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Natural orifice transluminal endoscopic surgery gastrotomy closure with an over-the-endoscope clip: a randomized, controlled porcine study (with videos)
ORIGINAL ARTICLE: Experimental Endoscopy
Natural orifice transluminal endoscopic surgery gastrotomy closure with an over-the-endoscope clip: a randomized, controlled porcine study (with videos) Daniel von Renteln, MD, Arthur Schmidt, MD, Melina C. Vassiliou, MD, Maria Gieselmann, BSc, Karel Caca, MD Ludwigsburg, Heidelberg, Germany, Lebanon, New Hampshire, USA
Background: Secure endoscopic closure of transgastric natural orifice transluminal endoscopic surgery (NOTES) access is of paramount importance. The over-the-scope clip (OTSC) system has previously been shown to be effective for NOTES gastrotomy closure. Objective: To compare OTSC gastrotomy closure with surgical closure. Design: Randomized, controlled animal study. Setting: Animal facility laboratory. Animals: Thirty-six female domestic pigs. Interventions: Gastrotomies were created by using a needle-knife and an 18-mm balloon. The animals were subsequently randomized to either open surgical repair with interrupted sutures or endoscopic repair with 12-mm OTSCs. In addition, pressurized leak tests were performed in ex vivo specimens of 18-mm scalpel incisions closed with suture (n Z 14) and of intact stomachs (n Z 10). Main Outcome Measurements: The mean time for endoscopic closure was 9.8 minutes (range 3-22, SD 5.5). No complications occurred during either type of gastrotomy closure. At necropsy, examination of all OTSC and surgical closures demonstrated complete sealing of gastrotomy sites without evidence of injury to adjacent organs. Pressurized leak tests showed a mean burst pressure of 83 mm Hg (range 30-140, SD 27) for OTSC closures and 67 mm Hg (range 30-130, SD 27.7) for surgical sutures. Ex vivo hand-sewn sutures of 18-mm gastrotomies (n Z 14) exhibited a mean burst pressure of 65 mm Hg (range 20-140, SD 31) and intact ex vivo stomachs (n Z 10) had a mean burst pressure of 126 mm Hg (range 90-170, SD 28). The burst pressure of ex vivo intact stomachs was significantly higher compared with OTSC closures (P ! .01), in vivo surgical closures (P ! .01), and ex vivo hand-sewn closures (P! .01). There was a trend toward higher burst pressures in the OTSC closures compared with surgical closures (P Z .063) and ex vivo hand-sewn closures (P Z .094). In vivo surgical closures demonstrated similar burst pressures compared with ex vivo hand-sewn closures (P Z .848). Limitations: Nonsurvival setting. Conclusion: Endoscopic closure by using the OTSC system is comparable to surgical closure in a nonsurvival porcine model. This technique is easy to perform and is suitable for NOTES gastrotomy closure. (Gastrointest Endosc 2009;70:732-9.)
Abbreviations: NOTES, natural orifice transluminal endoscopic surgery; OTSC, over-the-scope clip. DISCLOSURE: Material support (endoscopic equipment, funding of the animal procedures and endotherapeutic material) for this study
was provided directly to the animal facility by Ovesco AG, Tu ¨ bingen, Germany, and Olympus Deutschland GmbH, Hamburg, Germany. All authors disclosed no financial relationships relevant to this publication.
Copyright ª 2009 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2009.03.010
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von Renteln et al
Natural orifice transluminal endoscopic surgery (NOTES) is a novel method to access the peritoneal cavity through the mouth, vagina, rectum, or bladder, thereby making it possible to perform surgery without skin incisions. Since the first NOTES report in 2004, research interest in NOTES has grown steadily.1 Human transgastric intraperitoneal interventions were first performed in India in 2003.2 The first published human NOTES procedure in 2007 was a transgastric rescue of a prematurely dislodged PEG. That same year, the first NOTES cholecystectomy was performed.3,4 To date, only a limited number of pure human NOTES procedures have been reported worldwide. Most human NOTES interventions have been performed as hybrid procedures with laparoscopic assistance and/or observation.5 One of the major obstacles to pure transgastric NOTES is the need for a leakproof and reliable method for endoscopic closure of the gastrotomy.6-9 Several closure techniques have been described; however, no uniformly reliable technique or device has been reported to date. Animal studies suggest that the access site can be closed by using endoscopic clips, staplers, or suturing devices.10-31 NOTES gastrotomy closure by using the first generation of the over the-scope clip system (OTSC) (Ovesco Endoscopy AG, Tu ¨bingen, Germany) has been demonstrated in 2 small feasibility studies.32,33 The aim of this study was to compare the acute strength of the second-generation 12-mm gastric closure OTSC system with that of surgical closure in a randomized, controlled trial.
NOTES gastrotomy closure with an over-the-scope clip
Capsule Summary What is already known on this topic d
One of the major obstacles to pure transgastric natural orifice transluminal endoscopic surgery is the need for a leakproof, reliable method for endoscopic closure of the gastrotomy.
What this study adds to our knowledge d
In a randomized, controlled porcine study, endoscopic gastrotomy closure with an over-the-scope clip system was comparable to surgical closure, with both demonstrating complete sealing of gastrotomy sites without evidence of injury to adjacent organs.
