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Single-donor fibrin sealant for repair of urethrocutaneous fistulae following multiple hypospadias and epispadias repairs
Journal of Pediatric Urology (2011) 7, 422e427
Single-donor fibrin sealant for repair of urethrocutaneous fistulae following multiple hypospadias and epispadias repairs Abdol-Mohammad Kajbafzadeh a,*, Hassan Abolghasemi b, Peyman Eshghi b, Farshid Alizadeh a, Azadeh Elmi a, Saman Shafaattalab a, SeyedSaeid Dianat a, Naser Amirizadeh b, Mohammad Javad Mohseni a a
Pediatric Urology Research Center, Pediatric Center of Excellence, Children’s Hospital Medical Center, Tehran University of Medical Sciences, Tehran, Iran b Iranian Blood Transfusion Organization, Tehran, Iran Received 7 March 2010; accepted 10 June 2010 Available online 15 July 2010
KEYWORDS Fibrin glue; Fistula; Recurrence; Urethra
Abstract Purpose: To evaluate the efficacy of fibrin sealant for repair of urethrocutaneous fistula after multiple failed hypospadias and epispadias surgeries. Materials and methods: The study population comprised 11 boys (mean age 12.18 years) with history of hypospadias or epispadias and at least two failed fistula repair operations leading to recurrent urethrocutaneous fistula. During the operation, single-donor fibrin glue, either from the patient (7) or a parent (4), was applied over the suture lines and beneath the skin. A urethral catheter was kept in place for 7e10 days. Follow up ranged from 6 to 24 months (mean 12.63 months). Results: Nine patients had an uneventful postoperative course. In one patient with a large fistula, partial wound dehiscence occurred. In another patient with complete hypospadias, hematoma formation caused skin dehiscence but the urethra remained intact. Both cases recovered after 6 months with no further intervention. No fistula recurrence was reported during follow up. Conclusion: Single-donor fibrin glue could be a useful adjunct to surgical management of patients after multiple failed attempts at hypospadias or epispadias fistula repair. Moreover, this product improves the safety margin regarding the risk of disease transmission. ª 2010 Published by Elsevier Ltd on behalf of Journal of Pediatric Urology Company.
Abbreviation: FSs, Fibrin sealants; VEGF, vascular endothelial growth factor; BBP, blood bank products. * Corresponding author. No. 32, 2nd Floor, 7th Street, Saadat-Abad, Ave., Tehran 1998714616, Iran. Tel.: þ98 21 2208 9946; fax: þ98 21 2206 9451. E-mail address: [email protected] (A.-M. Kajbafzadeh). 1477-5131/$36 ª 2010 Published by Elsevier Ltd on behalf of Journal of Pediatric Urology Company. doi:10.1016/j.jpurol.2010.06.004
Single-donor fibrin sealant for fistula repair
Introduction Urethrocutaneous fistula is one of the most common complications occurring after hypospadias or epispadias repair [1,2]. The reported incidence of fistula formation following hypospadias surgery varies from 4 to 20% [3]. It has also been reported that nearly 26% of children who were operated on for bladder exstrophyeepispadias complex developed fistula [4]. Recurrent urethrocutaneous fistula after urethral reconstructive operations can be attributed to several factors, such as distal urethral obstruction, diverticulum, tissue ischemia and postoperative infection [3]. These factors should be considered to prevent recurrence of fistula formation. Regardless of surgical advancement in the management of hypospadias and epispadias, we still encounter patients after multiple failed operations who are referred to pediatric urology specialist centers for the management of recurrent urethral fistula. Recurrent fistula without any underlying and reversible factors is a frustrating complication of urethral reconstructive surgery. Extensive scar formation and compromised blood supply of the adjacent tissues limit the use of transposition flaps and highlight the need for advanced techniques with better wound-healing properties that might lessen the chance of recurrence. Fibrin sealants are used in different reconstructive surgeries, such as urethroplasty, prostatectomy, partial nephrectomy, ureteral anastomosis, and hypospadias repair [5,6]. The benefit is mainly in hemostasis, and use as a urinary tract sealant and/or a tissue adhesive. In addition, fibrin glue facilitates cellular migration and angiogenesis, and can act as a sustained-release reservoir for several growth factors. These characteristics make this product a great asset for tissue engineering techniques such as bladder augmentation, hypospadias repair and other complex urinary tract reconstructions [7]. Currently, commercially available fibrin glues prepared from pooled cryoprecipitated fibrinogen from multiple plasma donors have been utilized. Donor screening, heattreating, and the use of a solvent/detergent suspension for inactivation of lipid-enveloped blood-borne viruses in plasma derivatives have made these products safer. However, the possible risk of transmission of blood-borne infections and high cost of commercially available glue led us to evaluate the adjuvant role of single-donor fibrin glue, for the surgical management of children with recurrent urethrocutaneous fistulae.
