study designNo. of

subjects Type

anssens et al,1990196

Open label 10 Diabetic g

ull et al, 1990197 Open label 1 Scleroder

ozwecz et al,1990198

Open label 1 Postvagotgastrop

lutman andEisenach, 1992199

Open label 2 Idiopathic

rbas et al, 1993200 Single-blind,randomized,crossover

13 Diabetic g

ichards et al,1993201

Open label 10 Diabetic gIdiopathic

amirez et al,1994202

Open label 9 Postsurgicvagotomantrecto

amson et al,1997203

Double-blind, placebocontrolled,crossover

12 Diabetic g

alley et al, 2001204 Randomized, doubleblind, placebocontrolled, parallelgroup

270 Diabetic g

ID, 3 times a day; QID, 4 times a day.

astric emptying by erythromycin.169 m

Investigators have searched for macrolide compoundshat activate motilin receptors but do not exhibit thentimicrobial effects of erythromycin. One such motilideompound, ABT-229, was not effective for relief of post-randial dyspeptic symptoms in diabetic gastroparesis orunctional dyspepsia.204,209 Others are now being tested.

Domperidone. Domperidone is a benzimidazoleerivative and is a specific dopamine (D2) receptor an-agonist. The effects of domperidone on the upper gutre similar to those of metoclopramide, including stim-lation of antral contractions and promotion of antroduo-enal coordination (Table 8).8,210–218 Domperidone doesot readily cross the blood-brain barrier; therefore, it isuch less likely to cause extrapyramidal side effects thanetoclopramide.217 In addition to prokinetic actions in

he stomach, domperidone exhibits antiemetic propertiesia action on the area postrema, a brainstem region withporous blood-brain barrier.Domperidone has been studied primarily in patients

ith diabetic gastroparesis, in whom it increases botholid and liquid emptying.212 Symptomatic improve-

Motilides for Treatment of Gastroparesis

atients InterventionLength of

study Outcome results

paresis Erythromycin250 mgTID

4 wk Improved symptoms andgastric emptying

stroparesis Erythromycin200 mgTID

9 mo Improved symptoms andgastric emptying

sErythromycin

250 mgQID

2 wk Improved symptomsImproved gastric emptying

roparesis Erythromycin200 mgQID

6 mo Improved symptoms andgastric emptying


3 wk Symptoms improved in 11of 13 patients by 75%

Gastric emptying improvedby 26%

paresis (2)roparesis (8)

Erythromycin250 mgQID



tald

Erythromycin150 mgTID




2 wk No overall improvement insymptoms (15%decrease, notsignificant)

pathy ABT-229 4 wk No overall improvement insymptoms

and

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otor stimulatory actions; rather, its efficacy may stemrom its antiemetic effects.8,217 In controlled clinicalrials, domperidone provided relief of symptoms andmprovement in quality of life to greater degrees thanlacebo in patients with diabetic gastropathy; symptommprovement was similar to that observed for metoclo-ramide and cisapride but with fewer CNS side ef-ects.217 Furthermore, symptomatic diabetic patientsith normal gastric emptying reported beneficial effectsith domperidone therapy.214 The prokinetic actions ofomperidone may be transitory in nature. At 6 weeks,he effect of domperidone on solid-phase gastric empty-ng was lost, while that on liquid emptying was main-ained.212 Another investigation reported persistent re-uctions in nausea and vomiting after 6 weeks ofreatment with no acceleration of solid gastric empty-ng.214 Other studies report that improvements in gastricmptying and symptoms were still present after 1 year of

able 8. Systematic Review of Studies on Oral Domperidone

Author/year/reference Study designNo. of

subjects Type of pati

agler and Miskovitz,1981210

Randomized,placebocontrolled


atts et al, 1985211 Open label 3 Diabetic gastropare

orowitz et al,1985212

Open label 12 Diabetic gastropath

hampion et al,1987213

Double-blind,placebocontrolled,parallelgroup


avis et al, 1988214 Double-blind,randomized,placebo-controlled

9 Idiopathic gastropa

och et al, 19898 Open label 6 Diabetic gastropare

oykan et al, 1997215 Open label 17 Idiopathic gastropaDiabetic gastroparePostsurgical gastro

ilvers et al, 1998216 Single-blind 287 Diabetic gastropath

atterson et al,1999217

Multicenter,randomized,double blind

48 Diabetic gastropath

umitrascu andWeinbeck, 2000218

Double-blind 10 Diabetic gastropare

ID, 4 times a day; TID, 3 times a day.