The study was conducted at the animal facility in Beichlingen, Thu ¨ringen, Germany, after approval of the Animal Care and Use Committee. Thirty-six female domestic pigs with a mean weight of 32 kg (range 20-54 kg) were used. The animals were fasted from solid food for 48 hours before surgery, but were allowed full access to water and milk. Preanesthesia sedation consisted of ketamine 2 mg/kg and xylazine 2 mg/kg. General anesthesia was achieved by using isoflurane, nitrous oxide, and oxygen after endotracheal intubation. All procedures were performed in the supine position. A Veress needle (16-gauge) was inserted percutaneously in the left lower abdomen to measure intraperitoneal pressure during the NOTES procedure. With the animal under general anesthesia, extensive gastric lavage was performed with tap water. Time to gain peritoneal access was defined as the time from initial instrument insertion into the working channel to introduction of the endoscope into the peritoneal cavity. The anterior gastric wall was localized by applying external pressure to the anterior abdominal wall. To enable safe peritoneal access a preliminary pneumoperitoneum of 8 mm Hg was created. An endoscopic needle-knife sphincterotome (Boston Scientific Corp, Natick, Mass) was used to create a full-thickness 2-mm incision in the anterior gastric wall. An 18-mm esophageal
dilating balloon (Esophageal Balloon Dilator, BE-7, Olympus, Hamburg, Germany) was then advanced through the gastrotomy and was used to dilate the incision (Fig. 1A-C, Video 1 [available online at www.giejournal. org]). After gastrotomy creation, a 2T160 double-channel upper endoscope (Olympus, Hamburg, Germany) was passed through the gastric wall into the peritoneal cavity, and a standardized peritoneoscopy was performed (Fig. 1D, Video 1). During peritoneoscopy, all 4 abdominal quadrants were examined, and complete visualization of the diaphragm, liver, gallbladder, spleen, rectum, sigmoid colon, and fallopian tubes was attempted to examine for possible access-related injuries. After peritoneoscopy was performed, pigs were randomly assigned to either surgical repair (n Z 18) or endoscopic gastrotomy closure (n Z 18). Endoscopic repair was performed by means of the 2T160 double-channel upper endoscope, the Ovesco Twin Grasper (Ovesco AG), and the 12-mm gastric closure OTSC (Ovesco AG) (Fig. 2, Video 2 [available online at www.giejournal.org]). The mean time to close the gastrotomy was defined as the time from insertion of the twin grasper into the channel to final withdrawal of the instrument after satisfactory deployment of the clip. The clip is made of a nitinol alloy and is installed on an applicator cap mounted on the tip of the gastroscope. The clip is applied by pulling taut a wire threaded through the working channel of the endoscope similar to endoscopic band-ligation systems. The OTSC Twin Grasper has 2 jaws that move separately to approximate the edges of the gastrotomy into the cap before applying the clip (Fig. 2, Video 1). Surgical repair was achieved by open laparotomy with interrupted sutures (PDSII, Z311, 3-0; Ethicon, Somerville, NJ). The animals were subsequently killed with intravenously administered sodium pentobarbital, and laparotomy was performed to detect any injuries related to OTSC placement. Each stomach was then explanted. The esophagus was cannulated for air insufflation, and the specimens were sealed at both ends. While recording intragastric pressures, the stomachs were then gradually
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MATERIAL AND METHODS
NOTES gastrotomy closure with an over-the-scope clip
von Renteln et al
Figure 1. Gastrotomy creation by using an 18-mm dilating balloon (A-C). View of the gallbladder during peritoneoscopy (D).
inflated to maximum capacity and submerged in water to detect air leaks. The point of failure was defined as the pressure at which the first sign of air was seen bubbling from the serosal surface (Fig. 3). Pressures were recorded in millimeters of mercury. In addition, pressurized leak tests were performed in ex vivo specimens of 18-mm scalpel incisions closed with suture (n Z 14) and of intact stomachs (n Z 10). Tissue for ex vivo evaluation was obtained from freshly killed pigs. Pressurized leak tests for ex vivo control groups were conducted as described above. The Mann-Whitney U test for 2 independent samples was used to estimate differences in acute burst pressures (SPSS 14.0, SPSS Inc, Chicago, Ill). A P value !.05 was considered significant.
Transgastric access was easily achieved without complications in all animals. The mean time to gain peritoneal
access by using the preliminary pneumoperitoneum technique was 5.7 minutes (range 2-9 minutes, SD 1.9). The prototype Twin Grasper was used in all cases to approximate the gastrotomy edges into the applicator cap. Adequate sealing of the site was endoscopically observed by using a single clip in 17 of 18 cases. In 1 case, inadequate closure of the gastrotomy was observed, and a second OTSC was applied in a linear fashion (Fig. 4). Thus, gastrotomy closure by means of 2 serially placed OTSC systems was performed in 1 of 18 cases. The mean OTSC procedure time was 9.8 minutes (range 3-22 minutes, SD 5.5). After placement of the clips, the stomachs were fully distended by using air insufflation to confirm the adequacy of the closure. Intraperitoneal pressure measured through the Veress needle remained unchanged during extensive gastric insufflation in all cases, suggesting the absence of significant leaks. No acute adverse events occurred, and postprocedure laparotomies did not identify any injuries related to the gastrotomy closures. At necropsy,
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RESULTS
von Renteln et al
NOTES gastrotomy closure with an over-the-scope clip
Figure 2. OTSC procedure. Laparoscopic view of the Twin Grasper passed through the gastrotomy with 1 jaw opened and with both jaws opened (A). Tissue is incorporated into 1 jaw of the Twin Grasper (B). The other Twin Grasper jaw is opened and advanced to the other side of the gastrotomy (C). The Twin Grasper is closed, approximating both sides of the gastrotomy (D). The gastrotomy site is drawn into the applicator cap, and the clip is released (E-G). Closure site after OTSC application (H). Laparoscopic view after OTSC application (I).
