Endoscopic management for gastrointestinal leaks, perforations, and fistulae: Technical tips and outcomes

Abstract

Gastrointestinal (GI) tract defects can be classified into three distinct entities: Leak, perforation, and fistula. Each arises from different mechanisms and is managed accordingly. Leaks occur most often after surgery, while perforations arise due to flexible endoscopic maneuvers. Fistulae arise from a variety of mechanisms, including specific disease states. Endoscopic management is vital in treating such defects if the region of interest can be accessed with the appropriate endoscopic accessories. The primary goal of endoscopic therapy is to interrupt the flow of luminal contents across a GI defect. Considering the proper endoscopic approach to luminal closure, several basic principles must be considered. Outcomes are dependent on the size and exact location of the leak/fistula, as well as the viability of the surrounding tissue. Almost all complex leaks and fistulae must be approached in a multidisciplinary manner, collaborating with colleagues in nutrition, radiology, and surgery. With advances in technology, a myriad of devices and accessories are available that allow a tailored approach. In this review, we discuss these modalities, provide technical tips, and review published outcomes data regarding each approach, as well as practical considerations for the successful closure of these defects.

Key Words: Leak; Clip; Metal stent; Endoscopy; Surgery; Iatrogenic

Core Tip: This review comprehensively explores the endoscopic modalities for managing gastrointestinal (GI) tract defects like anastomotic leaks, perforations, and fistulae. The main highlights of this review are various endoscopic modalities like endoscopic clipping, endoscopic stenting, endoscopic suturing, endoscopic vacuum therapy, tissue sealants, endoscopic internal drainage, and novel device-assisted closure methods for management of these defects. We specifically emphasize application techniques and tricks of various endoscopic devices and their clinical outcomes in patients with GI tract defects.

INTRODUCTION

Gastrointestinal (GI) tract leaks, perforation, and fistulae are complex and serious events that can be life-threatening if not identified and intervened in a timely manner. GI leaks are the most common cause of surgery-related mortality (up to 60% if the diagnosis is delayed), and the incidence is increasing due to the complexity of surgeries performed[1,2]. GI leaks are defined as the pathological disruption of GI tract integrity, resulting in the escape of intraluminal contents to extraluminal compartments, and are usually related to anastomotic defects after complex GI surgeries. The prevalence of GI leaks varies with the type of surgery performed, with the highest prevalence reported after complex oncological surgeries, such as post-esophagectomy (prevalence of GI leaks: 8%-26%), post-gastrectomy (3%-12%), and colorectal surgeries (11%)[3-6]. Some benign conditions can also cause GI leaks, including proctocolectomy with ileal pouch-anal anastomosis (up to 20%) and bariatric procedures such as sleeve gastrectomy (1%-2%) or post-Roux-en-Y gastric bypass (2%-8%)[7,8]. Fistulae are defined as abnormal communications between two epithelial surfaces; examples include gastro- or entero-cutaneous, esophago-tracheal or -bronchial, colo-vesicle or -vaginal, and entero- or colo-enteric fistulae. They may arise from diseases such as Crohn’s disease, intestinal tuberculosis, or malignancy, or develop as a chronic consequence of long-standing leaks associated with extraluminal fluid collections or abscesses. Fistulae are typically chronic; when a leak persists, it can evolve into a fistula. In contrast, GI perforations are full-thickness breaches of the GI wall that may be spontaneous (as in Boerhaave’s syndrome), iatrogenic (e.g., post-endoscopic), or disease-related (e.g., perforated ulcer)[2]. They generally present acutely and often require emergent intervention.

The clinical presentation varies by condition: Leaks and perforations typically present acutely, whereas fistulae often follow a more chronic course. Symptoms depend on the location and size of the GI defect as well as the degree of contamination[9]. A high index of suspicion is essential for early identification and timely intervention to prevent sepsis and subsequent organ dysfunction caused by spillage of intraluminal contents. When a leak or perforation is suspected, prompt initiation of IV antibiotics and bowel rest is recommended[10]. A computed tomography (CT) scan with oral or rectal contrast, selected based on the suspected site of the leak, is recommended to identify the leak and evaluate any associated collections[10]. Enteral nutrition, even for a few days, is recommended to promote healing at the leak site and to maintain adequate nutritional status. It also facilitates faster recovery and helps prevent septic complications by reducing bacterial translocation[11]. The primary goals of intervention are to ensure adequate drainage of any collection and to restore GI tract continuity, thereby minimizing further spillage. Historically, surgical revision was the standard approach; however, it was associated with significant morbidity and mortality[12,13]. Advances in endoscopic closure techniques to restore bowel integrity have revolutionized the treatment of GI leak, perforation and fistulae and resulted in a paradigm shift from surgical to endoscopic management for a majority of these complications[14]. The treatment strategy depends on several factors, including the size and location of the defect, the degree of contamination, the presence of healthy surrounding tissue, the patient’s general condition, and the availability of expertise[15]. The fundamental principle in managing these defects is to create a barrier that prevents the flow of luminal contents across the defect. Advances in endoscopic technology have greatly expanded therapeutic options, allowing closure of GI defects using devices such as endoclips, metallic stents and endoscopic suturing devices. Additional modalities, including tissue sealants and endoscopic vacuum therapy (EVT), further enhance the ability to manage these complex cases through minimally invasive means[15,16]. Surgical intervention is generally reserved for cases involving large defects with gross contamination, such as peritonitis or overt sepsis. In this review, we discuss the various endoscopic modalities available for managing GI leaks, perforation, and fistulae, with a particular focus on technical considerations and outcomes associated with each approach.

IDENTIFICATION OF GI LEAKS AND FISTULAE

Certain risk factors can predispose to tissue hypoperfusion and ischemia, thereby increasing the risk of subsequent post-operative anastomotic leaks (AL). These risk factors can be broadly categorized as local or systemic. Arterial/venous insufficiency, tension, and torsion on the conduit tissue, gastric distension, infection, and extrinsic compression are important local factors. Systemic factors like malnutrition, hypoproteinemia, hypotension, and hypoxia increase the risk of post-operative leaks. Identification and correction of these factors pre- or intra-operatively is important for minimizing the risk of post-operative leaks[3].

Early identification of post-operative leaks, perforation, and fistulae is important for achieving favorable outcomes. Routine water-soluble contrast studies, such as a Conray or contrast follow-through study performed on postoperative days 4-5, can detect small asymptomatic leaks. However, these studies may yield false-negative results in up to one-third of patients, particularly following bariatric surgery[2,5,7]. Intraoperative drain placement is another diagnostic approach, allowing early detection through the appearance of enteric contents in the drain output, though the optimal duration of drain placement remains controversial. When drains are used, administration of oral methylene blue with subsequent observation of the drain output can further aid in leak detection[5,7].

Clinical features and vital signs can be suggestive of GI leaks and should not be overlooked. Fever, chest pain, or abdominal pain, tachycardia, tachypnea, hypotension, presence of subcutaneous emphysema, abdominal guarding, and rigidity in the post-operative period generally suggest a perforated viscus. Laboratory findings such as persistent or worsening leukocytosis and elevated C-reactive protein levels can support the diagnosis of a perforated viscus, particularly when no other sources of infections, such as urinary tract infection or pneumonia, are identified. In contrast to non-obese individuals, the classical clinal signs of viscus perforation are often unreliable in obese patients who have undergone bariatric surgery. Diagnosis in this group is further complicated by the limitations of imaging modalities, as upper GI contrast studies and abdominal ultrasound may yield false-negative results due to body size and morphology. The presence of persistent systemic inflammatory response syndrome and abdominal pain warrants cross-sectional imaging to confirm the diagnosis[7]. If the patient is stable, endoscopic examination should be performed to assess the size of the defect, facilitate placement of a nasoenteric feeding tube, and determine the feasibility of endoscopic closure. Together, a combination of clinical suspicion, vital signs, laboratory, endoscopic, and radiological evidence is required to identify GI tract defects.

