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Tissue adhesives: cyanoacrylate glue and fibrin sealant

      Abbreviations:

      RCT (randomized, controlled trial), TIPS (transcutaneous intrahepatic portosystemic shunt)
      The ASGE Technology Committee provides reviews of existing, new, or emerging endoscopic technologies that have an impact on the practice of GI endoscopy. Evidence-based methodology is used, performing a MEDLINE literature search to identify pertinent clinical studies on the topic and a MAUDE (U.S. Food and Drug Administration Center for Devices and Radiological Health) database search to identify the reported adverse events of a given technology. Both are supplemented by accessing the “related articles” feature of PubMed and by scrutinizing pertinent references cited by the identified studies. Controlled clinical trials are emphasized, but in many cases, data from randomized, controlled trials are lacking. In such cases, large case series, preliminary clinical studies, and expert opinions are used. Technical data are gathered from traditional and Web-based publications, proprietary publications, and informal communications with pertinent vendors. Technology Status Evaluation Reports are drafted by 1 or 2 members of the ASGE Technology Committee, reviewed and edited by the Committee as a whole, and approved by the Governing Board of the ASGE. When financial guidance is indicated, the most recent coding data and list prices at the time of publication are provided.
      For this review, the MEDLINE database was searched through August 2012 for relevant articles by using the key words cyanoacrylate, cyanoacrylate glue, cyanoacrylate and gastroenterology, cyanoacrylate and endoscopy, fibrin glue, fibrin sealant, tissue glue and endoscopy. Technology Status Evaluation Reports are scientific reviews provided solely for educational and informational purposes. Technology Status Evaluation Reports are not rules and should not be construed as establishing a legal standard of care or as encouraging, advocating, requiring, or discouraging any particular treatment or payment for such treatment.

      Background

      Tissue adhesives are compounds that can be used for hemostasis, wound closure, or fistula repair. The main classes of tissue adhesives are cyanoacrylate glues, fibrin glue, and thrombin. Cyanoacrylate glues are used primarily for endoscopic control of bleeding from gastric varices and less commonly for hemostasis of other bleeding lesions. They are also used for closure of fistulae and anastomotic leaks. Fibrin glue (fibrinogen and thrombin) and thrombin have also been used endoscopically for the treatment of bleeding. This status evaluation report reviews the described uses of cyanoacrylate glues, fibrin glue, and thrombin in endoscopy.

      Technology under review

      Cyanoacrylates

      Cyanoacrylates are a class of synthetic glues that rapidly solidify on contact with weak bases, such as water and blood.
      • Seewald S.
      • Sriram P.V.J.
      • Nagra M.
      • et al.
      The expert approach: cyanoacrylate glue in gastric variceal bleeding.
      Several manufacturers produce cyanoacrylate glues (Table 1). Some are available in the United States and are approved by the U.S. Food and Drug Administration for medical use (eg, wound closure). They are used off-label in the United States for endoscopic applications.
      Table 1List of different commercially available cyanoacrylate preparations available for medical use
      Trade nameManufacturerActive componentSold asPolymerization rateRequire lipiodolCost/ampoule (U.S.$)Available in the U.S.
      IndermilCovidienN-butyl-2-cyanoacrylate0.5-mL liquid/ampouleFasterYes26Yes
      HistoacrylTissueSealN-butyl-2-cyanoacrylate0.5-mL liquid/ampouleFasterYes27Yes
      DermabondEthicon2-Octyl-cyanoacrylate0.5-mL liquid/ampouleSlowerNo25Yes
      Glubran 2GEM, ItalyN-butyl-2-cyanoacrylate + methacryloxysulfolane0.25-, 0.5-, and 1-mL liquid/ ampouleSlowNoNo