macroscopic examination revealed complete closure of gastrotomy sites with OTSC in all cases. Pressurized leak tests demonstrated a mean burst pressure of 83 mm Hg (range 30-140 mm Hg, SD 27) for OTSC closures and 67 mm Hg (range 30-130 mm Hg, SD 27.7) for surgical sutures. Ex vivo suturing of 18-mm scalpel incisions exhibited a mean burst pressure of 65 mm Hg (range 20-140 mm Hg, SD 31) compared with ex vivo
intact stomachs at pressures of 126 mm Hg (range 90-170 mm Hg, SD 28). In 3 of 10 cases, the gastric wall ruptured at the fundic diverticulum. The burst pressure of ex vivo intact stomachs was significantly higher compared with that of OTSC closure (P ! .01), in vivo surgical closures (P ! .01), and ex vivo hand-sewn closures (P ! .01). There was a trend toward higher burst pressures in the OTSC closures
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The rapidly growing number of publications and lectures dedicated to NOTES clearly shows the growing interest in this field of interventional endoscopy. However,
no randomized, controlled trials have shown superiority of a NOTES approach compared with laparoscopy or open surgery, and appropriate clinical applications have yet to be defined.2,16 Although there are many unanswered questions regarding NOTES applications, there is consensus that a leakproof, practical, and secure closure must be developed to safely conduct human NOTES clinical trials.2,8,16 This randomized, controlled trial is the first study evaluating the modified 12-mm gastric closure OTSC. In addition, pressurized leak tests were conducted in ex vivo control groups to obtain reference values for surgical closures performed under optimal conditions and in intact stomachs. The mean burst pressure of recently explanted intact stomachs was significantly higher compared with any of the closure methods. Healthy gastric tissue ruptured in some cases at the fundic diverticulum where the porcine gastric wall is thinnest. Ex vivo hand-sewn closures were performed to obtain comparative values for optimally placed hand-sewn sutures. The OTSC closures seemed to rupture at slightly higher pressures compared with ex vivo and in vivo surgical sutures, but the differences were not significant. The reasons for this are thought to be related to the clip design. The novel gastric closure OTSC has jaws with longer spikes compared with the previous OTSC design in which they are quite close to each other. This not only increases the anchoring capabilities of the clip but compresses the tissue to tightly approximate the wound edges. Once the nitinol clip is released into the target tissue, it delivers a force of approximately 8 to 9 N. Physiologic intragastric pressures are influenced by body mass index, respiration, sex, the presence of hiatal hernias, intra-abdominal pressure, and age. They are reported to be in the range of 1 to 12 mm Hg at rest in an empty stomach.34-36 Intragastric pressure is increased by 2- to 3-fold in the presence of 300 to 600 mL of gastric fluid.37 Mean intragastric pressures during coughing, vomiting, retching, and weight lifting have been reported to be 35, 89, 62, and 2 mm Hg, respectively, with corresponding peak pressures of 233, 290, 281, and 52 mm Hg.36,38,39 In human cadavers, 100 to 150 mm Hg is necessary to cause mucosal disruption at the gastric cardia.39 Therefore, pressurized leak tests have been used to provide objective data about the strength of closures in several studies.21,23,30,31,33 It may be naive to assume, however, that higher burst pressures and acute closure strength are the most important factors for secure gastrotomy closure. Surgical principles of anastomotic healing mandate adequate tissue perfusion with minimal wound tension. Excessive tension can lead to ischemic changes and eventual breakdown of a wound or anastomosis. As such, the OTSC pins have been designed in a parallel fashion to imitate continuous sutures and permit adequate tissue perfusion. Long-term survival studies are necessary to
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Figure 2 (continued )
compared with surgical closures (P Z .063) and ex vivo hand-sewn closures (P Z .094). In vivo surgical closures demonstrated similar burst pressures compared with ex vivo hand-sewn closures (P Z .848).
DISCUSSION
von Renteln et al
NOTES gastrotomy closure with an over-the-scope clip
Figure 3. OTSC closure site. View of the serosal surface after stomach explantation (A and B). Endoluminal view of the OTSC closure after stomach explantation (C). While recording intragastric pressures, the stomachs were gradually inflated to maximum capacity and submerged in water to detect signs of air bubbling from the serosal surface (D and E).
assess tissue perfusion. Previous studies used a slightly different clip design and did not report absolute burst pressure values.32,33 As such, a valid comparison with previous studies regarding burst pressures is not possible. Although
this study provides information about the acute strength of OTSC closure compared with surgical closure, longterm complications such as infection, perforation, and ischemia could not be evaluated. Colonic perforation
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1. Kalloo AN, Singh VK, Jagannath SB, et al. Flexible transgastric peritoneoscopy: a novel approach to diagnostic and therapeutic interventions. Gastrointest Endosc 2004;60:114-7.
2. Rao GV, Reddy DN. Transgastric appendectomy in humans. Paper presented at: World Congress of Gastroenterology; 2006; Montreal, Quebec, Canada. 3. Marks JM, Ponsky JL, Pearl JP, et al. PEG ‘‘rescue’’: a practical NOTES technique. Surg Endosc 2007;21:816-9. 4. Marescaux J, Dallemagne B, Perretta S, et al. Surgery without scars: report of transluminal cholecystectomy in a human being. Arch Surg 2007;142:823-6. 5. Shih SP, Kantsevoy SV, Kalloo AN, et al. Hybrid minimally invasive surgery: a bridge between laparoscopic and translumenal surgery. Surg Endosc 2007;21:1450-3. 6. Ryou M, Pai RD, Pai R, et al. Evaluating an optimal gastric closure method for transgastric surgery. Surg Endosc 2007;21:677-80. 7. Ryou M, Fong DG, Pai RD, et al. Evaluation of a novel access and closure device for NOTES applications: a transcolonic survival study in the porcine model. Gastrointest Endosc 2008;67:964-9. 8. Rattner D, Kalloo A. ASGE/SAGES Working Group on Natural Orifice Translumenal Endoscopic Surgery. Surg Endosc 2006;20:329-33. 9. Swain P. A justification for NOTESdnatural orifice translumenal endosurgery. Gastrointest Endosc 2007;65:514-6. 10. Magno P, Giday SA, Dray X, et al. A new stapler-based full-thickness transgastric access closure: results from an animal pilot trial. Endoscopy 2007;39:876-80. 11. Ryou M, Fong DG, Pai RD, et al. Dual-port distal pancreatectomy using a prototype endoscope and endoscopic stapler: a natural orifice transluminal endoscopic surgery (NOTES) survival study in a porcine model. Endoscopy 2007;39:881-7. 12. Chiu PW, Lau JY, Ng EK, et al. Closure of gastrotomy after transgastric tubal ligation using the Eagle Claw VII: a survival experiment in a porcine model [abstract]. Gastrointest Endosc 2007;65:AB294. 13. Fritscher-Ravens A. Transgastric endoscopyda new fashion, a new excitement! Endoscopy 2007;39:161-7. 14. Ryou M, Fong DG, Pai RD, et al. Transluminal closure for NOTES: an ex vivo study comparing leak pressures of various gastrotomy and colostomy closure modalities. Endoscopy 2008;40:432-6. 15. Fong DG, Ryou M, Pai RD, et al. Transcolonic ventral wall hernia mesh fixation in a porcine model. Endoscopy 2007;39:865-70. 16. Hawes RH, Rattner DW, Fleischer D, et al. NOTES: where have we been and where are we going? Gastrointest Endosc 2008;67:779-80. 17. Dray X, Gabrielson KL, Buscaglia JM, et al. Air and fluid leak tests after NOTES procedures: a pilot study in a live porcine model (with videos). Gastrointest Endosc 2008;68:513-9. 18. Moyer MT, Pauli EM, Haluck RS, et al. A self-approximating transluminal access technique for potential use in NOTES: an ex vivo porcine model (with video). Gastrointest Endosc 2007;66:974-8. 19. Pauli EM, Moyer MT, Haluck RS, et al. Self-approximating transluminal access technique for natural orifice transluminal endoscopic surgery: a porcine survival study. Gastrointest Endosc 2008;67:690-7. 20. Bergstrom M, Swain P, Park PO. Measurements of intraperitoneal pressure and the development of a feedback control valve for regulating pressure during flexible transgastric surgery (NOTES). Gastrointest Endosc 2007;66:174-8. 21. Voermans RP, Worm AM, van Berge Henegouwen MI, et al. In vitro comparison and evaluation of seven gastric closure modalities for natural orifice transluminal endoscopic surgery (NOTES). Endoscopy 2008;40:595-601. 22. von Renteln D, Kaehler G, Eickhoff A, et al. Gastric full-thickness suturing following NOTES procedures for closure of the access site to the peritoneal cavity. Endoscopy 2008;40:E99-100. 23. McGee MF, Marks JM, Jin J, et al. Complete endoscopic closure of gastric defects using a full-thickness tissue plicating device. J Gastrointest Surg 2008;12:38-45. 24. Onders RP, McGee MF, Marks J, et al. Natural orifice transluminal Endoscopic surgery (NOTES) as a diagnostic tool in the intensive care unit. Surg Endosc 2007;21:681-3. 25. Ramos AC, Murakami A, Galvao Neto M, et al. NOTES transvaginal video assisted cholecystectomy: first series. Endoscopy 2008;40:572-5.
