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Journal of Pediatric Surgery 49 (2014) 13531359

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Lower esophageal sphincter augmentation by endoscopic injection of

dextranomer hyaluronic acid copolymer in a porcine gastroesophageal
reux disease model
Abdullah Alshehri a, Sherif Emil a,, Jean-Martin Laberge a, Sherif Elkady a, Miriam Blumenkrantz b,
Serge Mayrand c, Veronique Morinville d, Van-Hung Nguyen b

Division of Pediatric General and Thoracic Surgery, The Montreal Childrens Hospital, McGill University Health Centre, Montreal, Quebec, Canada
Division of Pediatric Pathology, The Montreal Childrens Hospital, McGill University Health Centre, Montreal, Quebec, Canada
Division of Gastroenterology, The Montreal General Hospital, McGill University Health Centre, Montreal, Quebec, Canada
Division of Pediatric Gastroenterology, The Montreal Childrens Hospital, McGill University Health Centre, Montreal, Quebec, Canada

a r t i c l e

i n f o

Article history:
Received 14 October 2013
Received in revised form 3 February 2014
Accepted 24 February 2014
Key words:
Lower esophageal sphincter

a b s t r a c t
Background: We previously demonstrated feasibility, safety, and a reproducible histologic bulking effect after
injection of dextranomer hyaluronic acid copolymer (DxHA) into the gastroesophageal junction of rabbits. In
the current study, we investigated the potential for DxHA to augment the lower esophageal sphincter (LES) in
a porcine model of gastroesophageal reux disease (GERD).
Methods: Twelve Yucatan miniature pigs underwent LES manometry and 24-hour ambulatory pH monitoring
at baseline, after cardiomyectomy, and 6 weeks after randomization to endoscopic injection of either DxHA or
saline at the LES. After necropsy, the foregut, including injection sites, was histologically examined.
Results: Pigs in both groups had similar weight progression. Cardiomyectomy induced GERD in all animals, as
measured by a rise in the median % of time pH b5 from 0.6 to 11.6 (p = 0.02). Endoscopic injection of DxHA
resulted in a higher median difference in LES length (1.8 cm vs. 0.4 cm, p = 0.03). In comparison with saline
injection, DxHA resulted in 120% increase in LES pressure, and 76% decrease in the mean duration of reux
episodes, but these results were not statistically signicant. Injection of DxHA induced a foreign body reaction
with broblasts and giant cells.
Conclusions: Porcine cardiomyectomy is a reproducible animal GERD model. Injection of DxHA may augment
the LES, offering a potential therapeutic effect in GERD.
2014 Elsevier Inc. All rights reserved.

Gastroesophageal reux disease (GERD) is a very common

condition affecting up to 20% of the pediatric population, with a
higher prevalence in those with neuromuscular disorders [1,2]. Proton
pump inhibitors are the mainstay of medical treatment of GERD in
both children and adults. However, the efcacy of these medications
in children has recently been challenged [35]. Surgical treatment,
namely laparoscopic fundoplication, is reserved for patients who fail
medical treatment or develop GERD-related complications. Although
this procedure is one of the most common pediatric surgical
operations performed in the United States, studies have shown a
wide range of outcomes, with success rates between 57% and 100%,
and complications occurring in 325% of patients [6,7]. In fact, studies
by Lee and colleagues have shown no reduction in GERD-related
admissions after fundoplication, and up to 75% of children continuing

Corresponding author at: Division of Pediatric General and Thoracic Surgery, The
Montreal Children's Hospital, 2300 Tupper Street; Room C-818, Montreal, Quebec,
Canada, H3H 1P3. Tel.: +1 514 412 4497; fax: +1 514 412 4289.
E-mail address: (S. Emil).
0022-3468/ 2014 Elsevier Inc. All rights reserved.

