New Generation Tissue Sealants and Hemostatic Agents: Innovative Urologic Applications

Treatment Update

RIU0261_08-12.qxd 8/12/06 3:05 PM Page 104 TREATMENT UPDATE New Generation Tissue Sealants and Hemostatic Agents: Innovative Urologic Applications Michael A. Traver, MD, Dean G. Assimos, MD Department of Urology, Wake Forest University School of Medicine, Winston-Salem, NC Control of blood loss during urologic surgery is paramount to the success of patient recovery. Hemostatic agents and tissue sealants are used routinely to prevent excess blood loss and in reconstruction during surgical repair. Some of the available products include thrombin sealant, fibrin glue, bovine serum/ albumin/glutaraldehyde, and gelatin matrix. Each of these agents differs in mechanism, cost, and application. Complications can include allergic reactions or thromboembolism and the risk of contracting bovine spongiform encephalitis or hepatitis. Many new hemostatic agents are being developed and approved. The benefits and risks of use of these agents versus conventional treatment need to be considered on a case-by-case basis by the surgeon. [Rev Urol. 2006;8(3):104-111] © 2006 MedReviews, LLC Key words: Hemostasis • Thrombin sealants • Fibrin glue • Gelatin matrix • Thrombin • Urologic surgery lood loss has always been a concern in surgery. Methods to control bleeding and repair wounds have existed for many years. Efforts have ranged from the use of raw meat by the Ancient Egyptians1 to the use of dried plasma in World War I to achieve hemostasis.2 More traditional techniques have included applying pressure, electrocautery, and suturing. Over the past 20 years, a number of hemostatic agents and tissue sealants have been developed and are currently used in various surgical disciplines. Hemostatic agents act to stop bleeding B 104 VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY RIU0261_08-12.qxd 8/12/06 3:05 PM Page 105 New Tissue Sealants and Hemostatic Agents The clotting cascade involves the sequential activation of proenzymes in a stepwise response, which ultimately provides local generation of fibrin lattices that reinforce the platelet plug (Figure 1). Overview of Coagulation Cascade either mechanically or by augmenting the coagulation cascade, whereas tissue sealants are products that bind to and close defects in tissue. Herein, we provide an overview of the various types of tissue sealants and hemosta- Hemostasis is blood clot formation at the site of vessel injury. It is a complex interaction between platelets, plasma proteins, and coagulation and Fibrin Glue Fibrin glue products were approved by the US Food and Drug Administration (FDA) in 1998 for reinforcement of colonic anastomoses, splenic trauma, and cardiothoracic surgery. These products provide topical hemostasis, have sealant properties, and promote tissue approximation. A precursor of Hemostatic agents stop bleeding either mechanically or by augmenting the coagulation cascade. tic agents. Their mechanisms of action, benefits, risks, and current urologic applications are described. fibrinolytic pathways. Platelets are activated at the site of injury and provide the initial hemostatic response. Figure 1. Coagulation cascade. HMW, high molecular weight. CONTACT ACTIVATION Collagen from damaged vascular endothelium Resting platelets INTRINSIC PATHWAY Pre-kallikrein EXTRINSIC PATHWAY Kallikrein Tissue damage VIIa HMW kininogen VIII vWFGP1b Fibronectin XII XIIa Platelet activation XI VII Tissue thromboplastin (tissue factor) Ca++ XIa Ca++ IX Platelet granule release factors X IXa PFC Ca++ VIII Xa Va V PF3 Ca++ Thrombin Prothrombin XIIIa Fibrinogen Fibrin monomer Ca++ XIII Fibrin polymer Fibrin clot VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 105 RIU0261_08-12.qxd 8/12/06 3:05 PM Page 106 New Tissue Sealants and Hemostatic Agents continued this product class, thrombin powder, was first used on the battlefields of World War I.2 It did not gain widespread acceptance due to high transmission rates of viral hepatitis. There has been increasing interest in this class of products since the 1970s. This is due to advancements in the ability to purify high concentrations of thrombin/fibrinogen as well as improved