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Figure 4. OTSC closure by using 2 clips in a linear fashion.
closure with the first-generation OTSC produced favorable results in a 12-week porcine survival study,40 but long-term survival studies are still warranted to assess safety of the OTSC gastric closure technique. Of note, the Twin Grasper used to approximate the tissue before clip placement is fundamentally important to the success of this closure device. We did not compare different techniques to bring the tissue into the applicator cap, but strongly believe that meticulous approximation of both edges, under direct vision, is paramount to a reliable closure. Using a double-channel endoscope can also help to facilitate optimal positioning of the Twin Grasper, but the closure technique described in this article can also be performed with a single-channel endoscope. Because OTSC closure is an entirely endoluminal method, drawing tissue into the cap, the risk of blindly injuring adjacent organs or incorporating them into the closure is considered to be minimal. Blindly puncturing the gastric wall by using transmural suturing systems seems inherently to incur a higher possibility of inadvertent injury. In this study, the clips were applied endoluminally and were located entirely within the stomach after the closure. Theoretically, the clips will eventually slough off after several weeks and be safely excreted, thereby eliminating concerns related to biocompatibility or erosion of permanent implants. This randomized, controlled animal trial demonstrates that NOTES gastrotomies can be safely and reliably closed by using the OTSC system. These clips are easy to apply and achieve excellent short-term closure comparable to that with surgical sutures. Survival studies are needed to establish the long-term effectiveness of this technique.
REFERENCES
von Renteln et al
NOTES gastrotomy closure with an over-the-scope clip
26. Hazey JW, Narula VK, Renton DB, et al. Natural-orifice transgastric endoscopic peritoneoscopy in humans: initial clinical trial. Surg Endosc 2007;22:16-20. 27. Zorron R, Maggioni LC, Pombo L, et al. NOTES transvaginal cholecystectomy: preliminary clinical application. Surg Endosc 2008;22:542-7. 28. Palanivelu C, Rajan PS, Rangarajan M, et al. Transvaginal endoscopic appendectomy in humans: a unique approach to NOTESdworld’s first report. Surg Endosc 2008;22:1343-7. 29. Meireles O, Kantsevoy SV, Kalloo AN, et al. Comparison of intraabdominal pressures using the gastroscope and laparoscope for transgastric surgery. Surg Endosc 2007;21:998-1001. 30. McGee MF, Marks JM, Onders RP, et al. Complete endoscopic closure of gastrotomy after natural orifice translumenal endoscopic surgery using the NDO plicator. Surg Endosc 2008;22:214-20. 31. von Renteln D, Eickhoff A, Kaehler G, et al. Endoscopic closure of the natural orifice transluminal endoscopic surgery (NOTES) access site to the peritoneal cavity by means of transmural resorbable sutures: an animal survival study. Endoscopy 2009;41:154-9. 32. Schurr MO, Arrezzo A, Ho CN, et al. The OTSC clip for endoscopic organ closure in NOTES: device and technique. Minim Invasive Ther Allied Technol 2008;17:262-6. 33. Kratt T, Ku¨per M, Traub F, et al. Feasibility study for secure closure of natural orifice transluminal endoscopic surgery gastrotomies by using over-the-scope clips. Gastrointest Endosc 2008;68:993-6. 34. El-Serag HB, Tran T, Richardson P, et al. Anthropometric correlates of intragastric pressure. Scand J Gastroenterol 2006;41:887-91. 35. de Vries DR, van Herwaarden MA, Smout AJ, et al. Gastroesophageal pressure gradients in gastroesophageal reflux disease: relations with hiatal hernia, body mass index, and esophageal acid exposure. Am J Gastroenterol 2008;103:1349-54.
36. Iqbal A, Haider M, Stadlhuber RJ, et al. A study of intragastric and intravesicular pressure changes during rest, coughing, weight lifting, retching, and vomiting. Surg Endosc 2008;22:2571-5. 37. Stadaas JO. Intragastric pressure/volume relationship in the normal human stomach. Scand J Gastroenterol 1975;10:135-40. 38. Man WD, Kyroussis D, Fleming TA, et al. Cough gastric pressure and maximum expiratory mouth pressure in humans. Am J Respir Crit Care Med 2003;168:714-7. 39. Atkinson M, Botrill MB, Edwards AT, et al. Mucosal tears at the oesophagogastric junction (the Mallory-Weiss syndrome). Gut 1961;2: 1-11. 40. Schurr MO, Hartmann C, Ho CN, et al. An over-the-scope clip (OTSC) system for closure of iatrogenic colon perforations: results of an experimental survival study in pigs. Endoscopy 2008;40:584-8.
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Received January 13, 2009. Accepted March 5, 2009. Current affiliations: Department of Gastroenterology (D.v.R., A.S., K.C.), Medizinische Klinik I, Klinikum Ludwigsburg, Ludwigsburg, Germany, Department of Surgery (M.C.V.), Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA, University Hospital Mannheim (M.G.), University of Heidelberg, Germany. Reprint requests: Karel Caca, MD, Department of Gastroenterology, Hepatology, and Oncology, Klinikum Ludwigsburg, 71640 Ludwigsburg, Germany. If you would like to chat with an author of this article, you may contact him at [email protected].