      Method

      Cyanoacrylate glue is a liquid that may be mixed with lipiodol, an oily contrast agent, before injection. Mixing cyanoacrylate glues with lipiodol slows the rate of solidification, thereby facilitating endoscopic administration via needle injection and reducing the risk of inadvertent adherence to catheters and endoscopes. It also allows visualization of the injected varix on fluoroscopy. Various ratios of glue and lipiodol are used, ranging from 1:1 to 1:1.6.
      • Seewald S.
      • Sriram P.V.J.
      • Nagra M.
      • et al.
      The expert approach: cyanoacrylate glue in gastric variceal bleeding.
      Overdilution may increase the risk of embolization before the glue can solidify at the time of injection. Some cyanoacrylates (eg, Dermabond, Ethicon, Somerville, NJ; Glubran, Aspide Medical, La Talaudière, France) polymerize more slowly and thus do not require the use of lipiodol for injection.
      The exact approach to glue injection for gastric varices is not standardized, although 1 retrospective study demonstrated good efficacy and safety with a standardized regimen.
      • Seewald S.
      • Ang T.L.
      • Imazu H.
      • et al.
      A standardized injection technique and regimen ensures success and safety of N-butyl-2-cyanoacrylate injection for the treatment of gastric fundal varices (with videos).
      In general, the following steps are taken. Before injection of the glue, silicone oil or other similar compounds can be used to coat the tip of the endoscope to minimize the risk of glue adherence and damage to the instrument. Additionally, lipiodol alone may be injected into the working channel of the endoscope to coat it and prevent glue adherence. A large-bore sclerotherapy needle (21-22 gauge) may be primed with either lipiodol or normal saline solution. The vessel targeted for treatment is then punctured, and 1 mL is injected (which will consist of the primer used). This should flow without resistance, indicating an intravascular puncture. The glue is then injected rapidly, followed by distilled water or saline solution to flush out the channel while the needle is still in the varix. Because the cyanoacrylate/lipiodol mixture is very viscous, a 2-mL syringe with a Luer lock (Becton, Dickinson and Company, Franklin Lakes, NJ) is recommended to allow rapid injection and to prevent spraying.
      • Park W.
      • Yeh R.
      • Triadafilopoulous G.
      Injection therapies for variceal bleeding disorders of the GI tract.
      Expert opinion suggests that individual injections of glue are limited to volumes of 0.5 to 1.0 mL to minimize the risk of embolization,
      • Seewald S.
      • Sriram P.V.J.
      • Nagra M.
      • et al.
      The expert approach: cyanoacrylate glue in gastric variceal bleeding.
      although data to support the optimal volume are lacking and may need to be tailored to the size of the varix.
      When injected intravascularly, cyanoacrylate glue solidifies, producing a cast of the vessel. Subtotal occlusion is immediate, and total occlusion occurs within hours.
      • Fujiki K.
      • Ohkusa T.
      • Tamura Y.
      • et al.
      Evaluation of the effects of esophageal varicosclerosants on local vascular occlusion and systemic blood coagulation.
      • Nguyen A.J.
      • Baron T.H.
      • Burgart L.J.
      • et al.
      2-Octyl-cyanoacrylate (Dermabond), a new glue for variceal injection therapy: results of a preliminary animal study.
      After injection into a gastric varix, the overlying mucosa sloughs off and the cast of glue begins extruding into the gastric lumen after about a month with complete extrusion by 3 months.
      • Seewald S.
      • Sriram P.V.J.
      • Nagra M.
      • et al.
      The expert approach: cyanoacrylate glue in gastric variceal bleeding.
      • Sharma M.
      • Goyal A.
      Bleeding after glue injection in gastric varices.
      Repeat endoscopy is generally performed to assess the response to therapy. Data regarding the optimal method for surveillance and time intervals at which it should be performed are lacking.

      Fibrin sealant

      Fibrin sealant contains 2 components: highly purified, freeze-dried human fibrinogen with factor XIII and a starter solution containing human thrombin. The component solutions are reconstituted in 2 separate syringes with sterile water immediately before use. When mixed, these agents form a clot by mimicking the terminal phase of the physiologic clotting cascade, initially producing fibrin monomers that subsequently assemble into a stronger cross-linked fibrin polymer. Thrombin also activates factor XIII, which facilitates the bonding of the fibrin polymer (Fig. 1).
      • Dunn C.J.
      • Goa K.L.
      Fibrin sealant. A review of its use in surgery and endoscopy.
      Fibrin glue is fully absorbed by macrophages and fibroblasts within 2 weeks of application.
      • Pescatore P.
      • Verbeke C.
      • Harle M.
      • et al.
      Fibrin sealing in peptic ulcer bleeding: the fate of the clot.
      Figure thumbnail gr1
      Figure 1Schema of fibrinogen and thrombin interaction to yield a mature fibrin glue clot.
      Adapted from Dunn et al.
      • Dunn C.J.
      • Goa K.L.
      Fibrin sealant. A review of its use in surgery and endoscopy.
      Fibrin glue is available commercially in the United States from several sources. Tisseel (Baxter, Westlake Village, Calif), Evicel (Johnson & Johnson, Somerville, NJ), and Hemaseel (Hemacure, Sarasota, Fla) are approved for topical application, hemostasis, and sealing of anastomoses in various surgical disciplines. Although fibrin glues have been used in Europe for endoscopic hemostasis in bleeding ulcers and varices, product labeling in the United States does not endorse intravascular injection.
      When used during endoscopy, fibrin sealants may be delivered through specialized double-lumen catheters that are available with the product; these are passed through the endoscope. Because of the rapidity of clot formation, injection of the 2 major components (fibrinogen and thrombin) usually is performed either sequentially or by using a double-plunger syringe, which allows mixing while the agents are injected.