viral detection. Mechanism Fibrin glue mimics the final steps of the coagulation cascade. In the presence of thrombin, fibrinogen is converted to fibrin. Thrombin also activates factor XIII, which stabilizes the clot, by promoting polymerization (cross linking) of the fibrin chains to long fibrin strands. This process occurs in the presence of calcium ions. It proceeds independently from the remainder of the coagulation cascade, and provides some degree of hemostasis even with defects in other portions of this pathway.3-5 There is subsequent proliferation of fibroblasts and formation of granulation tissue within hours of clot polymerization. Clot organization is complete 2 weeks after application. The fibrin clot caused by the sealant degrades physiologically. Fibrin sealant can be manufactured from pooled or single source donors. Currently, several products are available in the United States and abroad: Tisseel (Baxter HealthCare Corp., Irvine, CA), Hemaseel (Haemacure, Sarasota, FL), Beriplast P (Aventis Behring, Marburg, Germany), Bolheal (Fujisawa, Pharmaceuticals Osaka, Japan), and Quixil (Omrix, Brussels, Belgium). The composition of these products varies, but there are similarities: a 2-vial system containing fibrinogen, thrombin, factor XIII, and calcium (typically calcium chloride). Preparation takes approximately 15 minutes and once complete, the product is available for 106 VOL. 8 NO. 3 2006 use for 4 hours. The fibrin glue is applied with a double-barrel syringe onto a dry tissue bed. Fibrin sealants have been used in a variety of settings. Unfortunately, the evaluation of the efficacy of these compounds is hard to determine because they have been assessed only in animal models, case reports, and small series. Risks Bovine thrombin can cause an IgEmediated allergic reaction. Antibodies formed against bovine factor V or thrombin can cross react with human factor V, causing significant hemorrhage.3 Thromboembolic events can result if the sealant is introduced into large blood vessels. Bovine products have the theoretic risk of transmission of bovine spongiform encephalitis.4 The risk of transmitting hepatitis A, B, and C as well as HIV (type 1 or 2) exists. Methods for reducing the viral loads include vapor heating, filtration, pH modulation, and solvent detergent exposure, resulting in viral clearance greater than 10.6 log10.6 Urologic Applications Urinary Fistulas and Surgical Complications Papadopoulos and colleagues7 created a vesicovaginal fistula model in rabbits. Ten animals underwent repair with a conventional suture technique with a recurrence rate of 33%; a second group underwent suture repair augmented with fibrin glue (n
10) with no recurrences. Schneider and associates8 reported endoscopic treatment of vesicovaginal fistulas in 6 patients with a success rate of 66%, compared with an 88% success rate in 6 patients who underwent conventional open surgical repair. Morita and Tokue9 reported a “composite” approach for vesicovaginal fistula in which bovine collagen is initially injected to facilitate the retention of REVIEWS IN UROLOGY fibrin glue. Evans and colleagues10 reported their experience using fibrin sealants to treat 7 iatrogenic urinary tract injuries during gynecological and general surgical procedures, 7 complex urinary fistulas, and 5 urological surgical complications. Successful resolution of injuries/fistulas was obtained after a single application of sealant in 18 patients (94.7%). Although the aforementioned results are encouraging, there is limited experience with this approach; thus, patients should be carefully selected and duly informed that this is not standard therapy. Renal Sparing Surgery Some of the challenges facing urologists during a partial nephrectomy include control of bleeding and repair of the collecting system. Several groups have demonstrated the usefulness of fibrin glue during partial nephrectomy, where fibrin glue is applied to the cut surface of the kidney.11,12 Delayed hemorrhage was not reported, suggesting that fibrin sealant is effective for renal hemostasis. Pruthi and colleagues13 performed 15 consecutive hand-assisted laparoscopic partial nephrectomies using argon beam coagulation and fibrin glue, and