Natural orifice transluminal endoscopic surgery gastrotomy closure with an over-the-endoscope clip: a randomized, controlled porcine study (with videos) Daniel von Renteln, MD, Arthur Schmidt, MD, Melina C. Vassiliou, MD, Maria Gieselmann, BSc, Karel Caca, MD Ludwigsburg, Heidelberg, Germany, Lebanon, New Hampshire, USA
Background: Secure endoscopic closure of transgastric natural orifice transluminal endoscopic surgery (NOTES) access is of paramount importance. The over-the-scope clip (OTSC) system has previously been shown to be effective for NOTES gastrotomy closure. Objective: To compare OTSC gastrotomy closure with surgical closure. Design: Randomized, controlled animal study. Setting: Animal facility laboratory. Animals: Thirty-six female domestic pigs. Interventions: Gastrotomies were created by using a needle-knife and an 18-mm balloon. The animals were subsequently randomized to either open surgical repair with interrupted sutures or endoscopic repair with 12-mm OTSCs. In addition, pressurized leak tests were performed in ex vivo specimens of 18-mm scalpel incisions closed with suture (n Z 14) and of intact stomachs (n Z 10). Main Outcome Measurements: The mean time for endoscopic closure was 9.8 minutes (range 3-22, SD 5.5). No complications occurred during either type of gastrotomy closure. At necropsy, examination of all OTSC and surgical closures demonstrated complete sealing of gastrotomy sites without evidence of injury to adjacent organs. Pressurized leak tests showed a mean burst pressure of 83 mm Hg (range 30-140, SD 27) for OTSC closures and 67 mm Hg (range 30-130, SD 27.7) for surgical sutures. Ex vivo hand-sewn sutures of 18-mm gastrotomies (n Z 14) exhibited a mean burst pressure of 65 mm Hg (range 20-140, SD 31) and intact ex vivo stomachs (n Z 10) had a mean burst pressure of 126 mm Hg (range 90-170, SD 28). The burst pressure of ex vivo intact stomachs was significantly higher compared with OTSC closures (P ! .01), in vivo surgical closures (P ! .01), and ex vivo hand-sewn closures (P! .01). There was a trend toward higher burst pressures in the OTSC closures compared with surgical closures (P Z .063) and ex vivo hand-sewn closures (P Z .094). In vivo surgical closures demonstrated similar burst pressures compared with ex vivo hand-sewn closures (P Z .848). Limitations: Nonsurvival setting. Conclusion: Endoscopic closure by using the OTSC system is comparable to surgical closure in a nonsurvival porcine model. This technique is easy to perform and is suitable for NOTES gastrotomy closure. (Gastrointest Endosc 2009;70:732-9.)
Abbreviations: NOTES, natural orifice transluminal endoscopic surgery; OTSC, over-the-scope clip. DISCLOSURE: Material support (endoscopic equipment, funding of the animal procedures and endotherapeutic material) for this study
was provided directly to the animal facility by Ovesco AG, Tu ¨ bingen, Germany, and Olympus Deutschland GmbH, Hamburg, Germany. All authors disclosed no financial relationships relevant to this publication.
Copyright ª 2009 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2009.03.010
732 GASTROINTESTINAL ENDOSCOPY Volume 70, No. 4 : 2009
www.giejournal.org
von Renteln et al
Natural orifice transluminal endoscopic surgery (NOTES) is a novel method to access the peritoneal cavity through the mouth, vagina, rectum, or bladder, thereby making it possible to perform surgery without skin incisions. Since the first NOTES report in 2004, research interest in NOTES has grown steadily.1 Human transgastric intraperitoneal interventions were first performed in India in 2003.2 The first published human NOTES procedure in 2007 was a transgastric rescue of a prematurely dislodged PEG. That same year, the first NOTES cholecystectomy was performed.3,4 To date, only a limited number of pure human NOTES procedures have been reported worldwide. Most human NOTES interventions have been performed as hybrid procedures with laparoscopic assistance and/or observation.5 One of the major obstacles to pure transgastric NOTES is the need for a leakproof and reliable method for endoscopic closure of the gastrotomy.6-9 Several closure techniques have been described; however, no uniformly reliable technique or device has been reported to date. Animal studies suggest that the access site can be closed by using endoscopic clips, staplers, or suturing devices.10-31 NOTES gastrotomy closure by using the first generation of the over the-scope clip system (OTSC) (Ovesco Endoscopy AG, Tu ¨bingen, Germany) has been demonstrated in 2 small feasibility studies.32,33 The aim of this study was to compare the acute strength of the second-generation 12-mm gastric closure OTSC system with that of surgical closure in a randomized, controlled trial.
NOTES gastrotomy closure with an over-the-scope clip
Capsule Summary What is already known on this topic d
One of the major obstacles to pure transgastric natural orifice transluminal endoscopic surgery is the need for a leakproof, reliable method for endoscopic closure of the gastrotomy.
What this study adds to our knowledge d
In a randomized, controlled porcine study, endoscopic gastrotomy closure with an over-the-scope clip system was comparable to surgical closure, with both demonstrating complete sealing of gastrotomy sites without evidence of injury to adjacent organs.