on antireux medications one year postoperation [8,9]. Recent

randomized controlled trials have not proven the advantages of
laparoscopic fundoplication in children, previously presumed in
multiple published case series [10,11]. The American Pediatric
Surgical Association has encouraged research into alternative therapies for GERD in children [12]. The stronger enthusiasm for
fundoplication in the adult population has been also been tempered
by published medium and long-term results of randomized clinical
trials, which failed to show a signicant advantage of laparoscopic
fundoplication over proton pump inhibitors [13,14].
Animal and human studies have shown a potential role for
polymer injection into the lower esophageal sphincter (LES) as a
means of treating GERD [1521]. However, none of these therapies
have gained wide acceptance owing to concerns regarding safety and
efcacy, and most have been withdrawn. To our knowledge, no agents
are currently approved for this indication.
Dextranomer hyaluronic acid copolymer (DxHA), also known as
Deux (Salix Pharmaceuticals, Raleigh, NC), is a biocompatible
polymer composed of dextranomer microspheres, of 80250 m in
diameter, suspended in stabilized nonanimal hyaluronic acid. DxHA


A. Alshehri et al. / Journal of Pediatric Surgery 49 (2014) 13531359

induces a foreign body and brotic reaction at the site of injection. It

does not migrate, is nonimmunogenic, and is stable for long periods
with no reports of adverse long-term effects. Since its introduction
into pediatric urologic practice in the late 1990s, this agent has
resulted in a signicant paradigm shift from surgical to endoscopic
treatment of vesicoureteral reux disease [22,23]. The agent has also
been used for closure of recurrent tracheoesophageal stula,
umbilical hernia repair, and treatment of urinary and fecal
incontinence [2427].
Our group has been interested in a potential role for DxHA as a
treatment for GERD. We have previously demonstrated feasibility,
safety, and a predictable histologic bulking reaction after DxHA
injection into the rabbit gastroesophageal junction (GEJ) [28]. The
purpose of this study was to investigate the effect of the endoscopic
injection of DxHA into the LES in a porcine GERD model.
1. Methods

other and with a radial orientation of 90. This allowed for the
collection of four data sets for a given site within the esophagus with a
single dynamic measurement. At each level along the esophagus, a
mean pressure was obtained from all four sensors. Using a stationary
pull-back technique, the catheter was manually pulled out at a speed
of 5 mm/min through the LES, with registration of the pressure within
the LES by all four sensors. The lower border of the LES was
determined at the station that demonstrated a consistent rise of
pressure above the gastric baseline pressure, whereas the upper
border of the LES was determined at the station that showed a drop of
pressure to esophageal baseline pressure. Before removing the
catheter, the distance between the upper border of the LES and the
snout was measured for the subsequent insertion of the pH probe.
From the data obtained, which were automatically recorded as
pressure curves via a polygraph on a standard PC using GastroTrac
(version, Alpine Biomed ApS, Skovlunde, Denmark), we
measured the total length, abdominal length, and resting pressure of
the LES, as previously described by Zaninotto et al. [29].

1.1. Animal model

Fourteen Yucatan miniature swine weighing 8.4 1.3 kg were
used for the experiment. This strain was specically chosen because of
its slow growth curve. The swine were fed a basic research diet, Teklad
Miniswine (Harlan Laboratories, Indianapolis, IN). Pigs were started
on Ensure (Abbott Laboratories, North Chicago, IL) 48 hours before
each procedure, and given water only for 24 hours prior to the
procedure. All procedures were performed under general inhalational
anesthesia with 2% isourane, following sedation with intramuscular
injection of butorphanol (0.1 mg/kg), acepromazine (0.2 mg/kg),
atropine (0.05 mg/kg), and ketamine (0.14 ml/kg).
Prior to initiating the study, manometry and 24-hour ambulatory
pH monitoring were performed on two animals to conrm feasibility
and ascertain that the tracings obtained can be interpreted by the
research team. Subsequently, a laparoscopic cardiomyectomy was
attempted on both pigs. However, both procedures required conversion to laparotomy in order to adequately identify the gastroesophageal junction and all the muscle layers. Subsequently, all the animals
underwent open cardiomyectomy as described below. Fig. 1 depicts
the experimental protocol.
Approval of the research protocol was obtained from the McGill
University Animal Care Committee, Montreal General Hospital Site
1.2. LES manometry
Esophageal manometry was performed using a commercial
stationary water-perfused manometry system including a lowcompliance pneumohydraulic capillary infusion pump with a ow
rate of 0.5 ml/min (model PIP-4-8, MUI Scientic, Mississauga,
Ontario, Canada), a polygraph (Medtronic, Ontario, Canada), and a
commercial computer. The four-channel water perfused esophageal
catheter (PE4-3-3-3, MUI Scientic, Mississauga, Ontario, Canada)
was used for manometry with four sensors 3 cm apart from each