Materials and methods Patients Between September 2007 and January 2009, 11 patients with urethrocutaneous fistula after failed hypospadias or epispadias surgery were referred to our center. The background pathology was proximal penile hypospadias in eight patients, bladder exstrophyeepispadias complex in two, and epispadias in one patient. The fistulae were 2e3 mm in size (mean 2.6 mm). All patients had undergone at least two failed previous operations for fistula repair. Voiding
423 cystourethrography prior to surgery showed no urethral stricture. None of the patients had vesicoureteral reflux and bladder volume was normal for age in all of them. Ultrasound study of the genitourinary tract was also normal, and no signs of hydro-ureteronephrosis, bladder trabeculation or high post-voiding residual urine were reported. Patients underwent uroflowmetry before the operation. All patients had negative urine culture.
Surgical method Under general anesthesia, cystourethroscopy was performed to confirm the patency of the urethra both proximal and distal to the fistula. Then, after changing the position from lithotomy to supine, a proper-sized silicon urethral catheter was placed and a circumscribing incision was made around the fistula opening. The fistula tract was completely separated from the surrounding tissues and, after excising all scar tissues and freshening the edges of the fistula opening, inverting sutures using 6-0 Vicryl were inserted over it. In hypospadiac patients, a standard tubularized incised plate repair was made. Then, a layer of fibrin glue was applied over the closure area and a layer of dartos fascia was brought over it. Another layer of sealant was placed and skin closure was performed after ensuring appropriate hemostasis. Fibrin glue was supplied by the Iranian Blood Transfusion Organization by single-donor plasma donation either from the patient (in seven patients) or one of the parents (in four patients). Percutaneous punch cystostomy was performed using an 8-gauge needle suprapubic puncture and insertion of a 5-Fr catheter, and a tetracycline-soaked hypospadias foam dressing was placed at the end of the surgery. Fig. 1 illustrates the steps of urethrocutaneous fistula repair using fibrin sealants in hypospadias. Parenteral first-generation cephalosporin (cefazolin) and oral anticholinergics were administered and the dressing remained intact until the 3rd day postoperatively. After 7e10 days, the urethral catheter was removed and the cystostomy was clamped. If the patient was able to void properly and no urine leakage was observed from the fistula site, the cystostomy catheter was also removed on the next day.
Fibrin sealant preparation Patients with a body weight of over 40 kg, without any clinical restriction for plasmapheresis according to the national standards of the Iranian Blood Transfusion Organization, were selected for obtaining autologous fibrin sealant. All of the blood samples were tested for major viral markers, including hepatitis B, hepatitis C and HIV, as part of the routine screening of blood products. The principles of fibrin sealant preparation have been described before [23]. We used the cryoprecipitation method as the gold standard for fibrinogen preparation. On the operation day, protamine (Sigma Chemical Co., St. Louis, MO, USA) was added to the cryoprecipitates to precipitate the fibrinogen content, followed by centrifugation. Mean final fibrinogen concentration was 31 8 mg/ml. For the thrombin, 10 ml plasma and 4 ml reagent (calcium chloride and ethanol) were mixed in a glass tube and incubated for 30 min. The supernatant was used as
424
A.-M. Kajbafzadeh et al.
Figure 1 Repair of urethrocutaneous fistula using fibrin sealants in hypospadias. A) fistula opening. B) Inverting sutures placed over fistula opening. C, D) Applying fibrin glue over the closure. E) Immediate postoperative appearance of penis.
recovered human thrombin with activity of 59.6 0.6 NIH units. The whole process was done in a standard clean room and the products were delivered to the operation room in two separate sealed tubes.
Follow up Patients were evaluated for possible early postoperative complications. This was followed up by clinical examinations and ultrasonography, first at 3 months from the date of surgery and with visits every 3 months thereafter. On the follow up visits, the patients were evaluated for fistula recurrence and asked about the symptoms of urethral stricture; namely straining, reduction in force and caliber of the urine, and feeling of incomplete bladder emptying. Urethral calibration was performed using 10-Fr or 14-Fr plastic catheters. An ultrasound study was obtained as well to check for any possible hydronephrosis and postvoiding residue 3 months after the surgical repair. A successful operation was defined as no fistula recurrence or urethral stricture during the first 6 months. Uroflowmetry was performed during the 6 months of follow up in all patients.
The mean follow up interval was 12.63 (range: 6e24) months. Patients’ characteristics are outlined in Table 1. The mean hospital stay was 5.7 days (range: 3e7). All but two patients had an uneventful postoperative course. In one patient, partial wound dehiscence occurred and we had to hold the cystostomy tube in place for 3 weeks; he was the patient with the largest fistula (7 mm). After 3 months, only a pin-point fistula remained which healed completely 3 months later. In another patient with history of failed hypospadias repair, a subcutaneous hematoma developed that caused partial skin dehiscence, but the urethra remained intact. The wound was completely healed after 3 months and no fistula or stricture was observed on follow up visits. None of the patients showed either history of decreased force and caliber of urine or symptoms of obstructed voiding and difficulty in urination. The urethra could be calibrated to 10-Fr in the 6-year-old patient and to 14-Fr in the other patients. The ultrasound study showed no hydronephrosis and no change in the post-voiding residue as compared with the preoperation values. Median peak urinary flow rate was 6.2 ml/s (range: 5e8.6 ml/s) before and 9.7 ml/s (range: 5.6e10.3 ml/s) 6 months after the operation.
Discussion Results The mean age of the patients was 12.18 years (range: 6e15) and at least 6 months had elapsed since the last surgery.
