The Use of Bioglue In the Treatment of High Perianal Fistula: A Prospective study

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1 Kasr El Aini Journal of Surgery VOL., 10, NO 2 May The Use of Bioglue In the Treatment of High Perianal Fistula: A Prospective study Ahmed K. El Batanouny, M.D, Ayman El Samadoni, M.D, and Hisham El Sharkawy, M.D Department of Surgery, Faculty of Medicine, Cairo University ABSTRACT Purpose: this prospective study was done to evaluate the efficacy of Bioglue application in the treatment of high anal fistula. Methods: from April 2007 to November 2008, 15 patients (14 males) were enrolled. We excluded patients with Crohn s disease, HIV, chronic cavities related to fistula s track and pregnant females and those with rectovaginal fistula. After one day bowel preparation and intravenous antibiotic, the patients underwent anorectal examination for identification of the internal and external opening. Then the fistula track was scraped either by progressive diameter of tape gauze or microcurettes. Bioglue is then injected from the external opening making sure to fill the whole track. No dressing was applied with postoperative antibiotic therapy for one week and instruction to avoid path and sitting for long time. Patients were followed up for 18 months with a mean of 7.5 months (range 4-18 months). Results: all but one case had high transsphincteric anal fistula. Seven cases were recurrent and average symptom s duration of 32.7 months. We had no toxic or allergic reaction related to procedure. We had two anal septic complications related to application, two cases of closure failures and one case of late (11 month) recurrence through the original track. Our overall success was 66.7%. Conclusion: BioGlue can be a useful, easy and comparably safe alternative treatment for high transsphincteric perianal fistula as firstline treatment in selected patients. However, because of small sample size further larger, randomized studies with long period follow up are needed to validate the results of this study. Key words: Bioglue, surgical adhesive, high anal fistula INTRODUCTION The management of low anal fistulas is usually straightforward with excellent cure rate with fistulotomy, and if the fistula has been properly evaluated, continence disturbance is minimal [1,2]. However, the situation is not the same for high anal fistulas, because cure and continence are directly competing priorities [3]. The goal of surgical treatment of fistula-inano is to heal the fistula track with the lowest rate of recurrence and still maintaining continence. Surgical options for high fistulas include draining (loose), cutting setons, as well as rectal advancement flaps, yet these techniques have their disadvantages. Advancement flaps are very useful but can be technically demanding, furthermore their success in Crohn s fistulas and in repeat flaps is limited due to scarring associated with a failed previous flap [4]. Loose draining setons are useful to control a fistula and sometimes migrate caudally to cure high fistulas, but this is unpredictable while the use of cutting setons, is time consuming, painful and associated with concerns about continence disturbance [5]. In spite of the continuous advancement in the surgical techniques over the past two decades, high anal fistulas still hold a considerable fear for both recurrence and continence issues. [6,7] Biological adhesive glue is a novel, and in many ways ideal treatment for anal fistula. The technique is simple and repeatable and treatment failure does not compromise subsequent surgical options while continence is not jeopardized. All available biological glue share the common end product of a gel-like substance that, when solidify, can be used in surgery to achieve hemostasis and watertight seal. [8,9] Various biologic adhesives have been evaluated within the last decade to assess their ability to seal the fistula track. [8,10] Autologous cryoprecipitates, [11] reconstituted bovine thrombin, [3] recombinant fibrin [8] and, recently, donor plasma [12] all have been used to seal the fistula track. Unlike other glues, BioGlue Surgical Adhesive (CryoLife, Inc., Kennesaw, GA, USA) is composed of purified bovine serum albumin (BSA) and glutaraldehyde. Its use as an adjunct to the standard methods of surgical repair