1.3. 24-hour ambulatory esophageal pH measurements

After completing the manometry and under the same general
anesthetic, a single-sensor, internal reference pH catheter (MUI
Scientic, Mississauga, Ontario, Canada) was used for 24-hour pH
measurement. After successful calibration using a Digitrapper pH 400
(Medtronic, Minneapolis, MN), the probe was inserted through
intravenous tubing to gain more rigidity, and avoid coiling in the
nasopharynx. The tip of the probe was left exposed. Using multiple 2.0
silk sutures, the probe was xed to the overtube to prevent the probe
from sliding inside the tube, especially when the animal was
ambulatory. Subsequently, the pH probe with overtube was inserted
through the pig's snout and guided into the esophagus with the aid of
a laryngoscope. The tip of the probe was placed 2 cm above the
manometrically identied upper border of the LES, and marked at the
snout level to allow recognition of changes in its position. Fluoroscopy
was used in the rst few animals to document proper placement of
the probe. The probe was then secured externally with several
interrupted 0 silk sutures spaced 5 cm apart, starting from the snout
and proceeding to the animal's back, leaving enough slack to allow the
animal freedom of movement without displacing the probe. Finally, a
custom-made dorsal harness with a pocket was used to house the
Digitrapper. Upon recovery, the animal was allowed free access to
water and food in a private cage to avoid disruption of the system by
other pigs. After 24 hours, the sutures were cut and the probe was
removed. Data were uploaded to a computer using GastroTrac
software (version, Alpine Biomed ApS, Skovlunde, Denmark).
Acid reux was dened by a drop in esophageal pH below 5. Data
obtained were number of reux episodes, number of long reuxes
(N5 minutes), longest reux episode (minutes), total time pH b5
(minutes), percentage of time pH b5 (minutes), and mean duration of
reux episodes (minutes). DeMeester and Boix-Ochoa scores, modied to pH b5, were calculated.

Fig. 1. Experimental protocol. pH measurements all consisted of 24-hour ambulatory pH probe.

A. Alshehri et al. / Journal of Pediatric Surgery 49 (2014) 13531359


1.4. Cardiomyectomy
Prophylactic cefazolin (20 mg/kg) was given intravenously. A14French orogastric tube was inserted. The abdominal cavity was
accessed through an upper midline laparotomy incision from the
xiphoid to the umbilicus. The left lobe of liver and the spleen were
retracted in order to expose the area of the GEJ. The phrenoesophageal
membrane was incised, the anterior peritoneal reection covering the
esophagus was opened, and the anterior and posterior vagal trunks
were identied and preserved. At the GEJ, an anterior longitudinal
myotomy was performed by incising the longitudinal and the circular
muscle bers using a No. 15 blade and a ne Metzenbaum scissors.
The myotomy was extended 3 cm cephalad on the esophagus and
3 cm caudad on the gastric cardia. Once the submucosal plane was
entered, the esophageal muscle layers were gently peeled away 1 cm
on both sides. Both pieces of muscle were then excised creating a
myectomy segment that was 6 cm in length and 2 cm in width
centered at the GEJ (Fig. 2). A very essential part of the myectomy was
to ensure dividing the gastric sling and clasp muscle bers, a step that
required careful dissection and carried the highest risk of mucosal
perforation. Once hemostasis was ensured, the abdomen was closed
in the standard fashion with a monolament suture. The skin was
closed with subcuticular sutures to avoid the presence of any material
externally. OpSite waterproof spray was used as a dressing. The
animal was awakened and extubated. Intramuscular buprenorphine
0.010.1 mg/kg was administered for analgesia. The pigs were
allowed free access to food and water. Postoperatively, cephalexin
(25 mg/kg) was administered orally twice a day for 10 days.
1.5. Endoscopic injections
A 2-week recovery period was allowed after surgery, during which
computer-generated randomization to either DxHA or saline was
performed. Under general anesthesia, a 45 cm custom-made rigid
endoscope (Fiegert-Endotech, Sunrise, FL) was advanced through the
pigs mouth. After the GEJ was identied, a semirigid beveled needle
was advanced through a working channel in the scope. Submucosal
injections of DxHA or saline were performed in three different
quadrants away from the muscle-decient cardiomyectomy site to
avoid injecting outside the esophagus. A volume of 1 ml of DxHA or
saline was injected in each site. A 30-second waiting period was
allowed for the implant to stabilize before withdrawing the needle.
Immediate mucosal bulging indicated successful implantation (Fig. 3).
Six animals had DxHA injections, whereas four animals received
saline injections. After completing the injection session, the animal
was awakened and extubated. Free access to water and food was
allowed immediately after the procedure. During the ensuing