reported no acute or delayed bleeding, and no urinary leak in 2 cases where the collecting system was entered. Kouba and colleagues14 investigated the intrinsic strength of the fibrin sealant bond when applied to the parenchyma and urinary collecting system in a porcine partial nephrectomy model. Two groups underwent repair with fibrin glue only; half had an in vivo sealant hardening time of 10 minutes and half had a time of 60 minutes, whereas the controls were treated with monopolar electrocautery alone. The strength of the vascular and pelvicaliceal repair was evaluated by infusing saline into the renal artery or retrograde infusion of the collecting system. Fibrin RIU0261_08-12.qxd 8/12/06 3:05 PM Page 107 New Tissue Sealants and Hemostatic Agents sealant was successful at supraphysiologic levels with a mean renal vascular and pelvicaliceal burst pressure of 378 and 166 mm Hg, respectively, as compared with 250 and 87 mm Hg in the control subjects. Ureteral Reconstruction Laparoscopic pyeloplasty and ureteroureterostomy can be technically challenging and time consuming. To assess the feasibility of an alternative technique, Eden and associates15 performed fibrin sealant laparoscopic pyeloplasty in 9 patients. Two stay sutures were placed to approximate the urothelium and the anastomoses were then completed with fibrin glue. The average operating room time was 180 minutes, there were no postoperative urine leaks, and all ureters were unobstructed at 1 to 2 years of follow-up. The use of fibrin glue for ureteral surgery has been assessed in a number of animal models. Barrieras and colleagues16 performed pyeloplasty in a porcine model using standard technique or a suture-assisted fibrin glue anastomosis. Immediate anastomotic leak point pressure was significantly lower in the fibrin group (3.5  1.5 mm Hg) versus the control (17.3  5.4 mm Hg; P
.038). Of the animals in the fibrin glue group (n
9), 6 developed urinomas, whereas the remaining 3 had unobstructed pressure flow studies. These results suggest that this technique had limited efficacy in this model. In contrast, Wolf and colleagues17 demonstrated that fibrin glue produces good radiographic findings and flow characteristics, when fibrin glue was used to close ureterostomies in swine. Anidjar and colleagues18 performed laparoscopic ureteroureterostomy in swine using fibrin glue without stay sutures. The operative time was 15 minutes per anastomosis. Immediate fluoroscopy demonstrated patency in all 10 anastomoses; however, there was leakage in 2. The latter 2 animals died postoperatively, and necropsy demonstrated anastomotic disruption and large urinomas in both. The aforementioned findings suggest that fibrin glue may prove to be a useful adjunct for ureteral anastomosis. However, it does not appear that it will become a useful primary method for ureteral approximation. Infertility Vasovasotomy and vasoepididymostomy. A major advantage of a fibrin-assisted technique is time and simplicity. Several authors19,20 have demonstrated in animal models that fibrin glue–assisted vasovasotomy has comparable anatomic success. Vankemmel and colleagues19 compared conventional 1-layer closure versus 3 transmural sutures followed by fibrin sealant in rats. Patency rates were 85% for the former and 92% for the latter, with a significantly shorter operative time with the use of fibrin glue. Wagenknecht21 reported results using this technique in humans. Shekarriz and colleagues22 used fibrin glue for a modified invagination technique of vasoepididymostomy in a rat model and reported comparable patency rates in a standard end-toside approach. Further investigation of these techniques is required to establish their clinical utility. Pediatrics Reconstruction. Fibrin sealant has been used to augment hypospadias repairs. Kinahan and Johnson23 reported using Tisseel, a fibrin glue preparation, to augment hypospadias repairs in children. When this adjunct was used, the fistula rate was lower, 9% (n
78) versus 28% (n
