Transoral endoscopic esophageal myotomy based on esophageal function testing in a survival porcine model

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Transoral endoscopic esophageal myotomy based on esophageal function testing in a survival porcine model. Gastrointest Endosc ARTICLE in GASTROINTESTINAL ENDOSCOPY · JANUARY 2011 Impact Factor: 5.37 · DOI: 10.1016/j.gie.2010.09.009 · Source: PubMed

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Gianfranco Donatelli

Pierre Diemunsch

Hôpital Privé des Peupliers

CHRU de Strasbourg

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Available from: Gianfranco Donatelli Retrieved on: 04 February 2016

ORIGINAL ARTICLE: Experimental Endoscopy

Transoral endoscopic esophageal myotomy based on esophageal function testing in a survival porcine model Silvana Perretta, MD, Bernard Dallemagne, MD, Gianfranco Donatelli, MD, Pierre Diemunsch, MD, Jacques Marescaux, MD Strasbourg, France

Background: The most effective treatment of achalasia is Heller myotomy. Objective: To explore a submucosal endoscopic myotomy technique tailored on esophageal physiology testing and to compare it with the open technique. Design: Prospective acute and survival comparative study in pigs (n ! 12; 35 kg). Setting: University animal research center. Intervention: Eight acute— 4 open and 4 endoscopic—myotomies followed by 4 survival endoscopic procedures. Main Outcome Measurements: Preoperative and postoperative manometry; esophagogastric junction (EGJ) distensibility before and after selective division of muscular fibers at the EGJ and after the myotomy was prolonged to a standard length by using the EndoFLIP Functional Lumen Imaging Probe (Crospon, Galway, Ireland). Results: All procedures were successful, with no intraoperative and postoperative complications. In the survival group, the animals recovered promptly from surgery. Postoperative manometry demonstrated a 50% drop in mean lower esophageal sphincter pressure (LESp) in the endoscopic group (mean preoperative LESp, 22.2 " 3.3 mm Hg; mean postoperative LESp, 11.34 " 2.7 mm Hg; P # .005) and a 69% loss in the open procedure group (mean preoperative LESp, 24.2 " 3.2 mm Hg; mean postoperative LESp, 7.4 " 4 mm Hg; P # .005). The EndoFLIP monitoring did not show any distensibility difference between the 2 techniques, with the main improvement occurring when the clasp circular fibers were taken. Limitations: Healthy animal model; small sample. Conclusion: Endoscopic submucosal esophageal myotomy is feasible and safe. The lack of a significant difference in EGJ distensibility between the open and endoscopic procedure is very appealing. Were it to be perfected in a human population, this endoscopic approach could suggest a new strategy in the treatment of selected achalasia patients. (Gastrointest Endosc 2011;73:111-6.)

The idea behind natural orifice transluminal endoscopic surgery (NOTES) concerns performing traditional surgical procedures by using an alternative method, namely, a flexible one. But notably, the real revolution lies behind the evolution of the approach itself. The perfor-

mance of endoscopic submucosal transesophageal myotomy is a perfect example. The understanding of achalasia has so far centered on manometric studies and surgical treatment with myotomy and fundoplication. The operative management of this

Abbreviations: EGJ, esophagogastric junction; EndoFLIP, Endoscopic Functional Lumen Imaging Probe; GEJ, gastroesophageal junction; LESp, lower esophageal sphincter pressure; NOTES, natural orifice transluminal endoscopic surgery; POEM, peroral endoscopic myotomy.

Current affiliations: IRCAD, Department of Gastrointestinal and Endocrine Surgery (S.P., G.D., J.M.), IRCAD-EITS, Department of Gastrointestinal and Endocrine Surgery (B.D.), IRCAD, Department of Anesthesia (P.D.), University of Strasbourg, Strasbourg, France.

DISCLOSURE: All authors disclosed no financial relationships relevant to this publication.

Reprint requests: Dr. Silvana Perretta, University of Strasbourg, Department of Gastrointestinal and Endocrine Surgery, 1 Place de l’Hopital, Strasbourg, FR 67091 France.

Copyright © 2011 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2010.09.009 Received June 2, 2010. Accepted September 3, 2010.

