Endoflip after peroral_endoscopic_mytotomy_v0.1

1. Use of EndoFLIP system for the evaluation
of the effects of Peroral Endosqcopic
Myotomy. Results of a prospective
observational study on a consecutive
series of patients

BACKGROUND AND AIMS
Achalasia is an rare esophageal disease characterized by absence of efficacious
peristalsis of the esophageal body and impaired relaxation of the lower esophageal
sphincter (LES) in response to swallowing. ( Ghoshal UC, Daschakraborty SB, Singh R.
Pathogenesis of achalasia cardia. World J Gastroenterol. 2012 Jun 28;18(24):3050-7)
Achalasia is characterized by the progressive degeneration of the neurons of the
myoenteric Auerbac’s plexus. ( Chuah SK, Hsu PI, Wu KL, Wu DC, Tai WC, Changchien
CS. 2011 update on esophageal achalasia. World J Gastroenterol. 2012 Apr
14;18(14):1573-8.)
Degeneration is irreversible, and all the available treatments - medical, endoscopic and
surgical – aim to relief the symptoms of achalasia (dysphagia, regurgitation, chest pain
and weight loss) by reducing the basal and swallow induced residual LES pressure.
(Katada N, Sakuramoto S, Yamashita K, Shibata T, Moriya H, Kikuchi S, Watanabe M.
Recent trends in the management of achalasia. Ann Thorac Cardiovasc Surg.
2012;18(5):420-8.)



The classic surgical treatment of achalasia is Heller myotomy associated with and an
antireflux wrap. (Allaix ME, Patti MG. What is the Best Primary Therapy for Achalasia:
Medical or Surgical Treatment? Who Owns Achalasia? J Gastrointest Surg. 2013 Jun 19)

2. The disruption of the muscular fibers of the LES by using endoscopic pneumatic dilation
with large caliber balloons offers excellent short term results, with a minimal complication-
rate and invasiveness. (Yaghoobi M, Mayrand S, Martel M, Roshan-Afshar I, Bijarchi R,
Barkun A. Laparoscopic Heller's myotomy versus pneumatic dilation in the treatment of
idiopathic achalasia: a meta-analysis of randomized, controlled trials. Gastrointest Endosc.
2013 May 14) However, the benefits of balloon dilations seem to vanish with time, and in
young patients. (Boeckxstaens GE, Annese V, des Varannes SB, Chaussade S, Costantini
M, Cuttitta A, Elizalde JI, Fumagalli U, Gaudric M, Rohof WO, Smout AJ, Tack J,
Zwinderman AH, Zaninotto G, Busch OR; European Achalasia Trial Investigators
Pneumatic dilation versus laparoscopic Heller's myotomy for idiopathic achalasia. N Engl J
Med. 2011 May 12;364(19):1807-16. doi: 10.1056/NEJMoa1010502.)
More recently Peroral Endoscopic Myotomy has been introduced in the clinical practice as
as an endoscopic alternative to surgical myotomy.( Inoue H, Minami H, Kobayashi Y, et al.
Peroral endoscopic myotomy(POEM) for esophageal achalasia. Endoscopy 2010;42:265-
71). POEM may offer the same long term benefits of surgical myotomy, with the minimal
invasiveness of an endoscopic transoral procedure. POEM is gaining international
consensus, even if few data are available for a long term evaluation. (Stavropoulos SN,
Modayil RJ, Friedel D, Savides T. The International Per Oral Endoscopic Myotomy Survey
(IPOEMS): a snapshot of the global POEM experience. Surg Endosc. 2013 Apr 3)
The efficacy of the therapeutic interventions for achalasia is usually measured by
symptoms evaluation, appearance of Esophago-Gastric Junction (EGJ) at
EsophagoGastroDuodenoscopy (EGD) and timed esophagograms, and by esophageal
manometry.
The EndoFLIP (Endolumenal Functional Lumen Imaging Probe) System is a new
technology that provides real-time measurements of the diameter of EGJ and of its cross
sectional area (Regan J, Walshe M, Rommel N, Tack J, McMahon BP.New measures of
upper esophageal sphincter distensibility and opening patterns during swallowing in
healthy subjects using EndoFLIP®. Neurogastroenterol Motil. 2013 Jan;25(1):e25-34)
(Alqudah MM, Gregersen H, Drewes AM, McMahon BP. Evaluation of anal sphincter
resistance and distensibility in healthy controls using EndoFLIP ©. Neurogastroenterol
Motil. 2012 Dec;24(12):e591-9)

