Chapter 24

Endoscopic Management of GI Endoscopic Mucosal Resection and Endoscopic Submucosal Dissection Perforations

Selvi Thirumurthi, MD; Shashideep Singhal, MD, FASGE; and G.S. Raju, MD

Introduction

Endoscopic closure of gastrointestinal (GI) tract perforations, whether by clips or sutures, has revolutionized endoluminal surgery. It allows us to close perforations immediately, thereby eliminating the need for surgery and the morbidity and mortality associated with it. Soehendra’s group’s first successful closure of a gastric perforation after endoscopic resection of a leiomyoma in the 1990s opened up the field of endoscopic surgery.¹ In this chapter, we review endoscopic devices and closure techniques, and both animal and clinical studies on endoscopic closure of perforations.

Closure Devices

A number of devices are currently available to close defects (Figure 24-1):

• Clips delivered through the endoscope (through-the-scope clips [TTSCs]): the Quick Clip (Olympus); Resolution Clip (Boston Scientific); Instinct Clip (Cook Medical); and the Hemostatic Clip (Changzhou Jiuhong Medical Instrument Co, Ltd)
  
• Over-the-scope clip (OTSC) (OTSC System, Ovesco Endoscopy AG)
  
• Over-the-scope suturing device (OverStitch Endoscopic Suturing System, Apollo Endosurgery)

Experimental Studies of Endoluminal Closure

Experimental animal studies of perforation closure in laid the foundation for their successful use in clinical practice.^2–4

Experimental studies demonstrated the feasibility of successful endoscopic closure of esophageal perforations and submucosal esophageal tunnel openings after per-oral esophageal myotomy, which led to a novel endoscopic treatment option for achalasia.5–7 In addition, a randomized controlled animal survival study demonstrated that endoluminal closure with clips and sutures is comparable to the thoracoscopic closure of esophageal perforations.⁸ Although successful suture closure of endoscopic full-thickness esophageal resection defects is possible, tension pneumothorax and mediastinal infection remain as potential complications.⁵

Experimental Animal Studies—Gastric Perforation Closure

Kalloo and colleagues explored the possibility of endoscopic exploration of the peritoneal cavity through the stomach wall, followed by successful clip closure of the iatrogenic gastric perforation at the end of the procedure—this opened up a new field in medicine—the Natural Orifice Transluminal Endoscopic Surgery (NOTES).⁹ Subsequently, several investigators reproduced endoscopic closure of ports of entry in the gastric wall for NOTES, submucosal tunnels, and gastric wall defects after full-thickness resection in animal models.^9–32

Although small perforations (10 mm) can be closed with TTSC devices, larger defects (15 to 20 mm) may require an omental patch clip closure with TTSC devices or OTSC devices.³³ Gastric perforations larger than 20 mm are not amenable to closure with a single OTSC.^33,34 OTSC devices have also been used to close perforations in the fundus of the stomach.^33–35

Endoscopic suturing has been shown to be successful in the closure of submucosal tunnels created for endoscopic full-thickness gastric biopsy for analysis of neuromuscular cells.^32–35 Full-thickness transgastric and transduodenal myotomy followed by suture closure have been used to create endoscopic pyloroplasty in animal experiments.³⁶ Using a novel multifunctional prototype (EndoSAMURAI), transgastric small bowel segmental resection followed by end-to-end small bowel anastomosis have been successfully performed in animal studies.³⁷

A Japanese study showed the efficacy of closure of gastric endoscopic submucosal dissection (ESD) and endoscopic full-thickness resection defects using the endoscopic suturing device to be 85.7% and 100% respectively, in porcine experiments.³⁸

In porcine survival studies, TTSC were used to successfully close 1.5 to 2 cm colon perforations with healing; a leakproof seal both of linear and even circular perforations can be achieved; and compared to surgical closure of perforations, endoluminal closure decreases the risk of adhesions.39–43 In ex vivo, porcine colon model studies, TTSCs resulted in excellent closure of an 18 mm perforation, comparable to the hand-sewn parallel closure (gold standard) on air leak pressure testing.^22,44 However, TTSCs have one major drawback: they fail to close gaping perforations with sloping edges.^41,42,45