reatment.215 Domperidone has been advocated for ther- M

py of nausea and vomiting in patients with Parkinson’sisease, in whom symptoms may be secondary to gastro-aresis or to dopaminergic drugs used to treat the diseaseeg, L-dopa).215

Dosing of domperidone typically begins at 10 mgefore meals and at bedtime and can be increased asolerated to achieve symptom control. In many patients,he dose of domperidone can be more easily increased tomprove symptom control because of the near lack ofeuropsychiatric and extrapyramidal side effects. Theost common side effects of domperidone relate to in-

uction of hyperprolactinemia, with induction of men-trual irregularities, breast engorgement, and galactor-hea. An intravenous formulation of domperidone wasemoved in the 1980s due to generation of cardiac ar-hythmias. Domperidone is not approved by the Foodnd Drug Administration (FDA) for prescription in thenited States, although it can be obtained in Canada,

reatment of Gastroparesis

Dosage ofdomperidone

Length ofstudy Outcome results

10 mg QID 4 wk Symptoms improved in 2 of 3patients

10 mg QID 6 mo Symptoms improvedGastric emptying improved

20 mg TID 1–2 mo Symptoms improved in 11 of 12patients

No change in gastric emptying ofsolids, decrease in gastricemptying of liquids

20 mg QID 4 wk Improved symptomsImproved gastric emptying by 37%

20 mg QID 6 wk Symptoms improved in 7 of 9patients by 36%

No change in gastric emptying

20 mg QID 6 mo Symptoms improved in 5 of 6patients

Gastric emptying improved in 4 of6, not significant

(12)3)is (2)

20 mg QID 2 y Symptom score improved by 68%Gastric emptying improved by 34%

20 mg QID 4 wk Symptoms improved in 208/269patients by 63%

20 mg QID 4 wk Symptom score improved by 41%(similar efficacy tometoclopramide but less sideeffects)

10 mg TID N/A Symptoms improvedGastric emptying improved by 27%

(better than metoclopramide)

for T

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exico, New Zealand, Europe, and Japan. In the United

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tates, the drug had been prepared in capsules by com-ounding pharmacies.219 Recently, an investigationalew drug (IND) application can now be opened byhysicians through the FDA to provide domperidone toatients with gastroparesis refractory to other therapies.

Tegaserod. Tegaserod, an aminoguanidine in-ole compound, is a partial 5-HT4 receptor agonistpproved for the treatment of constipation-predomi-ant irritable bowel syndrome. In healthy volunteers,egaserod stimulates interdigestive small intestinalotility and postprandial antral and intestinal motil-

ty.220 Tegaserod has been shown to accelerate gastricmptying in some221 but not all studies of healthyolunteers.222 In unpublished studies, tegaserod washown to accelerate solid-phase gastric emptying inatients with gastroparesis in dose-dependent fashion,ith 6 mg 3 times daily and 12 mg twice daily

howing greater effect than the standard dose foronstipation (6 mg twice daily).223 Effects of tegaserodn symptoms have not been reported in patients withastroparesis. However, tegaserod has a marginalffect on symptoms in functional dyspepsia with somemprovement in early satiety and postprandialullness.224

Other prokinetic agents. Bethanechol is a non-pecific cholinergic muscarinic receptor agonist. It en-ances amplitude of contractions throughout the gastro-ntestinal tract. Unfortunately, bethanechol does notlicit coordinated contractions and acceleration of gastricmptying and small bowel transit is not reliably dem-nstrated. As a consequence, bethanechol is not a truerokinetic agent.225 Rarely, the drug may be helpful asn adjunct with other prokinetic medications in patientsefractory to standard treatment with prokinetic andntiemetic drugs. The typical dose is 25 mg orally 4imes daily. Side effects of bethanechol are prominentnd include increased salivation, blurred vision, abdom-nal cramps, and bladder spasm.

Acetylcholinesterase inhibitors, such as physostigminend neostigmine, stimulate gut motor activity by in-reasing acetylcholine levels with subsequent muscariniceceptor activation. As with bethanechol, anticholines-erase agents do not improve antroduodenal coordinationnd have inconsistent effects on gastric emptying.226 Innimal studies, gut transit is accelerated at lower dosesut inhibited at higher doses.227 This dual effect may beelated to activation of different muscarinic receptorubtypes. Their utility in gastroparesis has not beentudied.

