Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05695846 |
| Other study ID # |
PRO00020732 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 29, 2014 |
| Est. completion date |
June 30, 2025 |
Study information
| Verified date |
August 2023 |
| Source |
Medical College of Wisconsin |
| Contact |
Reza Shaker, MD |
| Phone |
4149556840 |
| Email |
rshaker[@]mcw.edu |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
After defining the manometric characteristics of UES incompetence associated with documented
pharyngeal reflux, we will determine the reproducibility of manometric criteria for UES
incompetence in prevention of pharyngeal reflux. We hypothesize that these criteria are
comprised of either a single or constellation of manometric abnormalities. After determining
the ability of externally applied cricoid cartilage pressure in preventing pharyngeal reflux,
we further hypothesize that this approach will eliminate or reduce esophago-pharyngeal reflux
by enhancing the UES pressure barrier. We anticipate there will be a close spatial
correlation between the site of applied pressure and area of increased pressure within UES
high pressure zone. Lastly, we will determine and characterize the effect of externally
applied cricoid cartilage pressure on related functions such as belch and swallow, testing
the hypothesis that these functions will not be impaired.
Description:
Study subjects: we will study gastroesophageal reflux disease (GERD) patients with complaint
of regurgitation and one of the following supra-esophageal symptoms attributed to reflux of
gastric content: chronic cough, frequent throat clearing, history of non-deglutitive
aspiration pneumonia, hoarse voice, chronic sinusitis and dental erosion i.e. Supraesophageal
gastroesophageal reflux disease (SE-GERD). The presence of GERD will be verified in their
records by result of prior endoscopy or pH monitoring within the past two years. It not, they
will undergo transnasal esophagogastroduodenoscopy (T-EGD). If negative, they will undergo pH
monitoring off medications to ascertain presence of GERD according to clinically accepted
criteria (AGA guidelines (39). We will not enroll patients with functional heartburn (Rome
III criteria (40). For Supra-esophageal complications we will use the endoscopic criteria
used in clinical Ear, Nose and Throat (ENT) practice and validated symptom severity index
questionnaire (developed by Belafsky et al) with the help of our otolaryngologist
co-investigator Dr. Joel Blumin.
Justification of study subjects and endo-detection of pharyngeal reflux: because so much is
unknown about Upper Esophageal Sphincter (UES) incompetence in various patient groups and
lack of a gold standard reliable method for documentation of pharyngeal reflux, we had to
make the following decision based on our preliminary studies to fulfill the goals of this
project efficiently: a. in order to be able to study adequate number of pharyngeal reflux
events in a manageable number of participants we chose GERD patients with complaint of
regurgitation and supra-esophageal symptoms because of their high likelihood of developing
pharyngeal reflux based on our preliminary studies and b. to avoid any doubt about occurrence
of pharyngeal reflux which is inherent to pH and impedance monitoring due to their recording
from a small section of the pharynx which may not be affected by refluxes of small volume in
addition to their performance ambiguity in the pharynx, we chose to use endoscopic
visualization of the refluxate after developing this technique as our gold standard.
Study position: studies will be done in supine postures due to vulnerability of the airway in
this position.
Instrumentation: all instrumentations will be trans-nasal following application of 2%
lidocaine limited to the nasal cavity.
Study technique: concurrent video-pharyngo-laryngoscopy and combined high-resolution
manometry and impedance recording along with pH monitoring.
All study participants will give written informed consent followed by filling out a general
health questionnaire. Additionally, a Belafsky Index will also be filled out in the same
session by the study participant to assess the level of symptoms within the last month
associated with supraesophageal reflux.
Combined manometric/impedance/pH recording: we will use combined solid-state high resolution
manometry and impedance catheter with 36 circumferential pressure sensors, spaced 1 cm apart
(Sierra Scientific, Los Angeles, CA) 18 impedance sensor couplets spaced 2 cm apart measuring
at a sample rate of 40 Hz (Given Imaging Duluth, GA), 3 pH sensors spaced 7 and 10 cm
respectively. The catheter will be introduced transnasally in a fashion that at least 3
proximal manometric sensors are in the pharynx and two impedance and one pH sensors are
located 2 cm proximal to upper margin of UES in the pharynx. With this arrangement 3-4
manometric and one or two impedance couplets will be positioned in the UES high pressure zone
while the remaining pressure sensors will cover the sub-sphincteric striated segment and the
rest of esophagus along with lower esophageal sphincter (LES) through very proximal portion
of stomach, although in very tall participants the full length of LES may not be covered. One
ph sensor will be 3cm distal to UES while the remaining impedance couplets will span the
proximal and distal esophagus.
