Tests of Gastric Neuromuscular Function

Gastric accommodation 

Gastric accommodation is a postprandial, vagally mediated reflex resulting in reduced gastric tone primarily in the proximal stomach that occurs with eating a meal (Figure 1).4 Gastric accommodation provides a reservoir for ingested foods in the stomach without a significant increase in intragastric pressure.

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Figure 1. Schematic of a stomach with regional gastric physiology/function. Gastric emptying reflects the coordinated function of the fundus, corpus, antrum, pylorus, and duodenum. Important events for gastric emptying include fundic relaxation and accommodation, antral contractions for trituration, pyloric opening, and overall fundic-antral-pyloric-duodenal coordination. Adapted with permission from Lacy et al.154

The accommodation reflex has 2 principal components. First, receptive relaxation occurs within seconds of eating and is triggered by both oropharyngeal and gastric stimulation. This response involves relaxation of both the lower esophageal sphincter and proximal stomach. Second, adaptive relaxation is a slower process triggered by gastric or duodenal distention and perhaps also modified by specific nutrients.5, 6 The accommodation reflex is vagally mediated and represents the balance between cholinergic excitatory drive and nonadrenergic, noncholinergic inhibitory input. The afferent signal is generated by activation of stretch-sensitive mechanoreceptors in the stomach wall and by activation of osmoreceptors and chemoreceptors in the stomach and duodenum.7 The efferent nonadrenergic, noncholinergic signal involves nitric oxide as the principal neurotransmitter.8, 9 A role for vasoactive intestinal polypeptide has also been suggested.10 Gastric tone is also modulated by sympathetic inputs acting directly through postjunctional α1-adrenoceptors and indirectly on cholinergic nerve terminals mediated by prejunctional α2-adrenoceptors.8, 9, 11

The accommodation reflex is most often recorded using either a gastric barostat or imaging methods such as single photon emission computed tomography (SPECT) or magnetic resonance imaging (MRI), yet these techniques do not allow discrimination of the active and receptive relaxation phases. Additionally, the roles for various nutritional parameters in modifying accommodation such as meal volume and rate of ingestion, caloric density, and macronutrient content require greater clarification and may have substantial clinical relevance.

Gastric emptying of a meal 

Normal gastric emptying reflects a coordinated effort between the fundus, antrum, pyloric sphincter, and duodenum (Figure 1).1, 2 Coordination of these fundic-antral-pyloric-duodenal motor events is carefully regulated and governed by gastrointestinal electrical activity through the interstitial cells of Cajal and neural connectivity through enteric nerves and vagal efferent nerves from the central nervous system. Feedback from nutrients and volume in the stomach and the small bowel impact on the process of gastric emptying and is conveyed though local enteric sensory nerves, vagal afferent nerves, and hormones.

Fundic and antral smooth muscle contractions are primarily cholinergically mediated. Rhythmic antral contractions, generally at 3 cycles/min, triturate large food particles into an appropriate size for intestinal digestion. The rate of these contractions is governed by the electrical pacemaker of the stomach and the interstitial cells of Cajal.

Pyloric sphincter relaxation, often synchronized with antral contractions, allows smaller food particles and chyme to pass out of the stomach into the duodenum.2 Pyloric relaxation is mediated through release of inhibitory nerves, especially NO and possibly vasoactive intestinal polypeptide.

Solid and liquid food empty from the stomach at different rates.2 Liquids empty from the stomach at an exponential rate because their emptying depends primarily on the gastric-duodenal pressure gradient with less importance on pyloric opening. Solids are initially retained selectively within the stomach until particles have been triturated to a size <2 mm, at which point they can be emptied at a linear rate from the stomach.

Ascending pathways 

Visceral sensation is transmitted from the digestive tract to the central nervous system primarily via afferent pathways in the vagus nerve and spinal afferent system. Afferent vagal neurons project mainly to the solitary tract nucleus, with secondary projections ascending to the thalamus and directly to other brain structures involved in arousal, homeostatic, and emotional behaviors.12, 13 These regions include the hypothalamus, locus coeruleus, amygdala, and periaqueductal gray. Third-order neurons project from the thalamus to the sensory cortex.