97). Hafez and colleagues24 reported an experimental model in rabbits using fibrin glue to patch a 15  15 mm defect created in the ventral tunica albuginea. The repair was evaluated at 2, 6, and 12 weeks. There were no hematomas, no evidence of corporal narrowing, and no venous leakage on cavernosography. Histopathologic evaluation demonstrated a fibrin sealant layer with angiogenesis and cellular infiltrate at 2 weeks, and regeneration of normal tunica albuginea without scarring at 6 and 12 weeks. These findings suggest that this might prove to be useful in the treatment of select patients with congenital or acquired chordee. Circumcision. Patients with hemophilia or other bleeding diatheses are at increased risk of hemorrhage when undergoing circumcision. Augmenting hemostasis could diminish postoperative bleeding and reduce the amount of factor replacement required; thus limiting costs as well.25-27 Avanoglu and colleagues25 demonstrated a significant decrease in the cost of circumcision when using fibrin glue as an adjunct. Miscellaneous Radical retropubic prostatectomy. Diner and colleagues28 examined fibrin sealants’ role in radical retropubic prostatectomy. One group underwent standard radical retropubic prostatectomy and fibrin sealant was applied to the completed anastomosis in the other. Drain output was significantly less in the latter cohort. However, the studies were not undertaken to determine if the drainage fluid contained urine. Therefore, the “true anastomotic sealant effect” could not be assessed. Gelatin Matrix/Thrombin Sealants FloSeal® Matrix Hemostatic Agent (FloSeal) (Baxter HealthCare, Deerfield, IL) is composed of thrombin and a proprietary gelatin matrix that is manufactured by extracting collagen from bovine corneal tissue. The collagen then undergoes gelatinization and cross linking/stabilization with glutaraldehyde. VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 107 RIU0261_08-12.qxd 8/12/06 3:05 PM Page 108 New Tissue Sealants and Hemostatic Agents continued This compound is then ground to 500to 600-m particles.29 The thrombin component, Thrombin-JMI® (King Pharmaceuticals, Inc., Bristol, TN), is of bovine origin and is supplied as a sterile freeze-dried powder that is reconstituted in 0.9% sodium chloride and mixed with the gelatin matrix in the operating room just before use. The preparatory time is approximately 1 minute and, once complete, the mixture is usable for 2 hours. Mechanism Both components work independently and synergistically to promote clot formation at the bleeding site. The granular nature of the compound conforms to the wound’s shape. The granules swell 10% to 20%, causing tamponade in the wound bed on contact with blood or other fluid. This reduces bleeding and provides a matrix on which a clot can form. The thrombin activates platelets; factors V, VII, and XII; and promotes the conversion of fibrinogen to fibrin. Fibrin traps the granular matrix, which promotes stability of this complex. Absorption of the gelatin complex typically occurs 6 to 8 weeks after application. The unique property of this product is the requirement for the presence of blood at its application site for activation. The FDA approval of FloSeal was based on results in which this agent was used in cardiothoracic, vascular, and general surgery in a multi-centered setting.30 The use of this product for urologic surgery has been mainly in trauma and partial nephrectomy where it has been assessed in animal models and clinical case series. Risks Treatment risks of this agent include developing bovine spongiform encephalitis,4 thromboembolic events if injected directly into medium to large blood vessels, immunologically induced coagulopathy, and IgE-mediated 108 VOL. 8 NO. 3 2006 anaphylaxis.1 There is also a theoretical risk of this substance serving as a nidus for infection, although this has not been reported. Urologic Applications Nephron Sparing Surgery FloSeal has been used to facilitate open and laparoscopic partial nephrectomy. Gill and colleagues31 reported on using FloSeal as an adjunct for laparoscopic partial nephrectomy. One cohort underwent conventional suture renorrhaphy, whereas FloSeal was applied to the resection bed before suturing in the other cohort. The amount of blood loss, duration of warm renal ischemia, and length of hospitalization were comparable between groups. However, the use of FloSeal resulted in significantly fewer major