Endoscopic Clipping and Application of Fibrin Glue for an Esophago-Mediastinal Fistula

1. Introduction

Anastomotic leakage is one of the most serious complications following surgery of the esophagus. Post-surgical fistula and anastomotic leakage are major causes of morbidity and mortality.The reported incidence of anastomotic leakage after an esophagectomy is between 2.3 % and 5.9 %[1,2]. It is associated with a high rate of mortality. Conservative treatment with nutritional support and antibiotic therapy is usually adopted at first, but this is sometimes insufficient to obliterate leakage or can take 20-30 days, even if it is successful.Anastomotic leakage is usually improved simply by draining the anastomotic site[3], but sometimes an esophago-respiratory fistula occurs due to penetration by the abscess to the trachea or main bronchus[4-6]. This causes a very serious clinical condition, predisposing the patient to life-threatening pneumonia.

If conservative therapy fails, re-surgery remains as a final option. These surgical operations are invasive. The cases in which it is impossible to accomplish primary closure require another operation that is selected on consideration of the patient’s general status and prognosis.There are reports of the use of a muscle flap in the pectoralis major to repair a tracheomediastinal fistula after esophagectomy [3].Surgical intervention such as suturing and covering with omentum or muscle flap and esophageal bypass is indicated for mediastinitis, widespread graft necrosis and abscesses due to leakage[7] and is thought to be necessary if the fistula leads to a respiratory tract because repetitive pneumonia would result in poor physical condition[8,9]. But occasionally it would have been invasive and then no surgical attempt to treat the fistula was considered.

Currently, there are a variousendoscopic techniques for the management of anastomotic leakage. Endoscopic techniques are useful and technically feasible in chronic fistulas. This procedure is a less invasive alternative to traditional surgical revision.

There are reports of closing a gastrointestinal fistula or anastomotic leakage using fibrin glue, but fibrin glue is sometimes insufficient and is used with growth hormone or a clip. Several investigators reported a failure to close the fistula with this technique.

A clip is used firstly for hemostasis and applied for spontaneous closure of a perforation or endoscopic mucosal resection and sub-mucosal dissection. Rodella reported that endoscopic clipping to close an anastomotic leakage after a gastrectomy was effective and required only a short hospital day[10]. There are hardly any reports of endoscopic clipping for anastomotic leakage after an esophagectomy, although this technique has been performed on rare occasions for anastomotic leakage of duodenal stump or colorectal surgery.

Esophageal stenting at the anastomotic site is an effective method for treating anastomotic leakage after an esophagectomy, but when the anastomotic site is not stenotic and located near the neck, so it was predicted that migration and odynophagia would occur after stenting.

In this chapter, the treatment process using endoscopic clipping with fibrin glue after an operation that leads to a favorable outcome in which an esophago-mediastinal fistula is successfully repaired is discussed.

2. The treatment method for esophago-mediastinal fistula and anastomotic leakage

2.1. Conservative management

Conservative treatment excludes surgical treatment.

Leakage and fistula of the esophagus often lead to a localised infection and systemicsepsis.In particular, mediastinitis is a serious complication of esophageal surgery. The use ofbroad-spectrum antibiotics is initiated.

Total parenteral or enteral nutrition is provided. Leakages and fistula are associated with malnutrition, due to protein loss, lack of foodintake and hypercatabolism, often associated with sepsis. Malnutrition causeshypoproteinaemia with an increased risk of wound dehiscence and infection anddecreases muscle bulk and function. In this situation fibroblastic activity is reduced andleads to failure of scar contraction, leading to fistula formation with a delayed healingtime.

Nasogastric decompression is performed, and the infected area iscleaned by orally administered saline. The region of theleak is drained and perianastomotic drainage is applied to thepatients.

Cervical anastomotic leaks are successfully treated with conservative approaches. Thoracic anastomotic leaks, inthe past, were related to high mortality rates[11]. When the abscess was limited to the pleural cavity, a chest tube could achieve adequate drainage. However previous studies had revealed that most of the contained leakswere limited to the mediastinum [4, 5]. It is difficult todeal with this type of leakage because abscess cavitiesclose to the mediastinumare difficult to reach with a conventionalchest tube. Thoracic drainage inserted through trans-nasal routemay be a helpfultreatment for this type of leak.Moreover endoluminalapplication of a vacuum-assisted wound closure (EVAC) system is reported as an available method for the leak of colon, gastric and esophageal anastomosis.