The study was conducted at the animal facility in Beichlingen, Thu ¨ringen, Germany, after approval of the Animal Care and Use Committee. Thirty-six female domestic pigs with a mean weight of 32 kg (range 20-54 kg) were used. The animals were fasted from solid food for 48 hours before surgery, but were allowed full access to water and milk. Preanesthesia sedation consisted of ketamine 2 mg/kg and xylazine 2 mg/kg. General anesthesia was achieved by using isoflurane, nitrous oxide, and oxygen after endotracheal intubation. All procedures were performed in the supine position. A Veress needle (16-gauge) was inserted percutaneously in the left lower abdomen to measure intraperitoneal pressure during the NOTES procedure. With the animal under general anesthesia, extensive gastric lavage was performed with tap water. Time to gain peritoneal access was defined as the time from initial instrument insertion into the working channel to introduction of the endoscope into the peritoneal cavity. The anterior gastric wall was localized by applying external pressure to the anterior abdominal wall. To enable safe peritoneal access a preliminary pneumoperitoneum of 8 mm Hg was created. An endoscopic needle-knife sphincterotome (Boston Scientific Corp, Natick, Mass) was used to create a full-thickness 2-mm incision in the anterior gastric wall. An 18-mm esophageal
dilating balloon (Esophageal Balloon Dilator, BE-7, Olympus, Hamburg, Germany) was then advanced through the gastrotomy and was used to dilate the incision (Fig. 1A-C, Video 1 [available online at www.giejournal. org]). After gastrotomy creation, a 2T160 double-channel upper endoscope (Olympus, Hamburg, Germany) was passed through the gastric wall into the peritoneal cavity, and a standardized peritoneoscopy was performed (Fig. 1D, Video 1). During peritoneoscopy, all 4 abdominal quadrants were examined, and complete visualization of the diaphragm, liver, gallbladder, spleen, rectum, sigmoid colon, and fallopian tubes was attempted to examine for possible access-related injuries. After peritoneoscopy was performed, pigs were randomly assigned to either surgical repair (n Z 18) or endoscopic gastrotomy closure (n Z 18). Endoscopic repair was performed by means of the 2T160 double-channel upper endoscope, the Ovesco Twin Grasper (Ovesco AG), and the 12-mm gastric closure OTSC (Ovesco AG) (Fig. 2, Video 2 [available online at www.giejournal.org]). The mean time to close the gastrotomy was defined as the time from insertion of the twin grasper into the channel to final withdrawal of the instrument after satisfactory deployment of the clip. The clip is made of a nitinol alloy and is installed on an applicator cap mounted on the tip of the gastroscope. The clip is applied by pulling taut a wire threaded through the working channel of the endoscope similar to endoscopic band-ligation systems. The OTSC Twin Grasper has 2 jaws that move separately to approximate the edges of the gastrotomy into the cap before applying the clip (Fig. 2, Video 1). Surgical repair was achieved by open laparotomy with interrupted sutures (PDSII, Z311, 3-0; Ethicon, Somerville, NJ). The animals were subsequently killed with intravenously administered sodium pentobarbital, and laparotomy was performed to detect any injuries related to OTSC placement. Each stomach was then explanted. The esophagus was cannulated for air insufflation, and the specimens were sealed at both ends. While recording intragastric pressures, the stomachs were then gradually
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MATERIAL AND METHODS
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Figure 1. Gastrotomy creation by using an 18-mm dilating balloon (A-C). View of the gallbladder during peritoneoscopy (D).
inflated to maximum capacity and submerged in water to detect air leaks. The point of failure was defined as the pressure at which the first sign of air was seen bubbling from the serosal surface (Fig. 3). Pressures were recorded in millimeters of mercury. In addition, pressurized leak tests were performed in ex vivo specimens of 18-mm scalpel incisions closed with suture (n Z 14) and of intact stomachs (n Z 10). Tissue for ex vivo evaluation was obtained from freshly killed pigs. Pressurized leak tests for ex vivo control groups were conducted as described above. The Mann-Whitney U test for 2 independent samples was used to estimate differences in acute burst pressures (SPSS 14.0, SPSS Inc, Chicago, Ill). A P value !.05 was considered significant.
Transgastric access was easily achieved without complications in all animals. The mean time to gain peritoneal
access by using the preliminary pneumoperitoneum technique was 5.7 minutes (range 2-9 minutes, SD 1.9). The prototype Twin Grasper was used in all cases to approximate the gastrotomy edges into the applicator cap. Adequate sealing of the site was endoscopically observed by using a single clip in 17 of 18 cases. In 1 case, inadequate closure of the gastrotomy was observed, and a second OTSC was applied in a linear fashion (Fig. 4). Thus, gastrotomy closure by means of 2 serially placed OTSC systems was performed in 1 of 18 cases. The mean OTSC procedure time was 9.8 minutes (range 3-22 minutes, SD 5.5). After placement of the clips, the stomachs were fully distended by using air insufflation to confirm the adequacy of the closure. Intraperitoneal pressure measured through the Veress needle remained unchanged during extensive gastric insufflation in all cases, suggesting the absence of significant leaks. No acute adverse events occurred, and postprocedure laparotomies did not identify any injuries related to the gastrotomy closures. At necropsy,
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RESULTS
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Figure 2. OTSC procedure. Laparoscopic view of the Twin Grasper passed through the gastrotomy with 1 jaw opened and with both jaws opened (A). Tissue is incorporated into 1 jaw of the Twin Grasper (B). The other Twin Grasper jaw is opened and advanced to the other side of the gastrotomy (C). The Twin Grasper is closed, approximating both sides of the gastrotomy (D). The gastrotomy site is drawn into the applicator cap, and the clip is released (E-G). Closure site after OTSC application (H). Laparoscopic view after OTSC application (I).