complications. Richter and colleagues32 performed partial nephrectomy with use of FloSeal in 25 consecutive patients with exophytic renal masses. Fifteen patients underwent open surgery; 10 patients underwent laparoscopic surgery. There were no hemorrhagic complications in either group. Trauma FloSeal may also facilitate renorrhaphy for trauma. Hick and colleagues33 assessed this in a porcine model of a grade 4 renal injury. One group (I) underwent repair with temporary occlusion of the renal artery and placement of gelatin foam in the defect followed by bolster suturing. FloSeal was applied to the exposed renal surface after renal artery occlusion in another group (II), and this was also done but without vascular control in another group (III). Mean operative blood loss in treatment groups II and III (81  50 mL and 99  94 mL, respectively) was substantially less than that in the control group (I) (192  140 mL, P
.036). Renal artery control did not have a significant impact on REVIEWS IN UROLOGY total blood loss but it did result in quicker times to achieve satisfactory hemostasis. Postoperative imaging studies demonstrated that urinary extravasation was less common in the FloSeal groups, suggesting that this agent may help seal the renal collecting system in traumatized kidneys. Percutaneous Nephrolithotomy Tubeless percutaneous nephrolithotomy has been performed in carefully selected patients at several centers. Lee and colleagues34 described a small series (n
7) in which the nephrostomy tract was occluded retrogradely with a balloon catheter and FloSeal was introduced to seal the tract. All patients in this small series had stable postoperative hemoglobin levels and no evidence of renal or perirenal bleeding as assessed with CT scans done on postoperative day 1. We question the utility of this practice because it increases the cost of percutaneous nephrolithotomy, and there is the theoretical risk of this substance migrating into the collecting system where it could cause obstruction or serve as a nidus for stone formation. Uribe and colleagues35 assessed the risks for the latter occurrences in an in vitro model where various hemostatic agents were placed in human urine. They found that FloSeal remained as a fine particle suspension (500-600 m) when in contact with urine. Fibrin glue formed a solid clot that was maintained through 72 hours, and at 5 days this clot became a cohesive mucoid gel. Polyethylene glycol forms a solid clot maintained through 5 days. The same group performed a study in which percutaneous access was obtained in swine, and Tisseel, FloSeal, CoSeal™ (Cohesion Technologies, Palo Alto, CA), or BioGlue® (Cryolife, Inc., Kennesaw, GA) was injected into the access tract and collecting system. Fifty percent of these renal units were demonstrated to RIU0261_08-12.qxd 8/12/06 3:05 PM Page 109 New Tissue Sealants and Hemostatic Agents be obstructed at both 1 and 5 days after injection. This study illustrates the potential for morbidity with this approach and if it is considered, a retrograde occlusion balloon catheter should be used to prevent migration of these agents into the collecting system. Cyanoacrylate Cyanoacrylate, better known as “superglue,” was first used as a tissue sealant in the 1940s; however, its use was limited due to the intense local inflammation it generated. Synthetic cyanoacrylate (2-octyl cyanoacrylate), Dermabond® (Ethicon, Inc., Somerville, NJ), was approved by the FDA in 1998 for skin closure. Several studies36,37 have since demonstrated that n-butyl2-cyanoacrylate and Dermabond have rience is needed with this approach to confirm its efficacy. Bovine Serum/Albumin/ Glutaraldehyde BioGlue (Cryolife, Inc.) is a proprietary compound approved in 2000 by the FDA as an adjunct to standard methods of hemostasis in adults undergoing vascular surgery. Mechanism BioGlue is a 2-component system consisting of purified bovine serum albumin and glutaraldehyde. Glutaraldehyde bridges the amine groups from the bovine serum albumin to extracellular matrix proteins of the target tissue forming a covalent bond between the tissue and adhesive. BioGlue has demonstrated efficacy in cardiac and peripheral vascular surgery. low toxicity and