Ancillary testing including barostat, SPECT, and satiety testing

Gastroduodenal hypersensitivity

Heightened visceral sensitivity as a potential pathogenic cause of symptom development has been most prominently described in generalized functional bowel disorders such as irritable bowel syndrome (IBS) . In these studies, perception of colorectal balloon inflation was increased in IBS patients with descriptions of both hyperalgesia (heightened symptoms compared to healthy controls for any given degree of distention) and allodynia (perception of distention at levels below the detection limits for healthy volunteers) . IBS patients also reported more generalized localization of pain with colon distention, reflective of altered patterns of pain referral. Similar methods have been adapted to gastric testing which have defined similar hypersensitivity to mechanical distention in patients with gastroparesis and functional dyspepsia. In general, perception of gastric distention requires activation of mechanoreceptor pathways . Different regions of the stomach exhibit distinct responses to distention in healthy subjects. Antral distention evokes nausea which can disrupt normal myoelectric findings including induction of gastric slow wave rhythm disturbances in normal human volunteers . Such findings are not observed with balloon inflation of the proximal stomach to similar pressures. Likewise, reports of bloating and upper abdominal pain are noted at lower pressures in association with lower compliance levels in the distal stomach compared to the gastric fundus. There is strong evidence for gastric hypersensitivity to distention in gastroparesis and functional dyspepsia as well as other manifestations of visceral hypersensitivity in these disorders including altered pain referral patterns . Furthermore, pain is more often reported during sham distention in functional dyspepsia patients compared to healthy controls indicating involvement of central nervous system pathways. In contrast, heightened perception of gastric distention is not noted with organic causes of dyspepsia.

Modulation of visceral sensation is a potentially important mechanism for treating functional gastroduodenal disorders including gastroparesis and functional dyspepsia. Medications with different receptor actions have been proposed as neuromodulators for these conditions. Tricyclic agents act by inhibiting norepinephrine reuptake with variable inhibition of serotonin and dopamine reuptake. Tricyclic drugs exhibit capabilities to reduce gut perception of distention and electrical stimulation in human and animal models . In an early, open-label study of refractory nausea and vomiting in diabetes, tricyclic prescription at median doses of 50 mg reduced symptoms in 88% and eliminated symptoms in nearly one-third of patients . Notably, 29% of these diabetic patients exhibited delayed gastric emptying consistent with gastroparesis. A follow-up randomized controlled trial (RCT) of tricyclic drugs in diabetic gastroparesis has not been conducted. However, a definitive RCT of the tricyclic agent nortriptyline was performed in 130 patients with idiopathic gastroparesis . In this study, 15 weeks of treatment with nortriptyline up to 75 mg daily dosing was not associated with greater decreases in overall or individual gastroparesis symptoms than placebo. Only anorexia significantly improved more on nortriptyline than on placebo. A different RCT comparing the tricyclic medication amitriptyline, the selective serotonin reuptake inhibitor escitalopram, and placebo showed selective improvements on amitriptyline compared to the other arms in a large cohort of functional dyspepsia patients . However in this dyspepsia study, symptom benefits with tricyclic therapy were prominent only in those with normal delayed gastric emptying and with epigastric pain. Taken together, these findings suggest that neuromodulatory tricyclic therapy may be most beneficial in patients with pain-predominant gastroparesis symptoms but only with normal emptying rates. Other antidepressants (e.g. mirtazapine, olanzapine) have antiemetic effects in individual cases and case reports of gastroparesis and functional dyspepsia. A small RCT has shown improvements with mirtazapine in functional dyspepsia, but no RCTs have been performed in gastroparesis and these agents do not have documented mechanisms to reduce gastric sensation . Likewise, other agents with pain modulating characteristics including gabapentin and pregabalin have not been rigorously investigated in gastroparesis.

