Scandinavian Journal of Gastroenterology. 2015; Early Online, 1–7
ORIGINAL ARTICLE
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A stepwise approach for peroral endoscopic myotomy for treating achalasia: from animal models to patients
YUTANG REN1,2*, XIAOWEI TANG1,2*, FACHAO ZHI1, SIDE LIU1, JIANUAN WU1, YANG PENG1, BO JIANG1,2 & WEI GONG1 1
Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China, and Department of Gastroenterology, Beijing Tsinghua Changgung Hospital Medical Center, Tsinghua University, China
2
Abstract Objectives. Peroral endoscopic myotomy (POEM) was initially developed for the treatment of achalasia. This study aimed to investigate the feasibility and safety of a stepwise approach for POEM in the management of achalasia. Methods. A total of five ex-vivo porcine esophagus-stomach training models were created and POEM was performed. Then, 25 patients with achalasia were treated similarly. The Eckardt score, barium esophagrams, and high-resolution manometry were used to evaluate its efficacy. Results. POEM procedures were completed in five stomach-esophagus models, with perforations in the initial three and success in the last two. A total of 25 achalasia patients (13 males, 12 females) with achalasia successfully underwent POEM. The mean operation time was 72.0 min (range, 45–180 min). There were two complications—one case each of severe bleeding and pneumothorax—that were both treated successfully. During the follow-up period, the median Eckardt score decreased dramatically from 8 to 1 (p = 0.000). The lower basal esophageal sphincter pressure decreased markedly (41.3 ± 12.6 vs. 11.3 ± 4.3 mmHg, p = 0.000), as well as the 4-s integrated relaxation pressure (37.1 ± 12.6 vs. 7.1 ± 2.4 mmHg, p = 0.000). Additionally, the maximum esophagus width was significantly reduced (mean reduced width: 1.6 ± 1.1 cm, p = 0.000). Conclusions. The ex-vivo porcine esophagus-stomach can be used as a simple and cheap training model that mimics the POEM procedure. POEM is a safe and effective therapy for achalasia patients.
Key Words: achalasia, animal model, peroral endoscopic myotomy
Introduction Achalasia is a primary esophageal motility disorder that is characterized by aperistalsis of the esophageal body and incomplete or absent relaxation of the lower esophageal sphincter (LES) [1]. Achalasia patients usually suffer greatly from major symptoms that include dysphagia, regurgitation, and chest pain [2]. Treatment options, which are either endoscopic or surgical, mainly focus on the relief of symptoms by reducing the LES pressure. Pneumatic dilation and endoscopic Botox injection are the main endoscopic therapies for these patients. However, endoscopic methods showed lower short-term efficacy compared
to laparoscopic Heller myotomy, which was the most effective. In the long-term, sustained therapeutic effects were observed in ~80% of patients [3]. Based on developments in Natural Orifices Translumenal Endoscopic Surgery (NOTES) and the continual improvement of devices for submucosal dissection, Pasricha et al. developed an endoscopic myotomy technique in an animal model in 2007, using a submucosal tunnel [4]. Then, 3 years later, Inoue et al. performed the first series of peroral endoscopic myotomy (POEM) to treat achalasia in 17 patients [5]. Their study demonstrated that there was significant improvement in dysphagia scores and a reduction in lower esophageal sphincter (LES)
Correspondence: Wei Gong, MD, PhD, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, No.1838, Guangzhou North Ave, 510515, Guangzhou, China. Tel: +8602061641888. Fax: +8602061641541. E-mail: [email protected] *These authors contributed equally to this work.
(Received 25 August 2014; revised 21 October 2014; accepted 22 October 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2015 Informa Healthcare DOI: 10.3109/00365521.2014.983152
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Figure 1. Peroral endoscopic myotomy on a porcine esophagusstomach model. A. A simple porcine esophagus-stomach model. B. Submucosal injection 10 cm above the EGJ. C. Creation of a mucosal entry into the submucosal layer. D. Creation of a submucosal tunnel. E The circular muscle was “hooked-up” and then cut-off. F. Completion of myotomy.