2 Kasr El Aini Journal of Surgery VOL., 10, NO 2 May to bond, seal, and/or reinforce tissues in vascular, thoracic, and neurosurgical procedures has been well established [13,14,15]. The biologic characteristics of BioGlue make it suitable for use in the treatment of anal fistulas. The aim of this study is to examine the effectiveness and safety of BioGlue in the treatment of high anal fistulas. PATIENTS & METHODS This prospective study was carried out to patients with high anal fistula presented during the period from April 2007 to Nov 2008 for assessment of efficacy and safety of BioGlue in their management. All patients presenting to outpatient surgical service with anorectal complaints were sorted out and those with suspected high anal fistulas were picked up for further work up. Patients known to have Crohn s disease, or HIV as well as pregnant females were excluded from the study. Patients presenting with localized tenderness and possible perianal suppuration were treated first for their acute septic condition to be enrolled once their acute illness subsides. Hydrogen peroxide enhanced endoanal ultrasonography was carried out as outpatient investigations to all sorted patients to verify the high nature of their fistulas. Hydrogen peroxide injected at the external opening during transrectal ultrasonography provides gas contrast within the fistula track. This contrast ultrasonography allowed us to spot fistulous tracks no matter how small they are, internal openings, and secondary extensions if any can be demarcated and most importantly the relation of the tract to anal sphincters. Patients with rectovaginal fistula and those with chronic cavities discovered during ultrasound were further excluded from our study. As a confirmatory test patients picked up at ultrasound were subjected to water soluble contrast fistulography, unless known hypersensitivity to contrast, for proper delineation of the fistulous track, further establishing of the fistula type diagnosis (Supra-, Trans-, or Extra-sphincteric) as well as state of branches. Demographic, possible etiology, symptoms duration prior to presentations, details of previous surgery and the state of continence were all obtained and recorded. After routine preoperative assessment and mechanical bowel preparation one day prior to their scheduled surgery, patients were admitted as day case with preoperative Ceftriaxone 500mg and Mitronidazole 500mg administered approximately one hour prior to induction of anesthesia. Under controlled general anesthesia in lithotomy position, the examination commences to identify the internal and external opening where their exact locations and the distance from the anal verge were measured and recorded. Once identified, Eisenhammer retractor is applied and gentle probing of the external opening with angled fistula probe to establish its continuity with the internal opening. Then the granulation tissue in the fistula track was thoroughly scraped using progressive diameters of tape gauze ranges 1/8, ¼, and ½ of an inch (Nugauze, Smith and Nephew, CT, USA) or different shapes and sizes of microcurettes. Once the track is prepared properly scraped, the offending cryptoglandular complex and external opening were electrocauterized. If during preparation any unsuspected suppuration was found, the procedure would be postponed till the suppuration completely subsides (Fig. 1). BioGlue is then injected slowly, using the supplied applicator tip at the external opening, while the Eisenhammer retractor in place, we watch the internal opening. Once a blob of instantly solidifying glue is seen at the internal opening, filling the proximal part of the track, then the applicator was slowly and steadily withdrawn while the glue continued to be discharged. This fills the distal part of the track with glue until the applicator emerged at the external opening, where another blob of glue was formed at the perianal skin. The glue was allowed to become even more stable and solid over approximately one to two minutes then the Eisenhammer retractor was removed. Care was taken as not to catch the internal blob between the jaws of the retractor and dislodge the plug (Fig. 2,3). The blob at the external opening was trimmed almost flush, but two slight flanges at either end of the plug were left to facilitate early retention of the plug in the track. No dressing was applied, and the patient was discharged on the same day after full recovery with advice to shower and not to bathe for several days and to avoid sitting for