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disease is still based on a procedure described as far back as 1913 when Heller1 treated outflow obstruction by an anterior and posterior myotomy performed by thoracotomy. The issue of the length of the myotomy has been debated for some time. A long myotomy could potentially induce reflux; a short myotomy may carry the risk of residual dysphagia.2 Today, the standard myotomy is 6 to 8 cm long, extended 2 to 3 cm onto the gastric cardia.3 Other investigators have shown the feasibility of performing an esophageal myotomy by using NOTES, although they have been less successful at extending the myotomy onto the body of the stomach in the attempt to exactly reproduce the conventional surgical strategy.4,5 A method for assessing completeness of myotomy is to perform intraoperative manometry to measure any residual high pressure across the gastro-esophageal junction (GEJ).6 Intraoperative persistently elevated pressures can allow immediate revision of the myotomy and therefore increase the postoperative success rate. Intraoperative endoscopy also has been described to assess the completeness of the myotomy but does not provide an objective evaluation of the effectiveness of the procedure. New measurement ideas around the concept of distending the esophagogastric junction (EGJ) suggest that a clinically usable test for compliance, or distensibility, at the junction could potentially help in determining EGJ dynamics and therefore appropriate therapy. As suggested by Harris and Pope,7 resistance to distention could be a more valuable criterion for fully and dynamically evaluating EGJ behavior. Therefore, a distensibility test may provide better information on the opening and closing dynamics of the EGJ, rather than just relying on the sphincter tonic state as measured by manometry, which would be of particular interest in achalasia.8,9 The EndoFLIP Imaging System (Crospon, Galway, Ireland) provides a dynamic representation of the luminal geometric changes in the EGJ based on impedance planimetry assessing how easily the high-pressure zone will stretch further for a given distending pressure. Our group focused on establishing a transoral incisionless stepwise approach to esophageal myotomy in a survival porcine model tailored on esophageal function testing, manometry, and impedance planimetry to objectively demonstrate changes at the EGJ before, during, and after the procedure. The aim of the study was to explore the effectiveness of submucosal endoscopic myotomy based on esophageal physiology and to compare it to the criterion standard open technique. The secondary aim was to investigate the intraoperative cardiopulmonary impact of such a procedure.

Take-home Message ●

Transesophageal endoscopic myotomy is safe and effective but not as good as open surgery in reducing the high-pressure zone at manometry. The EndoFLIP monitoring did not show any distensibility difference between the 2 techniques, with the main improvement occurring when the clasp circular fibers were taken. Manometry—today’s reference standard in assessing sphincter function—may provide an incomplete picture of the esophagogastric junction, providing surrogate information for the size of the lumen but not telling us how it stretches. The lack of significant difference in esophagogastric junction distensibility between the open and endoscopic procedure is very appealing. There is sufficient evidence to speculate that a tailored endoscopic myotomy, with selective cut of circular clasp fibers, may effectively relieve outflow obstruction. Were it to be perfected in a human population, we could be facing a new strategy in the treatment of selected achalasia patients.

care and the European Community Council Directive (No. 86/609/EEC). Four open and 4 endoscopic acute preliminary experiments were carried out both to assess the feasibility of the technique and to standardize the surgical steps. Preliminary necropsy study and histology examinations helped determine a safe window by which to enter into the esophageal wall for submucosal tunnel creation and to define the muscular architecture at the GEJ. This acute experimental phase was followed by a 4-week survival study in 4 pigs undergoing endoscopic myotomy.

Preparation for surgery

METHODS

Preoperatively, each pig was fasted for 48 hours. A premedication by intramuscular injection comprising 7 mL of ketamine and 3 mL of azaperone (Stresnil; Janssen-Cilag, Berchem, Belgium) was administered 1 hour before surgery, whereas induction was achieved with intravenous propofol (10 mL/30 kg) combined with pancuronium (0.4 mg/kg). Anesthesia was then maintained with 2.5% isoflurane after insertion of an endotracheal tube into the supine animal. Mechanical ventilation was set to an initial ETCO2 of 36.2 " 0.2 mm Hg, with FiO2 of 0.5 (Aisys Carestation; GE Healthcare, France). Monitoring included central temperature, electrocardiography, arterial blood pressure, SpO2, airway pressures, and ETCO2 every 5 minutes. Lactic acid levels were measured at baseline and at the end of surgery. Surviving animals also received antibiotic prophylaxis intravenously (1 g of cephalexin).