Abnormal proximal gastric accommodation

Accommodation is the reduction in gastric tone and increase in gastric volume occurring after meal ingestion. These effects are most prominent in the proximal stomach but are also seen in the antrum to lesser degrees . These actions produce a reservoir for the stored food without increasing intragastric pressure. Accommodation is comprised of initial receptive relaxation of the stomach occurring within seconds of exposure to an oropharyngeal or gastric stimulus followed by adaptive gastric relaxation which peaks roughly 15 minutes after eating . Afterwards, proximal gastric tone slowly increases which is postulated to contribute to regulation of meal delivery to the distal stomach and small intestine . Large subsets of patients with gastroparesis and functional dyspepsia exhibit blunting of accommodation after meal ingestion. This leads to increased intragastric pressure with abnormal redistribution of food residue to the distal stomach, impairing the postprandial reservoir function of the proximal stomach .

Medications to reverse blunted meal-induced proximal gastric accommodation have been proposed as potential treatments for gastroparesis and functional dyspepsia. In dyspeptic patients, the 5-HT _1A receptor agonist buspirone improves meal-induced gastric relaxation and reduces postprandial fullness, early satiety, and bloating to greater degrees than placebo . Similarly, tandospirone, a different 5-HT _1A receptor agonist, elicited greater symptom improvements versus placebo in an RCT in functional dyspepsia . In contrast to other therapies of gastroparesis symptoms, 5-HT _1A agonists elicit little antiemetic effect. To date, no similar RCT of either 5-HT _1A receptor agonist has been conducted in gastroparesis.

Small intestinal factors

Although gastroparesis and related conditions are considered to result from gastric sensory or motor dysfunction, some findings suggest important roles for small intestinal factors (especially in the duodenum) in causing delayed gastric emptying and dyspepsia. Historical research has found jejunal contractile bursts that act as an intestinal brake to impair gastric emptying in diabetic patients . Physiologic studies have characterized duodenogastric feedback responses by which intestinal nutrient or acid perfusions blunt antral function, increase pyloric contractions, or delay stomach emptying . In functional dyspepsia, increases in duodenal eosinophils correlate with severity of early satiety, fullness, and abdominal pain . Duodenal eosinophilic infiltration also increases mucosal permeability which correlates with delayed solid food gastric emptying in preliminary studies . The methodologies described in the following sections are considered to quantify stomach function, but it is clear that some measures can be influenced by post-pyloric activities as well. In studies to measure liquid gastric emptying or assess meal tolerance with satiety testing, it is possible that early duodenal filling could elicit enterogastric reflexes to inhibit subsequent emptying or increase dyspeptic symptoms that would halt further meal ingestion. In both cases, these stomach tests would be abnormal primarily due to duodenal dysfunction emphasizing the importance of understanding their limitations.

Methods

Barostat methods are the best characterized techniques for quantifying perception of gut lumen distention. A typical gastric barostat study involves oral passage of a stiff plastic infusion catheter with a deflated polyethylene bag up to 1200 mL in capacity affixed to its tip ( Fig. 17.1 ) . The barostat bag is then unfolded by inflating with 250–300 mL air for 2 minutes followed by gentle traction to retract the bag into the gastric fundus . After deflating the bag and allowing a 15–30 minute interval of gastric adaptation, a series of isobaric distentions to maintain constant intrabag pressure are performed with concurrent measurement of symptom severity to assess gastric sensitivity. The minimum distending pressure is initially determined by increasing the intrabag pressure by 1 mmHg every 2–3 minutes until either a stable balloon volume ≥30 mL is achieved or visible respiratory variations in the barostat volume recordings are observed . Afterwards, incremental 2–3 minute isobaric distentions of the barostat bag are made in either staircase or random staircase fashion increasing the pressure 1–3 mmHg with each step until a predefined maximal pressure (usually ~20 mmHg) or volume (usually ~1000 mL) is achieved or when the patient reports maximal discomfort or pain. Pressures and volumes needed elicit first perception, threshold for discomfort, and maximal tolerated distention are recorded.

Variations on standard barostat methods have been developed by some investigators to glean addition information relating to gastric sensory function. In one study in 14 healthy humans, a double barostat bag technique was employed to characterize differences and similarities in sensitivity in separate gastric regions . Using this protocol, compliance was lower in the distal versus the proximal stomach but intrabag pressures needed to elicit first perception and discomfort were not different in the two regions. Furthermore, concurrent distention of barostat bags in one of the two regions did not influence sensitivity in the other segment. Another method involves use of a tensostat which measures wall tension by correcting for changes in gastric volume using Laplace’s law . In a study in healthy subjects, graded isobaric inflation of a barostat bag elicited increased sensation during glucagon infusion . Although both gastric volume and wall tension were increased, used of the tensostat determined that perception was more closely influenced by changes in tension rather than volume.