Primary spinal visceral afferent nerves synapse in the dorsal horn of the spinal cord, with secondary neurons projecting proximally through the spinoreticular, spinomesencephalic, spinohypothalamic, and spinothalamic tracts.14, 15, 16 Spinoreticular inputs activate reflexive responses to visceral sensation without conscious awareness. The spinothalamic tract projects to the ventral posterior lateral, medial dorsal, and ventral medial posterior nuclei of the sensory thalamus, from which tertiary neurons relay digestive sensory signals to the primary somatosensory cortex (S1 and S2), the cingulate cortex, and the insula, respectively.

Gastrointestinal signaling systems are important in regulating eating behavior and metabolic control.17 Ghrelin is an identified hunger-driving hormone originating from the gastrointestinal tract, where it is mainly found in the mucosa of the proximal stomach. Neuropeptides in the brain, which influence food intake, are regulated by peptide signaling from the gut. Effects may take place directly through action of gut peptide in the brain or through neural signaling from the periphery to the brain; neuropeptide Y, agouti gene-related peptide, and orexins are stimulatory, while melanocortins and α-melanocortin–stimulating hormone are inhibitory. Satiety signals from the gastrointestinal tract act through the arcuate nucleus of the hypothalamus and the solitary tract nucleus of the brain stem, where neuronal networks directly linked to hypothalamic centers for food intake and eating behavior are activated. Gut hormone and neurotransmitters influencing satiation include cholecystokinin, glucagon-like peptide 1, and peptide YY.

The brain stem sensory apparatus, vomiting center, and area postrema are also relevant for the sensations of nausea and vomiting. Abdominal vagal afferents that detect intestinal luminal contents and gastric tone terminate in the nucleus tractus solitarius. Neurons from the nucleus tractus solitarius project to a central pattern generator, which coordinates the sequence of behaviors during emesis, as well as directly to diverse populations of neurons in the ventral medulla and hypothalamus (“vomiting center”).18

Cortical structures involved in sensory processing 

The cingulate cortex is referred to as the medial pain system and is mainly involved in the affective and motivational dimension of somatic and visceral stimuli.16 The anterior cingulate cortex functions primarily to integrate visceral, attentional, and emotional information and to regulate affect.19 The prefrontal cortex is involved in affective processing and in selecting and generating responses to this sensory input.20 The somatosensory cortex (S1/S2) is also referred to as the lateral pain system and functions to encode intensity and localization of somatic and visceral stimuli. The insular cortex is involved in encoding sensory and affective dimensions of pain and integrates visceral and somatic sensory input with emotional information.21 Signals from the insular cortex to the amygdala, hypothalamus, periaqueductal gray, and other limbic and brain stem regions provide cortical regulation of autonomic visceromotor responses.21

Descending pathways 

According to the gate control theory, the brain modulates afferent pain signals by dispersing inhibitory signals to the spinal cord.22 The perigenual anterior cingulate cortex sends inhibitory efferent signals directly and indirectly that travel by way of the opioidergic, serotoninergic, and noradrenergic systems to the dorsal horn of the spinal cord, where they presynaptically inhibit the afferent pain signals.23 Because brain regions involved in descending pain inhibition are also implicated in the processing of visceral, attentional, and emotional information, the dispersal of inhibitory efferent messages by these structures may be mediated by cognitive, emotional, and behavioral factors.

Psychological factors and visceral sensation 

Almost all of the brain regions involved in the processing and integration of visceral sensory information are part of a larger central neural network known as the limbic system, which is heavily involved in the identification, generation, and regulation of emotion.24, 25 It is also involved in the “top-down” modulation of visceral pain transmission as well as visceral perception.

Experimentally induced anxiety in healthy subjects is associated with increased epigastric symptom scores during a standard nutrient drink test and is also associated with decreased gastric compliance and accommodation to a test meal in healthy volunteers.26 Similarly, state anxiety in hypersensitive patients with functional dyspepsia is significantly and negatively correlated with discomfort threshold, pain threshold, and gastric compliance.27 Finally, functional neuroimaging studies combined with behavioral conditioning paradigms have shown that both actual and anticipated visceral pain activate the visceral pain matrix.28 These representative studies show the importance of affective and cognitive processes in modifying digestive sensations.