Animals

Esophageal function testing

Twelve 30- to 35-kg pigs were used and managed in accordance with both French laws for animal use and

A first endoscopy was performed to assess the location of the EGJ and to exclude any preexisting esopha-

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geal diseases. All animals underwent preoperative and postoperative esophageal physiology testing by means of manometry and impedance planimetry of the GEJ by using the EndoFLIP Functional Lumen Imaging Probe. A solid-state manometry catheter (Latitude Medical, Lyon, France) was placed across the GEJ under endoscopic control. The pull-through method was used to locate the lower esophageal sphincter (LES) and to measure its resting pressure and length. All manometric data were analyzed by using the polygram net module (Medtronic Functional Diagnostics, Skovlunde, Denmark). Next, the manometry probe was removed, and the EndoFLIP balloon was placed straddling the GEJ to coincide with the manometric location of the LES. The EndoFLIP comprises a measurement display unit and a sensing 25-mm balloon probe housing an array of 16 pairs of electrodes spaced 5 mm apart to measure multiple diameters and cross-sectional areas at fixed intervals along the catheter. The system determines the diameter at the midpoint of each pair of electrodes by using an impedance measurement technique. Pressure within the balloon probe also was measured by using a solid-state sensor. The diameters, so measured, were used to build a dynamic representation of the luminal geometric changes in the GEJ as the balloon was distended on the catheter. For the distension protocol, the balloon was inflated to 30 mL at a rate of 40 mL per minute. Data on 16 diameters, crosssectional areas, and pressure in the balloon were recorded, along with distensibility, defined as the minimum cross-sectional area of the junction divided by balloon distending pressure. The adequacy of endoscopic myotomy was evaluated by assessing the preoperative manometric LES profile and the postoperative LES pressure fall and by comparing EGJ diameter, cross-sectional areas, and distensibility patterns before and after the division of the esophageal muscular fibers by using the EndoFLIP. The distensibility measurements were taken at 3 time points: before the myotomy, after the muscular fibers at the EGJ were selectively taken, and after the myotomy had been prolonged to a standard length.

Open Heller myotomy In 4 pigs, an open Heller myotomy was performed via a standard median laparotomy. The initial myotomy comprised only the EGJ in order to selectively assess with the EndoFLIP the modification in distensibility achieved. Next, the myotomy was classically prolonged distally onto the stomach and proximally onto the esophageal wall, and the EndoFLIP measurements were repeated.

Endoscopic myotomy In the 4 endoscopic acute experiments, laparoscopy was carried out to monitor the different steps of the procedure. A double-channel gastroscope (Karl Storz Endoswww.giejournal.org

Transoral endoscopic esophageal myotomy

Figure 1. Endoscopic identification of the circular clasp muscular fibers at the esophagogastric junction.

kope; Karl Storz, Tuttlingen, Germany) was introduced perorally. The mucosa on the right posterolateral esophageal wall was cut with the needle-knife 15 cm above the LES. The initial incision was dilated with blunt dissection by using a soft-tipped biliary balloon to allow the passage of the endoscope. A submucosal tunnel was created toward the EGJ with blunt dissection assisted by lowpressure CO2 flow (8 mm Hg) through one of the endoscope’s channels. The GEJ could be identified as increased resistance was felt at endoscopic dissection. At this level, the circular fibers are thicker, slightly more oblique, and entangled with the outer longitudinal fibers (Fig. 1). The inner circular muscular layer was incised in a distal-toproximal fashion by using the IT knife and the hook knife (Olympus, Tokyo, Japan) without entering the abdominal cavity. The correct identification of the GEJ also was verified by laparoscopy. When all the circular fibers were cut and the EndoFLIP measurements taken at this stage, the myotomy was extended proximally, including the longitudinal fibers, onto the esophageal wall for 3 cm, creating a window to the mediastinum. The endoscope was then withdrawn back into the esophageal lumen and the mucosal flap sealed by application of multiple endoscopic clips (Olympus). In the 4 acute endoscopic experiments, necropsy was carried out to assess the location and quality of the myotomy as well as to identify any injury to adjacent structures and mediastinal contamination. The specimens were sent to pathology to objectively evaluate the exact location of the myotomy and the efficacy of the muscular dissection.