ENDOTHERAPY FOR GI LEAKS, PERFORATION AND FISTULAE

Endoclips

Endoclips are the most commonly used endoscopic modality for the closure of GI defects like perforation and fistulae. Endoscopic clips were first used for the closure of an upper GI perforation following snare excision of a gastric leiomyoma in 1993, and the first reported closure of an iatrogenic colonic perforation was performed by Yoshikane et al[17] in 1997. Since then, the indications for the use of endoscopic clips have expanded to include both intentional and unintentional iatrogenic mucosal or muscular breaches, leaks, and fistulae. Endoscopic clips are broadly categorized into through-the-scope clips (TTSCs) and over-the-scope clips (OTSCs), each with unique applications and advantages.

TTSCs

TTSCs are deployed through the working channel of a standard therapeutic endoscope and positioned to securely grasp both edges of the defect. These are small, metallic, spring-loaded clips that are typically suitable for defects < 20 mm in size, particularly those with healthy, non-everted and regular edges. Common indications include biopsy-related perforations, post-polypectomy perforations, and minor AL or staple-line disruptions. TTSCs have certain advantages, like being easy to deploy, rapid closure of small defects, wide availability, cost-effectiveness, and allowing multiple clips to be deployed sequentially. The clips can be applied directly without the need for withdrawal and reinsertion of the endoscope. There are various designs and makes of TTSCs available, each with its properties and features. A synopsis of the various commercially available clips is outlined in Table 1. While the EZ Clip^TM (Olympus Medical, Tokyo, Japan) has a reloadable clip system with a separate applicator handle, most other available clips have preloaded single-clip applicator devices. The newer generation of endoclips allows options of rotatability and re-opening of jaws for better approximation of the defect margins. Wang et al[18] compared five commercially available clips in vitro, for their rotatability in difficult scope positions, precision, tensile strength of lateral tissue manipulation, and tissue compression forces. They found that while lateral tissue manipulation was best with QuickClip Pro^TM (Olympus Medical, Tokyo, Japan), closure strength was better with Resolution 360^TM (Boston Scientific, United States) and Instinct Clip (Cook Medical, Indiana, United States)[18]. A newer clip, with TruGrip^TM anchor prongs, named Mantis^TM (Boston Scientific, United States), is now commercially available and can be used to anchor one side of the defect, mobilize, and oppose the two margins. Defects up to 3 cm can be closed with this clip (Figure 1).

Figure 1 Closure of gastric endoscopic submucosal dissection defect using mantis clips. A: Image of mantis clip showing anchor prongs; B: Mantis clip anchored to one edge of the distal part of a large post-endoscopic submucosal dissection gastric defect; C: The margin is pulled by clip for apposition and applied to the opposite margin; D: Second clip being anchored to defect margin; E: Margin mobilized and clip being applied to oppose the two margins; F: Multiple clips applied to completely close the defect.

Table 1 Characteristics of available through the scope clips.

Clip	Manufacturer	Opening diameter (mm)	Jaw length (mm)	Stem length (mm)	Material	Rotation
Resolution 360	Boston Scientific; United States	11 and 17	9	7	Stainless steel, Cobalt	360°
Instinct1	Cook Medical; United States	11 and 16	9	6	Stainless steel, Nitinol	Scope position dependent
Quick clip pro1,2	Olympus Medical; Japan	11	10	5	Elgiloy	Scope position dependent
Dura clip	ConMed; United States	11 and 16	7	3	Stainless steel	360°
Sure clip	Micro-Tech Endoscopy; United States	8, 11 and 16	11	3	Stainless steel	360°
Medorah	Medorah Meditek; India	11, 13 and 16	9	3	Stainless steel	360°

¹Highest compression strength.

²Highest lateral tissue manipulation strength.

Key tips for applying TTSCs include:

Optimal visualization of the defect with debris and clot clearing; scope positioning so that the clip is perpendicular to the defect line; for longitudinal defects, closure should be from distal to proximal (Zipper technique), while transverse defects should be closed from left to right; application of suction to oppose the walls before application. However, TTSCs have several limitations, including a limited clip arm width and grasping force. As a result, achieving adequate approximation in large or chronic defects with inflamed or necrotic edges can be difficult. They are also not suitable for full-thickness defects or extensive fibrotic areas. Moreover, TTSCs are designed to spontaneously detach within 2-4 weeks, which may predispose to recurrence, particularly long-standing leaks or fistulae. OTSCs can address some of these limitations. Although clip application is a safe procedure, it can rarely lead to embedded clips in tissues/plaques, perforation, and infection. Additionally, removal of maldeployed or misaligned clips can cause further damage and widening of the leak/perforations. However, most of these adverse events can be easily managed using similar or alternate endoscopic techniques. Surgery is rarely required (mainly for perforations)[19].

Modified techniques using TTSCs: Perforations secondary to endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are typically large (> 30 mm). In such cases, approximating the defect margins with standard TTSCs is challenging because of their limited arm width and grasping force, which restrict effective closure of defects > 20 mm. Similarly, the application of OTSCs can be difficult for defects larger than 30 mm. To address these challenges, several innovative techniques have been developed in which TTSCs are combined with adjunctive devices such as loops, threads, rubber bands, or surgical sutures to achieve secure closure of large defects. These other devices act as a vital bridge to approximate the two farthest points of defect edges together and serve as an anchor in the modified clip-closure techniques. There are various methods of modified clip-closure, but the most commonly used are the loop-clip technique and the clip-line techniques[20]. The loop-clip device was first designed in 2008, consisting of a nylon-string loop pre-attached with a clip[21]. The “clip-loop” is fixed on one farthest point on one defect side, and another TTSC is hooked and pulls the loop towards the other side to approximate the defect. Several modifications have been applied to this technique, like clip-band closure and King closure. In the King-closure technique, a detachable loop is first fixed to one edge of the defect using a clip. Subsequently, the loop is garlanded around the defect margins with the help of other clips. Finally, the defect is closed by tightening the loop in a purse-string manner (Figure 2)[22]. In the clip-line technique, a clip connected with a line is fixed at one defect margin, and another clip is hooked to the line and fixed to another margin of the defect. The defect edges are approximated by pooling and tightening of the line[23]. The details of the techniques of clip-loop and clip-line methods are summarized in Table 2[21,22,24-28]. The limitations of these techniques include: (1) technical complexity; (2) limited applicability in anatomically challenging or difficult scope positions; and (3) reduced success in managing chronic defects like fistulae.

Figure 2 Closure of post-endoscopic submucosal dissection perforation of a duodenal neuroendocrine tumor using endoscopic clip-and-loop technique (King’s closure). A: Clip applied to fix the loop along the defect margin; B: Multiple clips being applied; C: Clips along the defect margin holding the loop; D: Final clip applied at the proximal defect margin; E: Loop applicator being applied to the loop end for closure; F: Loop applied with defect closure.

Table 2 Techniques of the clip and line/Loop strategy for closure.