Cisapride is a 5-HT4 receptor agonist that facilitateselease of acetylcholine from myenteric cholinergic
erves throughout the gut.24 Cisapride stimulates antral m
nd duodenal contractions, improves antroduodenal co-rdination, and accelerates gastric emptying.44,72 Cisa-ride accelerates gastric emptying and decreases symp-oms in patients with gastroparesis, an effect that mayast for 1 year. Cisapride was approved by the FDA forocturnal heartburn in patients with GERD. However,ostmarketing surveillance identified a number of casesf cardiac arrhythmias and sudden death.24,225 Theseffects were not due to the 5-HT4 agonist properties ofisapride but rather were a direct action of cisapride onardiac potassium channels, which prolonged the QTnterval and predisposed patients to development of ven-ricular arrhythmias, including torsades de pointes. As aonsequence, cisapride was withdrawn from the US mar-et in 2000. It is only available under compassionate-se/limited-access programs with strict patient monitor-ng through Janssen Pharmaceutica.219 Its use is stronglyiscouraged in individuals with underlying cardiac dis-ase, especially of the conduction system, and in patientsn medications known to affect the QT interval.

Management of Refractory Gastroparesis

There is no consensus regarding management ofatients with gastroparesis who do not respond to simplentiemetic or prokinetic therapy or who develop severeedication-induced side effects. In one investigation of

10 patients with “refractory” gastroparesis, 74% re-ponded to use of another prokinetic agent while only6% were refractory to all prokinetic agents.1 Patientsith gastroparesis who did not respond to prokinetic

herapy were usually postgastrectomy patients, thoseith myopathic connective tissue disorders, those with

ype 1 diabetes mellitus with profoundly delayed gastricmptying, and those with idiopathic gastroparesis withbdominal pain.

Managing the patient with refractory gastroparesisncludes ensuring that gastroparesis is responsible forymptoms, optimizing current therapy, and changingrokinetic agents if maximal doses of the current treat-ent program are inadequate.225 It is unclear why some

atients respond to one prokinetic agent and not another.efractory patients often require treatment with bothrokinetic and antiemetic agents. For patients who areruly refractory to all attempts at pharmacotherapy ofastroparesis, placement of a feeding jejunostomy and/orenting gastrostomy can be considered. Use of TPNhould be temporary if possible due to the risk of com-lications. Newer therapies being evaluated are pyloricnjection of botulinum toxin and gastric electric stimu-ation. Gastric resection usually is of limited value for
ost etiologies of gastroparesis.

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Combination prokinetic therapy. Prokinetic agentsct via different mechanisms to enhance gastric emptyingTable 5). Theoretically, addition of a second prokineticgent may augment the response of the first drug if the 2gents act on different receptor subtypes. Dual prokineticherapy with domperidone and cisapride has been reportedo accelerate emptying and reduce symptoms in some pa-ients with refractory gastroparesis.228 Combinations ofvailable prokinetic agents in the United States, such asetoclopramide and erythromycin, have not been specifi-

ally studied.Psychotropic medications. Tricyclic antidepres-

ants may have significant benefits in suppressing symp-oms in some patients with nausea and vomiting as wells patients with abdominal pain.229 In one retrospectivenalysis, tricyclic antidepressants reduced symptoms inatients with functional vomiting.230 In 2 recent studiesn functional dyspepsia and one in diabetic gastropathy,ow-dose tricyclic antidepressants decreased dyspepticymptoms and abdominal pain.231,232 In an unpublishedetrospective evaluation of diabetic patients with nauseand vomiting, tricyclic antidepressants provided betterymptom reduction than prior trials of antiemetic androkinetic drugs.233 In this study, nearly one third ofatients exhibited delayed gastric emptying, suggestinghat the presence of impaired motor function is notecessarily a contraindication to use of this drug class.oses of tricyclic antidepressants used are lower thansed to treat depression. A reasonable starting dose for aricyclic drug is 10–25 mg at bedtime. If benefit is notbserved in several weeks, doses are increased by 10- to5-mg increments up to 50–100 mg. Side effects areommon with use of tricyclic antidepressants and cannterfere with management and lead to a change inedication in 25% of patients.229 The secondary amines,

ortriptyline and desipramine, may have fewer side ef-ects. There are limited data on the use of selectiveerotonin reuptake inhibitors in gastroparesis or func-ional dyspepsia.