2.1.1. Thoracic drainage inserted using interventional radiology (CT-guided)

Anastomotic leakage and a thoracic abscess are sometimes detected after the esophagectomy.Established options for sealing intrathoracic anastomoticleaksafteresophagectomyincludesurgical revisionand conservative treatments, such as percutaneous chesttube drainage (the traditional ‘‘three-tubemethod’’).The traditional ‘‘three-tube method’’ was themost widely applied method.However, it is difficult to insert a drain into a cavity that is very close to the trachea or aorta.(Fig.1. A) Percutaneous CT-guided abscess drainage is associated with high technical and clinicalsuccess rates. This minimally invasive form of therapymay have a role in the management of patients with potentiallylife-threatening mediastinal abscesses[12].

Figure 1.

A. The esophagomediastinal fistula had not closed after surgery. B. The abscess is located in the site surrounding lung tissue and close to the trachea and inferior subclavian artery and then thoracic drainage is difficult. C. A trans-nasal-gastric tube is inserted into the esophagomediastinal fistula.

2.1.2. Thoracic drainage inserted through trans-nasal route

Thoracic drainage through therans-nasal route is performed, when it is difficult to insert a drain into the cavity. This technique appears to be an effective, technicallyfeasible, and minimally invasive treatment option forintrathoracic esophagogastric anastomotic leak[13]. We performed trans-nasal drainage at the site of intrathoracic esophagogastric anastomotic leak.(Fig.1. A,B,C)Recently, the endoluminalapplication of a vacuum-assisted wound closure (EVAC) systemfor the closure of esophagogastric anastomotic fistulas has beenreported[14]. The spongeresults in formation of granulation tissue, and the vacuumremoves wound secretions, reduces edema, and improvesblood flow, leading to wound closure.EVAC is available and recommended for casesrefractory to established endoscopic treatment options[15].

2.2. Endoscopic management

A leakage or fistula will close with basic conservative treatment and local irrigation of between50 and 80%. The rate of spontaneous closure diminishes rapidly. Fistulae or leakages of anastomotic junctionsof the gastrointestinal tract used to be an indication forsurgery. However, patients are often severely ill andendoscopic therapeutic options have been suggested toavoid surgical intervention. When it fails to close the cavity of the esophago-mediastinal fistula (Fig.2. A), additional treatment is necessary, so endoscopic techniques are performed.The aim of the endoscopic treatment is also to shorten the closure time ofthe leakage.

Figure 2.

A. The drain is inserted into the mediastinal fistula and abscess cavity after operation showed by X-ray film.B. CT detects anastomotic leakage and a thoracic abscess cavity. C. An endoscopy revealsthat the fistula has failed to close after the operation. D. Endoscopic clipping with fibrin glue. E. An endoscopy indicates that we succeeded in closing the fistula. F. CT revealed no cavity or fistula.

2.2.1. Endoscopic management of anastomotic leakage using fibrin glue

Fibrin glue is used to support the growth of fibroblasts,stimulated from fibrin, thrombin and factorXIII.The Basic principle of sealing a fistula with fibrin is that the mixture of the two components(fibrinogen and thrombin) simulates the coagulation cascade in the fistulous tract whileforming a matrix of fibrin. The scar formation process is stimulated and in the processthe fibrin will be replaced slowly by collagen.Fibrin glue application has become an alternative and relatively novel method in clinical practice to avoid surgeryafter different kinds of leakages within the last few years.In 36.5% of cases, treatment success was reached with fibrin glueapplication as the sole endoscopic therapy[16].Endoscopicfibrin glue-based interventions are a valuable option in thetreatment of leakages or fistulae of the gastrointestinal tract[17].The endoscopist can perform this treatment easilyand safely; and it is not necessary to be very experiencedin this technique because it is based on the use ofthe needle injector[18]. H. Messmann reportedthat 1–4 ml of fibrin sealant is applied per session and performed an additional sub-mucosal injection of fibrin near the orifice after filling the fistula tract with fibrin if the orifice was small because the swelling induced by the sub-mucosal depot may contribute an additional closure effect. They also mentioned that this additional fluid volume may lead to washing part of the sealant into thegastrointestinal-tract. After application of the fibrin the endoscopist should refrain fromusing the suction system of the scope. Endoscopic sealing has to be repeated, in most cases, in intervals of a few days untilclosure achieved.

However, severe infection complications are associated with a poorsuccess rate. Moreover, the cost of fibrin glue is high but the advantageof a shorter hospital stay is significant in reducing global costs[17]. Treatment successwith further endoscopic procedures was seen. Vicryl plug or clipping are reported as additional endoscopic procedures because endoscopic treatment failure with consecutivesurgical intervention became necessary[15,19-22].