Diabetes mellitus 

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. Longitudinal studies, primarily from academic centers, suggest that delayed gastric emptying is present in 25%–55% of patients with type 1 diabetes mellitus.42, 43 Community studies suggest the prevalence of gastroparesis is lower, because only about 15% of diabetic patients have symptoms of gastroparesis. Gastroparesis has also been described in approximately 30% of patients with type 2 diabetes mellitus.32 However, highly variable rates of gastric emptying, including acceleration of transit, have been reported in both type 1 and type 2 diabetes mellitus, suggesting that development of gastroparesis is not universal or inevitable.43, 44, 45 Some 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 present.46

Clinical consequences of diabetic gastroparesis include gastrointestinal symptoms, alteration in drug absorption from delayed emptying of medications from the stomach, and poor glycemic control.42 Symptoms include 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.35 Symptom severity, however, does not necessarily correlate well with the degree of gastric stasis.32, 47 Some patients with severe symptoms may have near-normal to normal emptying. In these individuals, other abnormalities, including impaired fundic relaxation, gastric slow wave dysrhythmias, or visceral hypersensitivity, may be potentially responsible for dyspeptic symptoms.32 “Diabetic gastropathy” is commonly used because symptoms may not predict delays in gastric emptying and responses to prokinetic treatment may not be consequences of accelerated emptying.

Changes in gastric emptying may affect postprandial blood glucose concentrations because of unpredictable delivery of food into the duodenum.48 Conversely, poor glycemic control may adversely affect gastric function and be associated with symptoms such as nausea and vomiting. Long-term oral administration of prokinetic agents has had mixed results in decreasing plasma glucose and glycosylated hemoglobin levels in diabetic patients.49, 50, 51

Diabetic gastroparesis is likely to result from impaired neural control of gastric motility, possibly at the level of the vagus nerve or enteric nervous system.29 Other factors, including impairment of the inhibitory NO-containing nerves,52 damage of the pacemaker interstitial cells of Cajal,53 and underlying smooth muscle dysfunction, have been described in animal models and patients with diabetic gastroparesis.54, 55

Hyperglycemia alone also may reversibly impair vagal efferent function as well as gastric and pyloric motility and reduce the effectiveness of prokinetic agents.56 Hyperglycemia decreases antral contractility, decreases antral phase III of the migrating motor complex, increases pyloric contractions, causes gastric dysrhythmias (primarily tachygastria), delays gastric emptying, and even modulates fundic relaxation properties.57, 58 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.56

Patients with type 1 diabetes mellitus also appear to have sensory dysfunction and exhibit increased perception of gastric distention, with exaggerated nausea, fullness, and epigastric pain for a given distending stimulus.58 In addition to its effects on motor function, hyperglycemia increases nausea and fullness during proximal gastric distention.46, 59 Increased sensitivity of the proximal stomach may be responsible for postprandial dyspeptic symptoms when the stomach is distended by a meal.58, 59

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. Chronic intestinal pseudo-obstruction can be caused by a variety of systemic diseases, including scleroderma, amyloidosis, myxedema, long-standing 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. Antroduodenal manometry may assist in differentiating these 2 forms.2 In intestinal myopathy, low-amplitude contractions that propagate normally are seen. In intestinal neuropathy, contractions are normal in amplitude but disorganized in morphology, including disruption of phase III activity, bursts of nonpropagating activity during fasting, and failure to convert from the fasting to the postprandial fed motor pattern.

Cyclic vomiting syndrome 

Cyclic vomiting syndrome was first described in children but is now recognized to affect patients at any age. There is a typical vomiting pattern consisting of recurrent episodes of severe nausea and vomiting lasting hours or days, separated by symptom-free intervals.79 The syndrome is considered to be a manifestation of migraine diathesis.80 Prodromal symptoms often include nausea, lethargy, anorexia, and pallor, but migraine-like aura is rare. The nausea and vomiting is severe and can often be completely incapacitating. In adults, the average frequency of vomiting and retching is 8.5 times per hour, with a range of 0.5 to 20 times per hour.79 The emetic phase can last anywhere from 12 hours to 1 week.