Technique	Auxiliary instruments	Procedure details	Pros	Cons
Loop-clip closure	Loop–clip: Consists of a loop of nylon string attached to a metallic clip	Loop-clip device is fixed to the edge of the defect at the mid of distal side. Then, another TTSC is passed to hook and pull the loop to fix on the proximal defect margin. Afterwards, the complete closure is achieved by the use of regular TTSC	Suitable for large defects. Applicable for all GI segments. No need for a double-channel scope. No need for scope withdrawal and reinsertion	Need for a special device
Clip-band closure	Clip-band device: 3 interconnected elastic silicon bands (two 3.3 mm rings and one 15 mm ring) preloaded on the clip	The clip-band device is fixed to the edge of the defect at the distal side. Then, another TTSC is passed to hook and pull the band to fix on the proximal defect margin. Afterwards, the same clip-band sequence or standard TTSC can be applied to achieve complete closure
Endoscopic sliding closure	Ring-shaped surgical thread (8, 10 and 12 mm diameter)	The ring thread is clipped at two points across the maximum diameter of the defect margins. A third clip then grasps one side of the ring thread and then draws across the opposite end to bring the clips and defect margins closure. The process can be repeated at 2-3 sites, depending on size. Subsequently, complete closure can be achieved by the standard TTSC
Clip-line closure	Long nylon line tied on the arm of the endoclip	Endoclip (with attached nylon line on one arm) is fixed to healthy mucosa 5 mm from the defect margin on one side. The other side of the defect margin, along with the line, is then anchored by another endoclip. Both the defect margins, along with clips, are approximated by gentle pulling of the line. Further, additional clips with/without lines are placed to achieve complete closure
Ring/king closure	Detachable endoloop	The apex of the detachable endoloop is fixed to one edge of the defect using an endoclip. With the help of multiple clips, the loop is garlanded to the defect margins. The loop is tightened to close the defect in a purse-string manner
ROLM	Muscle layer grasping clips, a reopenable clip, and nylon line	Reopenable clip with a nylon line fixed on it clips the normal mucosa and muscle layer of the distal side of the defect margin. The end of the line exiting through the accessory channel of the endoscope is passed through the hole in one tooth of the second reopenable clip. This second clip with the line (ROLM) is placed on the opposite side of the defect, and the muscle layer is being grasped by the tooth through which the line has been passed. Repeating ROLM gradually closes the defect from the distal to the proximal side	Suitable for thick-walled sections of GI tract defects like gastric and rectal defects (risk of dead space with conventional closure methods). Teeth of the reopenable clips through which nylon line passes are continuously fixed by the line, preventing the clips from being buried into the muscle layer side	Need for muscle layer grasping clips, reopenable clips, and a nylon line

GI: Gastrointestinal; OTSC: Over the scope clips; ROLM: Re-openable clip on the line method; TTSC: Through the scope clips.

OTSCs: OTSCs provide more durable and full-thickness closure. Kirschniak et al[29] reported the initial clinical experiences with these clips in 2007. OTSCs are mounted externally on the endoscope tip and deployed over the defect. There are currently two OTSCs systems available: (1) the OVESCO clip (GmbH, Tubingen, Germany); and (2) the Padlock clip (STERIS, Mentor, Ohio, United States). While the two clips have distinct designs and loading methods, the basic principle is similar. Both have an applicator cap with a preloaded nitinol clip (size, 8.5 mm to 14 mm) to be attached to the outside of an endoscope and an external device for clip deployment. In the OVESCO system, the clip is deployed akin to the variceal band ligation system with the thread passing through the working channel of the scope, while in the Padlock system, the linking cable runs alongside the endoscope and is deployed by push of a thumb actuation. A twin grasper can also be used to hold the defect margins together. Because of larger jaws and stronger closure force (8-9 newtons), OTSCs are suitable for larger defects (up to 20 mm gastric and 30 mm colonic defects) and chronic fistulae[29] (Figure s 3 and 4). The key steps to optimize closure include: Orientation of the endoscope and the clip perpendicular to the defect; devices such as twin grasper or OTSC anchor may be used to hold the margins and pull inside the cap; ensuring that the margins are covered by the applicator cap; suction applied while deploying the clip. In cases of chronic fistulae with well-epithelialized tract tissues, de-epithelialization of the fistulous tract is advisable to increase the probability of a reliable closure. This can be performed using argon plasma coagulation (APC), abrasion with a biliary cytology brush, modified ESD, or multiple EMRs surrounding the fistulous opening[30]. OTSC has certain limitations, like withdrawal of the scope for OTSC loading, more technically demanding and limited maneuverability in tight anatomical areas, difficulty negotiating across the upper esophageal sphincter, and deployment in retroflexion or acute scope angulation[31]. In case of clip failure, removal of the OTSC poses some challenges with a need for a specific removal device or use of high-powered APC.

Figure 3 Closure of post-endoscopic retrograde cholangiopancreatography duodenal perforation using over-the-scope-clip. A: A large duodenal perforation on the lateral wall at D1-D2 junction with surrounding friable mucosa with bleeding is visualized using a double channel therapeutic scope with an over-the-scope-clip (OTSC) mounted clip; B: One edge of the perforation grasped using the OTSC twin grasper; C: The grasped edge was taken to the opposite end and other edge grasped using the OTSC twin grasper; D: After grasping and approximating both perforation edges, the whole complex was pulled inside the cap; E: After ensuring adequate clip position to ensure optimum margins closure, suction was applied and the OVESCO clip (size 12/6t, OVESCO Endoscopy AG, Tuebingen, Germany) was deployed; F: Post-procedure abdominal X-ray shows the deployed OTSC clip (yellow solid arrow), a naso-jejunal tube (solid orange arrow), subcutaneous emphysema (white asterisk) and air outlining the right peri-nephric area and under surface of liver (dotted white arrow), signifying retroperitoneal duodenal perforation.

Figure 4 Closure of rectovaginal fistula using over-the-scope-clip. A: Double channel therapeutic scope with over-the-scope-clip (OTSC) mounted clip shows rectovaginal fistula; B: OTSC anchor opened inside the fistulous opening; C: Tissue pulled inside the cap with Anchor along with application of suction; D: Final deployed OVESCO clip (14/6t) leading to closure of rectovaginal fistula.

The OTSC application is a generally safe procedure but can sometimes lead to complications; these are broadly divided into OTSC insertion-related complications and deployment technique-related complications. There are reports of bowel perforations in the areas of relative narrowing and acute angles during OTSC insertion, as well as accidental release in the tongue. Mal-deployment of clips can lead to enlargement of perforation, migration of clips through the GI tract defect, and entrapment of the twin grasper within the OTSC clips. Rarely, inadvertent entrapment of surrounding structures, like ureteric entrapment and small bowel fixation during treatment of colonic fixation, can occur and require surgical correction[32].

Outcomes of endoclips: In a case series of 20 patients with AL after surgery for gastric cancer where endoclips were used for defect closure, Lee et al[13] reported technical and clinical success in 95% of patients with no mortality. Conversely, 15 patients who were managed surgically had high mortality (n = 5, 33%). A systematic review of 24 studies (21 retrospectives, 3 prospective, n = 466) including patients with acute GI perforations reported successful endoscopic closure of the defect in 89% patients. A similar success rate was reported for TTS clips (90.2%, n = 359) and OTSC (87.8%, n = 58)[14]. A prospective, multi-center study of 36 patients with acute endoscopy-related iatrogenic perforation showed successful endoscopic closure using OTSC in 89% of patients (n = 32) with a mean procedure time of 5 minutes 44 seconds[33]. Certain factors, such as the size of the lesion (> 20 mm), site (upper and mid esophagus), delayed intervention (> 72 hours), and tissue surrounding the defect (mucosal ischemia, severe inflammation, necrosis and fibrosis) are associated with poor outcomes of clipping for perforation closure[34]. Similarly, the efficacy of clip-based closure is lower in patients with chronic leaks and fistulae compared to those with acute perforations. A retrospective multicenter study of 188 patients with OTSC use for GI tract defects showed a long-term success rate of 60.2% and was higher when OTSC was used as primary therapy (primary 69.1% vs rescue 46.9%; P = 0.004). The rate of successful closure of fistulae (42.9%) was significantly lower than the successful closure of perforation [success rate 90%; odds ratio (OR): 51.4] and leaks (success rate 73.3%; OR: 8.36) (P < 0.05)[35]. Similar findings were reported in other studies[36,37]. A meta-analysis focusing on OTSC performance for GI fistulae reported durable clinical success in 69% (95%CI: 51.8%-82.2%) of the patients[38]. Another review of 1517 cases of OTSC for various indications reported a fairly good clinical success for refractory bleeding (n = 559, 85% success) and acute perforation (n = 351, 85% success) but limited success for GI fistulae (n = 388, 52% success) and anastomotic dehiscence (n = 97, 66% success)[39]. Factors associated with favorable outcomes for fistulae are size between 10-30 mm, application of OTSC within 1 week of diagnosis, and low level of fibrosis[39]. The key factors deterring success in OTSC include: (1) Necrosis/inflamed margins; (2) Mucosal ischemia; (3) Fibrosis of perforated region; (4) Very large perforations (> 3 cm); and (5) > 72 hours after perforations. Outcomes of endoscopic clip-closure in GI tract defects are summarized in Table 3[13,14,34-39].