pressure after POEM without serious adverse events. Subsequently, several prospective studies have been conducted to evaluate the feasibility, efficacy, and safety of this innovative endoscopic technique for the treatment of achalasia [6]. Based on our experience with endoscopic submucosal dissection (ESD), we use a stepwise approach in which we shorten the learning curve of POEM by training on ex-vivo porcine esophagus-stomach models. Then, we successfully treat achalasia patients by POEM. Our aim is to examine the feasibility of this stepwise approach and to report our preliminary experience of POEM in this pilot study. Materials and methods Step 1: Training study in an ex-vivo porcine esophagus-stomach model To create the ex vivo animal model, the porcine esophagus-stomach was chosen because of a similar anatomy and histology to humans. The porcine esophagus-stomach was acquired 48–72 h after the porcine was slaughtered from the market in order to preservetheelasticpropertiesofitswall.Theorificeofthe esophagus was pinned to a fixed polyfoam and the orifice
of the duodenum was ligated using hemostatic forceps (Figure 1A). A surgical electrode was placed beneath the stomach. After the model was created, the POEM procedure was performed as described by Inoue et al. [5], (illustrated in detail in Figure 1B–F). A forward-viewing endoscope (GIFQ240Z; Olympus, Tokyo, Japan) was used with a transparent distal cap attachment. First, a submucosal injection with a natural saline, adrenaline, and indigo carmine mixture was made 10 cm above the gastro-esophageal junction (GEJ). Then, a 2-cm longitudinal incision was made using a hook knife or triangletip knife. Second, after the mucosal entry was made, the submucosal layer was dissected to create a submucosal tunnel along the esophagus and across the GEJ 2–3 cm into the proximal stomach. Third, the circular muscle was “hooked up” and cut gradually from 2–3 cm distal to the mucosal entry to 2–3 cm distal to the GEJ. The entire thickness of the circular muscle layer was cut with great care and the longitudinal muscle layer was identified and reserved. Forelectrosurgery,a VIO200Delectrogenerator (ERBE, Tübingen, Germany) was used in Endocut Q mode (effect 2) to open the mucosa, and in spray coagulation mode (effect 2, 50 W) to dissect the submucosal layer and circular muscle. Finally, the submucosal entry was closed using hemostatic clips (EZ-CLIP, HX- 110QR; Olympus) and then the outer layer of the model was examined for perforations. Step 2: Performing POEM to treat achalasia in patients After finishing training on the esophagus-stomach model, we performed POEM on patients with achalasia. Achalasia was diagnosed based on symptoms and a barium esophagram and/or high resolution esophageal manometry. Endoscopic examination was used to exclude malignancy and other diseases that could lead to esophageal stenosis. Patients that had previously undergone chest surgery or were unsuitable for general anesthesia (American Society of Anesthesiologists grades IV and V) were excluded from the study. The Eckardt score was used to assess symptoms (Table I). This trial was approved by the ethical committee of Nanfang Hospital, Southern Medical University. The procedure was carried out under general anesthesia with the patients intubated and ventilated
Table I. The Eckardt Scoring System to assess achalasia symptoms. Symptom Score
Weight loss (kg)
Dysphagia
Chest pain
Regurgitation
0 1 2 3
None 10 Eckardt stage 0 0–1
None Occasional Daily Every meal Eckardt stage 1 2–3
None Occasional Daily Each meal Eckardt stage 2 4–6
None Occasional Daily Each meal Eckardt stage 3 >7
Score
3
Peroral endoscopic myotomy for treating achalasia A
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B
E
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Procedure time (min) Submucosal tunnel (cm) Total myotomy (cm) Esophageal myotomy (cm) Gastric myotomy (cm) Clips for suture (N) Complications Mild percutaneous emphysema Flap perforation Pneumothorax with decreased oxygen saturation Major bleeding
F
Figure 2. Peroral endoscopic myotomy in the first achalasia patient. A. An entry into the submucosal layer was made. B. Creation of the submucosal tunnel. C. The circular muscle layer was exposed. D. All of the circular muscle was cut-off and longitudinal muscle layer was saved. E. Completion of the myotomy. F. Closure of the mucosal entry by hemoclips.
mechanically in a supine position. Patients were fasted for 3 days and were given parenteral nutrition. The esophagus was previously washed with water to remove the food residue and a third generation cephalosporin was used for prophylaxis 2 h before the procedure. Carbon dioxide (CO2) insufflation was used during all operations. The equipment used and the procedure for patients was the same as those used on the ex vivo animal model, which is illustrated in Figure 2, except for electrocoagulation for hemostasis and suction of all remaining fluids before closing the submucosal tunnel. If a patient had decreased blood oxygen saturation during the procedure that suggested pneumothorax, a closed thoracic drainage was made to drain the air. If percutaneous emphysema occurred without decreased blood oxygen saturation, the patient’s blood oxygen saturation was carefully monitored. After the procedure, all patients received antibiotics for 3 days. Patients began taking liquid food at least 3 days after the operation, and they were followed up Table II. Patient demographic information. Male/female ratio Age: mean (range) Course of achalasia: mean (range) Eckardt score: mean ± SD Eckardt stage Stage 0 Stage 1 Stage 2 Stage 3 Previous treatments None Medications Pneumatic dilation Botox injection
Table III. Operational information.
22/14 36.5 (16–68) years 5.4 (1–20) years 7.9 ± 2.0 0 0 9/36 27/36 26/36 0 10/36 1/36
72.8 16.4 12.2 8.9 3.6 8.6
± ± ± ± ± ±
26.2 3.2 4.0 3.4 1.2 3.3
8/36 (22.2%) 0 1/36 (2.8%) 2/36 (5.6%)
by Eckardt scoring, endoscopy, barium esophagrams, and high-resolution esophageal manometry. Statistical analyses All quantitative data were presented as mean ± standard variant or median values, and groups were compared by a paired Wilcoxon signed rank test or Student’s t-test as needed. p-Values < 0.05 (twosided) were considered to be statistical significant. Standard statistical software SPSS 19.0 (International Business Machines Corporation, Armonk, New York, United States) was used. Results Ex vivo animal model results The POEM procedure was performed in full in five porcine esophagus-stomach models. Among the initial three models, perforations were caused by a tear of the longitudinal muscle, excessive cutting of circular muscle, and a disruption of the mucosal layer at the GEJ. The last two procedures were successfully completed without any perforations. In vivo clinical results Because we had successfully completed the POEM procedures on esophagus–stomach models, we began to perform POEM on 36 achalasia patients (22 males, 14 females) who gave informed consent from June 2012 to December 2013 at our center (detailed patient demographic information is listed in Table II). They all had relatively severe symptoms (Eckardt stages 2–3) and complained of dysphagia at every meal. Most of the patients included (26/36) had not undergone any previous treatment. Detailed operational data are listed in Table III. The mean procedure time was 8±26.2 min. The mean submucosal tunnel length was 6.4±3.2 cm. Then mean esophageal myotomy length was 8.9±3.4 cm above the GEJ, while the mean gastric myotomy
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Table IV. Clinical outcomes at follow-up after peroral endoscopic myotomy.