2.2.2. Endoscopic management of anastomotic leakageusing clipping

The use of metallic clips has been reported for hemostasis and closure of a perforation caused by various matter. Endoscopic closure by clipping was found to be effective for idiopathic or iatrogenic esophageal perforation.

Application of an endoclip is a relativelysimple procedure and recently reported as a method for closing anastomotic leakage of gastrointestinal tract [10,23-28] (Table.1.). The clip fixing device with a loaded clip can be passed throughthe forceps channel of a standard endoscope. As soon as the Teflon coating is inendoscopic sight the clip can be pushed forward out of the coating. Stepwise pulling onthe handle of the fixing device leads to opening of the prongs. Through manipulation ofthe tip of the endoscope the clip can be brought into position to grasp the tissue flanksof the leakage. It may be helpful to apply suction during this manoeuvre so that leaks that have a larger diameter than the total span of the clip can be treated. Afurther pull on the handle mechanism closes the endoclip and detaches the whole clipfrom the fixing device. Usually several clips are applied, positioning the first clips to the extremities of theleak or even outside the leakage borders to obtain a kind of ‘zipper’effect whilegrabbing tissue step by step from the outside to the centre of the defect. With thismethod leaks up to 2 cm in diameter can be closed; larger leaks need more than onesession. Exact data on clipping for therapy of post-surgical leakage are rare; mostarticles relate to endoscopic clipping of perforations following endoscopicprocedures.

Author /year	Organ of Surgery	Aditional Treatment	Jounal, Year
Rodella L. et al.	Stomach		Endoscopy. 1998
Familiari P. et al.	Colon		Dig Liver Dis. 2003
Messmann H. et al.	Esophagus	fibrin glue	Best Practice & Research Clinical Gastroenterology., (2004)
Teitelbaum JE. et al.	Stomach		Gastrointest Endosc. 2005.
Merrifield BF. et al.	Stomach		Gastrointest Endosc .2005
Dolay K. et al.	Rectum	fibrin glue	J Endourol., 2007
Grupka MJ. et al.	Stomach		J Dig Dis. 2008
Ibis M.et al.	Rectum		Am J Gastroenterol. 2010
Makino H. et al.	Esophagus	fibrin glue	Esophagus. 2011

Table 1.

Endoscopic clipping to close the anastomotic leakage of gastrointestinal tract

2.2.3. Endoscopic clipping with fibrin glue

A contrast instillation and radiological visualisation of the fistula system or cavity was performed during theendoscopic procedure of every therapeutic closure, both with fibrin and clips.H. Messmann reported that a double-lumen catheter can be placed over the guidewireinto the fistula[18].If a single-lumen catheter is used instead of a double-lumen probe for sealing, thecatheter lumen has to be flushed between the instillation of fibrinogen and thrombin. The sealing of the fistula begins as far aspossible away from the orifice; thus the risk of fluid retention can be minimised.

Metallic endoclips were applied, controlling the closure of the leakage by endoscopy.

A combination of clipping and fibrin sealing is probably more effective,　especially in treatment of larger leakages [10,28,29]. H. Messmann et al.applied several careful injections into the tissue using a double-lumen needle between the placed clips and also mentioned that their own experience with clips alone is not as positive as it is mentioned.Clips are used to close the fistula while suction is applied to reduce the size of the fistula hole after filling the fistula with fibrin glue. Application only of synthetic glues via endoscopy or clipping is not available.

2.2.4. Endoscopic stenting

Esophageal stenting at the anastomotic site is reported as an effective method for treating anastomotic leakage after an esophagectomy and is one of the most popular endoscopic treatments. The use of a removable coveredstent in the setting of anastomotic leak or spontaneous perforation,alone or as an adjunct to conventional surgical management, isfeasible in sealing the leak, resolving sepsis, and expediting returnto enteral nutrition [30].Stent migration is acommonly observed complication in other reported seriesoccurring in up to 50% of patients and frequently requiresrestenting to regain control of a leak[31]. We had a case of stent migration after leak closure. (Fig.3.A,B) The rate of distal stent migrationis possibly even higher following stenting of malignant stenoses due to thelack of a stricture.The patients whohad the stent sutured, all required operative intervention fordebridement of the necrotic and contaminated tissue so thestent and suture were placed at the time of this surgery. It is also predicted that odynophagia would occur after stenting if the anastomotic site is close to the neck. However new plastic stents areeasy to remove, very effective and might have therapeutic potential to replace fibrin glue application and clipping.