3. through a specific catheter with balloon attached at the distal end, using specific
algorithms and impedence planimetry. EndoFLIP may allow to immediately evaluate the
effects of any therapeutic interventions on the LES and EGJ, including antireflux procedure
(Video. Perretta S, Dallemagne B, McMahon B, D'Agostino J, Marescaux J Improving
functional esophageal surgery with a "smart" bougie: Endoflip. Surg Endosc. 2011
Sep;25(9):3109) (Lin Z, Kahrilas PJ, Xiao Y, Nicodème F, Gonsalves N, Hirano I,
Pandolfino JE. Functional luminal imaging probe topography: an improved method for
characterizing esophageal distensibility in eosinophilic esophagitis. Therap Adv
Gastroenterol. 2013 Mar;6(2):97-107) , and treatment of achalasia (Massey BT. EndoFLIP
assessment of achalasia therapy: interpreting the distensibility data is a bit of a stretch.
Gastroenterology. 2013 Apr;144(4):e17-8.) . However few studies evaluate the possible
benefits of the use of EndoFLIP after POEM . (Verlaan T, Rohof WO, Bredenoord AJ,
Eberl S, Rösch T, Fockens P. Effect of peroral endoscopic myotomy on esophagogastric
junction physiology in patients with achalasia. Gastrointest Endosc. 2013 Jul;78(1):39-44)
(Rieder E, Swanström LL, Perretta S, Lenglinger J, Riegler M, Dunst CM. Intraoperative
assessment of esophagogastric junction distensibility during per oral endoscopic myotomy
(POEM) for esophageal motility disorders. Surg Endosc. 2013 Feb;27(2):400-5)
Aims of this prospective observational study is to report on the effects of POEM on the
LES, as evaluated with EndoFLIP.

METHODS
All the patients who underwent POEM in a single tertiary referral center between April
2013 and July 2013 were enrolled in the study,
POEM was offered to patients with a confirmed diagnosis of achalasia and an Eckardt
score greater than 3. Diagnostic workup for achalasia, included, as usual, high resolution
manometry, timed barium esophagograms, and EGD.
POEM technique
POEM was performed by two endoscopist (GC and PF) according the technique
previously described by Inoue et al. (Endoscopy 2010). The mucosa of the esophagus was
lifted with a 10% glycerol solution, and incised approximately 10-13 cm above the GEJ. A

4. TT-knife was used to create a tunnel into the esophageal submucosal, extended for three
cm beyond the GEJ. After dissection was completed, myotomy was performed, and
included preferably the circular bundles of the esophageal and cardial muscularis propria.
The mucosal defect was sutured with endoscopic clips.
EndoFLIP system and catheter
The EndoFLIP® System technology uses impedance planimetry to characterize the
geometry of cross sectional measurement areas. Impedance planimetry uses AC voltage
measurements made between pairs of electrodes to estimate the extent of the diameter of
the medium (a conductive fluid) at the mid-point between those electrodes. This can be
done provided the voltage drop across the medium is generated from a constant AC
current source and the conductivity of the medium is constant and known for a given
temperature. If the conductive medium is contained in a flexible balloon and an array of
voltage electrodes used, the shape of the balloon can be reproduced based on the voltage
readings. This is the basis of the EndoFLIP imaging technique. (Picture 1)
The EndoFLIP EF-825 catheter was used for the study. This catheter has attached at the
distal end a 14cm long balloon, with 17 electrodes (5 mm apart) inside providing an 8 cm
long image field, for volume controlled measurements. No pressure sensors are
embedded in this catheter.
EndoFLIP measurements were performed on the same day, immediately before and
immediately after the POEM procedure, with the patient under general anesthesia and oro-
tracheal intubation. The catheter was advanced transorally to the stomach, alongside the
endoscope, under direct visual control. The balloon was inflated with 30mL of balanced
saline solution, and pulled back into the EGJ to a point where the EGJ was observed to be
located centrally within the balloon. The narrowest cross-sectional area identified the lower
esophageal sphincter and the GEJ, and was used as reference diameter.
Still images of the EndoFLIP measurements were acquired and stored for comparisons,
before and after the POEM.
Management after POEM and follow-up
Patients resumed oral feeding 1 or 2 days after POEM and were discharged on the 3
rd
or
4
th
post-operative days. Follow-up visits for symptoms assessment were performed 30
days after the procedure. At 3-month follow-up patients underwent again symptoms
evaluation, esophageal high resolution manometry and pH-metry.