produce limited local inflammation. Grummet and colleagues38 studied 2-octyl cyanoacrylate and concluded it is not suitable as the sole method for the vesicourethral anastomoses during radical retropubic prostatectomy. Seifman and associates36 reported that 2-octyl cyanoacrylate was suitable for closure of a large cystotomy in a rabbit model while producing an inflammatory response similar to that in conventional suture closure. Bardari and colleagues39 reported use of n-butyl-2cyanoacrylate to treat 7 patients with a variety of urinary fistulas not responding to catheter drainage or stenting. Patients underwent endoscopic filling of a fistula with sealant. When the fistula involved the bladder, the urethral catheter was removed 48 to 96 hours after treatment. This resulted in eradication of the fistula in 5 of 7 patients (71%) at a median follow-up of 24 months. Further expe- Hewitt and colleagues40 used BioGlue during vascular anastomoses in an animal model, and, at 3 months, found minimal to no absorption of this adhesive and lack of an inflammatory response. to provide sealant and hemostatic aid in tissues other than arteries. There is an issue of possible tissue-related toxicity. As previously described, Hewitt and associates40 observed no fibrotic, granulomatous, or giant cell reaction. However, some researchers have reported otherwise.42,43 Furst and Banerjee42 allowed BioGlue to polymerize and then overlaid saline, and the resultant supernatant contained 100 to 200 mg/mL of glutaraldehyde. This was then applied to the liver, aorta, and lung of rabbits. This tissue was evaluated 2 and 7 days later. The lung and hepatic tissue were found to have severe inflammation, edema, and toxic necrosis, whereas aortic inflammation was less intense. BioGlue has demonstrated efficacy in cardiac and peripheral vascular surgery.44,45 Long-term studies are needed to better define its inflammatory profile. Its role in urology has not been assessed but it may prove to be useful to help control bleeding in procedures where intense inflammation already exists and the major blood vessels need to be exposed and skeletonized, such as post-chemotherapy retroperitoneal lymphadenectomy. Polyethylene Glycol Hydrogels Application The 2 component systems are mixed in a predefined ratio at the time of application. It works optimally when applied to a dry target field, with complete polymerization occurring in approximately 3 minutes. Applications Rotker and colleagues41 performed vascular anastomoses in an animal model where BioGlue was the only method of approximation. Four months after the procedure, all anastomoses were patent, intact, and without aneurysm or hematoma. The characteristics of this compound could lead it to be an excellent agent CoSeal (Cohesion Technologies, Inc.) and AdvaSeal-S (Genzyme Corp., Cambridge, MA) are polyethylene glycol (PEG)–based substances that polymerize at the site of application. They were approved by the FDA in 2000 for use as pulmonary sealants. Both are applied after being reconstituted in a syringe. They are degraded approximately 30 days after application. Ramakumar and colleagues46 demonstrated that PEG hydrogels are polymerized on the resection bed in a porcine laparoscopic partial nephrectomy model and provide an adherent bond that is hemostatic at physiologic renal perfusion pressures. Furthermore, Park and colleagues47 VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 109 RIU0261_08-12.qxd 8/12/06 3:05 PM Page 110 New Tissue Sealants and Hemostatic Agents continued noted no detectable humoral- or cellmediated immune responses at 2 weeks after application. 5. 6. 7. Conclusion There are a number of tissue sealants and hemostatic agents available to facilitate urologic surgery. The efficacy of some applications has been established, but others are awaiting further evaluation and confirmation. When one of these adjuncts is used, the surgeon must be sure that this approach will provide equal or better results than results with standard methods. They should also consider the cost, pitfalls, and potential complications associated with these agents when choosing to use 1 or more of them. We think that this is an exciting and innovative area and anticipate that further product development and refinement is on the horizon. References 1. 