Hemostatic Agents and Tissue Glues in Urologic Injuries and Wound Healing

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Hemostatic Agents and Tissue Glues in Urologic Injuries and Wound Healing
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  Hemostatic Agents and Tissue Glues in UrologicInjuries and Wound Healing L. Andrew Evans, MD, Allen F. Morey, MD* Urology Service, Brooke Army Medical Center, 3851 Roger Brooke Drive, Fort Sam Houston, TX, USA Although most applications are off-label, tissuesealants and hemostatic agents are being usedincreasingly across all surgical disciplines. Biosur-gical compounds can serve as adjuncts to primarysurgical therapy or may assist in managing orpreventing surgical complications. In urology,hemostatic agents and tissue sealants are findingincreasing roles in managing traumatic and iatro-genic urologic injuries and promoting optimalwound healingAmong the variety of hemostatic products nowavailable in the United States (Table 1), fibrinsealant and gelatin matrix thrombin are themost widely used biosurgical agents in urologicsurgery. This article details the diverse urologicapplications of these products for hemostasis, tis-sue adhesion, and urinary tract sealing. Fibrin sealant Development Mixtures of coagulation factors have been usedin surgery for almost a century, dating back to theuse of a fibrin emulsion by Bergel in 1909 topromote wound healing [1]. Purified thrombin be-came available in 1938 and was first combinedwith fibrinogen in 1944 to enhance adhesion of skin grafts to burned soldiers [2]. Although com- mercial fibrin sealant has been widely used in Eu-rope since the 1970s, concerns about possible viraltransmission limited sealant use in the UnitedStates until recently. In 1998, Tisseel   (BaxterHealth care, Deerfield, Illinois) became the first fi-brin sealant approved by the Food and Drug Ad-ministration (FDA) for use in the United States.Although the three FDA-approved indicationsfor fibrin sealant are reoperative cardiac surgery,colon anastomosis, and treatment of splenic in- jury, fibrin sealants have been successfully used incountless numbers of nonurologic surgical appli-cations, including liver laceration [3], hepatic re- section [4], bowel and vascular anastomoses [5,6], enterocutaneous [7] and anorectal fistulae [8] clo- sure, cardiothoracic surgery [9], neurosurgery [10], and embryo transfer [11]. A review in 2002 by Shekarriz and Stoller [12] was the first majorcontemporary urologic publication addressingthe use of fibrin sealant in urologic surgery, andan increasing number of urologic sealant applica-tions have followed. Composition Fibrin sealant contains two major components(thrombin and highly concentrated fibrinogen)that replicate and augment the final stage of thecoagulation cascade d the cleavage of fibrinogeninto fibrin by the action of thrombin d whenmixed together. The fibrinogen concentration of sealant is supraphysiologic, 15 to 25 times higherthan that of circulating plasma. The resultant clottends to form more rapidly and more reliably thannormal. Other key components of fibrin sealantare Factor XIII, which covalently crosslinks thefibrin polymer to produce an insoluble fibrincoagulum, and an antifibrinolytic agent whichinhibits fibrinolysis thus preserving the stablefibrin clot (Fig. 1). The views expressed in this article are those of theauthors and do not reflect the official policy or posi-tion of the Department of Defense or other depart-ments of the US Government.* Corresponding author. E-mail address:  allen.morey@amedd.army.mil(A.F. Morey).0094-0143/06/$ - see front matter. Published by Elsevier Inc.doi:10.1016/j.ucl.2005.10.004  urologic.theclinics.com Urol Clin N Am 33 (2006) 1–12  Tisseel   (Baxter Health care, Deerfield, Illi-nois) and Crosseal   (Omrix Biopharmaceuticals,Ltd, Israel) are the two fibrin sealants currentlymarketed in the United States. Tisseel containsbovine aprotinin as its antifibrinolytic agent.Aprotinin is a serine protease inhibitor derivedfrom bovine lung that works to limit fibrinolysisby inhibiting plasmin, kallikrein, and trypsin.Crosseal uses only human-derived proteins byincluding tranexamic acid as its antifibrinolyticagent instead of bovine aprotinin. Tranexamicacid is a synthetic analog of the amino acid lysineand competes for lysine binding sites on plasmin-ogen and plasmin, preventing binding to fibrinand inhibiting fibrinolysis [13]. Safety All approved fibrin sealant preparations usea combination of donor screening, serum testingand retesting after 90 days storage, and a two-stepvapor heating process to ensure viral safety[14,15]. These steps are highly effective in