Although through-the-scope suturing devices (T-tags) are not widely available at present, it is useful to review their role in the management of colon perforations. T-tags can be utilized to bring the edges of a wide defect together for successful closure in linear perforations and full-thickness resection of the colon. Colon polyps can become tethered to the underlying wall and do not lift after submucosal injection, usually when there is prior manipulation with biopsy or injection. If resection is attempted in these cases, regardless of the nonlifting sign and perforation results, T-tag closure could be a potential option for management.^43,46,47 Although T-tag closure results in the successful approximation of the edges, everted suture closure results in slow seepage of fecal matter in between the gaps of closure and result in peritonitis.^22,43,44 Another concern is the inadvertent puncture of adjacent organs during T-tag insertion.⁴³ Successful clip closure of colotomy allowed exploration of the possibility of transcolonic small bowel resection using a combination of NOTES and laparoscopy.^43,48

Over-the-Scope Clips

Ex vivo porcine colonic model studies using OTSC devices produced results comparable to hand-sewn parallel closure (gold standard) when air leak pressures were tested immediately after closure.^22,44 Colon perforations of 5 ± 10 mm on the serosal side were successfully closed with the OTSC devices, with an uneventful clinical course during 12 weeks of follow up.⁴⁹ In a randomized controlled animal trial managing 18 mm colonic perforations, the OTSC devices achieved a strong closure that was comparable to the strength of surgical suture closures. However, the risk of suctioning adjacent tissue, especially adjacent intestine, into the closure was a concern.⁵⁰ A single OTSC device resulted in an excellent, full-thickness closure of colon perforations up to 25 mm; although adequate closure of up to 30 mm perforations in the colon was possible, the burst pressures in such cases were lower than those achieved with smaller perforations.³⁴ The ability to endoscopically close perforations permitted endoscopic full-thickness resection of the colon to study of the myenteric plexus and neuromuscular transmission in the colon.⁵¹

Over-the-Scope Suturing Devices

Use of an endoscopic suturing machine (Eagle Claw, Apollo Endosurgery) for closure of a perforation can be technically challenging given the multistep process and the infrequency of its use by endoscopists, and need for specialized training.⁵²

Closure Technique

It is important for an endoscopist to master one or more perforation closure techniques using TTSCs, OTSCs, and endoscopic suturing devices (Figure 24-2). OTSCs and the suturing device require removal of the endoscope from the perforation site to load the device on to the end of the endoscope, reinsert the endoscope, followed by closure of the perforation. In contrast, TTSC can be utilized immediately after recognition of the perforation to close the defect. OTSCs and the suturing device can close larger defects compared to through-the-scope devices. Unlike the surgical parallel of suture closure of perforations, endoscopic closure with TTSCs and OTSC devices results in inverted closure. In contrast, T-tag suturing results in everted type of closure.

Clips tend to retract during closure and one should compensate for this shortening of the clip by either gently pushing the clip or the endoscope as the clip is slowly being closed to allow a deep approximation of the wall defect. If this maneuver of compensating for the clips closure is not performed, it results in a superficial closure of the defect, which is not ideal closure (Figures 24-3 and 24-4).

Before closure, it is a good idea to vent the colon by removing the biopsy valve to allow air to escape from the lumen; this allows the clip to approximate one edge of the perforation to the other as the colon is not tense and distended. If only a superficial clip closure can be achieved, consider deep approximation immediately next to the superficially placed clip.

These techniques involve use of a device in addition to the TTSC to facilitate closure of larger perforations (Figure 24-5). A dual-channel therapeutic endoscope is usually needed.⁵³

• Hold-and-Drag Closure Technique Using Repositionable Clips: By grasping and dragging the anal edge to the oral side with a clip, both edges can approach each other. The defect is finally closed by reopening and placing the clip.
  
• Closure Technique With Small Mucosal Incisions: The defect is closed with hemoclips by hooking the small incisions and dragging the mucosal layer from one side to the other.
  
• Endoloop + Through-the-Scope Clips (King Closure): An Endoloop is delivered through one channel of the endoscope. TTSCs are used to clip the Endoloop to the defect circumferentially, followed by tightening of the endoloop to close the defect.^54,55
  
• Eight-Ring in Combination With Hemoclips: After placement of the first clip with 8-ring, the second clip hooking the 8-ring is placed on the contra edge.
  