Disturbances in gastric motility have been reported in cyclic vomiting syndrome, although no consistent disturbance is seen. Gastric and intestinal hypomotility have been identified in a subgroup of patients between vomiting episodes.81, 82 Recently, several investigators have reported gastric emptying to be accelerated when these patients are feeling well.82

Central disorders associated with altered gastric physiology 

Gastric emptying scintigraphy 

Scintigraphic determination of the emptying rate of a solid meal from the stomach is regarded as the standard measurement technique for gastric emptying (Table 3, Table 4). Determination of emptying rates of liquid meals is less sensitive and generally reserved for the evaluation of dumping syndrome and postgastric surgical disorders. The usefulness of gastric scintigraphy in directing therapy and predicting response, however, has been debated.38, 97

Table 3. Disorders With Abnormalities in Gastric Physiology/Function

	Delayed gastric emptying
	Gastroparesis
	Chronic intestinal pseudo-obstruction
	Functional dyspepsia
	Rapid gastric emptying
	Dumping syndrome
	Cyclic vomiting syndrome
	Postfundoplication
	Functional dyspepsia
	Disorders with sensory abnormalities
	Functional dyspepsia

Table 4. Tests of Gastric Motility and Function

	Gastric emptying
	Barium
	Radiopaque markers
	Scintigraphy
	Breath tests (13C-octanoic acid)
	Ultrasonography
	MRI
	Applied potential tomography/epigastric impedance
	Wireless capsule motility (SmartPill pH/pressure capsule)
	Contractile pressures
	Antroduodenal manometry
	Dynamic antral scintigraphy
	Gastric barostat
	Gastric myoelectric activity
	EGG
	Biomagnetic field recording - SQUID
	Accommodation
	Gastric barostat
	Gastric mucosal labeling with SPECT imaging
	Satiety
	Water loading
	Nutrient loading

For solid-phase testing, most centers use a 99mTc sulfur colloid–labeled egg sandwich as a test meal1 (Figure 2). A recent consensus statement from the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine recommends a standardized method for measuring gastric emptying by scintigraphy.98 A low-fat egg white meal (Eggbeaters egg whites; ConAgra Foods, Inc, Downers, IL) with imaging at 0, 1, 2, and 4 hours after meal ingestion, as described by a published multicenter protocol,99 provides standardized information about normal, delayed, and rapid gastric emptying and is currently the best way to conduct a scintigraphic gastric emptying test. Extending scintigraphy to 4 hours is advocated to improve the accuracy in determining the presence of delayed gastric emptying.100, 101 Adoption of this standardized protocol will resolve the lack of uniformity of testing, add reliability and credibility to the results, and improve the clinical utility of the gastric emptying test.98 This test meal has a low fat content and theoretically might produce different results than conventional meals. Imaging periods of ≤2 hours have been shown to have significant day-to-day variability (up to 20%) in rates of gastric emptying, which increase as the postprandial imaging period decreases.102

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Figure 2. Gastric emptying scintigraphy. After ingestion of a radioactive egg sandwich meal, images are obtained immediately after eating (T = 0) and at 1, 2, 3, and 4 hours postprandially (upper panel). The percent remaining in the stomach is depicted over time (lower panel).

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 a markedly inaccurate determination of the half-emptying time.2

Patients should discontinue medications that may affect gastric emptying for an adequate period before this test based on drug half-life. Generally, this is for 3 days before the test. The drugs to be primarily concerned about include narcotic opioid analgesics as well as anticholinergic agents that can delay gastric emptying and prokinetic agents that can accelerate gastric emptying. Other agents may also impact on gastric emptying, including those used to treat diabetes, such as pramlintide (an amylin-like compound) and exenatide (a GPL-1 receptor agonist). 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.56 Deferring gastric emptying testing until relative euglycemia is achieved is reasonable to obtain a reliable determination of emptying parameters in the absence of acute metabolic derangement. Premenopausal women have slower gastric emptying than men,103, 104 so some advocate using separate reference values for premenopausal women.30

Regional gastric emptying can assess intragastric meal distribution and transit from the proximal to distal portions of the stomach and may provide greater information regarding fundal and antral function (Figure 3). The routine gastric emptying imaging can be used to measure both regional and total gastric emptying. Visual inspection of fundal and antral gastric emptying and quantification of regional emptying with fundic and antral regions of interest can be helpful for defining abnormal physiology and explaining dyspeptic symptoms, especially when global gastric emptying values are normal.105, 106, 107, 108 Studies have shown an association between symptoms of nausea, early satiety, abdominal distention, and acid reflux with proximal gastric retention, whereas vomiting is associated more with delayed distal gastric emptying.106

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Figure 3. Regional gastric emptying with delayed distal gastric emptying in functional dyspepsia. The figure demonstrates selective retention in the distal stomach, notably seen at 240 minutes after meal ingestion.