3. 4. 9. 10. 11. 12. 13. 14. 15. Shekarriz B, Stoller ML. The use of fibrin sealant in urology. J Urol. 2002;167:1218-1225. Bergel S. Ueber wirkungen des fibrins. Dtsch Med Wochenschr. 1909;35:633.[ME1] Radosevich M, Goubran HI, Burnouf T. Fibrin sealant: scientific rationale, production methods, properties, and current clinical use. Vox Sang. 1997;72:133-143. Martinowitz U, Saltz R. Fibrin sealant. Curr Opin Hematol. 1996;3:395-402. 2. 8. 16. 17. Spotnitz WD. Commercial fibrin sealants in surgical care. Am J Surg. 2001;182:8S-14S. Joch C. The safety of fibrin sealants. Cardiovasc Surg. 2003;11:23-28. Papadopoulos I, Schnapka B, Kelami A. [Use of human fibrin glue in the closure of vesicovaginal fistulas]. Urol Int. 1985;40:141-144. Schneider JA, Patel VJ, Hertel E. [Closure of vesicovaginal fistulas from the urologic viewpoint with reference to endoscopic fibrin glue technique]. Zentralbl Gynakol. 1992;114:70-73. Morita T, Tokue A. Successful endoscopic closure of radiation induced vesicovaginal fistula with fibrin glue and bovine collagen. J Urol. 1999; 162:1689. Evans LA, Ferguson KH, Foley JP, et al. Fibrin sealant for the management of genitourinary injuries, fistulas and surgical complications. J Urol. 2003;169:1360-1362. Kram HB, Ocampo HP, Yamaguchi MP, et al. Fibrin glue in renal and ureteral trauma. Urology. 1989;33:215-218. Levinson AK, Swanson DA, Johnson DE, et al. Fibrin glue for partial nephrectomy. Urology. 1991;38:314-316. Pruthi RS, Chun J, Richman M. The use of a fibrin tissue sealant during laparoscopic partial nephrectomy. BJU Int. 2004;93:813-817. Kouba E, Tornehl C, Lavelle J, et al. Partial nephrectomy with fibrin glue repair: measurement of vascular and pelvicaliceal hydrodynamic bond integrity in a live and abbatoir porcine model. J Urol. 2004;172:326-330. Eden CG, Sultana SR, Murray KH, et al. Extraperitoneal laparoscopic dismembered fibringlued pyeloplasty: medium-term results. Br J Urol. 1997;80:382-389. Barrieras D, Reddy PP, McLorie GA, et al. Lessons learned from laser tissue soldering and fibrin glue pyeloplasty in an in vivo porcine model. J Urol. 2000;164:1106-1110. Wolf JS Jr, Soble JJ, Nakada SY, et al. Comparison of fibrin glue, laser weld, and mechanical suturing device for the laparoscopic closure of 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. ureterotomy in a porcine model. J Urol. 1997;157:1487-1492. Anidjar M, Desgrandchamps F, Martin L, et al. Laparoscopic fibrin glue ureteral anastomosis: experimental study in the porcine model. J Endourol. 1996;10:51-56. Vankemmel O, Rigot JM, Burnouf T, et al. Delayed vasal reanastomosis in rats: comparison of a microsurgical technique and a fibrin-glued procedure. Br J Urol. 1996;78:271-274. Kucukaydin M, Okur H, Kontas O, et al. Fibrin glue and conventional sutured vasal anastomosis in the rat. J Surg Res. 1995;59:601-605. Wagenknecht LV. [Seminal tract reconstruction: 15 years experience]. Prog Urol. 1994;4:10001008. Shekarriz BM, Thomas AJ Jr, Sabanegh E, et al. Fibrin-glue assisted vasoepididymostomy: a comparison to standard end-to-side microsurgical vasoepididymostomy in the rat model. J Urol. 1997;158:1602-1605. Kinahan TJ, Johnson HW. Tisseel in hypospadias repair. Can J Surg. 1992;35:75-77. Hafez AT, El-Assmy A, El-Hamid MA. Fibrin glue for the suture-less correction of penile chordee: a pilot study in a rabbit model. BJU Int. 2004;94:433-436. Avanoglu, A, Celik A, Ulman I, et al. Safer circumcision in patients with haemophilia: the use of fibrin glue for local haemostasis. BJU Int. 1999;83:91-94. Martinowitz U, Schulman S. Fibrin sealant in surgery of patients with a hemorrhagic diathesis. Thromb Haemost. 