Fig. 3. Endoscopic injection of DxHA at the GEJ. A volcano-like effect results owing to
installation of the polymer in the submucosa and muscularis.

6 weeks, the animals were weighed weekly. Behavior and feeding

patterns were recorded. At six weeks after injection, animals underwent a third manometry and 24-hour ambulatory pH measurement,
prior to sacrice and necropsy the following day.
1.6. Euthanasia and necropsy
After induction of anesthesia with 5% isourane, an intravenous
injection of sodium pentobarbital (120 mg/kg) was used to euthanize
the animal. Necropsy was performed through a midline sternotomy
and laparotomy. En bloc resection of esophagus, stomach, liver, and
lungs was performed.
1.7. Histological assessment
Gross and histological examinations were performed by two
pathologists. Several sections were made from the GEJ at different
levels and stained with hematoxylin ploxine saffron. Specimens were
examined for esophagitis, response to the GEJ injection, type of
cellular reaction, signs of implant migration, reaction outside the
esophagus, stenosis, or perforation. Additionally, liver and lungs were
examined for abnormal reaction and evidence of aspiration
1.8. Statistical analyses
Weight progression was compared using ANCOVA, controlling for
the weight at time of injection. Paired continuous data were compared
using paired Wilcoxon signed rank test. Unpaired comparison of
continuous data was performed using Mann-Whitney U test. P-value
of less than 0.05 was considered signicant. Analysis was performed
using IBM SPSS 20.0 and reviewed by a biostatistician. Pathology
results were reported qualitatively.
2. Results

Fig. 2. Appearance of the completed cardiomyectomy. The mucosa is seen to bulge after
the overlying muscle is removed.

During the study period, two pigs randomized to saline injection

died during the rst week after uneventful cardiomyectomy, before
endoscopic injection. One animal had recurrent vomiting, with
aspiration pneumonia diagnosed on necropsy. The second animal
had evidence of congestive heart failure of unclear etiology. The other
10 pigs continued to gain weight as shown in Fig. 4, with no signicant
difference between DxHA or saline groups as determined by ANCOVA
(p = 0.98).
The manometry and pH measurements precardiomyectomy and
postcardiomyectomy are shown in Table 1. Cardiomyectomy resulted


A. Alshehri et al. / Journal of Pediatric Surgery 49 (2014) 13531359

Fig. 4. Weekly weight progression in each group.

in reductions in LES pressure, total length, and abdominal length, but

the differences did not reach statistical signicance. Signicantly
increased acid exposure was demonstrated by increase in the total
and percentage time pH less than 5.
When comparing the six pigs in the DxHA group and the 4 pigs in
the saline group, there were no statistically signicant differences in
median LES pressure and percentage of time pH b5 as determined by
Mann-Whitney U test. In order to control for the difference between
baseline values, another comparison was performed between postoperative and postinjection median differences. We noted a longer
LES in the DxHA compared to saline group (1.8 cm vs. 0.4 cm, p =
0.03). This observation was consistent when performing subgroup
analysis of the DxHA group only, comparing postoperative and post
injection median LES length (1.8 cm vs. 3.3 cm, p = 0.06), as shown
in Fig. 5.
We also calculated the percentage change in each median value
between postmyectomy and postinjection data sets. In comparison to
saline, DxHA had resulted in 120% increase in LES pressure (median
change of pressure 0.5 mm Hg in saline group, 0.1 mm Hg in DxHA
group, p = 0.8), and 124% decrease in the number of reux episodes
(median change of number of reux episodes 22 in DxHA group,
91.5 in saline group, p = 0.6).
The histologic results are shown in Table 2. Gross examination of
the specimens revealed an area of increased thickness with no luminal
narrowing in DxHA injected animals. Microscopically, DxHA implants
were identied tracking from the submucosa to the muscularis
propria of all 6 specimens accompanied by foreign body brous tissue

