American Gastroenterological Association Technical Review on

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