5. Data analysis and statistics
Demographics, preoperative and procedural data, results of the EndoFLIP measurements
and follow-up data were recorded into a prospectively collected database on Microsoft
Excel, encrypted and stored.
The data collected before and after POEM were compared with the preoperative and post-
operative EndoFLIP measurements. Data are presented as mean + standard deviation
when parametric and as median (interquartile range [IQR]) when nonparametric.
Parametric variable were tested by using a t test. Paired nonparametric data were tested
by using the Wilcoxon signed rank test. A P value of .05 was considered as statistically
significant.

RESULTS
During the study periods 23consecutive patients (12 males, mean age 51.7 years)
underwent POEM and EndoFLIP, and were enrolled in the study. Mean Eckardt score
before POEM was 8.6. 13 patients had a type I achalasia at HRM; 10 a type-II.
Preoperative mean basal LES pressure was XX mmHg and mean 4sIRP was XXXmmHg.
The procedure were completed successfully in 21 of 23 patients. In one patients, with
history of mammalian cancer and mediastinal irradiation mucosal lifting failed and POEM
procedure aborted; the patient underwent pneumatic dilation using a 30mm balloon.
EndoFLIP was successfully performed in all the cases. The day after the procedure the
patients underwent EGD and esophageal Gastrografin® study, demonstrating no
complications, and the patients were fed with a soft diet. Patients were discharged an
average 3 days after the procedure.
EndoFLIP measurements
Baseline EndoFLIP data are available for all the patients. Before POEM, the EGJ diameter
and cross sectional area - as measured with EndoFLIP and a balloon inflated with 30ml of
saline solution – were on average 5.1 mm (+ 1.8 SD) and 32.9 mm
2
(+ 23.7SD),
respectively.
After treatment, the mean diameter and cross-sectional area of the EGJ were
substantially increased, 11.3 mm (+ 0.35SD) and 102.38 mm2 (+ 28.9 SD) respectively.
All the patients had a variation of more of XX mm in diameter before and after POEM.

6. In a patient, after the initial myotomy, the diameter of the EGJ was not substantially wider
compared to the preoperative results (6.7 mm vs 7.1 mm, respectively). The endoscope
was thus reinserted in the submucosal tunnel, and some more circular bundles of the LES
were cut using electrocoagulation. At the final measurement using EndoFLIP, the mean
diameter of LES at 30ml was now 12.7 mm.
Follow-up
Only a short follow.-up is available for the patients. No complications occurred in the study
population. After a mean of XX months (xx weeks – xx months), the entire study
population referred complete dysphagia relief, with a mean Eckard score of XX. Non
symptoms of GERD were referred by the patients. pH-metry reveal pathological reflux total
reflux time > 4%) in xx% of patients. At the 3-month HRM, average basal LES pressure
was xx mmHg (+ SD) and 4sIRP xx mmHg (+ SD).
At univariate analysis, no statistically significant correlations were observed between the
postoperative EndoFLIP measurement of the EGJ, and the Eckardt score, GERD
incidence and LES pressures.
DISCUSSION
POEM is now considered effective and safe for the treatment of esophageal achalasia.
The aim of any therapy of achalasia, surgical or endoscopic, is to improve the esophageal
emptying, by reducing the basal- and swallow-induced resting LES pressure, by improving
the compliance of the EGJ to the passage of food.
Previous studies demonstrated that the long term benefits of surgical and endoscopic
treatment of achalasia are directly related with the reduction of the basal LES pressure.
Recurrences of dysphagia have been observed more frequently in case of LES pressure >
10mmHg. Some authors support re-interventions after pneumatic dilation in case the LES
pressure after treatment is > 10mmHg, even in case of absence of symptoms, to prevent
recurrences.
Unfortunately manometric studies cannot be performed during POEM, being the patients
under general anesthesia, and any evaluation of the effects of myotomy on LES pressure
and esophageal emptying should be performed in the post-operative time.