Table 3 Outcomes of through the scope clips and over the scope clips in the management of gastrointestinal tract defects.

Ref.	Study design	Population characteristics	Outcomes in the clip cohort	Outcomes in control cohort	Additional information
Kirschniak et al[29], 2011	Retrospective	n = 50, GI Bleed: n = 27. Perforation: n = 11. Fistulae: n = 8. Pre-op marking: n = 4	Primary success: 100%. Recurrence of GI bleed: 2 (7.4%). Recurrence of fistulae: 5 (62.5%). No recurrence of perforation	NA	High recurrence of fistulae despite initial success
Hagel et al[34], 2012	Prospective	n = 17 (Iatrogenic perforations: n = 6. AL: n = 3. Complication of PEG: n = 5. Duodenal ulcer perforation: n = 3). Median age: 71 ± 7 years	Successful closure: 11 (64.7%)	NA	Six unsuccessful cases had larger perforation defects and had necrotic or soft inflammatory margins
Voermans et al[33], 2012	Prospective, multicenter	n = 36. Acute iatrogenic perforations. Location: Esophageal: n = 5. Gastric: n = 6. Duodenal: n = 12. Colonic: n = 13. M: 15; F: 21	Successful closure: 33 (92%). Clinical success: 32 (89%). Surgery: n = 4. Death: n = 1	NA	Death occurred in one patient with colonic perforation (even after surgery)
Lee et al[13], 2013	Retrospective	35 patients with AL after surgery for gastric cancer. M: n = 27, F: n = 8. Median age: 64 Y	n = 20. Technical clinical success: 19 (95%). Surgery due to failed endoscopic t/t: n = 1. Death: n = 0	n = 15. Death: n = 5. Cause of death: Sepsis, bleeding, HAP	Endoscopic modality: Hemoclips: n = 17. Detachable snare: n = 2. Additional fibrin glue: n = 14
Haito-Chavez et al[35], 2014	Multicenter, retrospective	n = 188. Fistulae: n = 108. Perforations: n = 48. AL: n = 32	Overall success: 60.2%. Success rate for perforations: 90%. Success rate for AL: 73.3%. Success rate for fistulae: 42.9%	NA	Success rate is significantly higher for acute defects (like perforations/AL) than for chronic defects (fistulae). Success rate is significantly higher if OTSC is applied for primary therapy (69.1%) than for rescue therapy (46.9%; P = 0.004)
Law et al[37], 2015	Retrospective	n = 47. Mean age: 57 ± 14. M: 24; F: 23. Fistula location: Esophagus: n = 3. Stomach: n = 16. Small bowel: n = 18. Colo-rectum: n = 10	Initial technical success: 42 (89%). Fistula recurrence: 25 (53%) at median f/u of 178 days	NA	Poor long-term outcomes of OTSC: Fistula recurrence around 50% despite OTSC retention
Verlaan et al[14], 2015	SRMA	24 studies; 21 retrospective, 3 prospective, no RCT. n = 466 Hemoclips: n = 398. OTSC: n = 66. Stents: n = 2	Successful outcome: 419 (89.9%). Success rate of hemoclips: 359 (90.2%). Success rate of OTSC: 58 (87.8%). Success rate of stents: 2 (100%)	NA	Limited by the low methodological quality of included studies
Kobara et al[39], 2019	SRMA	30 studies. n = 1517	Clinical success rate: For perforation: 85% (n = 351). For AL: 66% (n = 97). For fistulae: 52% (n = 388)	NA	Overall complications: 1.7% (n = 23). Severe complications: 0.59% (n = 9)

AL: Anastomotic leak; HAP: Hospital-acquired pneumonia; F: Female gender; F/u: Follow-up; M: Male gender; NA: Not available; OTSC: Over the scope clips; PEG: Percutaneous endoscopic gastrostomy; Pre-op: Pre-operative; RCT: Randomised control trial; SRMA: Systematic review and meta-analysis; t/t: Treatment.

Endoscopic stents

Stents has been traditionally used to relieve obstructions, such as palliative stenting for malignant lesions or short-term stenting for benign conditions. In cases of leaks and fistulae, fully covered stents can help cover the defect and prevent extra-luminal spillage of luminal contents. Endoscopic stenting enables early resumption of oral intake and early discharge from the hospital. Pre-procedure CT scan is needed to assess the extent of the defect and extraluminal collection, and if required, drainage of the collection should be considered before stent deployment. Before stenting, the points that need to be ensured are: (1) Precise localization of the defect and its size; (2) Marking of anatomical landmarks to anticipate proximal and distal landing zones; and (3) Choosing the appropriate length and diameter of the stent. A stent should be 4-6 cm longer than the lesion size to ensure the stent covers the defect with 2-3 cm margins on either end. After endoscopic assessment, a guidewire is placed under direct endoscopic vision, and the stent is deployed under the dual guidance of endoscopy and fluoroscopy for optimal accuracy.

Endoscopic stents, especially use of covered self-expandable metal stents (SEMS), are limited by stent migration, and it is a factor that contributes to poor fistula closure rates. There are different ways to prevent stent migration, like oversized stent placement, the use of anchoring devices like endoscopic clipping, and suturing at the proximal end, or the use of the newer Stentfix OTSC^® System (GmbH, Tubingen, Germany) (Figure 5). This Stentfix system has properties and deployment mechanisms similar to the standard Ovesco OTSC system, but with a specific fish-mouth applicator cap design to enable easy alignment to the stent mesh and the adjacent tissue. This has been shown to have good technical and clinical success in the prevention of stent migration. A systematic review and meta-analysis (SRMA) including nine studies showed pooled technical and clinical successes of OTSC fixation following SEMS were 0.98 (0.81-1.0) and 0.79 (0.64-0.88), respectively. The pooled risk ratio of stent migration following OTSC Stentfix was lower compared to no Stentfix [relative risk (RR): 0.24; 95%CI: 0.13-0.43][40]. A baseline two-way X-ray should be taken to ensure optimum stent placement.

Figure 5 Management of mega stent migration placed for an anastomotic dehiscence (leak) using a Stentfix over-the-scope-clip system. A and B: Under endoscopic and fluoroscopic guidance using a standard gastroscope with a mounted over-the-scope-clip (OTSC) cap and OTSC system, the edge of the previously placed mega stent was approached, which was targeted to be fixed; C and D: Suction was applied and clip was deployed, which anchored the stent and prevented further stent migration.

Endoscopic suturing is an effective modality for stent anchorage, with a success rate of > 90% for the prevention of stent migration. Fujii et al[41] reported their experience with Over Stitch suturing device in 18 cases, wherein stent migration 33% compared to previous reports of 74%, at median 21 days vs 19 days. Similarly, Sharaiha et al[42] reported multicenter data on 122 cases wherein clinical success was 91.4% after stent anchorage[42]. Other complications of esophageal SEMS include chest pain, fever, bleeding, gastroesophageal reflux disease, and esophago-airway fistula due to necrosis of the tumor, leading to herniation of the esophageal stent into the trachea/bronchus. Minor bleeding is common after esophageal stenting, but delayed massive bleeding can be due to stent erosion into major vessels and cardiac chambers. Herniation of the esophageal stent requires stent removal and placement of another fully covered esophageal stent. If the defect size is large, both tracheal and esophageal stents may be necessary[43].