Wireless capsule motility for assessment of gastric emptying 

The SmartPill pH/pressure capsule is an ingestible capsule that measures pH, pressure, and temperature using miniaturized wireless sensor technology as the capsule travels through the digestive tract. Gastric emptying of the SmartPill is identified by the abrupt acidic pH profile of the stomach to the alkaline pH of the duodenum (Figure 4). In addition, pressure profiles provide motility indices for the stomach, small intestine, and colon. The SmartPill GI Monitoring System has been approved by the US Food and Drug Administration for the assessment of gastric pH, gastric emptying, and total gastrointestinal transit time. Gastric emptying as measured by the SmartPill is closely correlated with the T-90% for gastric emptying109 and appears to empty with the phase III migrating motor complex, signifying completion of the postprandial phase and return to the fasting condition.110 In validation studies conducted with simultaneous gastric emptying scintigraphy in healthy subjects and patients with symptoms of gastroparesis, the gastric emptying time of the wireless pH and pressure capsule was significantly correlated (r = 0.73) with scintigraphic gastric emptying.109 Using a 5-hour cutoff for gastric emptying, the capsule discriminated between normal or delayed gastric emptying with a sensitivity of 0.87 and a specificity of 0.92. In addition to measuring gastric emptying, this nondigestible pH and pressure capsule can measure small bowel transit and colonic transit.111

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Figure 4. Capsule assessment of gastric emptying using a pH/pressure-sensing capsule. After capsule ingestion at time 0, the pH tracing (red line) decreases to a pH of about 1.4. This is followed by an increase in pH representing the buffering of the gastric acid by a meal, followed by a decline of the gastric pH to about 1. At 2¾ hours after capsule ingestion, there is an abrupt increase in pH from 1 to 6 representing the expulsion of the capsule from the acidic stomach to the alkaline duodenum. This gastric emptying of the capsule is preceded by high-amplitude contractions (blue line).

Breath testing for gastric emptying 

Stable isotope breath tests for gastric emptying represent a promising way to evaluate gastric emptying noninvasively and without radiation exposure. 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 medium-chain triglyceride, is bound into a solid meal such as a muffin.112, 113, 114 Other studies have bound 13C to acetate or proteinaceous algae (Spirulina platensis).115 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 (Figure 5). The rate-limiting step is the rate of solid gastric emptying. Thus, 13C breath testing provides a measure of solid-phase emptying. The 13C breath test provides reproducible results that correlate with findings on gastric emptying scintigraphy.112, 113, 114 Because these tests do not involve radiation exposure, they can be used in the clinic or at the bedside. Breath samples can be preserved and shipped to a laboratory for analysis. Stable isotope breath testing is currently used mainly in a research setting. Validation of this test in patients with emphysema, cirrhosis, celiac sprue, and pancreatic insufficiency is needed, because rates of substrate digestion and excretion may be impaired in these disorders. Although widely used in Europe, presently this test is not approved for routine clinical practice in the United States. The current lack of a commercially available standard meal prevents widespread adoption of this technology for clinical use. Promising validation studies have been performed with a shelf-stable product consisting of a freeze-dried egg mix labeled with 13C platensis, saltine crackers, and meal.115 This meal was simultaneously evaluated with scintigraphy in 38 normal subjects and 129 patients with gastroparetic symptoms. Individual breath samples were collected at 45, 150, and 180 minutes after meal ingestion with 89% sensitivity for identifying delayed gastric emptying and 93% sensitivity for identifying accelerated gastric emptying.