macroscopic examination revealed complete closure of gastrotomy sites with OTSC in all cases. Pressurized leak tests demonstrated a mean burst pressure of 83 mm Hg (range 30-140 mm Hg, SD 27) for OTSC closures and 67 mm Hg (range 30-130 mm Hg, SD 27.7) for surgical sutures. Ex vivo suturing of 18-mm scalpel incisions exhibited a mean burst pressure of 65 mm Hg (range 20-140 mm Hg, SD 31) compared with ex vivo
intact stomachs at pressures of 126 mm Hg (range 90-170 mm Hg, SD 28). In 3 of 10 cases, the gastric wall ruptured at the fundic diverticulum. The burst pressure of ex vivo intact stomachs was significantly higher compared with that of OTSC closure (P ! .01), in vivo surgical closures (P ! .01), and ex vivo hand-sewn closures (P ! .01). There was a trend toward higher burst pressures in the OTSC closures
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The rapidly growing number of publications and lectures dedicated to NOTES clearly shows the growing interest in this field of interventional endoscopy. However,
no randomized, controlled trials have shown superiority of a NOTES approach compared with laparoscopy or open surgery, and appropriate clinical applications have yet to be defined.2,16 Although there are many unanswered questions regarding NOTES applications, there is consensus that a leakproof, practical, and secure closure must be developed to safely conduct human NOTES clinical trials.2,8,16 This randomized, controlled trial is the first study evaluating the modified 12-mm gastric closure OTSC. In addition, pressurized leak tests were conducted in ex vivo control groups to obtain reference values for surgical closures performed under optimal conditions and in intact stomachs. The mean burst pressure of recently explanted intact stomachs was significantly higher compared with any of the closure methods. Healthy gastric tissue ruptured in some cases at the fundic diverticulum where the porcine gastric wall is thinnest. Ex vivo hand-sewn closures were performed to obtain comparative values for optimally placed hand-sewn sutures. The OTSC closures seemed to rupture at slightly higher pressures compared with ex vivo and in vivo surgical sutures, but the differences were not significant. The reasons for this are thought to be related to the clip design. The novel gastric closure OTSC has jaws with longer spikes compared with the previous OTSC design in which they are quite close to each other. This not only increases the anchoring capabilities of the clip but compresses the tissue to tightly approximate the wound edges. Once the nitinol clip is released into the target tissue, it delivers a force of approximately 8 to 9 N. Physiologic intragastric pressures are influenced by body mass index, respiration, sex, the presence of hiatal hernias, intra-abdominal pressure, and age. They are reported to be in the range of 1 to 12 mm Hg at rest in an empty stomach.34-36 Intragastric pressure is increased by 2- to 3-fold in the presence of 300 to 600 mL of gastric fluid.37 Mean intragastric pressures during coughing, vomiting, retching, and weight lifting have been reported to be 35, 89, 62, and 2 mm Hg, respectively, with corresponding peak pressures of 233, 290, 281, and 52 mm Hg.36,38,39 In human cadavers, 100 to 150 mm Hg is necessary to cause mucosal disruption at the gastric cardia.39 Therefore, pressurized leak tests have been used to provide objective data about the strength of closures in several studies.21,23,30,31,33 It may be naive to assume, however, that higher burst pressures and acute closure strength are the most important factors for secure gastrotomy closure. Surgical principles of anastomotic healing mandate adequate tissue perfusion with minimal wound tension. Excessive tension can lead to ischemic changes and eventual breakdown of a wound or anastomosis. As such, the OTSC pins have been designed in a parallel fashion to imitate continuous sutures and permit adequate tissue perfusion. Long-term survival studies are necessary to
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Figure 2 (continued )
compared with surgical closures (P Z .063) and ex vivo hand-sewn closures (P Z .094). In vivo surgical closures demonstrated similar burst pressures compared with ex vivo hand-sewn closures (P Z .848).
DISCUSSION
von Renteln et al
NOTES gastrotomy closure with an over-the-scope clip
Figure 3. OTSC closure site. View of the serosal surface after stomach explantation (A and B). Endoluminal view of the OTSC closure after stomach explantation (C). While recording intragastric pressures, the stomachs were gradually inflated to maximum capacity and submerged in water to detect signs of air bubbling from the serosal surface (D and E).
assess tissue perfusion. Previous studies used a slightly different clip design and did not report absolute burst pressure values.32,33 As such, a valid comparison with previous studies regarding burst pressures is not possible. Although
this study provides information about the acute strength of OTSC closure compared with surgical closure, longterm complications such as infection, perforation, and ischemia could not be evaluated. Colonic perforation
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1. Kalloo AN, Singh VK, Jagannath SB, et al. Flexible transgastric peritoneoscopy: a novel approach to diagnostic and therapeutic interventions. Gastrointest Endosc 2004;60:114-7.
2. Rao GV, Reddy DN. Transgastric appendectomy in humans. Paper presented at: World Congress of Gastroenterology; 2006; Montreal, Quebec, Canada. 3. Marks JM, Ponsky JL, Pearl JP, et al. PEG ‘‘rescue’’: a practical NOTES technique. Surg Endosc 2007;21:816-9. 4. Marescaux J, Dallemagne B, Perretta S, et al. Surgery without scars: report of transluminal cholecystectomy in a human being. Arch Surg 2007;142:823-6. 5. Shih SP, Kantsevoy SV, Kalloo AN, et al. Hybrid minimally invasive surgery: a bridge between laparoscopic and translumenal surgery. Surg Endosc 2007;21:1450-3. 6. Ryou M, Pai RD, Pai R, et al. Evaluating an optimal gastric closure method for transgastric surgery. Surg Endosc 2007;21:677-80. 7. Ryou M, Fong DG, Pai RD, et al. Evaluation of a novel access and closure device for NOTES applications: a transcolonic survival study in the porcine model. Gastrointest Endosc 2008;67:964-9. 8. Rattner D, Kalloo A. ASGE/SAGES Working Group on Natural Orifice Translumenal Endoscopic Surgery. Surg Endosc 2006;20:329-33. 9. Swain P. A justification for NOTESdnatural orifice translumenal endosurgery. Gastrointest Endosc 2007;65:514-6. 10. Magno P, Giday SA, Dray X, et al. A new stapler-based full-thickness transgastric access closure: results from an animal pilot trial. Endoscopy 2007;39:876-80. 11. Ryou M, Fong DG, Pai RD, et al. Dual-port distal pancreatectomy using a prototype endoscope and endoscopic stapler: a natural orifice transluminal endoscopic surgery (NOTES) survival study in a porcine model. Endoscopy 2007;39:881-7. 12. Chiu PW, Lau JY, Ng EK, et al. Closure of gastrotomy after transgastric tubal ligation using the Eagle Claw VII: a survival experiment in a porcine model [abstract]. Gastrointest Endosc 2007;65:AB294. 13. Fritscher-Ravens A. Transgastric endoscopyda new fashion, a new excitement! Endoscopy 2007;39:161-7. 14. Ryou M, Fong DG, Pai RD, et al. Transluminal closure for NOTES: an ex vivo study comparing leak pressures of various gastrotomy and colostomy closure modalities. Endoscopy 2008;40:432-6. 15. Fong DG, Ryou M, Pai RD, et al. Transcolonic ventral wall hernia mesh fixation in a porcine model. Endoscopy 2007;39:865-70. 16. Hawes RH, Rattner DW, Fleischer D, et al. NOTES: where have we been and where are we going? Gastrointest Endosc 2008;67:779-80. 17. Dray X, Gabrielson KL, Buscaglia JM, et al. Air and fluid leak tests after NOTES procedures: a pilot study in a live porcine model (with videos). Gastrointest Endosc 2008;68:513-9. 18. Moyer MT, Pauli EM, Haluck RS, et al. A self-approximating transluminal access technique for potential use in NOTES: an ex vivo porcine model (with video). Gastrointest Endosc 2007;66:974-8. 19. Pauli EM, Moyer MT, Haluck RS, et al. Self-approximating transluminal access technique for natural orifice transluminal endoscopic surgery: a porcine survival study. Gastrointest Endosc 2008;67:690-7. 20. Bergstrom M, Swain P, Park PO. Measurements of intraperitoneal pressure and the development of a feedback control valve for regulating pressure during flexible transgastric surgery (NOTES). Gastrointest Endosc 2007;66:174-8. 21. Voermans RP, Worm AM, van Berge Henegouwen MI, et al. In vitro comparison and evaluation of seven gastric closure modalities for natural orifice transluminal endoscopic surgery (NOTES). Endoscopy 2008;40:595-601. 22. von Renteln D, Kaehler G, Eickhoff A, et al. Gastric full-thickness suturing following NOTES procedures for closure of the access site to the peritoneal cavity. Endoscopy 2008;40:E99-100. 23. McGee MF, Marks JM, Jin J, et al. Complete endoscopic closure of gastric defects using a full-thickness tissue plicating device. J Gastrointest Surg 2008;12:38-45. 24. Onders RP, McGee MF, Marks J, et al. Natural orifice transluminal Endoscopic surgery (NOTES) as a diagnostic tool in the intensive care unit. Surg Endosc 2007;21:681-3. 25. Ramos AC, Murakami A, Galvao Neto M, et al. NOTES transvaginal video assisted cholecystectomy: first series. Endoscopy 2008;40:572-5.