• Clip Assisted by Foreign-Body Forceps: A large foreign-body forceps is passed through one channel of the therapeutic scope and the edges of the defect are approximated followed by use of a TTSC through the other channel to close the defect.
  
• String Clip Suturing Method: The mucosal edges are approximated by pulling the string, which is anchored to both edges with hemoclips.
  
• Omental Patch Closure Method: The omentum is visualized through the perforation site and then suctioned into the gastric lumen before being grasped by the endoclips and securing it to the gastric mucosa thus creating an omental patch.
  
• Closure Technique—Over-the-Scope Clip Device: The OTSC system (Ovesco Endoscopy AG) is a superelastic, nitinol clip that is biocompatible and is magnetic resonance imaging conditional. It is mounted on a clear distal cap at the end of an endoscope and is deployed by turning a wheel on the shaft of the endoscope, similar to the mechanism used for band ligation. The OTSC creates full-thickness closure by using teeth arranged in the shape of a bear trap. Although the technique of OTSC application is simple and straightforward, it is important to follow the steps carefully to close a perforation: Align the lesion at a 6 to 12 o’clock position, if possible (Figure 24-6).
  
  
  
  • Grasp all layers of the GI wall, including the serosa, with the Twin Grasper (Ovesco Endoscopy AG) positioned in the center of each perforation edge.
    
  • Withdraw the grasper with the tissue into the center of the distal cap to ensure the entire perforation site is within the clips’ reach. Caution: Avoid capturing the Twin Grasper with the clip.
    
  • Suction to pull a sufficient amount of tissue surrounding the lesion into the cap.³⁴
  
  

  For small defects that can be aligned head-on with the endoscope, the defect can be suctioned into the cap of the OTSC followed by deployment of the OTSC.⁵⁶ For larger defects or in case OTSC deployment is misaligned leaving partial defect a second OTSC can be deployed adjacent to the first one to complete defect closure.⁵⁷

  
  
• Closure Technique—OverStitch Endoscopic Suturing Device: The OverStitch suturing device (Apollo Endosurgery) can provide tissue approximation of large defects. The device is loaded on a double-channel therapeutic endoscope and incorporates a curved suturing needle that can be reloaded multiple times without scope withdrawal.⁵⁸ Suturing is started at the furthest edge with placement of either continuous or interrupted sutures. One or 2 sets of sutures can be applied depending on the size and accessibility of the defect. After completion of each set of sutures, the anchor at the end of the suture is dropped, and the suture is tightened to approximate the defect followed by cinching.

Overall, the incidence of perforations after ESD of the esophagus, stomach, and colon is dependent on the expertise of each center and its volume of cases. In a review of 7 articles that were based on data derived from nationwide large-scale databases from Japan, the complication rates (including perforation, peritonitis, and bleeding) were 3.5% for gastric ESD, 3.3% for esophageal ESD, and 4.6% for colorectal ESD; there was a linear association between a higher hospital volume and a lower frequency of complications following ESD.59

Endoscopic mucosal resection (EMR) and ESD perforations could be prevented by paying attention to several procedural details as outlined below.

Prevention of Perforation

A number of precautions could be utilized to minimize the risk of perforation and peritoneal contamination.

• Preparation: A clean, dry area of operation is critical for endoluminal resection. The outcome of colon perforation is better in patients who undergo colon EMR or ESD in the setting of a clean preparation. Dirty colon preparation may lead to escape of colon contents and precipitate fecal peritonitis that may require a colostomy instead of simple closure.60
  
• Sedation: General anesthesia with endotracheal intubation offers a stable operating field and prevents aspiration. Mediastinal emphysema may develop without perforation during esophageal ESD involving deeper submucosal layers due to lack of a serosal layer and a lower intramediastinal pressure compared to the esophageal lumen. Endotracheal intubation and general anesthesia increase intrathoracic pressure and prevent mediastinal emphysema, especially for prolonged ESD cases. The senior author prefers to use general anesthesia during colon EMR to minimize the movement of the operating field; this allows controlled cut as well as the ability to control bleeding or close a perforation efficiently.
  