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Figure 5. 13C-Octanoate breath test for gastric emptying. Sequential breath samples every 15 minutes are obtained after ingestion of a 13C-octanoate containing meal. These are analyzed for the fractional excretion of 13C and can be expressed as the fraction remaining or the percent dose per hour (A). B illustrates the good correlation between breath testing and scintigraphy in assessing gastric emptying when tests are performed simultaneously. Reprinted with permission from Chey et al.155

Ultrasonography 

Transabdominal ultrasonography measures several parameters of gastric motor function, including emptying, gastroduodenal flow, contractility, and accommodation.116 Serial changes in antral cross-sectional area can provide an index of gastric emptying. Duplex sonography can quantify transpyloric flow of liquid gastric contents. Ultrasonography also has been used to measure accommodation in the proximal stomach. 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. Ultrasonography is most commonly used only in research settings. Recent studies suggest that 3-dimensional ultrasonography may allow a precise measure of gastric emptying, given the capacity for accurate volume calculations of the stomach.117

MRI 

MRI can measure gastric emptying and gastric volume, an index of gastric accommodation. In this test, transaxial abdominal scans are generally obtained in the supine position every 15 minutes before and after a predominately liquid meal, applying a spin-echo technique with T1-weighted images.116 MRI can differentiate between gastric meal volume and total gastric volume, allowing determination of gastric secretory rates. This noninvasive test is appealing because MRI can be used to measure gastric emptying, volume, and wall motion without radiation exposure. In addition, MRI has the ability to separately assess the emptying of fat and water from the stomach. Recent studies suggest that postprandial gastric expansion is accompanied by increased gastric air.118 Further studies are needed to understand the contribution of gastric relaxation and swallowed air to postprandial volume changes. The specialized equipment, time needed for interpretation, and expense have limited the role of MRI in assessing gastric motility to use in clinical research. The supine position of the patient for imaging is also a potential limitation because this is not the normal position postprandially. Studies suggest that body position does not affect gastric relaxation and initial postprandial gastric volumes; however, meal emptying is slower in the supine position than when sitting.119

Antroduodenal manometry 

Antroduodenal manometry provides information regarding the amplitude and patterns of gastric and duodenal contractions in both fasting and postprandial periods.2, 120 Antroduodenal manometry is performed in stationary settings over a 5- to 8-hour period or in ambulatory fashion over 24 hours using solid-state transducers. Ambulatory studies allow up to 24-hour recordings with better assessment of the migrating motor complex cycle during the night period and provide the advantage of correlating symptoms with abnormal motor patterns. However, catheter migration in ambulatory studies may limit interpretation of antral motility. The proposed indications for gastroduodenojejunal manometry include (1) clarification of the diagnosis in patients with unexplained nausea, vomiting, or symptoms suggestive of upper gastrointestinal dysmotility, (2) differentiation between neuropathic and myopathic gastric or small bowel dysfunction, (3) identification of generalized dysmotility in patients with colonic dysmotility (eg, chronic constipation), particularly before subtotal colectomy, (4) confirmation of the diagnosis in suspected chronic intestinal pseudo-obstruction syndromes when the diagnosis is unclear on clinical or radiologic grounds, (5) assessment for possible mechanical obstruction when clinical features suggest, but radiologic studies do not reveal, obstruction, and (6) confirmation of a diagnosis of rumination syndrome.2, 111

In gastroparesis, antroduodenal manometry may exhibit a decrease in the frequency or amplitude of antral contractions and phase III contractions may originate in the duodenum rather than antrum. In some individuals, increased tonic and phasic activity of the pylorus (“pylorospasm”) or irregular bursts of small intestinal contractions may be observed.121 The prevalence of concomitant small intestinal motor dysfunction in patients with gastroparesis ranges from 17% to 85% in different studies.122, 123 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, a reduced postprandial distal antral motility index correlates with delayed gastric emptying of solids.124 Normal findings on manometry coupled with a normal transit test result suggest that antral motor dysfunction is not the cause of symptoms.2

Antroduodenal manometry may differentiate between small intestinal neuropathic and myopathic disease and may suggest unsuspected small bowel obstruction or a rumination syndrome.2, 125 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.126 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.96

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.127 Other studies have suggested that findings of antroduodenal manometry may influence treatment decisions in small numbers of patients (∼20%) with dysmotility syndromes.128 In pediatric studies, the absence of migrating motor complexes predicts a poor response to prokinetic agents.129 However, validation of manometry as a critical diagnostic test for managing patients with suspected gastric or small intestinal dysmotility is incomplete.