7. Some authors demonstrated that the distensibility of the EGJ can substantially affects the
esophageal emptying, and this parameter could correlate with long term efficacy and
adverse events (including GERD).
EndoFLIP allows a real-time measurement of the diameter of the esophagus and of the
EGJ by using an impedentiometry-based catheter, with a distal balloon that is inflated with
a certain volume of saline solution. The probe used for the measurements is thin, has a
very soft, atraumatic and flexible tip, and can be easily pushed through the cardia before
and after POEM. Because of the small caliber, the position of the catheter can be check
using an endoscope alongside the probe. The measurement of the diameters and cross-
sectional areas using the balloon based catheter does not require any collaboration by the
patient (swallowing, breathing…), and thus EndoFLIP can be used during the operation
under general anesthesia, to tailor the myotomy and verify the effects of POEM on the
GEJ and LES.
Currently during POEM, the effects and completeness of myotomy can be only assessed
subjectively and empirically, by evaluating the appearance of myotomy at EGD and by
passing the endoscope through the cardia, trying to appreciate any resistance to the
transit. In order to have a complete myotomy at the level of the LES, submucosal
dissection and myotomy are usually extended for 2-3 cm beyond the cardias on the gastric
wall. However, again endoscopic measurements are subjective and imprecise, and be
affected by many bias.
On the counterpart, the possibility to measure the diameter of the GEJ and distensibility
before and after the POEM can be particularly useful to reveal cases of incomplete
myotomy, before the closure of the entry of submucosal tunnel with clips. In one of our
cases, even if the myotomy seemed complete at the end of the procedure, EndoFLIP did
not reveal any substantial change of the diameter of the GEJ, with the balloon inflated at
30ml. Hence, some additional muscular bundles were cut at the level of the GEJ, with a
substantial improvement of diameter at the end.
Differently from the other ones, the EndoFLIP probes used in this study (EF-825) does not
measure pressure, and consequently a real distensibilty of the EGJ has not been
assessed during the study. Even if attractive from a scientific point of view, “distensibility”
(by meaning of a direct function of pressure – mm
2
/mmHg), can be practically
meaningless, since surgeon and endoscopists want to set the lumen size and not

8. compliance of EGJ. Thus, the “diameter of GEJ” or its “crossectional area” are more
intuitive parameters, and probably more useful during the procedure. Measuring the
diameter that the EGJ opens out to with 30mL in the balloon is giving us a different
measure of distensibility, how much the EGJ opens for a given volume in the balloon.
30mL simulates a bolus pressure of around 10-15mmHg, probably more similar to what
happens during physiological swallowing. Furthermore, pressure is very variable and
susceptible to changes for the smallest of reasons. Therefore the diameter or the cross-
sectional area are more robust measurements
One of the most common adverse events after POEM is GERD. Differently from surgical
Heller Myotomy, an antireflux procedure is not performed after POEM, leading to a
possible increased incidence of GERD. Incidence of GERD is very variable in published
series, from 5% to 46%. A wider opening of the GEJ, as seen with the EndoFLIP system,
may theoretically favor GERD, as demonstrated by previous studies. The average
diameter of the GEJ after POEM varied in the literature from xx to xx. In the present study
the GEJ diameter passed from xx mm preoperatively to xx postoperatively, similarly to
previous studies. However, it is still unknown which should be the correct EGJ diameter
that allow a quick esophageal emptying by avoiding at the same time GERD. Furthermore,
the effects of POEM on the distensibility of the EGJ are often unpredictable, and not really
controllable, and unfortunately it is not possible to narrow and restrict the GEJ after POEM.
EndoFLIP system is a safe and effective technology for the evaluation of the effects of
myotomy on the GEJ and LES. The data obtained from the measurements of the diameter
of the lower esophageal sphincter associated with clinical and instrumental data of the
follow-up of patients may be useful to improve POEM technique by assessing and
establishing the correct diameter of the EGJ that allow a quick esophageal emptying with a
minimal the risk of GERD.