• Carbon dioxide (CO₂) use: CO₂ insufflation is preferred since it is associated with lower rates of pneumomediastinum and lower C-reactive protein levels after esophageal ESD.⁶¹ Routine use of CO₂ instead of air for colonoscopy reduces the risk of procedure-related pain as well minimizing the risk of tension pneumoperitoneum if a perforation were to occur.
  
• Use of a cap or special hood at the distal end of the colonoscope: Use of a distal attachment to the endoscope facilitates EMR and ESD as well as in-clip closure of defects. The hood helps to retract tissue for dissection during ESD. In addition, the hood is also useful in deflecting previously placed clips to better approach the site for clip application.
  
• Positioning the lesion: Keep the lesion in the nondependent position by repositioning the patient if necessary so that fluid pools away from the lesion; this will prevent escape of fluid if a perforation were to occur and also facilitates easy identification of a bleeding vessel if hemorrhage were to occur. Keep the field dry by suctioning fluid before and during resection.
  
• Submucosal injection: Either normal saline, a colloid, or high-viscosity agents (hyaluronic acid or glycerol) can be used. The submucosal injection cushion reduces the risk of snare entrapment of the muscularis propria and prevents deep thermal injury and perforation. Use of a contrast dye (indigo carmine or methylene blue) within the injectate binds avidly to the submucosal tissue but does not stain the muscularis propria, thereby allowing any exposed muscle to be easily seen as white on a blue background; this helps identify the depth of injury. A colloid plasma volume expander, succinylated gelatin (Gelofusine; Braun) was found to be superior to saline with regard to reducing the number of injections, resections, and overall EMR procedure time.⁶² Injection of hypertonic solutions (glycerol25 and MucoUp, Johnson and Johnson), which produce longer-lasting and higher submucosal elevation cushions, are necessary to minimize the risk of perforation during ESD.^63–65
  
• Electrosurgical generator: Microprocessor-controlled electrosurgical generators deliver short pulsed, high-frequency cutting with more prolonged coagulation current. In addition, these generators sense tissue impedance and adjust power accordingly to avoid deep tissue injury (VIO300D, Erbe; ESG100; Olympus).⁶⁶
  
• Snare selection: Snares with thinner wires (< 0.4 mm monofilament snares) allow swifter tissue transection and thereby limit unintentional thermal injury to the colonic wall compared with polyfilament wire.
  
• Snare resection technique: Adequate submucosal lifting is crucial to separate the lesion from the muscularis propria to prevent entrapment of muscle or cautery damage to the muscle during EMR. It is important to avoid entrapment of the muscularis propria during resection. This can be confirmed by free mobility of the ensnared tissue relative to the colonic wall, ability to close the snare fully with a distance of < 1 cm between thumb and fingers, and a quick cut (usually 1 to 3 pulses). Whenever the muscularis propria is entrapped in the snare, the mobility sign can be absent and in such cases, the snare can be loosened slightly, along with tenting it up to let the muscle layer fall out of the snare. Excessive cautery close to the muscle should be avoided as this predisposes to delayed perforation.
  
• Knife selections: A number of knives are available for ESD and one should be familiar with a few different knife types to perform ESD and minimize the risk of perforation. Use of a bipolar knife prevents electric current from passing to the muscle layer and limits damage to the muscle.

Although earlier studies reported a higher perforation risk with ESD, 2 recent meta-analyses showed similar perforation rates with EMR and ESD.67–69 In a recent meta-analysis of 8 studies reporting on 676 patients who underwent complete EMR of Barrett’s esophagus, perforation occurred in 2.3% of patients.⁷⁰ Isomoto et al reported a perforation rate of 0% to 10% in a review of 10 studies of ESD for management of esophageal neoplasms in more than 800 patients.⁷¹

Recently, the European Society of Gastrointestinal Endoscopy classified esophageal perforations into immediate or delayed perforations.⁷² The former could be closed with endoluminal clips, while the latter requires surgery. Extensive dissection of more than 75% of the luminal circumference is a risk factor for perforation. Perforation of the esophagus tends to occur on the left lateral wall of the esophagus.⁷³