Despite the different surgical options available for repairing urethrocutaneous fistulae occurring after hypospadias or epispadias repair, recurrent fistula formation is still
Single-donor fibrin sealant for fistula repair Table 1
425
Patients’ demographic and surgical characteristics.
No.
Age (years)
Basic pathology
Existing pathology
Fistula l ocation
No. previous repairs
Peak flow rate (preoperative)
Peak flow rate (postoperative)
Follow up (months)
1 2 3 4 5 6 7 8 9 10 11
15 14 6 12 7 15 8 8 9 11 9
BEEC Proximal Hypos Proximal Hypos Proximal Hypos Proximal Hypos Proximal Hypos BEEC Epispadias Proximal Hypos Proximal Hypos Proximal Hypos
Fistula Complete failure Fistula Complete failure Fistula Fistula Fistula Fistula Fistula Fistula Fistula
Penopubic e Distal shaft e Distal shaft Proximal shaft Penopubic Distal shaft Distal shaft Distal shaft Mid shaft
3 3 2 3 2 8 2 3 2 3 3
5.1 8.6 6.1 8.5 6.2 6.0 5.0 5.1 7.3 8.3 8.4
6.2 10.3 8.2 9.8 9.7 6.9 5.6 6.0 10.1 9.8 10.0
16 10 18 9 13 19 24 7 6 8 16
BEEC: bladder exstrophy complex, Hypos: hypospadias.
challenging and occasionally repeated attempts to reconstruct such fistulae may be unsuccessful [8]. Simple closure of the fistula can be performed in patients with sufficient penile skin. This procedure may be complicated by the potential risk of recurrent fistula formation through the overlying suture lines [9]. Interposition of a waterproofing layer between the urethral and skin closures between the suture lines reduces but does not eliminate recurrence [10]. It is noteworthy that each repair attempt may diminish the local tissue resources for efficient further repair that may be required. Several techniques have been described, using local penile subcutaneous tissue [11], tunica vaginalis [12], dartos [13] or fascia lata [14], but less invasive techniques are needed for the repair of fistula formation. In the current study, we investigated the potential of fibrin sealant as an adjunct to the surgical repair of hypospadias and epispadias fistulae to prevent further recurrence at suture lines. Fibrin sealant has important characteristics in reconstructive surgery that may contribute to its role as a bioadhesive and tissue matrix allowing cellular influx and tissue regeneration. In fistula repair, it reduces the risk of fistula recurrence and urethroplasty failure. It prevents urinary extravasation from the suture line, approximates anastomosed tissues and facilitates hemostasis and woundhealing [15]. The glue adhesive matrix is semi-permeable and allows cellular migration and the passage of nutrients to the healing site. Thrombin and factor XIII stimulate fibroblast proliferation and growth during the healing process, as well [16]. Kinahan and Johnson initially reported the use of fibrin sealant in hypospadias surgery. They found out that the rate of fistula formation, postoperative edema and duration of hospitalization were all reduced using Tisseel, the commercially available fibrin glue, on suture lines [5]. Other studies have confirmed the reduction in the incidence of postoperative urethrocutaneous fistula using fibrin glue [17,18]. Fibrin sealants can also be useful in complex anterior and posterior urethral surgeries, when skin or buccal mucosal grafts are used. These agents have shortened graft revascularization and operation time in bulbar urethroplasty [6,19], and have made early catheter removal possible after pendulous urethroplasty [15].
It has also been shown by Gopal et al. that use of fibrin sealant in hypospadias surgery may reduce but not eliminate the risk of fistula formation after hypospadias repair. Fistulae developed in six patients (10%) with hypospadias in whom fibrin glue was also used, while 19 (32%) of those cases without it developed a fistula postoperatively [18]. These promising results encouraged us to use fibrin glue in the surgical treatment of recurrent urethrocutaneous fistula that developed after failed hypospadias and epispadias surgeries. We have demonstrated the high efficacy of single-donor fibrin sealant, mainly autologous, for the repair of urethrocutaneous fistula after multiple failed hypospadias and epispadias surgeries. In the current study, we observed a favorable outcome in children with recurrent fistula after hypospadias or epispadias repair and no recurrence was detected during follow up. Fibrin glue enhances angiogenesis in healing tissues by several mechanisms. Fibroblast growth factor-2, vascular endothelial growth factor (VEGF), and platelet-derived growth factor mRNA concentration have all been shown to increase in fibrin glue treated tissues [20,21]. Thrombin, as one of the components of fibrin glue, is also a potent angiogenic factor and, in addition to this direct effect, sensitizes cells to the action of VEGF. The mitogenic activity of thrombin plus VEGF is more than twofold higher than that expected from the additive effects of each substance alone [22]. All the above-mentioned mechanisms may have contributed to successful urethral closure in our patients. The components of fibrin sealant can be prepared either from large pools of plasma or from single-donor plasma donations (autologous or homologous), which are often described as commercial and blood bank products, respectively. Commercially available sealants are extracted from pooled blood plasma, which makes it possible to produce a product with very high concentrations of fibrinogen (75e115 mg/ml) [23]. The final fibrinogen concentration of our fibrin sealant was 31 8 mg/ml, which was due to the single-donor nature of the product in comparison with the pooled plasma applied in commercially available sealants. Although increasing the fibrinogen concentration would result in enhancement of the
