Comparison of Acid Reflux at Two Levels in the Esophagus Using the BRAVO Capsule

Upper gastrointestinal symptoms and diseases, specifically dyspepsia and acid reflux are
common problems faced by the adult U.S. population. These symptoms frequently necessitate an
upper gastrointestinal endoscopy, which is performed to rule out anatomic diseases. Moreover,
these symptoms can be associated with complications such as erosive esophagitis, Barrett's
esophagus, peptic ulcer disease and gastric cancer. The role and the level of acid (pH
levels) in patients presenting with these symptoms has been poorly defined in previous
studies since they have used catheter based pH systems which provided recordings only for 24
hours, at only a single location in the esophagus or stomach, and has been associated with
patient discomfort leading to inconsistent results. This pilot project will attempt to study
the level of acid exposure in the distal esophagus and proximal stomach of patients and
correlate it with their symptoms.

Many individuals in the Western world are troubled by heartburn, acid regurgitation,
abdominal pain (dyspepsia), or bowel habit disturbances; up to one in two subjects in cross
sectional population based studies report such symptoms. Gastro-esophageal reflux (GERD) is
probably the commonest chronic disease of the population of the Western world. The reported
prevalence of symptomatic GERD has ranged, on average, from 15% to 25%. Similarly, dyspepsia
is a common condition in the general population; the reported prevalence range in populations
is 15-40%. The majority of patients have functional (or non-ulcer) dyspepsia in that they do
not have any underlying structural explanation for their symptoms, such as peptic ulcer
disease or reflux esophagitis. However, given the significant morbidity and absence from work
associated with the condition, the pathogenesis and treatment of patients with dyspepsia
still requires further research. Studies are thus needed to determine the long term effects
of these symptoms on healthcare costs but in the short run to determine the correlation of
symptoms to acid levels and acid exposure.

Upper Gastrointestinal Diseases & pH Recording: Continuous esophageal pH recordings are
widely used to study GERD and its treatment (5). Gastric pH recordings are less used
clinically, but monitoring of gastric pH has been used for the pharmacological comparison of
various anti-secretory agents. Continuous pH recordings in the esophagus and stomach are
usually displayed as graphs of pH versus time or as percentage of time with pH above or below
a particular value (often 4.0).

Although there is no doubt that gastric acidity is directly involved in GERD pathogenesis,
relationships between gastric and esophageal acidity are not clear. Lack of focus on gastric
acid may relate to the general belief that gastric acid secretion is usually normal in GERD.
Distinct patterns of esophageal acidity in GERD have been previously reported. There is a
clear relationship between these descriptors and the present findings of integrated
esophageal acidity. Previous pH-based analyses have nicely correlated esophagitis grade with
acid exposure, but gastric acidity has been somewhat neglected as the major determinant of
esophageal acid exposure in GERD aside from observations that acid inhibition could diminish
esophageal acid exposure. Hirschowitz reported basal and pentagastrin-stimulated gastric acid
secretion in esophagitis comparable to unspecified medical conditions without esophagitis.
Others, however, have reported increased basal, peak, or maximal gastric acid secretion in
GERD compared to healthy subjects. In studies of gastro-esophageal reflux, the esophageal pH
electrode is traditionally positioned above the proximal limit of the lower esophageal
sphincter (LES). This convention was adopted early on to avoid the electrode slipping into
the stomach during swallowing when the esophagus shortens by 2-3 cm. As consequence, a
conventionally placed electrode will only detect acid refluxing into the distal esophagus if
it reaches this point 5 cm above the LES. If acid exposure of the most distal esophagus and
proximal stomach is greater than that of the conventional measuring point proximal to the
LES, it could have significance clinically. This reflux in the distal esophagus and proximal
stomach may explain the high incidence of metaplasia and neoplasia of the most distal
esophagus that occurs in the general population.