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Pre-operative (range) Symptomatic outcomes (N = 35)# Total Eckardt score (median) Dysphagia Chest pain Regurgitation Weight loss Manometric outcomes (N = 19)* Basal LES pressure, mmHg 4-s IRP, mmHg LES length, cm Esophageal length, cm Radiologic outcomes (N = 22)* Max esophageal diameter, mm
8 3 1 2 2 36.1 32.9 2.7 28.5
(4–12) (2–3) (0–3) (1–3) (0–3) ± ± ± ±
Post-operative (range) 1 1 0 0 0
14.3 13.0 0.5 2.4
(0–4) (0–3) (0–1) (0–1) (0–1)
0.000 0.000 0.000 0.000 0.000
± ± ± ±
4.6 2.9 0.4 2.0
0.000 0.000 0.047 0.002
30.6 ± 9.1
0.000
11.9 6.6 2.3 27.1
46.5 ± 15.0
p-Value
Abbreviations: LES = Lower esophageal sphincter; IRP = Integrated relaxation pressure. #Wilcoxon rank sum test. *Student’s t-test.
length was 3.6±1.2 cm below the GEJ. A total of 36 (22.2%) patients were found to have mild cervical percutaneous emphysema with stable vital signs and oxygen saturation during the operation; the vital signs of these patients were closely monitored. Only one patient had decreased oxygen saturation and was treated with closed thoracic drainage. Two patients had a relatively more severe bleeding event and were treated successfully by electric coagulation. After POEM, parenteral nutrition was initiated in all patients, along with intravenous cephalosporin and proton pump inhibitor administration for the initial 3 days. They reported mild chest pain after the operation, but it was relieved 2 to 3 days later. Patients who had mild cervical emphysema without decreased oxygen saturation received a chest X-ray. Mild pneumothorax was discovered and they were placed on clinical monitoring. Only one patient who had decreased oxygen saturation was on thoracic drainage until a serial chest X-ray confirmed that the air had been absorbed. On average, the patients started to ingest clear liquid on day 4 (range, day 3–6) and were discharged on day 6 (range, day 5–14). They were instructed to gradually change back to their normal diet. During the follow-up period, all patients received a telephone survey using the same Eckardt score to assess the improvement of symptoms; 35 patients completed the survey and 1 patient was lost during follow-up. The median follow-up time was 2 months (range, 1–14 months). Patients’ median Eckardt score improved from 8 to 1 after the operation (p = 0.000; Table IV). Median scores for chest pain and regurgitation dropped to 0. By contrast, the median dysphagia score improved from 3 to 1 (p = 0.000) and 23/ 35 (65.7%) patients reported relatively mild dysphagia (median dysphagia score = 1) after POEM. A total
of 26 patients agreed to receive another endoscopic examination. By endoscopy, scars of the submucosal tunnel could be observed to be closed with the remaining 3–4 metal clips. Among these re-examined patients, 9/26 (34.6%) were found to have mild reflux esophagitis (4 LA-A and 5 LA-B), and they were treated with oral standard proton pump inhibitors. Additionally, 22 patients received a barium meal test. The maximum width of the esophagus, which was measured in the barium esophagram, shrunk significantly (46.5 ± 14.5 vs. 30.6 ± 9.1 cm, p = 0.000). Finally, 19 patients accepted a high-resolution manometry study. Their basal LES pressure decreased markedly (36.1 ± 14.3 vs. 11.9 ± 4.6 mmHg, p =0.000). There was also a significant improvement in the 4-s integrated relaxation pressure (12.9 ± 13.0 vs. 6.6 ± 2.9 mmHg, p = 0.000; Figure 3). Discussion In 2007, Pasricha and colleagues successfully performed submucosal endoscopic esophageal myotomy by creating a submucosal tunnel in porcines [4]. In 2010, Inoue and coworkers first reported 17 achalasia patients who were successfully treated with POEM [5]. At the end of a 5 month follow-up period, POEM showed promising short-term results. Subsequently, other centers from China and Europe also reported their experience of POEM for achalasia. Similar to the results of Inoue and coworkers, these reports showed excellent short-term efficiency and fewer complications. POEM combines the benefits of a minimally invasive endoscopic procedure with potential longterm outcomes of surgical myotomy; thus, it brings together the advantages of both methods in a single technique. Although there have been few long term
Peroral endoscopic myotomy for treating achalasia A
mmHg
5
6.31.3 min
150.0
140 130 120 110 100 90 80 70
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60 50 40 35 30 25 20 15 10 5 0 -5
4s-IRP 17.9mmHg
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2 sec
B
mmHg
4.30.4 min
150.0
140 130 120 110 100 90 80 70 60 50 40 35 30 25 20 15 10 5 0 -5
4s-IRP 5.3mmHg
-10.0
2 sec
Figure 3. Pressure topography of high resolution manometry changes before (A) and after (B) peroral endoscopic myotomy in one achalasia patient, suggesting significant reduction of lower esophageal sphincter relaxation pressure and a reduction of esophageal pressurization. Abbreviation: 4s-IRP = 4-s integrated relaxation pressure.