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Figure 4. OTSC closure by using 2 clips in a linear fashion.
closure with the first-generation OTSC produced favorable results in a 12-week porcine survival study,40 but long-term survival studies are still warranted to assess safety of the OTSC gastric closure technique. Of note, the Twin Grasper used to approximate the tissue before clip placement is fundamentally important to the success of this closure device. We did not compare different techniques to bring the tissue into the applicator cap, but strongly believe that meticulous approximation of both edges, under direct vision, is paramount to a reliable closure. Using a double-channel endoscope can also help to facilitate optimal positioning of the Twin Grasper, but the closure technique described in this article can also be performed with a single-channel endoscope. Because OTSC closure is an entirely endoluminal method, drawing tissue into the cap, the risk of blindly injuring adjacent organs or incorporating them into the closure is considered to be minimal. Blindly puncturing the gastric wall by using transmural suturing systems seems inherently to incur a higher possibility of inadvertent injury. In this study, the clips were applied endoluminally and were located entirely within the stomach after the closure. Theoretically, the clips will eventually slough off after several weeks and be safely excreted, thereby eliminating concerns related to biocompatibility or erosion of permanent implants. This randomized, controlled animal trial demonstrates that NOTES gastrotomies can be safely and reliably closed by using the OTSC system. These clips are easy to apply and achieve excellent short-term closure comparable to that with surgical sutures. Survival studies are needed to establish the long-term effectiveness of this technique.
REFERENCES
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26. Hazey JW, Narula VK, Renton DB, et al. Natural-orifice transgastric endoscopic peritoneoscopy in humans: initial clinical trial. Surg Endosc 2007;22:16-20. 27. Zorron R, Maggioni LC, Pombo L, et al. NOTES transvaginal cholecystectomy: preliminary clinical application. Surg Endosc 2008;22:542-7. 28. Palanivelu C, Rajan PS, Rangarajan M, et al. Transvaginal endoscopic appendectomy in humans: a unique approach to NOTESdworld’s first report. Surg Endosc 2008;22:1343-7. 29. Meireles O, Kantsevoy SV, Kalloo AN, et al. Comparison of intraabdominal pressures using the gastroscope and laparoscope for transgastric surgery. Surg Endosc 2007;21:998-1001. 30. McGee MF, Marks JM, Onders RP, et al. Complete endoscopic closure of gastrotomy after natural orifice translumenal endoscopic surgery using the NDO plicator. Surg Endosc 2008;22:214-20. 31. von Renteln D, Eickhoff A, Kaehler G, et al. Endoscopic closure of the natural orifice transluminal endoscopic surgery (NOTES) access site to the peritoneal cavity by means of transmural resorbable sutures: an animal survival study. Endoscopy 2009;41:154-9. 32. Schurr MO, Arrezzo A, Ho CN, et al. The OTSC clip for endoscopic organ closure in NOTES: device and technique. Minim Invasive Ther Allied Technol 2008;17:262-6. 33. Kratt T, Ku¨per M, Traub F, et al. Feasibility study for secure closure of natural orifice transluminal endoscopic surgery gastrotomies by using over-the-scope clips. Gastrointest Endosc 2008;68:993-6. 34. El-Serag HB, Tran T, Richardson P, et al. Anthropometric correlates of intragastric pressure. Scand J Gastroenterol 2006;41:887-91. 35. de Vries DR, van Herwaarden MA, Smout AJ, et al. Gastroesophageal pressure gradients in gastroesophageal reflux disease: relations with hiatal hernia, body mass index, and esophageal acid exposure. Am J Gastroenterol 2008;103:1349-54.
36. Iqbal A, Haider M, Stadlhuber RJ, et al. A study of intragastric and intravesicular pressure changes during rest, coughing, weight lifting, retching, and vomiting. Surg Endosc 2008;22:2571-5. 37. Stadaas JO. Intragastric pressure/volume relationship in the normal human stomach. Scand J Gastroenterol 1975;10:135-40. 38. Man WD, Kyroussis D, Fleming TA, et al. Cough gastric pressure and maximum expiratory mouth pressure in humans. Am J Respir Crit Care Med 2003;168:714-7. 39. Atkinson M, Botrill MB, Edwards AT, et al. Mucosal tears at the oesophagogastric junction (the Mallory-Weiss syndrome). Gut 1961;2: 1-11. 40. Schurr MO, Hartmann C, Ho CN, et al. An over-the-scope clip (OTSC) system for closure of iatrogenic colon perforations: results of an experimental survival study in pigs. Endoscopy 2008;40:584-8.
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Received January 13, 2009. Accepted March 5, 2009. Current affiliations: Department of Gastroenterology (D.v.R., A.S., K.C.), Medizinische Klinik I, Klinikum Ludwigsburg, Ludwigsburg, Germany, Department of Surgery (M.C.V.), Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA, University Hospital Mannheim (M.G.), University of Heidelberg, Germany. Reprint requests: Karel Caca, MD, Department of Gastroenterology, Hepatology, and Oncology, Klinikum Ludwigsburg, 71640 Ludwigsburg, Germany. If you would like to chat with an author of this article, you may contact him at [email protected].