Previous studies in patients with dyspepsia have revealed either normal levels of pH or
mildly elevated levels in the stomach. The correlation between the symptoms and the acid
levels has been tested only in a few previous studies. The most distal esophagus and the
gastroesophageal junction is exposed to significant amounts of gastric acid, even in subjects
without reflux or dyspeptic symptoms. This is of importance for not only understanding the
pathophysiology of these diseases but also for treatment with acid suppressive medication.
Data are lacking on the benefits of effective acid inhibition with proton pump inhibitors in
dyspepsia. In two large, double blind multicenter clinical trials, BOND and OPERA , patients
(n=1262) with functional dyspepsia were randomized to four weeks of treatment with omeprazole
20 mg or 10 mg once daily, or placebo. The primary efficacy variable was complete absence of
symptoms. The BOND but not the OPERA trial showed a significant benefit of omeprazole over
placebo. Pooling the BOND and OPERA trials, complete relief of symptoms was achieved in 38.2%
of the 20 mg omeprazole group (p=0.002) and in 36.0% of the 10 mg omeprazole group (p=0.02)
compared with 28.2% in the placebo group suggesting that acid suppression may play a role in
the treatment of these symptoms. However, before future treatment studies are conducted,
correlation of patient symptoms with levels of esophageal and gastric pH levels will be
important.

Current practice for measuring esophageal and gastric pH: The current catheter based 24-hr pH
system involves placement of a catheter into the esophagus and stomach via the nostril. The
tip of the catheter has sensors to measure esophageal and gastric pH. The patient is then
sent home (after the catheter is placed, tip coming out of one nostril) and is given a box
that measures pH exposure. This is uncomfortable to the patient, leading to change in their
daily activities, diet, etc. with resulting data probably not reflective of their "daily
habits". Moreover, since the catheter is passed blindly into the esophagus and stomach, the
exact location of pH measurement is probably not accurate.

The Bravo pH System: The Bravo pH system (FDA approved) is a novel capsule based and wireless
testing system, which allows a capsule, size of a kidney bean, to be attached in the
esophagus or the stomach once the endoscopy has been performed. This attachment is helped
with the use of a small clip, which then detaches and is passed through the patient in the
stool. Preliminary studies using this Bravo pH capsule have shown good tolerability of using
this, presence of 48-hour results as well as good correlation with acid suppressive therapy
in these patients. To study the level of acid exposure in the stomach and the distal
esophagus in patients with upper gastrointestinal diseases and symptoms, specifically in
those with dyspepsia and acid reflux using a novel pH system.

Study Design: Patients presenting to the gastroenterology endoscopy unit for upper
gastrointestinal symptoms will be invited to participate in the study. The patient's symptoms
will be accurately noted using standardized and validated questionnaires. All patients will
undergo standard upper endoscopy. The patient demographics including age, gender, ethnicity
will be noted. The findings at the time of upper endoscopy such as presence of hiatal hernia,
erosive esophagitis, ulcer disease, H. pylori infection, and cancer will be recorded. After
the endoscopic procedure is over, two Bravo pH capsules will be placed in the distal
esophagus and the proximal stomach after the landmarks have been determined endoscopically.
The patients will be provided with a single pH recorder and will be asked to return to the
Gastroenterology unit lab, 24-48 hours after placement. Patients will be encouraged to
continue with their routine activity including meals. They will fill out a second
questionnaire at the end of the study regarding any discomfort that they may have experienced
with the Bravo capsule. Data will then be recorded regarding the levels of acid exposure at
the sites in the esophagus and stomach, patient demographics and comfort.

Safety Evaluation: Patients who have undergone Bravo in previous studies have reported chest
discomfort, chest pain, abdominal pain, and nausea. No major complications have been
reported. Thus, there is not a significant risk to the patient undergoing the procedure,
except that of the standard endoscopy, for which they have already been scheduled.

Inclusion Criteria:

1. Patients referred for upper endoscopy for any reason including those with acid reflux,
dyspepsia, weight loss, Barrett's esophagus,suspected Helicobacter pylori infection.

2. Patients able to provide written informed consent.

Exclusion Criteria:

1. Lack of severe comorbid conditions precluding an upper endoscopy.

2. Patients with history of esophageal or gastric cancer.

3. Patients status post esophageal or gastric resection.

4. Patients with esophageal varices.

5. Patients with severe esophageal strictures.

6. Patients with acute upper gastrointestinal bleeding.

7. Inability to provide informed written consent.