426 tensile and adhesion strength of the sealant, the clotting time decreases. It has been demonstrated that a fibrinogen concentration of 30e60 mg/ml gives a tensile strength equivalent to that of the commercial fibrin sealant Tisseel [24]. The use of commercial sealants has been associated with some safety issues. One of the major concerns is the possible risk of transmission of blood-borne diseases. In order to minimize this risk, plasma undergoes a series of procedures that lead to avoiding, inactivating and eliminating potential contaminants. These include donor selection and heat inactivation, nanofiltration and solvent/detergent treatment [25]. However, despite all these safety measures the risk of viral contamination cannot be completely eliminated. The other risk concerns allergic reactions and bleeding. Fatal intraoperative anaphylaxis and bleeding diathesis due to acquired factor V inhibitor (as a result of antibody formation against bovine factor V) have been reported [26]. By replacing human thrombin in sealants, this risk can be avoided as well. Homologous, blood bank product, fibrin sealants, which are prepared from single-unit plasma, carry less risk of allergic reactions and infection transmission in comparison with commercial fibrin sealants prepared from the pooled plasma of multiple donors. The use of autologous blood as the source of fibrinogen greatly reduces the risk of infection or allergic reactions. However, time-consuming production and non-uniform fibrinogen concentration should be considered as disadvantages of using fibrin sealants. In addition, there is no guideline regarding suitable fibrin concentrations to be used in this procedure. Autologous fibrin sealants have been successfully used in other fields, such as hernia repair and lung volume reduction surgery [27,28]. In the current study, the use of fibrin glue in patients with recurrent fistula following hypospadias or epispadias repair did effectively prevent further recurrence. The major limitation was the small number of patients enrolled as well as lack of a control group. Future studies should be designed to compare the results of fibrin sealants as an adjuvant to surgical repair.
A.-M. Kajbafzadeh et al.
[2]
[3]
[4]
[5] [6]
[7] [8]
[9]
[10] [11] [12]
[13]
[14]
[15]
[16]
[17]
Conclusions Single-donor fibrin glue could be a useful adjunct for the surgical management of patients who have undergone multiple failed attempts at hypospadias or epispadias fistula repair. Moreover, this product improves the safety margin regarding the possible risk of disease transmission, and its application is feasible for both the patient and surgeon.
[18]
[19]
[20]
Conflict of interest statement The authors have no conflict of interest.
[21]
References [22] [1] Santangelo K, Rushton HG, Belman AB. Outcome analysis of simple and complex urethrocutaneous fistula closure using
a de-epithelialized or full thickness skin advancement flap for coverage. J Urol 2003;170:1589e92. discussion 92. Schaeffer AJ, Purves JT, King JA, Sponseller PD, Jeffs RD, Gearhart JP. Complications of primary closure of classic bladder exstrophy. J Urol 2008;180:1671e4. discussion 74. Sunay M, Dadali M, Karabulut A, Emir L, Erol D. Our 23-year experience in urethrocutaneous fistulas developing after hypospadias surgery. Urology 2007;69:366e8. Baird AD, Mathews RI, Gearhart JP. The use of combined bladder and epispadias repair in boys with classic bladder exstrophy: outcomes, complications and consequences. J Urol 2005;174:1421e4. Kinahan TJ, Johnson HW. Tisseel in hypospadias repair. Can J Surg 1992;35:75e7. Barbagli G, De Stefani S, Sighinolfi MC, Pollastri CA, Annino F, Micali S, et al. Experience with fibrin glue in bulbar urethral reconstruction using dorsal buccal mucosa graft. Urology 2006;67:830e2. Kumar U, Albala DM. Fibrin glue applications in urology. Curr Urol Rep 2001;2:79e82. Waterman BJ, Renschler T, Cartwright PC. Variables in successful repair of urethro-cutaneous fistula after hypospadias surgery. J Urol 2002;168:726e30. Latifoglu O, Yavuzer R, Unal S, Cavusoglu T, Atabay K. Surgical treatment of urethral fistulas following hypospadias repair. Ann Plast Surg 2000;44:381e6. Shankar KR, Losty PD, Hopper M, Wong L, Rickwood AM. Outcome of hypospadias fistula repair. BJU Int 2002;89:103e5. Cimador M, Castagnetti