3 Kasr El Aini Journal of Surgery VOL., 10, NO 2 May long periods of time and they were instructed for fluid diet during first day with gradual step up to regular diet within 2-3 days (Fig. 4). Ciprofloxacin (500 mg twice daily) and metronidazole (250 mg three times per day) were prescribed for the first postoperative week and Paracetamol (500 mg) in the event of pain. All patients were instructed to return immediately in any event of throbbing pain or unusual discharge regardless of their follow up schedule. Patients were scheduled for their first follow up visit within 7-10 days post discharge where only history taking and inspection was carried out for fear of dislodgement of the recently deployed plug. Much interest was paid to the amount of soiling or discharge, its character & smell and whether decreasing or increasing as well as anal pain s character and intensity, the need for analgesics constitutional manifestations. If perianal suppuration was suspected the patients were offered examination under anesthesia with potential surgical drainage if any suppuration was found. Patients then were called for their subsequent follow up visits starting from their 4 th postoperative week at biweekly basis for 12 weeks where each visit full history taking and physical examination were carried out with special interest for the discharge, pain and tenderness if any. On their 8 th postoperative week, all patients had follow up endorectal ultrasonography on outpatient s basis to confirm fistula healing and absence of any cavities related to the treated fistula track. Treatment failure in our study was defined as primary where the fistula persists after 10 th postoperative week or occurrence of perianal suppuration and hence failure of the procedure during that period and secondary failure if the patient s original fistula recurred within one year of intervention after previous assumption of the fistula healing at a prior time. According to the patient s preference, cases of failure were offered either regluing or surgery (rectal advancement flaps Vs fistulotomy) yet they were excluded from further analysis. RESULTS During the period from April 2007 to Nov 2008 we recruited 18 patients with high anal fistula yet on subsequent hydrogen peroxide endorectal ultrasonography 3 cases were excluded from the study because of chronic cavities related to the fistula track in two cases and one female with rectovaginal fistula following previous obstructed vaginal delivery. Fifteen patients had water soluble contrast fistulography (14 males, mean age 38.2 ranged from 24 to 61) with trans-sphincteric in all except one male patients with high suprasphincteric fistula. Seven patients had recurrence of their fistula following fistulotomy in six patients and one case following rectal advancement flap. Branched fistulas were evident in five patients (4 cases recurrent). Average duration for symptom evolution was 32.7 months ranged from 2 to 82 months. At initial examination under anesthesia, 12 patients had their opening at posterior position (80%) with almost 50% (7/15) had more than one external opening. The average distance of the external opening from the anal verge averaged 2.57 cm ranged 2 to 6 cm. On probing 3 cases showed evident suppuration of the fistula track and were deferred for a second procedure of glue application on disappearance of the purulent discharge that ranged between 2 to 4 months. We experienced no difficulty in either openings identification and application techniques in all except one of our early cases where we removed the Eisenhammer retractor too soon before adequate time for the glue to solidify resulting in partial glue extrusion from the track. No toxic or allergic reactions were experienced by any of our patients and no operative related mortality in the first 30 days of surgery. During the follow up period (mean 7.5 months ranges from 4 to 18 months) we had 4 patients with primary treatment failure. In two patients presented on the 5 th and 9 th postoperative day to the ER department with severe agonizing perianal pain, on examination a perianal abscess related to their treated fistula track and both were surgically drained under regional anesthesia with fistula relapse on abscess healing. The other two cases with primary failure presented with persistence of their discharge beyond the 10 th postoperative week; one of them had the suboptimal glue application we mentioned earlier and the other one had early extrusion of his BioGlue plug together with some discharge in the first 10 days post procedure.

4 Kasr El Aini Journal of Surgery VOL., 10, NO 2 May Secondary failure was observed in one case with recurrent supra-sphincteric high anal fistula presented on the 11 th postoperative month after assumption of its complete healing on the 3 rd month with recurrence of discharge from the original fistula track yet from a new external opening as confirmed by follow up hydrogen peroxide endoanal ultrasonography. None of the remaining 10 patients (66.6%) experienced recurrence during their follow up with no change of their continence status from preoperative condition. Cases of relapse were afforded either regluing (two cases) or surgery which included rectal advancement flaps (two cases) and laid open fistulotomy (one case) yet all were excluded from further analysis. Fig 3: The Glue is left to solidify Fig 4: Final image Fig 1: Preoperative image of recurrent perianal