Pyloric botulinum toxin injection. Gastric empty-ng is a highly regulated process reflecting the integra-ion of the propulsive forces of proximal fundic tone andistal antral contractions with the functional resistancerovided by the pylorus. Manometric studies of patientsith diabetic gastroparesis show prolonged periods of

ncreased pyloric tone and phasic contractions, a phe-omenon termed pylorospasm.45 One unpublished inves-igation has reported symptom benefits with surgicalyloromyotomy in patients with diabetic gastropare-is.234 Botulinum toxin is a potent inhibitor of neuro-uscular transmission and has been used to treat spastic

omatic muscle disorders as well as achalasia.235 Several t

tudies have tested the effects of pyloric injection ofotulinum toxin in patients with diabetic and idiopathicastroparesis (Table 9).236–242 These studies have all beennblinded in small numbers of patients from singleenters and have observed mild improvements in gastricmptying and modest reductions in symptoms for severalonths. Double-blind controlled studies are needed to

upport the efficacy of this treatment.Gastric electric stimulation. Gastric electric

timulation is an emerging treatment for refractory gas-roparesis (Table 10).243–249 There are several techniquesor stimulating the stomach. Electrical stimulation at arequency 10% higher than that of the intrinsic slowave entrains and paces gastric myoelectric activity withigh-energy, long-duration pulses. This technique haseen reported to accelerate gastric emptying and improveyspeptic symptoms in a small uncontrolled series.244

ore recently, an implantable neurostimulator that de-ivers a high-frequency (12 cpm), low-energy signal withhort pulses has been studied in patients with idiopathicnd diabetic gastroparesis. The higher-frequency stimu-us does not entrain slow waves or reverse underlyinglow wave dysrhythmias. With this device, stimulatingires are sutured into the gastric muscle along thereater curvature during laparoscopy or laparotomy.hese leads are attached to the electric stimulator, which

s positioned in a subcutaneous abdominal pouch. Annitial study showed effectiveness in 20 of 26 patients,ith decreases in nausea and vomiting at 3 and 6onths.248 In this investigation, gastric neurostimula-

ion promoted gastric emptying of liquids but not solids.n long-term follow-up, 3 patients underwent total gas-rectomy due to unsatisfactory results and 3 requiredevice removal secondary to erosion or infection. A sec-nd study of 33 patients with chronic gastroparesis con-isted of an initial double-blind sham stimulation-con-rolled trial for 2 months followed by an open phase inhich the device was activated for 1 year.249 During thelinded phase of the investigation, patients felt betterhen the stimulator was turned on with a small but

ignificant reduction in vomiting frequency. The im-rovement was seen primarily in patients with diabeticather than idiopathic gastroparesis. Long-term fol-ow-up over 1 year showed a decrease in the meanomiting frequency from 25 to 6 times per week with anssociated improvement in quality of life. Subsequenttudies have reported improvements in nutritional pa-ameters and decreased requirements for supplementaleedings.250 Some open-label studies have not shownenefit.251 The main complication of the implantableeurostimulator has been infection, which has necessi-
ated device removal in approximately 5%–10% of cases.

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ecause of potential benefits, the gastric electric neuro-timulator was granted humanitarian approval from theDA for the treatment of chronic, refractory nausea andomiting secondary to idiopathic or diabetic gastropare-is. Presently, reimbursement for implantation of thisevice is obtained by petitioning third-party payers onn individual basis. Further investigation is needed toonfirm the effectiveness of gastric stimulation in long-erm blinded fashion, which patients are likely to re-pond, the optimal electrode position, and the optimaltimulation parameters, none of which have been rigor-usly evaluated to date. Future improvements may in-lude devices that sequentially stimulate the stomach inperistaltic sequence to promote gastric emptying.252