Performance characteristics

Performance characteristics of barostat testing of gastric sensitivity have been validated in small studies in healthy controls. In one report of 6 volunteers, isobaric proximal gastric distention produced threshold perception at first sensation at 12+4 mmHg, moderate sensation at 18+4 mmHg, and sensation of discomfort at 21+4 mmHg . These perceptions were not influenced by atropine, confirming the lack of impact of muscarinic pathways on this gastric response. It should be noted that proximal gastric distention elicited large amplitude antral contractions which diminished with onset of reports of discomfort, reinforcing that this testing does not measure baseline function of the stomach but rather is disruptive of normal gastric activity. When repeated testing is performed on separate days, threshold pressures for first sensation and for reports of discomfort are highly reproducible in both healthy controls and patients with dyspepsia . Pressure thresholds show lesser variabilities than volume thresholds for perception.

Findings in gastroparesis and similar disorders

Some studies have been conducted which characterize gastric hypersensitivity in patients with gastroparesis from different etiologies. In an early barostat study in patients with postsurgical gastroparesis, isobaric gastric distention reproduced the presenting symptoms of epigastric fullness, abdominal pain, and nausea . A subsequent article reported reductions in gastric volumes needed to induce discomfort in patients with prior truncal vagotomy compared to healthy individuals . Of 58 idiopathic gastroparesis patients with severely delayed emptying in another investigation, 29% exhibited hypersensitivity to isobaric distention with associated lower balloon volumes which related to increased prevalence of epigastric pain, early satiety, and weight loss . Symptom severity correlated with sensitivity to gastric distention (r=−0.39). In 18 patients with diabetic gastroparesis, perceptual thresholds for discomfort during isobaric distention were lower than for controls . Ten of 18 diabetics (55%) showed gastric hypersensitivity to distention during fasting (threshold <12 mmHg). Eight patients could not tolerate meal ingestion, but the other 10 patients reported lower thresholds for discomfort and increased perception scores with graded distention during the fed period.

Other studies in diabetic patients with unexplained upper gastrointestinal symptoms have reported similar findings. In 8 symptomatic type 1 diabetic patients, gastric compliance during progressive isobaric distention was higher than in healthy controls and was associated with increased distention-evoked nausea, bloating, and abdominal pain . Similar heightened sensitivity to gastric distention was observed in type 1 diabetics with dyspepsia during maintenance of euglycemia .

The largest volume of data on gastric barostat measures of sensitivity have been published on patients with functional dyspepsia. An older study reported that lower median gastric volumes were needed to elicit discomfort in functional dyspeptics than healthy controls (210 vs. 660 mL) . Several investigations have examined the role of organic factors as contributors to hypersensitivity in functional dyspepsia. One study found no relation of Helicobacter pylori infection to gastric sensation, while a second observed more frequent gastric hypersensitivity to isobaric distention in H. pylori positive versus negative patients with functional dyspepsia . A third report found increases in sensitivity in functional dyspepsia patients but not in those with organic causes of dyspepsia . Gastric sensation in functional dyspepsia subtypes has been examined with one study noting hypersensitivity to barostat testing in those with epigastric pain predominance, whereas another investigation related gastric sensitivity to the postprandial distress variant on confirmatory factor analyzes .