fistula note two external openings Fig 2: the Bioglue application DISCUSSION Simple lay open fistulotomy is not an option for patients with high perianal fistulas or patients with impaired continence. In high anal fistula division of a large portion of the external sphincter muscle frequently results in a significant deterioration in fecal continence. [16] For that reason sphincter-preserving techniques must be adopted in these cases which include either rectal advancement flaps or the use of setons loose or cutting, yet with their own share of disadvantages and setbacks. Use of surgical adhesives in treatment of anal fistulas has been tried for almost two decade with variable reports of their success. [3,8,10-12] Using surgical adhesives, mainly fibrin glue, has increased considerably during the past two decades for its ease and simplicity of the technique However, recent reports with longer

5 Kasr El Aini Journal of Surgery VOL., 10, NO 2 May follow-up periods show higher recurrence rates than originally reported. [17] BioGlue launched early in this decade had proved efficiency in haemostatic and sealing purposes. It is four times stronger than fibrin glue and is composed of bovine serum albumin and glutaraldehyde. The glutaraldehyde molecules covalently bond (crosslink) BSA molecules to each other and to the tissue proteins at the repair site thus creating a flexible mechanical seal independent of the body's clotting mechanism [18]. BioGlue begins to polymerize within 20 to 30 seconds and reaches its full bonding strength within 2 minutes. Because BioGlue is a protein-based hydrogel, it is resorbed slowly like the silk sutures and is replaced by normal tissue. Experimental studies have shown that BioGlue remains intact for up to two years after application without causing a chronic inflammatory response [17]. In addition, its use in other fields of surgery has been documented [13-15]. It possesses certain advantages over fibrin glue such as rapid polymerization, resistance and flexibility. It has long durability without producing an inflammatory phenomenon with simple and quick injection system [18]. Another rather rare but realistic fear is viral transmission in case of fibrin derived surgical adhesives being dependant on pooled human plasma in their manufacture while BioGlue is not. In spite of the fact that surgical adhesives are being used for anal fistula over two decades, no consensus exists regarding their effectiveness. That in part is due to the heterogeneity of the published series and the non unification of the selection criteria [4]. The use of surgical adhesives in anal fistula has been associated with diverse treatment failure rates. Reports of 0% [19] and of 83.3% (95.7% in high transsphincteric) [20] success rate have been published. There much unknowns about the treatment of the anal fistula by surgical adhesives [21] However, several fundamental components are necessary for an effective treatment protocol, including the application of strict selection criteria, a perfect and meticulous perioperative patient management system, a comprehensive patient follow-up plan, and a controlled definition of fistula tract eradication [21]. In there opinion De La Portilla & colleagues [21] for any treatment plan to be efficacious, absence of associated abscesses and secondary tracts is imperative. Clinical exploration combined with endoanal ultrasonography, fistulography or magnetic resonance imaging before injection of glue is mandatory, because it may be advisable to drain the fistula track before sealing it. The endoanal ultrasound was found by other investigators to have more than 90% sensitivity in the diagnosis of perianal inflammatory condition, with great benefit of being more or less, a less invasive and simple procedure [22]. In our study we excluded patients with chronic cavities related to the offending fistulous track and for that we believe had contributed largely to our improved results. Sepsis elimination and infection eradication is of paramount importance to achieve fistula healing. It is believed that the technique used to curette the fistula tract is fundamental to the elimination of granulation tissue. [11,22], in our study we used the same curettage technique as De La Portilla [21] yet without the temporary use of setons as he did because we excluded patients with abscess or chronic cavities related to the fistula; nevertheless we had our share of treatment failure which we believe it was due to application failure (2 cases), septic complications (2 cases) and failure of side branch closure (one case). Factors responsible for observed treatment failures could be inadequate curettage, persistence of sepsis within the intersphincteric space, low resistance to infection of the BioGlue, and fragmentation and/or inadequate distribution of the product in the fistula tract and the secondary tracts [8,10,21,23]. Like De La Portilla [21] we observed no relations of the length, position and distance from the anal verge to our treatment failure. Conclusion: The overall treatment success rate by fistula closure was 66.7 percent in our study consistent with other reports using similar substances. [21,25] we can conclude that BioGlue can be a useful alternative treatment for high transsphincteric perianal fistula as first-line treatment in selected patients. However, because of small sample size further larger, randomized studies with long period follow up are needed to validate the