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clinical evaluations, POEM could be anticipated to be another novel, effective, and more minimally-invasive method compare to laparoscopic Heller myotomy. However, endoscopists who are qualified for POEM should also be skilled in ESD. Even for an endoscopist skilled in ESD, POEM remains a relatively risky procedure because it requires dissection of the circular muscle while ESD does not. Therefore, model training is of paramount importance before performing POEM in patients with achalasia [7]. Herein, we selected a porcine ex-vivo stomachesophagus training model, which has a structure similar to that of humans. In these models, we succeeded in performing POEM in five cases. Although we had complications of “perforation” in the initial three models, we succeeded in the last two models without any perforations. The ex vivo stomach–esophagus model could provide trial-and-error practice for endoscopists to master POEM before they successfully performed this procedure without perforations on achalasia patients. However, it would be somewhat more rigorous to dissect the circular muscular layer on an ex vivo model, which could be different from practicing this procedure on patients. Unlike the stepwise POEM study of Chiu and colleagues who used live porcine models [8], our model seems easier to make and is much cheaper. However, the shortcoming of this model was that it cannot simulate bleeding or pneumothorax during the procedure, and the postoperational recovery status cannot be observed. Therefore, when performing POEM on achalasia patients, the endoscopist should also learn how to manage hemorrhage or tension pneumothorax. Nevertheless, the stomach-esophagus model is a simple way to learn POEM quickly. Since we successfully performed POEM on ex vivo stomach-esophagus models without leakage, we began to utilize this operation on achalasia patients. Nevertheless, we encountered complications, of which most were mild. As shown in Table III, 8 of 36 patients had only mild percutaneous emphysema with stable vital signs and oxygen saturation. Postprocedural chest X-rays suggested mild pneumothorax. Only three patients had relatively severe complications—one case of pneumothorax with decreased oxygen saturation and two cases of major bleeding—that were all successfully treated. Percutaneous emphysema of our initial trial was as equal as in other POEM studies (22.2% vs. 20–22.7%) [4,8], with only one severe pneumothorax case with decreased oxygen saturation. We kept examining the patient vital signs, oxygen saturation, and cervical and thoracic skin of those patients during the procedure, and mild emphysema was only accompanied bymild pneumothorax and didnot leadto unstable vital signs or decreased oxygen saturation.
This occurred because we used CO2 insufflation throughout the procedure. Based on a previous study, POEM was a very safe method if CO2 insufflation was used [3,9,10]. No delayed bleeding occurred in any of our cases. During the follow-up period, our POEM procedure proved to be effective in relieving achalasia symptoms in a relatively short term. Eckardt scoring suggested the three major symptoms of achalasia, including dysphagia, chest pain, and regurgitation, were all relieved dramatically. Most of our patients gained weight as a result. High resolution esophageal manometry showed dramatic improvement in LES function in those patients. Additionally, we discovered that POEM could restore malformations of achalasia esophagus; the mean maximum esophageal width was reduced by 1.6 cm, suggesting that POEM could prevent malformation of the long tortuous endstage “sigmoid and stomach-like esophagus.” Our follow-up endoscopy found mild reflux esophagitis in 9/26 (34.6%) patients, and these patients did not report any reflux symptoms such as heartburn or acid regurgitation. This finding was similar that to a study that reported 1 of 16 patients developed LA-A reflux esophagitis after POEM, but none exhibited reflux symptoms [11]. However, according to the study of Chiu and colleagues, 3/18 (20%) had abnormal esophageal acid exposure after POEM [8]. This finding is perhaps a consequence of decreased chemical sensitivity in achalasia esophagus [12]. They were treated with standard oral proton pump inhibitors and still required long-term endoscopic follow-up for gastroesophageal reflux disease complications, such as stricture or Barrett esophagus. Those complications could be the long-term consequences of POEM, but were not noticed by patients with a hyposensitive esophagus that were worthy of our attention. In conclusion, the ex vivo stomach-esophagus model was an easy and effective training method for endoscopists to practice POEM, from which we moved into an in vivo preliminary trial for 36 achalasia patients. POEM was an effective treatment that significantly relieved achalasia symptoms, improved esophageal functions, and restored esophageal malformations.
Acknowledgments This study was supported by a grant from the National Natural Science Foundation of China (No. 81101610). Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Peroral endoscopic myotomy for treating achalasia
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References [1] Ghosh SK, Pandolfino JE, Rice J, Clarke JO, Kwiatek M, Kahrilas PJ. Impaired deglutitive EGJ relaxation in clinical esophageal manometry: a quantitative analysis of 400 patients and 75 controls. Am J Physiol Gastrointest Liver Physiol 2007;293:878–85. [2] Natasha W, Ikuo H. Achalasia. Gastroenterol Clin North Am 2008;37:807–25. [3] Weber CE, Davis CS, Kramer HJ, Gibbs JT, Robles L, Fisichella PM. Medium and long-term outcomes after pneumatic dilation or laparoscopic heller myotomy for achalasia: a meta-analysis. Surg Laparosc Endosc Percutan Tech 2012; 22:289–96. [4] Pasricha PJ, Hawari R, Ahmed I, Chen J, Cotton PB, Hawes RH, et al. Submucosal endoscopic esophageal myotomy: a novel experimental approach for the treatment of achalasia. Endoscopy 2007;39:761–4. [5] Inoue H, Minami H, Kobayashi Y, et al. Peroral endoscopic myotomy (POEM) for esophageal achalasia. Endoscopy 2010;42:265–71. [6] Bredenoord AJ, Rösch T, Fockens P. Peroral endoscopic myotomy for achalasia. Neurogastroenterol Motil 2014;26:3–12.
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[7] Eleftheriadis N, Inoue H, Ikeda H, Onimaru M, Yoshida A, Hosoya T, et al. Training in peroral endoscopic myotomy (POEM) for esophageal achalasia. Ther Clin Risk Manag 2012;8:329–42. [8] Chiu PW, Wu JC, Teoh AY, et al. Peroral endoscopic myotomy for treatment of achalasia: from bench to bedside (with video). Gastrointest Endosc 2013;77:29–38. [9] Ren Z, Zhong Y, Zhou P, Xu M, Cai M, Li L, et al. Perioperative management and treatment for complications during and after peroral endoscopic myotomy (POEM) for esophageal achalasia (EA). Surg Endosc 2012;26:3267– 72. [10] Costamagna G, Marchese M, Familiari P, Tringali A, Inoue H, Perri V. Peroral endoscopic myotomy (POEM) for oesophageal achalasia: Preliminary results in humans. Dig Liver Dis 2012;44:827–32. [11] von Renteln D, Inoue H, Minami H, Werner YB, Pace A, Kersten JF, et al. Peroral endoscopic myotomy for the treatment of achalasia: a prospective single center study. Am J Gastroenterol 2012;107:411–17. [12] Stephen B, Guoxiang S, Ikuo H. Diminished mechanosensitivity and chemosensitivity in patients with achalasia. Am J Physiol Gastrointest Liver Physiol 2003;285:1198–203.