Analyzes have been performed to identify other variables which are associated with increased perception of isobaric distention on barostat testing in functional dyspepsia. In a large study of 160 functional dyspepsia patients, hypersensitivity to gastric distention was observed in 34% of patients including both lower pressure and volume for perception of discomfort and lower wall tension at levels producing discomfort which were associated with increased symptoms confirming worsening of sensory abnormalities after meals . On multivariate analyzes, weight loss was associated with hypersensitivity and pain and belching were associated with relevant or severe hypersensitivity while BMI inversely related to the risk of hypersensitivity. In another study, postprandial sensitivity to gastric distention was greater than fasting sensitivity in patients with dyspepsia ( Fig. 17.2 ) . Postprandial thresholds needed to elicit discomfort correlated with overall symptom severity with an r value of −0.43. On multivariate analyzes, postprandial discomfort threshold and postprandial compliance were determinants of postprandial symptom severity. In an evaluation of other motor parameters that contribute to gastric sensation, barostat bags were inflated to volumes just under the threshold for detection (208+14 mL) in 12 functional dyspepsia patients with prior barostat testing showing hypersensitivity as well as normal fundic accommodation and gastric emptying . Seventy-eight phasic contractions were recorded during barostat recording at these subthreshold volumes, of which 39 (50%) were perceived 6+0.4 s after their occurrence. Of 88 transient increases in symptom intensity, 39 (44%) were accompanied by phasic contractions. These findings suggest that both tonic and phasic motor activity correlate with symptoms in functional dyspepsia.

Responsiveness to pharmaceutical and other intervention

Barostat quantification of gastric sensitivity has shown good responsiveness to a range of medication and non-medicinal stimuli in healthy cohorts. In one study of 18 normal volunteers, the 5-HT ₄ receptor agonist prokinetic drug cisapride decreased pressures needed to elicit threshold perception and discomfort during isobaric gastric distention . In contrast, use of another agent with prokinetic properties—intravenous ghrelin—did not influence pressures needed to induce threshold or discomfort perception after meals in normal volunteers during gastric barostat testing . Examining agents with potential to modify gastric sensitivity, capsaicin administration in healthy subjects increased proximal gastric compliance but also increased perception scores across a range of distending pressures and reduced pressures needed to elicit discomfort showing involvement of vanilloid receptor 1 pathways in fundic sensation . In healthy volunteer studies in which experimental anxiety was evoked by exposure to disturbing facial expressions and audiotapes with anxious autobiographical reports reduced gastric volumes but not pressures required to elicit discomfort on isobaric gastric distention .

Limited investigation has been performed in functional dyspepsia to confirm pharmacologic responsiveness of gastric barostat methods. In one investigation of 20 patients with functional dyspepsia with known hypersensitivity, treatment with the 5-HT _1A receptor agonist sumatriptan reduced perception scores across a range of gastric pressures and increased the pressures need to induce threshold and discomfort perception .

Comparisons with other methods

The barostat remains the definitive means of measuring gastric sensation in patients with gastroparesis symptoms. Other small studies have examined other methods to assess perception of gastric stimulation. In a comparison study in functional dyspepsia, 30 patients exhibited hypersensitivity to distention of both the proximal and distal stomach compared to healthy controls using tensostats . Functional dyspeptics in a different report exhibited increased symptom scores compared to normal subjects after consuming 0.75 mg capsaicin, reflecting chemical hypersensitivity in affected patients .

Barostat measures of gastric perception have been contrasted with findings of other physiologic tests to relate hypersensitivity to other potential pathogenic factors of symptom generation. Several studies have related sensation to gastric emptying in functional dyspepsia. One study observed combined decreased thresholds to perception of isobaric and isovolumetric distention and prolonged gastric emptying half times in patients compared to healthy controls, however only volumes required to induce symptoms correlated with emptying rates . In two other studies, there was no correlation of gastric hypersensitivity with delayed gastric emptying in functional dyspepsia patients or volunteers . Using another methodology proposed to relate to nausea generation, isobaric antral distention induced greater symptoms and disrupted gastric slow wave rhythm more than with proximal gastric distention in healthy volunteers . Finally, gastric sensitivity has been related to central nervous system pathways in functional dyspepsia. In one study, thresholds for discomfort on isobaric testing were associated with lack of pregenual anterior cingulate activation and no dorsal pons and amygdala deactivation on H ₂ ¹⁵ O-PET testing during distention . In these dyspeptic individuals, degrees of anxiety showed negative correlation with pregenual anterior cingulate and midcingulate activation and positive correlation with dorsal pons activation suggesting involvement of emotional factors in pain modulation.