M, De Grazia E. Urethrocutaneous fistula repair after hypospadias surgery. BJU Int 2003;92:621e3. Routh JC, Wolpert JJ, Reinberg Y. Tunneled tunica vaginalis flap is an effective technique for recurrent urethrocutaneous fistulas following tubularized incised plate urethroplasty. J Urol 2006;176:1578e80. discussion 81. Richter F, Pinto PA, Stock JA, Hanna MK. Management of recurrent urethral fistulas after hypospadias repair. Urology 2003;61:448e51. Kargi E, Yesilli C, Akduman B, Babuccu O, Hosnuter M, Mungan A. Fascia lata grafts for closure of secondary urethral fistulas. Urology 2003;62:928e31. discussion 31. Hick EJ, Morey AF. Initial experience with fibrin sealant in pendulous urethral reconstruction. Is early catheter removal possible? J Urol 2004;171:1547e9. Karacal N, Cobanoglu U, Ambarcioglu O, Kutlu N. The effect of fibrin glue on fat graft survival. J Plast Reconstr Aesthet Surg 2007;60:300e3. Ambriz-Gonza ´lez G, Vela ´zquez-Ramı´rez GA, Garcı´aGonza ´lez JL, de Leo ´n-Go ´mez JM, Mucin ˜o-Herna ´ndez MI, Gonza ´lez-Ojeda A, et al. Use of fibrin sealant in hypospadias surgical repair reduces the frequency of postoperative complications. Urol Int 2007;78:37e41. Gopal SC, Gangopadhyay AN, Mohan TV, Upadhyaya VD, Pandey A, Upadhyaya A, et al. Use of fibrin glue in preventing urethrocutaneous fistula after hypospadias repair. J Pediatr Surg 2008;43:1869e72. Barbagli G, De Stefani S, Sighinolfi MC, Annino F, Micali S, Bianchi G. Bulbar urethroplasty with dorsal onlay buccal mucosal graft and fibrin glue. Eur Urol 2006;50:467e74. Becker JC, Domschke W, Pohle T. Biological in vitro effects of fibrin glue: fibroblast proliferation, expression and binding of growth factors. Scand J Gastroenterol 2004;39:927e32. Becker JC, Beckbauer M, Domschke W, Herbst H, Pohle T. Fibrin glue, healing of gastric mucosal injury, and expression of growth factors: results from a human in vivo study. Gastrointest Endosc 2005;61:560e7. Maragoudakis ME, Tsopanoglou NE, Andriopoulou P. Mechanism of thrombin-induced angiogenesis. Biochem Soc Trans 2002;30:173e7.
Single-donor fibrin sealant for fistula repair [23] Shekarriz B, Stoller ML. The use of fibrin sealant in urology. J Urol 2002;167:1218e25. [24] Alston SM, Solen KA, Broderick AH, Sukavaneshvar S, Mohammad SF. New method to prepare autologous fibrin glue on demand. Transl Res 2007;149:187e95. [25] Joch C. The safety of fibrin sealants. Cardiovasc Surg 2003;11: 23e8. [26] Hong YM, Loughlin KR. The use of hemostatic agents and sealants in urology. J Urol 2006;176:2367e74.
427 [27] de Hingh IH, Nienhuijs SW, Overdevest EP, Scheele K, Everts PA. Mesh fixation with autologous platelet-rich fibrin sealant in inguinal hernia repair. Eur Surg Res 2009;43: 306e9. [28] Moser C, Opitz I, Zhai W, Rousson V, Russi EW, Weder W, et al. Autologous fibrin sealant reduces the incidence of prolonged air leak and duration of chest tube drainage after lung volume reduction surgery: a prospective randomized blinded study. J Thorac Cardiovasc Surg 2008;136:843e9.
Single-donor fibrin sealant for repair of urethrocutaneous fistulae following multiple hypospadias and epispadias repairs Abdol-Mohammad Kajbafzadeh a,*, Hassan Abolghasemi b, Peyman Eshghi b, Farshid Alizadeh a, Azadeh Elmi a, Saman Shafaattalab a, SeyedSaeid Dianat a, Naser Amirizadeh b, Mohammad Javad Mohseni a a
Pediatric Urology Research Center, Pediatric Center of Excellence, Children’s Hospital Medical Center, Tehran University of Medical Sciences, Tehran, Iran b Iranian Blood Transfusion Organization, Tehran, Iran Received 7 March 2010; accepted 10 June 2010 Available online 15 July 2010
KEYWORDS Fibrin glue; Fistula; Recurrence; Urethra
Abstract Purpose: To evaluate the efficacy of fibrin sealant for repair of urethrocutaneous fistula after multiple failed hypospadias and epispadias surgeries. Materials and methods: The study population comprised 11 boys (mean age 12.18 years) with history of hypospadias or epispadias and at least two failed fistula repair operations leading to recurrent urethrocutaneous fistula. During the operation, single-donor fibrin glue, either from the patient (7) or a parent (4), was applied over the suture lines and beneath the skin. A urethral catheter was kept in place for 7e10 days. Follow up ranged from 6 to 24 months (mean 12.63 months). Results: Nine patients had an uneventful postoperative course. In one patient with a large fistula, partial wound dehiscence occurred. In another patient with complete hypospadias, hematoma formation caused skin dehiscence but the urethra remained intact. Both cases recovered after 6 months with no further intervention. No fistula recurrence was reported during follow up. Conclusion: Single-donor fibrin glue could be a useful adjunct to surgical management of patients after multiple failed attempts at hypospadias or epispadias fistula repair. Moreover, this product improves the safety margin regarding the risk of disease transmission. ª 2010 Published by Elsevier Ltd on behalf of Journal of Pediatric Urology Company.