Given its location in the mediastinum and proximity to vital structures, esophageal perforation can be associated with a high mortality rate. Intra-abdominal perforations were associated with a higher mortality rate than a thoracic or cervical esophageal location. In a pooled analysis of 75 studies, mortality rate was 11.9% with a mean hospital stay of 33 days.⁷⁴ The mortality was lower after prompt treatment within 24 hours of the event compared to those who were treated later (7.4% vs 20.3%).⁷⁴ Older patients with greater comorbidity may opt for EMR or ESD of esophageal lesions rather than take the risk of a thoracic surgical intervention. However, when esophageal perforation occurs, mortality can be significantly higher in patients over age 80 compared with younger patients (39.4% vs 13%, P = .001).75

Endoscopists must be trained to recognize and manage a perforation during ESD or after EMR as they are visible in the majority of the cases.⁷⁶ Conditions that favor successful endoscopic management of iatrogenic esophageal perforation include recognition and treatment within 24 hours, smaller defect (< 1 cm for TTSC and < 2 cm for OTSC), limited passage of esophageal contents into the mediastinum, and a patient with few comorbidities who is clinically stable postprocedure and is managed by an experienced endoscopist.⁷² Surgery instead of endoscopic closure should be considered in patients who are clinically unstable postprocedure, in whom perforation is detected later than 24 hours, and in whom fluid collections are seen in the mediastinum on imaging.

Closure of acute esophageal perforations may be achieved with TTSCs or OTSCs.^{72,73,77–81} TTSCs are effective to close smaller perforations (< 25 mm), while larger perforations may require OTSC. Of note, esophageal perforation caused by introduction of the endoscope fitted with the OTSC cap to treat a duodenal perforation has been reported.^73,79 This emphasizes the need for extra caution when introducing the OTSC device loaded on the end of the endoscope. This device should be used only by those with experience in introducing and deploying it.

The fully covered esophageal stent is an option for mid-esophageal perforations, especially in patients with larger esophageal perforations in which endoclips can be difficult to deploy. Stenting allows for diversion of esophageal contents and seals the perforation. Fully covered stents are easier to remove compared to partially covered stents after sealing the leak. Van Boeckel and colleagues⁸⁰ performed a systematic review of 25 studies with 267 spontaneous and iatrogenic esophageal perforations treated with esophageal stenting. Sixty-six patients had esophageal rupture/leak postendoscopy (which included esophageal dilation and EMR). The size of the leak was reported between 10 and 30 mm and ranged between 20% and 100% of the esophageal circumference. Of note, more than one-half of the patients had concurrent drainage of extraesophageal fluid. Technical success was 99% and clinical success was 85%, without a difference among the stent types. Stent migration was more common with fully covered metal stents and plastic stents (26% vs 13%, P < .001).⁸⁰

Gastric Perforations

EMR and ESD are used to resect early gastric cancers that by definition have a negligible risk of lymph node metastasis as well as gastric carcinoids in the setting of chronic atrophic gastritis.⁸² EMR has also been used to resect premalignant lesions such as gastric adenomas with low-grade dysplasia (under 2 cm) with some success.^82,83 Other benign gastric lesions including lipomas, granular cell tumors, and hyperplastic/inflammatory polyps have been also resected using EMR/ESD.^84–86

Iatrogenic gastric perforations can occur with EMR and ESD.⁷² In recent meta-analyses gastric perforation was higher for ESD compared with EMR.^87,88 Some studies have shown higher rates of perforation for lesions in the proximal gastric body while others have shown no difference.^78,89,90 It is encouraging to note that no evidence of peritoneal dissemination and/or lymph node metastasis caused by gastric perforation has been reported.⁹¹

Through-the-Scope Clips

Defects less than 10 mm can usually be addressed with TTSCs. Advancing the TTSC through-the-scope can be challenging, especially if the defect is in the proximal gastric body, requiring a retroflexed view. Often multiple TTSCs must be deployed to adequately seal the defect.