Concurrent videopharyngo-laryngoscopy: to monitor concurrently the pharynx and larynx for
entry of simulated refluxate we will use a Pentax FNL-10AP laryngopharyngoscope passed
through the other nostril and positioned within the pharynx such that the UES inlet, vocal
cords and pyriform sinuses are visualized. The laryngopharyngoscopic images will be
synchronized with manometric/impedance/pH recordings by importing and superimposing the
endoscopic images onto high resolution manometric recordings. Using a specially designed
timer (Thalner Electronics Labs, Inc, Ann Arbor, MI) time in hundredths of a second will be
superimposed on the video images for durational analyses of endoscopic images.
Slow and rapid intraesophageal infusion: A 3 mm outer diameter injection tube will be placed
through the same nostril in a fashion that the injection port will be located 5-7cm above the
manometrically determined upper border of lower esophageal sphincter (LES). With this
arrangement gastroesophageal reflux events will be simulated by intra-esophageal injection of
body temperature infusates namely,1/2 normal saline (its ionic nature helps impedance
recording and identification of intra-esophageal distribution), 0.1 N HCl. As stated above
infusions will be done in three sessions. Slow acid and slow1/2saline sessions will test two
volumes (20 and 60ml) and two rates (.05 and 1.0 ml pre second). Since our preliminary data
suggest a strong differentiating capacity for slow infusion (1ml/sec) in uncovering UES
abnormalities we propose to test two slow infusions to identify the one with most
differentiating capacity. We study slow acid and saline perfusion in two sessions to avoid
the issue of esophageal sensitization effect on saline distension in addition to reasons
describe above. The rapid injection session will test two volumes (20 and 60 ml) and one rate
(10 ml per second). In this session we will test both acid and saline due to short contact
time of the acid which make the sensitization less likely. A modified Harvard pump will be
used for infusions. Each infusion will be repeated three times. The order of infused material
as well as the volume of infused material in all sessions will be randomized. Also
randomized, will be the three different study sessions. Liquid infusates will be colored
green using food dye for ease of recognition of pharyngeal reflux. Exact timing and type of
the injection will be documented using the event marker feature of the Manoscan® system. Each
perfusion will be performed only when the UES, esophagus and LES are at baseline for at least
three tidal volume respiratory cycles and 20s after a preceding peristaltic event. After each
perfusion, manometry will be carefully monitored for 20s and then subjects will be cued to
swallow and clear their esophageal contents. Esophageal clearance will be verified by the
presence of an effective peristalsis and return of intra-esophageal impedance and pressure to
baseline. As stated above infusions will be done in three sessions within the same two hour
study visit.. Endoscopic views of pharynx will be watched carefully during infusions. At the
first sign of reflux, perfusion will be stopped and participants will be instructed to
swallow to avoid any potential airway compromise. This technique has been used in our
laboratory for the past three years without any problem.
Pressure Data Analysis: All pressure measurements will be recorded at a 35HZ frequency and
measured in reference to the atmospheric pressure UES and LES pressures will be measured
utilizing the e-sleeve function of the Manoview ® software. All UES, LES and esophageal
baseline pressures will be measured as peaks and troughs over 3 tidal volume respiratory
cycles at stable resting conditions when no pharyngeal, gastric, esophageal, UES or LES
events are present. Type, frequency, amplitude, onset, and duration of the UES response along
with the LES and esophageal body response will be recorded.
UES pressure response to intraesophageal infusion: Percent UES relaxation and percent UES
contraction will be calculated as a fraction of the maximum possible relaxation (baseline UES
pressure-proximal esophageal pressure) and as a fraction of the maximum UES contraction
pressure, respectively. UES relaxation will be considered complete (100%) if an audible belch
is documented or the nadir UES pressure at least equalizes to the proximal esophageal
pressure. Due to considerable variability of the resting UES pressure even at rest we have
set a conservative threshold (10 mmHg) for determining the UES response (43-44). UES response
will be categorized as an ordinal variable: contraction (UES pressure exceeds the peak
baseline pressure by more than 10 mmHg); relaxation (UES pressure drops more than 10 mmHg
below baseline trough pressure); or no response. It has been observed that often prior to and
almost always after a swallow related UES relaxation (as UES participates in
pharyngoesophageal peristaltic wave) there is an increase in UES tone that has been linked to
the preceding relaxation rather than an independent event therefore, we will consider the UES
contraction as a response only if it is not preceded by a UES relaxation response and not
followed by UES relaxation within 3 seconds.