Follow-up and survival study After surgery, the pigs were given the analgesic/antiinflammatory agent flunixin meglumine (Flogend; Gellini International, Aprilia, Italy) and were extubated, recovered, and housed individually. Fluids were given ad libitum on the first postoperative day, with a lowfiber, oral diet being introduced thereafter. Oral antibiotics (300 mg of cephalexin) were given with the chow Volume 73, No. 1 : 2011 GASTROINTESTINAL ENDOSCOPY

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Figure 2. EndoFLIP monitoring resistance to distension of the esophagogastric junction for the same tested volumes after open (A) and endoscopic (B) myotomy.

for the first 5 postoperative days. Dietary intake, bowel habit, weight, and well being were monitored daily. Manometry and endoscopy were repeated 2 weeks postoperatively. Four weeks after surgery, all animals underwent endoscopy and necropsy. Laparotomy and thoracotomy were performed to assess healing of the esophageal closure sites and to examine for infectious complications. All animals were then humanely killed by a lethal dose of potassium administered intravenously after deepening of anesthesia.

Statistical analysis The paired t test was applied to analyze manometry and EndoFLIP data before and after myotomy. A P value # .05 was considered significant.

RESULTS All the open and endoscopic procedures were successfully accomplished with no injury to the esophagus or breach of the esophageal mucosa. In the endoscopic group, no hemodynamic or respiratory instability or any untoward event could be observed, with a median operative time of 45 minutes (range, 35-60 minutes). The 114 GASTROINTESTINAL ENDOSCOPY

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blood pressure, heart rate, and ventilation parameters stayed in the normal range all the time. The ETCO2 and SpO2 proved stable and constantly in the normal range (32-40 mm Hg and 97%-100%, respectively). No major increase in lactic acid levels could be observed. In the endoscopic group, postoperative manometry demonstrated a significant consistent modification in lower esophageal sphincter pressure (LESp), with a 50% loss in mean pressure in all animals (mean preoperative LESp, 22.2 " 3.3 mm Hg; mean postoperative LESp, 11.34 " 2.7 mm Hg; P # .005), which persisted at the 2-week follow-up manometry in the 4 survival animals (12 " 2.4 mm Hg, P # .005). A more significant drop in LESp of 69% was achieved with the open technique (mean preoperative LESp, 24.2 " 3.2 mm Hg; mean postoperative LESp, 7.4 " 4 mm Hg; P # .005). The EndoFLIP monitoring did not show any significant difference between the open Heller and endoscopic procedures, both producing a similar improvement in the resistance to distension (Fig. 2), approximately doubling distensibility for the same tested volumes (30 mL) (Fig. 3). In addition, the EndoFLIP showed that the diameter and distensibility of the EGJ were clearly improved as soon as the clasp circular fibers of the Laimer www.giejournal.org

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Transoral endoscopic esophageal myotomy

Figure 3. Distensibility before and after open and endoscopic myotomy. Data are expressed as mean and standard deviation. (*P # .005). postop, postoperative; preop, preoperative.

bracket were taken, and no significant further improvement occurred when the myotomy was prolonged with both techniques. In the endoscopic survival group, all animals recovered promptly from surgery and showed appropriate weight gain. Two-week and 4-week follow-up endoscopies demonstrated a well-healed, well-vascularized esophageal mucosa. The mucosa in correspondence to the myotomy site was intact, and no stricture was observed at the GEJ. All the myotomies were on the right posterolateral wall of the esophagus and cut through the circular muscular structure of the GEJ (Fig. 4). There were no adhesions or signs of infection in the mediastinum or abscess formation within the esophageal wall and the thoracic cavity.

DISCUSSION The future of NOTES lies not only in the reduction of the invasiveness of selected surgical procedures but mainly in the development of innovative surgical concepts and revisitation of old surgical dogmas. Diagnosis and surgical treatment of achalasia have been established, even if still debated, for a long time. The extent of open or laparoscopic esophagogastric myotomy was defined on the basis of clinical and manometric results. Revisitation of the concept was initiated by Pasricha et al,4 who, on the wave of NOTES, described submucosal endoscopic esophageal myotomy in an experimental setting. Most impressively perhaps, Inoue et al10 has recently reported the first clinical experience of submucosal endoscopic esophageal myotomy for esophageal achalasia with a peroral endoscopic myotomy (POEM)–modified Pasricha4 technique in 17 patients, including 5 with sigmoid-type www.giejournal.org