2.2.5. Other endoscopic therapy

To reduce the necessity ofanother surgical intervention and enhance natural healing other endoscopy-based therapeutic options are available.

Endoscopic suturing seemsto be a promising new treatment.

Figure 3.

A. Endoscopy indicated distal covered metallic stent migrated to the stomach. B.A fistula is observed in the non-covered part of a migrated metallic stent.

Pross et al. presented a successful closure method with a resorbable vicryl cylinderused as a plug [21]. The plug was inserted into the defect after repeated fibrin therapy. Little data has beenpublished regarding these methods and is still lacking.

2.3. The treatment process

2.3.1. Thoracic drainage inserted using interventional radiology or through trans-nasal route

A chest X-P revealed pneumothorax, and anastomotic leakage and a thoracic abscess were detected after the operation via CT (Fig. 2B). For approximately one month, thoracic drainages,and the nasogastric placement ofsumptubethrough the leakwere performed and conservative therapy with total enteral nutrition was continued. The cavity of the thoracic abscess caused by the leakage reduced in size, but the esophago-mediastinal fistula and the air cavity were still present 33 days after the operation. An additional thin drain was inserted using interventional radiology, but it failed to close the fistula 68 days after the operation (Fig. 2C).

Additional treatment to the thoracic drainages was necessary, so we decided to perform other endoscopic techniques.

2.3.2. Endoscopic clipping with fibrin glue

First we applied synthetic glues via endoscopy. The nasogastric placement oftubethrough the leak is already performed. We flushed the fistula system with physiologicalsodium chloride solution. Andthen fibrin was applied through the nasogastric tubelocated at the lowest position of the anastomosis. In the next stepwe usually insert a standard sump tube and apply thrombin into the fistula; a guidewire can be helpful to advance the probe to the distal endof the fistulawith complicatedor very long fistulae.A contrast medium was used through the endoscope we could confirm no leakage after filling with fibrin glues. However, an X-P taken three days after this technique indicated air leakage. Next we applied clipping to close the fistula twice, but within one week after clipping a clip had dropped out.We use metallic endoclips (MD 850,Olympus Corp., Tokyo, Japan) which have afully opened distance between the clip prongs of 12 mm long and 6 mm wide. In our case a clip dropped out a few days after clipping at the first and second sessions, and we expected that a single clip would not allow a successful closure. Esophageal pressure in swallowing at the neck site is high and the movement of air entering a gap in the fistula appeared to dislodge the clip. Finally, we succeeded in closing the fistula using three clips with fibrin glue because we eliminated the gap in the fistula(Fig. 2D). It was important to apply suction by endoscope when we attempted to close the fistula by clipping as the suction reduced the size of the fistula and facilitated the clipping.At the third treatment, we also filled with fibrin glue at the right lateral position where the fistula was located at the lowest position of the anastomosis and then followed this with endoscopic closure. An endoscopy indicated that we had succeeded in closing the fistula(Fig. 2E). A gastrographin swallow showed no leakage (data not shown) and CT revealed no cavity or fistula 7-10 days after clipping (Fig. 2F). We had succeeded in closing the fistula with clip and fibrin glue in our case [29].

3. Conclusion

Several investigators reported a failure to close a fistula with only fibrin glue. Rodella reported that endoscopic clipping to close an anastomotic leakage after a gastrectomy was effective [10].Endoscopic closure by clipping was found to be effective for idiopathic or iatrogenic esophageal perforation. Clippingalone also sometimes fails to close an anastomotic leak or fistula. Esophageal pressure in swallowing at the neck site is high and the movement of air entering a gap in the fistula appeared to dislodge the clip. It is important to apply suction by endoscope when we attempt to close the fistula by clipping as the suction reduced the size of the fistula and facilitated the clipping.Endoscopic clipping is recommended by Rodella et al. to treat leakages less than 2 cm in diameter.

The endoscopic clipping with fibrin glue treatment is effective and not invasive. Fibrinsealant and clipping are effective and probably established methods. It results in a steady improvement of the patient’s condition and minimized surgical stress, so it should be started earlier.

Furthermore a reduced hospitalstay will obviously decrease the costs of treatment.

The cost of fibrin glue is high but the advantageof a shorter hospital stay is significant in reducing global costs.In conclusion, the endoscopicuse of fibrin glue and clip are easy, safe and can shortenthe time of closure of fistula, in selected cases, withan apparent reduction of global costs.

Acknowledgement

The authors want to acknowledge Dr.Tsutomu Nomura and Dr.Nobutoshi Hagiwara for theirclinical support.