Historically, there are three types of stents used for full-thickness GI tract defects: Biodegradable stents (BDS), self-expandable plastic stents (SEPS), and SEMS. BDS and SEPS are rarely used nowadays because of the limited availability and weaker radial force of the former and the very high migration rate (about 50%) of the latter[44-47]. SEMS are the most commonly used stents for the closure of GI tract defects and are typically made of Nitinol, although Elgiloy has also been used. The latter has more radial force and is resistant to corrosion, while the former is more flexible and suitable for sharp angles[48]. Only covered SEMS (biocompatible covering over the metallic framework) are used for sealing and diversion of benign conditions like leaks and fistulae. The other advantage of the biocompatible covering of SEMS is to prevent tissue ingrowth, thus facilitating subsequent removal, but at the disadvantage of enhanced risk of spontaneous migration (up to 30%)[49].

Because stents have an inherent tubular design, they are best suited for locations such as the esophagus, colon, and duodenum. Thus, they are commonly used in conditions such as Boerhaave’s syndrome, AL, perforations after stricture dilation, or foreign body impactions. Using such stents in gastric perforations can sometimes be complicated due to the high migration rate and poor sealing efficacy due to the capacious stomach. In these situations, mega stents can be beneficial, which are primarily used to bypass the leak and the stomach, and are used mostly for post-bariatric leaks. Esophageal mega stents (Niti-S^® Taewoong Medical, Gyeonggi-do, South Korea) have a special design with a soft and flexible body to fit into the laparoscopic sleeve gastrectomy (LSG) pouch and they were originally designed for post-LSG leaks. Mega stents are fully covered by a silicon coating for effective AL sealing and easy removal[50]. There is emerging evidence that mega stents are effective as primary therapy as well as rescue treatment after failed conventional methods for post-LSG and other AL (Figure 6)[51-53].

Figure 6 Management of esophageal-jejunal anastomotic leak using a mega stent in a case of post-operative Whipple procedure with total gastrectomy for periampullary carcinoma with contiguous stomach involvement. A: Endoscopic appearance of the anastomotic site, which shows the site of leak (white dotted arrow), efferent jejunal loop opening (yellow solid arrow), afferent jejunal loop opening (black solid arrow) and esophageal-jejunal anastomosis (white solid asterisk); B: Oral contrast study shows visible active leak at the site of anastomosis; C: Under fluoroscopic and endoscopic guidance, a steel guidewire was placed in the efferent limb of the jejunum and stent was loaded on the guidewire; D: A 24 mm × 23 cm mega stent (Niti-S fully covered self-expanding metal stent, Taewoong Medical, South Korea) was deployed in the efferent limb covering the anastomosis site and leak; E: Contrast study showing no leak and contrast flowing into the distal jejunum; F: Repeat endoscopy after 1 week, showing optimally placed stent into the distal jejunum, covering the leak site.

The other concern is malignant tracheoesophageal fistulae (TEF), which may complicate 5%-15% patients with esophageal malignancies. The presence of TEF suggests unresectability, and these patients usually have terminal stages of malignancy. The presentation may vary from incidental detection to mild coughing and overt sepsis due to aspiration pneumonia. The primary aims of treatment are to control sepsis with broad-spectrum antibiotics and to separate the esophagus from the respiratory tract to prevent further soilage and restoration of oral feeding. A pulmonary medicine consultation for bronchoscopy and tracheal/bronchial stenting is advised for fistulae or airway compromise before placement of an endoscopic stent. For malignant colo-gastric or colo-duodenal fistulae, surgical resection is preferred if the malignancy is resectable; otherwise, diversion can be considered. Endoscopic options are limited by the presence of unhealthy mucosa for clipping and limited availability of fully covered enteral/colonic SEMS. In inoperable cases of colo-gastric fistula, one can place Megastent (Taewoong Medical) coursing from the esophagus to the duodenum, bypassing the stomach as mentioned above. For colo-duodenal fistula, EUS-guided gastrojejunostomy and pyloric exclusion using suturing can be considered.

Outcomes of endoscopic stents for GI leaks, perforation and fistulae: A study of fully covered esophageal SEMS placement for gastroesophageal AL in 14 patients reported clinical success in 13 (92.8%) patients[54]. Another retrospective study included 88 patients with benign GI tract defects like bariatric and other AL, iatrogenic perforation and Boerhaave’s syndrome. Resolution of leaks and perforations occurred in 77.6% of patients, with spontaneous migration of the SEMS occurring in 11.1% of the patients[55]. The outcomes of SEMS for AL after colorectal cancer surgery are also promising. A prospective study of 22 patients showed successful closure of the defects in 19 (86%) patients, with placement of SEMS along with proximal diverting ileostomy[56]. Contrary to these results, a retrospective study of 35 patients with esophageal stent placement for benign esophageal conditions (strictures in 19 patients, leak/fistulae in 12, and perforation in 4 patients) showed only 44% success long-term. Additionally, there was a high rate of stent migration (n = 12, 34%)[49]. However, a pooled analysis of 20 retrospective studies where SEMS were used for benign esophageal leaks, perforation and fistulae reported promising outcomes. A total of 643 patients were included, and common indications were AL (n = 415, 64.5%), iatrogenic perforation (n = 126, 19.6%), Boerhaave’s syndrome (n = 50, 7.8%), and fistulae (n = 24, 3.7%). Successful defect closure was achieved in 81.4% of AL, 86% for iatrogenic perforation, and 64.7% for fistulae, and the pooled stent migration rate was 16.5%[57].

The clinical efficacy of the different types of covered stents, like FCSEMS, PCSEMS, and SEPS, was comparable. A study comparing short-term (5-6 weeks) placement of different types of covered stents for AL and perforations reported equal clinical efficacy (73% for PCSEMS and 83% for both FCSEMS and SEPS). The most common adverse events were stent migration in 19.2% of patients (FCSEMS/SEPS > PCSEMS) and tissue ingrowth in 15.4% of patients (PCSEMS)[58]. The efficacy of mega stent is also promising, especially in the management of post-LSG leaks. A retrospective study from Egypt, including 58 patients of bariatric surgery complications (50 Leaks, 8 obstruction/stenosis), showed that the primary use of a mega stent alone had successful outcomes in 72.4% patients. Of 16 patients with failed initial treatment, 14 could be successfully managed by another endoscopic method[51]. Another retrospective study, including 8 patients with post-LSG leaks, showed successful outcomes in 7 (87.5%) patients with a simultaneous OTSC and mega stent strategy[52]. Mega stents can also be used as a rescue therapy for AL after esophagectomy/gastrectomy. Brito et al[53] reported 2 cases of AL that were managed by esophageal mega stents as a rescue measure after failed closure using OTSC in one case and conventional esophageal SEMS in another case[53].

Endoscopic suturing

With the advent of endoscopic suturing, full-thickness defects can be closed akin to surgical closures using a flexible endoscope. This overcomes the defect size limitations of TTS or OTSC. While various suturing platforms have been developed over the years, the three commercially available suturing devices are: (1) OverStitch^TM Endoscopic Suturing system (initially marketed by Apollo Endosurgery, Texas and now by Boston Scientific, Massachusetts, United States); (2) Incisionless Operating Platform (POSE, USGI Medical, California); and (3) Endomina Plication system (Endo Tools Therapeutics, Belgium). Of these, the most commonly used suturing system applicable for the closure of GI defects is the OverStitch system[59]. Endoscopic suturing can be used for a wide variety of indications like GI leaks, perforation, fistulae, post-EMR and ESD defects, as well as anchorage of metallic stents to prevent migration[41,60-63].