AGGIUNGERE UN PARAGRAFO SU STUDI PRECEDENTI SU ENDOFLIP E POEM

10. I know we have done some cases with you where the minimum diameter started out above 8mm, and for
these cases I personally believe that the POEM benefit is derived not from removing outflow obstruction,
but something else in the procedure. As a rule of thumb, in fundoplication, a target of around 8mm at
crural repair and 6-6.5mm after the wrap seems to be about right. One would expect the GEJ to be set
looser in an achalasic with poor peristalsis, so 8mm seems to make sense in a qualitative sense. In terms of
extremes, most Heller pts seem to come in around 5mm pre-procedure, whereas bad GERD patients come
in around 10mm (think of a 9.2mm scope passing easily through the junction). So measurement of
diameter is a more practical intra-operative and cost effective tool. We do have another catheter that also
measures balloon pressure and distensibility (EF-325).
Pressure is vary variable and susceptible to changes for the smallest of reasons. Say you had a cross
sectional area of 50mm2 and the pressure varied by 3mm (very little) e.g. from 10 to 13, the distensibility
would go form 50/10 (= 5) to 50/13 (=3.85) .. a change of 30%. I therefore also feel that diameter is a more
robust measurement. Most people doing work with pressure on EndOFLIP will tell you that this takes a lot
of post-processing and filtering of the data. Personally I am little less than convinced in relation to its
robustness.





You are correct. The EF-825 does not measure pressure. Whereas some people are measuring distensibility,
most of our day to day work (and most recent fundoplication work) is focussed on the cross sectional area
or diameter of the junction (please see the attached presentation as it relates to fundoplication). The
reason for this is that setting the compliance of the junction is a bit meaningless, since
surgeons/endoscopists want to set the lumen size. e.g. if I told you the lumen size was 5mm but the
distensibility was 2.8, what would you do, well you likely would open the lumen out to 9+mm of course. So
whereas distensibility is nice science, it is not really assisting in a real practical sense during the procedure
(though maybe perhaps it is a nice check at the end). We are trying to encourage the use of diameter as it is
more intuitive and practical i.e. you want to open or close the junction to establish a new geometry as

11. opposed to creating a new degree of spring-iness (thought he latter might be nice to know, the former will
be the real procedural intent !).



EndoFLIP in POEM
- Diametro PRE…..Diametro POST (Tab 1)
- CSA PRE…………..CSA POST (Tab 2)
- Caso particolare di Coppola Giuseppa che diametro PRE simile a diametroPOST rientrati
ed estesa miotomia a tutto spessore con Diametro POST POST allargato.

EndoFLIP in Pneumatic Dilation
- Diametro PRE…..Diametro POST (Tab 3)
- CSA PRE…………..CSA POST (Tab 4)

12. Picture 1


Picture 2

13. Picture 3
Se riesci a fare 3 frame consecutivi da filmato di posizionamento e gonfiaggio
EndoFlip.


Tab 1 POEM : Diametri singoli PRE e POST , Diametro medio PRE e POST

0
2
4
6
8
10
12
14
16
Diametro PRE Diametro POST
1 2 3
4 5 6
7 8 9
10 11 12
13 14 15
16 17 18
19 20 21

14. Tab 2 POEM : CSA singoli PRE e POST CSA medio PRE e POST

0
2
4
6
8
10
12
Med Diametro PRE Med Diametro POST
Diam
0
20
40
60
80
100
120
140
160
180
CSA PRE CSA POST
1 2 3
4 5 6
7 8 9
10 11 12
13 14 15
16 17 18
19 20 21

15. Tab 3 Pneumatic Dilation : Diametri singoli PRE e POST , Diametro medio PRE e POST




0
20
40
60
80
100
120
Med CSA PRE Med CSA POST
CSA

16. Tab 4 Pneumatic Dilation : CSA singoli PRE e POST , CSA medio PRE e POST


0
20
40
60
80
100
120
140
160
180
200
Diametro PRE Diametro POST
1
2
3
0
20
40
60
80
100
120
Med CSA PRE Med CSA POST
CSA