      Thrombin

      Thrombin promotes the conversion of fibrinogen to fibrin, producing a local fibrin clot. Human-derived thrombin is available commercially and from local blood bank sources and has largely supplanted bovine thrombin. It is a liquid preparation delivered topically to a bleeding lesion through a catheter by a method similar to the use of fibrin sealant.
      A newer thrombin-containing compound, Floseal (Baxter), has been used for hemostasis in a few case reports.
      • Farinella E.
      • Ronca P.
      • La Mura F.
      • et al.
      Upper gastrointestinal massive bleeding successfully treated intra-operatively with a collagen and thrombin-based high-viscosity gel for haemostasis. Case report.
      • Hammes C.
      • Moersdorf G.
      • Refeidi A.
      • et al.
      Endoscopic application of hemostatic thrombin-gelatin matrix (FloSeal) in anticoagulated pigs.
      • Dimitroulis D.
      • Antoniou E.
      • Karidis N.P.
      • et al.
      Surgical control of life-threatening post-ERCP bleeding with a gelatin matrix-thrombin hemostatic agent.
      It consists of a bovine-derived matrix of gelatin granules that is mixed with a human-derived thrombin component to produce a gel-like complex. This can effect hemostasis in excavated lesions.

      Efficacy and comparison with available technologies

      Cyanoacrylates for bleeding

      Gastric varices

      Gastric variceal bleeding is a difficult clinical problem because band ligation and sclerotherapy are much less effective in this location compared with therapy for esophageal varices.
      • Trudeau W.
      • Prindiville T.
      Endoscopic injection sclerosis in bleeding gastric varices.
      • Chey W.D.
      • Elta G.H.
      Natural history of gastric varices.
      Placement of a transcutaneous intrahepatic portosystemic shunt (TIPS) has been the first line therapy in the United States. However, many patients are not good candidates for TIPS or other radiologic interventions, and this therapy is not available in all facilities. Cyanoacrylate glues have been used commonly in the treatment of gastric varices outside the United States.
      One randomized, controlled trial (RCT) of 37 patients comparing cyanoacrylate injection with sclerotherapy with alcohol for bleeding fundal varices found that initial hemostasis rates were similar (89% vs 62%, P = not significant), but glue was more effective in obliterating varices (100% vs 44%, P < .05).
      • Sarin S.
      • Jain A.
      • Jain M.
      • et al.
      A randomized controlled trial of cyanoacrylate versus alcohol injection in patients with isolated fundic varices.
      A nonrandomized study comparing cyanoacrylate with ethanolamine sclerotherapy found that glue was superior for initial hemostasis (93% vs 67%, P = .014).
      • Oho K.
      • Iwao T.
      • Sumino M.
      • et al.
      Ethanolamine oleate vs. butyl cyanoacrylate for bleeding gastric varices: a nonrandomized study.
      Cyanoacrylate injection was compared with band ligation for bleeding gastric varices in an RCT; this study of 60 patients found that cyanoacrylate had a higher initial hemostatic rate (87% vs 45%, P = .03) and a lower rate of rebleeding (31% vs 54%, P = .005).
      • Lo G.
      • Lai K.
      • Cheng J.
      • et al.
      A prospective, randomized trial of butyl cyanoacrylate injection versus band ligation in the management of bleeding gastric varices.
      Two retrospective studies compared cyanoacrylate injection with TIPS for bleeding gastric varices. One found no difference in rebleeding rates at 72 hours, 3 months, and 1 year, and no difference in 3-month survival.
      • Procaccini N.
      • Al-Osaimi A.
      • Northup P.
      • et al.
      Endoscopic cyanoacrylate versus transjugular intrahepatic portosystemic shunt for gastric variceal bleeding: a single-center U.S. analysis.
      The other found that cyanoacrylate therapy had a higher 30-day rebleed rate than TIPS, although notably the rebleed rate in this study was higher than that reported previously in the literature. As secondary prophylaxis, cyanoacrylate glue injection has been shown to reduce rebleeding rates compared with band ligation
      • Tan P.C.