achalasia. The innovation brought by Inoue’s technique consisted of dividing selectively the circular muscular bundles, leaving the outer longitudinal esophageal musculature intact. Length of the myotomy reproduced the classical 6-cm esophageal and 2-cm gastric surgical standards. In all cases, POEM achieved significant reduction of resting LESp (from mean 52.4 mm Hg to 19.9 mm Hg) and significant improvement of dysphagia persisting at 5 months’ follow-up. No intraoperative or postoperative complications were reported, and the occasions of inadvertent entry into the cardiac mucosa (2 patients) and the exposure of mediastinal tissue (4 patients) were without incident. Our work adds a further step to Inoue’s revisitation of myotomy concept by comparing open surgical and endoscopic approaches and addressing the impact of the length of the myotomy on the physiological results measured with standard manometry and a new method measuring the distensibility of the EGJ, the EndoFLIP. With all the limitations related to the use of a healthy non-achalasic animal model, our data show that transesophageal endoscopic myotomy is safe and effective but not as good as open surgery in reducing the high-pressure zone at manometry. The EndoFLIP shows that both open and endoscopic techniques achieve similar results and that, for both, the main change in distensibility and diameter is related to the cut of circular fibers at the level of the EGJ. Extending the myotomy proximally of the esophagus is not beneficial. The issue of a limited myotomy has been studied clinically.11,12 However, this technique encompasses division of the longitudinal and the circular muscular bundles. Our study showed that a selective (circular bundles) and short myotomy may achieve a good functional outcome. This concept may have an impact on the Volume 73, No. 1 : 2011 GASTROINTESTINAL ENDOSCOPY

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occurrence of postoperative gastroesophageal reflux and is currently under investigation. This may open new frontiers in the understanding of esophageal physiology and may suggest that we are facing a change not only in surgical technique but in the preoperative and intraoperative evaluation of achalasia patients. Animal data and preliminary human studies show that transesophageal endoscopic myotomy is safe not only in terms of infection risk but also in terms of hemodynamic, respiratory, and metabolic tolerance. Although these findings need to be confirmed in a larger, randomized, comparative study, the fact that the main improvement in the opening pattern of the sphincter occurred at the division of the clasp fibers is very appealing. Were it to be perfected in a human population, this targeted esophageal endoscopic myotomy could represent a step forward in the evolution of POEM to treat selected achalasia patients. REFERENCES

Figure 4. A, Endoscopic myotomy. B, Corresponding gross anatomy. C, Histology (H&E, orig. mag. X10).

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1. Heller E. Extramucose Cardiaplastik beim chronischen Cardiospasmus mit Dilatation des Oesophagus [German]. Mitteil Grenzgeb Med Chir 1913;27:141. 2. Patti MG, Molena D, Fisichella PM, et al. Laparoscopic Heller myotomy and Dor fundoplication for achalasia: analysis of successes and failures. Arch Surg 2001;136:870-7. 3. Wright AS, Williams CW, Pellegrini CA, et al. Long-term outcomes confirm the superior efficacy of extended Heller myotomy with Toupet fundoplication for achalasia. Surg Endosc 2007;21:713-8. 4. Pasricha PJ, Hawari R, Ahmed I, et al. Submucosal endoscopic esophageal myotomy: a novel experimental approach for the treatment of achalasia. Endoscopy 2007;39:761-4. 5. Woodward T, McCluskey D 3rd, Wallace MB, et al. Pilot study of transesophageal endoscopic surgery: NOTES esophagomyotomy, vagotomy, lymphadenectomy. J Laparoendoscop Adv Surg Tech Part A 2008; 18:743-5. 6. Chapman JR, Joehl RJ, Murayama KM, et al. Achalasia treatment: improved outcome of laparoscopic myotomy with operative manometry. Arch Surg 2004;139:508-13; discussion 513. 7. Harris LD, Pope CE, 2nd. “Squeeze” vs. resistance: an evaluation of the mechanism of sphincter competence. J Clin Invest 1964;43:2272-8. 8. McMahon BP, Frokjaer JB, Drewes AM, et al. A new measurement of oesophago-gastric junction competence. Neurogastroenterol Motil 2004;16:543-6. 9. McMahon BP, Odie KD, Moloney KW, et al. Computation of flow through the oesophagogastric junction. World J Gastroenterol 2007;13:1360-4. 10. Inoue H, Minami H, Kobayashi Y, et al. Peroral endoscopic myotomy (POEM) for esophageal achalasia. Endoscopy 2010;42:265-71. 11. Di Martino N, Monaco L, Izzo G, et al. The effect of esophageal myotomy and myectomy on the lower esophageal sphincter pressure profile: intraoperative computerized manometry study. Dis Esophagus 2005;18: 160-5. 12. Di Martino N, Bortolotti M, Izzo G, et al. 24-hour esophageal ambulatory manometry in patients with achalasia of the esophagus. Dis Esophagus 1997;10:121-7.

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