ORIGINAL ARTICLE
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A stepwise approach for peroral endoscopic myotomy for treating achalasia: from animal models to patients
YUTANG REN1,2*, XIAOWEI TANG1,2*, FACHAO ZHI1, SIDE LIU1, JIANUAN WU1, YANG PENG1, BO JIANG1,2 & WEI GONG1 1
Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China, and Department of Gastroenterology, Beijing Tsinghua Changgung Hospital Medical Center, Tsinghua University, China
2
Abstract Objectives. Peroral endoscopic myotomy (POEM) was initially developed for the treatment of achalasia. This study aimed to investigate the feasibility and safety of a stepwise approach for POEM in the management of achalasia. Methods. A total of five ex-vivo porcine esophagus-stomach training models were created and POEM was performed. Then, 25 patients with achalasia were treated similarly. The Eckardt score, barium esophagrams, and high-resolution manometry were used to evaluate its efficacy. Results. POEM procedures were completed in five stomach-esophagus models, with perforations in the initial three and success in the last two. A total of 25 achalasia patients (13 males, 12 females) with achalasia successfully underwent POEM. The mean operation time was 72.0 min (range, 45–180 min). There were two complications—one case each of severe bleeding and pneumothorax—that were both treated successfully. During the follow-up period, the median Eckardt score decreased dramatically from 8 to 1 (p = 0.000). The lower basal esophageal sphincter pressure decreased markedly (41.3 ± 12.6 vs. 11.3 ± 4.3 mmHg, p = 0.000), as well as the 4-s integrated relaxation pressure (37.1 ± 12.6 vs. 7.1 ± 2.4 mmHg, p = 0.000). Additionally, the maximum esophagus width was significantly reduced (mean reduced width: 1.6 ± 1.1 cm, p = 0.000). Conclusions. The ex-vivo porcine esophagus-stomach can be used as a simple and cheap training model that mimics the POEM procedure. POEM is a safe and effective therapy for achalasia patients.
Key Words: achalasia, animal model, peroral endoscopic myotomy
Introduction Achalasia is a primary esophageal motility disorder that is characterized by aperistalsis of the esophageal body and incomplete or absent relaxation of the lower esophageal sphincter (LES) [1]. Achalasia patients usually suffer greatly from major symptoms that include dysphagia, regurgitation, and chest pain [2]. Treatment options, which are either endoscopic or surgical, mainly focus on the relief of symptoms by reducing the LES pressure. Pneumatic dilation and endoscopic Botox injection are the main endoscopic therapies for these patients. However, endoscopic methods showed lower short-term efficacy compared
to laparoscopic Heller myotomy, which was the most effective. In the long-term, sustained therapeutic effects were observed in ~80% of patients [3]. Based on developments in Natural Orifices Translumenal Endoscopic Surgery (NOTES) and the continual improvement of devices for submucosal dissection, Pasricha et al. developed an endoscopic myotomy technique in an animal model in 2007, using a submucosal tunnel [4]. Then, 3 years later, Inoue et al. performed the first series of peroral endoscopic myotomy (POEM) to treat achalasia in 17 patients [5]. Their study demonstrated that there was significant improvement in dysphagia scores and a reduction in lower esophageal sphincter (LES)
Correspondence: Wei Gong, MD, PhD, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, No.1838, Guangzhou North Ave, 510515, Guangzhou, China. Tel: +8602061641888. Fax: +8602061641541. E-mail: [email protected] *These authors contributed equally to this work.
(Received 25 August 2014; revised 21 October 2014; accepted 22 October 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2015 Informa Healthcare DOI: 10.3109/00365521.2014.983152
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Y. Ren et al. A
Scand J Gastroenterol Downloaded from informahealthcare.com by Kainan University on 04/26/15 For personal use only.
D
C
B
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F
Figure 1. Peroral endoscopic myotomy on a porcine esophagusstomach model. A. A simple porcine esophagus-stomach model. B. Submucosal injection 10 cm above the EGJ. C. Creation of a mucosal entry into the submucosal layer. D. Creation of a submucosal tunnel. E The circular muscle was “hooked-up” and then cut-off. F. Completion of myotomy.