However, the use of endoscopic suturing is limited by high equipment cost, the need for specific training and expertise, and double-channel therapeutic endoscope. Furthermore, the procedure can be technically demanding when endoluminal space is limited and the suturing site is tangential. Additionally, an adequate amount of healthy surrounding tissue is essential for successful closure, particularly in large defects. To overcome these aspects, a newer version of OverStitch NXT^TM (Boston Scientific, United States) will soon be available, which can be mounted on a single-channel gastroscope with retroflexion capabilities to tackle difficult-to-reach anatomy. Endoscopic suturing-related complications remain rare; however, bleeding, mucosal injury, intra-abdominal fluid collections, leaks, and perforations have been reported with the use of this device[64].

Outcomes of endoscopic suturing for GI leaks, perforation and fistulae: A large multicenter study including 122 patients from eight centers who underwent endoscopic suturing (OverStitch) for management of GI defects or stent anchorage showed a considerable success rate, except for the management of post-surgical leaks. Endoscopic suturing was used for stent anchorage in 47 (38.5%), fistulae in 40 (32.7%), perforation in 20 (16.4%), and post-surgical leaks in 15 (12.3%) patients, with long-term clinical success achieved in 91.4%, 80%, 93% and 27%, respectively[42]. A multicenter retrospective study included 56 patients with GI fistulae who were managed with endoscopic suturing. Successful fistulae closure was achieved in 30.2% (n = 13) patients after a single procedure, and an additional 9.3% (n = 4) after a second procedure. Despite repeated endoscopic attempts, 60% (26 of 43) of the fistulae persisted, and many of these patients (n = 14, 53.8%) ultimately required surgery[65]. A large European registry data of endoscopic suturing in 137 patients for various GI conditions showed a clinical success of 64.7% (n = 23) for leaks/fistulas, 85% (n = 38) for stent fixation and 94.7% (n = 22) for perforations[66]. A recent meta-analysis for endoscopic treatment of post-sleeve gastrectomy leaks, including 2896 leaks, showed that the overall success rate of endoscopic interventions was 88%. Interestingly, endoscopic suturing had the highest success rate (91%) among all other modalities[67].

EVT

EVT or endosponge provides a minimally invasive option for controlled drainage and defect closure in selected patients with GI leaks, perforations, and fistulae[68-70]. The concept of EVT is largely extrapolated from the negative pressure wound therapy for managing non-healing skin wounds and was first reported for a colorectal AL in 2003[71,72]. EVT involves placing a specially designed sponge or open-pore dressing connected by a suction tube to a vacuum pump at the site of the GI defect[73]. Negative pressure is applied, which has a multitude of effects to help in the healing of the defects. This includes: (1) Continuous drainage of GI fluids and debris and thus reduce bacterial load and control sepsis; (2) Reduction of edema; (3) Stimulates perfusion and improves blood flow by stimulating neovascularization; (4) Promote healing through the mechanism of macro- and micro-deformation; and (5) Promotes tissue granulation, which helps in enhancing wound contraction and closure[74,75].

There are various types of EVT devices, depending on sponge material and delivery devices. The most commonly used EVT devices are open-pore polyurethane foam (PUF) sponge, open-pore silicon-coated sponge and open-pore film drainage system. Every device has its advantages. For example, PUF sponge has excellent fluid drainage and tissue adherence and is most preferred, while the silicon-coated sponge is soft and flexible, and thus suitable for delicate tissues like the esophagus. The film drainage system is thinnest, making it useful for narrow and tortuous locations[69,74,75]. The defect should first be localized and characterized using radiologic and endoscopic evaluation to determine its size, extent and any associated collections. Endosponge placement is performed under endoscopic guidance. For larger defects, an intracavitary sponge is placed, while intraluminal sponge covering the defect can be considered for smaller defects. The sponge is attached to the vacuum using a suction tube, and a constant negative pressure between -75 mmHg to -125 mmHg is applied for effective drainage and healing (Figure 7). The efficacy of the procedure is monitored by the resolution of sepsis and reduced drain output. Endoscopy is repeated every 3-5 days for residual collection, size of cavity, status of wound, and sponge replacement for effective drainage. The therapy is continued until the defect is completely closed, which usually takes 2-6 weeks depending on the size of the defect[76].

Figure 7 Endoscopic vacuum therapy for post-esophagectomy with gastric pull-up surgery anastomotic leak with cavity. A: The cavity after cleaning debris and slough removal (green asterisk-esophageal lumen); B: Endosponge fashioned as per the shape and size of the cavity and sewed over a 12 Fr Ryle's tube; C: Placement of the endosponge inside the cavity using foreign body forceps; D: Endosponge placed inside the cavity completely covering the cavity; E: Follow-up image showing endosponge in place with adherent pus and debris; F: Cavity collapsed after six sessions of endoscopic vacuum therapy.

This method is especially suitable for large GI defects associated with cavity or collection formation, as it facilitates both effective drainage and promotion of defect healing through the mechanisms mentioned above. EVT has been used for the GI defects of the esophagus, stomach, duodenum, colorectal, and even for biliopancreatic leaks[68,77-80]. EVT has a limited role in the management of complete dehiscence of anastomosis and gastric conduit necrosis, where surgical revision is needed[81]. EVT may help in collection drainage and sepsis control before revision surgery[76,81]. Also, the ability to achieve negative suction is critically important for its effectiveness. Due to the inability to achieve negative suction, EVT is not effective for gastro-enteric/colonic fistulae, esophago-tracheal/bronchial fistulae, and colo-vaginal/vesicle fistulae[82]. EVT has a limited role in the management of enterocutaneous fistulae due to its inability to provide sustained negative pressure[76]. There are no absolute contraindications for EVT, but it should be avoided if the defect is close to major vessels or the tracheobronchial tree, or if the patient is on anticoagulation medications. Uncontrolled, uncontained perforation with diffuse peritonitis, non-compliant patients to tolerate repeated endoscopic procedures, severe bleeding at the defect site, and GI-cutaneous fistulae with a thin (< 5 mm) and long-epithelized tract (> 2 cm) are other contraindications for EVT[70,76,82]. The most common complications reported with EVT are bleeding, stricture and persistent fistulae[83].

Outcomes of EVT for GI defects: A retrospective study including 77 patients (59 AL and 18 perforations) showed that complete healing of the esophageal defect was achieved in 78% (n = 60) of patients with EVT. The mean duration of EVT application was 11 days, and the median was 2.75 EVT systems per patient[68]. A prospective study of 52 patients with UGI tract defects (AL 39 and perforations in 13) showed that successful outcomes with EVT could be achieved in 94.2% (n = 49) of patients[70]. A systematic review included 209 patients with AL after post-surgical resection of esophageal and gastric cancers, showing that successful closure of defects ranged between 67% to 100% in different studies. Anastomotic stricture was the most frequent long-term complication (n = 18, 8.6%)[84]. Another SRMA included 366 patients with esophageal transmural defect, showing pooled clinical success rates of 86.5% and 89% with EVT for ALs and perforations, respectively[85]. Similar results were observed for post-bariatric surgery leaks and lower GI tract defects. An SRMA revealed 87.2% clinical success and 6% moderate adverse events with EVT in post-bariatric surgery leaks and fistulae[86]. A prospective study including 30 patients with AL after total mesorectal excision for rectal cancer was offered vacuum-assisted cleaning of the presacral cavity, followed by early trans-anal surgical closure of the defect. At 1-year follow-up, defect closure and stoma reversal was achieved in 70% and 67% of patients, respectively. The outcomes were better if EVT was considered within 3 weeks of the index surgery (defect closure in 11/14 patients; 78.6%)[77]. A recent SRMA included 6 observational studies (n = 273) and compared EVT with standard care for colorectal AL. EVT was associated with a significantly higher closure rate (RR: 1.18; 95%CI: 1.03-1.35; P = 0.02) and shorter treatment duration (-30.6 days; 95%CI: -43.5 to -17.7; P < 0.0001)[87].