ensuringviral safety and, to our knowledge, in 2005, notransmissions of blood-borne viral pathogens as-sociated with the use of FDA-approved fibrinsealants have yet been reported [14]. One parvovirus B19 transmission involving a non-FDA approved fibrin sealant was reported fromJapan, but most adults have preexisting antibod-ies to this virus and the infection is usuallya self-limited diarrhea [16]. Delivery methods Fibrin sealants are administered using a dual-chamber delivery system in which one chambercontaining fibrinogen and factor XIII is admixedwith the other chamber containing thrombindirectly at the site of application using a ‘‘Y’’adaptor, allowing an immediate conversion of fibrinogen to fibrin as the solutions exit thesyringe [17]. Dual lumen catheters ensure smooth,rapid sealant delivery, and various specializedcatheters and cannulae are available for endo-scopic, laparoscopic, and open surgical applica-tion. A dual lumen peripherally inserted centralcatheter line for percutaneous transrenal applica-tion also has been used successfully [18]. Polymer-ization into the biocompatible fibrin clot iscompleted within 3 minutes [19], and the clot isbroken down gradually and removed from thesite by macrophages within 2 to 4 weeks, eventu-ally becoming histopathologically invisible, with-out fibrosis or foreign-body reaction [20]. Urologic applications Commercial fibrin sealant is used for threemajor reasons in urologic surgery d as a hemo-static agent, a urinary tract sealant, or a tissueadhesive. A list of the most common urologicapplications is presented in Box 1. Fibrin sealant’sunique properties as a hemostatic agent, urinarytract sealant, and tissue adhesive make it an Fibrinogen Fibrin Monomers Fibrin Monofilaments Stable Fibrin ClotFactor XIII Activated Thrombin Fig. 1. Mechanism of action of liquid fibrin sealant inrecapitulating the terminal portion of the coagulationcascade.Table 1Hemostatic agents and tissue adhesive available in theUnited StatesComponent Brand Name ManufacturerHemostatic AgentsFibrin sealant Tisseel VH   Baxter HealthcareCrosseal   OmrixBiopharmaceuticals,LtdGelatin Matrixthrombin sealantFloSeal   Baxter HealthcareThrombin Thrombin-JMI  Jones PharmaGelatin sponge Gelfoam   Pharmacia UpjohnOxidized cellulose Surgicel   EthiconCollagen sponge Actifoam   CR BardCollagen fleece Avitene   CR BardRecombinantFactor VIIaNovoSeven   Novo Nordisk A/STissue AdhesivesFibrin sealant Tisseel VH   Baxter HealthcareCrosseal   OmrixBiopharmaceuticals,LtdPolyethyleneglycolCoSeal   Baxter HealthcareCyanoacrylate Dermabond   Ethicon2  EVANS & MOREY  effective adjunct for managing complex urologicinjury and promoting wound healing in the geni-tourinary tract. HemostasisPartial nephrectomy Fibrin sealant has been used since 1979 in openpartial nephrectomy [21,52]. The recent advent of  minimally invasive techniques for nephron spar-ing surgery has resulted in widespread fibrin seal-ant use during laparoscopic partial nephrectomytoday [22–25]. A recent survey of 193 membersof the World Congress of Endourology discovered68% of surgeons routinely used fibrin sealant toassist with hemostasis during laparoscopic partialnephrectomy [26]. Application of fibrin sealant tothe cut surface of the renal parenchymal woundafter segmental vascular and collecting system su-ture ligation during partial nephrectomy enhanceshemostasis. The fibrin sealant layer can then besupported by a gelatin or collagen bolster, whichis glued effectively into the renal defect by holdingmanual pressure on the bolster ‘‘sandwich.’’ Invivo testing of fibrin sealant in a porcine modelof open partial nephrectomy demonstrated supra-physiologic sealing pressures of the renal paren-chymal vasculature (mean 378 mm Hg) andcollecting system (mean 166 mm Hg) comparedwith unsealed controls [53]. Renal trauma In 1989, Kram and colleagues first reported fi-brin sealant use in 14 patients who presented withtraumatic renal injuries; renal salvage wasachieved always with no postoperative infection,delayed hemorrhage, or urinoma formation [54].In 2004, the authors’ laboratory reported the ef-fective use of FDA-approved fibrin sealant in cen-tral porcine renal stab wounds when used inconjunction with a bolster of absorbable gelatinsponge or microfibrillar collagen [55]. Thoughnot yet available commercially, the absorbable fi-brin adhesive bandage, a similar product consist-ing of dry fibrin sealant on a polyglactin meshbacking developed in conjunction with the Amer-ican Red Cross, significantly reduced bleeding inaddition to operative and ischemic times in repairof porcine models of lower renal pole amputation[56] and Grade IV renal stab wounds [57]. Miscellaneous hemostatic applications Noller and colleagues reported no hemorrhagiccomplications in 10 consecutive renal units treatedwith fibrin sealant-assisted tubeless percutaneousnephrolithotomy (PCNL) [27]. The instillation of 2 to 3 mL of fibrin sealant into the parenchymaldefect is performed as the sheath is removed atthe conclusion of PCNL in lieu of nephrostomydrainage. Postoperative computed tomography(CT) imaging has confirmed the absence of perire-nal hematomas in these ‘‘tubeless’’ procedures.Intraoperative splenic injury during left ne-phrectomy is managed easily with direct applica-tion of fibrin sealant to the bleeding parenchyma,thereby promoting prompt hemostasis and avoid-ing the need for splenectomy [28]. Fibrin sealantalso has been used successfully to control ‘‘medi-cal’’ bleeding caused by warfarin use or other Box 1. Urologic applications of fibrinsealant I. Hemostasis  Partial nephrectomyOpen [21,22]Laparoscopic [23–26]Percutaneous nephrolithotomy [27]Management of splenic injury [28]Hemophilia and other coagulopathy[29–31]Circumcision [30,31]Hemorrhagic cystitis [32] II. Urinary tract sealant  Laparoscopic and open pyeloplasty[33–46]Ureteral anastomoses [33–36]Urethral reconstruction [37]Simple retropubic prostatectomy [38]Radical retropubic prostatectomy [39]Vasovasostomy andvasoepididymostomy [40–42]Bladder injury [29]Lymphadenectomy [43,44]Percutaneous nephrolithotomy tractclosure [27] III. Tissue adhesion  Fournier’s gangrene reconstruction[45,46]Fistula closure [29,47,48]Skin grafting [46]Orchiopexy [49,50]Penile chordee [51]Complex urethroplasty [37] 3 UROLOGIC INJURIES AND WOUND HEALING  coagulopathiesduringurologicsurgicalprocedures[29–31]. Other urologic hemostatic applications in-clude sealing the oral mucosal donor site duringbuccal graft urethroplasty [58] and cystoscopic ap-plication of fibrin sealant after fulguration to pro-vide hemostasis in refractory radiation-inducedhemorrhagic cystitis after supravesical urinarydiversion [32]. Urinary tract sealant Various nonurologic studies have suggestedthe increased strength of sealed anastomoses.Skin sutures supported by a layer of fibrin sealantprovided watertight anastomoses immediatelyafter surgery and withstood significantly higherhydrostatic pressures than nonsealed anastomoses[59]. Han and colleagues noted that microvascularsutured anastomoses supported by fibrin sealanthad enhanced re-endotheliazation [59,60,61], andPark and colleagues reported significantly in-creased tensile strength in sealed skin closure ver-sus controls [42]. Ureteral anastomosis Kram and colleagues first reported the success-ful use of fibrin sealant as a bolster over the sutureline for ureteral anastomosis in 1989 [54]. The au-thors have found fibrin sealant to be a useful ad- junct in managing various ureteral injuries,iatrogenic and traumatic, and frequently have per-formed ‘‘drain-free’’ sealed repairs. Between 2001and 2003, 10 patients underwent definitive man-agement of ureteral injury at the authors’ institu-tion. The authors’ experience has shown thatsealant effectively prevents ureteral urinary extrav-asation and has not been associated with postoper-ative infection, leak, or scar formation (Fig. 2).The authors’ believe that a sealed, stented ureteralrepair is prudent in cases where a transabdominalapproach has been performed because transabdo-minal drains are avoided. The authors also believethe sealant should be applied as a means of ‘‘suturesupport’’ by reinforcing standard suture lines, notin lieu of careful suture repair.The increasing performance of laparoscopicrenal reconstruction surgery may lead to increasedsealant use. Fibrin sealant has been shown tosupport approximating sutures successfully ina porcine model of laparoscopic ureteral anasto-moses [33] and has improved radiographic out-comes compared with free needle suturing andlaser weld closure [34]. Various studies have shownfibrin sealant to be effective as a bolster for laparo-scopic pyeloplasty or collecting system repair [35],and satisfactory drainage has been confirmed byradiologic imaging at 1 to 2 years [36]. Prostatectomy Drain-free, simple, retropubic prostatectomyhas been performed successfully in over 25 casesin the authors’ institution, and a faster return toregular diet and shortened hospital stay whencompared with conventional simple prostatecto-my have been demonstrated [38]. Again, the seal-ant should be applied outside the urinary tract,over the sutured prostatic capsular closure, to en-sure that the fibrin clot does not occlude urinarycatheter drainage. Similarly, Diner and colleagues Fig. 2. ( A ) Stab wound to right flank with medial