pressure after POEM without serious adverse events. Subsequently, several prospective studies have been conducted to evaluate the feasibility, efficacy, and safety of this innovative endoscopic technique for the treatment of achalasia [6]. Based on our experience with endoscopic submucosal dissection (ESD), we use a stepwise approach in which we shorten the learning curve of POEM by training on ex-vivo porcine esophagus-stomach models. Then, we successfully treat achalasia patients by POEM. Our aim is to examine the feasibility of this stepwise approach and to report our preliminary experience of POEM in this pilot study. Materials and methods Step 1: Training study in an ex-vivo porcine esophagus-stomach model To create the ex vivo animal model, the porcine esophagus-stomach was chosen because of a similar anatomy and histology to humans. The porcine esophagus-stomach was acquired 48–72 h after the porcine was slaughtered from the market in order to preservetheelasticpropertiesofitswall.Theorificeofthe esophagus was pinned to a fixed polyfoam and the orifice
of the duodenum was ligated using hemostatic forceps (Figure 1A). A surgical electrode was placed beneath the stomach. After the model was created, the POEM procedure was performed as described by Inoue et al. [5], (illustrated in detail in Figure 1B–F). A forward-viewing endoscope (GIFQ240Z; Olympus, Tokyo, Japan) was used with a transparent distal cap attachment. First, a submucosal injection with a natural saline, adrenaline, and indigo carmine mixture was made 10 cm above the gastro-esophageal junction (GEJ). Then, a 2-cm longitudinal incision was made using a hook knife or triangletip knife. Second, after the mucosal entry was made, the submucosal layer was dissected to create a submucosal tunnel along the esophagus and across the GEJ 2–3 cm into the proximal stomach. Third, the circular muscle was “hooked up” and cut gradually from 2–3 cm distal to the mucosal entry to 2–3 cm distal to the GEJ. The entire thickness of the circular muscle layer was cut with great care and the longitudinal muscle layer was identified and reserved. Forelectrosurgery,a VIO200Delectrogenerator (ERBE, Tübingen, Germany) was used in Endocut Q mode (effect 2) to open the mucosa, and in spray coagulation mode (effect 2, 50 W) to dissect the submucosal layer and circular muscle. Finally, the submucosal entry was closed using hemostatic clips (EZ-CLIP, HX- 110QR; Olympus) and then the outer layer of the model was examined for perforations. Step 2: Performing POEM to treat achalasia in patients After finishing training on the esophagus-stomach model, we performed POEM on patients with achalasia. Achalasia was diagnosed based on symptoms and a barium esophagram and/or high resolution esophageal manometry. Endoscopic examination was used to exclude malignancy and other diseases that could lead to esophageal stenosis. Patients that had previously undergone chest surgery or were unsuitable for general anesthesia (American Society of Anesthesiologists grades IV and V) were excluded from the study. The Eckardt score was used to assess symptoms (Table I). This trial was approved by the ethical committee of Nanfang Hospital, Southern Medical University. The procedure was carried out under general anesthesia with the patients intubated and ventilated
Table I. The Eckardt Scoring System to assess achalasia symptoms. Symptom Score
Weight loss (kg)
Dysphagia
Chest pain
Regurgitation
0 1 2 3
None 10 Eckardt stage 0 0–1
None Occasional Daily Every meal Eckardt stage 1 2–3
None Occasional Daily Each meal Eckardt stage 2 4–6
None Occasional Daily Each meal Eckardt stage 3 >7
Score
3
Peroral endoscopic myotomy for treating achalasia A
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D
B
E
C
Procedure time (min) Submucosal tunnel (cm) Total myotomy (cm) Esophageal myotomy (cm) Gastric myotomy (cm) Clips for suture (N) Complications Mild percutaneous emphysema Flap perforation Pneumothorax with decreased oxygen saturation Major bleeding
F
Figure 2. Peroral endoscopic myotomy in the first achalasia patient. A. An entry into the submucosal layer was made. B. Creation of the submucosal tunnel. C. The circular muscle layer was exposed. D. All of the circular muscle was cut-off and longitudinal muscle layer was saved. E. Completion of the myotomy. F. Closure of the mucosal entry by hemoclips.
mechanically in a supine position. Patients were fasted for 3 days and were given parenteral nutrition. The esophagus was previously washed with water to remove the food residue and a third generation cephalosporin was used for prophylaxis 2 h before the procedure. Carbon dioxide (CO2) insufflation was used during all operations. The equipment used and the procedure for patients was the same as those used on the ex vivo animal model, which is illustrated in Figure 2, except for electrocoagulation for hemostasis and suction of all remaining fluids before closing the submucosal tunnel. If a patient had decreased blood oxygen saturation during the procedure that suggested pneumothorax, a closed thoracic drainage was made to drain the air. If percutaneous emphysema occurred without decreased blood oxygen saturation, the patient’s blood oxygen saturation was carefully monitored. After the procedure, all patients received antibiotics for 3 days. Patients began taking liquid food at least 3 days after the operation, and they were followed up Table II. Patient demographic information. Male/female ratio Age: mean (range) Course of achalasia: mean (range) Eckardt score: mean ± SD Eckardt stage Stage 0 Stage 1 Stage 2 Stage 3 Previous treatments None Medications Pneumatic dilation Botox injection
Table III. Operational information.
22/14 36.5 (16–68) years 5.4 (1–20) years 7.9 ± 2.0 0 0 9/36 27/36 26/36 0 10/36 1/36
72.8 16.4 12.2 8.9 3.6 8.6
± ± ± ± ± ±
26.2 3.2 4.0 3.4 1.2 3.3
8/36 (22.2%) 0 1/36 (2.8%) 2/36 (5.6%)
by Eckardt scoring, endoscopy, barium esophagrams, and high-resolution esophageal manometry. Statistical analyses All quantitative data were presented as mean ± standard variant or median values, and groups were compared by a paired Wilcoxon signed rank test or Student’s t-test as needed. p-Values < 0.05 (twosided) were considered to be statistical significant. Standard statistical software SPSS 19.0 (International Business Machines Corporation, Armonk, New York, United States) was used. Results Ex vivo animal model results The POEM procedure was performed in full in five porcine esophagus-stomach models. Among the initial three models, perforations were caused by a tear of the longitudinal muscle, excessive cutting of circular muscle, and a disruption of the mucosal layer at the GEJ. The last two procedures were successfully completed without any perforations. In vivo clinical results Because we had successfully completed the POEM procedures on esophagus–stomach models, we began to perform POEM on 36 achalasia patients (22 males, 14 females) who gave informed consent from June 2012 to December 2013 at our center (detailed patient demographic information is listed in Table II). They all had relatively severe symptoms (Eckardt stages 2–3) and complained of dysphagia at every meal. Most of the patients included (26/36) had not undergone any previous treatment. Detailed operational data are listed in Table III. The mean procedure time was 8±26.2 min. The mean submucosal tunnel length was 6.4±3.2 cm. Then mean esophageal myotomy length was 8.9±3.4 cm above the GEJ, while the mean gastric myotomy
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Table IV. Clinical outcomes at follow-up after peroral endoscopic myotomy.