Gastrostomy and jejunostomy placement. In re-ractory patients with severe nausea and vomiting, place-ent of a gastrostomy tube for intermittent decompres-

ion by venting or suctioning may provide symptomelief, especially of interdigestive fullness and bloatingecondary to retained intragastric gas and liquids. Thispproach also has been suggested for patients with re-ractory vomiting that responds to nasogastric decom-

able 9. Systematic Review of Studies on Botulinum Toxin In


No. ofsubjects Types of

harma et al,1998236

Open label 1 Diabetic gastro

acy et al, 2000237 Open label 3 Diabetic gastrouddasani andIsmail-Beigi,2001238


zzeddine et al2002239


acy et al, 2002240 Open label 8 Diabetic gastro

iller et al,2002241

Open label 10 Idiopathic gast

rts et al, 2003242 Open label 20 Diabetic gastroIdiopathic gastr

ression.253 Venting gastrostomies may be placed endo- d

copically, surgically, or by interventional radiology. Inne series, symptoms were reduced, patients gainedeight, and 6 of 8 patients were able to return to

ull-time work or school.254

For patients with gastroparesis who are unable toaintain nutrition with oral intake, placement of a feed-

ng jejunostomy may decrease symptoms and reduceospitalizations.255 Jejunostomy tubes are effective forroviding nutrition, fluids, and medications if there isormal small intestinal motor function.255,256 Except inases of profound malnutrition or electrolyte disturbance,nteral feedings are preferable to chronic parenteral nu-rition because of the significant risks of infection andiver disease with the latter treatment, especially in di-betic patients. In contrast, home intravenous hyperali-entation may be needed for individuals with general-

zed dysmotility unresponsive to dietary and medicationanagement. The therapeutic response to jejunostomy

nfusion may be predicted by a trial of nasojejunal feed-ngs,253 which should precede placement of a permanentejunostomy tube if small bowel dysmotility is sus-ected. Jejunostomy tubes usually are surgically placed

on Into the Pyloric Sphincter for Treatment of Gastroparesis

nts

Dose ofbotulinum

toxinLength of


is 80 U 4 mo Symptoms improvedGastric emptying improved

by 33%is 200 U 4–10 wk Symptoms improvedis 200 U 4.5 mo Symptoms improved


is 100 U 6 wk Symptoms decrease by55% at 2 and 6 weeks

Gastric emptying improvedby 43% at 2 and 6weeks

is 200 U 12 wk Symptoms improved by58%

One half of patients hadimprovement in gastricemptying

esis 80–100 U 4 wk Symptoms improved by38% at 1 month

Gastric emptying improvedby 48% at 1 month

Many required subsequenttreatments over 6-month follow-up

is (3)esis (17)

100 U 1 mo Symptoms improved by29% at 1 month

Gastric emptying of solidsimproved by 35% at 1month

jecti

patie

pares

parespares

pares

pares

ropar

paresopar

uring laparoscopy or laparotomy, although a few centers

psneisprmiwt

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lace these endoscopically.257 Nutrient feedings aretarted at low infusion rates of 20 mL/h with dilutedutrient meals and advanced slowly (increase of 10 mL/hvery 12 hours) until the goal of daily nutritional intakes obtained with iso-osmolar infusions. Glucose levelshould be checked frequently in diabetic patients, withrovision for supplemental insulin as necessary. Carefullyegulated enteral nutrient infusion may improve glyce-ic control in diabetic patients with refractory vomit-

ng.256 Nocturnal feedings only may permit daytimeorking and functioning. Complications include infec-

ion, tube dysfunction, and tube dislodgment.253,255

Surgical treatment of gastroparesis. There areimited controlled data concerning surgical treatment ofiabetic or idiopathic gastroparesis.253 In general, mostncontrolled studies report disappointing responses toperative resection in these patients.24 Surgery is per-ormed only as a last resort in carefully evaluated patientsith profound gastric stasis.253 The procedure usuallysed is a partial gastrectomy with Roux-en-Y gastroje-unostomy. Subtotal gastrectomy (70%) with resection ofntrum and pylorus, closure of the duodenum, and res-oration of gastrointestinal continuity with a 60-cmoux-en-Y jejunal loop has been reported to be of benefit

able 10. Systematic Review of Studies on Gastric Electric S


No. ofsubjects Types of patients

amiloni etal, 1997243

Open label 1 Diabetic gastroparesis

cCallum etal, 1998244

Open label 9 Diabetic gastroparesis (5)Idiopathic gastroparesis (3)Postsurgical gastroparesis

orster et al,2001245

Open label 25 Diabetic gastroparesis (19)Idiopathic gastroparesis (3)Postsurgical gastroparesis

obrino et al,2002246

Open label 15 Diabetic gastroparesis (9)Idiopathic gastroparesis (5)Postvagotomy gastroparesi