      • Hou M.C.
      • Lin H.C.
      • et al.
      A randomized trial of endoscopic treatment of acute gastric variceal hemorrhage: N-butyl-2-cyanoacrylate injection versus band ligation.
      and propranolol.
      • Mishra S.R.
      • Sharma B.C.
      • Kumar A.
      • et al.
      Endoscopic cyanoacrylate injection versus b-blocker for secondary prophylaxis of gastric variceal bleed: a randomised controlled trial.
      As primary prophylaxis, cyanoacrylate glue therapy has been shown to reduce the risk of bleeding and mortality from varices more than 10 mm diameter compared with propranolol alone.
      • Mishra S.R.
      • Sharma B.C.
      • Kumar A.
      • et al.
      Primary prophylaxis of gastric variceal bleeding comparing cyanoacrylate injection and beta-blockers: a randomized controlled trial.
      Taken together, these data suggest that endoscopic therapy with tissue glue achieves initial hemostasis of bleeding gastric varices in 80% to 90%, is more effective than band ligation or sclerotherapy for primary control of gastric variceal hemorrhage, and is probably equivalent to TIPS. Glue therapy is likely superior to band ligation and β-blocker therapy for secondary prophylaxis against rebleeding.
      Cyanoacrylate injection has been traditionally performed under endoscopic guidance only. A case series described the use of EUS to guide injection and monitor the results.
      • Lee Y.T.
      • Chan F.K.L.
      • Ng E.K.W.
      • et al.
      EUS-guided injection of cyanoacrylate for bleeding gastric varices.
      Another small series used EUS to identify and inject feeding “perforator” varices.
      • Romero-Castro R.
      • Pellicer-Bautista F.J.
      • Jimenez-Saenz M.
      • et al.
      EUS-guided injection of cyanoacrylate in perforating feeding veins in gastric varices: results in 5 cases.
      Another new technique described intravariceal deployment of a metal coil (similar to that used by interventional radiologists) before glue injection under direct EUS guidance. The coil is intended to act as a scaffold to retain the glue within the varix and decrease the risk of embolization. Hemostasis was achieved in 100% of 30 patients in the study, with complete obliteration of gastric varices in 96% patients after a single treatment, as seen on follow-up endoscopy. No procedure-related adverse event or evidence of glue embolization was seen in this patient cohort.
      • Binmoeller K.F.
      • Weilert F.
      • Shah J.N.
      • et al.
      EUS-guided transesophageal treatment of gastric fundal varices with combined coiling and cyanoacrylate glue injection (with videos).
      No comparison of EUS-guided glue injection with glue injection without EUS guidance is available.

      Esophageal varices

      Two randomized trials compared cyanoacrylate glue injection with band ligation for acute bleeding
      • Ljubicić N.
      • Bisćanin A.
      • Nikolić M.
      • et al.
      A randomized-controlled trial of endoscopic treatment of acute esophageal variceal hemorrhage: N-butyl-2-cyanoacrylate injection vs. variceal ligation.
      and for primarily prophylaxis of high-risk esophageal varices.
      • Santos M.M.
      • Tolentino L.H.
      • Rodrigues R.A.
      • et al.
      Endoscopic treatment of esophageal varices in advanced liver disease patients: band ligation versus cyanoacrylate injection.
      Overall, control of bleeding by using cyanoacrylate glue appears similar to band ligation, but rebleeding rates are higher with glue injection. For primary prophylaxis, variceal eradication was similar, but adverse events and bleeding rates were higher in the glue arm. In addition, glue injection has been associated with esophageal sinus formation
      • Kim E.K.
      • Sohn J.H.
      • Kim T.Y.
      • et al.
      Esophageal sinus formation due to cyanoacrylate injection for esophageal variceal ligation-induced ulcer bleeding in a cirrhotic patient.
      and esophagovascular fistulae, potentially with catastrophic results.
      • Barclay S.
      • Cameron I.
      • Stewart I.
      • et al.
      Massive hemorrhage from a pulmonary vein–esophageal fistula: a late complication of Histoacryl glue injection.