reaction with giant cells and collagen deposition (Fig. 6). No brous
tissue reaction was seen in the saline group. In 4 out of 6 DxHA
specimens, acute inammatory cells (microabscess) were identied
close to injection site. No evidence of perforation or periesophageal
inammation was noted. DxHA did not migrate above or below the
site of injection. There was no histologic evidence of esophagitis in
any of the specimens.

3. Discussion
GERD is a very common condition affecting both adults and
children [29]. Current medical and surgical options do not yield
optimal therapeutic results in a signicant proportion of patients. A
search for alternative treatments has continued. Augmenting the LES
with polymer injections has been investigated over the last decade as
a potential anti-GERD strategy [1521]. Some of these polymers were
synthetic, while others were biocompatible. Enteryx is a liquid
agent, composed of ethylene vinyl alcohol and dimethyl sulfoxide that
consolidates after being endoscopically injected at the GEJ. Initial
results in animal studies and adult patients were promising [18,20].
However, serious side effects resulted from improper placement of
this bulking agent. Intraaortic injection of Enteryx caused aortoenteric stula and renal failure from arterial occlusion leading to its
voluntary recall [30]. Another injectable agent, Plexiglas, consists of
a suspension of polymethylmethacrylate microspheres in gelatin
solution. Once injected, it is phagocytized by macrophages and

Table 1
Manometry (median and interquartile ranges) and pH data precardiomyectomy and postcardiomyectomy in 10 pigs.
Preoperative data

LES pressure (mm Hg)
LES total length (cm)
LES abdominal length (cm)
PH measurement:
Number of reuxes
Number of long reuxes
Time of pH b5 (min)
Percentage of time pH b5
Mean duration of reux episodes (min)
Duration of longest reux episode (min)
DeMeester score
Boix-Ochoa score

Postoperative data





















Comparisons were performed using paired Wilcoxon signed rank test.

A. Alshehri et al. / Journal of Pediatric Surgery 49 (2014) 13531359

Fig. 5. Box plots of the LES total length in the (A) DxHA group and (B) Saline group at
baseline, post cardiomyectomy, and 6 weeks post injection. Transverse lines represent
median values.

subsequently replaced by broblasts and collagen. A signicant

decrease in both GERD symptoms and esophageal acid exposure
was achieved [19,31]. However, this agent was also withdrawn. To our
knowledge, there is currently no injectable agent approved for the
treatment of GERD.


Nevertheless, there is still strong evidence that augmentation of

LES pressure alone may be an effective antireux measure. Ganz et al.
recently reported three-year outcomes of a exible magnetic ring that
exerts its effect exclusively by augmenting LES pressure, showing
effective treatment of GERD in most patients [32]. DxHA represents a
potentially ideal injectable agent because of its appealing properties.
Its main component, hyaluronic acid, is a naturally present compound
that is nonimmunogenic. Studies have shown that DxHA does not
migrate from the original site up to 3 years after injection [33]. A
granulomatous inammatory reaction and brotic encapsulation
likely contribute to the durability of the implant long after DxHA is
hydrolyzed by the body [23]. DxHA has been effectively used for more
than two decades in the treatment of vesicoureteral reux, and has
been recently introduced for a variety of other pediatric applications
[22,23,2527]. In adults, transanal submucosal injection of DxHA has
been shown to be effective for the management of fecal incontinence
[24]. This application is particularly pertinent to our current work.
Whereas DxHA injection in the bladder is thought to work by
changing the vesicoureteral angle, injection in the anal sphincter is
thought to be effective owing to higher sphincter pressure.
In previous work, we have found that injection of DxHA into the
rabbit GEJ was well tolerated, and did not result in esophageal
obstruction or perforation. Histologically, DxHA was able to induce
brous tissue reaction at the GEJ, very similar to the reaction observed
at the ureterovesical junction [28]. Eosinophilia observed in the rabbit
esophagus after DxHA injection was not seen in the pig, and may be
species specic. The rabbit foregut anatomy is remarkably similar to
humans. However, despite several attempts, we were not able to
create a reliable GERD model in the rabbit. The muscular layer of the
GEJ in the rabbit is quite thin, rendering myectomy without
perforation difcult. The rabbit esophagus is narrow, and endoscopic
injection was not possible. In addition, the rabbits stomach never
completely empties and always contains large bezoars from ingested
hairs. Ambulatory pH measurements in rabbits were not possible.
Several GERD large animal models have been published, but few
have been reproducible [3441]. There is no consensus on the most
reliable experimental procedure to induce GERD. However, a partial
cardiomyectomy appears to be superior to cardiomyotomy with
respect to the degree of acid reux [34]. We developed our animal
model based on pilot work in pigs reported by Schopf et al. [39]. We
learned important lessons during development of our model. The
porcine GEJ is quite complex because of well-developed clasp and
sling oblique gastric bers that act as a natural partial fundoplication.
These bers have to be divided to induce GERD. We found the
dissection of the GEJ by laparoscopy to be quite difcult owing to the
ease of entering the pleura and causing a pneumothorax. In addition,
an adequate myectomy required signicant mobilization of the GEJ
and deliberate division of each muscular layer, which we found