(1)kole et al,2002247

Open label 11 Diabetic gastroparesis (7)Idiopathic gastroparesis (4)

bell et al,2002248

Open label,multicenter

38 Idiopathic gastroparesis (24Diabetic gastroparesis (9)Postsurgical gastroparesis

bell et al,2003249

Double-blind,multicenter

33 Diabetic gastroparesis (17)Idiopathic gastroparesis (16

n 2 small studies of 4 and 7 patients with type 1 t

iabetes mellitus who had gastroparesis and intractableomiting, although 3 of the 7 patients in the seconderies developed renal failure and 2 died within 5 monthsf surgery.79,258

Gastric resection may be a more viable therapy forelected patients with postsurgical gastroparesis who arenresponsive to treatment with prokinetic or antiemeticrugs or in whom complications such as malnutrition orspiration develop. These patients may require this rad-cal surgery to eliminate stasis in an atonic stomach andreation or revision of a Roux limb to prevent entero-astric reflux. Most commonly, the remainder of thetomach is resected (completion gastrectomy), leavingnly a small rim (�1 cm) of proximal stomach foronstruction of an anastomosis.259,260 A Roux limb of ateast 45 cm to the rim of the stomach is constructed.tudies have suggested that this extensive surgery leadso improvement in 43%–67% of patients.259,261,262 Theombination of nausea, the need for TPN, and the pres-nce of retained food at endoscopy predicted a poorutcome. Reports of completion gastrectomy for post-urgical gastroparesis are uncontrolled case series or ret-ospective reviews; prospective investigation is warranted

lation for Treatment of Gastroparesis

InterventionLength of


Gastric electric stimulation(high frequency, lowamplitude)

1 y Symptoms improvedGastric emptying

improvedGastric pacing (low frequency,

high amplitude)1 mo Symptoms decreased by

46%Gastric emptying

improved by 26%Gastric electric stimulation

(high frequency, lowamplitude)

12 mo Improved symptoms by34%

Gastric emptyingimproved in 14 of 21,not significant


7.3 mo Symptoms improved in14 of 15 patients


6 mo Symptoms improved in6 of 11 patients


2–4 wk11 mo

Symptoms improved in33 of 38 patients

Improved symptomsGastric electric stimulation

(high frequency, lowamplitude)

1 mo12 mo

Double blind: symptomsdecreased by 15%

Open label: symptomsdecreased by 39%

Gastric emptyingimproved by 19%

timu

(1)

(3)

s

)

(5)

)

o confirm the benefits of this operation.253

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Pancreas transplants and simultaneous kidney-pan-reas transplants are being increasingly performed foratients with type 1 diabetes mellitus. With success-ul pancreatic transplantation, postprandial hypergly-emia resolves and treatment with insulin can beiscontinued.263 Simultaneous kidney-pancreas trans-lantation may correct both uremia and hyperglyce-ia. Pancreatic transplantation has been shown to halt

rogression and slightly improve diabetic peripheralolyneuropathy.264 The literature is sparse concerningffects on gastric emptying. One study reported im-rovement in gastric emptying of liquids in 6 of 8atients with previously delayed emptying but nomprovement in emptying of solids 6 months afterransplantation.263 Another study observed improvedmptying in 8 of 23 patients 1 year after kidney-ancreas transplantation.265 Some investigators re-orted improved symptoms and improved gastric dys-hythmias in diabetic patients after transplantationespite minimal acceleration of emptying.263,265

New Directions in the Treatment of GastricDysmotility Syndromes

Novel prokinetic agents. New prokinetic agentseing tested for gastroparesis include 5-HT4 receptorgonists (tegaserod and mosapride), dopamine recep-or antagonists (levosulpiride), cholecystokinin recep-or antagonists (dexloxiglumide), and motilin receptorgonists (mitemcinal [GM-611]). Levosulpiride, withoth antiemetic and prokinetic effects, may relieveymptoms and accelerate gastric emptying in diabeticatients with gastroparesis.266 Loxiglumide, a chole-ystokinin-A receptor antagonist, increases antralontractility and accelerates gastric emptying inealthy subjects, suggesting possible utility inastroparesis.267