      Nonvariceal hemostasis

      Older case series described the use of cyanoacrylate glue in the treatment of bleeding peptic ulcers, but it has not been compared with the current standard treatments (epinephrine plus thermal therapy or clips). A case series describes the use of EUS to guide successful cyanoacrylate injection into a feeding vessel of a bleeding duodenal ulcer in 1 patient and into bleeding GI stromal tumors in 2 patients.
      • Levy M.J.
      • Wong Kee Song L.M.
      • Farnell M.B.
      • et al.
      Endoscopic ultrasound (EUS)-guided angiotherapy of refractory gastrointestinal bleeding.
      Two case series of 4 and 5 patients, respectively, described the successful use of topically sprayed cyanoacrylate glue to achieve hemostasis in bleeding GI tumors, an EMR site, and duodenal ulcer that were not controlled with epinephrine injection.
      • Shida T.
      • Takano S.
      • Miyazaki M.
      • et al.
      Spraying N-butyl-2-cyanoacrylate (Histoacryl) might be a simple and final technique for bleeding gastrointestinal lesions.
      • Prachayakul V.
      • Aswakul P.
      • Kachinthorn U.
      Histoacryl as a rescue therapy for gastrointestinal malignant tumor bleeding after failed conventional therapy.

      Fibrin glue/thrombin for bleeding

      Fibrin glue and thrombin have not been adequately evaluated in the treatment of bleeding peptic ulcers or varices compared with standard therapy used today. Several older trials compared injection of fibrin glue or thrombin with other hemostatic modalities for the treatment of bleeding gastroduodenal ulcers.
      • Berg P.L.
      • Barina W.
      • Born P.
      Endoscopic injection of fibrin glue versus polidocanol in peptic ulcer hemorrhage: a pilot study.
      • Rutgeerts P.
      • Rauws E.
      • Wara P.
      • et al.
      Randomised trial of single and repeated fibrin glue compared with injection of polidocanol in treatment of bleeding peptic ulcer.
      • Pescatore P.
      • Jornod P.
      • Borovicka J.
      • et al.
      Epinephrine versus epinephrine plus fibrin glue injection in peptic ulcer bleeding: a prospective randomized trial.
      • Song S.Y.
      • Chung J.B.
      • Moon Y.M.
      • et al.
      Comparison of the hemostatic effect of endoscopic injection with fibrin glue and hypertonic saline-epinephrine for peptic ulcer bleeding: a prospective randomized trial.
      • Heldwein W.
      • Avenhaus W.
      • Schonekas H.
      • et al.
      Injection of fibrin tissue adhesive versus laser photocoagulation in the treatment of high risk bleeding peptic ulcers: a controlled randomized study.
      • Koyama T.
      • Fujimoto K.
      • Iwakiri R.
      • et al.
      Prevention of recurrent bleeding from gastric ulcer with a non bleeding visible vessel by endoscopic injection of absolute ethanol: a prospective, controlled trial.
      • Benedetti G.
      • Sablich R.
      • Lacchin T.
      Endoscopic injection sclerotherapy in non-variceal upper gastrointestinal bleeding.
      • Balanzo J.
      • Villanueva S.
      • Sainz J.
      • et al.
      Injection therapy of bleeding peptic ulcer. Randomized trial using adrenaline and thrombin.
      • Kubba A.K.
      • Murphy W.
      • Palmer K.R.
      Endoscopic injection for bleeding peptic ulcer: a comparison of adrenaline alone with adrenaline plus human thrombin.
      • Lin H.J.
      • Hsieh Y.H.
      • et al.
      Endoscopic injection with fibrin sealant versus epinephrine for arrest of peptic ulcer bleeding: a randomized, comparative trial.
      None evaluated fibrin glue compared with currently standard multimodality treatment by using epinephrine injection plus contact thermal probes or endoclips.
      Fibrin glue has been injected for arrest of variceal bleeding in small uncontrolled series.
      • Datta D.
      • Vlavianos P.
      • Alisa A.
      • et al.
      Use of fibrin glue (Beriplast) in the management of bleeding gastric varices.
      • Heneghan M.A.
      • Byrne A.
      • Harrison P.M.
      An open pilot study of the effects of a human fibrin glue for endoscopic treatment of patients with acute bleeding from gastric varices.
      Thrombin also has been evaluated for use in endoscopic hemostasis of variceal bleeding. Thrombin plus ethanolamine was equivalent to ethanolamine alone in 1 RCT.
      • Kitano S.
      • Hashizume M.
      • Yamaga H.
      • et al.
      Human thrombin plus 5 percent ethanolamine oleate injected to sclerose oesophageal varices: a prospective randomized trial.
      In 2 retrospective studies, thrombin reportedly achieved hemostasis in bleeding gastric varices in 75% to 94%.
      • Przemioslo R.T.
      • McNair A.
      • Williams R.
      Thrombin is effective in arresting bleeding from gastric variceal hemorrhage.
      • Yang W.L.
      • Tripathi D.
      • Therapondos G.
      • et al.
      Endoscopic use of human thrombin in bleeding gastric varices.
      However, product labeling states that intravascular injection of fibrin glue is contraindicated because of the risk of embolization.