6 Kasr El Aini Journal of Surgery VOL., 10, NO 2 May results of this study and to objectively define and measure proper eradication of infection which is a major contributor to treatment failure observed with biological glue. REFERENCES 1. Shouler PJ, Grimley RP, Keighley MR, Alexander-Williams J. (1986) Fistula-inano is usually simple to manage surgically. Int J Colorectal Dis;1: Kronborg O. (1985) To lay open or excise a fistula-in-ano: a randomized trial. Br J Surg;72: Lindsey I, Smilgin-Humphreys MM, Cunningham C, Mortensen NJM, George BD. (2002) A randomized, controlled trial of fibrin glue vs. conventional treatment for anal fistula. Dis Colon Rectum;45: Whiteford MH, Kilkenny J III, Hyman N, et al. (2005) Practice parameters for the treatment of perianal abscess and fistula inano (revised). Dis Colon Rectum;48: Isbister WH, Al Sanea N. (2001) The cutting seton: an experience at King Faisal Specialist Hospital. Dis Colon Rectum;44: Garcia-Aguilar J, Belmonte C, Wong DW, Goldberg SM, Madoff RD. (1998) Cutting seton versus two-stage seton fistulotomy in the surgical management of high anal fistula. Br J Surg;85: Garcia-Aguilar J, Belmonte C, Wong WD, Golberg SM, Madoff RD. (1996) Anal fistula surgery: factors associated with recurrence and incontinence. Dis Colon Rectum;39: Venkatesh KS, Ramanujam P. (1999) Fibrin glue application in the treatment of recurrent anorectal fistulas. Dis Colon Rectum:42: Khafagy W, Zedan S, Setiet A, El-Awady S, Shobaky MT. (2001) Autologous fibrin glue in treatment of fistula in ano. Coloproctology;23: Cintron JR, Park JJ, Orsay CP, Pearl RK, Nelson RL, Abcarian H. (1999) Repair of fistulas-in-ano using autologous fibrin tissue adhesive. Dis Colon Rectum; 42: Buchanan GN, Bartram CI, Phillips RK, et al. (2003) Efficacy of fibrin sealant in the management of complex anal fistula. Dis Colon Rectum;46: Zmora O, Mizrahi N, Rotholtz N, et al. (2003) Fibrin glue sealing in the treatment of perineal fistulas. Dis Colon Rectum;46: Herget GW, Kassa M, Riede UN, Lu Y, Brethner L,Hasse J. (2001) Experimental use of an albumin-glutaraldehyde tissue adhesive for sealing pulmonary parenchyma andbronchial anastomoses. Eur J Cardiothorac Surg; 19: Hewitt CW, Marra SW, Kann BR. (2001) Bioglue surgical adhesive for thoracic aortic repair during coagulopathy: efficacy and histopathology. Ann Thorac Surg; 71: Kumar A, Maartens N, Kaye A. (2003) Evaluation of the use of Bioglue in neurosurgical procedures. J Clin Neurosci;10: Ramanujam PS, Prasad ML, Abcarian H, Tan AB. (1984) Perianal abscesses and fistulas. A study of 1023 patients. Dis Colon Rectum;27: Loungnarath J, Dietz DW, Mutch MG, Birnbaum EH, Kodner IJ, Fleshman JW. (2004) Fibrin glue treatment of complex anal fistula has low success rate. Dis Colon Rectum; 47: Schepers J: (2004). CryoLife Inc. Bioglue Kit. Product description Abbas MA, M.D. and Tejirian T, M.D. (2008) Bioglue for the Treatment of Anal Fistula is Associated with Acute Anal Sepsis. Dis Colon Rectum;51: Maralcan G, Konus I, Aybastı N, and Gökalp A (2006) The Use of Fibrin Glue in the Treatment of Fistula-In-Ano: A Prospective Study. Surg Today; 36: De la Portilla F, Rada R, Leon E, Cisneros N, Maldonado VH, Espinosa E. (2006) Evaluation of the use of BioGlue in the treatment of high anal fistulas: preliminary results of a pilot study. Dis Colon Rectum;50: Buchanan GN, Bartram CI, Williams AB, Halligan S, Cohen CRG. (2005) Value of hydrogen peroxide enhancement of three-

7 Kasr El Aini Journal of Surgery VOL., 10, NO 2 May dimensional endoanal ultrasound in fistulain-ano. Dis Colon Rectum;48: Chan K, Lau CW, Lai KK. (2002) Preliminary results of using a commercial fibrin sealant in the treatment of fistula inano. J R Coll Surg Edinb;47: Abel M, Chiu YS, Russell TR, Volpe PA. (1993) Autologous fibrin glue in the treatment of rectovaginal and complex fistulas. Dis Colon Rectum;36: Lovvik KM. (2004) A new adhesive in the treatment of anal fistulas. Budapest, Hungry: XXth Biennial Congress of ISUCRS, June 6 10, 2004.

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