Electrogastrography 

Electrogastrography (EGG) records gastric myoelectrical activity, known as the slow wave, using cutaneous electrodes affixed to the anterior abdomen overlying the stomach (Figure 6).130 The slow wave is responsible for controlling the maximal frequency and the controlled aboral propagation of distal gastric contractions. 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, which moves it in closer proximity to the recording electrodes. EGG testing quantifies the dominant frequency and regularity of gastric myoelectrical activity, 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.2 In general, an abnormal EGG is defined when the percent time in dysrhythmias exceeds 30% of the recording time and/or when meal ingestion fails to elicit an increase in signal amplitude.131

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Figure 6. EGG. A shows the regular 3-cycle/min pattern with an increase in amplitude postprandially. B shows examples of bradygastria and tachygastria.

Gastric dysrhythmias (tachygastria, bradygastria) and decreased EGG amplitude responses to meal ingestion have been characterized in patients with idiopathic and diabetic gastroparesis, idiopathic nausea and vomiting, motion sickness, and nausea and vomiting of pregnancy.2, 131 EGG abnormalities are present in 75% of patients with gastroparesis versus 25% of symptomatic patients with normal gastric emptying.131 Hyperglycemia may provoke dysrhythmias in diabetic patients.57

Some investigators suggest that EGG abnormalities and delayed gastric emptying may define slightly different patient populations with dyspeptic symptoms.131 Symptomatic responses to antiemetic or prokinetic drug treatments have been associated with resolution of gastric dysrhythmias.33 Unfortunately, patterns of EGG abnormalities do not guide prokinetic therapy.

Some clinical investigators consider EGG an adjunct to gastric emptying scintigraphy as part of a comprehensive evaluation of patients with refractory symptoms suggestive of an upper gastrointestinal motility disorder.2, 131 The EGG may be helpful in identifying patients with a gastric myoelectrical disorder in those patients with a normal gastric emptying test result. However, to date, there has been little investigation to validate the utility of EGG in the management of patients with suspected gastric dysmotility.

Gastric barostat 

The gastric barostat is a well-established method for measuring gastric accommodation and sensation. It is regarded as the gold standard to which other methods are compared and validated.132 This is an invasive technique requiring the oral introduction of a balloon into the gastric fundus. The balloon is highly compliant up to a maximum volume of 1.0–1.2 L and is attached to a barostat machine, which allows isobaric or isovolumic expansion of the balloon with continual monitoring of intraballoon volume or pressure. In this way, the accommodation response of the gastric fundus or antrum to various interventions can be recorded. However, because the technique is invasive, uncomfortable, and requires considerable expertise, it is used primarily in only a few centers almost exclusively in a research application. Gastric volumes can be measured by maintaining a constant pressure in the balloon and noting changes in balloon volume that correspond to changes in gastric volume. Gastric sensation can also be assessed by using protocols that vary the intraballoon pressure in either progressive or random fashions.133

While not a universal finding, most studies have reported that impaired accommodation is present in a high proportion of patients with functional dyspepsia and that this is associated with symptoms of bloating, distention, nausea, early satiation, and weight loss.78, 134, 135 In patients with type 1 diabetes mellitus, acute hyperglycemia increases proximal gastric compliance and this may contribute to the delay in gastric emptying associated with hyperglycemia.136 Also in type 1 diabetes mellitus, barostat testing has shown impaired accommodation related to autonomic neuropathy.137, 138 Similar findings have been reported in patients with systemic sclerosis.139 Approximately one third of patients with functional dyspepsia have heightened sensitivity to distention of the proximal stomach, and this finding is associated with symptoms of postprandial pain, belching, and weight loss.77 Not all investigators have confirmed these associations.8, 140

Gastric barostat remains the standard method for assessing gastric sensation to distention, compliance, and meal-induced accommodation. It is well suited for studies investigating the impact of various therapeutic interventions on gastric function and sensation. The major disadvantage of this technique is its invasiveness and complexity of operation. Additionally, it is possible that the presence of the gastric balloon may influence the gastric response to the test meal used to induce accommodation. During the study, air leaks can hinder interpretation in a small percentage of studies and occasionally low volumes used in the test can hamper interpretation of the accommodation response.141 At present, gastric barostat remains an important investigational device that has not crossed over into the realm of clinical applicability.