perirenal contrast extravasation on preoperative trauma computedtomography (CT). A 4-cm laceration to the right renal pelvis successfully repaired using 5-zero PDS suture with the ap-plication of a bolster of 5 mL of fibrin sealant over the suture line to reinforce urinary tract seal. No drain was placed. ( B )Postoperative CT image obtained 72 hours later demonstrates drain-free intact repair over ureteral stent without evi-dence of extravasation or urinoma.4  EVANS & MOREY  reported in 2004 that a significant decrease inpostoperative drain output was noted in 16 pa-tients following radical retropubic prostatectomywhen 5 mL of fibrin sealant was applied to the su-ture line of the urethrovesical anastomosis [39].Earlier drain removal should facilitate a more ex-pedient recovery and earlier discharge from thehospital leading to cost savings. Urethroplasty Fibrin sealant seems to allow earlier catheterremoval, improved patient satisfaction, and en-hanced wound healing after pendulous urethro-plasty [37]. In our experience of applying fibrin sealant directly over a suture line of 5-zero poly-diaxanone during pendulous urethroplasty in 18patients, a completely healed anastomosis wasconfirmed by voiding cystourethrography per-formed 1 week postoperatively in 83% of patients;all 18 patients demonstrated complete healingwithin 14 days compared with 8% of patients inthe control group who had persistent extravasa-tion at 21 days postoperatively ( P ! .05). Pendu-lous urethral reconstruction seems to beuniquely well-suited for sealant use because thesuperficial nature of the urethra in this locationdoes not provide the robust surrounding spongytissues that are found routinely in the bulbar ure-thra (Fig. 3). Complication management Fibrin sealant seems to promote the successfultransvaginal management of iatrogenic cystotomysustained during transvaginal hysterectomy. Theauthors observed that direct transvaginal fibrinsealant injection functions well as a bolster in-terposition over the cystotomy repair thus pre-venting the additional time and morbidityrequired for abdominal bladder repair or tissueinterposition with a Martius or omental flap [29].Fibrin sealant also has been used to prevent lym-phocele formation after lymphadenectomy [43].Used as a sclerosant after percutaneous drainageof postoperative lymphoceles in renal transplan-tation, instillation of fibrin sealant achievedcomplete resolution of the lymphocele in 75% of patients without the need for open surgical man-agement [44]. Percutaneous transrenal applicationof 5 mL of fibrin sealant across a refractory caly-ceal urinary leak secondary to gunshot wound hasproven effective in sealing refractory collectingsystem injury [18]. Tissue adhesionTissue planes The fibrin polymer resulting from fibrin sealantapplication facilitates wound healing by increas-ing tissue plane adherence thus eliminating deadspace, accelerating revascularization, reducinghemorrhage, preventing seroma, and minimizinginflammation [62,63].Tissue sealant properties of fibrin sealant havebeen applied to reduce air leaks and bronchopleu-ral fistulae after pulmonary resection and decorti-cation [64,65], secure skin grafts in reconstructiveand burn surgery [66], and occlude chronic entero-cutaneous [7] and anorectal [8] fistulous tracts. Fibrin sealant now is used routinely at theauthors’ institution during complex urethroplasty,especially cases requiring panurethral reconstruc-tion (Fig. 4). The scrotum is bivalved completely to provide wide access to the underlying diseasedurethra, and the scrotal wings are glued togetherwith sealant after urethral repair to prevent edemaand hematoma. Similar efficacy has been reportedin 17 patients undergoing complex genital recon-structive surgery, such as spit-thickness skin graft-ing and thigh flap surgery for Fournier’s gangrenesequelae and invasive penile cancer: 94% of pa-tients recovered without infection, seroma, hema-toma, or other complications (Fig. 5) [45,46]. Urinary tract fistulae In addition to sealing tissue planes, fibrinsealant promotes closure of urinary fistulae bypromoting the local proliferation of fibroblastsand subsequent replacement by connective tissue,allowing for occlusion of the fistulous tract [15].The fibrin polymer promotes the ingrowth of fi-broblasts during wound healing and an influx of immune cells is stimulated in a paracrine fashion[67]. The complex interaction of neutrophils, mac-rophages, and fibroblasts provides the basis of  Fig. 3. Application of fibrin sealant as a bolster over thesuture line of pendulous urethroplasty.5 UROLOGIC INJURIES AND WOUND HEALING
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