There are few studies comparing outcomes of EVT with covered SEMS[88-90]. A retrospective study included 32 patients who underwent EVT and 39 patients who underwent SEMS/SEPS placement for the closure of esophageal intrathoracic leaks. The successful closure rate of esophageal defects was significantly higher in the EVT group compared to the stenting group (84.4% vs 53.8%; hazard ratio: 2.99; 95%CI: 1.57-5.72). Additionally, the stent group had a higher rate of stricture formation (28.2% vs 9.4%; P < 0.05)[88]. Another retrospective study comparing SEMS (n = 76) with EVT (n = 35) for AL treatment after oncological gastroesophageal surgery reported no significant difference in successful defect closure (72.4% vs 85.7%; P = 0.152), hospital stay (P = 0.81), or intensive care unit stay (P = 0.7)[89]. A retrospective study including 62 patients with AL after esophagectomy compared outcomes of EVT, endoscopic stenting, and surgery. In the APACHE II matched cohort, the EVT group had the lowest mortality (12%) compared to revision surgery (50% mortality; P = 0.01) and endoscopic stenting groups (83% mortality; P = 0.0014)[90]. However, a SRMA including 274 patients from 5 studies reported superiority of EVT over stenting for AL in terms of successful closure, as well as lower adverse events and mortality. There was a 21% increase in fistula closure (P = 0.0003), a 12% reduction in mortality (P = 0.006), and a 24% reduction in adverse events (P = 0.0001) in the EVT group[91].

EVT is a generally safe procedure, with adverse events ranging between 4%-12%. Most adverse events are mild, like the discomfort of repeated endoscopy, sponge dislodgment, and minor bleeding during sponge exchange. Anastomotic strictures are reported in long-term follow-up after successful closure of defects using EVT[70,84,88]. Rarely, EVT-related life-threatening GI hemorrhages have been reported due to the formation of aorto-enteric fistulae when major vessels lie close to the cavity[70]. Therefore, CT scans should be carefully reviewed to exclude major vessels near the cavity before placing the endoscope. If major bleeding occurs during EVT treatment, suction should be removed immediately, and urgent CT angiography should be performed to guide the best possible treatment[70,76].

Tissue adhesives

Tissue sealants have been used for the management of GI defects and low-output fistulae[92]. They are categorized by their biological or synthetic origin, and the most commonly used sealants are fibrin glue, cyanoacrylate glue, and collagen-based sealants[2]. Fibrin glue is derived from human plasma (made of fibrinogen and thrombin), and it acts by mimicking the natural coagulation cascade; it forms a fibrin clot and seals the defect. Fibrin glue acts more efficiently in dry areas, so debris and purulent material need to be removed before its application. The advantages of fibrin glue are biocompatibility and full absorbability[93]. It is primarily suitable for small (< 10 mm) defects and low-pressure leaks. The major limitations are poor efficacy for high-pressure leaks due to limited strength and the risk of infection if not properly sterilized[93]. Cyanoacrylate glue is a synthetic adhesive that polymerizes on contact with moisture and forms a rapid, strong seal by creating a mechanical barrier. It causes tissue necrosis and foreign body inflammatory reactions, thus inducing tissue healing[2]. Cyanoacrylate glue is suitable for chronic, refractory GI fistulae, high-output enterocutaneous fistulae, and high-pressure areas like esophageal leaks. Additionally, cyanoacrylate glue is suitable for infected areas due to its antibacterial properties. The major limitation is an inability to remove if misplaced[2]. Collagen-based sealants are derived from bovine or porcine collagen and promote healing by providing a scaffold for tissue regeneration[94]. The Surgisis^® anal fistula plug is an advanced tissue repair graft derived from porcine submucosa and is developed for the management of perianal fistulae. It has also been used for the management of refractory enterocutaneous and bariatric surgery-related fistulae[90]. Because of limited tensile strength, collagen sealants are primarily suitable for small, low-pressure leaks. Another limitation is hypersensitivity reactions to collagen in susceptible individuals.

Outcomes of tissue adhesives for GI defects closure: A retrospective study of the endoscopic application of tissue sealants for AL reported that technical and clinical success was achieved in 96.8% of patients[92]. Another retrospective study of 52 patients where tissue adhesive fibrin glue was used for the management of GI tract defects exhibited successful healing in 29 patients (55.7%). The presence of major infectious complications was associated with poorer outcomes[95]. A systematic review of 20 studies (14 studies addressing foregut/midgut defects and 6 studies addressing hindgut defects) including 203 patients showed a cumulative success rate of 81% with a very low rate of adverse events (n = 3, 1%)[96]. There is limited evidence for the use of collagen-based sealants in managing GI tract defects. A case series of 7 patients with gastro-cutaneous fistulae (3 AL and 4 with non-healing gastrostomies) who were poor surgical candidates were managed with Surgisis^® anal fistula plug, which is a type of collagen-based sealant. There was 100% technical and clinical success, and a repeat endoscopy at 8 weeks confirmed re-epithelialization of the fistulous tract. At long-term follow-up (ranging between 30-59 months), there was no fistula recurrence in any of the patients, suggesting long-term efficacy[94]. Another case series of 25 patients with gastro-cutaneous fistulae following Roux-en-Y gastric bypass for weight reduction demonstrated good efficacy of Surgisis. The overall success rate was 80% (n = 20), and there were no procedure-related complications[97]. These results for tissue adhesives for GI tract defects are promising, but the evidence is limited by small case series and retrospective studies. There is a need for larger prospective studies and comparisons with other available endoscopic techniques.

Endoscopic internal drainage

Recently, there has been increasing evidence for the successful management of GI tract defects using endoscopic internal drainage (EID), especially in patients with leaks and fistulae after bariatric surgery[98,99]. The mechanisms of EID are internal drainage of collection, thus helping in sepsis control as well as cavity collapse, obstruction of the leak orifice, and internal drains acting as a foreign body, which promotes re-epithelization of the fistulous tract[100]. Additionally, EID allows the removal of external surgical drains, thus reducing the risk of chronic fistula formation along the drainage tract[99]. Careful radiological review and endoscopic assessment are required to assess the size of the defect, collection, and cavity; these parameters ultimately determine the size, number, and diameter of stents for EID. Enteral nutrition with naso-jejunal tube feeding after EID allows hyper-alimentation for these patients[99].

A large retrospective study of EID in 617 patients with GI tract defects after LSG showed complications in 4.5% of patients. The most common complications were bleeding, infection, perforation, air embolism, and stent migration. Bleeding secondary to pseudo-aneurysm requires endovascular intervention, while perforation and internal migration of the stents require surgical intervention[101]. Pequignot et al[98] reported the first experience of EID in patients with gastric leaks after LSG. A total of 25 patients were included; 14 patients (56%) developed an early leak, and the symptoms were characterized by systemic inflammation and peritonitis. The remaining 11 patients developed late-onset gastric leaks, and the most common symptom was intra-abdominal abscess in 8 (73%) patients. Early-onset leaks were managed by revision surgery and delayed-onset leaks were managed by endoscopic modalities. Patients with intra-abdominal abscess in the delayed leak group were managed by stent EID, and the defect was closed in all of them at a median follow-up of 45 days; none of them required surgery or percutaneous drainage and there was no mortality[98]. Another study included 67 patients with AL after LSD, where EID was used for drainage and defect closure and showed high technical success (n = 66, 98.5%)[99]. A comparative study including endoscopic closure using clips or stents and EID for treatment of fistulae after sleeve gastrectomy included 99 patients; 77 underwent endoscopic closure, and 22 underwent EID. In the endoscopic closure group, there was 63% (n = 49) success compared to a significantly higher success rate in the EID group (n = 22, 86% defect closure; P = 0.043). On multivariate analysis, collection size > 5 cm, presence of purulent flow at endoscopy, > 6 months delay, and revision surgery before endoscopic closure using clips/stents were associated with a high failure rate. In these cases, EID may be considered as a first line option[102]. There is limited evidence of EID for AL other than bariatric surgery. A case series of 11 patients, including 5 patients with ALs following upper GI cancer surgery, 4 patients with duodenal leaks following pancreaticobiliary surgery and 2 patients with colonic leaks following colorectal surgeries reported high technical (100%) and clinical (n = 9, 82%) success for EID after an average 44 days and median of 2.3 endoscopic sessions[103].