Abbreviation: FSs, Fibrin sealants; VEGF, vascular endothelial growth factor; BBP, blood bank products. * Corresponding author. No. 32, 2nd Floor, 7th Street, Saadat-Abad, Ave., Tehran 1998714616, Iran. Tel.: þ98 21 2208 9946; fax: þ98 21 2206 9451. E-mail address: [email protected] (A.-M. Kajbafzadeh). 1477-5131/$36 ª 2010 Published by Elsevier Ltd on behalf of Journal of Pediatric Urology Company. doi:10.1016/j.jpurol.2010.06.004
Single-donor fibrin sealant for fistula repair
Introduction Urethrocutaneous fistula is one of the most common complications occurring after hypospadias or epispadias repair [1,2]. The reported incidence of fistula formation following hypospadias surgery varies from 4 to 20% [3]. It has also been reported that nearly 26% of children who were operated on for bladder exstrophyeepispadias complex developed fistula [4]. Recurrent urethrocutaneous fistula after urethral reconstructive operations can be attributed to several factors, such as distal urethral obstruction, diverticulum, tissue ischemia and postoperative infection [3]. These factors should be considered to prevent recurrence of fistula formation. Regardless of surgical advancement in the management of hypospadias and epispadias, we still encounter patients after multiple failed operations who are referred to pediatric urology specialist centers for the management of recurrent urethral fistula. Recurrent fistula without any underlying and reversible factors is a frustrating complication of urethral reconstructive surgery. Extensive scar formation and compromised blood supply of the adjacent tissues limit the use of transposition flaps and highlight the need for advanced techniques with better wound-healing properties that might lessen the chance of recurrence. Fibrin sealants are used in different reconstructive surgeries, such as urethroplasty, prostatectomy, partial nephrectomy, ureteral anastomosis, and hypospadias repair [5,6]. The benefit is mainly in hemostasis, and use as a urinary tract sealant and/or a tissue adhesive. In addition, fibrin glue facilitates cellular migration and angiogenesis, and can act as a sustained-release reservoir for several growth factors. These characteristics make this product a great asset for tissue engineering techniques such as bladder augmentation, hypospadias repair and other complex urinary tract reconstructions [7]. Currently, commercially available fibrin glues prepared from pooled cryoprecipitated fibrinogen from multiple plasma donors have been utilized. Donor screening, heattreating, and the use of a solvent/detergent suspension for inactivation of lipid-enveloped blood-borne viruses in plasma derivatives have made these products safer. However, the possible risk of transmission of blood-borne infections and high cost of commercially available glue led us to evaluate the adjuvant role of single-donor fibrin glue, for the surgical management of children with recurrent urethrocutaneous fistulae.
Materials and methods Patients Between September 2007 and January 2009, 11 patients with urethrocutaneous fistula after failed hypospadias or epispadias surgery were referred to our center. The background pathology was proximal penile hypospadias in eight patients, bladder exstrophyeepispadias complex in two, and epispadias in one patient. The fistulae were 2e3 mm in size (mean 2.6 mm). All patients had undergone at least two failed previous operations for fistula repair. Voiding
423 cystourethrography prior to surgery showed no urethral stricture. None of the patients had vesicoureteral reflux and bladder volume was normal for age in all of them. Ultrasound study of the genitourinary tract was also normal, and no signs of hydro-ureteronephrosis, bladder trabeculation or high post-voiding residual urine were reported. Patients underwent uroflowmetry before the operation. All patients had negative urine culture.
Surgical method Under general anesthesia, cystourethroscopy was performed to confirm the patency of the urethra both proximal and distal to the fistula. Then, after changing the position from lithotomy to supine, a proper-sized silicon urethral catheter was placed and a circumscribing incision was made around the fistula opening. The fistula tract was completely separated from the surrounding tissues and, after excising all scar tissues and freshening the edges of the fistula opening, inverting sutures using 6-0 Vicryl were inserted over it. In hypospadiac patients, a standard tubularized incised plate repair was made. Then, a layer of fibrin glue was applied over the closure area and a layer of dartos fascia was brought over it. Another layer of sealant was placed and skin closure was performed after ensuring appropriate hemostasis. Fibrin glue was supplied by the Iranian Blood Transfusion Organization by single-donor plasma donation either from the patient (in seven patients) or one of the parents (in four patients). Percutaneous punch cystostomy was performed using an 8-gauge needle suprapubic puncture and insertion of a 5-Fr catheter, and a tetracycline-soaked hypospadias foam dressing was placed at the end of the surgery. Fig. 1 illustrates the steps of urethrocutaneous fistula repair using fibrin sealants in hypospadias. Parenteral first-generation cephalosporin (cefazolin) and oral anticholinergics were administered and the dressing remained intact until the 3rd day postoperatively. After 7e10 days, the urethral catheter was removed and the cystostomy was clamped. If the patient was able to void properly and no urine leakage was observed from the fistula site, the cystostomy catheter was also removed on the next day.
Fibrin sealant preparation Patients with a body weight of over 40 kg, without any clinical restriction for plasmapheresis according to the national standards of the Iranian Blood Transfusion Organization, were selected for obtaining autologous fibrin sealant. All of the blood samples were tested for major viral markers, including hepatitis B, hepatitis C and HIV, as part of the routine screening of blood products. The principles of fibrin sealant preparation have been described before [23]. We used the cryoprecipitation method as the gold standard for fibrinogen preparation. On the operation day, protamine (Sigma Chemical Co., St. Louis, MO, USA) was added to the cryoprecipitates to precipitate the fibrinogen content, followed by centrifugation. Mean final fibrinogen concentration was 31 8 mg/ml. For the thrombin, 10 ml plasma and 4 ml reagent (calcium chloride and ethanol) were mixed in a glass tube and incubated for 30 min. The supernatant was used as
424
A.-M. Kajbafzadeh et al.