      Cyanoacrylates for fistulae

      Case series have described the successful use of cyanoacrylate glues for the endoscopic treatment of refractory bile leaks,
      • Seewald S.
      • Groth S.
      • Sriram P.V.
      • et al.
      Endoscopic treatment of biliary leakage with n-butyl-2 cyanoacrylate.
      pancreatic fistulae
      • Labori K.J.
      • Trondsen E.
      • Baunes T.
      • et al.
      Endoscopic sealing of pancreatic fistulas: four case reports and review of the literature.
      • Seewald S.
      • Brand B.
      • Groth S.
      • et al.
      Endoscopic sealing of pancreatic fistula by using N-butyl-2-cyanoacrylate.
      • Mutignani M.
      • Tringali A.
      • Khodadadian E.
      • et al.
      External pancreatic fistulas resistant to conventional endoscopic therapy: endoscopic closure with N-butyl-2-cyanoacrylate (Glubran 2).
      • Romano A.
      • Spaggiari M.
      • Masetti M.
      • et al.
      A new endoscopic treatment for pancreatic fistula after distal pancreatectomy: case report and review of the literature.
      and a variety of other GI tract fistulae
      • Barthelemy C.
      • Audigier J.C.
      • Fraisse H.
      A Non-tumoral esophago-bronchial fistula managed by isobutyl-2-cyanoacrylate.
      • Melmed G.Y.
      • Kar S.
      • Geft I.
      • et al.
      A new method for endoscopic closure of gastrocolonic fistula: novel application of a cardiac septal defect closure device (with video).
      • Devière J.
      • Quarre J.P.
      • Love J.
      • et al.
      Self-expandable stent and injection of tissue adhesive for malignant bronchoesophageal fistula.
      • Santos F.
      • Campos J.
      • Freire J.
      • et al.
      Enterocutaneous fistulas: an unusual solution.
      • Yellapu R.K.
      • Gorthi J.R.
      • Kiranmayi Y.
      • et al.
      Endoscopic occlusion of idiopathic benign esophago-bronchial fistula.
      • Rotondano G.
      • Viola M.
      • Orsini L.
      • et al.
      Uncommon cause of early postoperative colonic fistula successfully treated with endoscopic acrylate glue injection.
      ; however, there are no controlled trials.