Table 2
Histology results.


DxHA implant

Foreign body
reaction present?

Giant cells

























No inammation noted
No inammation noted
No inammation noted
No inammation noted
DxHA identied outside the muscularis propria
DxHA identied in the muscularis propria.
Presence of abscess with a small amount of DxHA
outside the muscularis propria
DxHA tracks outside the muscularis propria
DxHA identied outside the muscularis propria
Abscess identied in the submucosa
DxHA identied in the muscularis propria
DxHA present within a 4 cm abscess located outside
the muscularis propria and near the myomectomy site


A. Alshehri et al. / Journal of Pediatric Surgery 49 (2014) 13531359


Fig. 6. High power slide showing a DxHA microshphere within a giant cell surrounded
by brosis and collagen deposition (yellow). Hematoxylin ploxine saffron stain.

signicantly more involved than in human operations. Nevertheless,

others have reported achieving the same goal in pigs by laparoscopy
[36]. Interestingly, despite a generous myectomy, we found identication of the myectomy site quite difcult on subsequent endoscopy.
This may have prevented us from injecting exactly at the myectomy
site, and may have inuenced our results. Although quite involved,
our procedure of 24-hour ambulatory pH monitoring in pigs was
successful and reproducible. The lack of esophagitis seen in all animals
did not allow for evaluation of this endpoint or its prevention. The
survival period of six weeks after cardiomyectomy was likely too short
for esophagitis to be demonstrated.
This study demonstrates the feasibility and safety of DxHA
injection into the GEJ in a porcine GERD model. Implantation of
DxHA at the GEJ is technically feasible using a rigid scope with a
beveled needle. However, the tip of the needle must not traverse
the esophageal wall. This occurred in some of our injections, with
DxHA found outside the wall of the esophagus, in some cases
surrounded by an inammatory reaction. However, none of those
pigs experienced any complications. Nevertheless, the endoscopic
injection technique requires signicant renement. More accurate
injection may be facilitated by use of a needle with limited
extension, such as a sclerotherapy needle, or by employing
endoscopic ultrasound. All injected animals survived and thrived
without evidence of esophageal obstruction or perforation. There
was some evidence that DxHA injection augmented the LES and
decreased the amount of reux. A predictable histologic effect
resulted after injection.
It should be emphasized that this is a small pilot study that does
not conclusively offer data supporting a therapeutic role for DxHA
in the treatment of GERD. The small sample size in each arm and
the short survival period limit the power of the study. In addition,
no animal model can duplicate the pathophysiology of human
GERD. However, the data presented here continue to raise the
possibility of a therapeutic role for this agent in GERD treatment in
both children and adults. Further renements in experimental
techniques are necessary in order to produce stronger evidence and
potentially allow for translational research in patients through a
limited trial.

We are grateful for the assistance of Emily Kay-Rivest in the
laboratory, as well as for the statistical review provided by Xianming
Tan, Ph.D. of the Biostatistics Core Facility, McGill University Health
Centre Research Institute.

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