SPECT 

99mTc-pertechnetate administered intravenously is taken up from the circulation and excreted by parietal and mucous cells in the gastrointestinal tract. While this property has been used in the identification of ectopic gastric tissue as seen with Meckel's diverticulum, SPECT imaging after gastric mucosal labeling with 99mTc-pertechnetate has also been used to noninvasively measure gastric volumes to evaluate gastric accommodation.

SPECT to assess gastric volume is performed by administering an intravenous dose of 99mTc-pertechnetate and then obtaining tomographic images in an axial plane with the patient in the supine position with a large field-of-view dual-head gamma camera system.132, 142 Data are computer processed to create a 3-dimensional image of the stomach. Using these images, gastric volume can be determined. Comparisons of gastric volume in fasting and postprandial periods allow for the meal-induced accommodation response to be estimated. The differences in fasting and postprandial volumes are typically expressed as either volume difference or volume ratio. Gastric volumes estimated by SPECT have been compared with gastric volumes estimated by barostat.142 Ratios of fasting to postprandial volumes measured by SPECT and barostat were highly correlated (r = 0.8; P = .0001). Gastric volumes in both the fasting and postprandial states measured by SPECT were significantly greater than volumes measured by barostat, although the volumes were significantly correlated (fasting: r = 0.60; P = .02; postprandial: r = 0.64, P = .008). This is not surprising because SPECT measures total gastric volume while the barostat can measure volume in either the proximal or distal stomach but not both simultaneously. Fasting and postprandial gastric volumes measured by SPECT are comparable to MRI, but the postprandial changes measured by SPECT are higher than those measured by MRI.116 The ability to assess volumes for the entire stomach and its noninvasive nature are advantages of SPECT over barostat. In addition to its ability to evaluate the entire stomach, SPECT has the additional advantage over barostat in that it is noninvasive and requires no intubation.

SPECT has been used in the evaluation of patients with functional dyspepsia and prior fundoplication.75, 142 In patients with functional dyspepsia, impaired postprandial accommodation is identified in more than 40% of subjects and symptom associations, while not consistently seen, have been identified with bloating, pain, weight loss, and fullness.75, 142 SPECT, along with barostat, confirms the decreased proximal gastric volumes expected in the postfundoplication patient.75

The disadvantages of SPECT are that it is not routinely available and involves radiation exposure. In addition, the imaging is performed with the patient in the supine position, eliminating the influence of gravity. The image capture time of SPECT makes it less responsive than barostat with respect to changes in gastric volume. The physiologic relevance of this is unclear because postprandial changes typically occur in a time frame that is easily and accurately captured by both methods.

Thus, SPECT is a noninvasive technique that allows for the evaluation of both total and regional gastric volumes as well as postprandial changes in gastric volumes. SPECT is not widely available, and it currently is not used in clinical practice. It is currently used primarily in clinical research to assess the effects of various potential therapeutic agents on gastric function.

Drink tests 

Drink tests were originally developed as a noninvasive means to assess upper digestive sensation and, perhaps, gastric accommodation.143 They are well tolerated, inexpensive, and easy to perform. Drink tests can be performed using either water or nutrient-containing solutions.143 Variability in test performance includes the type of liquid used (water or nutrient) and the rate of administration; this variability has limited our understanding of the exact physiologic parameters measured by the test.

Drink tests are most commonly performed in patients with functional dyspepsia or gastroparesis, and many patients with these conditions will achieve satiation or develop dyspeptic symptoms at ingested volumes below those typically required to achieve these end points in controls. However, specific dyspeptic symptoms are not associated with an abnormal drink test.71, 143 Some patients report fullness at volumes (<50 mL) that clearly defy physiologic parameters, suggesting that central factors clearly influence test results. Experimentally induced anxiety is associated with decreased gastric compliance and increased symptom scores during a standard nutrient drink challenge26; correlations between drink test volumes and general psychiatric distress in patients with functional dyspepsia have been modest at best.143, 144