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Pre-operative (range) Symptomatic outcomes (N = 35)# Total Eckardt score (median) Dysphagia Chest pain Regurgitation Weight loss Manometric outcomes (N = 19)* Basal LES pressure, mmHg 4-s IRP, mmHg LES length, cm Esophageal length, cm Radiologic outcomes (N = 22)* Max esophageal diameter, mm
8 3 1 2 2 36.1 32.9 2.7 28.5
(4–12) (2–3) (0–3) (1–3) (0–3) ± ± ± ±
Post-operative (range) 1 1 0 0 0
14.3 13.0 0.5 2.4
(0–4) (0–3) (0–1) (0–1) (0–1)
0.000 0.000 0.000 0.000 0.000
± ± ± ±
4.6 2.9 0.4 2.0
0.000 0.000 0.047 0.002
30.6 ± 9.1
0.000
11.9 6.6 2.3 27.1
46.5 ± 15.0
p-Value
Abbreviations: LES = Lower esophageal sphincter; IRP = Integrated relaxation pressure. #Wilcoxon rank sum test. *Student’s t-test.
length was 3.6±1.2 cm below the GEJ. A total of 36 (22.2%) patients were found to have mild cervical percutaneous emphysema with stable vital signs and oxygen saturation during the operation; the vital signs of these patients were closely monitored. Only one patient had decreased oxygen saturation and was treated with closed thoracic drainage. Two patients had a relatively more severe bleeding event and were treated successfully by electric coagulation. After POEM, parenteral nutrition was initiated in all patients, along with intravenous cephalosporin and proton pump inhibitor administration for the initial 3 days. They reported mild chest pain after the operation, but it was relieved 2 to 3 days later. Patients who had mild cervical emphysema without decreased oxygen saturation received a chest X-ray. Mild pneumothorax was discovered and they were placed on clinical monitoring. Only one patient who had decreased oxygen saturation was on thoracic drainage until a serial chest X-ray confirmed that the air had been absorbed. On average, the patients started to ingest clear liquid on day 4 (range, day 3–6) and were discharged on day 6 (range, day 5–14). They were instructed to gradually change back to their normal diet. During the follow-up period, all patients received a telephone survey using the same Eckardt score to assess the improvement of symptoms; 35 patients completed the survey and 1 patient was lost during follow-up. The median follow-up time was 2 months (range, 1–14 months). Patients’ median Eckardt score improved from 8 to 1 after the operation (p = 0.000; Table IV). Median scores for chest pain and regurgitation dropped to 0. By contrast, the median dysphagia score improved from 3 to 1 (p = 0.000) and 23/ 35 (65.7%) patients reported relatively mild dysphagia (median dysphagia score = 1) after POEM. A total
of 26 patients agreed to receive another endoscopic examination. By endoscopy, scars of the submucosal tunnel could be observed to be closed with the remaining 3–4 metal clips. Among these re-examined patients, 9/26 (34.6%) were found to have mild reflux esophagitis (4 LA-A and 5 LA-B), and they were treated with oral standard proton pump inhibitors. Additionally, 22 patients received a barium meal test. The maximum width of the esophagus, which was measured in the barium esophagram, shrunk significantly (46.5 ± 14.5 vs. 30.6 ± 9.1 cm, p = 0.000). Finally, 19 patients accepted a high-resolution manometry study. Their basal LES pressure decreased markedly (36.1 ± 14.3 vs. 11.9 ± 4.6 mmHg, p =0.000). There was also a significant improvement in the 4-s integrated relaxation pressure (12.9 ± 13.0 vs. 6.6 ± 2.9 mmHg, p = 0.000; Figure 3). Discussion In 2007, Pasricha and colleagues successfully performed submucosal endoscopic esophageal myotomy by creating a submucosal tunnel in porcines [4]. In 2010, Inoue and coworkers first reported 17 achalasia patients who were successfully treated with POEM [5]. At the end of a 5 month follow-up period, POEM showed promising short-term results. Subsequently, other centers from China and Europe also reported their experience of POEM for achalasia. Similar to the results of Inoue and coworkers, these reports showed excellent short-term efficiency and fewer complications. POEM combines the benefits of a minimally invasive endoscopic procedure with potential longterm outcomes of surgical myotomy; thus, it brings together the advantages of both methods in a single technique. Although there have been few long term
Peroral endoscopic myotomy for treating achalasia A
mmHg
5
6.31.3 min
150.0
140 130 120 110 100 90 80 70
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60 50 40 35 30 25 20 15 10 5 0 -5
4s-IRP 17.9mmHg
-10.0
2 sec
B
mmHg
4.30.4 min
150.0
140 130 120 110 100 90 80 70 60 50 40 35 30 25 20 15 10 5 0 -5
4s-IRP 5.3mmHg
-10.0
2 sec
Figure 3. Pressure topography of high resolution manometry changes before (A) and after (B) peroral endoscopic myotomy in one achalasia patient, suggesting significant reduction of lower esophageal sphincter relaxation pressure and a reduction of esophageal pressurization. Abbreviation: 4s-IRP = 4-s integrated relaxation pressure.