Figure 1 Repair of urethrocutaneous fistula using fibrin sealants in hypospadias. A) fistula opening. B) Inverting sutures placed over fistula opening. C, D) Applying fibrin glue over the closure. E) Immediate postoperative appearance of penis.
recovered human thrombin with activity of 59.6 0.6 NIH units. The whole process was done in a standard clean room and the products were delivered to the operation room in two separate sealed tubes.
Follow up Patients were evaluated for possible early postoperative complications. This was followed up by clinical examinations and ultrasonography, first at 3 months from the date of surgery and with visits every 3 months thereafter. On the follow up visits, the patients were evaluated for fistula recurrence and asked about the symptoms of urethral stricture; namely straining, reduction in force and caliber of the urine, and feeling of incomplete bladder emptying. Urethral calibration was performed using 10-Fr or 14-Fr plastic catheters. An ultrasound study was obtained as well to check for any possible hydronephrosis and postvoiding residue 3 months after the surgical repair. A successful operation was defined as no fistula recurrence or urethral stricture during the first 6 months. Uroflowmetry was performed during the 6 months of follow up in all patients.
The mean follow up interval was 12.63 (range: 6e24) months. Patients’ characteristics are outlined in Table 1. The mean hospital stay was 5.7 days (range: 3e7). All but two patients had an uneventful postoperative course. In one patient, partial wound dehiscence occurred and we had to hold the cystostomy tube in place for 3 weeks; he was the patient with the largest fistula (7 mm). After 3 months, only a pin-point fistula remained which healed completely 3 months later. In another patient with history of failed hypospadias repair, a subcutaneous hematoma developed that caused partial skin dehiscence, but the urethra remained intact. The wound was completely healed after 3 months and no fistula or stricture was observed on follow up visits. None of the patients showed either history of decreased force and caliber of urine or symptoms of obstructed voiding and difficulty in urination. The urethra could be calibrated to 10-Fr in the 6-year-old patient and to 14-Fr in the other patients. The ultrasound study showed no hydronephrosis and no change in the post-voiding residue as compared with the preoperation values. Median peak urinary flow rate was 6.2 ml/s (range: 5e8.6 ml/s) before and 9.7 ml/s (range: 5.6e10.3 ml/s) 6 months after the operation.
Discussion Results The mean age of the patients was 12.18 years (range: 6e15) and at least 6 months had elapsed since the last surgery.
Despite the different surgical options available for repairing urethrocutaneous fistulae occurring after hypospadias or epispadias repair, recurrent fistula formation is still
Single-donor fibrin sealant for fistula repair Table 1
425
Patients’ demographic and surgical characteristics.
No.
Age (years)
Basic pathology
Existing pathology
Fistula l ocation
No. previous repairs
Peak flow rate (preoperative)
Peak flow rate (postoperative)
Follow up (months)
1 2 3 4 5 6 7 8 9 10 11
15 14 6 12 7 15 8 8 9 11 9
BEEC Proximal Hypos Proximal Hypos Proximal Hypos Proximal Hypos Proximal Hypos BEEC Epispadias Proximal Hypos Proximal Hypos Proximal Hypos
Fistula Complete failure Fistula Complete failure Fistula Fistula Fistula Fistula Fistula Fistula Fistula
Penopubic e Distal shaft e Distal shaft Proximal shaft Penopubic Distal shaft Distal shaft Distal shaft Mid shaft
3 3 2 3 2 8 2 3 2 3 3
5.1 8.6 6.1 8.5 6.2 6.0 5.0 5.1 7.3 8.3 8.4
6.2 10.3 8.2 9.8 9.7 6.9 5.6 6.0 10.1 9.8 10.0
16 10 18 9 13 19 24 7 6 8 16
BEEC: bladder exstrophy complex, Hypos: hypospadias.
challenging and occasionally repeated attempts to reconstruct such fistulae may be unsuccessful [8]. Simple closure of the fistula can be performed in patients with sufficient penile skin. This procedure may be complicated by the potential risk of recurrent fistula formation through the overlying suture lines [9]. Interposition of a waterproofing layer between the urethral and skin closures between the suture lines reduces but does not eliminate recurrence [10]. It is noteworthy that each repair attempt may diminish the local tissue resources for efficient further repair that may be required. Several techniques have been described, using local penile subcutaneous tissue [11], tunica vaginalis [12], dartos [13] or fascia lata [14], but less invasive techniques are needed for the repair of fistula formation. In the current study, we investigated the potential of fibrin sealant as an adjunct to the surgical repair of hypospadias and epispadias fistulae to prevent further recurrence at suture lines. Fibrin sealant has important characteristics in reconstructive surgery that may contribute to its role as a bioadhesive and tissue matrix allowing cellular influx and tissue regeneration. In fistula repair, it reduces the risk of fistula recurrence and urethroplasty failure. It prevents urinary extravasation from the suture line, approximates anastomosed tissues and facilitates hemostasis and woundhealing [15]. The glue adhesive matrix is semi-permeable and allows cellular migration and the passage of nutrients to the healing site. Thrombin and factor XIII stimulate fibroblast proliferation and growth during the healing process, as well [16]. Kinahan and Johnson initially reported the use of fibrin sealant in hypospadias surgery. They found out that the rate of fistula formation, postoperative edema and duration of hospitalization were all reduced using Tisseel, the commercially available fibrin glue, on suture lines [5]. Other studies have confirmed the reduction in the incidence of postoperative urethrocutaneous fistula using fibrin glue [17,18]. Fibrin sealants can also be useful in complex anterior and posterior urethral surgeries, when skin or buccal mucosal grafts are used. These agents have shortened graft revascularization and operation time in bulbar urethroplasty [6,19], and have made early catheter removal possible after pendulous urethroplasty [15].