1995;74:486-492. Martinowitz U, Varon D, Jonas P, et al. Circumcision in hemophilia: the use of fibrin glue for local hemostasis. J Urol. 1992;148:855-857. Diner EK, Patel SV, Kwart AM. Does fibrin sealant decrease immediate urinary leakage following radical retropubic prostatectomy? J Urol. 2005;173:1147-1149. Oz MC, Rondinone JF, Shargill NS. FloSeal Matrix: new generation topical hemostatic sealant. J Card Surg. 2003;18:486-493. Main Points • Hemostatic agents and tissue sealants are used in a number of surgical disciplines. Hemostatic agents stop bleeding either mechanically or by augmenting the coagulation cascade, whereas tissue sealants are products that bind to and close defects in tissue. • Fibrin glue products provide topical hemostasis, have sealant properties, and promote tissue approximation; however, they require further study in humans. • The granular nature of the thrombin and gelatin matrix compound allows conformation to the wound’s shape—the granules swell 10% to 20%, causing tamponade in the wound bed on contact with blood or other fluid. • More experience is required with cyanoacrylate to assess its efficacy in clinical use. • BioGlue (bovine serum albumin and glutaraldehyde) works best in a dry-field application. • Polyethylene glycol hydrogels cause minimal inflammation and allergic reactions with superior hemostasis. • Surgeons must consider cost, application, side effects, and efficacy when choosing a hemostatic agent or tissue sealant for use in certain surgical procedures. 110 VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY RIU0261_08-12.qxd 8/12/06 3:05 PM Page 111 New Tissue Sealants and Hemostatic Agents 30. 31. 32. 33. 34. 35. Summary of safety and effectiveness: FloSeal matrix hemostatic sealant. United States Food and Drug Administration. PMA, P990009, 2000. Gill IS, Ramani AP, Spaliviero M, et al. Improved hemostasis during laparoscopic partial nephrectomy using gelatin matrix thrombin sealant. Urology. 2005;65:463-466. Richter F, Schnorr D, Deger S, et al. Improvement of hemostasis in open and laparoscopically performed partial nephrectomy using a gelatin matrix-thrombin tissue sealant (FloSeal). Urology 2003;61:73-77. Hick EJ, Morey AF, Harris RA, et al. Gelatin matrix treatment of complex renal injuries in a porcine model. J Urol. 2005;173:1801-1804. Lee DI, Uribe C, Eichel L, et al. Sealing percutaneous nephrolithotomy tracts with gelatin matrix hemostatic sealant: initial clinical use. J Urol. 2004;171:575-578. Uribe CA, Eichel L, Khonsari S, et al. What happens to hemostatic agents in contact with urine? An in vitro study. J Endourol. 2005;19: 312-317. 36. 37. 38. 39. 40. 41. 42. Seifman BD, Rubin MA, Williams AL, et al. Use of absorbable cyanoacrylate glue to repair an open cystotomy. J Urol. 2002;167:1872-1875. Montanaro L, Arciola CR, Cenni E, et al. Cytotoxicity, blood compatibility and antimicrobial activity of two cyanoacrylate glues for surgical use. Biomaterials. 2001;22:59-66. Grummet JP, Costello AJ, Swanson DA, et al. Vesicourethral anastomosis with 2-octyl cyanoacrylate adhesive in an in vivo canine model. Urology. 2002;60:935-938. Bardari F, D’Urso L, Muto G. Conservative treatment of iatrogenic urinary fistulas: the value of cyanoacrylic glue. Urology. 2001;58:1046-1048. Hewitt CW, Marra SW, Kann BR, et al. BioGlue surgical adhesive for thoracic aortic repair during coagulopathy: efficacy and histopathology. Ann Thorac Surg. 2001;71:1609-1612. Rotker J, Trosch F, Grabosch D, et al. Vascular anastomosing by gluing—an experimental study. Thorac Cardiovasc Surg. 2004;52:6-9. Furst W, Banerjee A. Release of glutaraldehyde from an albumin-glutaraldehyde tissue adhesive causes significant in vitro and in vivo toxicity. Ann Thorac Surg. 2005;79:1522-1528. 43. Erasmi AW, Sievers HH, Wolschlager C. Inflammatory response after BioGlue application. Ann Thorac Surg. 2002;73:1025-1026. 44. Chao HH, Torchiana DF. BioGlue: albumin/ glutaraldehyde sealant in cardiac surgery. J Card Surg. 2003;18:500-503. 45. Coselli JS, Bavaria JE, Fehrenbacher J, et al. Prospective randomized study of a protein-based tissue adhesive used as a hemostatic and structural adjunct in cardiac and vascular anastomotic repair procedures. J Am Coll Surg. 2003; 197:243-252. 46. Ramakumar S, Roberts WW, Fugita OE, et al. Local hemostasis during laparoscopic partial nephrectomy using biodegradable hydrogels: initial porcine results. J Endourol. 2002;16: 489-494. 47. Park EL, Ulreich JB, Scott KM, et al. Evaluation of polyethylene glycol based hydrogel for tissue sealing after laparoscopic partial nephrectomy in a porcine model. J Urol. 2004;172:2446-2450. VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 111