Fundic relaxing agents. Agents that relax theundus and improve accommodation may be helpful inome patients with gastroparesis and functional dyspep-ia, especially when early satiety is prominent. 5-HT1

eceptor agonists (sumatriptan, buspirone),268 �-adren-rgic receptor agonists (clonidine), and NO donors (ni-roglycerin) have been evaluated in physiologic stud-es.269 Clonidine reduces proximal gastric tone and painerception with gastric distention in healthy subjects.269

n dyspeptic patients, clonidine reduces symptoms bymproving gastric accommodation.269 Clonidine has beeneported to decrease symptoms and accelerate gastricmptying in diabetic patients with gastroparesis, al-hough others have observed slowing of emptying withhe drug.270,271 The 5-HT1 agonists evoke fundic relax-
tion through an NO-mediated pathway.268 Sumatriptan s
llows accommodation of larger volumes before percep-ion or discomfort is reached and improves meal-inducedatiety in patients with functional dyspepsia.268 Buspi-one, another oral 5-HT1 agonist, has anxiolytic proper-ies in addition to its fundic relaxant capabilities. Un-ublished observations suggest that sildenafil augmentsastric accommodation by enhancing the effects ofO.272 In an animal study, sildenafil promoted pyloric

elaxation and accelerated gastric emptying.81 However,subsequent investigation in rats reported that sildenafilelayed liquid gastric emptying and small bowel transitnd an unpublished study in humans also observed delayf gastric emptying.273

Gastric slow wave antidysrhythmics. Many pro-inetic drugs (metoclopramide, domperidone, cisapride)lso stabilize dysrhythmic slow wave activity in patientsith gastroparesis.8,274 In some studies, resolution of

low wave rhythm disturbances correlates better withymptomatic improvement than does acceleration of gas-ric emptying.8 Prostaglandin inhibitors have beenhown to resolve tachygastrias during hyperglycemia.85

n some patients, indomethacin has reduced symptomsnd reversed gastric myoelectrical abnormalities.275 Un-ortunately, indomethacin is also ulcerogenic.

Alternative and unconventional medical thera-ies. Complementary therapies and alternative medi-ines are used frequently by patients with gastroparesisnd functional dyspepsia. Ginger, a traditional Chineseerbal remedy, reduces nausea and associated tachy-astria caused by experimental motion sickness. Gingerlso reduces hyperglycemia-induced gastric dysrhyth-ias and nausea.276 Psychodynamic interpersonal psy-

hotherapy and hypnotherapy have been reported to beelpful in functional dyspepsia.277,278 Biofeedback andypnotic techniques to accelerate gastric emptying inastroparetic patients are being explored.279 Stimulationf the PC6 point on the wrist with acupuncture, elec-roacupuncture, electrical stimulation, or acupressureay control postoperative nausea, chemotherapy-

nduced nausea, and nausea during the first trimester ofregnancy.280–283 The Zusanli point (ST36) located be-ow the patella is another site of acupuncture stimulationith effects on gastric motility.284 Animal studies sug-est that electroacupuncture accelerates gastric emptyingy stimulation of vagal pathways.283 Electroacupunctures postulated to modulate serotonin, substance P, andndogenous opioid pathways in the CNS.285 Naloxone,n opioid receptor antagonist, blocks the analgesic effectf acupuncture and worsens symptoms of motion
ickness.285

meTmaiaEdt


Conclusion

This report has reviewed the diagnosis and treat-ent of gastroparesis. Several tests are available for the

valuation of patients with suspected gastroparesis.reatments of gastric dysmotility rely on dietary, phar-acologic, and surgical therapies that relieve symptoms

nd maintain adequate nutrition. This is an area of activenvestigation because the current therapy is suboptimalnd existing treatments have not been well studied.vidence-based investigation will be required to betterefine appropriate approaches to this challenging condi-ion.

HENRY P. PARKMANTemple University School of MedicinePhiladelphia, Pennsylvania

WILLIAM L. HASLERUniversity of Michigan Medical CenterAnn Arbor, Michigan

ROBERT S. FISHERTemple University School of MedicinePhiladelphia, Pennsylvania

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Address requests for reprints to: Chair, Clinical Practice Committee,GA National Office, c/o Membership Department, 4930 Del Rayvenue, Bethesda, Maryland 20814. Fax: (301) 654-5920.The Clinical Practice Committee acknowledges the following indi-

iduals whose critiques of this review paper provided valuable guid-nce to the authors: Jeffrey A. Barnett, MD, Manoop S. Bhutani, MD,
ay Pascricha, MD, and John C. Rabine, MD.

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