Extent of esophageal intraluminal pressure increase during infusions: will be recorded as an
ordinal variable: 1) if esophageal pressure increase more than 3 mmHg above baseline during
perfusion, esophageal pressure and peak rate of pressure increase (dp/dt) within a 0.1 s
window will be measured during the perfusion in the proximal and distal esophageal segments
as continuous variables.
Esophageal clearing response to intra-esophageal perfusion: will be classified into four
categories: 1/ simultaneous esophageal contraction (>20 mmHg); 2/ secondary peristalsis as a
sequential esophageal contraction of at least 5cm length and amplitude greater than 20 mmHg
without preceding swallow related pharyngeal contraction); 3/ primary peristalsis (>20 mmHg)
as an orderly sequential esophageal contraction of at least 5cm length and amplitude greater
than 20 mmHg preceded by pharyngeal contraction and UES relaxation ; and, 4/ no response as
the esophageal body pressure changes less than 20 mmHg or 5cm length during 20 second
analysis window. We will monitor clearance of the infusate from esophagus by impedance
monitoring up to 60 seconds and then subjects will be instructed to swallow until esophageal
contents clear.
LES response to intraesophageal perfusion: Although LES function is not the center of present
proposal when available its response to infusion will be classified into three types: 1/
complete relaxation defined as equalization of the LES pressure to gastric pressure; 2/
partial relaxation defined as a pressure drop > 5 mmHg; and, 3/ no response. The predominant
UES, LES and esophageal response will be considered mode of three trials and recorded as an
ordinal variable.
Videoendoscopic data analysis: onset of the entry of colored refluxate into the pharynx
though the UES inlet will be determined and correlated with the UES, esophageal and LES
pressure phenomena, impedance and pH events. Endoscopic documentation of pharyngeal reflux
will be considered the gold standard and impedance and pH data will be compared to it.
Identification of biologic events: Glottal kinetics and movements as well as changes in the
geometry of pharyngeal cavity will be used to identify swallow esophago-glottal closure
reflex and belch. Belch and swallow will also be identified by their characteristic pressure
and impedance signatures, investigator observation and participant signaling using a marker
and correlated with endoscopic findings for certainty.
Criteria for abnormal UES barrier function: Based on our preliminary data these include,
presence of one or any constellation of the following: absence of sustained UES contraction,
transient partial or complete relaxation. Additional criteria may include absence of striated
esophagus peristalsis or absence of secondary peristalsis. Presence of simultaneous
contraction or lack any contraction. These criteria will be applied to infusion period (60
sec) plus two minute post-infusion.
Criteria for normal UES barrier function: sustained contraction of at least 20mmHg above
pre-infusion period (three respiratory cycles) in response to infusion for the duration of
infusion and lack of the abnormal criteria stated above.
Determine the ability of externally applied cricoids cartilage pressure on preventing
pharyngeal reflux: Our preliminary studies have shown that externally applied pressure on the
cricoid cartilage (20mmHg) can increase the intraluminally recorded UES pressure. These
studies have also shown that this technique can prevent experimentally induced pharyngeal
reflux in patients with SE-GERD and regurgitation. UES high pressure zone ranges from 3-4cm
and is generated by participation of inferior pharyngeal constrictor, cricopharyngeus muscle
and most proximal part of the esophagus. The spatial relationship of externally applied
pressure and the UES pressure profile has not been studied. It is also not known whether
external pressures applied, not exactly on the cricoid could impart the same effect. Our
preliminary data suggests location dependent effect on UES pressure profile. Because this
approach may have practical clinical ramification, in this sub-aim, we will characterize the
effect of a 20mmHg pressure, externally applied to and several points distal and proximal to
the cricoid cartilage on UES pressure profile. We have chosen 20 mmHg pressure based on our
preliminary data. This procedure will be performed on all EPR patients recruited into our
study. Each apparatus for exerting external cricoid pressure is custom fitted for each
subject at the time of the study. Furthermore, the ICF for this protocol has been edited to
include this procedure in the description of test performed during each experiment
Determine and characterize the effect of externally applied cricoid cartilage pressure on
related functions such as belch and swallow: We will test dry, 5 and 10 ml ½ saline
swallowsX3 in random order. In addition we will test belching by injecting various volumes of
air into the esophagus through the previously paced infusion catheter. We will test 20 and 40
ml room TX3. Studies will be done with and without application of cricoid pressure. Cricoid
pressure will be applied at 20mmHg by using our laboratory made neck band as described above
with the exception that the pressure bar will be 10X30mm to cover the width of the cricoid
cartilage for maximum effect. These studies will be carried out with the test subjects in the
upright and supine positions.