      Fibrin glue for fistulae

      An RCT of 13 patients with persistent enterocutaneous fistulae found that fibrin glue achieved closure after a mean of 2 days compared with 13 days with conservative therapy (P < .01).
      • Hwang T.L.
      • Chen M.F.
      Randomized trial of fibrin tissue glue for low output enterocutaneous fistula.
      An RCT compared fibrin glue with fistulotomy for anal fistulae; no advantage was found for simple fistulae, but the glue healed more complex fistulae.
      • Lindsey I.
      • Smilgin-Humphreys M.M.
      • Cunningham C.
      • et al.
      A randomized, controlled trial of fibrin glue vs. conventional treatment for anal fistula.
      Other series found lower success rates and high short-term recurrence rates, however.
      • Loungnarath R.
      • Dietz D.W.
      • Mutch M.G.
      • et al.
      Fibrin glue treatment of complex anal fistulas has low success rate.
      • Adams T.
      • Yang J.
      • Kondylis L.A.
      • et al.
      Long-term outlook after successful fibrin glue ablation of cryptoglandular transsphincteric fistula-in-ano.
      A recent randomized trial comparing fibrin glue with observation only for Crohn’s patients with anal fistulae found higher closure rates in the glue patients (38% vs 16%, P = .04).
      • Grimaud J.C.
      • Munoz-Bongrand N.
      • Siproudhis L.
      • et al.
      Fibrin glue is effective healing perianal fistulas in patients with Crohn's disease.
      Numerous case series report achieving prompt closure with the use of fibrin glue for enterocutaneous fistulae,
      • Eleftheriadis E.
      • Tzartinoglou E.
      • Kotzampassi K.
      • et al.
      Early endoscopic fibrin sealing of high-output postoperative enterocutaneous fistulae.
      • Rabago L.R.
      • Ventosa N.
      • Castro J.L.
      • et al.
      Endoscopic treatment of postoperative fistulae resistant to conservative management using biological fibrin glue.
      • Papavramidis S.T.
      • Eleftheriadis E.E.
      • Apostolidis D.N.
      • et al.
      Endoscopic fibrin sealing of high-output non- healing gastrocutaneous fistulae after vertical gastroplasty in morbidly obese patients.
      • Cellier C.
      • Landi B.
      • Faye A.
      • et al.
      Upper gastrointestinal tract fistulae: endoscopic obliteration with fibrin sealant.
      • Shand A.
      • Pendlebury J.
      • Reading S.
      • et al.
      Endoscopic fibrin sealant injection: a novel method of closing a refractory gastrocutaneous fistula.
      including persistent gastrocutaneous fistulae after gastrostomy tube removal.
      • Gonzalez-Ojeda A.
      • Avalos-Gonzalez J.
      • Mucino-Hernandez M.
      • et al.
      Fibrin glue as adjuvant treatment for gastrocutaneous fistula after gastrostomy tube removal.
      • Papavramidis T.S.
      • Kotzampassi K.
      • Kotidis E.
      • et al.
      Endoscopic fibrin sealing of gastrocutaneous fistulas after sleeve gastrectomy and biliopancreatic diversion with duodenal switch.
      Fibrin glue has been used to close esophageal perforations in case reports.
      • Fernandez F.F.
      • Richter A.
      • Freudenberg S.
      • et al.
      Treatment of endoscopic esophageal perforation.
      • Rábago L.R.
      • Castro J.L.
      • Joya D.
      • Herrera N.
      • et al.
      Esophageal perforation and postoperative fistulae of the upper digestive tract treated endoscopically with the application of Tissucol.
      A single case report exists of successful closure of a duodenal perforation with fibrin glue.
      • Mutignani M.
      • Iacopini F.
      • Dokas S.
      • et al.
      Successful endoscopic closure of a lateral duodenal perforation at ERCP with fibrin glue.
      These data are scant but suggest that fibrin glue is a reasonable option for persistent enterocutaneous fistulae.

      Safety

      The major risk of glue injection treatment of gastric varices is systemic embolization.
      • Watanabe K.
      • Kimura K.
      • Matsutani S.
      • et al.
      Portal hemodynamics in patients with gastric varices. A study in 230 patients with esophageal and/or gastric varices using portal vein catheterization.
      Reported embolic adverse events include pulmonary embolism, stroke, and multiorgan infarction via patent foramen ovale or arteriovenous pulmonary shunts, splenic infarction, splenic vein and portal vein thrombosis, and recurrent sepsis caused by embolized glue acting as a septic focus.
      • Berry P.A.
      • Cross T.J.
      • Orr D.W.
      Clinical challenges and images in GI. Pulmonary embolization of histoacryl "glue" causing hypoxia and cardiovascular instability.
      • Chang C.J.
      • Shiau Y.T.
      • Chen T.L.
      • et al.
      Pyogenic portal vein thrombosis as a reservoir of persistent septicemia after cyanoacrylate injection for bleeding gastric varices.
      • Saracco G.
      • Giordanino C.
      • Roberto N.
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      A retrospective radiologic study showed a 4.3% rate of pulmonary embolism after glue injection.
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      There are several reports of adverse events with the use of cyanoacrylate glue to treat nonvariceal hemorrhage by direct injection including duodenal ulcer perforation and esophageal sinus formation.
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      Inadvertent intra-arterial injection of fibrin glue or thrombin may risk systemic embolization.