Initial case reports of successful clip closure of gastric perforations after resection of polyps led to its adoption by others.^1,92,93 In a large series from Japan of 789 gastric EMRs/ESDs over a 4-year period, 7 gastric perforations were encountered (0.9% perforation rate) and all were successfully closed with TTSCs. One patient underwent EMR with an insulated knife (ie, ESD) and produced the largest defect of 25 mm, which required 8 TTSCs for closure using the omental patch method. The greatest number of TTSCs used was 11 for a 10 mm defect caused by EMR with cap-fitted mucosectomy.94

Minami et al⁸⁹ described their experience of 2460 patients who underwent resection of early gastric cancer with 121 perforations (overall 5% perforation rate, similar for EMR and ESD). Early in their center’s experience, 4 patients underwent surgical management. Subsequently, 117 patients were treated with TTSCs with a 98% success rate. Smaller defects were closed with TTSCs, and larger defects were closed using the omental patch method described earlier. Two patients required surgical intervention for severe bleeding, etc.^89,94

In an ESD series from Fujishiro and colleagues⁷⁸, 14 of the 27 perforations occurred in the stomach. Eleven of these perforations were detected during the resection and were closed immediately using TTSCs. In 3 of the patients, free air was noted on postprocedure imaging studies and they were managed conservatively. Repeat endoscopy was performed but no further intervention performed.⁷⁸

Over-the-Scope Clips

While OTSCs have been used as a tool to perform full-thickness resection in the GI tract including the stomach, they are used more often to close fistulae and leaks and treat bleeding rather than defects due to perforation after EMR/ESD.⁹⁵ In 1 series that included 2 patients with perforation after gastric ESD, they were treated successfully with 2 OTSCs each. The defects were 25 mm and 40 mm (delayed perforation was larger than the immediate).⁹⁶ In another series evaluating 7 perforations in the upper GI tract, one of which was after ESD, the patients were successfully treated with an OTSC.⁹⁷ At this time, OTSC is not widely used to close perforation defects due to EMR or ESD. Because the lesions resected by EMR are smaller, as are the perforation defects usually, these are amenable to TTSCs. For ESD, while the target lesions are larger and the size of the perforation can be as well, often the defect is closed with TTSCs and the resection completed. Placement of a larger OTSC can impede completion of the procedure.

Small-Bowel Perforations

Endoscopic resection of nonampullary superficial duodenal tumors can be technically challenging because of the thin muscle layer of duodenal wall, reduced maneuverability of the endoscope due to limited luminal space, curved shape of the duodenum, and abundant blood vessels in the submucosal layer.

There are limited studies on EMR and ESD of nonampullary superficial duodenal tumors. Immediate perforations are usually small and if recognized can be closed with TTSCs. Few initial studies from Japan have shown the use of TTSCs to close post-EMR/ESD defects to be helpful. A large retrospective, multicenter study of 421 duodenal EMR and ESD cases showed higher perforation rates with ESD without a difference in the overall perforation rate between lesions located in the first or second portion of the duodenum. Delayed perforation was mostly observed in the distal duodenum. Prophylactic placement of TTSCs has shown to decrease the risk for post-EMR/ESD bleeding but evidence in preventing delayed perforation is debatable.⁹⁸ Lesions located in the posterior wall of the distal duodenum are more difficult to close than those located in the bulb of the duodenum because of poor maneuverability. Delayed perforation of 3.2% (2/63) due to the dislodgement of clips was reported in a retrospective cohort study.⁹⁹

Use of OTSCs to close post-ESD defects/ulcers was shown to be efficacious in preventing delayed perforation in 2 cases.¹⁰⁰ A study by Mori et al¹⁰¹ compared the efficacy of postendoscopic duodenal resection defects using TTSCs and OTSCs. OTSCs were effective in closing larger defects and there was a significantly decreased risk of bleeding. There were no delayed perforations in either group.101 The OTSC group had higher costs. The principles of duodenal defect closure using OTSCs in iatrogenic duodenal perforations can be applied to closure of most polypectomy-related perforations.⁵⁷

Related posts:

Introduction and History of Endoscopic Resection Techniques Endoscopic Resection Outcomes and Postresection Surveillance of Barrett-Associated Neoplasia Electrosurgical Equipment and Principles of Electrosurgery Endoscopic Resection Outcomes and Postresection Surveillance in the Colon Prevention and Management of Postendoscopic Resection Luminal Strictures Endoscopic Submucosal Dissection Technique to Conquer Difficult Cases

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