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clinical evaluations, POEM could be anticipated to be another novel, effective, and more minimally-invasive method compare to laparoscopic Heller myotomy. However, endoscopists who are qualified for POEM should also be skilled in ESD. Even for an endoscopist skilled in ESD, POEM remains a relatively risky procedure because it requires dissection of the circular muscle while ESD does not. Therefore, model training is of paramount importance before performing POEM in patients with achalasia [7]. Herein, we selected a porcine ex-vivo stomachesophagus training model, which has a structure similar to that of humans. In these models, we succeeded in performing POEM in five cases. Although we had complications of “perforation” in the initial three models, we succeeded in the last two models without any perforations. The ex vivo stomach–esophagus model could provide trial-and-error practice for endoscopists to master POEM before they successfully performed this procedure without perforations on achalasia patients. However, it would be somewhat more rigorous to dissect the circular muscular layer on an ex vivo model, which could be different from practicing this procedure on patients. Unlike the stepwise POEM study of Chiu and colleagues who used live porcine models [8], our model seems easier to make and is much cheaper. However, the shortcoming of this model was that it cannot simulate bleeding or pneumothorax during the procedure, and the postoperational recovery status cannot be observed. Therefore, when performing POEM on achalasia patients, the endoscopist should also learn how to manage hemorrhage or tension pneumothorax. Nevertheless, the stomach-esophagus model is a simple way to learn POEM quickly. Since we successfully performed POEM on ex vivo stomach-esophagus models without leakage, we began to utilize this operation on achalasia patients. Nevertheless, we encountered complications, of which most were mild. As shown in Table III, 8 of 36 patients had only mild percutaneous emphysema with stable vital signs and oxygen saturation. Postprocedural chest X-rays suggested mild pneumothorax. Only three patients had relatively severe complications—one case of pneumothorax with decreased oxygen saturation and two cases of major bleeding—that were all successfully treated. Percutaneous emphysema of our initial trial was as equal as in other POEM studies (22.2% vs. 20–22.7%) [4,8], with only one severe pneumothorax case with decreased oxygen saturation. We kept examining the patient vital signs, oxygen saturation, and cervical and thoracic skin of those patients during the procedure, and mild emphysema was only accompanied bymild pneumothorax and didnot leadto unstable vital signs or decreased oxygen saturation.
This occurred because we used CO2 insufflation throughout the procedure. Based on a previous study, POEM was a very safe method if CO2 insufflation was used [3,9,10]. No delayed bleeding occurred in any of our cases. During the follow-up period, our POEM procedure proved to be effective in relieving achalasia symptoms in a relatively short term. Eckardt scoring suggested the three major symptoms of achalasia, including dysphagia, chest pain, and regurgitation, were all relieved dramatically. Most of our patients gained weight as a result. High resolution esophageal manometry showed dramatic improvement in LES function in those patients. Additionally, we discovered that POEM could restore malformations of achalasia esophagus; the mean maximum esophageal width was reduced by 1.6 cm, suggesting that POEM could prevent malformation of the long tortuous endstage “sigmoid and stomach-like esophagus.” Our follow-up endoscopy found mild reflux esophagitis in 9/26 (34.6%) patients, and these patients did not report any reflux symptoms such as heartburn or acid regurgitation. This finding was similar that to a study that reported 1 of 16 patients developed LA-A reflux esophagitis after POEM, but none exhibited reflux symptoms [11]. However, according to the study of Chiu and colleagues, 3/18 (20%) had abnormal esophageal acid exposure after POEM [8]. This finding is perhaps a consequence of decreased chemical sensitivity in achalasia esophagus [12]. They were treated with standard oral proton pump inhibitors and still required long-term endoscopic follow-up for gastroesophageal reflux disease complications, such as stricture or Barrett esophagus. Those complications could be the long-term consequences of POEM, but were not noticed by patients with a hyposensitive esophagus that were worthy of our attention. In conclusion, the ex vivo stomach-esophagus model was an easy and effective training method for endoscopists to practice POEM, from which we moved into an in vivo preliminary trial for 36 achalasia patients. POEM was an effective treatment that significantly relieved achalasia symptoms, improved esophageal functions, and restored esophageal malformations.
Acknowledgments This study was supported by a grant from the National Natural Science Foundation of China (No. 81101610). Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Peroral endoscopic myotomy for treating achalasia
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[7] Eleftheriadis N, Inoue H, Ikeda H, Onimaru M, Yoshida A, Hosoya T, et al. Training in peroral endoscopic myotomy (POEM) for esophageal achalasia. Ther Clin Risk Manag 2012;8:329–42. [8] Chiu PW, Wu JC, Teoh AY, et al. Peroral endoscopic myotomy for treatment of achalasia: from bench to bedside (with video). Gastrointest Endosc 2013;77:29–38. [9] Ren Z, Zhong Y, Zhou P, Xu M, Cai M, Li L, et al. Perioperative management and treatment for complications during and after peroral endoscopic myotomy (POEM) for esophageal achalasia (EA). Surg Endosc 2012;26:3267– 72. [10] Costamagna G, Marchese M, Familiari P, Tringali A, Inoue H, Perri V. Peroral endoscopic myotomy (POEM) for oesophageal achalasia: Preliminary results in humans. Dig Liver Dis 2012;44:827–32. [11] von Renteln D, Inoue H, Minami H, Werner YB, Pace A, Kersten JF, et al. Peroral endoscopic myotomy for the treatment of achalasia: a prospective single center study. Am J Gastroenterol 2012;107:411–17. [12] Stephen B, Guoxiang S, Ikuo H. Diminished mechanosensitivity and chemosensitivity in patients with achalasia. Am J Physiol Gastrointest Liver Physiol 2003;285:1198–203.