Newer devices: Novel helix tacking system (X-Tack)

This novel helix tacking system is a through-the-scope, suture-based device for the closure of large, transmural defects. The device is designed to pass through the standard gastroscope or colonoscope (compatible with up to 155 cm gastroscope and up to 235 cm colonoscope with a 2.8 mm working channel). The device is primarily designed to overcome the limitations of OTSC and TTSC (not limited by jaw size like OTSC/TTSC) and traditional endoscopic suturing devices (requiring double channel scopes). This device is especially suitable for defects > 30 mm, irregular-shaped defects, and defects located in the proximal colon. Closure can be achieved without the need for removal and reinsertion of the scope. This last indication is particularly important because the proximal colon is relatively inaccessible with traditional endoscopic suturing. Currently, the X-Tack Endoscopic Helix Tacking System (Apollo Endosurgery) has been approved by the Food and Drug Administration and is commercially available for transmural GI tract defect closure. To achieve effective closure, independent barbed helical tacks, each tethered by a single polypropylene suture, are placed around the defect. The ideal position of barbed tacks is around 0.5-1 cm from the periphery of the defect in four quadrants (four tacks are required) to achieve effective closure (Figure 8). After deploying and fixing of tacks, tension is applied on the suture for margin approximation, and cinching is performed similar to the traditional suturing system[104]. A multicenter retrospective study of 93 patients with large GI tract defects (41.6 ± 19 mm) showed a high technical success (n = 83, 89.2%) of X-Tack in these patients. Around one-fourth of patients required a supplemental closure. The procedure was very well tolerated, with only two adverse events, both of which were mild to moderate in severity[105].

Figure 8 Closure of post-endoscopic submucosal dissection defect of gastric subepithelial lesion using X-Tack™ endoscopic HeliX tacking system. A: Application of the first tack at the apex of the defect; B: Second tack applied along the left margin of the defect; C: Two tacks placed with continuous suture line visible; D: Third tack applied along the right margin of the defect and traction on the suture line to oppose the margin; E: Fourth tack applied at the proximal margin of the defect; F: Suture cinch being applied to close the defect.

Pragmatic approach: The management of GI leaks, perforation and fistulae can be challenging, and a multi-disciplinary team approach is required with the use of multiple treatment modalities like surgical, endoscopic and radiological interventions. Medical management, including appropriate antibiotics and adequate nutritional support, is the initial step. Early diagnosis is of paramount importance for better outcomes, both for surgical and endoscopic management. A high index of suspicion is essential for early diagnosis. If a leak or perforation is suspected, patients should be kept nil per oral, initiated on IV fluids and broad-spectrum antibiotics, and undergo an urgent CT scan to assess the defect and any associated extraluminal collections. If the patient is having signs of systemic inflammation and sepsis or if there are signs of peritonitis/mediastinitis, surgical intervention may be contemplated. The need for revision surgery may be warranted in cases of complete anastomotic dehiscence and conduit necrosis. In the absence of these indications, minimally invasive options, primarily endoscopic methods, are preferred over surgery because of better outcomes. For acute perforations (iatrogenic and spontaneous), in the absence of extraluminal collections and healthy surrounding margins, primary closure of the defects using endoscopic clips or sutures are the preferred treatment options. The advantages of these procedures are high clinical success, no need for repeated endoscopy, early initiation of oral feeding, and shorter hospital stays. An additional advantage is the lower risk of stricture formation on long-term follow-up. For small defects (< 10 mm), TTS clips are preferred. OTS are preferred for larger defects, up to 20 mm defects in the upper GI tract and up to 30 mm in the lower GI tract. For larger perforations, modified TTS clip-loop techniques, endoscopic suturing or covered stents should be considered, depending on the site, margin status, availability of expertise and timing of intervention[106]. A double-channel upper GI scope is especially useful for defect closure using OTSC (for grasping of the margins) and endoscopic suturing.

For small AL, management is similar to acute perforation if there are no associated extraluminal collections. If associated collections are present, then EID or E-VAC is preferred over the combination of external drainage of collections along with covered stents. The advantages of E-VAC and EID are higher success rates and the absence of external drainage. All of these endoscopic modalities require repeated endoscopic procedures and may be associated with stricture formation on long-term follow-up. Management of chronic fistulae is the most challenging, given the lowest rate of successful closure. Endoscopic closure using TTS/OTS and endoscopic suturing may be considered first for small fistulae. De-epithelialization of the surrounding mucosa using APC, biliary cytology brush, or mucosectomy before the application of closure devices increases the chances of successful closure. Tissue adhesives like fibrin glue or cyanoacrylate can also be considered for small, low-output fistulae. For larger fistulae, endoluminal drainage using E-VAC or EID is preferred. Failure of closure after repeated endoscopic drainage may warrant surgical repair.

Dual access is sometimes possible to tackle difficult fistulae, such as recto-vaginal fistula or TEF. In such situations, two scopes, one in the GI lumen and the other through the vagina (for recto-vaginal) or trachea (for trachea-esophageal fistula) can be placed to ensure better visibility and control of the fistulous tract during closure[107]. If the defect persists after an endoscopic intervention, a repeat endoscopic procedure may be considered using the same or different therapeutic modality, depending on size, site, and availability of expertise. Referral to a higher center where an advanced endoscopic facility is available may be required. A multidisciplinary approach is suggested with close collaboration between endoscopists, surgeons, and radiologists, as a comprehensive analysis of etiology, stage, and surrounding tissue structure by relevant departments can optimize the approach. A failed repeated endoscopic procedure may warrant surgical repair. A proposed algorithm for the management of GI leaks/perforation and fistulae is provided in Figure s 9 and 10, respectively.

Figure 9 Algorithm for the management of gastrointestinal leaks or perforations. NPO: Nil per oral; IV: Intravenous; CT: Computed tomography; TTSC: Through the scope clip; OTSC: Over the scope clip; UGI: Upper gastrointestinal; LGI: Lower gastrointestinal.

Figure 10  Algorithm for the management of gastrointestinal fistulae. TTSC: Through the scope clip; OTSC: Over the scope clip.

CONCLUSION

GI tract defects are serious complications, and the incidence is rising due to the complexities of endoscopic and surgical interventions performed nowadays. Prompt identification is the key to successful outcomes. The majority of these can be managed by endoscopy, while surgery is generally reserved for complete wound dehiscence, peritonitis, sepsis, and resultant multi-organ dysfunction. There are various endoscopic modalities for the management of GI tract defects, the selection of which depends on the extent, location, extraluminal contamination, and the availability of expertise. A multidisciplinary approach is suggested with close collaboration between endoscopists, surgeons, radiologists, and nutritionists. Every technique has its benefits and limitations, and the efficacy can be maximized by following the proper technique. Nonetheless, if unable to achieve complete closure using one technique, switching to another technique is suggested, depending on the site and size of the defect. One should not hesitate to seek help from more experienced colleagues and surgeons.