It has also been shown by Gopal et al. that use of fibrin sealant in hypospadias surgery may reduce but not eliminate the risk of fistula formation after hypospadias repair. Fistulae developed in six patients (10%) with hypospadias in whom fibrin glue was also used, while 19 (32%) of those cases without it developed a fistula postoperatively [18]. These promising results encouraged us to use fibrin glue in the surgical treatment of recurrent urethrocutaneous fistula that developed after failed hypospadias and epispadias surgeries. We have demonstrated the high efficacy of single-donor fibrin sealant, mainly autologous, for the repair of urethrocutaneous fistula after multiple failed hypospadias and epispadias surgeries. In the current study, we observed a favorable outcome in children with recurrent fistula after hypospadias or epispadias repair and no recurrence was detected during follow up. Fibrin glue enhances angiogenesis in healing tissues by several mechanisms. Fibroblast growth factor-2, vascular endothelial growth factor (VEGF), and platelet-derived growth factor mRNA concentration have all been shown to increase in fibrin glue treated tissues [20,21]. Thrombin, as one of the components of fibrin glue, is also a potent angiogenic factor and, in addition to this direct effect, sensitizes cells to the action of VEGF. The mitogenic activity of thrombin plus VEGF is more than twofold higher than that expected from the additive effects of each substance alone [22]. All the above-mentioned mechanisms may have contributed to successful urethral closure in our patients. The components of fibrin sealant can be prepared either from large pools of plasma or from single-donor plasma donations (autologous or homologous), which are often described as commercial and blood bank products, respectively. Commercially available sealants are extracted from pooled blood plasma, which makes it possible to produce a product with very high concentrations of fibrinogen (75e115 mg/ml) [23]. The final fibrinogen concentration of our fibrin sealant was 31 8 mg/ml, which was due to the single-donor nature of the product in comparison with the pooled plasma applied in commercially available sealants. Although increasing the fibrinogen concentration would result in enhancement of the
426 tensile and adhesion strength of the sealant, the clotting time decreases. It has been demonstrated that a fibrinogen concentration of 30e60 mg/ml gives a tensile strength equivalent to that of the commercial fibrin sealant Tisseel [24]. The use of commercial sealants has been associated with some safety issues. One of the major concerns is the possible risk of transmission of blood-borne diseases. In order to minimize this risk, plasma undergoes a series of procedures that lead to avoiding, inactivating and eliminating potential contaminants. These include donor selection and heat inactivation, nanofiltration and solvent/detergent treatment [25]. However, despite all these safety measures the risk of viral contamination cannot be completely eliminated. The other risk concerns allergic reactions and bleeding. Fatal intraoperative anaphylaxis and bleeding diathesis due to acquired factor V inhibitor (as a result of antibody formation against bovine factor V) have been reported [26]. By replacing human thrombin in sealants, this risk can be avoided as well. Homologous, blood bank product, fibrin sealants, which are prepared from single-unit plasma, carry less risk of allergic reactions and infection transmission in comparison with commercial fibrin sealants prepared from the pooled plasma of multiple donors. The use of autologous blood as the source of fibrinogen greatly reduces the risk of infection or allergic reactions. However, time-consuming production and non-uniform fibrinogen concentration should be considered as disadvantages of using fibrin sealants. In addition, there is no guideline regarding suitable fibrin concentrations to be used in this procedure. Autologous fibrin sealants have been successfully used in other fields, such as hernia repair and lung volume reduction surgery [27,28]. In the current study, the use of fibrin glue in patients with recurrent fistula following hypospadias or epispadias repair did effectively prevent further recurrence. The major limitation was the small number of patients enrolled as well as lack of a control group. Future studies should be designed to compare the results of fibrin sealants as an adjuvant to surgical repair.
A.-M. Kajbafzadeh et al.
[2]
[3]
[4]
[5] [6]
[7] [8]
[9]
[10] [11] [12]
[13]
[14]
[15]
[16]
[17]
Conclusions Single-donor fibrin glue could be a useful adjunct for the surgical management of patients who have undergone multiple failed attempts at hypospadias or epispadias fistula repair. Moreover, this product improves the safety margin regarding the possible risk of disease transmission, and its application is feasible for both the patient and surgeon.
[18]
[19]
[20]
Conflict of interest statement The authors have no conflict of interest.
[21]
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