      Baxter Healthcare. Tissue sealing [cited 2003 Feb 5]. Available at: http://www.tissuesealing.com/us/products/biological/monograph.cfm. Accessed August 1, 2012.

      Air embolization and death have occurred during fistula treatment with injection of both cyanoacrylate and fibrin glues. This has been attributed to overinsufflation within the fistula track.
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      When treating aerodigestive fistulae through the GI lumen, there is a risk of tracheobronchial accumulation and airway plugging from overflow of excessive volumes of glue.

      Ease of use

      Although most endoscopists are familiar with injection therapy in the GI tract, cyanoacrylates can be technically challenging to use because of the number and necessary rapidity of the process, and familiarity with the exact steps of the procedure planned is advisable before initiating treatment. Given the potential risks associated with the use of cyanoacrylate glue for gastric variceal treatment, preparation and arrangement of equipment and glue components before therapy are important for safe and efficient use. Extra personnel should be available to assist with the procedure. Staff and patients should use protective eyewear during preparation and injection. The cyanoacrylates should be refrigerated.
      Fibrin glue is somewhat easier to use than cyanoacrylate glue. Premature clotting can occlude injection catheters, particularly single-channel varieties. There is no risk to the endoscope from contact with the fibrin clot.

      Financial considerations

      Comparisons between TIPS and cyanoacrylate glue for bleeding caused by gastric varices have shown that glue is more cost-effective.
      • Mahadeva S.
      • Bellamy M.C.
      • Kessel D.
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      Cost effectiveness of n-butyl-2-cyanoacrylate (Histoacryl) glue injections versus transjugular intrahepatic portosystemic shunt in the management of acute gastric variceal bleeding.
      • Greenwald B.D.
      • Caldwell S.H.
      • Hespenheide E.E.
      • et al.
      N-2-butyl cyanoacrylate for bleeding gastric varices, a United States pilot study and cost analysis.
      Damage to the endoscope with cyanoacrylate glue can sometimes be repaired but may require disposal and replacement of the entire instrument.
      Pharmacy costs for the various cyanoacrylate and fibrin glue preparations are shown in Table 1. Endoscopic applications of biologic or synthetic glues also may require use of a dual-plunger syringe and single- or dual-channel injection needles.
      The CPT code used for esophagoscopy with injection sclerosis of varices is 43204. For EGD with injection of gastric or esophageal varices, the CPT is 43243.

      Areas for future research

      Evidence-based, standardized protocols for use of cyanoacrylate glue in gastric variceal bleeding need to be developed. Comparisons of different glue formulations should be performed. Randomized controlled trials should be conducted comparing TIPS to cyanoacrylate glues in patients who are candidates for TIPS. Further evaluation of methods to reduce the risk of systemic embolization from glue therapy is needed. Definition of the role of EUS in the treatment of gastric varices would be helpful. Exploring the best methods for surveillance after treatment of gastric varices is needed. Finally, comparisons of fibrin glue with other closure devices and treatment modalities for therapy of fistulae are needed.

      Summary

      Tissue glues are used for control of bleeding and closure of fistulae and anastomotic leaks. Cyanoacrylate glues are effective at achieving initial hemostasis for bleeding gastric varices and are commonly used outside the United States, but this remains an off-label use in the United States. Future research demonstrating the safety and efficacy of these compounds may lead to wider adoption in this country.

      Disclosure

      The authors disclosed no financial relationships relevant to this article.

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      Linked Article

      • Controlled trial of TIPS versus cyanoacrylate glue for gastric variceal bleeding
        Gastrointestinal EndoscopyVol. 79Issue 1
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          I read with interest the article by the ASGE Technology Committee regarding the tissue adhesive cyanoacrylate.1 The authors cited 2 retrospective studies that compared cyanoacrylate injection with transcutaneous intrahepatic portosystemic shunt (TIPS) for gastric variceal bleeding, and they presumed that glue injection is probably equivalent to TIPS. Actually, we performed a prospective, randomized, controlled trial comparing glue injection and TIPS in the prevention of gastric variceal rebleeding.
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